SEARCH RESULTS FOR: 2024

Aspiration Pneumonia

Aspiration Pneumonia: Pathogenesis and clinical findings Intractable vomiting ↑ Likelihood of oropharyngeal and gastric contents exiting the esophagus, entering the trachea to the lung If the acidic gastric contents are sterile, then aspirating this results in inflammation and lung injury without development of infection Aspiration pneumonitis Alveolar macrophages recruit neutrophils to local site of infection. Subsequent cytokine release compromises the vascular endothelial cell wall barrier and ↑ alveolar-capillary permeability ↑ inflammation due to fluid and cellular debris build-up in alveoli overdose (e.g. opioids) (e.g. stroke) Altered level of consciousness and impaired cough/clearance Tube Poor Alcohol and Substance Medications Neurologic diseases Esophageal and gastric motility disorders Impaired swallowing Chronic obstructive pulmonary disorder feeding oral health Bacteria adhere to epithelial surfaces and ↑ risk of airway and lung bacterial colonization Aspirated oropharyngeal and gastric contents can also contain bacteria ↓ Elimination and clearance of foreign bacteria from airway and lung Macroaspiration (large volume aspiration) of oropharyngeal bacteria, during eating and drinking Bacteria and fluid fill bronchi and alveolar space Aspiration Pneumonia Alterations to lung microbial flora An infectious lung process caused by inhalation of foreign bacterial and oropharyngeal and gastric contents Aspiration of acidic fluid and pneumonia causative pathogen (typically anaerobes or bacteria in normal oral flora) with resultant inflammation Infiltrate develops in a gravity-dependent pattern in patches around bronchi segments. Produces proinflammatory cytokines, (e.g. tumor necrosis factor-alpha, and interleukin-1) Hypothalamic production of prostaglandin E2 results in thermogenesis Fever Authors: Luiza Radu Reviewers: Mao Ding, *Yan Yu, *Jonathan Liu *MD at time of publication Aspiration to the right lung more common due to large diameter and more vertical orientation of the right main bronchus Crackles and ↑ lung vibrations (fremitus) on auscultation Productive Cough Impaired alveolar gas exchange Chemoreceptor detection of ↓ pO2 triggers ↑ ventilation Hypoxemia Dyspnea Consolidation in lower lobes (particularly superior segments) and posterior segments of upper lobes If untreated, a pus-filled lung cavity develops (e.g. abscess) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 11, 2024 on www.thecalgaryguide.com

Bacterial Tracheitis

Bacterial Tracheitis: Pathogenesis and Clinical Findings Authors: Fasika Jembere Reviewers: Simran Sandhu Mao Ding Danielle Nelson * MD at time of publication Recent upper respiratory viral infection Age typically <6 years old (more common in males) Children at higher risk due physiologic narrowing of airway Recent upper respiratory viral infection (often in Fall/Winter; respiratory virus season) Damage to airway mucosa Activation of systemic inflammatory response Inflammatory cytokines release into systemic circulation ↑ Thermo-regulatory set- point at the hypothalamus ↑ Work of breathing to adequately ventilate lungs Respiratory distress (nasal flaring, grunting) Activation of local inflammatory response Results in thick mucopurulent secretions, ulcerations, and shedding of tracheal mucosa Mucopurulent discharge secretion of fluid contains mucus and pus ↑ Production of mucous results in more accumulation Predisposition to bacterial infection Bacterial pathogen invades trachea Ex: S. aureus (common), S. pyogenes, M. catarrhalis, or H. influenzae Often high fever Trachea is narrowed with purulent debris Upper airway obstruction causes turbulent airstreams Hoarse voice Tachypnea Stridor (with inhalation & exhalation; may be biphasic) Tracheal tenderness ↓ Mucous clearance from the airways Excess airway mucous triggers cough reflex Cough (may be barky) ↑ Use of accessory respiratory muscles (sternocleidomastoid and scalene muscles) Toxic appearance (lethargy, cyanosis) ↓ Level of consciousness (due to hypoxia & hypercarbia) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 11, 2024 on www.thecalgaryguide.com

Shoulder Impingement Syndrome

Shoulder Impingement Syndrome: Signs and Symptoms Calcific deposition Abnormal shoulder morphology Static subacromial narrowing Abnormal scapular rotation and tilt Scapular winging Weakness Degenerative changes to rotator cuff tendons Weakness Dynamic subacromial narrowing Repetitive overhead activity/shoulder overuse Muscle fatigue Repetitive compression forces on subacromial space Glenohumeral instability or stiffness Authors: Janelle Wai Dalal Awwad Reviewers: M. Patrick Pankow Reza Ojaghi Usama Malik Sunawer Aujla Ryan Shields* * MD at time of publication Internal/ Posterior Impingement Compression of rotator cuff tendons between humeral head and posterosuperior glenoid edge during end stage of throwing Pain with passive extension and lateral rotation + Posterior Internal Impingement Test Instability: Laxity of glenohumera l joint Stiffness: Scapular winging with downward tilt, shoulder protraction Primary/ Structural Impingement Any anatomical abnormalities Secondary/Functional Impingement Normal anatomy with motion abnormalities Impingement of underlying rotator cuff muscle-tendon unit and inflammation of subacromial bursa Rotator Cuff Syndrome External/ Subacromial Impingement Compression of subacromial bursa and rotator cuff (i.e. supraspinatus tendon) on the anterolateral acromion and coracoacromial ligament X-Ray: Normal Ultrasound: +/- Tendinopathy, muscle atrophy Pain with overhead movement Pain at night (e.g., sleep position, gravity) Pain with lifting (e.g., weight- training, groceries) Pain (between 60°-120°) with passive shoulder abduction + Painful arc Test Pain with passive shoulder flexion + Neer’s Test Pain with passive shoulder flexion (to 90°) + internal rotation + Hawkins-Kennedy test Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First published May 27, 2018; updated Jan 11, 2024 on www.thecalgaryguide.com

Cranial Nerve IV Palsy

Cranial Nerve IV Palsy: Pathogenesis and clinical findings Congenital (e.g. Möbius Syndrome) Dysgenesis (defective development) of CN IV Microvascular Disease (e.g. Stroke) Damage or occlusion (complete or partial blockage) to the blood vessels supplying CN IV Trauma Temporary or permanent damage to the nerve fibers Neoplasm Metastasis (e.g. Leptomeningeal) Compression of the nerve fibers along the nerve tract Primary (e.g. Schwannoma) Tumor develops new blood vessels that redirect blood flow to the malignancy, away from the nerve Ischemia of CN IV Infection (a rare cause) (e.g. Ehrlichia chaffeensis, Tuberculosis meningitis) Infectious process in the subarachnoid space Damage to axons of CN IV Cranial Nerve (CN) IV Palsy Superior oblique musculature weakness due to CN IV dysfunction Lesion to the fascicle of CN IV (extending from midbrain to cavernous sinus) Impaired ability to conduct motor commands from nucleus to superior oblique muscle in the eye Weak superior oblique innervation Difficult abduction and intorsion of the eye Contralateral superior oblique weakness Lesion to the nucleus of CN IV (located in the midbrain) Disturbed signal production occurring prior to demarcation of fibers to contralateral side The pathophysiology above can cause damage to structures surrounding CN IV in the midbrain Impacting ipsilateral sympathetic chain descending from the hypothalamus prior to reaching the superior cervical ganglion Authors: Shahab Marzoughi Reviewers: Sunawer Aujla Yvette Ysabel Yao Yan Yu* Gary Michael Klein* * MD at time of publication Vertical/oblique Diplopia (double vision) Hypertropia (one eye is deviated upward compared to the other) Perinaud’s Syndrome (upgaze palsy, convergence retraction nystagmus, and pupillary hyporeflexia) See relevant Calgary Guide slide on Parinaud’s Syndrome Loss of eye muscle movement coordination and function of other structures relating to gait Ataxia Ipsilateral Primary Horner’s Syndrome (miosis, anhidrosis, ptosis) See relevant Calgary Guide slide on Horner Syndrome Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 16, 2024 on www.thecalgaryguide.com

Sugammadex

Sugammadex: Mechanism of action and adverse side effects A direct reversal agent with a high affinity for rocuronium and lesser affinity for vecuronium, capable of reversing even deep neuromuscular blockade. Binds rocuronium and vecuronium (non-depolarizing neuromuscular blocking drugs (nNMBs)) in plasma when administered IV ↓ Concentration of functional nNMBs in plasma Creates a concentration gradient from muscle tissue (high) to plasma (low) nNMBs move from muscle compartment to plasma Sugammadex in plasma encapsulates nNMBs that moved to the plasma ↓ Concentration of functional nNMBs in the plasma ↓ Concentration of nNMBs at the nicotinic acetylcholine receptor within the skeletal neuromuscular junction Reverses neuromuscular blockade created by nNMBs Sugammadex Progesterone is similar in structure to nNMBs Sugammadex binds progesterone ↓ Progesterone activity in the body Progesterone is critical for maintenance of early pregnancy Unknown significance, avoid use in early pregnancy Sugammadex-nNMB complex is cleared by the kidneys Higher concentrations of sugammadex facilitate faster nNMB clearance Unknown mechanisms Post operative nausea and vomiting Headache Bradycardia Cardiovascular Collapse ↓ Effectiveness of progesterone-based contraception for 7 days ↓ Clearance in patients with severe renal impairment Reversal of profoundly deep neuromuscular blockade at higher doses Binds to IgG or IgE receptors on sensitized basophils/mast cells in allergic reactions Activation of basophils/mast cells Degranulation of basophils/mast cells Release of granulation products Anaphylaxis Bronchospasm Hypotension Authors: Arzina Jaffer, Kayleigh Yang Reviewers: Jasleen Brar, Mao Ding Joseph Ahn* * MD at time of publication Movement of limbs or body during anesthesia Coughing during anesthesia Grimacing or suckling on the endotracheal tube Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 16, 2024 on www.thecalgaryguide.com

Arachnoid Cysts MRI Findings

Arachnoid Cysts: Findings on MRI Imaging source: radiopaedia.org Authors: George S. Tadros Reviewers: Matthew Hobart, Shahab Marzoughi, James Scott* * MD at time of publication Extra-Axial Location Cyst is visualized outside of brain parenchyma Clear Demarcation Since the arachnoid cyst is bound by arachnoid membrane, it has well-defined margins CSF collection contained within a split arachnoid membrane that occurs during embryological development (primary) Cerebrospinal Fluid (CSF) collection within arachnoid membrane adhesions following trauma, infection, inflammation or surgery (secondary) Arachnoid cyst (fluid-filled sac) formation within the layers of the arachnoid membrane, outside of brain parenchyma (for full pathogenesis, see Calgary Guide slide Arachnoid Cysts: Pathogenesis and clinical findings) Use Diffusion Weighted Imaging (DWI) and Fluid-Attenuated Inversion Recovery (FLAIR) to distinguish from other cysts Isointense to CSF on T1 and T2 Arachnoid cyst contents should appear isointense to CSF on each MR sequence, including diffusion-weighted imaging Axial T2 MRI Head. Clearly demarcated hyperintense (bright) arachnoid cyst is seen (red arrows) Axial T1 MRI Head. Clearly demarcated hypointense (dark) arachnoid cyst is seen (red arrows) FLAIR allows for suppression of free water signal to enhance fluid with ↑ protein concentration Arachnoid cysts contain CSF-like fluid with very little to no protein Complete suppression on FLAIR Cysts are mostly fluid and contains no protein, so it is suppressed and appears darker in FLAIR images. Axial FLAIR MRI Head. Hypointense cyst is seen on FLAIR (red arrows), showing low protein content in CSF-like fluid inside arachnoid cyst DWI measures water diffusion in different directions and whether there is restriction on the direction of flow Fluid within the cyst can flow freely, with no restriction on the direction of movement Non-restricted diffusion There is no directional restriction on flow within the cyst (unrestricted diffusion), so it appears dark on DWI. Axial DWI MRI Head. Hypointense cyst is seen on DWI (red arrows), showing unrestricted diffusion within arachnoid cyst Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 20, 2024 on www.thecalgaryguide.com

Arachnoid Cysts Pathogenesis and clinical findings

Arachnoid Cysts: Pathogenesis and clinical findings Authors: George S. Tadros Reviewers: Yvette Ysabel Yao Shahab Marzoughi Gary Michael Klein* * MD at time of publication Failure in the embryological duplication or division of the arachnoid membrane Cerebrospinal fluid (CSF)-like fluid is trapped within the erroneous membrane Formation of a primary, congenital arachnoid cyst (most common cause) Head trauma, intracranial hemorrhage, or infection Inflammation and deposition of cellular matrix Adhesion of the arachnoid membrane CSF accumulates in the subarachnoid space (space between the arachnoid mater and pia mater) Formation of a secondary arachnoid cyst (less common) Cyst remains stable in size and does not expand (most common) Patients are asymptomatic Arachnoid cyst is diagnosed incidentally on unrelated neuroimaging (see Calgary Guide slide Arachnoid Cysts: Findings on MRI) Arachnoid Cyst Cyst grows in size and expands (rare but more common in children under four years of age) Cyst exerts pressure on other structures (mass effect) Suprasellar region Cyst ruptures into the subdural space (rare) CSF-like fluid accumulates in the subdural space Subdural hygroma (collection of non-bloody CSF) Intracranial hypertension (↑ intracranial pressure) Generalized symptoms Middle fossa Compression and irritation of the temporal cortex Seizures Focal symptoms depending on cyst location Cerebellopontine angle Compression of vestibulocochlear nerve (Cranial Nerve VIII) Compression and interruption of cochlear blood supply Cyst presses on the third ventricle and aqueduct buildup of CSF in the ventricles Obstructive hydrocephalus Cyst presses on the optic chiasm, hypothalamus, and pituitary Visual impairments and endocrinopathies Headache (most common) Vomiting Nausea Progressive hearing loss Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 25, 2024 on www.thecalgaryguide.com

Avascular Necrosis AVN of the Femoral Head Findings on MRI

Avascular Necrosis (AVN) of the Femoral Head: Findings on MRI Traumatic or atraumatic disruption of blood supply to the proximal femur (for full pathogenesis, see Calgary Guide slide Avascular Necrosis: Pathogenesis and clinical findings) Ischemia of the femoral head (usually unilateral for traumatic and bilateral for non-traumatic) Prolonged anoxia (total oxygen deprivation) within the femoral head Cell death (necrosis) of osteocytes and marrow cells in the femoral head, forming a focal lesion (sequestrum) Histiocytes and giant cells (immune cells) aggregate around the sequestrum, forming a “reactive zone” around the periphery of the sequestrum Apoptotic osteocytes in the anoxic reactive zone cannot be phagocytosed leading to dysregulated bone remodeling and osteosclerosis (hardening of bone and ↑ bone mineralization and density due to ↓ resorption and ↑ bone formation) Femoral head becomes progressively weaker while the mechanical load on it remains the same Progressive femoral head/subchondral bone collapse Osteoarthritis Areas with ↑ fluid content appear darker on T1w images Areas with ↑ fluid content appear brighter on T2w images Areas with ↑ bone density and ↓ fat content appear darker on T1w images Areas with ↑ bone density and ↓ fat content appear darker on T2w images Basic MRI Physiology Edema and inflammation increases fluid content Sclerotic areas have ↑ bone density and thus ↓ fat content Location of Signs Inflamed reactive zones are darker on T1w images Inflamed reactive zones are brighter on T2w images Sclerotic areas are darker on both T1w and T2w images Authors: George S. Tadros Reviewers: Matthew Hobart, Mao Ding Shahab Marzoughi David Cornell* * MD at time of publication T1w Signs on both T1-weighted and T2-weighted images are most commonly seen on the superior anterolateral aspect of the femoral head Single dark band on T1-weighted MRI A single band-like crescentic lesion of low signal intensity is seen on T1-weighted MRI images (white arrows). This band represents the edematous reactive zone between the necrotic and normal tissue, and typically extends to the subchondral plate Double Line Sign on T2-weighted fat-saturated MRI An outer distal low signal intensity line is seen (white arrows) representing reactive bone sclerosis Image source: radiologymasterclass T2w An inner proximal high signal intensity line is also seen (red arrows) representing vascular and repair tissue at the periphery of the sequestrum Image source: radiologymasterclass Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 27, 2024 on www.thecalgaryguide.com

Bacterial Infections from Transfusion

Bacterial Infections from Transfusion: Signs and Symptoms Caused by bacterial contamination of any blood product, most commonly platelets due to room-temperature storage Bacteria enters bloodstream directly through transfusion Immune cells (ex. macrophages, dendritic cells, monocytes, neutrophils) recognize bacteria Immune cells release pyrogens (either bacterial components or signalling molecules) upon recognition Pyrogens bind to receptors on the hypothalamus Hypothalamus ↑ body temperature set point Body generates and conserves heat to reach set point Immune cells release pro- inflammatory cytokines (messenger protein) Cytokines activate sympathetic nervous system via hypothalamus Adrenal glands release stress hormones (epinephrine and norepinephrine) into bloodstream Stress hormones bind to receptors on cardiomyocytes (heart muscle cells) ↑ Heart contractility ↑ Heart rate Cytokines circulate throughout the body Cytokines interact with endothelial cells of the blood vessels ↑ Nitric oxide production Relaxes smooth muscle cells of blood vessel walls Vasodilation (↑ blood vessel diameter) Hypotension Systemic inflammation Stimulate nerve endings in muscles Stimulate nerve endings in gastrointestinal tract’s lining Blood brain barrier’s integrity is compromised Nitric oxide reacts with oxygen to form reactive nitrogen species Tissue damage Fatigue Weakness Muscle aches Nausea and vomiting Immune and inflammatory cells enter the brain Authors: Arzina Jaffer Kayleigh Yang Reviewers: Nimaya De Silva Raafi Ali Michelle J. Chen Yan Yu* Kareem Jamani* * MD at time of publication Inflammation in the brain Activates pain processing centers in the brain Headache Damages neurons and disrupts cell communication Confusion and altered mental state Shivering Fever Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 30, 2024 on www.thecalgaryguide.com

Acute Wound Healing

↓ Blood supply and oxygenation to local skin tissue Ischemia Degradation of intact skin Abrasion (damage by scrape/rub) Puncture (small piercing caused by sharp object) Acute injury to the skin Crush (damage by compression) Acute Wound Healing: Pathogenesis and clinical findings Author: Amanda Eslinger Mina Youakim Reviewers: Heena Singh Shahab Marzoughi Yan Yu Laurie Parsons* * MD at time of publication 8 – 365+ days post-injury Remodeling (↓ blood vessels & organized collagen) Extensively cross-linked type 1 collagen replaces the disorganized collagen laid down in the proliferative phase ↑ Protein content in collagen Scarring (fibrotic tissue replaces previously healthy tissue) Disruption of structure and function of dermis, epidermis and subdermal tissues Subendothelial and endothelial damage activates the coagulation pathway Formation of a platelet plug Bleeding is slowed or stopped by hemostatic plug (hemostasis) Clot unifies wound edges 0 – 7 days post-injury Inflammation (In disrupted skin layers) 4 - 14 days post-injury Proliferation of collagen, extracellular matrix & blood vessels TGF-β attracts fibroblasts to the site of the wound Fibroblast & macrophage stimulate tissue growth & angiogenesis which replaces hemostatic plug Scabbing (protective crust overlying damaged tissue) Re-epithelialization beneath the scab sloughs it off Healing (newly replaced tissue replaces damaged one) In response to irritant, mast cells release histamine Complement activation causing nearby endothelial cells to release prostaglandins Vasodilation occurs around the wound area Localized ↑ vascular supply (reception of blood and fluid from vessels) ↑ Hydrostatic pressure forces fluid from vessels into surrounding tissue Edema (swelling from fluid buildup) Erythema (redness) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First Published Sept 19, 2013; updated Jan 30, 2024 on www.thecalgaryguide.com

Carbonic Anhydrase Inhibitor Diuretics

Carbonic Anhydrase Inhibitor Diuretics: Renal mechanism and side effects Authors: Stephanie Happ Reviewers: Matthew Hobart Raafi Ali Adam Bass* * MD at time of publication Carbonic Anhydrase Inhibitors (CAI) Inhibition of carbonic anhydrase on the apical surface of the brush border cells in the proximal convoluted tubule (PCT) Activation of the Renin- Angiotensin-Aldosterone Systemfromvolume depletion Activation of principle cell Epithelial sodium channels (ENaC) on principal cells of the CCD reabsorb ↑ Na+ and waste K+ ↓ K+ in serum Hypokalemia See Hypokalemia: Clinical Findings slide ↑ Na+ delivery to the cortical collecting duct (CCD) H2O follows Na+ into the CCD to maintain a balanced osmotic pressure ↑ H2O available for excretion Mild diuresis (increase in frequencyandvolumeof urine) ↓ Blood volume Hypotension ↓ Na+ and HCO3- reabsorption in the PCT ↑ HCO3- delivery to cortical collecting duct Urine alkalization (increased pH) Chronic urine alkalization ↓Solubilityof citrate ↓ Urinary citrate ↓ Citrate binding with Ca2+à↑ Ca2+ complexing with oxalate ↑ Spontaneous nucleation, growth and agglomeration of calcium oxalate crystals Formation of calcium oxalate renal calculi ↑ HCO3- is lost in the urine ↓ pH of the blood Type II Renal Tubular Acidosis See Type II/Proximal Renal Tubular Acidosis slide CAI prevents the up- regulationofglutamine transporters in the PCT Inability to correct the metabolic acidosis and impaired urinary NH3 excretion Hyperammonemia (↑ serum NH3 ) ↑ Risk of hepatic encephalopathy in individuals with cirrhosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 3, 2024 on www.thecalgaryguide.com Carbonic Anhydrase Inhibitor Diuretics: Renal Mechanism and Side Effects Carbonic Anhydrase Inhibitors (CAI) Inhibition of carbonic anhydrase on the apical surface of the brush border cells of the proximal convoluted tubule (PCT) Authors: Stephanie Happ Reviewers: Matt Hobart Name Name* * MD at time of publication ↓ Na+ and HCO3- reabsorption in the PCT ↑ Na+ delivery to the cortical collecting duct (CCD) H2O follows Na+ into the CCD to maintain a balanced osmotic pressure ↑ H O available for 2 excretion Mild diuresis ↓ Blood volume Hypotension ↑ HCO3- delivery to cortical collecting duct Epithelial sodium channels (ENaC) on principal cells of the CCD reabsorb ↑ Na+ ↑ Intracellular Na+ drives Na+/K+ ATPase activity on the principal cells (moving 2 K+ into cell and 3 Na+ out into the peritubular capillary) ↑ Intracellular K+ drives H+/K+ ATPase activity on the intercalated cells (moving 1 H+ into cell and 1 K+ out into the tubular filtrate) ↓ K+ in serum Hypokalemia See Hypokalemia: Clinical Findings slide Urine alkalization ↑ HCO3- is lost in the urine, leading to ↓ pH of the blood Renal Tubular Acidosis Type II See Type II/Proximal Renal Tubular Acidosis slide CAI inhibit the up-regulation of glutamine transporters in the PCT Inability to correct the metabolic acidosis and impaired urinary NH3 excretion Hyperammonemia ↑ Risk of hepatic encephalopathy in individuals with cirrhosis Chronic urine alkalization leads to marked ↓ in urinary citrate ↓ Ability of citrate to bind to Ca2+ and calcium oxalate stones ↓ Inhibition of spontaneous nucleation ↓ Prevention of growth and agglomeration of crystals Formation of calcium oxalate renal calculi Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com

Epiglottitis

Epiglottitis: Pathogenesis and clinical findings Infectious cause: Bacterial (Staphylococcus aureus, Streptococcus pneumoniae, Neisseria meningitidis, or most commonly Haemophilus influenzae in unimmunized children), viral or fungal Authors: Alisha Ebrahim Reviewers: Simran Sandhu Mao Ding Michelle J. Chen Danielle Nelson* * MD at time of publication Infectious agent invades the bloodstream and/or the epithelial layer of the epiglottis, aryepiglottic folds and adjacent structures, allowing for spread Non-infectious cause: Ingestion of toxin or foreign body, thermal injury, or trauma The potential space between the squamous epithelial layer and the epiglottal cartilage fills with inflammatory cells such as neutrophils and eosinophils Exudate of inflammatory cells spreads through the lymphatic and blood vessels in the lingual surface of the epiglottis and periepiglottic tissues Fluid and inflammatory cells accumulate between the squamous epithelial layer and epiglottal cartilage Swelling of the entire supraglottic larynx Tripod/sniffing position (Anxious- looking and sitting with trunk leaning forward, neck hyper-extended and chin pushed forward to maximize airway diameter) Stridor (High-pitched sound that is produced by obstruction in the larynx or just below) Stertor (Low-pitched noise created in the nose or the back of the throat) Retraction of the intercostal and suprasternal muscles Tachypnea (Rapid breathing) Increased weight and mass of the epiglottis Epiglottis curls posteriorly and inferiorly Ball-valve effect (Airflow obstructed during inspiration as epiglottis is pulled over airway but not during expiration as epiglottis moves back into position) ↓ Diameter of upper airway Epiglottis obstructs the esophagus Dysphagia (Difficulty swallowing) Cyanosis (Blue tint to skin) Turbulent inspiratory airflow Aspiration of oropharyngeal secretions Hypoxemia (Low oxygen levels in blood) ↓ Air entry to lungs Airway obstruction ↑ Work of breathing Drooling Pain when swallowing Muffled/”hot potato” voice Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 5, 2024 on www.thecalgaryguide.com

Stable Angina

Angina Pectoris/Stable Angina: Pathogenesis and clinical findings Authors: Ryan Iwasiw Alexander Arnold Julia Gospodinov Reviewers: Mandy Ang Sarah Weeks* Frank Spence* Shahab Marzoughi * MD at time of publication Atherosclerosis (Fatty plaque accumulates inside the intimal walls of arteries) ↓ Blood vessel lumen diameter ↓ Volume of blood is supplied to the heart Predictable period of physical activity or emotional stress ↑ Heart rate ↓ Time for coronary arteries to fill heart with blood (diastole) ↑ Heart contractility ↑ Oxygen demand of heart muscle tissue (myocardium) ↓ Myocardial blood supply Imbalance between blood supply & oxygen demand causes myocardial ischemia Angina Pectoris/Stable Angina Myocardial ischemia causes cardiac muscle cells (cardiomyocytes) to switch from oxygen-dependent (aerobic) to oxygen-absent (anaerobic) metabolism Anaerobic metabolism produces metabolites that stimulate cardiac spinal afferent nerves Myocardial visceral afferent & somatic sensory nerve fibers mix & enter the spinal cord via T1-T4 nerve roots Brain interprets ↑ nerve signaling as nerve pain coming from the skin of T1-T4 dermatomes (referred pain) ↑ lactic acid production & ↓ cellular pH impairs cardiomyocytes’ function Damaged cardiomyocytes impair myocardial relaxation & cause ↓ left ventricular contractility & cardiac output Blood backs up into left ventricle, atrium, & pulmonary vasculature ↑ Pulmonary capillary pressures pushes fluid out & into the lung’s alveoli ↓ Gas exchange & oxygenation ↑ Respiratory rate & Dyspnea (shortness of breath) Blood flow begins at the epicardium (outer heart layer) & ends at endocardium (inner layer) Subendocardium (innermost heart layer) receives the least blood flow causing non-transmural (partial thickness) heart wall ischemia Anterior/septal & lateral wall ischemia triggers ↑ sympathetic nervous system (SNS) activity given the proximity of cardiac SNS innervation Inferior wall ischemia triggers involuntary ↑ in Vagus nerve activity given the nerve’s proximity Bradycardia (↓ heart rate) Nausea Adrenal medulla releases Norepinephrine hormone Activation of sweat glands via SNS acetylcholine neurotransmitter release Hypotension (↓ blood pressure) Pain radiation to left arm, jaw, abdomen & upper back Chest pain, pressure, or discomfort Unstable Angina (unpredictable & worsening chest pain) See relevant Calgary Guide slide on Unstable Angina Binds arterial smooth muscle α1 receptors ↑ Coronary arteries’ vascular tone (vasoconstriction) Hypertension (↑ blood pressure) Activates β1 receptors in the heart Tachycardia (↑ heart rate) Diaphoresis (↑ sweating) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 8, 2013; updated Feb 5, 2024 on www.thecalgaryguide.com

Acute Otitis Externa Complications

Acute Otitis Externa (Swimmer’s Ear): Complications Acute Otitis Externa (AOE) Authors: Charmaine Szalay-Anderson Vaneeza Moosa Reviewers: Shayan Hemmati Shahab Marzoughi Ben Campbell Justin Lui* * MD at time of publication Spread to subcutaneous tissue Chronic otitis externa (>6 weeks) Chronic inflammation of the outer ear Fibroblast activation for collagen and extracellular matrix components production for tissue repair Excess accumulation of tissue Ear canal fibrosis (thickening) Ear canal stenosis (narrowing) Damage/obstruction to ear canal structures with impaired fluid drainage & pressure buildup Inflammation of the outer ear Recurrent or non-resolving acute otitis externa Dissemination of infection Spread to connective tissue and cartilage Perichondritis (inflammation of ear cartilage) Spread of Pseudomonas aeruginosa in an immunocompromised host or due to antibiotic resistance Rapid infectious spread through soft tissue to mastoid and/or temporal bone Malignant (necrotizing) otitis externa *can be life threatening Inflammation of connective tissue and bony structures Spread to tympanic membrane Myringitis (inflammation of tympanic membrane) Swelling and thinning of tissue Tympanic membrane perforation (tear) Immune reaction with inflammation Dead white blood cell, bacteria & tissue debris accumulation in the ear canal Pus formation with purulent otorrhea (discharge from ear) Localized pus accumulation Abscess Ear canal blockage Periauricular/ pinna (outer ear) cellulitis Facial cellulitis Erosion of temporal bone decreasing bony sound conduction Permanent conductive hearing loss Direct toxicity of pathogens to surrounding nerves Cranial nerve (CN) VII (facial) palsy (+/- CN X, XI, XII) Out-of- proportion primary otalgia (ear pain) Sensation of fullness in the ear Temporary hearing loss Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 4, 2022; updated Feb 7, 2024 on www.thecalgaryguide.com

Chancroid

Chancroid: Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication Condomless sex Multiple sexual partners Genital injury (i.e. cuts, friction) Micro-abrasions occur in the epidermal tissue of the genital area Sexual Transmission of Haemophilus ducreyi (H. ducreyi) bacteria from an infected sexual partner H. ducreyi enters the epidermis through micro abrasions H. ducreyi infects epithelial cells H. ducreyi secretes Large Supernatant Proteins LspA1 and LspA2 (which inhibit phagocytosis by neutrophils and macrophages) T cells activate and release cytokines IL-6 and IL-8 Neutrophils are recruited to the site of infection Local macrophages form a collar around the base of the papule to try to reach and engulf H. ducreyi ↑ Localized buildup of immune cells While infection persists, H. ducreyi release lipooligosaccharides (LOS) LOS travels to lymph nodes in the inguinal region Lymph nodes synthesize and proliferate T cells specific to H. ducreyi antigen Inguinal lymph nodes swell due to ↑ number of T cells Inguinal buboes (swollen inguinal lymph nodes) Neutrophils surround the bacteria and attempt to engulf it Localized epidermal buildup of neutrophils and H. ducreyi Papules (small protrusions on the skin) Continued build-up of H. ducreyi, neutrophils, dead white blood cells (pus), and macrophages Pustules (pus-filled skin lesion) ↑ Local pressure from growing pustule compresses surrounding vessels ↓ Local blood flow erodes and sloughs off the local epidermal roof Ulcers (open skin sore) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 8, 2024 on www.thecalgaryguide.com

Dantrolene

Dantrolene: Mechanism of Action and Adverse Side Effects Medication indicated for the treatment of muscle spasms associated with malignant hyperthermia (reaction to certain anesthetics resulting in a rapid and dangerous increase in body temperature, muscle rigidity, and other symptoms), and spasticity associated with various neurological disorders such as multiple sclerosis, cerebral palsy, and spinal cord injury. Dantrolene Authors: Madison Amyotte, Arzina Jaffer Reviewers: Jasleen Brar, Mao Ding Luiza Radu Joanna Moser* * MD at time of publication Metabolized in the liver by the cytochrome P450 enzyme Metabolic process forms a high concentration of hydroxylamine Hydroxylamine is a highly toxic metabolite associated with dantrolene induced liver injury Impaired Liver Function Binds to ryanodine receptors (RYR1) in the sarcoplasmic reticulum of skeletal muscle cells Prevents ryanodine channel from opening when triggered by the action potential in the muscle Prevents calcium release from the sarcoplasmic reticulum Prevents binding of calcium to troponin on the actin filaments in the cytosol of the skeletal muscle cells Myosin-binding site on the actin remains covered by the tropomyosin Prevents cross-bridge formation between myosin and actin within the sarcomere Prevents muscle contraction ↓ Progression of muscle rigidity and spasms ↓ Heat produced by muscular contraction Skeletal & respiratory muscle weakness ↓ Body temperature ↓ Inspiratory capacity Dyspnea Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 18, 2024 on www.thecalgaryguide.com

Infective endocarditis

Infective Endocarditis: Pathogenesis, complications, and clinical findings Subacute Endocarditis Pre-existing valvular stenosis or regurgitation Non-laminar flow across valve damages valve endothelium A sterile thrombus forms Thrombus forms on the surface of a cardiac valve Acute Endocarditis Poor dental hygiene/recent dental procedure Invasive procedure/indwelling device Positive blood cultures Activation of immune system Valve Trauma Invading bacterium Intravenous (IV) drug use (mostly causes right sided endocarditis) Bacteria enter the bloodstream (bacteremia) In subacute cases, valvular abnormality usually present beforehand In all cases, vegetation forms on affected valve Immune complex deposit in kidney Immune complexes cause vasculitis in retinal vessels Immune complexes deposit subcutaneously ↓ Blood flow to organs perfused by the obstructed arteries Valve endothelium is damaged Bacteria adhere to thrombi on the cardiac valve endothelium Infective Endocarditis Infection of the thrombus typically produces a vegetation on the flow surface of a valve Immune complexes (complexes of antibody bound to antigen) form secondary to infection Generalized immune response Malaise Chills Fever (> 38°C) Author: Sean Spence George S. Tadros Reviewers: Yan Yu Jason Baserman Danny Guo Steve Vaughan* *MD at time of publication Parts of vegetation embolize systemically, obstructing arteries Infection destroys infected valve Smaller emboli block smaller vessels on hands/feet Microinfarctions Mitral regurgitation, Aortic stenosis, Aortic insufficiency (Valve involvement: Mitral > Aortic > Tricuspid) Vegetation seen on ultrasound/echocardiogram Damage to Glomerulonephritis glomeruli (Inflammation of glomeruli) Roth’s spots (retinal hemorrhages with pale centers due to coagulated fibrin) Osler nodes (tender, raised, red lesions found on the hands and feet) Organ infarction (tissue death) Splinter hemorrhages (small red streaks under nails) Janeway lesions (non-tender, red macules/nodules on palms/soles – only a few millimeters wide) Regurgitation (blood leaks back through the insufficient valve despite it being closed) Valve unable to fulfill normal functions (valve insufficiency) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 20, 2013, updated Feb 24, 2024 on www.thecalgaryguide.com

Gestational Diabetes Risk factors and pathogenesis

Gestational Diabetes: Risk factors and pathogenesis Normal metabolic changes occurring in pregnancy (e.g., increased lipid storage, increase renal filtration, increased glucose production etc.) Authors: Amyna Fidai Maharshi Gandhi Reviewers: Laura Byford-Richardson Shahab Marzoughi Yan Yu* Hanan Bassyouni* * MD at time of publication High risk population (Aboriginal, Hispanic, South Asian, Asian, African) Previous or current macrosomia (>4000g) or polyhydramnios Other conditions associated with Diabetes Mellitus such as polycystic ovarian syndrome, hypertension, metabolic syndrome Placental counter regulatory hormones (particularly Human Placental Growth Hormone) oppose the action of insulin ↑ Insulin resistance (liver, muscle, adipose tissues become less responsive to insulin) ↑ Fetal demands after 18 weeks gestation (fetus requires 80% of its energy from maternal glucose) ↑ Carbohydrate intake to keep up with the demands Previous history of gestational diabetes or glucose intolerance Family history of diabetes Advanced maternal age Obesity Previous unexplained stillbirth Multiples (larger placental mass and activity) Corticosteroid use ↑ Risk for pregnancy induced glucose intolerance (mechanism unclear and/or complex) ↑ Insulin requirements Initially pancreatic beta cells work overtime to keep up with the ↑ insulin demands Eventually insulin demands are not met due to the exhaustion of pancreatic beta cells Plasma glucose rises (Fasting plasma glucose ≥5.3 mmol/L) Gestational Diabetes (or exacerbation of pre-existing DM) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 28, 2017, updated Feb 24, 2024 on www.thecalgaryguide.com

Eisenmenger Syndrome

Eisenmenger Syndrome: Pathogenesis and clinical findings Ventricular septal defect Patent ductus arteriosus Authors: George S. Tadros Reviewers: Stephanie Happ Shahab Marzoughi Kim Myers* * MD at time of publication Atrial septal defect Blood shunted from systemic to pulmonary circulation Long-standing “left-to-right” shunt with too much pulmonary blood flow ↑ Flow of blood through the pulmonary circulation (from right ventricle to pulmonary arteries) ↑ Shear stress and circumferential stress on the pulmonary arteries and arterioles Atrioventricular septal defect Truncus arteriosus (Only one common artery arises from the heart rather aorta and pulmonary artery) Long-standing “right-to-left” shunt with too much pulmonary blood flow Structural changes occur in pulmonary arteries and arterioles to adapt to ↑ flow and pressure Hypertrophy of the smooth muscles (media) of pulmonary arteries and arterioles Thickening of the intima (innermost layer) of pulmonary arteries and arterioles ↑ Pulmonary vascular resistance (pressure in the pulmonary arteries) Pressure within the right ventricle gradually ↑ Right ventricular pressure is equal to, or exceeds left ventricular pressure Shunt changes from left-to-right to right-to-left “Right-to-Left” Shunt De-oxygenated blood originating from the right ventricle bypasses the lungs and goes into systemic circulation ↓ Oxygen delivery to tissue across the body Pulmonary hypertension (mean pulmonary artery pressure at rest ≥ 25mmHg) Right ventricular hypertrophy (enlarging) Hypertrophied right ventricle cannot contract effectively Right ventricle loses ability to pump blood efficiently Right heart failure Megakaryocytes (platelet precursors) are shunted away from the capillary beds of the lungs, where they usually get fragmented into platelets Chronic central cyanosis (generalized bluish discoloration) Induction of vascular endothelial growth factor (VEGF) in fingers Terminal digit clubbing (uniform swelling of the fingers and toes) Hypoxemia (<90% O2 saturation) Thrombocytopenia (↓ platelet count) Spontaneous bleeding events Body tries to compensate for ↓ O2 by ↑ oxygen-carrying capacity of the blood Polycythemia (↑ in red cell count) and ↑ hemoglobin concentration ↑ blood viscosity Hypercoagulable and prothrombotic state Not enough O2 to meet the body’s demands Fatigue Epistaxis (nose bleeds) Minor (non-life-threatening) Major (life-threatening) Pulmonary hemorrhage Dental bleeds Menorrhagia (heavy periods) Pulmonary Embolism (clot in pulmonary vessels) Stroke Deep vein thrombosis (clot in deep veins) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 5, 2024 on www.thecalgaryguide.com

Pagets Disease pathogenesis and clinical findings

Paget’s Disease: Pathogenesis and clinical findings Author: Payam Pournazari George S. Tadros Reviewers: Yan Yu Spencer Montgomery Luiza Radu David Hanley* * MD at time of publication Mutations in different genes (SQSTM1 gene most common) Epigenetic modifications of different genes Bone marrow cells (precursor of osteoclasts) get infected with measles or respiratory syncytial virus ↑ Osteoclast formation from progenitor (precursor) cells Malfunction of genes involved in bone remodeling and regulation Genetic predisposition ↑ Osteoclast quantity (10- 100X), size, and activity Release of bone matrix proteins and collagen breakdown products such as C-terminal telopeptide ↑ Serum C-terminal telopeptide (marker of bone resorption) Osteoclasts secrete acid and enzymes that dissolve the mineralized bone and matrix (bone resorption) The breakdown leaves physical holes in the bone that show up as radio-lucent spots on x-ray Radiolucent lytic bone lesions on x-ray (mostly seen in pelvis, vertebral bodies, tibia, femur and skull) ↑ Osteoblast activity as a compensatory mechanism Disorganized new bone formation Abnormal new bone is weak, but bone continues to bear regular stresses Skeletal deformities E.g., Skull involvement (↑ hat size), bowed tibias, kyphosis (excessive forward curve of the upper spine) Osteoblasts release alkaline phosphatase from the bone into the blood ↑ Serum alkaline phosphatase (marker of bone formation) Damage to the auditory labyrinth (bones in the ear) Bilateral progressive hearing loss Disorganized remodeling, lytic lesion expansion and bowing of bone all stimulate nociceptive (pain-sensing) nerve endings on the periosteum (membrane covering the surfaces of bones) Bone pain (dull, often at night-time) Damage to bone surrounding joints Osteoarthritis Bone fractures Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 26, 2012, updated Mar 5, 2024 on www.thecalgaryguide.com Paget’s Disease: Pathogenesis and clinical findings Author: Payam Pournazari George S. Tadros Reviewers: Yan Yu Spencer Montgomery David Hanley* * MD at time of publication Mutations in different genes (SQSTM1 gene most common, but also TNFRSF11A, ZNF687 and PFN1) Epigenetic modifications of different genes (including RANKL, OPG, HDAC2, DNMT1, and SQSTM1) Malfunction of genes involved in bone remodeling and regulation Possible viral exposure (measles or respiratory syncytial virus) Genetic predisposition ↑ Osteoclast quantity (10- 100X), size, and activity Release of bone matrix proteins and collagen breakdown products such as C-terminal telopeptide (CTx) ↑ Serum C-terminal telopeptide marker of bone resorption Osteoclasts secrete acid and enzymes that dissolve the mineralized bone and matrix (bone resorption) The breakdown leaves physical holes in the bone that show up as radio-lucent spots on x-ray Radiolucent Lytic bone lesions on x-ray (mostly seen in pelvis, vertebral bodies, tibia, femur and skull) ↑ Osteoblast activity as a compensatory mechanism Disorganized new bone formation Abnormal new bone is weak, but bone continues to bear regular stresses Skeletal deformities E.g., Skull involvement (↑ hat size), Bowed tibias, kyphosis (excessive forward curve of the upper spine) Osteoblasts release Alkaline Phosphatase (ALP) from the bone into the blood ↑ Serum Alkaline Phosphatase marker of bone formation Damage to the auditory labyrinth (bones in the ear) Bilateral progressive hearing loss Disorganized remodeling, lytic lesion expansion and bowing of bone all stimulate nociceptive (pain-sensing) nerve endings on the periosteum (membrane covering the surfaces of bones) Bone pain (dull, often at night-time) Damage to bone surrounding joints Osteoarthritis Bone fractures Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 26, 2012 on www.thecalgaryguide.com Paget’s disease: Pathogenesis, Clinical Findings Author: Payam Pournazari Reviewers: Yan Yu Spencer Montgomery David Hanley* * MD at time of publication Genetic predisposition (possibly in RANK encoding gene) Possible viral exposure (measles and respiratory syncytial virus) ↑ in number (10-100X), size, and activity of osteoclasts Osteoclasts cause excessive bone resorption, which also stimulates osteoblasts Release of bone matrix proteins and collagen breakdown products such as C-terminal telopeptide of pyridinoline crosslinks (CTx) ↑ serum CTx marker of bone resorption Osteoclasts secrete acid and enzymes that dissolve the mineralized bone and matrix Leaves physical holes in the bone that show up as radio- lucent spots on x-ray Lytic bone lesions (mostly seen in pelvis, vertebral bodies, tibia, femur and skull) Marked ↑ osteoblastic activity results in disorganized new bone formation Abnormal new bone bone is weak, but bone continues to bear regular stresses Skeletal deformities: e.g. Skull involvement (↑ hat size), Bowed tibias, kyphosis and fractures Osteoblasts release Alkaline Phosphatase (ALP) from the bone into the blood ↑ serum ALP marker of bone formation Disorganized bone remodelling, lytic lesion expansion, fracture and bowing of bone all stimulate nociceptive nerve endings on the periosteum Bone pain (dull, often night-time) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 26, 2012 on www.thecalgaryguide.com

Onychomycosis

Dermatophyte Onychomycosis: Pathogenesis and clinical findings Authors: Holly Zahary Loreman Reviewers: Mina Youakim Elise Hansen Shahab Marzoughi Jodi Hardin* * MD at time of publication Host Risk Factors Environmental Risk Factors Immuno- compromised ↓ Immune response to infection Older age Peripheral vascular disease Reduced blood circulation Diabetes Pre-existing nail dystrophy Previous nail trauma Integrity of nail unit is compromised Micro- traumatic pressure on nail Dark, warm shoe environment Optimal conditions for fugal growth Exposure to tinea pedis or onychomycosis Direct spread of infection to nail unit High blood sugar favoring infection Dermatophytes invade corneocytes on stratum corneum, the uppermost non- living layer of keratinized skin Compromise/breaking of hyponychial seal or cuticle (connection between hyponychium and nail plate) Proximal Subungual White Superficial Tinea infection (e.g. Tinea Pedis, Corporis, Capitis) Infection spreads to distal hyponychial space Dermatophytes colonize local tissue in nail plate and nail bed Dermatophytes feed on keratinized tissue General Symptoms (All Subtypes) Spongiosis (Intercellular edema) Acanthosis (Thickening of stratum spinosum layer of epidermis) Hyperkeratosis (Thickening of stratum corneum In effort to rid infection) Papillomatosis (Projections of dermal papillae) Secondary damage to nail matrix Loss of nail Keratinocytes produce an acute, low-grade inflammatory cytokine response Onychomycosis Dermatophytic infection of the nail bed Inflammation promotes ↑ fluid to tissues for ↑ immune cell delivery Widespread inflammation thickens parts of the epidermis in efforts to shed the infection Inflammation and epidermal hyperplasia (↑ growth of cells) influence local dermal papillae (group of cells just beneath the hair follicle) to proliferate and project above the skin Distal Subungual Superinfecting bacteria or other fungi proliferate beneath the compromised nail imparting a yellowish appearance Distal Subungual Subtype (Thick yellow nails, keratin and debris accumulate distally underneath nail plate) Dermatophytes invade the proximal end of the nail plate Dermatophytes penetrate through the cuticle to the newly forming nail plate moving distally Proximal Subungual Subtype (Whitish discolouration of nail plate that begins proximally and moves distally, indicative of immunosuppression) Fungi predominantly invade various areas of the superficial nail plate layers eventually joining together White Superficial Subtype (Chalky white scale that spreads slowly beneath nail plate, well-defined “white islands” that coalesce as disease progresses) The entirety of the nail plate is infected by the dermatophytes Widespread inflammation thickens the nail plate as well as beneath the nail (subungual hyperkeratosis) in efforts to shed the infection Total Dystrophic Subtype (End-stage nail disease, entire nail becomes thick and dystrophic) Local spread of infection Dermatophytes spread causing cracks in the skin deeper into toe Abnormal keratinization in hyponychium Keratin accumulates between nail plate and hyponychium Fissure (splits in the skin) Bacteria enters lymphatics and bloodstream Cellulitis Sepsis Onycholysis (nail plate separates from nail bed) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 13, 2024 on www.thecalgaryguide.com Dermatophyte Onychomycosis: Pathogenesis and clinical findings Authors: Holly Zahary Loreman Reviewers: Mina Youakim Elise Hansen Shahab Marzoughi Jodi Hardin* * MD at time of publication Host Risk Factors Environmental Risk Factors Immuno- compromised ↓ Immune response to infection Older age Peripheral vascular disease Reduced blood circulation Diabetes Pre-existing nail dystrophy Previous nail trauma Integrity of nail unit is compromised Micro- traumatic pressure on nail Dark, warm shoe environment Optimal conditions for fugal growth Exposure to tinea pedis or onychomycosis Direct spread of infection to nail unit High blood sugar favoring infection Dermatophytes invade corneocytes on stratum corneum, the uppermost non-living layer of keratinized skin Compromise/breaking of hyponychial seal or cuticle (connection between hyponychium and nail plate) Proximal Subungual White Superficial Distal Subungual Superinfecting bacteria or other fungi proliferate beneath the compromised nail imparting a yellowish appearance Distal Subungual Subtype (Thick yellow nails, keratin and debris accumulate distally underneath nail plate) Infection spreads to distal hyponychial space Dermatophytes colonize local tissue in nail plate and nail bed Dermatophytes feed on keratinized tissue Keratinocytes produce an acute, low-grade inflammatory cytokine response Onychomycosis Dermatophytic infection of the nail bed Inflammation promotes ↑ fluid to tissues for ↑ immune cell delivery Widespread inflammation thickens parts of the epidermis in efforts to shed the infection Inflammation and epidermal hyperplasia (↑ growth of cells) influence local dermal papillae (group of cells just beneath the hair follicle) to proliferate and project above the skin General Symptoms (All Subtypes) Spongiosis (Intercellular edema) Acanthosis (Thickening of stratum spinosum layer of epidermis) Hyperkeratosis (Thickening of stratum corneum In effort to rid infection) Papillomatosis (Projections of dermal papillae) Secondary damage to nail matrix Loss of nail Tinea infection (e.g. Tinea Pedis, Corporis, Capitis) Dermatophytes invade the proximal end of the nail plate Dermatophytes penetrate through the cuticle to the newly forming nail plate moving distally Proximal Subungual Subtype (Whitish discolouration of nail plate that begins proximally and moves distally, indicative of immunosuppression) Fungi predominantly invade various areas of the superficial nail plate layers eventually joining together White Superficial Subtype (Chalky white scale that spreads slowly beneath nail plate, well-defined “white islands” that coalesce as disease progresses) The entirety of the nail plate is infected by the dermatophytes Widespread inflammation thickens the nail plate as well as beneath the nail (subungual hyperkeratosis) in efforts to shed the infection Total Dystrophic Subtype (End-stage nail disease, entire nail becomes thick and dystrophic) Dermatophytes spread deeper into toe Bacteria enters lymphatics and bloodstream Abnormal keratinization in hyponychium Keratin accumulates between nail plate and hyponychium Local spread of infection causing cracks in the skin Fissure (splits in the skin) Cellulitis Sepsis Onycholysis (nail plate separates from nail bed) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com Dermatophyte Onychomycosis: Pathogenesis and clinical findings Authors: Holly Zahary Loreman Reviewers: Mina Youakim Elise Hansen Shahab Marzoughi Jodi Hardin* * MD at time of publication Host Risk Factors Environmental Risk Factors Immuno- Older compromised age ↓ Immune response to infection Peripheral vascular disease Reduced blood circulation Diabetes Pre-existing nail dystrophy Previous nail trauma Integrity of nail unit is compromised Micro- traumatic pressure on nail Dark, warm shoe environment Optimal conditions for fugal growth Exposure to tinea pedis or onychomycosis Direct spread of infection to nail unit High blood sugar favoring infection Dermatophytes invade corneocytes on stratum corneum, the uppermost non-living layer of keratinized skin Compromise/breaking of hyponychial seal or cuticle (connection between hyponychium and nail plate) Tinea infection (e.g. Tinea Pedis, Corporis, Capitis) Infection spreads to distal hyponychial space Dermatophytes colonize local tissue in nail plate and nail bed Dermatophytes feed on keratinized tissue Keratinocytes produce an acute, low-grade inflammatory cytokine response Onychomycosis Dermatophytic infection of the nail bed General Symptoms (All Subtypes) Spongiosis (Intercellular edema) Acanthosis (Thickening of stratum spinosum layer of epidermis) Papillomatosis (Projections of dermal papillae) Hyperkeratosis (Thickening of stratum corneum In effort to rid infection) Secondary damage to nail matrix Loss of nail Proximal Subungual White Superficial Distal Subungual Distal Subungual Subtype (Thick yellow nails, keratin and debris accumulate distally underneath nail plate) Proximal Subungual Subtype (Whitish discolouration of nail plate that begins proximally and moves distally, indicative of immunosuppression) White Superficial Subtype (Chalky white scale that spreads slowly beneath nail plate, well-defined “white islands” that coalesce as disease progresses) Total Dystrophic Subtype (End-stage nail disease, entire nail becomes thick and dystrophic) Local spread of infection causing cracks in the skin Dermatophytes spread deeper into toe Abnormal keratinization in hyponychium Keratin accumulates between nail plate and hyponychium Onycholysis (nail plate separates from nail bed) Fissure (splits in the skin) Bacteria enters lymphatics and bloodstream Cellulitis Sepsis Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com Dermatophyte Onychomycosis: Pathogenesis and clinical findings Authors: Holly Zahary Loreman Reviewers: Mina Youakim Elise Hansen Shahab Marzoughi Jodi Hardin* * MD at time of publication Host Risk Factors Environmental Risk Factors Immuno- Older compromised age ↓ Immune response to infection Peripheral vascular disease Reduced blood circulation Diabetes Pre-existing nail dystrophy Previous nail trauma Integrity of nail unit is compromised Micro- traumatic pressure on nail Dark, warm shoe environment Optimal conditions for fugal growth Exposure to tinea pedis or onychomycosis Direct spread of infection to nail unit High blood sugar favoring infection Dermatophytes invade corneocytes on stratum corneum, the uppermost non-living layer of keratinized skin Compromise/breaking of hyponychial seal or cuticle (connection between hyponychium and nail plate) Tinea infection (e.g. Tinea Pedis, Corporis, Capitis) Infection spreads to distal hyponychial space Dermatophytes colonize local tissue in nail plate and nail bed Dermatophytes feed on keratinized tissue Keratinocytes produce an acute, low-grade inflammatory cytokine response Onychomycosis Dermatophytic infection of the nail bed Proximal Subungual White Superficial General Symptoms (All Subtypes) Spongiosis (Intercellular edema) Acanthosis (Thickening of stratum spinosum layer of epidermis) Papillomatosis (Projections of dermal papillae) Hyperkeratosis (Thickening of stratum corneum In effort to rid infection) Secondary damage to nail matrix Loss of nail Distal Subungual Distal Subungual Subtype (Thick yellow nails, keratin and debris accumulate distally underneath nail plate) Proximal Subungual Subtype (Whitish discolouration of nail plate that begins proximally and moves distally, indicative of immunosuppression) White Superficial Subtype (Chalky white scale that spreads slowly beneath nail plate, well- defined “white islands” that coalesce as disease progresses) Total Dystrophic Subtype (End-stage nail disease, entire nail becomes thick and dystrophic) Local spread of infection causing cracks in the skin Dermatophytes spread deeper into toe Abnormal keratinization in hyponychium Keratin accumulates between nail plate and hyponychium Onycholysis (nail plate separates from nail bed) Bacteria enters lymphatics and bloodstream Fissure (splits in the skin) Cellulitis Sepsis Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com Dermatophyte Onychomycosis (Tinea Unguium): Pathogenesis, clinical findings, Authors: Holly Zahary Loreman Reviewers: Elise Hansen Name Name* * MD at time of publication and complications Host Risk Factors Environmental Risk Factors Immuno- compromised ↓ immune response to infection Older age Peripheral vascular disease Diabetes Pre-existing nail dystrophy Previous Nail Trauma Integrity of nail unit is compromised Micro-traumatic pressure on nail Dark, warm shoe environment Optimal conditions for fugal growth Exposure to tinea pedis or onychomycosis Direct spread of infection to nail unit Reduced blood circulation High blood sugar, favoring infection Tinea pedis infection (see ‘Tinea Capitis, Tinea Corporis, and Tinea Pedis’) Infection spreads to distal hyponychial space Dermatophytes colonize local tissue in nail plate and nail bed Dermatophytes feed on keratinized tissue Proximal Subungual White Superficial Dermatophytes invade corneocytes on stratum corneum, the uppermost non-living layer of keratinized skin Compromise/breaking of hyponychial seal or cuticle (connection between hyponychium and nail plate) Keratinocytes produce an acute, low-grade inflammatory cytokine response Onychomycosis (Tinea Unguium) (dermatophytic infection of the nail bed) Distal Subungual General Symptoms (All Subtypes) Spongiosis Intercellular edema Acanthosis Thickening of stratum spinosum layer of epidermis Papillomatosis Projections of dermal papillae Hyperkeratosis Thickening of stratum corneum In effort to rid infection Secondary damage to nail matrix Loss of nail Distal Subungual Subtype Thick yellow nails, keratin and debris accumulate distally underneath nail plate Proximal Subungual Subtype Whitish discolouration of nail plate that begins proximally and moves distally, indicative of immunosuppression White Superficial Subtype Chalky white scale that spreads slowly beneath nail plate, well-defined “white islands” that coalesce as disease progresses Total Dystrophic Subtype End-stage nail disease, entire nail becomes thick and dystrophic Local spread of infection causing cracks in the skin Dermatophytes spread deeper into toe Abnormal keratinization in hyponychium Keratin accumulates between nail plate and hyponychium Onycholysis (nail plate separates from nail bed) Tissue Damage Cellulitis Sepsis Bacteria enters lymphatics and bloodstream Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com

MI Complication Ventricular Wall Rupture

Atrial Septal Defect Pathogenesis and Clinical Findings

Atrial Septal Defect (ASD): Pathogenesis and clinical findings Genetic syndromes (e.g., Holt- Oram, Noonan, and Down) Gene mutations (e.g., TBX5, GATA4, and NKX2-5) Authors: Ryan Wilkie George Tadros Reviewers: Julena Foglia Haotian Wang Shahab Marzoughi Tim Prieur* * MD at time of publication Spontaneous Abnormal formation of the septum of the atria Atrial Septal Defect (ASD) An abnormal connection between the left and right atria of the heart Following birth, lungs fill with air and resistance to blood flow in the lung vasculature ↓ Pressure within the right ventricle and right atrium ↓ Left atrial pressure exceeds right atrial pressure Blood passes from left to right through the ASD (left-to-right shunt) ↑ Blood flow through the right heart ↑ Blood flow through tricuspid valve Mid-diastolic murmur Right-sided heart dilation (enlargement of the right ventricle) Enlarged ventricle cannot pump blood effectively Congestive Heart Failure ↑ Blood flow through pulmonary valve and pulmonary vasculature Right ventricular heave (visible or palpable chest wall impulse around sternum) ↑ Right atrial wall stress Inspiration produces no net pressure change between communicating atria Delayed closure of pulmonary valve (relative to aortic valve) Morphologic changes in pulmonary vasculature from long standing exposure to high blood flow Pulmonary vascular resistanceáover time, may surpass systemic vascular resistance **Pulmonary Hypertension** Mid-systolic ejection murmur Heart is unable to pump enough blood to meet demand during activity (including feeding) ↑ Backup of blood in lungs ↑ Hydrostatic pressure in lung vasculature Pulmonary edema Damage to normal conduction of electrical signal from the atria to the ventricles ECG Changes: Prolonged PR and QRS intervals, right bundle branch block, right axis deviation Fixed split S2 (two distinct sounds are heard as part of S2) Reduced exercise capacity ↓ Eating Failure to thrive Fatigue Atrial arrhythmias (atrial fibrillation or flutter) Irregular beats are felt in the chest wall Palpitations Dyspnea ↓ Ability to clear foreign particles from interstitium due to presence of extra fluid Respiratory tract infections ** See Relevant Calgary Guide Slide ** Pulmonary Hypertension: Pathogenesis and clinical findings Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 1, 2014; updated Mar 21, 2024 on www.thecalgaryguide.com

Angioedema Bradykinin Mediated

Angioedema – Bradykinin Mediated: Pathogenesis and clinical findings Drug Induced Angiotensin converting enzyme inhibitor, dipeptidyl peptidase-4 inhibitor, or neprilysin inhibitor use Hereditary Type II Acquired Thrombolytic use Activate factor XII Factor XII initiates bradykinin synthesis Type I Type III Gain of function gene mutation in bradykinin cascade activators (factor XII) & precursors (kininogen), triggered by ↑ systemic estrogen Rheumatologic disorders & B- cell lymphoproliferative disease Complement cascade activation results in ↑ C1 protease production C1 esterase inhibitor is utilized to neutralize C1 protease, with its consumption exceeding its synthesis Plasma cell proliferation (i.e., dyscrasia/ monoclonal gammopathy) Immunoglobulin G antibodies act against C1 esterase inhibitor to render it non-functional Genetic or spontaneous mutation in C1 esterase inhibitor gene C1 esterase inhibitor deficiency C1 esterase inhibitor dysfunction Inhibition of angiotensin converting enzyme, dipeptidyl peptidase-4, or neprilysin induced metabolism of bradykinin ↓ Bradykinin (peptide hormone) degradation in plasma Misfunctioning C1 esterase inhibiter is unable to inactivate bradykinin cascade members ↓ C1 esterase inhibiter results in inadequate inactivation of bradykinin cascade members ↑ Bradykinin protein production in plasma Cutaneous Tissue Mucosal Tissue Epidermal layer Dermal-Epidermal Junction Dermal layer Subcutaneous layer Systemic bradykinin excess Bradykinin-2 receptor binding on endothelial and vascular smooth muscle cells Hyperpermeability pathway activation, with the transcription of some signalling molecules taking hours Released pro-inflammatory mediators act on venules & arterioles in subcutaneous & submucosa tissues Relaxation of vascular smooth muscle Dissociation of endothelial cell junctions ↑ Capillary blood flow ↑ Vascular permeability ↑ Plasma release into interstitial tissues (specific regions of the body hypothesized to be affected due to local differences in endothelial structure and its response to permeability inducing stimuli) Dilation & ↑ permeability of vasculature results in fluid release into surrounding tissues Mucosal Layer Muscularis mucosae Submucosal layer Muscularis externa Intestinal edema (Fluid buildup in Intestine tissues) Intestinal swelling (↑ intra-abdominal pressure) Laryngeal edema (Fluid buildup in larynx) Swelling in larynx ↓ air flow into & out of lungs Asphyxia (body is deprived of oxygen) Dyspnea (difficult in breathing) Author: Aaron Varga Reviewers: Tracey Rice Sunawer Aujla Shahab Marzoughi Maharshi Gandhi Jori Hardin* Yan Yu* * MD at time of publication Peripheral edema (Fluid buildup in extremities such as the hands, ankles, and feet) Ascites, bowel obstruction, &/or hypovolemic shock Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 21, 2024 on www.thecalgaryguide.com

Macrosomia Pathogenesis and Complications

Macrosomia: Pathogenesis and complications Fetal congenital disorders (e.g. Fragile X syndrome, Weaver syndrome) Genes encoding cellular growth are mutated and induce ↑ cell proliferation Fetus with XY chromosomes Y chromosome predisposes fetus to excess growth factor Pregnancy longer than 42 weeks Birth weight ↑ as gestational age ↑ Pregnant parent with BMI > 30 kg/m2 ↑ Central adipose tissue release insulin- desensitizing factors ↑ Insulin resistance promotes hepatic glucose production Macrosomia Parent has previously had ≥ 2 births Average birth weight ↑ with each successive pregnancy Pregnant parent with type 2 diabetes or gestational diabetes (1-hour 50 g glucose challenge test >140 mg/dL at 24-28 weeks gestation) Parent’s glucose-rich blood is carried to the fetus through the placenta ↑ Levels of glucose present in fetal circulation promotes excessive growth (Fetus grows beyond absolute birth weight (> 4000 g) regardless of gestational age) Fetal dysregulation of glucose and fetal programming of later adiposity Metabolic syndromes (e.g. hypoglycemia, hyperinsulinemia) ↑ Insulin levels delay pulmonary maturation Respiratory distress Large fetal size in the uterus Cardiac mass ↑ in proportion to body size Fetal cardiac remodeling (e.g. ↑ left ventricular mass) Uterine muscle wall stretched beyond optimal range Uterine rupture Parent pushes fetus into birth canal Maternal nutrition supply is unable to meet fetus’ increased metabolic demands ↑ Uterine distension prevents uterine muscles from contracting (uterine atony) Fetus takes longer to descend through the birth canal Large fetal size overstretches pelvic structures Perianal trauma (e.g. lacerations to pelvic floor, vagina, rectum) Less space in birth canal prevents the parent from delivering the anterior fetal shoulder after the fetal head Shoulder dystocia (baby’s shoulder stuck during birth) Arrested labour (slow cervical dilation) Insufficient space in birth canal to deliver fetus Assisted vaginal birth/ cesarian section Protracted labour (slow fetal descent) Stillbirth Fetal distress (↓ heart rate) Lack of mechanical contraction of the spiral arteries, normally provided by uterine muscles Blood loss (≥ 500-1000 mL 24 hours post birth) Postpartum hemorrhage Authors: Akaya Blair Reviewers: Dasha Mori Michelle J. Chen Dr. Ian Mitchell* * MD at time of publication ↑ Frequency/ prolonged admission (≥ 3 days) to neonatal intensive care unit Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 21, 2024 on www.thecalgaryguide.com

Apnea of Prematurity

Apnea of Prematurity: Pathogenesis, Signs & Symptoms, and Complications Physiologic immaturity from birth at < 37 weeks gestation Authors: Akaya Blair Reviewers: Dasha Mori Michelle J. Chen Danielle Nelson* * MD at time of publication ↓ Synaptic connection & poor myelination Fetal brain areas responsible for breathing are poorly developed Immature neurologic respiratory function Immature mechanical respiratory function Poor hypopharyngeal muscle tone (soft upper airway helps with size and compliance of airway) Nasal obstruction (e.g. anatomic and/or iatrogenic [suctioning, NG tubes]) Neonate is reliant on nose breathing Airway is unable to remain open (patent) Laryngeal/tracheal abnormalities (e.g. tracheomalacia, laryngeal edema, tracheal stenosis) Anatomical narrowing leading to ↑ airway resistance ↑ Risk of mechanical airway obstruction Disruption of central respiratory drive ↓ Sensitivity to increased CO2 in the ventral medulla oblongata Disruption of peripheral respiratory reflex pathways ↓ Sensitivity to CO2 levels in peripheral carotid bodies and aortic bodies Large head size forces neck into flexion when laying supine Immature airway sensitive to collapse when in flexion ↑ Hypotonia (decreased muscle tone) in REM sleep ↓ Signaling to brainstem Brainstem unable to mount appropriate ventilatory response to insufficient oxygen Upper airway collapse Apnea of prematurity Respiratory pauses >20 sec or pauses <20 sec with bradycardia (<100 beats per minute), central cyanosis, and/or oxygen saturation <85% in neonates born at <37 weeks gestation and with no underlying disorders causing apnea. Most apneas in apnea of prematurity are central or mixed. ↓ Breathing rate Bradycardia (<100 bpm) ↓ Oxygen to brain Poor neurodevelopmental outcomes (e.g. cognitive function, brain adaptive potential and plasticity) Hypoxemia (↓blood oxygen levels where SpO2 <85%) ↓ Oxygen and hemoglobin to mucous membranes (e.g. lips) & fingers and toes (periphery) Central & peripheral cyanosis (bluish discoloration) ↓ Oxygen to retina Abnormal growth of blood vessels in eyes Retinopathy of prematurity (changes in visual acuity and possible blindness) Death/impairment in cell function from lack of oxygen ↑ Risk of infant mortality Imbalanced oxygen intake and CO2 output in lungs Body transiently ↑ HR to unsuccessfully try to compensate for ↓ tissue oxygenation Respiratory failure Respiratory rate >60 ↓ Heart rate ↓ Blood pressure Head bobbing Abdominal breathing Skin mottling Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 21, 2024 on www.thecalgaryguide.com

Neonatal Necrotising Enterocolitis in Premature Neonates

Neonatal Necrotising Enterocolitis (NEC) in Premature Neonates: Pathogenesis and clinical findings Prematurity risk factors ↓ Intestinal motility ↑ Intestinal stasis allows bacteria more time to proliferate Bacterial overgrowth in gut ↓ Goblet cells in intestinal epithelium ↓ Intestinal mucus layer production leads to impaired mechanical defense against pathogenic bacteria Immature tight junctions in intestinal epithelium ↑ Permeability of intestinal epithelial barrier ↑ Toll-like receptor 4 (TLR4) expression on intestinal epithelial cells Aberrant bacterial colonization of gut Impaired gut barrier allows for ↑ bacterial translocation across intestinal epithelium TLR4 on intestinal mesentery endothelial cells bind lipopolysaccharides (LPS) on Gram-negative gut bacteria Immune cells release proinflammatory mediators (TNF, IL-12, IL-18) Cytokines mediate ↑ enterocyte apoptosis (including enteric stem cells) and ↓ enterocyte proliferation Intestinal mucosa healing is impaired, leading to local inflammation & injury TLR4 on intestinal epithelial cells binds LPS from Gram-negative gut bacteria Authors: Rachel Bethune Naima Riaz Reviewers: Nicola Adderley Michelle J. Chen Kamran Yusuf* Jean Mah* * MD at time of publication Endothelial nitric oxide synthase expression is reduced Vasoconstriction from ↓ NO reduces blood flow to intestines Prolonged ↓ in O2 perfusion results in irreversible intestinal mucosal cell death (necrosis) Gas escapes into abdominal cavity Leakage of intestinal contents irritates parietal peritoneum Bacteria enter bloodstream Pneumo- peritoneum Abdominal distention Peritonitis Sepsis Blood from tissue damage mixes with intestinal contents Bloody stool Intestinal sensory neurons detect damage and send signals to medullary vomiting centre Bilious vomiting Damaged intestinal cells are unable to absorb nutrients Short gut syndrome Persistent intestinal mucosal injury creates penetrating lesions through intestinal wall Intestinal perforation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 6, 2019; updated Mar 21, 2024 on www.thecalgaryguide.com

Lichen Sclerosus

Lichen Sclerosus (genital manifestation): Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation (i.e. chronic infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) ↑ Activation of CD4+ and CD8+ T cells released from macrophages (white blood cell) in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation Fibroblasts (contributes to the formation of connective tissue) proliferate and persist producing altered collagen under the epidermis Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the overall skin thickness Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors Localized area appears red Erythema (reddening of the skin) Erosion/ulceration Skin fissures (linear cleavage of skin) Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Normal Skin Lichen Sclerosus Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Hypopigmented patches (localized, pale areas of skin) Epidermal atrophy (crinkling paper-type skin appearance) Thinned skin is weakened and prone to physical stress or trauma ↑ fluid in the extracellular space due to capillary leakage from ↑ blood flow Superficial dermal edema (swelling) Fibrotic tissue deposition following healing of damaged tissue Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Scarring Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 25, 2024 on www.thecalgaryguide.com Lichen Sclerosus (genital manifestation): Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation (i.e. chronic infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) ↑ Activation of CD4+ and CD8+ T cells released from macrophages (white blood cell) in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation Fibroblasts (contributes to the formation of connective tissue) proliferate and persist producing altered collagen under the epidermis Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors ↑ fluid in the extracellular space due to capillary leakage from ↑ blood flow Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Thinned skin is weakened and prone to physical stress or trauma Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Erosion/ulceration Skin fissures (linear cleavage of skin) Normal Skin Lichen Sclerosus Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Progressive basal layer degeneration thins the overall skin thickness Hypopigmented patches (localized, pale areas of skin) Fibrotic tissue deposition following healing of damaged tissue Scarring Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com Chronic inflammation (i.e. chronic Reviewers: Dermal layer Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Activation of CD4+ and CD8+ T cells released from macrophages (white blood cell) in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts (contributes to the formation of connective tissue) proliferate and persist producing altered collagen Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors ↑ fluid in the extracellular space due to capillary leakage from ↑ blood flow Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Thinned skin is weakened and prone to physical stress or trauma Lichen Sclerosus Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Erosion/ulceration Skin fissures (linear cleavage of skin) Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Normal Skin Progressive basal layer degeneration thins the overall skin thickness Hypopigmented patches (localized, pale areas of skin) Epidermal layer Basal layer Dermal-Epidermal Junction Fibrotic tissue deposition following healing of damaged tissue Scarring Chronic inflammation (i.e. chronic Reviewers: Dermal layer Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Activation of CD4+ and CD8+ T cells released from macrophages in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro- inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the overall skin thickness Hypopigmented patches (localized, pale areas of skin) Epidermal layer Basal layer Dermal-Epidermal Junction Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Normal Skin Lichen Sclerosus Skin fissures (linear cleavage of skin) Erosion/ulceration Fibrotic tissue deposition following healing of damaged tissue Scarring Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Reviewers: Dermal layer Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation (i.e. chronic infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Activation and infiltration of CD4+ and CD8+ T cells into the dermal-epidermal junction T-cells proliferate in a band (horizontal linear) formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the epidermis Hypopigmented patches (localized, pale areas of skin) Epidermal layer Basal layer Dermal-Epidermal Junction Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Localized histamine release Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Skin fissures (linear cleavage of skin) Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Scarring Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Erosion/ulceration Fibrotic tissue deposition following healing of damaged tissue Normal Skin Lichen Sclerosus Chronic inflammation (i.e. chronic Elise Hansen Unknown triggers Genetic predisposition infection, chronic toxin exposure) Medications (e.g. carbamazepine, (HLA-DQ7 and HLA-DR12) and trauma pembrolizumab, nivolumab, ipilimumab) ↑ Activation and infiltration of CD4+ and CD8+ T cells into the dermal-epidermal junction Sunawer Aujla Shahab Marzoughi Name Name* * MD at time of publication T-cells proliferate in a band (horizontal linear) formation Pro-inflammatory response activation (increase in pro-inflammatory cytokines such as Interleukins 1-alpha and 1-beta) ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the epidermis Hypopigmented patches (localized, pale areas of skin) Histamine receptor binding stimulates sensory nerve endings Localized area appears red Localized histamine release Localized vasodilation (↑ blood flow) Superficial dermal edema (swelling) Pruritus Erythema Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Normal Skin Sclerotic plaques (localized areas of thickened skin) Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Skin fissures (linear cleavage of skin) Bleeding Erosion/Ulceration Epidermal atrophy (crinkling paper- type skin appearance) Lichen Sclerosus Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Fibrotic tissue deposition following healing of damaged tissue Scarring Lichen Sclerosus (genital manifestation): Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Name Name* * MD at time of publication Pruritus Histamine receptor binding stimulates sensory nerve endings Localized area appears red Erythema Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) ↑ Activation and infiltration of CD4+ and CD8+ T cells into the dermal-epidermal junction T-cells proliferate in a band formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) Localized histamine release Localized vasodilation (↑ blood flow) Superficial dermal edema (swelling) Collagen deposits and hyalinizes beneath the atrophic epidermal layer Hypopigmented patches (localized, pale areas of skin) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the epidermis Skin fissures Lichen Sclerosus Epidermal atrophy (crinkling paper- type skin appearance) Sclerotic plaques (localized areas of thickened skin) Bleeding Scarring Erosion/Ulceration Normal Skin Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Infectious Small Bowel Diarrhea

Infectious small bowel diarrhea: Pathogenesis and Signs/Symptoms Undercooked poultry, beef, pork, other foods Food, or travel to underdeveloped countries E. coli (ETEC) May produce Shiga toxins (a specific family of toxins that can lead to complications) Authors: Noriyah Al Awadhi Yan Yu Sara Cho Reviewers: Paul Ratti Jason Baserman Shahab Marzoughi Kerri Novak* * Indicates MD at time of publication Y. enterocolitica (also milk, cheese) Shellfish, undercooked seafood V. parahaemolyticus V. cholerae Enterohemorrhagic E. coli (EHEC) Daycare centers/nurseries Drinking/swimming in bad water — mountains/wells S. aureus B. cereus Noroviruses Rotavirus G. lamblia C. parvum May produce emetic toxins (toxins that cause vomiting) Adequate amount of organism and/or toxin is ingested Organism adheres to the intestinal liningàorganism colonizes the small intestine Organism releases enterotoxin (a toxin that affects the intestines) Binds to and disrupts intestinal transporters used in secretion and absorption of water and electrolytes Toxin enters systemic vasculature Shiga toxins inhibit ADAMTS13 (cleaving enzyme) Failure to cleave von Willebrand Factor (vWF) multimers Accumulation of vWF multimers Platelets and thrombi accumulate in microvasculature Hemolytic uremic syndrome (hemolytic anemia, thrombocytopenia, and acute renal damage) ↑ Water and electrolyte secretion ↓ Fluid absorption Chemoreceptor trigger zone in medulla detects circulating emetic toxins Nausea & vomiting Triggers release of inflammatory mediators and cytokines that travel to the central nervous system Prostaglandin is synthesized and released Neurotransmitter cyclic AMP (cAMP) is released cAMP ↑ hypothalamic thermoregulation set point Fever Large volume profuse diarrhea Loss of water Distention (swelling) of intestines stimulates visceral sensory pain fibers Visceral pain fibers crosstalk with somatic nerves from the same spinal cord level Occasional referred pain/cramping (typically diffuse pain around the abdomen) Loss of bicarbonate, sodium, potassium, magnesium, and chloride Dehydration Electrolyte deficiency Metabolic acidosis (pH < 7.4 & serum bicarbonate < 24) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 7, 2012; updated Mar 25, 2024 on www.thecalgaryguide.com

Post-Renal Acute Kidney Injury AKI

Post-Renal Acute Kidney Injury (AKI): Pathogenesis and clinical findings Blood clot or cellular debris Foreign body Neurogenic bladder Obstruction intrinsic to urine excretion system Nephrolithiasis (kidney stones) Anatomical defect(s) Intra- abdominal adhesions Retroperitoneal fibrosis (scar-like tissue) Benign or malignant masses Prostate cancer Benign prostatic hyperplasia ↓ Urine flow across point of obstruction Obstruction extrinsic to urine excretion system Urine buildup distends urine collecting system (hydronephrosis) Compression of renal vasculature due to mass effect ↑ Volume/pressure proximal to obstruction ↑ Intratubular pressure ↓ Pressure gradient between glomerular afferent arteriole and Bowman’s space Casts occlude tubules ↓ Filtration of plasma into nephrons ↓ Glomerular Filtration Rate (GFR) Obstruction is relieved ↓ Intratubular pressure Rapid GFR ↑ Rapid diuresis of fluid and electrolytes Dilated pelvicalyceal system on ultrasound ↓ Urine output ↓ Venous drainage and arterial supply Local ischemia and inflammation of kidney Impaired resorption, excretion, and fine tuning by tubules Acute Tubular Necrosis (ATN) with granular casts ↓ Urine output ↓ Clearance of free water and solutes ↑ Intravascular volume ↑ Serum creatinine ↓ Medullary solute concentration, ischemia, ↓ response of collecting ducts to antidiuretic hormone Lasts > 24hrs Post-obstructive diuresis causes hypovolemia and electrolyte derangements Authors: David Campbell, Matthew Hobart Reviewers: Raafi Ali, Luiza Radu Huneza Nadeem, Marissa Zhang, Julian Midgley* * MD at time of publication Resolves < 24hrs in euvolemia Physiologic post- obstructive diuresis ↑ Na+ and Cl- delivery to distal convoluted tubule is sensed by macula densa Secretion of adenosine by macula densa Adenosine constricts afferent arterioles ↓ GFR ↓ Renal clearance of drugs and waste products ↑ Venous hydrostatic pressure ↑ Volume in arterial system overwhelms pressure regulation mechanisms Hypertension Fluid extravasation from veins and capillaries Generalized Edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 25, 2024 on www.thecalgaryguide.com

Irritant Contact Dermatitis Pathogenesis and Clinical Findings

Irritant Contact Dermatitis: Pathogenesis and clinical findings Authors: Zaini Sarwar, Mina Youakim Reviewers: Shahab Marzoughi, Ryan T. Lewinson, Yan Yu*, Laurie M. Parsons* * MD at time of publication Repeated/chronic exposure causes damage to cell membranes Skin barrier disruption Chronic non-specific inflammatory response Repetitive keratinocyte cytokine-mediated injury Keratinocytes exhibit ↑ proliferation as a compensatory response Rapid turnover of stratum corneum (outermost layer of the epidermis) Hyperkeratotic skin is less amenable to skin stretching and pressure Skin fissures (cracks in the skin) Irritant agents (abrasives, cleaning solution, oxidative & reducing agents, dust, soils, water) Acute exposure triggers inflammatory response Keratinocytes undergo cytotoxic damage with ↑ neutrophil & cytokine release Common occupational exposures (housekeeping, cleaning, catering, medical/dental, construction) Risk factors (atopy, fair skin, low temperature, low humidity) Stimulation of local nociceptors (free nerve endings extend into the mid epidermis) Perivascular (around the blood vessel) inflammation causes histamine release from mast cells Damaged keratinocytes are destroyed via apoptosis (programmed cell death) Epidermal Necrosis (death of epidermal tissue) Shedding of necrotic tissue Ulceration (deep open wound on skin) Burning pain (uncomfortable stinging sensation) Pruritus (itching) Histamine causes local blood vessel dilation and ↑ blood flow to the area of skin affected Erythema (area appears red from ↑ blood flow) Burning & Itching Spongiosis Neutrophils Neutrophils Histamine causes local blood vessel walls to have ↑ permeability, thereby ↑ leakage of fluid Spongiosis (↑ fluid between keratinocytes in the epidermis) Fluid continues to build up from ongoing inflammation Vesiculation (fluid collections in the epidermis) Long-term skin scratching causes chronic irritation which eventually hardens the skin Lichenification (thick, hardened patches of skin) ↑ Overall keratin production Hyperkeratosis (thickening of the outermost skin layer) Further fluid buildup bursts vesicles leaving behind erosions and dried crust on the epidermis Crust (scaling over the skin) Lichenification Erosions (open sore on skin) Ulcer Epidermis Perivascular Inflammation Hyperkeratosis Dermis Dermal-epidermal junction Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 19, 2016; updated Mar 30, 2024 on www.thecalgaryguide.com

Febrile Neutropenia Pathogenesis and clinical findings

Febrile Neutropenia (Neutropenic Fever): Pathogenesis and clinical findings Administration of cytotoxic chemotherapy for cancer treatment Acquired aplastic anemia Autoreactive T cells destroy bone marrow stem cells Congenital mutations in ELA2 gene (encodes neutrophil elastase) ↑ Neutrophil apoptosis Chemotherapy eliminates beneficial bacterial species from gut microbiota New microbiota composition allows for growth of colonizing bacteria Indwelling catheters inserted to deliver chemotherapy Skin-colonizing bacteria access tissues through catheters Bacteria penetrate tissue barriers Chemotherapy injures gastrointestinal mucosa Broken mucosal barrier increases susceptibility to infections Chemotherapy destroys circulating neutrophils Chemotherapy impairs bone marrow stem cells ↓ Production of neutrophils Neutropenia (Absolute Neutrophil Count (ANC) < 0.5x109 cells/L ↓ Immune cell ↓ Production of engulfment of microbes inflammatory mediators Fewer circulating neutrophils blunts the innate immune response Pathogens enter bloodstream from tissues Systemic infection Authors: Max Lazar Braxton Phillips Reviewers: Naman Siddique Michelle J. Chen Lynn Savoie* * MD at time of publication Dormant viral infections reactivate (e.g. cytomegalovirus, herpes simplex virus) ↑ Susceptibility to common bacterial infections Positive blood bacterial cultures Fever (T ≥ 38.3 oC or sustained T ≥ 38 oC for 1 hour) Immune system mounts an excessive inflammatory response that damages tissues and organs Sepsis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 5, 2018; updated Mar 30, 2024 on www.thecalgaryguide.com

Overview of Ischemic Heart Disease

Ischemic Heart Disease (IHD): Pathogenesis of the various types of IHD Authors: Sean Spence Vaneeza Moosa Reviewers: Tristan Jones Jason Baserman Yan Yu Michelle J. Chen Frank Spence* * MD at time of publication ↑ Serum low-density lipoprotein (LDL) ↑ Availability of lipids that deposit in arterial wall ↓ Serum high-density lipoprotein (HDL) ↓ LDL removal from coronary artery walls (transport of LDL to liver is impaired) Atherosclerosis Conditions predisposing to vessel wall endothelial cell dysfunction (e.g. metabolic syndrome, smoking, hypertension, physical inactivity) Vessel wall vulnerable to infiltration by LDL and immune cells Arterial wall degeneration, characterized by fat deposition (atheromatous plaque) in and fibrosis of the inner layer of arteries Stable atheromatous plaque in coronary arteries Fibromuscular cap (formed by smooth muscle cells) overlying fatty plaque contents remains intact & plaque contents are not released into vessel lumen Plaque serves as a fixed lumenal obstruction to blood flow If vessel stenosis (narrowing) is significant (≥70%) myocardial oxygen demand starts to exceed supply (especially with exertion) Heart experiences a predictable & transient reduction in blood flow (myocardial ischemia) Unstable atheromatous plaque in coronary arteries The fibromuscular cap overlying fatty plaque ruptures Thrombogenic plaque contents (especially tissue factor) are exposed to the coagulation factors in the vessel lumen Activation of platelets & the clotting cascade at the site of rupture Thrombus forms over already partially occlusive plaque and further partially or completely occludes lumen ↓ Perfusion (blood flow) of myocardium Cardiomyocytes experience a transient decrease in blood flow (transient ischemia) Unstable Angina Cardiomyocytes experience death (infarction) Myocardial Infarction (MI) Stable Angina Acute Coronary Syndromes (ACS) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 8, 2013; updated Mar 30, 2024 on www.thecalgaryguide.com

Bullous Pemphigoid

Bullous Pemphigoid: Pathogenesis and clinical findings Certain medications (e.g. antibiotics, diuretics, biologics) Author: Danny Guo Mina Youakim Reviewers: Yan Yu Shahab Marzoughi Jason Baserman Laurie Parsons* Régine Mydlarski* * MD at time of publication Preceding disease triggers Infections (e.g. Human Herpes Physical/Environmental triggers (e.g. (e.g. Psoriasis, Lichen Planus) virus, Epstein-Barr virus) Phototherapy, radiotherapy, burns) Development of autoantibodies against the basement membrane antigens (i.e. BPAG1 and BPAG2) (can occur anywhere on the body) Autoimmune destruction of the basement membrane Antibodies activate the complement system and recruit inflammatory cells Further weakened adhesion between epidermis and dermis Accumulation of extracellular serous fluids in a pseudo- pocket between the epidermis and the dermis Unknown etiologies Circulating Immunoglobulin G & E antibodies trigger either a prodrome or concurrent itch response (exact mechanism unknown) Pruritis (itch) Epidermal layer Serous fluid pocket Urticaria (hives) Widespread Bullae (serum-filled lesions) Epidermal layer Dermal-Epidermal Junction Dermal layer Antibody against keratinocytes and Disrupted Dermal-Epidermal Junction Y hemidesmosomes Normal Skin Bullous Pemphigoid Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 1, 2012; updated Apr 20, 2024 on www.thecalgaryguide.com Y Y Y

Deep Partial Thickness Burns Pathogenesis and Clinical Findings

Deep Partial Thickness Burns: Pathogenesis and clinical findings Radiation (Sunlight, x-ray, nuclear emission/explosion) Ionizing radiation gets into contact with DNA Damage to keratinocytes Fire (Flash fire or direct contact with flame) Contact (Hot solid objects) Scalding (Hot liquid via immersion, spill or splash) Chemical (Strong acid, alkali or irritant gas) Electrical (Contact with exposed electrical wiring/appliances) Author and Illustrator: Amanda Eslinger Maharshi Gandhi Reviewers: Alexander Arnold Shahab Marzoughi Duncan Nickerson* * MD at time of publication Direct transfer of heat energy Coagulation necrosis (cell death due to ischemia) is induced Deep Partial Thickness Burn Injury to the epidermal layer and both the papillary and a portion of the reticular layer of the dermis Transfer of heat energy & direct injury to cellular membranes Epidermis Papillary dermis Reticular dermis Sub- cutaneous Tissue ↑ vascular permeability due to damage Fluid leak results in edema between dermal & epidermal layer Blisters (a bubble on the skin containing fluid) Thin epidermal layer forming fluid-filled vesicle breaks open Cutaneous capillary bed is destroyed Blood flow to injured area is compromised Pressing on the skin doesn’t easily force blood cells out of the area Non-blanchable skin Vasodilation in fascia (a thin casing of connective tissue) underlying subcutaneous tissue Inflammatory mediators such as cytokines and prostaglandins activate fibroblasts Collagen deposition and subsequently induration (thickening of skin) Some healthy dermal appendages surrounded by islands of undamaged epithelial cells Possible spontaneous re-epithelialization in 2-9 weeks During re-epithelization of burns there can be excessive deposition of collagen and other extracellular matrix components Thick raised scars in dermis due to excess collagen deposition Somatosensory structures (nociceptors, thermoreceptors, and mechanoreceptors) are completely injured within the dermis Analgesia of impacted area (the inability to feel pain) Ongoing Inflammation and dilated blood vessels Red Induration (Thickened skin appearing red) Compromised blood flow and more extensive tissue damage White Induration (Thickened skin appearing white) Moist Wound Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 2, 2013, updated Apr 20, 2024 on www.thecalgaryguide.com

Fetal Complications of Labour and Vaginal Delivery

Fetal complications of labour and vaginal delivery Fetus passing through cervix and birth canal puts pressure and physical stress on the head Labour/vaginal delivery Fetus is not presented head- first in the vaginal canal (e.g. breech, shoulder, transverse) Abnormal positioning increases risk of umbilical cord becoming entangled or dropping in front of the fetus in the birth canal Passage of the fetus through birth canal compresses the umbilical cord Edema Perinatal hypoxia Signs of fetal distress (e.g. late decelerations, changes in fetal heart rate, ↓ fetal movement) Infant death Uterine contractions are too weak to progress labour Prolonged time in labour results in increased total number of contractions Fractures (most commonly affecting the clavicle) Uterine contractions compress blood vessels in the placenta, resulting in reduced blood flow Severe obstetric hemorrhage causes circulating blood flow to decrease as blood volume is lost (see relevant slide for pathogenesis) Small birth canal to baby size ratio Lack of space traps the fetal shoulders following delivery of the head (shoulder dystocia) Excessive lateral traction or stretching damages nerves in the brachial plexus Erb’s palsy (paralysis of the arm caused by injury to C5-C6 of the brachial plexus) Shearing force on the skull and scalp ruptures blood vessels Cephalohematoma (blood accumulation below periosteum) Boggy, soft lump on infant’s head Soft tissue injury triggers release of inflammatory signaling molecules, which ↑ vascular permeability Caput succedaneum (scalp swelling) Boggy, soft swelling of infant’s head that extends across suture lines Mild soft tissue injury Hypoxic ischemic encephalopathy Variable signs of brain injury: seizures, hypotonia, difficulty feeding, etc. Cerebral palsy Developmental delay, hypotonia, spasticity, etc. Authors: Jasmine Nguyen Reviewers: Akanksha Bhargava Michelle J. Chen Sarah Glaze* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 29, 2024 on www.thecalgaryguide.com

Costochondritis

Costochondritis: Pathogenesis and clinical findings Systemic infection originating in upper respiratory tract (commonly Staphylococcus aureus and Streptococcus bacterial infections) Infection spreads through blood to ribcage and chest wall Age-related degeneration of cartilage within ribcage joints Immune cells present in joints secrete proinflammatory cytokines Cytokines sensitize nociceptors (pain receptors) in joints Repetitive trauma or strain to chest wall muscles (e.g. chronic cough, chest wall injury, overexertion of chest wall muscles) Excessive stretch and tearing of ribcage cartilage and ligaments Autoimmune disease (e.g. rheumatoid arthritis) Antigen presenting cells display self-antigens to CD4+ T cells Mechanical stimuli (e.g. Damaged cells release cytokines Pathogens activate immune cells at site of stretch) activate nociceptors that recruit immune cells inflammation Costochondritis Benign inflammation of the ribcage (costal) cartilage, particularly at the costosternal junctions (connection between sternum and cartilage) and the costochondral junctions (connection between the cartilage and rib) Authors: Michelle J. Chen Reviewers: Raafi Ali Yan Yu* Gerhard Kiefer* * MD at time of publication Cartilage, ligament, or muscle injury Presence of foreign pathogen in costal cartilage Injury or pathogen activates inflammatory cascade in the ribcage cartilage Immune cells proliferate so that they exceed the available space in the cartilage matrix of the ribcage Cartilage swelling compresses intercostal nerves Compression acts as a mechanical stimulus to activate nociceptors Sharp, localized pain reproducible upon palpation over ribcage Immune cells secrete cytokines Cytokines activate nociceptors so that they become more sensitive to mechanical stimuli Muscle or ligament stretch from normal use activates sensitized nociceptors Pain increases with inspiration or cough Natural resolution of inflammation over time Macrophages phagocytose apoptotic cells (immune and cartilage cells) and cellular debris Immune cells release factors that degrade proinflammatory cytokines Fewer cytokines reduce immune cell recruitment into costal cartilage Pain usually self-resolves Immune cells release lipid molecules that bind to the same cells (autocrine signaling) to inhibit further production of inflammatory cytokines and chemokines Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 29, 2024 on www.thecalgaryguide.com

Acute Otitis Media Complications

Acute Otitis Media: Complications Prolonged mucus buildup or swelling in Eustachian tube due to colds/allergies obstructs the Eustachian tube Fluid unable to drain through tube and accumulates in middle ear Acute Otitis Media Infection and inflammation of the middle ear Mastoid air cells are in physical contact with distal middle ear Pathogens move into mastoid air spaces Inflammation & infection in air spaces Mastoiditis Bacterial and immune cell debris (pus) accumulates in mastoid air spaces Untreated middle ear infection allows further bacterial proliferation Persistent effusion causes ion channel changes in inner ear Composition of endolymph and perilymph in inner ear changes Vestibular/Labyrinth dysfunction Feelings of Vertigo imbalance Purulent discharge from middle ear through perforation Otorrhea (ear discharge) ↑ Pressure in middle ear Pressure stretches tympanic membrane Cytokines reach hypothalamus through the bloodstream Hypothalamus responds to stimulation and ↑ thermoregulatory set-point High-grade fever Infection spreads into bloodstream Sepsis Cytokines alter metabolism pathways of neurotransmitters in the brain Cerebral cortex dysfunction Infection spreads to cranium Intracranial complications (e.g., meningitis, brain abscess, thrombus) Author: Jody Platt Stephanie de Waal Reviewers: Yan Yu Elizabeth De Klerk William Kim Annie Pham Michelle J. Chen Danielle Nelson* * MD at time of publication Helper T cells and macrophages release inflammatory cytokines into the bloodstream Perforation of tympanic membrane ↓ Conduction of sound waves Conductive hearing loss Pressure in middle ear diffuses out of perforation ↓ Tympanic membrane stretching Otalgia (ear pain) fades Accumulated debris compresses cranial nerve VII Facial nerve palsy Mastoid abscess Febrile seizures Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 28, 2013, updated Apr 29, 2024 on www.thecalgaryguide.com

Circle of Willis Anatomy and Physiology

Circle of Willis: Anatomy & physiology Ischemic stroke Ischemic stroke Inadequate blood flow & oxygenation of brain tissue Occlusion or narrowing of A2 segment Supplies medial portions of frontal & parietal lobes (lower extremity regions of motor/sensory cortices) Anterior Cerebral Artery (ACA) Ischemic stroke (brain damage due to ischemia) Inadequate blood flow & oxygenation of brain tissue Occlusion or narrowing Supplies midbrain, thalamus, & occipital lobe Posterior Cerebral Artery (PCA) Vertebral Arteries (VA) Inadequate blood flow & oxygenation of brain tissue Occlusion or narrowing Supplies lateral portions of frontal, temporal & parietal lobes (upper extremity & facial regions of motor/sensory cortices) Middle Cerebral Artery (MCA) P2 segment A1 segment Supplies the MCA & ACA A2 segment Collateral circulation redistributes blood flow to maintain continuous blood supply Occlusion or narrowing of vessels within the Circle of Willis Anterior Communicating Artery (Acomm) Weakness in the blood vessel walls Aneurysm formation causes mass effect (displacement) on nearby structures Supplies BA & PCA, lateral medulla & cerebellum via posterior inferior cerebellar artery (PICA), & upper spinal cord via anterior spinal artery (ASA) Basilar Artery (BA) Supplies occipital lobe, cerebellum & brainstem Thromboembolism (blood clot obstruction) Inadequate blood flow & oxygenation of brain tissue Ischemic stroke Damage to the ventral pons Locked-in syndrome (quadriplegia, loss of voluntary breathing & speaking, intact cognition & blinking) Internal Carotid Arteries (ICA) Posterior Communicating Artery (Pcomm) Weakness in the blood vessel walls Aneurysm formation causes mass effect (displacement) on nearby structures Oculomotor nerve (cranial nerve III): double vision & absent pupil response to light Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 5, 2018, updated Apr 29, 2024 on www.thecalgaryguide.com P1 segment Ruptured aneurysm: subarachnoid hemorrhage Inadequate blood flow & oxygenation of brain tissue Hemorrhagic stroke (brain damage due to bleeding) Optic nerve (cranial nerve II): ↓ visual acuity Frontal lobe: headache & psychological changes Authors: Josh Kariath, Rafael Sanguinetti Reviewers: Andrea Kuczynski, Luiza Radu Gary Klein* * MD at time of publication

Sickle Cell Disease Pathogenesis Clinical Findings and Complications

Sickle Cell Disease: Pathogenesis, Clinical Findings, and Complications DNA point mutation in chromosome 11 causes a substitution of glutamate to valine for the sixth amino acid of the β-globin chain Authors: Yang (Steven) Liu Priyanka Grewal Reviewers: Alexander Arnold Luiza Radu JoyAnne Krupa Yan Yu* Lynn Savoie* * MD at time of publication Hemoglobin S (HbS) variant formed instead of normal Hemoglobin A (HbA) Hb electrophoresis shows approximately 45% HbS, 52% HbA (ααββ), 2% HbA Hb electrophoresis shows approximately 90% HbS, 8% HbF, & 2% HbA . No HbA present (ααδδ), & 1% HbF (ααγγ;2 fetal hemoglobin) Heterozygous: point mutation in one of the two chromosomes (Hb AS) Sickle cell trait (asymptomatic unless severely hypoxic) Homozygous: point mutation in both chromosomes (Hb SS) Sickle cell disease An inherited blood disorder characterized by defective hemoglobin that leads to red blood cells sickling 2 Dehydration Hypoxemia Acidosis ↓ Volume of RBC cytoplasm ↓ O2 Saturation of Hb O morereadily 2 released from Hb in low pH environment ↑ Concentration of deoxygenated HbSinred blood cells (RBCs) Hydrophilic glutamate→ hydrophobic valine substitution makes HbS less soluble in the cytoplasm & more prone to polymerization & precipitation in its deoxygenated state ↑ Concentration of deoxygenated Hb in RBC leads to ↑ polymerization rate Polymerized & precipitated HbS forms long needle-like fibers RBC shape becomes sickled Sickle cells on peripheral blood smear Vaso-occlusion (sickled RBCs lodge in small vessels, blocking bloodflow to organs & tissues) Blockage of venous outflow Occlusion of vessels in lungs ↑ pulmonary blood pressure Fluid extravasates into interstitial tissue leading to pulmonary edema Acute chest syndrome (chest pain, hypoxemia (↓blood oxygen), etc.)** to the penis: to the spleen: Priapism (persistent, painful erection) Splenic Sequestration (blood pools in spleenà splenomegaly & hypotension) Extravascular hemolysis (macrophages in the spleen phagocytose sickled RBCs) Normocytic anemia ↑Marrow erythropoiesis (RBC production) to compensate for hemolysis Infarction of bone Pain crises If occurring in hands Dactylitis (inflammation of digits) Blockage of arteries ↓ oxygenation of organs & tissues Vaso-occlusion of the splenic artery Splenic infarction (↓ blood supply leads to tissue death) RBC inclusions (structures found in RBCs) not removed by spleen Howell-Jolly bodies (RBC DNA remnants) on blood smear Vaso-occlusion of other arteries (cranial, renal, etc) Stroke, renal failure ↑ RBC breakdown ↑ Unconjugated bilirubin released from RBC breakdown RBC precursors (reticulocytes) are released into the blood stream Reticulocytosis (increased number of immature red blood cells) on peripheral blood smear Patient’s RBC level becomes dependent on increased marrow activity Bone marrow infarction or viral infections (i.e. Parvovirus B19) suppresses bone marrow activity Aplastic crises (profound anemia) ** See corresponding Calgary Guide slide(s) ↑ Serum level of unconjugated bilirubin Some of the circulating unconjugated bilirubin deposits in the skin Jaundice (yellowing of skin) ↑ Conjugation of bilirubin in liver ↑Amounts of conjugated bilirubin released into bile Gallstone formation Cholelithiasis (presence of gallstones in the gallbladder) Spleen releases invasive encapsulated bacteria (eg. Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis) into circulation, which causes infections Meningitis Sepsis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 16, 2013, updated Apr 29, 2024 on www.thecalgaryguide.com

Wiskott-Aldrich Syndrome

Wiskott-Aldrich Syndrome (WAS): Pathogenesis and clinical findings X-linked recessive inheritance (mostly males impacted) Spontaneous DNA mutation Genetic mutations in Wiskott-Aldrich Syndrome Protein (WASP) impair actin cytoskeleton remodeling in hematopoietic cells (immature blood cells) Authors: Mina Mina Reviewers: Hana Osman Mao Ding Maharshi Gandhi Shahab Marzoughi Louis-Philippe Girard* * MD at time of publication Megakaryocytes (platelet precursor cells) depend on the cytoskeleton changing shape to form pseudopodia (arm-like projections) which bud off forming cellular fragments (platelets) Abnormal cytoskeleton reorganization leads to ineffective thrombocytopoiesis (production of platelets) Microthrombocytopenia (↓ platelet size and quantity) Issues with formation of a platelet plug due to abnormal platelets (dysfunction of primary hemostasis) Reduced ability for platelet adhesion, activation, and/or aggregation Natural killer cells depend on the cytoskeleton reorganization to form immunological synapses (communication) with body cells in order to have effective surveillance T cells depend on the cytoskeleton remodeling to form pseudopods which allow them to synapse with other cells when a pathogen is encountered Defective immune synapse formation ↓ Cancer immunosurveillance ↑ Risk of malignancy Helper T cells cannot activate B cells which generate antibodies (immunoglobulins) to destroy pathogens Regulatory T cells can not sufficiently downregulate effector cells which typically limit the immune response and prevent autoimmune conditions ↑ Risk of autoimmune diseases Recurrent opportunistic infections Immune dysregulation Impaired immune response ↓ Number and function of T cells Immune responses contribute to Type 2 immune responses Atopic dermatitis (AD; chronic inflammation that causes itchy skin) ↑ Immunoglobulin (Ig) A Epistaxis (nosebleed) Red blood cells leak from capillaries Menorrhagia (heavy menstrual bleeding) Petechiae (small, flat, red spots that appear on the skin) Inflammation in AD triggers release of interleukins (modulatory proteins during inflammatory and immune responses) leading to Immunoglobulin (Ig) class switching ↑ IgE levels Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 20, 2024 on www.thecalgaryguide.com

Scabies pathogenesis and clinical findings

Scabies: Pathogenesis and clinical findings Direct person-person transmission of Sarcoptes Scabiei var. hominis to new host Fertilized females secrete proteolytic enzymes that allow them to burrow through the stratum corneum (2 mm/day) Authors: Heena Singh Amanda Eslinger Nirav Saini Reviewers: Shahab Marzoughi Danny Guo Yan Yu Richard Haber* * MD at time of publication Mechanical irritation and immunological reaction Mast cell activation and histamine release Itch (> 10 Mites) Stratum corneum Stratum lucidum Stratum granulosum Stratum spinosum Stratum basale Females lay 2-3 ova/day which hatch in the stratum corneum in pockets after 3 days The larvae molt and mature for 2 weeks and mate within the pockets of the stratum corneum Following mating, female mites begin burrowing Cycle is propagated as new female mites create more burrows in stratum corneum Superficial, Linear, Tortuous (i.e., Twisted) +/- Scaly Burrows ↑ Exposure to mite antigens such as Sar s 14.3 and Sar s 14.2 Type 2 helper T-cells produce proteins IL-4, IL-5, IL-13 ↑ Serum Immunoglobulin G & E ↑ Eosinophil Count in Peripheral Blood Inappropriate T helper-type immune response in skin (mechanism unknown) Antigens forming from mite feces, ova, or decomposing bodies Type IV hypersensitivity reaction (delayed immune response 2-4 weeks following initial contact) Skin barrier dysfunction from inflammation and histamine release Pre-existing immunosuppression Chronic inflammatory response Allergic reaction to ↑ mite activity at night Uncontrollable Itch (Worse At Night) + Excoriations (Scratch Marks) Urticarial (Hive-Like) Crusted Papules Eczematous Plaques Skin breakdown Opening for bacteria (commonly S. aureus) 2° Bacterial infection Pustules Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 17, 2013; updated Jun 9, 2024 on www.thecalgaryguide.com

Gynecomastia

Gynecomastia: Pathogenesis Authors: Sara Cho Reviewers: Michelle J. Chen Samuel Fineblit* *MD at time of publication Physiologic causes Puberty Placenta transfers maternal estrogens to newborn male babies Older age (>60 years) Hyperthyroidism Klinefelter Syndrome (males with > 1 X chromosome) Liver cirrhosis Certain tumors (e.g., germ cell, adrenal, Leydig cell, Sertoli cell) Anabolic steroid usage (containing testosterone) Finasteride (treatment for benign prostate hyperplasia and male pattern baldness) Cimetidine - inhibits stomach acid production Spironolactone (diuretic used to treat high blood pressure and heart failure) Ketoconazole (antifungal) Cytotoxic agents (e.g. alkylating agents, vincristine, methotrexate) Imbalance between estrogens and androgens Estrogen stimulates breast tissue growth in newborn Changes in metabolic rate ↑ fat production Unclear mechanism ↑ Proinflammatory mediators and cytokines (e.g. prostaglandin E2, TNF⍺, IL-1, IL-6, cyclooxygenase-2) Prostaglandin E2 and IL- 6 upregulate aromatase enzyme expression Available estrogen is higher than available testosterone ↑ Aromatase enzyme activity, converting androgens to estrogen ↓ Testosterone release from the testes ↓ Testosterone ↑ Serum sex hormone binding globulin (SHBG) SHBG binds estrogen with less affinity to testosterone Thyroid hormone stimulates liver to express more sex hormone binding globulin Thyroid hormone stimulates aromatase activity Overexpression of aromatase enzyme Seminiferous tubules in the testes hyalinize and fibrose Suppression of the hypothalamic pituitary thyroid axis through an unclear mechanism Tumor may produce estradiol Tumor produces β- human chorionic gonadotropin (β-HCG) ↑ serum testosterone Inhibits 5-α reductase Blocks binding of 5-DHT to androgen receptors ↓ 2-hydroxylation of estradiol Mimics structures of testosterone Inhibits 17,20 desmolase and 17α-hydroxylase Damage to Leydig cells in testes ↑ Estrogen to androgen ratio Pathological causes Impaired spermatogenesis and testosterone production ↓ GnRH secretion from hypothalamus ↓ Testosterone ↓ Luteinizing hormone (LH) release from anterior pituitary ↓ 5-DHT and/or testosterone binding to androgen receptors in chest tissue ↓ inhibition of breast development Normal or increased estrogen acts on estrogen receptor on chest tissue Estrogen receptors stimulate breast development Estradiol negatively feedbacks on luteinizing hormone β-HCG stimulates LH receptors on Leydig cells in the testes Aromatase enzyme converts excess testosterone into estrogen and estradiol ↓ conversion of testosterone to 5- dihydrotestosterone (5-DHT), a more potent form of testosterone Glandular proliferation in male breasts Gynecomastia (development of breast tissue in males) Drug side- effects ↓ Metabolism of estradiol Competitively binds to androgen receptors ↑ Serum estradiol levels Exhibits physical attributes that do not align with gender identity Psychological distress In some cases, hormones stabilize Involution and atrophy of ducts Gynecomastia resolves ↓ Steroid synthesis ↓ Androstenedione produced (testosterone precursors) ↓ Serum testosterone levels ↓ Testosterone production Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jun 9, 2024 on www.thecalgaryguide.com

Posterior Cruciate Ligament PCL Injury Pathogenesis and Clinical Findings

Posterior Cruciate Ligament (PCL) Injury: Pathogenesis and clinical findings Authors: Luc Wittig Stephanie de Waal Michelle J. Chen Reviewers: Reza Ojaghi Usama Malik Sunawer Aujla Nojan Mannani Mankirat Bhogal Dr. R. Buckley* Dr. Gerhard Kiefer* * MD at time of publication Sport-related trauma Dashboard knee injury from a motor vehicle collision Tibia contacts dashboard at high velocity with knee in flexed position Tibia is forced posteriorly, relative to knee joint The PCL undergoes sudden & forceful strain Hyperextension injury (knee joint moves past its normal extension limit) Extreme tibia movement anteriorly past knee joint overstretches PCL Hard fall on flexed knee Posterior Cruciate Ligament Injury Strain & overstretching of the PCL, which connects the anterior distal femur to the posterior proximal tibia to prevent posterior translocation of the tibia relative to the femur, can result in a partial or complete tear. The tear can be isolated (rare) or be one of multiple ligaments that are torn (multi-ligamentous tear). Mild injurious force causes a partial tear Intact portion of PCL prevents extreme tibial translocation posterior to the femur. Torn portion still allows 1-5 mm of posterior tibial translocation (Grade 1) Positive posterior drawer test Knee injury tests • Posterior drawer test – Push against leg below the knee to test for posterior tibial translocation relative to femur • Lachman test – Pull leg below the knee to test for anterior tibial translocation relative to femur • McMurray test – Tests for medial and lateral meniscus tears • Varus & valgus stress test – Tests for medial and Strong injurious force causes a complete, isolated tear PCL is unable to prevent posterior translocation of the tibia relative to the femur, allowing 6-10 mm of posterior tibial translocation (Grade 2) Positive posterior Negative Lachman, McMurray, drawer test and varus & valgus stress test Very strong injurious force causes a multi- ligamentous tear and damage to the knee joint capsule (capsuloligamentous injury) Absence of stability from PCL combined with absence of stability from other knee ligaments allows for > 10 mm of posterior tibial translocation (Grade 3) Positive posterior Positive Lachman OR McMurray drawer test OR varus & valgus stress test PCL unable to stabilize knee by preventing posterior tibial translocation (chronic PCL insufficiency) Body uses quadriceps tendon for knee stabilization to compensate for PCL insufficiency Inflammation from injury contributes to progressive degenerative articular changes lateral collateral ligament tears Post-traumatic patellofemoral pain Osteoarthritis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 20, 2018; updated Jun 9, 2024 on www.thecalgaryguide.com

Metastatic Bone Lesions

Metastatic Bone Cancer: Pathogenesis & Clinical Findings Primary solid tumours from breast, prostate, or lung commonly migrate into bones Bone Metastases Migration of primary solid tumours (commonly from the breast, prostate, or lungs) into bones. Once tumours metastasize to bone, they are generally incurable and contribute to significant morbidity prior to a patient’s death Authors: Curtis Ostertag Reviewers: Mankirat Bhogal Nojan Mannani Michelle J. Chen Dr. Gerhard Kiefer* * MD at time of publication Cell-to-cell communication between tumour cells & bone cells (osteoclasts & osteoblasts) Tumours release TNF-⍺, RANK-L, and PTHRP which ↑ osteoclast activity & ↓ osteoblast activity Change in relative activity of bone cells results in osteolysis (breakdown of bone) Calcium is released into the bloodstream Hypercalcemia Osteoblastic metastasis (common in prostate cancer) Tumor growth Secondary bone formation in response to bone destruction TGF-β, PDGF, & IGF are released from the degraded bone matrix, which can stimulate tumors & osteoblasts Weakened bone increases risk of fracture Pathologic fracture ↑ Mortality Bone tissue expands into surrounding space Nerve compression Disruption of cortical bone or surrounding soft tissues Diffuse & achy rest/night pain Long bone masses compress peripheral nerves Neuropathy Vertebral masses compress spinal nerves/cord Radiculopathy /Myelopathy ↓ Quality of life Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jun 9, 2024 on www.thecalgaryguide.com

Migraines and auras pathogenesis and clinical findings

Migraines and Auras: Pathogenesis and clinical findings Genetic mutations at certain loci (e.g., Familial hemiplegic migraine mutation in gene encoding P/Q-type Ca2+ channels) Personal triggers (e.g., lack of food, emotional stress) “Cortical Spreading Depolarization” followed by “Cortical Spreading Depression” across one cortical hemisphere Cortical spreading depression creates “auras” via unknown mechanism(s) Expanding scotoma (area of visual blurriness) Spreading paraesthesias (numbness that travels across body) Dysphasic language (trouble finding words) Brainstem symptoms (e.g., vertigo, tinnitus) Motor symptoms (e.g., hemiplegia) Triggering of a depolarization wave in a unilateral region of the cortex with associated ↑ blood flow to that region Neurons and glia release K+ into extracellular space that spreads depolarization wave to nearby cortical areas Ion gradient imbalances cause Prolonged vasoconstriction neurons in original cortical area to and ↓ blood flow swell and become inhibited Activation of the hypothalamus (responsible for maintaining homeostasis) Prodromal symptoms (↑ thirst, hunger, yawning, ↓ cognitive function) Author: Yan Yu Braxton Phillips Reviewers: Shahab Marzoughi Owen Stechishin Dustin Anderson Scott Jarvis* Sina Marzoughi* * MD at time of publication Release of hypothalamic neurotransmitters (e.g., orexins, neuropeptide Y) at the trigeminalcervical complex (TCC) of the brainstem and cervical spinal cord Depolarizing wave passes over pseudounipolar neurons (neurons with two axons) of the trigeminal ganglion which synapse in brainstem & dura matter These neurotransmitters reduce the activation threshold of spinal trigeminal nucleus neurons in the TCC Neuropeptides (e.g., calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide) are released at the TTC, triggering local inflammation (termed neurogenic inflammation) Ongoing neurogenic inflammation activates secondary nociceptive neurons in the TTC Central sensitization (↓ response threshold of secondary nociceptive neurons in the TTC) Brain perceives referred pain from the face as the TTC also receives convergent nociceptive input from the face Facial allodynia (pain with normally non-painful stimuli) Serotonin & histamine are released on dural blood vessels triggering neurogenic inflammation in the dura matter Ongoing neurogenic inflammation activates primary nociceptive neurons in the dura matter Peripheral sensitization (↓ response threshold of primary nociceptive neurons around the dural blood vessels_ Unknown mechanisms no longer believed to be related to dural blood vessel dilation Unilateral throbbing headache Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 22, 2012, updated Jul 1, 2024 on www.thecalgaryguide.com

Anesthetic Considerations in Pregnancy

Anesthetic Considerations in Pregnancy: Pathophysiology driving anesthetic management Authors: Calah Myhre Reviewers: Jasleen Brar Luiza Radu Leyla Baghirzada* Yan Yu* * MD at time of publication Airway ↑ Estrogen serum levels Mucosal capillary engorgement ↑Airway tissue friability & edema ↑ Laryngoscopy difficulty & intubation time Secure airway & avoid hypoxemia Consider video laryngoscopy Preoxygenate with ↑100% oxygen Optimize intubation positioning (e.g. “Sniffing position”) ↑ Progesterone serum levels ↓ Esophageal tone & sphincter pressure ↑ Aspiration risk >20 weeks gestation & during labor Aspiration prophylaxis Rapid sequence induction Nonparticulate antacid prophylaxis (e.g., sodium citrate, famotidine) Pre-operative fasting & gastric ultrasound to assess volume Breathing ↑ Minute ventilation ↓ PaCO2 at baseline Uterine artery vasoconstriction with maternal PCO2 levels exceeding 32 mmHg Impaired uteroplacental perfusion Maintain physiologic alkalosis, avoid maternal hypercapnia Maintain maternal arterial PCO2 28–32 mmHg Avoid permissive hypercapnia ↑ Progesterone serum levels Disproportionate ↑ in plasma volume ↓ Serum colloid osmotic pressure Drug-specific alterations in absorption, distribution, metabolism & excretion (e.g. ↑ distribution of acidic drugs due to ↓ albumin; ↑ clearance of renally- metabolized drugs) Optimize anesthetic dosing for altered pharmacokinetics Adjust dosages based on drug recommendations Circulation ↑ Maternal blood volume Peripheral vasodilation ↓In systemic vascular resistance by 25–30% ↓ Blood pressure ↑Abdominal pressure Compression of the aorta & inferior vena cava Supine hypotension Impaired uteroplacental perfusion Fetal ischemia Optimize placental blood flow Position patient on left side to maintain uterine displacement Diaphragmatic elevation & lung compression ↓ Functional residual capacity ↑ Risk of rapid desaturation Fetal hypoxemia Maintain maternal & fetal oxygenation Optimize positioning (e.g., patient on left side to maintain uterine displacement) & supplement oxygen as needed Heart rate ↑ 15-25% ↑ Cardiac output Manifestations of significant blood loss are delayed Avoid hypotension ↑ Stroke volume Avoid fluid overload Treat abnormal variation in blood pressure at lower values Fetus Requirement to assess & treat two patients Achieve optimal anesthetic dosing for mother while maintaining fetus safety Maintain oxygenation of both mother & fetus & ensure adequate uteroplacental perfusion Consider fetal-drug transfer & adjust agent & dose accordingly Monitor maternal vital sign & fetal heart rate Utilize a multidisciplinary team (e.g., pharmacy, nursing, physical & occupational therapy) Legend: Pathophysiology Mechanism Goal Management Published July 5, 2024 on www.thecalgaryguide.com

Diabetes Mellitus Pathophysiology Behind Lab Findings

Diabetes Mellitus: Pathophysiology behind laboratory findings Author: Nathan Archibald Reviewers: Gurreet Bhandal, Julia Gospodinov, Luiza Radu Samuel Fineblit* * MD at time of publication ↓ Transit of glucose transporter GLUT4 to cell surface (mainly adipose & muscle cells) ↓ Glucose uptake into cells Autoimmune destruction of pancreatic beta cells (type 1 diabetes mellitus) Insulin resistance (type 2 diabetes mellitus) Other causes of diabetes mellitus (genetic, drug- induced, pregnancy, etc.) ↑ Lipolysis (fat breakdown) in adipose tissue ↑ Free fatty acids & glycerol in bloodstream ↑ Oxidation of fatty acids in liver to form acetyl CoA ↑ Conversion of acetyl CoA to ketone bodies (ketogenesis) to be used as fuel for the brain Relative or absolute insulin deficiency ↓ Activation of adipose (fat tissue) & muscle cell transmembrane insulin receptors ↓ Activation of intracellular insulin signaling pathways (PI3K & MAP kinase) Cells cannot use glucose as a source of energy; thus body reacts as if it is starving ↑ Protein breakdown in muscle tissue ↑ Amino acids & lactate in bloodstream ↑ Substrates (glycerol, amino acids & lactate) available to produce glucose in the liver ↑ Glycogenolysis (breakdown of stored glucose - glycogen) & gluconeogenesis (production of glucose) in liver Glucose in bloodstream glycates (coats) hemoglobin in red blood cells; thus ↑ blood glucose leads to ↑ glycated hemoglobin ↑ Hemoglobin A1C ↑ Fasting blood glucose level ↑ Random blood glucose level ↑ Blood glucose following oral glucose tolerance test Diabetic ketoacidosis (DKA) in absolute insulin deficiency *See DKA slide Filtered ketone bodies exceed the reabsorption capacity of renal tubules Ketonuria (↑ ketones in urine) ↑ Glucose in bloodstream Build-up of glycation end products causes damage to glomerular tissue Transient glomerular hyperfiltration followed by long-term ↓ in glomerular filtration rate Albuminuria (↑ albumin in urine) Diabetic nephropathy *See slide Filtered glucose exceeds reabsorption capacity of renal tubules in the kidney Glucosuria (↑ glucose in urine) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 8, 2024 on www.thecalgaryguide.com

Neonatal Hypoglycemia Pathogenesis

Neonatal Hypoglycemia: Pathogenesis Normal physiology Placenta supplies fetal circulation with glucose Clamping of the umbilical cord stops the source of glucose Blood glucose level declines rapidly in the first 2-3 hours of life Low glucose causes an ↓ in insulin and an ↑ in epinephrine, cortisol and glucagon Glucagon and epinephrine act on receptors in the liver and skeletal muscle to promote gluconeogenesis (glucose production from non- carbohydrate sources), glycogenolysis (breakdown of glycogen into glucose), and fatty acid oxidation (conversation of fatty acids to ATP) Low glucose levels stimulate the neonate’s appetite, allowing them to adapt to intermittent feeds Infant feeding regularly on a diet with sufficient carbohydrates creates a consistent plasma glucose concentration Pregnant Parent Causes Impaired Glucose Production Inadequate Glucose Supply Pregnant parent using β-blockers β-blockers prevent epinephrine from binding to adrenergic receptors in skeletal muscle and liver Blocked sympathetic signaling in these organs prevents glycogenolysis ↓ Breakdown of glycogen into glucose Infant of a parent with diabetes Parent has a high level of glucose in their blood The fetus receives a glucose-rich blood supply Fetal pancreatic β cells ↑ insulin production Post-birth, glucose levels in the infant’s circulation ↓ but insulin levels remain high Excessive glucose uptake into cells Fetus born with a metabolism disorder (e.g. organic amino acid disorder, disorder of glycogen metabolism, disorder of gluconeogenesis) Genes that make proteins or hormones responsible for production, breakdown and regulation of glycogen are mutated Fetus born with an endocrine disorder (e.g. congenital adrenal hyperplasia, hypopituitarism, Turner Syndrome) Pituitary and/or adrenal gland dysfunction ↓ release of hormones that regulate glucose balance Fetal growth is restricted, fetus is small for gestational age, or is premature (<37 weeks gestation) Glycogen is deposited during the 3rd trimester of pregnancy. Infants born early have fewer stores; smaller infants born at term have ↓ stores, ↑ insulin sensitivity, & poorly coordinated counter- regulatory hormones ↑ Glucose demand for the transition to life out of the womb Glycogen stores used up quickly Perinatal stress (e.g. sepsis, asphyxia) Stress stimulates fetal adrenal glands to ↑ epinephrine secretion Fetal pancreatic ⍺- cells ↑ glucagon secretion ↑ Breakdown of muscles and fat for glucose- building blocks Glycogen stores used up quickly ↑ Glucose usage as fetal metabolic demands ↑ to manage stress Fetal β-cells secrete inappropriately high levels of insulin despite hypoglycemic state; this hyperinsulinism state can last for months & resolve spontaneously ↓ Serum glucose Neonatal hypoglycemia Authors: Dasha Mori Reviewers: Michelle J. Chen *Dr. Danielle Nelson *MD at time of publication Blood glucose < 2.6 mmol/L in term & preterm infants within 72 hours of birth or < 3.3 mmol/L after 72 hours of birth Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 19, 2024 on www.thecalgaryguide.com

Legg Calve Perthes Disease

Legg-Calvé-Perthes Disease: Signs and Symptoms Idiopathic abnormalities in the common pathway of the blood clotting cascade ↑ blood thickness Initial stage (6 months) Early interruption of blood supply to femoral head ↓ Venous outflow from intraosseous vasculature ↑ pressure within bone Fragmentation stage (8 months) Body replaces resorbed necrotic bone with structurally weaker bone Backup of blood within bone vasculature impedes arterial inflow Temporary interruption of blood supply to proximal femoral epiphysis primarily during childhood Residual stage Differential growth of proximal femoral epiphysis Overgrowth of greater trochanter Healing stage (4 years) Body gradually replaces necrotic bone with stronger, more dense bone Lack of O2 & nutrients disrupts normal bone growth Bone tissue begins dying from loss of O2 & nutrients (osteonecrosis) Osteonecrosis is associated with inflammation of synovial tissue (synovitis) at the femoral head Metaphyseal cyst (area of bone resorption) grows on proximal femoral neck metaphysis Growth plate abnormalities Femoral bone head deformity Limited hip internal rotation & abduction Antalgic gait Femoral epiphysis collapses laterally and extrudes from acetabulum Femoral head now composed of dense and less dense bone Scattered radiolucency & radiodensity on plain radiographs Femoral head deformity becomes set in place and limits hip range of motion Femoral bone head deformity Limb length discrepancy Normal bone density on plain radiographs Abnormal articulo- trochanteric distance (vertical distance between highest point of greater trochanter & highest point of femoral head) Remodeling of femoral head & acetabulum seen on plain radiographs Growth plate irregularity ↓ Range of motion Widened medial joint space Antalgic gait Femoral head is displaced laterally Fragmented epiphysis on plain radiographs Groin pain & referred pain to anteromedial thigh or knee region Authors: Janelle Wai Michelle J. Chen Reviewers: Patrick Pankow Nojan Mannani Kirat Bhogal Dr. Gerhard Kiefer* * MD at time of publication Findings on magnetic resonance imaging (MRI) & plain radiographs Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 19, 2024 on www.thecalgaryguide.com

Generalized Anxiety Disorder GAD

Generalized Anxiety Disorder (GAD): Pathogenesis and clinical findings Authors: Keira Britto Reviewers: Sara Cho, Luiza Radu, *Margaret Oakander *MD at time of publication Altered cognition Scan environment for perceived threats Genetic predisposition & family history: polygenic, >30% heritability Adverse childhood & life experiences: e.g., abuse, neglect, divorce, bereavement Morbidity & stressors from chronic medical conditions Hypersensitivity & reactivity to stimuli áHPA axis activity Neurobiological differences Trait neuroticism (emotional instability & nervousness) Reacts to unfamiliarity with withdrawal & fear áLevel of uninhibited excitatory signaling Psychomotor agitation Frequent sympathetic nervous system (fight or flight) activation to perceived threats Cycles of epinephrine surges Inadequate recovery State of hyperarousal Disturbed sleep Ongoing sleep deprivation Easily fatigable áACTH released from hypothalamus áCortisol released from adrenal glands áSerotonin uptake âSerotonin Impaired neuroplasticity &âcomplexity of synaptic connections in amygdala & hippocampus âAbility to deal with emotional stressors Impaired engagement of prefrontal cortex âRegulation of emotional reactions áAnticipatory emotional responses âInhibition from GABA áAmygdala volume & activity áFear & anxiety circuits Attentional focus directed towards worries & perceived threats Divert blood to muscles Skeletal muscle activation Muscle tension Psychomotor agitation (excessive motor activity associated with a feeling of inner tension) áEmotional intensity Chronic state of high physiological stress âHippocampal BDNF (brain derived neurotrophic factor) Hippocampal atrophy &â hippocampal neurogenesis â Inhibitory control of the hippocampus over the HPA axis áAlertness & wakefulness Disturbed sleep Strengthening of memories rooted in fear, to prevent encounters with future threats Behavioural & cognitive changes to facilitate coping with threats Irritability **Excessive, persistent Bottom up, stimulus driven attention áDistractibility Difficulty concentrating anxiety & worry that is distressing &/or impairs functioning Irritability Generalized Anxiety Disorder: **occurring more days than not for ≥ 6 months; **difficult to control; presence of ≥ 3 remaining symptoms Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 21, 2024 on www.thecalgaryguide.com

Underfill Edema Pathogenesis

Underfill Edema: Pathogenesis Acute respiratory Sepsis, burns, distress syndrome, trauma anaphylaxis ↑ Inflammatory mediators Gaps form between epithelial cells lining blood vessels ↑ Capillary permeability Fluid extravasation into interstitial space Blood backing up in vena cava ↑ capillary hydrostatic pressure in venous system Pressure creates net fluid movement from vascular space into interstitial space Authors: Matthew Hobart Richard Chan Nojan Mannani Michelle J. Chen Reviewers: Raafi Ali Varun Suresh Saif Zahir Andrew Wade* Adam Bass* * MD at time of publication Nephrotic syndrome ↑ Renal albumin loss Scarring of liver tissue (cirrhosis) Vasodilatory medications Various mechanisms Right-sided heart failure Compromised right heart function ↓ forward flow ↓ Hepatic albumin synthesis Blood is unable to pass through hepatic vessels disrupted by cirrhosis and backs up in portal vein ↑ Blood pressure in portal vein (portal hypertension) Less blood volume in hepatic veins and vena cava (underfilling) Pregnancy ↑ Estrogen, progesterone and relaxin Vasodilation Gravity causes fluid accumulation in peripheral veins ↑ Capillary hydrostatic pressure ↑ Net fluid movement into interstitial space ↓ Serum albumin ↓ Capillary oncotic pressure Fluid extravasation into interstitial space More blood in portal vein ↑ capillary hydrostatic pressure in venous system Pressure creates net fluid movement from vascular space into interstitial space Less blood volume in arteries (underfilling) ↓ Effective arterial blood volume (EABV) ↓ Renal blood flow activates the renin-angiotensin-aldosterone system (RAAS) Angiotensin and aldosterone ↑ Anti-diuretic hormone released by tubular Na+ and H2O resorption posterior pituitary ↑ H2O resorption ↑ Fluid in circulation, worsening existing venous congestion ↑ Hydrostatic capillary pressure and fluid extravasation into interstitial space Underfill edema (edema worsened by activation of RAAS) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 19, 2015; updated Aug 5, 2024 on www.thecalgaryguide.com

Anterior Shoulder Dislocation Pathogenesis and clinical findings

Anterior Shoulder Dislocation: Pathogenesis and clinical findings Direct distal impact to abducted, externally rotated arm (e.g. fall on outstretched hand) Authors: Molly Joffe Miles Hunter Reviewers: Kristi Billard Stephanie de Waal Nojan Mannani Michelle J. Chen Jordan Raugust*, Ryan Shields* *MD at time of publication Force travels proximally, forcing the head of the humerus anteriorly Anterior force of humeral head exceeds tensile strength of soft tissue stabilizers Detachment of anterior band of inferior glenohumeral ligament Anterior translation of humeral head relative to the glenoid Humeral head causes the axial nerve to stretch Anterior shoulder dislocation Posterolateral aspect of humeral head impacts anterior portion of glenoid Damage to surrounding soft tissues & sensory nerve branches Numbness/altered sensation over lateral deltoid Weakness with shoulder abduction Visible deformity Humeral head palpable anteriorly Posterolateral humeral head fractures Hill-Sachs lesion Decreased range of motion Detachment of antero-inferior glenoid labrum Shoulder pain Rupture of small surrounding blood vessels Bruising Swelling Capsule stiffness Permanent axillary nerve deficit Avulsion of anterior glenoid rim Bony Bankart lesion Soft Bankart lesion (isolated soft tissue injury) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 3, 2016; updated Aug 5, 2024 on www.thecalgaryguide.com

Acute Otitis Media Pathogenesis and Clinical Findings in Children

Acute Otitis Media in Children: Pathogenesis and clinical findings Congenital conditions (e.g. Down Syndrome, Pierre Robin syndrome) Exposure to tobacco smoke Impaired macrophage function in nasopharynx Lack of immunizations Lack of breastfeeding Infant does not receive antibodies from breast milk Overcrowding Age 6 – 16 months Immune system deficiencies Close proximity of kids & ↓ sanitation (e.g. daycare) ↑ Infection risk Upper Respiratory Tract Infection (i.e. bacterial (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis), viral) Immature Eustachian tube anatomy which facilitates pathogen transmission to middle ear Author: Jody Platt Stephanie de Waal Reviewers: Yan Yu Elizabeth De Klerk William Kim Annie Pham Michelle J. Chen Danielle Nelson* * MD at time of publication Abnormal anatomical structure (e.g. cleft palate) ↑ Nasopharyngeal streptococcus pneumoniae Lack of immunity to pathogens ↑ Colonization of nasopharynx with bacterial pathogens Inflammation & edema of respiratory mucosa including the nose, nasopharynx, and Eustachian tube Obstruction of the Eustachian tube Air from middle ear resorbs into circulation which creates a low-pressure environment Negative pressure gradient pulls viral/bacterial pathogens into middle ear Degenerating white blood cells, tissue debris, and microorganisms accumulate & develops into purulent effusion Inflammation & infection of middle ear Complications of acute otitis media** ↑ Pressure in middle ear Stretching of tympanic membrane Helper T cells & macrophages release cytokines into the bloodstream Cytokines trigger hypothalamus to ↑ thermoregulatory set-point Effusion behind tympanic membrane Effusion obstructs visualization of ossicles Neutrophils infiltrate middle ear & phagocytose pathogens Pus accumulates behind the tympanic membrane Blood vessels of the tympanic membrane vasodilate Bulging tympanic membrane Otalgia (ear pain) Discomfort disrupts daily activities in young children Fever Irritable Poor feeding Tympanic membrane erythema Painful blisters on tympanic membrane (e.g. Bullous myringitis) Can persist for up to 3 months after infection resolves Loss of tympanic membrane landmarks (i.e. handle of malleus, light reflex) ** See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 28, 2013; updated Aug 25, 2024 on www.thecalgaryguide.com

Pediatric Pneumonia Pathogenesis and Clinical Findings

Pediatric Pneumonia: Pathogenesis and clinical findings Authors: Jasmine Nguyen Nicola Adderley Reviewers: Midas (Kening) Kang Usama Malik Annie Pham Eric Leung* Jean Mah* * MD at time of publication Immunological: unvaccinated, primary immunocompromise, pre-existing illness (e.g. HIV, measles), malnutrition Environmental: smoke, air pollution, mold, crowded housing Recent hospitalization or antibiotic-use Physiological: neonates, low-birth weight, underlying lung disease These factors make the host more susceptible to infection Infection and proliferation of pathogen in lower respiratory tract/parenchyma Pediatric pneumonia: Inflammatory response to infection/proliferation of microbial pathogens at the alveolar level Exposure to pathogen via inhalation, hematogenous, direct exposure, or aspiration Epithelial cells in respiratory tract release cytokines that recruit neutrophils & plasma proteins to infection site, initiating a local inflammatory response Cytokines released into the bloodstream (e.g. TNF, IL-1) initiate a systemic inflammatory response ↑ Vascular permeability Accumulation of exudate, cellular debris, serous fluid, fibrin, or bacteria in the airway spaces ↑ Respiratory drive Tachypnea ↑ Excitability of the peripheral somatosensory system Circulating cytokines induce prostaglandin synthesis Airway irritation as cilia are unable to efficiently clear fluid buildup Crackles, ↓ breath sounds Fluid, protein, or inflammatory cells leak into pleural space Pleural effusion Pulmonary edema Fluid buildup in interstitial spaces ↑ gas diffusion distance Bacteria enter the bloodstream (if bacterial pneumonia) Sepsis Fluid buildup in the alveoli ↓ available surface area for gas diffusion ↓ Efficiency of gas exchange Intra- and extracranial arteries dilate Headache ↑ Thermo-regulatory set-point of the hypothalamus Fever Myalgia Hypoxemia Malaise Cough Fluid accumulation in the pleural space prevents full lung expansion ↑ Work of breathing (tracheal tug, paradoxical abdominal breathing, subcostal/suprasternal indrawing) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 28, 2018; updated Aug 25, 2024 on www.thecalgaryguide.com Pediatric Pneumonia: Pathogenesis and clinical findings Authors: Jasmine Nguyen Nicola Adderley Reviewers: Midas (Kening) Kang Usama Malik Annie Pham Eric Leung* * MD at time of publication Immunological: unvaccinated, primary immunocompromise, pre-existing illness (e.g. HIV, measles), malnutrition Environmental: smoke, air pollution, mold, crowded housing Recent Hospitalization: length of stay, recent antibiotics, mechanical ventilation Physiological: neonates, low-birth weight, underlying lung disease (ciliary dysfunction, asthma, cystic fibrosis, bronchiectasis) Host is more susceptible to infection Exposure to pathogen: inhalation, hematogenous, direct, aspiration Infection and proliferation of pathogen in lower respiratory tract/parenchyma Pediatric pneumonia: Inflammatory response to infection/proliferation of microbial pathogens at the alveolar level Notes: • Additional findings in pediatric pneumonia may include increased irritability, nausea/vomiting, diarrhea, otitis, and headache • Viral pathogens most common in children <2yrs; bacterial pathogens most common in children >2yrs Local inflammatory response: epithelial cells release cytokines in response to infection, which recruit neutrophils and plasma proteins to site of infection ↑ Vascular permeability causes accumulation of plasma exudate, cellular debris, serous fluid, fibrin, or bacteria in the airway spaces Systemic inflammatory response: Cytokine release (eg. TNF, IL-1) ↑ respiratory drive Airway irritation as cilia are unable to efficiently clear fluid buildup Crackles, ↓ breath sounds Fluid, protein, or inflammatory cells leak into pleural space Pleural effusion Pulmonary edema Fluid buildup in interstitial spaces increases gas diffusion distance Fluid buildup in the alveoli decreases available surface area for gas diffusion ↓ efficiency of gas exchange Bacteria invade into the bloodstream (if bacterial pneumonia) Sepsis Hypoxemia Circulating cytokines induce prostaglandin synthesis, which raise the thermoregulatory set-point of the hypothalamus paradoxical abdominal breathing, subcostal/suprasternal indrawing) Fever Cough Fluid accumulation in the pleural space prevents full lung expansion, resulting in ↓ lung volumes Tachypnea ↑ Work of breathing (tracheal tug, Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Month Day, Year on www.thecalgaryguide.com Pediatric Pneumonia: Pathogenesis and clinical findings Immunological: immunization status, immune compromise Environmental: second-hand smoke, air pollution Hospitalization: length of stay, recent antibiotics, mechanical ventilation Neonates, immunocompromise, underlying lung disease (ciliary dysfunction, Cystic Fibrosis, bronchiectasis) Authors: Nicola Adderley Reviewers: Midas (Kening) Kang Usama Malik Eric Leung* * MD at time of publication Additional findings in pediatric pneumonia may include nausea, otitis, headache Viral pathogens most common in children <2yrs; bacterial pathogens most common in children >2yrs Interstitial pattern: suspect Mycoplasma pneumoniae, Influenza A + B, Parainfluenza Lobar pattern: suspect S. pneumonia, H. influenzae, Moraxella, S. aureus Systemic inflammatory response: Cytokine release (eg. TNF, IL-1) Exposure to pathogen: inhalation, hematogenous, direct, aspiration Susceptible host and/or virulent pathogen Infection and proliferation of pathogen in lower respiratory tract/parenchyma Pediatric pneumonia: Inflammatory response to proliferation of microbial pathogens at the alveolar level Notes: • • • • Local inflammatory response: neutrophils recruited to site of infection (LOBAR or INTERSTITIAL PATTERN, depending on pathogen) by epithelial cytokine release Irritation of contiguous structures and/or referred pain (mechanism unclear) Acute abdominal pain Cough Accumulation of plasma exudate (from capillary leakage at sites of inflammation), cell-debris, serous fluid, bacteria, fibrin ↑ respiratory drive Disruption of hypothalamic thermoregulation Fever/chills Irritation of airways and failure of ciliary clearance to keep up with fluid buildup Crackles, ↓ breath sounds Fluid buildup in spaces between alveoli (INTERSTITIAL PATTERN) Interstitial opacity on CXR Fluid buildup in alveoli (LOBAR PATTERN) ↓ efficiency of gas exchange (↑ diffusion distance in INTERSTITIAL, ↓ surface area in LOBAR) Hypoxemia Tachypnea Lobar consolidation on CXR Respiratory accessory muscle use (chest indrawing, paradoxical breathing, muscle retractions) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 28, 2018 on www.thecalgaryguide.com gin

Pityriasis Tinea Versicolor

Pityriasis (Tinea) Versicolor: Pathogenesis and clinical findings Authors: Kerry Yang Reviewers: Mina Youakim Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Loosening of the stratum corneum Scaling of skin Hyperhidrosis (↑ sweating) Poor ↑ Sebaceous nutrition gland secretions Development of a lipid- rich environment Use of oils on skin ↑ Environmental heat & humidity Immunosuppression Lipophilic Malassezia (normal constituent of skin flora) yeast cells transform into the pathogenic, mycelial (fungal thread) form, commonly occurring on the trunk, neck, and proximal extremities Malassezia infect the stratum corneum (the outer layer) of the skin ↑ Malassezia – associated ligand – activated transcription factors Rate of different gene transcriptions modified ↑ Melanin production by melanocytes ↑ In melanin more than the ↓ in melanin Hyperpigmented macules, patches, and plaques ↑ Production of the enzyme keratinase ↑ Activation of Langerhans cells (macrophages in the skin) Alteration in the expression of cytokines and chemokines in keratinocytes (epidermal skin cells) ↑ Inflammatory response Activation of cutaneous nerve fibers Itch signal transduction Mild pruritis (itchiness) Ligand-activated transcription factors produced by Malassezia ↑ Degradation of keratin in the skin ↑ Production of dicarboxylic acids by certain Malassezia species Competitively inhibits the rate- limiting enzyme in melanin production tyrosinase ↓ Production of melanin ↓ In melanin more than the ↑ in melanin Hypopigmented macules, patches, and plaques ↑ Production of inflammatory mediators Dyspigmentation Malassezia, particularly M. globosa, M. furfur, and M. sympodialis Loosened Epidermal layer Dermal-Epidermal Junction Dermal layer Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 25, 2024 on www.thecalgaryguide.com

Anti-Emetics Mechanism of Action

Anti-emetics: Mechanism of action Migraine, chemotherapy, post-operative, gastroenteritis nausea Chemotherapy, post-operative, gastroenteritis nausea Vestibular nausea Chemotherapy nausea D2 receptor antagonists (e.g. metoclopramide) Migraineurs are hypersensitive to dopamine D2 receptor antagonists bind to D2 (dopamine) receptors in brain ↓ Binding of endogenous dopamine to dopamine receptors Emetogenic stimuli (e.g. chemotherapy) in blood and cerebrospinal fluid Chemoreceptor trigger zone in area postrema of 4th ventricle that lies outside blood-brain barrier Emetogenic stimuli in the bloodstream stimulate dopamine receptors in area postrema D2 receptor antagonists bind to D2 (dopamine) receptors in chemoreceptor trigger zone ↓ Binding of dopamine in area postrema 5HT-3 receptor antagonists (e.g. ondansetron) Emetogenic stimuli (e.g. chemotherapy) in blood and cerebrospinal fluid Area postrema has no blood- brain barrier Emetogenic stimuli in the bloodstream stimulate serotonin receptors in area postrema 5HT-3 receptor antagonists bind to 5HT-3 (serotonin) receptors in chemoreceptor trigger zone in area postrema of 4th ventricle ↓ Binding of serotonin in area postrema Emetogenic stimuli (e.g. toxins, chemotherapy) and pathologies in gastrointestinal (GI) tract ↑ Local release of serotonin from enterochromaffin cells of GI tract 5HT-3 (serotonin) receptor antagonists bind to 5HT-3 receptors on vagal afferent (sensory) fibres in GI tract ↓ Binding of endogenous serotonin to vagal afferent fibres ↓ Innervation of medulla via vagal afferent fibres H1 receptor antagonists (e.g. dimenhydrinate) Brain receives conflicting information about body’s movement from visual, vestibular, proprioceptive senses Motion sickness (nausea triggered by slow lateral or vertical movement) ↑ Activation of histaminergic neuronal system in hypothalamus Antihistamine H1 receptor antagonists bind to H1 (histamine) receptors in chemoreceptors trigger zone in area postrema ↓ Binding of endogenous histamine in area postrema Muscarinic antagonists (e.g. scopolamine) Motion sickness activates vestibular afferent fibres Vestibular afferents release acetylcholine Muscarinic receptor antagonists bind to muscarinic receptors in posterior cerebellum ↓ Binding of endogenous acetylcholine to posterior cerebellum ↓ Diffusion of acetylcholine into 4th ventricle ↓ Binding of acetylcholine to area postrema Cannabinoids* (e.g. synthetic tetrahydrocannabinol) Emetogenic stimuli (e.g. chemotherapy) in blood and CSF Area postrema has no blood- brain barrier Emetogenic stimuli stimulate serotonin receptors in area postrema Cannabinoids bind to 5HT-3 (serotonin) receptors in area postrema ↓ Binding of dopamine to area postrema *Still under research ↓ Stimulation of vomiting center in medulla by emetogenic stimuli Coordination of respiratory, gastrointestinal, abdominal muscle contraction ↓ Vomiting Authors: Catherine Jung Reviewers: Claire Song Shahab Marzoughi Sylvain Coderre* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 25, 2024 on www.thecalgaryguide.com

Massive Transfusion Protocol

Massive Transfusion Protocol: Considerations and rationale Massive transfusion protocol (MTP) is a tool used by clinicians when there is a need to rapidly administer a large amount of blood products, including packed red blood cells (pRBCs), fresh frozen plasma (FFP), and platelets. Complications of MTP are commonly referred to as “The Lethal Triad” referring to hypothermia, acidosis and coagulopathy. Authors: Kayleigh Yang Arzina Jaffer Reviewers: Jasleen Brar, Luiza Radu, Karl Darcus* * MD at time of publication Intervention Indications Initial Response Pathophysiology Transfusion Targets ≥ 3 pRBCs unit transfusion requirement in 1 hour Shock index (heart rate/systolic blood pressure) > 1 Blood volume loss >50% in ≤3 hours ABC Score ≥ 3 of: 1. Penetrating mechanism of injury 2. Systolic blood pressure < 90 mmHg 3. Heart rate > 120 beats per minute 4. Evidence of hemoperitoneum or hemopericardium on ultrasound (positive FAST U/S exam) RABT Score ≥ 2 of: 1. Penetrating mechanism of injury 2. Shock index > 1 3. Positive FAST U/S 4. Known or suspected pelvic fracture Call for help Activate institution's MTP protocol Send for STAT type and screen Establish large-bore intravenous access Fluid resuscitation Collect and send STAT bloodwork including hemoglobin, platelet, INR, fibrinogen, electrolytes, creatinine and arterial blood gas (ABG). Citrate present in blood products to avoid clotting during storage Stored pRBCs break down and release potassium due to time mediated degeneration Temporary accumulation of citrate in patient's blood with rapid use of blood products Citrate chelates calcium Less negative cell membrane resting potential Anaerobic metabolism Promotes hypocalcaemia Changes in membrane excitability Lactic acid buildup Coagulopathy (see coagulation cascade slide) Cardiac dysrhythmias (peaked T-waves, atrial block, “sine wave”, asystolic EKG changes) Metabolic acidosis End organ damage Continued blood loss Volume overload Avoid hypocalcemia Avoid hyperkalemia pH 7.35-7.45 Bleeding source control Hemoglobin >70-90 Platelets >50 INR <1.5 Fibrinogen >1.5 Avoid dilutional coagulopathy (clotting factor dilution) Mean Arterial Pressure (MAP) >60mmHg Temperature >35.0°C Slow (over 5-10 minutes) IV calcium administration Inhaled beta agonists Insulin/Dextrose EKG monitoring Sodium bicarbonate Increase minute ventilation Fastest control method to prevent further blood loss (i.e., packing wounds) Early tranexamic acid administration Administer pRBCs, FFP, and platelets in a 1:1:1 ratio (fibrinogen replacement indicated if <1.5 despite FFP) Minimize crystalloid use Administer crystalloids in a 3:1 ratio to estimated blood loss until blood products available Administer vasopressors to meet target, do not overshoot Temperature monitoring Fluid warming ↑ [Potassium] in pRBCs solution Administration of pRBCs ↑ potassium in patient's blood Blood loss ↓ Hemoglobin Tissue hypoperfusion Tissue hypoxia ↑ Diluent volume ↓ Concentration of clotting factors Tissue death ↓ Coagulation ability ↑ Transfusion requirements Early fluid resuscitation Rapid transfusion of cooled or room-temperature blood products/fluids ↑ Blood pressure Development of hypothermia ↑ Bleeding and clot dislodgement potential ↓ Enzyme activity in the coagulation cascade ↓ Coagulation ability Legend: Pathophysiology Mechanism Targets Intervention Published Sept 5, 2024 on www.thecalgaryguide.com

IgA Nephropathy

IgA Nephropathy: Pathogenesis & clinical findings Authors: David Campbell Matthew Hobart Reviewers: Huneza Nadeem Raafi Ali Ran Zhang Luiza Radu Julian Midgley* * MD at time of publication Galactose-deficient IgA1 (GD- IgA1) created by mucosa- bound IgA1 plasma cells is secreted into plasma instead of onto mucosal surface IgA1 plasma cells hyper- responsive to triggers (eg. URTIs, gastroenteritis) ↑ synthesis of GD-IgA1 → spill-over into plasma Immunoglobulin A1 (IgA1) plasma cells destined to reside in mucosa (eg. gut or respiratory tract) travel to and reside in inappropriate site(s) (eg. bone marrow) releasing GD-IgA1 into plasma GD-IgA1 is not cleared from plasma as quickly as IgA1 → ↑ plasma GD-IgA1 levels Hit 3: GD-IgA1-IgG complexes deposit in mesangium C3 predominant complement activation amplifies inflammatory response Renal biopsy: IgA deposits in mesangium (100% sensitive) Renal biopsy: Complement in mesangium (C3 predominant) (90-95% sensitive) A cascade of multiple immunologic hits is initiated Hit 1: ↑ Serum levels of GD-IgA1 multiple immunologic hits GD-IgA1 hinge region is structurally distinct from IgA1 that would normally circulate in plasma (lack of galactosyl groups) GD-IgA1 hinge region may mimic pathogens (ex. bacteria and viruses) or other antigens Cross reactivity of IgG against GD-IgA1, or synthesis of anti-GD-IgA1 IgG antibodies Immunoglobulin G (IgG) binds GD-IgA1 hinge region Hit 2: GD-IgA1-IgG immune complex formation Circulating GD-IgA1-IgG complexes have high affinity for glomerular endothelial cells where they damage the glycocalyx → ↑ permeability of immunoglobulins into the mesangium ↑ Production of chemokines, cytokines and complement → ↑ mesangial cell proliferation and matrix expansion Leukocyte recruitment and activation damages glomerulus and mesangium Hit 4: Inflammatory response to GD-IgA1 complexes in mesangium induce glomerular structure disruption (endothelium, basement membrane, podocytes, mesangium) and impaired glomerular function Loss of barrier functions of glomerulus allows for extravasation of blood & proteins into Bowman’s space and subsequently through tubules Renal biopsy: Glomerulosclerosis, tubulointerstitial fibrosis, glomerular vasculitis, podocyte damage Eventual end-Stage Renal Disease (ESRD) Progressive ↓ of filtration surface area within glomeruli and ↓ number of functional glomeruli Proteinuria Synpharyngitic hematuria (hematuria with dysmorphic red cells co-occurring with pharyngitis) ↓ Glomerular Filtration Rate (GFR) Nephrotic Syndrome ↑ Serum creatinine Chronic kidney disease and eventually ESRD IgAN is an autoimmune disease where IgA deposition in the glomerulus leads to an inflammatory cascade, endothelial dysfunction and mesangial expansion that damages glomeruli causing kidneys to leak blood and protein into urine and decreased kidney function. IgA nephropathy is a multifactorial disease requiring multiple immunologic hits IgA Nephropathy (IgAN) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 5, 2024 on www.thecalgaryguide.com

Cystocele

Cystocele: Pathogenesis & Clinical Findings Authors: Emily Cox Reviewers: Riya Prajapati Michelle J. Chen Dr. Rebecca Manion* * MD at time of publication Obesity Pregnancy Chronic constipation Chronic cough Vaginal childbirth Vacuum-assisted or forceps-assisted vaginal birth Pelvic surgeries (e.g. hysterectomy) Connective tissue disorders (e.g. Marfans, Ehlers- Danlos Syndrome) Genetic susceptibility (e.g. Type III collagen gene abnormality Menopause Visceral fat places pressure on pelvic floor structures Growing fetus places pressure on pelvic floor structures Straining and bearing down on pelvic floor Muscle tearing and damage Disruption of nerves, loss of bladder structural support, and disruption of fascia and muscles Collagen impairment Depletion of ovarian follicles leading to ↓ in estrogen production ↑ Intra-abdominal pressure Transfer of intra- abdominal pressure to pelvic floor Pelvic floor muscles and pelvic floor fascia become weakened Pelvic tissue and muscular atrophy Loss of tissue function and structure support that collagen provided ↓ Stimulation of collagen production ↓ Estrogen levels Pelvic Organ Prolapse Quantification (POP-Q) System: Grade 1: Bladder descends 1 cm above the hymen Grade 2: Bladder descends to ≤ 1 cm above or below hymen Grade 3: Bladder descends past the hymen but 2 cm less than total vaginal length Grade 4: Complete vaginal prolapse Mechanical obstruction of bladder and urethra Urinary retention Descended bladder creates pressure in vagina Pressure/bulging sensation Symptoms of voiding dysfunction (e.g. incomplete emptying/frequency/ urgency/nocturia) Vaginal intercourse puts pressure on descended bladder Activates pain receptors Dyspareunia (painful sex) for some patients Cystocele Descent of bladder through anterior vaginal wall Hydronephrosis/ hydroureter Recurrent UTI Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 5, 2024 on www.thecalgaryguide.com

Cauda Equina Syndrome

Cauda Equina Syndrome: Signs and Symptoms Author: Yan Yu Stephanie de Waal Reviewers: Sunawer Aujla Spencer Montgomery Owen Stechishin Michelle J Chen W. Bradley Jacobs* * MD at time of publication Large lumbar degenerative disc herniation Severe lumbar spondylosis Neoplasm in lumbar spine Trauma or epidural hematoma Infection (e.g. abscess) in lumbar spine Mechanical compression of sacral and lumbar nerve roots between L2 and S1 Cauda Equina Syndrome Damage to motor neurons within the compressed nerve roots Acute ↓ stimulation/control of lower limb and pelvic floor muscles Damage to fragile, smaller sacral nerves Saddle anesthesia Loss of sensation in perineum, perianal area, and medial aspect of thighs Patient unable to sense when bladder/ bowels are full Damage to sensory neurons within the compressed nerve roots Mechanically damaged nociceptive sensory neurons send ectopic impulses to the brain Neuropathic pain in low back, radiating to one or both legs Dermatomal pattern specific to the affected nerve root Decreased rectal tone Fecal incontinence Flaccid paralysis in one or both legs Permanent paralysis Areflexia (absence of deep tendon reflexes) Absent Achilles tendon reflex from compression of S1 nerve Urinary detrusor muscle areflexia Cannot overcome the residual tone of the internal urethral sphincters Urinary retention Compression of L2 nerve root Sensory disturbance along anterior and medial thigh Compression of L3 nerve root Sensory disturbance along anterior thigh, medial knee, and medial leg Compression of L4 nerve root Sensory disturbance along lateral knee, anterior leg, and dorsal aspect of foot Compression of S1 nerve root Sensory disturbance along posterior thigh, posterolateral aspect of leg, and lateral foot Sexual dysfunction Overflow incontinence Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 1, 2012; updated Sept 6, 2024 on www.thecalgaryguide.com

Diffuse Axonal Injury

Diffuse Axonal Injury: Pathogenesis and Clinical Findings Authors: Stephanie de Waal Reviewers: Braxton Phillips Shahab Marzoughi Gary Michael Klein* * MD at time of publication Shear injury to small intracranial vessels Fall from height High-speed motor vehicle accident Blunt trauma Unrestricted head movement with impact Rotational acceleration and/or deceleration forces applied to brain Shearing forces applied to white matter tracts of brain Sphenoid bone causes shear injury to pituitary stalk Primary Axotomy Shear force disconnects neurons at white-grey matter junctions Secondary Axotomy Stretch injury to axons create mechanical damage to axon sodium channels Uncontrolled sodium influx into neurons Reversal of sodium- Shear injury to hypothalamo- neurohypophysial portal system Intra-parenchymal Hemorrhage Panhypopituitarism (decreased production and secretion of pituitary hormones) Increased intracellular sodium creates increased osmotic pressure between extracellular and intracellular space Water moves passively along osmotic gradient into intracellular space Neuron swelling Hemorrhagic lesion on MRI calcium exchangers Activation of voltage gated calcium channels Calcium enters the damaged neuron Proteolytic activity increases with elevated intracellular calcium Activated proteases cause delayed cytoskeleton damage Damage to neuron cytoskeleton impairs transport of axonal proteins Protein accumulates within axon creating bulb structure at the terminal Disconnection of axon terminal from adjacent dendrites and cell bodies Diffuse Axonal Injury Axonal bulbs on pathology Damage to cortical, subcortical, and brainstem white matter tracts leads to a constellation of symptoms Post-traumatic seizures Damage to temporal lobe Damage to primary motor cortex Lesions in ascending reticular activating system impact consciousness Memory deficits Motor deficits Coma & brain death Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sep 18, 2024 on www.thecalgaryguide.com

S3 Pathogenesis

S3: Pathogenesis & Clinical Findings Pathological Physiological Pregnancy High-output state (↑ volume flow in heart) Author: Yvette Ysabel Yao Reviewers: Stephanie Happ George Tadros Shahab Marzoughi Jonathaan Howlett* * MD at time of publication Athletes Prolonged training causes ↑ left ventricle size and ↑ blood volume in ventricle Tricuspid +/- mitral regurgitation (leaky tricuspid/ mitral valve) Heart Failure (See Left Heart Failure slide) Dilated cardiomyopathy (See Dilated cardiomyopathy slide) Pulmonary +/- aortic regurgitation (leaky pulmonary / aortic valve) Children and young adults Compliant ventricle rapidly expands in early diastole Diastole S1 Systole Diastole ↑ Blood volume flowing into ventricle from atrium after semilunar valves close (S2 heart sound) Diastolic overload (↑ filling of ventricles) Sudden intrinsic limitation of longitudinal expansion of the ventricular wall Large volume of blood striking a very compliant ventricular wall S3 (Low pitched, heard in early diastole, best heard apex in left lateral decubitus position with bell of stethoscope) S2 S3 Left ventricle is located more posteriorly and is relatively unaffected by changes in intrathoracic pressure Left ventricle S3 (unchanged or sometimes increased with expiration) Anterior right ventricle more sensitive to negative intrathoracic pressure ↑ Venous return to right ventricle during inspiration Right ventricle S3 (best heard along the lower left sternal border, intensity increases with inspiration) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sep 18, 2024 on www.thecalgaryguide.com

Malignant Hyperthermia

Malignant Hyperthermia: Pathogenesis & clinical findings Authors: Haotian Wang, Jen Guo Reviewers: Julena Foglia, Priyanka Grewal, Luiza Radu Kevin Gregg* * MD at time of publication Depolarizing muscle relaxant (e.g., succinylcholine) & volatile anesthetic (e.g., sevoflurane, desflurane, isoflurane, halothane, NOT nitrous oxide) Autosomal dominant mutation in ryanodine receptor (RyR1; RyR1 transports calcium out of the sarcoplasmic reticulum during muscle depolarization) LowerthresholdforactivationofRyR1 state Prolonged opening of RyR1 ↑ Ca2+ in myocyte cytoplasm Capacity of the reuptake protein to carry Ca2+ is overwhelmed Sustained muscle contraction à hypermetabolic state Malignant Hyperthermia Vigorous exercise & heat (rare) Rare life-threatening clinical syndrome that occurs in genetically susceptible patients upon exposure to a triggering agent Skeletal muscle rigidity (i.e., masseter muscle spasm) Sustained muscle contraction Myocytes (muscle cells) deplete available ATP Hypermetabolic state ↑ O2 consumption ↑ Heart rate to meet O2 demand ↑ CO2 production Unexplained ↑ end tidal CO2 (early sign) ↑ Temperature Hyperthermia (late sign) ↓ O2 supply ↑ Anaerobic metabolism ↑ Lactic acid production Metabolic acidosis Cell death Leakage of muscle contents into circulation ↑ Serum creatinine kinase Development of rhabdomyolysis (rapid breakdown of muscle tissue) Myoglobinuria (presence of excess myoglobin in urine) Acute kidney injury** Hyperkalemia Electrolyte imbalances (i.e., hyperkalemia) Abnormal myocyte contraction Cardiac dysfunction Dysrhythmias Cardiovascular collapse Release of thromboplastin (converts prothrombinàthrombin) & other prothrombotic substances (promotes clot formation) Imbalance between thrombotic & antithrombotic pathway ↑ Clot formation from activation of the extrinsic & common pathways Disseminated intravascular coagulation** Tachypnea (in absence of prominent mechanical ventilation) Tachycardia (early sign) Cardiovascular collapse Vital organ failure Coma **See corresponding Calgary Guide slide(s) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 25, 2015; updated Oct 2, 2024 on www.thecalgaryguide.com

Obesity Pathogenesis

Obesity: Pathogenesis Authors: Angela Mak, Run Xuan (Karen) Zeng Reviewers: Gurreet Bhandal, Raafi Ali, Mizuki Lopez Energy homeostasis dysregulation (Peptide hormones regulating hunger/satiety that influence the hypothalamic control of eating behaviours) Luiza Radu, Dr. Sam Fineblit* * MD at time of publication Endocrine dysregulation Neurological (↓ caloric reserve activates the neurological system) Adiposity-related Hypothalamus (hemostatic area) ↑ Production of ghrelin (peptide hormone) ↑ Activation of agouti-related protein (A Neuropeptide Y (NPY) neuron clusters in the hypothalamus via vagus nerve ↑ Appetite Mesolimbic area (hedonic area) Reward Driven Eating (meso-limbic region of brain) ↑ Food consumption ↑ Dopamine & endogenous opioid signals ↑ Pleasure & desire to consume more food Prefrontal cortex (executive functioning) ↓ Glucagon-like peptide-1 (GLP-1) & pancreatic peptide YY (PYY) secretion post- meal ↓ Stimulation of Proopiomelanocortin (POMC) neuron clusters in hypothalamus ↓ Beta-melanocyte stimulating hormone (MSH) (endogenous peptide) production Defect in leptin receptor gene ↓ Circulating soluble leptin receptors (SLR) ↑ Serum leptin levels Leptin resistance Inactive leptin gene ↓ Adipocyte leptin production & secretion ↓ Leptin transport across blood brain barrier ↓ Hypothalamus suppression of hunger ↓ Satiety sensation ↑ Caloric intake & weight gain ↑ Dietary carbohydrate intake ↑ Insulin production & secretion ↓ Cellular response to insulin ↑ Insulin resistance ↑ Insulin production & secretion to compensate for insulin resistance Impaired glycemic control Metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease ** Metabolic adaptation to reduced-caloric intake efforts ↑ Body energy conservation ↓ Baseline energy expenditure ↓ Resting metabolic rate (the amount of energy body requires to function while at rest) ↓ Ability to lose weight & fat mass ↑ Hunger ↑ Caloric intake & weight gain Obesity (A combination of metrics including ↑ BMI, ↑ weight circumference, ↑ waist-to-hip ratio, skinfold thickness, and other standardized measures varied by equipment available at various institutions resulting in a negative impact on the health of the individual) **See slide on Pathogenesis of Type II Diabetes Mellitus Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 13, 2024 on www.thecalgaryguide.com

Hyperthyroidism in Pregnancy

Hyperthyroidism in Pregnancy: Pathogenesis and clinical findings Authors: Delaney Duchek Reviewers: GurreetBhandal,JuliaGospodinov Luiza Radu , Samuel Fineblit* * MD at time of publication ↑ Human chorionic gonadotropin (hCG) hormone stimulates TSH receptors which ↑T3/T4 & ↓ physiologic TSH production in 1st trimester & normalizes in 2nd trimester Transient hyperthyroxinemia in pregnancy (often benign) Autoantibodies ↑ stimulation of thyroid stimulating hormone (TSH) receptors Transplacental passage of TSH- receptor antibodies (can occur with normal thyroid function) Graves’ disease Transient ↓TSH & ↑T3/T4 Persistent ↓TSH & ↑T3/T4 Low birth weight Maternal congestive heart failure Pre-eclampsia (high blood pressure in pregnancy) Thyroid storm (excessive release of T3/T4 leading to a life-threatening hypermetabolic state) ↑ Triiodothyronine (T3) & thyroxine (T4) production independent of TSH Abnormal differentiation of trophoblast embryonic cells ↑ hCG levels (cells that provide nutrition to the embryo) Gestational trophoblastic disease Toxic multinodular goiter Toxic adenoma Viral infection Subacute thyroiditis (thyroid inflammation) Hyperthyroidism in Pregnancy Anterior pituitary gland releases stored TSH ↑Sympathetic nervous system stimulation ↑Thermogenesis (heat production, regulated by thyroid & variousbraincentres) ↑Hyaluronic acid in dermis & subcutis tissue of the skin (Graves’ disease specific) Transplacental passage of ↑T3/T4 to fetus Gut hypermobility Central nervous system overstimulation ↑Weight loss ↑Appetite Heat intolerance Diarrhea & ↑ bowel movements Nervousness & anxiety Hyperkinesia (excessive activity of a body part) Hyperreflexia (overactive muscle reflex response) Tremor Poor attention span ↑ Heart rate Palpitations (noticeable abnormal heartbeats) Bruit (turbulent blood flow) heard over thyroid ↓ Exercise tolerance ↑ Cardiac output De novo synthesis of TSH (synthesis of TSH independent of normal regulatory signals & processes as seen in toxic adenoma & toxic multinodular goiter) Pregnancy Complications (abnormallyhighfreeT4&thyroid stimulating antibodies in the blood impacts fetal thyroid function) ↑ Renin angiotensin aldosterone system (RAAS) activation (important regulator of electrolytes, blood volume, & systemic vascular resistance) ↑ Erythropoietin (EPO, hormone made by kidneys that stimulates red blood cell production) Pretibial myxedema (condition causing skin lesions from deposition of hyaluronic acid) Spontaneous abortion (pregnancy loss naturally ≤20 weeks gestation) Premature labour (labour ≤37 weeks gestation) Stillbirth (fetal death >20 weeks gestation) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 29, 2024 on www.thecalgaryguide.com

Secondary hypoglycemia Insulin Mediated

Hypoglycemia: Insulin mediated secondary causes Insulinoma (pancreatic beta islet cell tumour) Non-insulinoma pancreatic islet cell disorder (e.g. Non-insulinoma pancreatogenous hypoglycemia syndrome) Nesidioblastosis (pancreatic islet tissues formed from pancreatic duct budding) formation ↑ In number & size of abnormal pancreatic beta islet cells throughout the entire pancreas ↑ Insulin production & secretion by abnormal pancreatic islet cells ↑ Glycogen synthesis Insulin autoimmune syndrome Autoantibodies bind to insulin molecules released post-meal Insulin molecules unable to exert effects Hyperglycemia Promotes insulin release ↓ Plasma glucose concentration ↓ Insulin release & ↓ total insulin levels Insulin molecules dissociate from autoantibodies ↑ Free insulin levels (inappropriate for the ↓ plasma glucose levels) ↓ Glycogenolysis (glycogen breakdown to glucose) Hypoglycemia (serum glucose of <3mmol/L) Intake of insulin secretagogues (e.g. Sulphonylureas, Meglitinide analogues) Binds to adenosine triphosphate (ATP) dependant potassium channels on pancreatic islet cells Inhibit potassium ion efflux through ATP-dependent potassium channels Pancreatic islet cell depolarization Opens voltage-gated calcium channel Calcium influx into pancreatic islet cells ↑ Insulin release ↓ Gluconeogenesis (glucose synthesis from non-carbohydrate compounds) Exogenous insulin intake Suppress endogenous insulin production (by beta cells) Low C-peptide levels (byproduct of endogenous pro- insulin being converted to insulin) 90% caused by somatic mutations of pancreatic beta islet cells 10% due to genetic changes linked to MEN1(Multipl e endocrine neoplasia type-1) gene mutation ↑ Pancreatic islet cells proliferation ↑ Insulin secretion by hyperplastic (increasing in number) pancreatic islet cells Neuroglycopenic symptoms (altered mental status, seizures) Neurogenic symptoms (palpitations, tremulousness, diaphoresis Authors: Iffat Naeem Run Xuan (Karen) Zeng Reviewers: Gurreet Bhandal Luiza Radu Yan Yu* Samuel Fineblit* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 29, 2024 on www.thecalgaryguide.com

Major Depressive Disorder 2024

Major Depressive Disorder (MDD): Pathogenesis and clinical findings Self blaming tendency Major stressor(s) ↑ Emotional reactivity Monoamine deficiency Regional brain area alterations ↓ Behavioral activation (engagement in meaningful activities to improve mood) Hunger interoception (perception & awareness of hunger) changes Attributes the occurrence of negative events to internal/personal factors Expectation that future events are uncontrollable & internally caused Feelings of worthlessness or excessive guilt Recurrent thoughts of death or suicide Insomnia (melancholic MDD) Dysregulation of negative feedback control on the hypothalamus–pituitary– adrenal (HPA) axis ↓ Serotonin & norepinephrine signaling ↑ HPA axis sensitivity Heightened responses to stressors Major Depressive Disorder ≥5 symptoms/complications during the same 2-week period; at least 1 of **symptoms; causing clinically significant distress or impairment in social, occupational, or other important areas of functioning ↑ Amygdala activity Changes to neuronal activity Altered prefrontal cortex & limbic functioning Depressed mood** Mechanism unknown; can precede MDD or be a symptom Psychomotor agitation (restlessness) ↓ Dopaminergic transmission in ventral striatum Overactivation of the insula (brain region involved in integrating activity in reward & interoception circuitry) Under activation of the insula Mechanism unknown ↓ Activation of mesolimbic system (reward system) ↓ Motivation & anticipation for rewards ↑ Activation of mesolimbic system Psychomotor retardation (slowing) Poor concentration ↑ Motivation & anticipation for rewards Anhedonia (loss of interest/pleasure)** Anergia (lack of energy) ↑ Eating (particularly high- sugar foods) Hypersomnia (atypical MDD) ↓ or ↑ Appetite &/or weight Authors: Keira Britto Sara Cho JoAnna Fay Reviewers: Luiza Radu Sara Meunier Jojo Jiang Alexander Arnold Brienne McLane* Phillip Stokes* *MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First published Mar 10, 2014, updated Sept 29, 2024 on www.thecalgaryguide.com

Hypomagnesemia

Hypomagnesemia: Physiology Hyperglycemia An increased amount of glucose enters renal tubules as glomerulus performs blood filtration ↑ [Solute] in renal tubules from ↑ glucose content exerts osmotic force that pulls water & electrolytes, including Mg2+, into renal tubules ↑ Urinary Mg2+ excretion Lack of insulin Lack of insulin receptor signaling in distal convoluted tubule (DCT) ↓ glucose uptake from renal tubules Hypercalcemia Ca2+ binds to Ca2+ sensing receptors on thick ascending limb (TAL) of loop of Henle, where resorption of Ca2+ & Mg2+ occurs Receptor activation ↓ Na-K- 2Cl (NKCC) transporter activity which maintains electro- chemical gradient in TAL Passive paracellular resorption of Ca2+ and Mg2+, dependent on electrochemical gradient, ↓ ↑ Extra- cellular fluid ↓ Resorption of Na+ & H2O from renal tubules Genetic disorders (e.g. Bartter syndrome, familial hypomagnesemia) Medications (e.g. loop & thiazide diuretics, certain antibiotics, calcineurin inhibitors) Some metabolic byproducts of these drugs are nephrotoxic Inability to absorb free fatty acids (FFAs) Mg2+, which associates with FFAs, is not absorbed through the gut Steatorrhea (fat in the stool) Mal- absorption (often due to inflammation or infection) & diarrhea Acute pancreatitis ↓ Lipase secretion from pancreas ↑ levels of undigested fats in small intestine ↓ Passive Mg resorption from tubules Mg saponification in necrotic fat 2+ Varying mechanisms causing defective Mg2+ re-absorption (e.g. impacts to PCT, TAL, DCT disrupting transporters and ion shifting; ↓ gut resorption of Mg2+) Nutrients & 2+ electrolytes are lost in stool undergoes Renal loss of magnesium Gastrointestinal loss of magnesium Hypomagnesemia Serum [Mg2+] < 0.7 mmol/L Impairs production and release of parathyroid hormone responsible for ↑ blood Ca2+ Hypocalcemia Muscle cells are unable to activate Mg2+ dependent ATP hydrolysis Impairs muscle relaxation and reduces the ability to stop muscular contraction Lack of Ca2+ disrupts neurotransmitter release and neuronal signaling Impairs rapid depolarization and repolarization during muscle contraction Neuromuscular excitability (large, rapid change in membrane voltage due to small stimulus) Delirium Apathy QRS widening and peaking of T waves on ECG Torsade de Pointes Constant muscle contraction compresses blood vessels Reduced blood supply to hands, wrists, feet, and ankles Trousseau sign (carpopedal spasm with inflation of BP cuff) Authors: Caroline Kokorudz Reviewers: Shyla Bharadia Allesha Eman Michelle J. Chen Dr. Adam Bass* * MD at time of publication Chvostek sign (facial muscle twitch with cheek touch) Seizures Tetany Weakness Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Transient Tachypnea of the Newborn

Transient Tachypnea of the Newborn: Pathogenesis and clinical findings Cesarean delivery without labour Author: Tanis Orsetti Reviewers: Annie Pham Michelle J. Chen Dr. Jean Mah* * MD at time of publication Smoking during pregnancy Uncontrolled maternal asthma Uncontrolled maternal diabetes Dilution of surfactant ↑ Surface tension in alveoli ↓ Expansion/contraction of lungs (↓ pulmonary compliance) ↑ Work of breathing Maternal factors leading to impaired fetal lung development Lack of labour-induced hormone changes (i.e. cortisol, catecholamines) ↓ Alveolar fluid reabsorption through epithelial aquaporin channels ↑ Alveolar fluid in lungs Disruption of laminar flow in airways ↑ Resistance to airflow ↑ Lung expansion to compensate Limited surface area for gas exchange in the alveoli ↓ Ventilation Fluid buildup in the major bronchi in the perihilar region Prominent perihilar streaking on chest x-ray ↑ Intrathoracic pressure pushes the diaphragm down Blunting of costophrenic angle on chest x-ray Hyperinflation of lungs Expanded lung fields on chest x-ray ↑ Deoxygenated hemoglobin in the bloodstream Blue/purple discoloration of the skin particularly around the lips & fingers (cyanosis) ↓ Oxygenated hemoglobin in the bloodstream ↑ Nasal passage size allows for more air to enter the lungs with each breath Nasal flaring Scalene/intercostal/ sternocleidomastoid /abdominal muscle activation to assist with breathing Accessory muscle use ↓Oxygen saturation (SpO2) Neonate takes more breaths to compensate for limited oxygenation Respiratory rate > 60 breaths/minute (tachypnea) Transient Tachypnea of the Newborn Temporary respiratory condition in newborns characterized by impaired lung function and rapid breathing Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Neonatal Hypoglycemia Clinical Presentation

Neonatal Hypoglycemia: Clinical Presentation Normal physiology Glucose is produced from endogenous lactate, glycerol, and amino acids until glucose supply is established through feeds Hepatic glycogen is broken down to produce glucose in the first 8-12 hours of life Glucose is absorbed in the small intestine and transported into the bloodstream The pancreas responds to ↑ glucose blood concentration by releasing insulin Insulin acts on glucose transporters that line the cell membrane to bring glucose into the cell Glucose is broken down into ATP, which is used by cells for energy Authors: Dasha Mori Reviewers: Michelle J. Chen Dr. Ian Mitchell* *MD at time of publication Neonates with predisposing factors that Neonates that are unable to feed for > 60-120 Infant is large for gestational age (> 90th percentile) or was born to pregnant person with diabetes Fetus was exposed to high levels of glucose through placental circulation Fetus adapted to high blood glucose by producing high amounts of insulin After birth, placental glucose supply is stopped but insulin remains high ↑ Insulin promotes inappropriately ↑ uptake of glucose into cells put them at high risk for hypoglycemia Cells cannot produce enough ATP from glucose to power physiological functions Immature nervous system, use of fatty acids or proteins as an alternate ATP source, or adaptation to low glucose in utero can mask symptoms of hypoglycemia Asymptomatic hypoglycemia Neonates with low blood glucose often don’t show any symptoms and are detected by screening infants who are at a high risk for hypoglycemia min are at risk for hypoglycemia Infant is small for gestational age or experienced fetal growth restriction Smaller neonates have smaller glycogen stores Preterm infants born < 37 weeks Glycogen is stored during the 3rd trimester; preterm infants did not have opportunity to build up stores Loss of glucose source from placental circulation after birth puts preterm neonate at risk for low blood sugar Body’s sympathetic system detects low glucose and triggers physical symptoms (neurogenic symptoms) Symptomatic hypoglycemia Neurons in brain are unable to produce enough ATP and thus function properly, triggering symptoms related to low sugar in the CNS (neuroglycopenic symptoms) Non-specific symptoms are not exclusive to hypoglycemia and warrant further investigation to exclude other differential diagnosis (sepsis, inborn errors of metabolism, neonatal abstinence syndrome, neonatal encephalopathy, perinatal asphyxiation) Jitteriness or tremors Sweating Irritability Tachypnea Pallor Pathologic poor feeding Weak or a high- pitched cry Change in level of consciousness (lethargy or coma) Seizures Pathologic hypotonia for gestational age Apnea Bradycardia Cyanosis Hypothermia Neonates with perinatal stress (e.g. birth asphyxia, meconium aspiration) Body uses more glucose to produce ATP to manage condition causing physiological stress Glucose stores are used up more quickly Born to pregnant person with beta-blocker use Body in stress releases epinephrine to promote sympathetic responses including glycogen breakdown into glucose Beta blockers from placental circulation prevent epinephrine from binding to its receptor in infant’s body Neonatal Hypoglycemia: Asymptomatic and symptomatic hypoglycemia satisfy the criteria of blood glucose < 2.6 mmol/L in both term and preterm infants within 72 hours of birth, and after 72 hours of age glucose < 3.3 mmol/L Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Spontaneous Rupture of Membranes

Pre-Labour Rupture of Membranes: Pathogenesis and clinical findings Gestational age approaching term (>37 weeks) Authors: Wendy Xu Reviewers: Riya Prajapati Michelle J. Chen Dr. Jadine Paw* * MD at time of publication Intrauterine inflammation Fetal maturation Fetal growth Uterine contractions ↑ Pro-inflammatory cytokine & chemokine release in fetal membranes & amniotic fluid ↑ Stretch forces on fetal membranes ↑ Pro-apoptotic factors induces cellular apoptosis of fetal membranes Changes in collagen and protein composition drive extracellular matrix remodeling in fetal membranes ↓ Tensile strength Structural weakening of fetal membranes Occurs primarily in the focal area of fetal membranes overlying the cervix ↑ Matrix metalloproteinases triggers extracellular matrix degradation in fetal membranes Amnion and choriodecidua separation Amniotic fluid flows from vagina Amniotic fluid pools in posterior fornix on speculum exam Pre-labour rupture of membranes Membranes rupture before onset of uterine contractions Chorioamnionitis (infection of the fetal membranes and amniotic fluid) Neonatal infection Endometritis (infection of the endometrium) Amniotic fluid leaks through the cervix Prolonged rupture of membranes (>18hrs) before delivery Microbes ascend through vaginal canal Low amniotic fluid volume on ultrasound Amniotic fluid (pH 7.0-7.5) mixes with normal vaginal fluid (pH 4.5-6.0) which increases vaginal fluid pH to > 6.5 Positive nitrazine (pH indicator) test Ion- and estrogen-containing amniotic fluid enters vaginal canal Ferning (branching pattern) of vaginal fluid under microscope Accompanies uterine contractions, cervical effacement & cervical dilation Delivery/birth Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Precocious Puberty

Precocious Puberty: Pathogenesis and clinical findings Secondary sex characteristics appearing at age < 8 years in girls and < 9 years in boys. Early growth acceleration Bone age (skeletal maturity determined on x-ray) > chronological age Gonadotropin releasing hormone (GnRH)-dependent causes involve activation of the hypothalamic-pituitary-gonadal (HPG) axis. Also known as central precocious puberty GnRH-independent causes of precocious puberty are related to increased amounts of hormone in the body. Also known as peripheral precocious puberty Neurogenic (previous CNS insult) and CNS tumors (e.g. hypothalamic hamartoma, germinoma, astrocytoma) Idiopathic Tumours causing ↑ hormone levels Exogenous hormones causing ↑ hormone levels Genetics causing ↑ hormone levels 21-hydroxylase enzyme deficiency Growth of ovarian cysts/tumors (ex. germinoma, teratoma, choriocarcinoma) Growth of β-HCG-secreting tumours (e.g. germinomas, dysgerminomas, hepatomas Growth of benign or malignant adrenal tumours (e.g. adenoma, carcinoma) ↑ Estrogen and/or progesterone ↑ Beta-HCG stimulates ↑ testosterone production ↑ Cortisol, androgens, and/or aldosterone Exposure to exogenous sex steroids (e.g. anabolic steroids, topical testosterone, oral contraceptives) Steroid dependent features (e.g. exposure to estrogen creams in males may lead to breast development) Missense mutation in LH receptor gene (male limited) ↑ Activation of LH receptors ↑ Testosterone production Café au lait lesions Polycystic fibrous dysplasia Puberty onset ages 1-4 ↑ Activation and mutation of GNAS1 gene (McCune Albright Syndrome) Various endocrinopathies Growth acceleration Congenital adrenal hyperplasia ↓ Cortisol, ↑ ACTH Bone age > chronological age Absence of testicular enlargement Female ambiguous genitalia Authors: MacKenzie Horn Reviewers: Dasha Mori Michelle J. Chen Dr. Jean Mah* * MD at time of publication Normal variations in hormone production ↑ Sensitivity to estrogen Early adrenal androgen secretion Idiopathic premature thelarche Idiopathic premature adrenarche Unilateral or bilateral breast development No other secondary sex characteristics Bone age = chronological age Development of pubic hair ± axillary hair No other secondary sex characteristics Bone age = chronological age Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Acute Diverticulitis

Acute Diverticulitis: Pathogenesis and clinical findings Low fiber diet Authors: Candace Chan Yan Yu Wayne Rosen* Reviewers: Laura Craig Noriyah AlAwadhi Danny Guo Erica Reed Maitreyi Raman* Claire Song Shahab Marzoughi * MD at time of publication ↓ Colonic motility ↑ Stool transit time Formation of small dry stool Stool build-up and ↑ strain with bowel movements ↑ Pressure in the colonic lumen Constipation (difficulty passing stool) Obstipation (inability to pass any feces) Inherent weakness in the muscle layers of the colonic wall associated with immature collagen fibers and diminished wall elasticity Mucosal and submucosal layers of the colon wall push through a weak spot of the circular muscle layer Formation of diverticulum (sac-like protrusion of the colonic wall) Continued stress on diverticula causes micro- perforations of the diverticulum Inflammation of diverticula Mesentery and pericolic fat (fat surrounding the colon) attempt to wall off inflammation or perforations Stool bacteria escapes the colon Formation of abscess (accumulation of pus in response to the bacteria ) Pro-inflammatory cytokine release from nearby adipose tissue Hypothalamic thermoregulatory center increases core temperature set point Fever Irritation of parietal peritoneum Inflamed vessels are more permeable and fluid leaks from colonic vessels into the abdominal cavity Chronic low-grade inflammation triggers activation of pro-fibrotic factors and fibroblasts Excess production of extracellular matrix proteins Stimulation of somatic nerves sends pain signals to the brain Lower left quadrant abdominal pain Peritoneal signs (abdominal guarding, rigidity, rebound tenderness) ↓ Total circulating blood volume ↑ heart rate ↓ Jugular venous pressure Orthostatic hypotension (low blood pressure when standing after sitting/lying down) Gastrointestinal strictures and/or colonic obstruction Accumulation of micro- perforations further weakens intestinal wall Complete bowel perforation (medical emergency) Development of an abnormal connection (fistula) through the bladder, vagina, skin, or gut Abscesses Accumulation of fibrotic tissue narrows the intestinal lumen Fibrosis of colon Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published Oct 4, 2024 on thecalgaryguide.com

Tuberous Sclerosis Complex Dermatologic Manifestations

Tuberous Sclerosis Complex (TSC): Dermatologic Manifestations De novo mutation of tumour suppressor genes (TSC1 (on chromosome 9q34) or TSC2 (on 16p13.3)) Encode hamartin & tuberin proteins that regulate cell division & growth Hamartin & tuberin proteins are mediated by mammalian target of rapamycin (mTOR) Mutations ↑ mTOR signalling Irregular, dysfunctional cell proliferation - often affecting embryonic cells Author: Jasmine Gill Reviewers: Maharshi Gandhi Elise Hansen Sunawer Aujla Shahab Marzoughi Jodi Hardin* * MD at time of publication Dysfunctional melanocytes that have an impaired ability to produce & transfer melanin Dysregulated melanocyte migration during embryogenesis Overgrowth of normal skin components (hamartomas) Clonal patches of melanocytes produce increased pigment Café-au-lait macules Facial angiofibromas and fibrous cephalic plaque (red, pink papules) Clonal patches of melanocytes are unable to produce sufficient pigment and/or there is impaired production and distribution of melanin Hypopigmented macules Affects dermal cells Shagreen patch (cobblestone, yellow plaques often over lumbosacral area) Affects epidermal cells Molluscum pendulum (soft papules) Affects epidermal & dermal cells Ungual fibromas (flesh coloured or red papules around nails) Insufficient melanin production by melanocytes leads to insufficient pigmentation Ash leaf spot (rounded at 1 end and tapered at the other) Overgrowth of dermis causes fibrous papules Guttate/ ”confetti” macules Epidermal layer Melanocytes in basal layer Fibroma expands and creates localized pressure and mass effect Distortion of nail bed Irregular, overgrowth of epidermal &/or dermal cells Facial disfigurement Dermal layer Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Chronic Subdural Hematoma

Chronic Subdural Hematoma (SDH): Pathogenesis and Clinical Features Atraumatic SDH risk factors Authors: Cora Laidlaw Reviewers: Braxton Phillips Shahab Marzoughi Gary Michael Klein* * MD at time of publication For more information on acute subdural hematoma, see Calgary Guide slide - Acute Subdural Hematoma (SDH): Traumatic SDH mechanisms Intoxication leading to decreased balance and coordination Neurodegenerative disease causes cerebral atrophy (such as ALS, MS, and dementia) General cerebral atrophy with increased age Chronic alcohol use dilates blood vessels, thinning the walls Thinner, developing vessels in infants Age related risks: decreased vision, decreased mobility, decreased balance Low Impact trauma such as minor falls Child abuse Increased tension on bridging veins as ↓ brain volume ↑ distance they must span Bridging veins are more delicate Abusive head trauma Cytokines increase the leaky nature of vessels Blood degradation over time releases proinflammatory cytokines Atraumatic risk factors combined with traumatic mechanisms results in the breaking of bridging veins Low pressure venous blood slowly accumulates between the dura and arachnoid meningeal layers (increased with anticoagulation, hypertension, or other bleeding risk factors) Damaged tissue release inflammatory factors that promote angiogenesis through secondary intention (the use of granular tissue to fill in the non-approximated edges of the blood vessels) As the vessels are not approximated (connected to be rejoined), the granular tissue does not create a solid blood vessel wall Vessels are partially repaired and leaky in nature Recurrent bleeding due to small traumas and fluid accumulation due to leaky vessels results in expansion Chronic Subdural Hematoma (Bleeding within potential space between dura and arachnoid meningeal layers present >14 days) Dural attachments limits fluid expansion Local increased pressure and a mass effect on underlying brain tissue Cerebral atrophy (specific areas and therefore symptoms will depend on lesion location) Mesial temporal lobe Impaired memory (including verbal) Acute blood is present in small volumes with larger volume chronic hematoma Damaged tissues release proinflammatory cytokines from immune cells (astrocytes, peripheral immune cells, neurons, and microglial cells) Acute blood appears hyperintense on T2 MRI Chronic blood appears hypointense on T2 MRI Cytokines inflame nociceptive neurons (such as the trigeminal neuron) Recurrent headaches Altered mental status (confusion) Personality changes Damage to neuronal tissue Mass compression of underlying vasculature Hypoperfusion of brain tissue T2 MRI Brain shows lesions with hyperintensive cores surrounded by hypointensive Pressure placed indirectly onto cerebellum with inferior displacement of brain mass Gait ataxia Frontal lobe atrophy (specifically in orbitofrontal area) Orbitofrontal area Prefrontal cortex Impaired working memory (short term memory used for rapid executive, phonological visuospatial thought processes) Atrophy of focal brain structure Contralateral homonymous hemianopsia (loss of the half visual fields in both eyes) Somatic motor cortex Contralateral hemiplegia (inability to move the body opposite to the side of lesion) Primary visual cortex Pontine micturition centre Urinary incontinence (uncontrolled leakage of urine) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Epilepsy in Older Adults

Epilepsy in Older Adults: Pathogenesis and clinical findings Cerebrovascular disease (1⁄3 of cases), primarily ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage Ischemic and hemorrhagic injuries cause inflammation and nerve cell degeneration Glial cells (astrocytes and oligodendrocytes) proliferate around the lesion area to repair the damaged tissue Glial scar formation impedes neuronal reconnection and growth Alzheimer’s or Vascular Dementia Central nervous system disease (e.g. traumatic brain injury, prior meningitis, mass) Medications associated with hyponatremia (e.g. diuretics, antidepressants, antipsychotics, etc.) Cerebral edema Increased intracranial pressure Compression on structures and blood vessels Sleep deprivation Tau or amyloid deposition (abnormal protein aggregates in brain) Small vessel disease Increased delta wave activity Heightened neural excitability Decreased seizure threshold Elevated stress hormones (e.g. cortisol) Increased neuronal excitability and decreased inhibition Areas of tissue death, white matter changes & cortical irritability Structural and electrical brain changes Epilepsy: Neurological disorder characterized by increased susceptibility to recurrent unprovoked seizures Excessive, hypersynchronous & oscillatory network function Imbalance between excitatory and inhibitory activity Resultant seizure activity Atypical Seizure pattern; e.g. seem confused, stare into space, wander, make unusual movements, inability to answer questions Often atypical location in brain (limbic or neocortical) Focal seizures are more common than generalized Postictal paresis can last for days & disorientation, hyperactivity, wandering and incontinence may persist for 1 week Neurotransmitter dysregulation, neural network disruption, genetic factors, psychosocial factors Psychiatric comorbidities Authors: Anna Crone Reviewers: Anika Zaman, Rachel Carson, Raafi Ali, Luiza Radu, Gary Michael K Klein* * MD at time of publication Widespread structural changes and hippocampal atrophy Dementia Sub-optimal treatment results in ongoing and more frequent epileptic seizures Status epilepticus (higher mortality among older adults) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Cholesteatoma of middle ear

Cholesteatoma (of middle ear): Pathogenesis and clinical findings Authors: Emma Holmes Angela Mak Reviewers: Stephanie Cote Vaneeza Moosa Shahab Marzoughi William Kim Sunawer Aujla Kristine Anne Smith* * MD at time of publication Tympanic membrane perforation (e.g., acute otitis media, trauma) Squamous epithelium invasion & migration into middle ear Eustachian tube dysfunction (e.g., craniofacial abnormalities) Negative pressure Invagination of tympanic membrane Retraction pocket with keratin trapping & ingrowth Inflammation (e.g., upper respiratory tract infection, rhinitis) Mucosal lining of middle ear become hyperproliferative Squamous metaplasia Basal cell hyperplasia Invagination & epithelial ingrowth in basement membrane of the middle ear Theory of implantation due to trauma (e.g., during surgery) Implantation of skin into the middle ear through a defect in the eardrum Traps moisture Bacterial infection Erosion of external auditory canal Conductive hearing loss Labyrinthine fistula (abnormal communication between the inner ear and the surrounding structures) Leakage of perilymph Cholesteatoma Destructive growth of keratinizing squamous epithelium in the middle ear Bone erosion allows for secondary infection from outside the middle ear Chronic otitis media Migration of bacteria from middle to inner ear Intracranial infection (e.g., meningitis, parenchymal abscess) Acute otitis media Accumulation of keratinous debris Release of inflammatory molecules Release of osteoclasts Secretion of acid and proteinases Erosion of temporal bone Pressure change in the middle ear Aural polyp (growth in external or middle ear canal) Vertigo Coalescent mastoiditis (bone is remodeled and resorbed from pressure necrosis, inflammation, and increased osteoclastic activity) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Acute Subdural Hematoma

Acute Subdural Hematoma (SDH): Clinical Presentation Subdural Hematoma Authors: Cora Laidlaw Reviewers: Braxton Phillips Shahab Marzoughi Sina Marzoughi* * MD at time of publication Ischemia of cranial nerve tissue in brainstem Cranial nerve palsies ↓ Level of consciousness Generalized or focal seizures Uncal herniation Compression of oculomotor nerve (CN III) – responsible for eye movement (adduction, elevation, and depression) and parasympathetic tone Eyes fixed outwards and down with pupillary dilation ↑ Pressure compresses intracranial tissue Compression of brain structures Compression of arterial vasculature in brain ↓ Global perfusion to intracranial tissue Uncus (mediobasal aspect of temporal lobe) herniates into the infratentorial via the tentorial notch Cerebellar tonsils (part of posterior lobe of cerebellum) herniates through foramen magnum (opening in base of skull) Cerebellar tonsil herniation Tonsils compress brainstem Brainstem loses ability to control vital functions of life (such as respiration, heart rate, blood pressure) Coma or death Blood accumulation results in ↑ intracranial pressure (Bleeding within potential space between dura and arachnoid meningeal layers ) Compression of nociceptors in meninges and meningeal vasculature Headache Compression of medulla (contains emetic center) Stimulation of emetic centers Loss of function of primary sensory cortex (posterior to central sulcus) Contralateral hemisensory loss (including proprioception, fine touch, and two point discrimination) Loss of function of primary motor cortex (anterior to central sulcus) Contralateral hemiparesis (upper motor neuron) Ischemia and necrosis of brain parenchyma Cerebral disturbances altering neuronal networks Vomiting Nausea See Calgary Guide slide - Chronic Subdural Hematoma (SDH): Clinical Presentation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Primary Combined Hyperlipidemia

PrimaryCombinedHyperlipidemia:Pathophysiology&clinicalfindings Authors:GurreetBhandal,KarenZeng Rupali Manek Primary combined hyperlipidemia (genetic abnormalities) Reviewers: Raafi Ali, Luiza Radu *Samuel Fineblit *MD at time of review Familial dysbetalipoproteinemia or “Remnant Removal Disease” (autosomal recessive inheritance) Apolipoprotein E (ApoE) mutation (ApoE is found on triglyceride-rich lipoproteins, such as chylomicron & very low-density lipoprotein (VLDL)) Impaired triglyceride-rich lipoprotein particle binding to lipoprotein receptors ↓ Chylomicron & VLDL remnant clearance Familial combined hyperlipidemia Common, occurs in 1/50 to 1/100 (Polygenic, involving multiple genes, with variable expression & penetrance. Not all individuals will experience all clinical signs or complications) Adipose tissue dysfunction Impaired lipolysis (triglyceride breakdown in adipose tissue) ↓ Triglyceride storage in adipocytes ↑ Lipid levels ↓ Low-density lipoprotein (LDL) receptor function Impaired LDL particle endocytosis into cells ↓ LDL clearance ↑ Plasma LDL levels Hepatic fat accumulation ↑ Apolipoprotein B production ↑ Very low- density lipoprotein (VLDL) production ↑ Plasma VLDL levels Lipoprotein lipase dysfunction ↓ Triglyceride breakdown Delayed clearance of very low-density lipoprotein (VLDL), intermediate- density lipoproteins (IDL) & low-density lipoprotein (LDL) particles ↑ Plasma VLDL, IDL & LDL levels ↑ Triglycerides & cholesterol ↑ VLDL in serum Xanthomas (build up of cholesterol deposits on skin, eyelids, palms or tendons of ankles, elbows & knees) ↓ Conversion of VLDL to low-density lipoproteins (LDL) ↓ LDL in serum Atherosclerosis progression & ↑ risk of metabolic syndrome (↑Blood pressure, ↑ triglycerides, ↑ blood glucose, ↑ body mass index) Coronary artery disease & peripheral vascular disease Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Bone Remodeling Physiology

Bone Remodeling: Physiology Glucocorticoids ↓ Osteoblast (bone building cells) activity, ↑ osteoclast (bone cells that break down bone) activity Hyperparathyroidism ↓ Blood Ca2+ ↑ Parathyroid hormone (serum Ca2+ concentration increasing hormone) Trauma Osteoblasts detect breach in matrix integrity Hyperthyroidism ↑ Triiodothyronine (T3) ↑ Bone turnover Puberty ↑ Growth hormone ↑ Blood calcium (Ca2+) ↑ Calcitonin (reduces serum Ca2+ by ↓ renal Ca2+ reabsorption & ↑ osteoclast activity) Net bone resorption process (bone tissue released from bones) Surveillance osteoblasts produce receptor activator of nuclear activator kappa beta (RANKL; osteoclast stimulating protein) Monocytes fuse into osteoclasts (cells for bone breakdown) Osteoclast actions Secrete HCl to dissolve hydroxyapatite (bone matrix forming inorganic mineral) Serum markers of bone resorption: C-Telopeptide (CTX) P-Telopeptide (PTX) Net bone formation process Hormones activate osteoblast Osteoblast actions Secrete osteoprotegerin that binds RANKL Secrete osteoid seam (a new layer of unmineralized organic bone matrix) Osteoblasts deposit hydroxyapatite on seam Phagocytose osteocytes within bone matrix Authors: Andrew Wu, Jason Kreutz Reviewers:Mizuki Lopez, Gurreet Bhandal, Luiza Radu *Samuel Fineblit * MD at time of publication Secrete collagenase enzyme to help digest collagen ↓ Osteoclast activity Osteoblasts become osteocytes (mature cells) within bone Serum markers of bone formation: ↑ Alkaline phosphatase (ALP) ↑ Bone-specific alkaline phosphatase (BSAP; an enzyme produced by osteoblasts during mineralization of bone) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Persistent Truncus Arteriosus

Persistent Truncus Arteriosus: Pathogenesis and clinical findings Genetic Factors (e.g., 22a11 mutation resulting in DiGeorge syndrome) Spontaneous Authors: Inioluwa Adeboye Reviewers: Juliette Hall George S. Tadros Shahab Marzoughi Kim Myers* * MD at time of publication Persistent Truncus Arteriosus Congenital heart defect Cardiac neural crest (cells that form the outflow tract in fetal development) ablation defect Dysplasia (abnormal cell growth) of the truncal valve Common ventricular outflow tract (merged aorta and pulmonary trunk) Valvular deformity: a single truncal valve 1-4 thick deformed leaflets During normal fetal development and first week of life, pulmonary vascular resistance (PVR) is high to bypass undeveloped lungs Peripheral vascular resistance (PVR) ↓ post-birth Blood preferentially enters pulmonary circulation (left-to-right shunt) Mixed oxygenated and deoxygenated blood is pumped to the pulmonary, systemic, and coronary circuits Mild cyanosis and oxygen saturation <95% Difficulty opening and closing abnormally enlarged, stiff and/or rubbery valves Ejection click (high-pitched early systolic sound) Truncal valve regurgitation (inadequate valve closure) Turbulent backflow through valve into the ventricles Diastolic murmur Truncal valve stenosis (inadequate valve opening) ↑ Ejection time Systolic murmur Runoff from aorta to pulmonary vasculature during diastole and systole ↓ Diastolic pressure in aorta ↑ Pulse pressure (difference between diastolic and systolic aortic pressure) Bounding peripheral pulse Pulmonary blood flow (PBF) ↑ while systemic and coronary blood flow ↓ ↑ Blood return to left atrium Volume overload of the left heart Eccentric hypertrophy ↑ PBF causes vascular remodeling of the pulmonary vasculature ↑ PVR ↑ Pressure in the right ventricle and irreversible pulmonary hypertension Right-to-left shunt development (Eisenmenger syndrome) Congestive heart failure ↓ Cardiac output causing backup of blood into venous system and ↑ heart rate and respiratory rate to attempt to compensate ↑ Heart rate, ↑ respiratory rate, and peripheral edema Deoxygenated blood bypasses the lungs and is pumped systemically causing lower oxygen concentration in arterial circulation Severe cyanosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Thyroid Eye Disease

Thyroid Eye Disease: Pathogenesis and Clinical Findings Author: Liam Connors Reviewers: Lucy Yang, Mao Ding Julia Gospodinov Luiza Radu Samuel Fineblit* * MD at time of publication Environmental factors (smoking & stress, etc. mechanism unknown) Thyroid eye disease Genetic factors (mechanism unknown) An autoimmune condition wherein antibodies that target the thyroid & the periorbital tissues induce tissue swelling around the eye Auto-antibody production Type 1 insulin-like growth factor receptor (IGF-1, regulates cell growth) & thyroid stimulating hormone (TSH) receptor activation in CD34+ fibrocytes & orbital fibroblasts (cells part of the formation of connective tissue) Chemokine production (cells part of the inflammatory response) ↑ Immune response in the tissue around the eye (orbit) Fibrosis (overgrowth/scarring) & swelling of orbital tissues Eyelid retraction & lid lag on downward gaze ↑ Ocular surface exposure Corneal trauma, dryness, & microbe exposure Exposure keratopathy (corneal damage from ↑ exposure to air) Mechanical force causes eye misalignment Restrictive strabismus (both eyes do not line up in the same direction) Double vision Burning/foreign body sensation & epiphora (excess tears) Exophthalmos (bulging of one or both eyes) Mechanical strain on optic nerve Compressive optic neuropathy (damage to the optic nerve) Vision loss Afferent pupillary defect (altered pupil dilation) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 5, 2024 on www.thecalgaryguide.com

Subtrochanteric Femur Fracture

Subtrochanteric Femur Fracture: Pathogenesis and clinical findings High energy mechanism of fracture High energy trauma typically seen in younger patients (e.g. motor vehicle collision, fall from height) Strong lateral or axial force directed through femur Low energy mechanism of fracture Low energy trauma typically seen in elderly or patients with osteoporotic (e.g. falls) Atypical fractures Chronic bisphosphonate use (drug that inhibits osteoclasts from resorbing bone) Chronic suppression of bone resorption prevents natural bone building and breakdown (remodeling) Microscopic damage accumulates, weakening bone Pathologic fracture Primary or metastatic bone tumor Cancer cells in bone disrupt physiological bone remodeling Subtrochanteric Femur Fracture Fracture in the region of the femur that is 5 cm distal to lesser trochanter Muscle forces on proximal femur Muscle forces on distal femur Gracilis & adductor muscles exert shortening & adduction forces Gluteus medius & gluteus minimus muscles exert abduction force Iliopsoas muscles exert flexion forces Short external rotator muscles exert external rotation forces Bleeding from tissue & vascular damage Swelling & ecchymosis at fracture site Injury stimulates nerve fibres Displaced proximal femur Inability to weight bear Authors: Nojan Mannani Jack Fu Reviewers: Annalise Abbott Reza Ojaghi Usama Malik Michelle J. Chen Dr. Richard Buckley* Dr. Meredith Stadnyk* * MD at time of publication Shortened leg Hip & thigh pain Pain on motion Surgery is required to fix fracture. Complications may arise after operation. Femoral head & neck have limited blood supply which is required for fracture healing (union). Delay in surgery may ↑ time without supply Non-union of fracture Bone is unable to be aligned, leaving a space between broken bones Malunion of fracture (limb length discrepancy, rotation of limb) Surgical procedures ↑ risk of exposing incision to bacteria on contaminated instruments, skin, or in air Infection (acute or chronic) often associated with malunion Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 24, 2017; updated Oct 14, 2024 on www.thecalgaryguide.com

Complex Regional Pain Syndrome

Complex Regional Pain Syndrome (CRPS): Pathogenesis and clinical findings Type 1 origin: CRPS arises spontaneously or from trauma without confirmed damage to nerves (e.g. surgery, nerve compression, fracture, tissue trauma, ischemia, sprain) Type 2 origin: CRPS arises from trauma with confirmed evidence of nerve damage Intense psychological stress is associated with ↑ severity of CRPS Peripheral nerve endings release ↑ levels of neuropeptides (e.g. substance P, bradykinin, calcitonin gene-related peptide) Vasodilation & protein extravasation in tissues ↑ Perfusion to motor cortex ↓ Grey matter volume in cortical pain regions ↓ Cortical grey matter volume & ↓ perfusion of cortex in limbic & sensorimotor areas Dysregulation of sympathetic nerve fibres Autonomic dysfunction Central nerve fibres ↑ release of proinflammatory cytokines while ↓ release of anti- inflammatory cytokines Central sensitization (threshold at which a central nerve transmits a signal is lowered so that it more readily transmits signals) Mechanical hyperalgesia (hallmark of central sensitization) Authors: Jessica Hammal Calvin Howard Reviewers: Sina Marzoughi Michelle J. Chen Scott Jarvis* * MD at time of publication Nociceptors (nerve endings detecting pain) on skin become activated ↑ Cytokine & nerve growth factor release Primary afferent (sensory) neurons release ↑ levels of inflammatory neuropeptides Peripheral sensitization (threshold at which a nerve transmits a signal is lowered so that it more readily transmits signals) Widespread neurogenic inflammation (inflammation due to activation of peripheral nerve fibres) Sustained and dysregulated pro-inflammatory state Hyperalgesia (↑ sensitivity to feeling pain) Sweat gland related changes: Edema, sweating changes, asymmetric sweating Allodynia (pain from a stimulus that doesn’t normally cause pain) Trophic changes (wasting of skin, muscle, tissues; thinning of bones; thickening/thinning of nails) Motor dysfunction ↓ Range of motion Immobile due to severity of pain Impaired vasodilation & vasoconstriction Temperature asymmetry Altered skin color (red, blue, pale) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 28, 2024 on www.thecalgaryguide.com

Newborn Disorders of Sexual Development

Newborn Differences of Sexual Development: Pathogenesis and clinical findings 46XY Genotype Authors: Mahrukh Kaimkhani, Iqra Rahamatullah, Julia Gospodinov Reviewers: Gurreet Bhandal, Luiza Radu 46XY gonadal dysgenesis (underdeveloped testes) & Swyer syndrome (complete gonadal dysgenesis) Lack or inactivation of sex determining region of the Y chromosome (SRY gene – responsible for testicular differentiation) Testes produce ↓ testosterone & variable amounts (either ↓/ ↑) of anti- müllerian hormone (AMH – hormone produced by Sertoli cells in male fetuses that signals the regression of the müllerian ducts) 17-beta-hydroxysteroid dehydrogenase 3 deficiency (functional testes with variants in testosterone production) Variant in any of 5 enzymes involved in the conversion of cholesterol to testosterone Testes produce insufficient testosterone with no change to AMH production Wolffian & Müllerian ducts regress Development of female at birth external genitalia (clitoris, labia majora) or male at birth external genitalia (micropenis, hypospadias) Puberty may develop secondary sexual characteristics typical of males at birth (deep voice, male pattern facial/body hair) 5-alpha reductase deficiency Variation in the SRD5A2 gene that codes for 5-alpha-RD2 enzyme (responsible for differentiation of gonads into male reproductive system) 5-alpha-RD2 enzyme is impaired & unable to convert testosterone into dihydrotestosterone (DHT) DHT unable to block formation of female at birth genitalia & promote development of penis & scrotum Development of ambiguous external genitalia resembling female at birth (unfused labioscrotal folds, undescended testes) Puberty may develop secondary sexual characteristics typical of males at birth Complete androgen insensitivity Impairment of androgen receptors causes unresponsiveness of testicles to testosterone & no change to AMH production Testes unable to respond to exogenous testosterone treatment Wolffian & Müllerian ducts regress Development of female at birth external genitalia Puberty may develop secondary sexual characteristics typical of females at birth (breast enlargement, menarche) Aromatase deficiency Variations in the CYP19A1 gene that codes for aromatase enzyme Aromatase enzyme is impaired & unable to convert androgens (testosterone) into estrogen in the placenta ↑ Testosterone levels & absence of anti-Mullerian hormone Regression of Wolffian ducts & Mullerian ducts differentiate into fallopian tubes & uterus Development of normal female at birth internal reproductive structures & ambiguous genitalia that is not clearly female or male at birth Hypergonadotropic hypogonadism at puberty (↓ function of gonads & do not develop secondary sexual characteristics) 46XX Genotype XX Ovotesticular disorder of sex development Functional SOX9 gene that codes for testicular Sertoli cells differentiation despite lack of SRY gene Fetus exposed to only X chromosome (responsible for female gonadal development) due to absence of testicular determinant (SRY) Prescence of estradiol in developing ovarian follicles inhibits spermatogenesis (sperm production) & no exposure to AMH Mullerian ducts differentiate into oviduct, uterus, cervix, upper vagina & regression of Wolffian ducts Development of ambiguous external genitalia (labioscrotal fusion, hypospadias) & bilateral ovotestes (both ovarian & testicular tissue) or combination of a unilateral ovary or testis with ovotestis on contralateral side Puberty may develop secondary sexual characteristics typical of femalea at birth (breast enlargement, menarche) *Samuel Fineblit *MD at time of publication Ovaries with 21-hydroxylase deficiency Congenital adrenal hyperplasia (↑ adrenal tissue cell production due to disruption in cortisol synthesis pathway) ↓ Cortisol/aldosterone production from adrenal glands & ↑ Adrenocorticotropic hormone (ACTH) to compensate Incomplete development of Wolffian ducts (precursor to male internal genitalia) & Müllerian ducts (precursor to female reproductive tract) Development of ambiguous external genitalia (one testicle undescended; hypospadias where the urethra position is atypical; clitoromegaly) Puberty may develop secondary sexual characteristics typical of males or females at birth Swyer syndrome specific: Wolffian & Müllerian ducts regress Development of normal female internal reproductive structures (uterus & fallopian tubes) & gonadal streaks (underdeveloped ovaries replaced with fibrous scar tissue) Puberty is stalled unless treated with hormone replacement therapy ACTH stimulates adrenal gland to ↑ hormone production (both testosterone & estrogen) Despite ↑ testosterone production, the levels are not sufficient for development of Wolffian ducts & ovaries cannot produce AMH Wolffian ducts regress & Müllerian ducts develop Male typical genitalia (male XY) with microorchidism, hyperpigmented scrotum, & enlarged penis Signs of salt-wasting: low sodium, low potassium, low blood pressure, failure to thrive Ambiguous external genitalia (female XX: fusion of labial fold, clitoromegaly, penile urethra, urogenital sinus abnormality, hyperpigmentation) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 11, 2024 on www.thecalgaryguide.com

Primary Hypercholesterolemia

Primary Hypercholesterolemia: Pathophysiology & clinical findings Familial hypercholesterolemia (FH) Authors: Gurreet Bhandal Run Xuan (Karen) Zeng Rupali Manek Reviewers: Raafi Ali Luiza Radu Samuel Fineblit* *MD at time of publication Autosomal co-dominant disease (disease will manifest with one mutated allele, but those with two mutated alleles have a more severe phenotype) impacting only one gene Polygenic hypercholesterolemia (hypercholesterolemia involving multiple genetic abnormalities) Multiple gene mutations Accumulation of small effects on cholesterol synthesis, metabolism and clearance ↑ Low-density lipoprotein cholesterol (LDL-C) levels Development of atherosclerosis** (plaque build up around coronary artery or peripheral blood vessels in the rest of the body) Heterozygous familial hypercholesterolemia (one pathogenic variant allele; common, especially in French Canadians) Homozygous familial hypercholesterolemia (both alleles are pathogenic variants; rare & presents in childhood) Proprotein convertase subtilisin/ kexin type 9 (PCSK9, an enzyme holding low-density lipoprotein receptor complex together) gain- of-function mutation ↑ Breakdown of low-density lipoprotein (LDL) receptor in the liver Low-density lipoprotein- receptor related protein- associated protein 1 (LDLRAP1;protein coding gene) mutation ↓ Internalization of LDL receptor from cell surface ↓ LDL clearance Apolipoprotein B (ApoB; protein on LDL) mutation ↓ ApoB/LDL binding to LDL receptor LDL receptor gene mutation (>90% of cases) ↓ LDL receptor production ↑ Hypercholesterolemia (↑ LDL-C in blood) Development of aortic valve sclerosis (calcification & thickening of trileaflet aortic valve) Cholesterol deposit accumulation in tendons & ligaments Tendon xanthomas (nodules along tendons, typically at Achilles tendon & knuckles) Cholesterol deposit accumulation on skin at pressured areas Tuberous xanthomas (shiny red/orange nodules around knees, elbows & heels; less common) Cholesterol deposit accumulation in the edges of cornea Corneal arcus (white rings around iris) Cholesterol deposit buildup under skin near corner of eyelids Xanthelasmas (yellow plaques on or by the corners of eyelids) ↑ Risk of coronary artery disease **See Calgary Guide slide on Atherosclerosis: Complications Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 11, 2024 on www.thecalgaryguide.com

Suboxone & Methadone

Suboxone & Methadone: Mechanism of action and side effects Authors: Mahrukh Kaimkhani Iqra Rahamatullah Reviewers: Sara Cho, Keira Britto, Luiza Radu Kate Colizza* *MD at time of publication Suboxone (Buprenorphine + Naloxone) Methadone (a long-acting, full agonist) acts at mu-opioid receptors Buprenorphine (a long-acting, partial agonist with high affinity properties) displaces full-agonists at mu-opioid receptors (e.g., fentanyl). Naloxone (a mu-opioid receptor antagonist) displaces buprenorphine at mu-opioid receptors ↓ Effects of buprenorphine in intramuscular and intranasal forms ↓ Potential for abuse of buprenorphine Repeated intake of increasing doses of methadone Accumulation of methadone ↑ Potency compared to partial agonist (e.g., buprenorphine) ↓ Inhibitory GABAergic neuronal activity Disinhibition of dopamine at nucleus accumbens ↑ Dopamine levels at the nucleus accumbens and reward pathways Euphoria ↑ Adherence ↑ Adherence especially in those with severe opioid dependence Maintained stimulation of opioid receptors ↑ Buprenorphine required to occupy receptors to produce the same level of effect compared to full-agonists Saturation of mu- opioid receptors (ceiling effect) Further intake of buprenorphine does not ↑ stimulation of mu-opioid receptors at the locus coeruleus in the brainstem Locus coeruleus maintains sensitivity to carbon dioxide concentrations Ventilation is maintained ↓ Risk of overdose and respiratory depression ↓ Stimulation of mu-opioid receptors ↓ Analgesia ↑ Withdrawal Potassium channels open Post-synaptic hyperpolarization of cells Presynaptic inhibition of neurotransmitter (glutamate and substance P) release Inhibition of locus coeruleus which is in a hyperexcitable state from chronic opioid use ↓ Noradrenaline release from locus coeruleus ↓ Autonomic excitability throughout brain, spinal cord, peripheral nerves and GI tract. ↓ Withdrawal symptoms (restlessness, anxiety, lacrimation, nausea, vomiting, diarrhea) ↓ Euphoria Methadone blocks channels involved in repolarization of myocytes Prolonged repolarization of myocytes Prolonged QTc interval & cardiac arrythmias Inhibition of locus coeruleus’ ability to sense carbon dioxide and maintain ventilation ↑ Risk of overdose & respiratory depression ↓ Pain signal transmission Analgesia Opioid agonist therapy Further intake of buprenorphine does not ↓ inhibitory GABAergic neuronal activity GABAergic neurons maintain inhibitory effect on dopamine at the nucleus accumbens No ↑ in euphoric effects ↓ Adherence to therapy especially in those with severe opioid dependence (↓ cravings and withdrawal symptoms thereby reducing risk of relapse) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 11, 2024 on www.thecalgaryguide.com

Cannabis Use Disorder

Cannabis Use Disorder: Clinical findings and Complications Authors: Iqra Rahamatullah Mahrukh Kaimkhani Reviewers: Keira Britto Sara Cho Luiza Radu Alex Kennedy* *MD at time of publication Tetrahydrocannabinol (THC) in cannabis binds human cannabinoid receptor 1 (CB1) receptors in ventral tegmental area Biological factors: earlier age of cannabis use onset, male gender, genetic predisposition Psychosocial factors: stress, aggression, depression, anxiety, parent/peer cannabis or other substance use, ↓ SES, family dysfunction, bullying, occupational difficulties Disinhibits dopaminergic signaling and reward response ↑ Motivation to continue cannabis use Cannabis Use Disorder Cannabis use that may lead to significant distress or impairment in psychological, physical, or social functioning Cannabis (CB1 receptor agonist), especially with ↑ THC, acutely causes burst firing of ventral tegmental area ↑ Dopamine in striatal and prefrontal areas ↑ Dopaminergic transmission in the mesolimbic pathway (neuronal network involved in mediation of psychosis) Delusions, hallucinations, & paranoia occurring with acute or chronic use Cannabis induced psychotic disorder ↑ THC activates CB1 receptors on GABAergic terminals & ↓ THC activates CB1 receptors on glutaminergic terminals GABA & glutamate dysregulation and imbalance (can occur with acute or chronic use) Repeated exposures to ↑THC results in serotonin (5- HT) receptor upregulation ↑ Neuro- endocrine responses of stress hormones, which may ↑ serotonin reuptake Sedative action of low dose THC on CB1 receptors causes ↓ sleep latency and ↑ slow wave sleep with acute cannabis use Tolerance with chronic usage causes reversal of acute effects ↑ Sleep latency & ↓ slow wave sleep ↓ Sleep time & quality; ↓ cerebral restoration & recovery Cannabis induced sleep disorder Chronic cannabinoid receptor overstimulation Receptor dysregulation, desensitization, and downregulation Hypothalamic pituitary adrenal (HPA) axis dysregulation Inhibited gastrointestinal motility and digestion Nausea & vomiting & abdominal pain after cannabis use Cannabinoid hyperemesis syndrome (cyclic vomiting with cannabis use) Down regulation of CB1 receptors due to long term cannabis usage, paired with sudden discontinuation of cannabis use ↓ Cannabinoid in ↑CB1 receptors disrupts emotional processing, sleep and appetite homeostasis within the endocannabinoid system Anxiety, irritability, anger, depression, sleep disruption, appetite loss. Cannabinoid withdrawal Mood changes, anxiety and/or panic attacks Cannabis induced mood and anxiety disorders Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 11, 2024 on www.thecalgaryguide.com Sympathetic nervous system dysregulation

Renal manifestations of SLE

Systemic Lupus Erythematosus (SLE): Renal Manifestations Authors: Madison Turk Reviewers: Modhawi Alqanaie Mao Ding Luiza Radu Glen Hazlewood* * MD at time of publication Genetic susceptibility and potential environmental triggers (smoking, silica, Epstein-Barr Virus, hormones, ect) ↓Clearance of dead cell debris in the body (exact mechanisms unknown; See slide on pathogenesis of SLE) Extracellular exposure of nuclear proteins (which bind DNA and regulate gene expression) Immune cells respond to nuclear proteins as if they are non-self, as they usually don’t ‘see’ them Systemic Lupus Erythematosus An autoimmune disease characterized by anti-nuclear-antibody production resulting in widespread inflammation and tissue damage in varying affected organs, including one, or a combination of, joints, skin, brain, lungs, kidneys, and blood vessels Production of auto-antibodies against self nuclear proteins IC deposition in renal vessels Activation of inflammatory cells against IC’s causing vascular injury/inflammation ↑Clot formation in vessels leading to ↓vessel lumen diameter and ↓blood flow ↑Reninàcleavage of angiotensinogen to angiotensin Ià cleavage by angiotensin converting enzyme into angiotensin II Vessel constriction to ↑blood pressure (to ↑ renal blood flow) IC deposition in tubule basement membrane of the kidney Formation of immune complexes (IC) (collections of antigen(s), antibodies, and/or complement proteins bound together) Tubulointerstitial nephritis: (Inflammation of the renal tubules and interstitium, sparing the glomeruli) Renal ischemia IC deposition in the glomerulus Activation of complement, initiating an inflammatory response Recruitment of myeloid cells (monocytes/ neutrophils) Production of reactive oxygen species, cytokines and release of cytotoxic granules Tubular inflammation and damage resulting in ↓sodium reabsorption Renal release of reninà ↑ angiotensin I/II and resulting ↑ aldosterone ↑Sodium reabsorption, and potassium excretion in the collecting duct ↓Potassium secretion from the Distal Convoluted Tubule Hyperkalemia Hypokalemia ⍺-intercalated cell damage ↓Acid excretion Metabolic acidosis End stage kidney disease (all manifestations can result in this) Hypertension Tissue damage from the inflammatory response Glomerular nephritis (inflammation/damage of the filtering part of the kidneys) Fibrosis (thickening or scarring of tissue) Mesangial and parietal cell proliferation Podocyte injury ↑blood and protein excretion due to damage to the glomerular filtration membrane ↓protein in blood Edema Proteinuria Hematuria ↓Functional renal tissue to filter creatinine from blood ↓ Glomerular filtration rate ↑ Plasma creatinine Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 11, 2024 on www.thecalgaryguide.com

Learning Disability

Learning Disability: Pathogenesis and clinical findings Authors: Erin Brintnell Reviewers: Annie Pham Michelle Chen Dr. Jean Mah* * MD at time of publication Genetics (largest impact) E.g. Changes to neuronal migration genes (DCDC2 & ROBO1) in dyslexia Co-morbid neurodevelopmental disorder, especially ADHD Difficulty concentrating impedes learning Home environment ↓ Reading at home, ↓ parental education, socio-economic status Acquired (brain injury) Learning Disability Persistent impairment in reading (dyslexia), writing (dysgraphia) and/or arithmetic (dyscalculia) beyond what is expected for age Differences in brain activation during learning Dyslexia Dysgraphia Dyscalculia ↓ Activation of left temporal parietal cortex (sounding words out) ↓ White matter connections between brain regions important for reading ↓ Activation of visual-word form area (representing sounds as symbols) ↑ Activation of Broca’s area (spoken word) ↓ Letter & sound recall Difficulty sounding out words Poor spelling Difficulty naming objects Difficulty identifying words ↑ Sounding-out in later reading Cerebellar activation differences Cortical & subcortical damage to functional language regions Anterior thalamic radiation differences (executive functioning) Cingulum differences (cognitive control) Illegible & very slow writing Poor spelling & writing fatigue ↓ White matter in inferior longitudinal fasciculus (object recognition) ↓ Gray matter in inferior parietal lobe (understanding numbers & quantities) ↓ Gray matter in bilateral supramarginal gyri (retrieving arithmetic facts) ↓ White matter in fronto- occipital fasciculus & anterior thalamic radiation (goal-oriented behavior & executive functioning) Difficulty recognizing patterns & numbers Difficulty with basic arithmetic Difficulty with mathematic operations Difficulty with number processing Work-avoidance ↓ Self-esteem Difficulty forming relationships Depression Impulsivity Opposition to authority Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 11, 2024 on www.thecalgaryguide.com

Anticholingeric Syndrome in Older Adults

Anticholinergic Syndrome in Older Adults: Pathogenesis and clinical findings Age-related physiological changes Authors: Jasmine Nguyen Reviewers: Anika Zaman Luiza Radu, Taylor Wong* *MD at time of publication ↑ Degree of disease comorbidity in older adults ↑ Likelihood of polypharmacy and medication interactions ↓ Ability of the kidneys to excrete (↓ glomerular filtration rate) ↓ Ability of the liver to metabolize drugs effectively Breakdown of the blood- brain barrier Relative cholinergic deficit compared to younger adults Use of anticholinergic medication(s) (e.g. antihistamines, antipsychotics, antidepressants, urinary incontinence medications) Higher anticholinergic burden in older adults Anticholinergic Syndrome Sequelae of symptoms following accidental or intentional overdose of compound(s) with anticholinergic activity Anticholinergic drug competitively binds against acetylcholine at muscarinic cholinergic receptors Inhibition of peripheral muscarinic cholinergic receptors Inhibition of muscarinic cholinergic receptors in the central nervous system Dysregulation of acetylcholine levels in the brain, which is responsible for memory, attention, learning, and arousal Cardiovascular: Sudoriferous glands: inability to produce or excrete sweat Gastro- intestinal: impaired gut motility Constipation Blurry vision Bladder: impaired detrusor muscle contraction & urethral Eyes: impaired pupillary contraction & ability to accommodate Inhibition of muscarinic- sensitive delayed rectifying potassium efflux channels on cardiomyocytes Impaired ability to slow heart rate & lower blood pressure Impaired thermoregulation Hyperthermia Compensatory cutaneous vasodilation to release heat Flushed skin Dry sphincter skin opening Urinary retention Urinary stasis allows for bacterial overgrowth Urinary tract infection Abnormal pupillary dilation (mydriasis) Hypertension Delayed cardiomyocyte repolarization Prolonged QT interval in cardiac cycle (on ECG) Seizures Tachycardia Inattention Agitation/ Aggression Delirium develops Coma Fluctuating cognition Visual Hallucinations Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 11, 2024 on www.thecalgaryguide.com

Benzodiazepine mechanism of action

Benzodiazepines: Mechanism of action Sedative-hypnotic, anxiolytic & anti-convulsive agents composed of a fused benzene and diazepine ring that is administered orally or intravenously to produce desired effect (ie., lorazepam, midazolam, diazepam) Authors: Tracey Rice Usama Malik Amy Fowler Victoria Silva Reviewers: Sara Cho Keira Britto Luiza Radu Brienne McLane* Aaron Mackie* * MD at time of publication Benzodiazepine binds to gamma-aminobutyric acid (GABAA) receptors in vascular smooth muscle & the central nervous system (CNS) ↑ Opening of chloride channels Influx of chloride ions into the neuron Hyperpolarization of nerve membrane causing it to be more negative The cell membrane falls below the normal resting potential Medulla oblongata inhibition ↓ Respiratory drive; ↓ depth & rate of respirations Temporary cessation of breathing leads to reduced oxygen supply to the brain ↓ Level of consciousness Pharyngeal muscle relaxation leading to obstruction Hypoventilation and/or apnea General CNS inhibition ↓ Neuronal activity ↓ Electrical brain activity ↓ Seizure activity & hypnotic effect Thalamic & hypothalamic inhibition Disruption of short & long- term memory consolidation Limbic system inhibition ↓ Fear emotions (panic & phobia) Anxiolytic effect (↓ Anxiety) Smooth muscle inhibition Smooth muscles become relaxed &/or less spastic Vasodilation ↓ Preload Hypotension ↓ Cerebral blood flow Pre-syncope or syncope Anterograde amnesia ↓ Visuospatial ability, speed of processing & verbal learning Confusion ↓ Deep stage of non-REM sleep & delayed REM sleep Rapid sleep Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 21, 2024 on www.thecalgaryguide.com

Diabetic Polyneuropathy

Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Gurreet Bhandal Amanda Eslinger Reviewers: Raafi Ali Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia (↓ Intracellular insulin levels) ↓ Insulin induces expression of neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, insulin-like growth factor (IGF), & vascular endothelial growth factor (VEGF)) ↓ Stimulus for peripheral nerve maintenance & repair Impaired peripheral nerve repair Hyperglycemia (↑ Intracellular glucose levels) ↑ Glycolysis (breakdown of glucose) ↑ Intermediates & products of glycolysis (i.e. Protein Kinase C, AGE, polyols (sorbitol & fructose), NADH) Protein Kinase C Pathway activated & ↑ inflammation in endothelium, vascular smooth muscle, fibroblasts of blood vessels Prothrombotic state with ↑ vascular fibrosis, ↑ smooth muscle proliferation, ↑ chance of blood clots, ↑ impaired endothelial- mediated vasodilation Arterial stiffening & ischemia Advanced Glycation End Products (AGEs): end products of glycolysis that have carbohydrates attached AGEs bind AGE receptors on endothelium & white blood cells ↑ Inflammation, vascular permeability, procoagulant activity & monocyte influx Immune cells generate toxic reactive oxygen species as part of their defense system Polyol pathway activated in kidney, retina, nerves Excess glucose converted to sorbitol & fructose Metabolism of sorbitol & fructose produces intermediates that undergo auto-oxidation ↑ Reactive oxygen species ↑ NADH (reducing agent) overloads the electron transport chain ↑ Leakage of electrons in the electron transport chain ↑ Free radical formation (type of reactive oxygen species that is toxic to cells & tissues when in excess) ↑ Oxidative stress Diabetic Polyneuropathy (damage to & loss of peripheral nerve function due to nerve hypoxia & impaired repair mechanisms) Sensory axonal loss Damage to small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesia (pins & needles feeling), dysthesia (burning, tingling, itching) X-ray: destruction of weight-bearing foot joints Damage to large myelinated fibers Loss of vibratory sensation in glove & stocking pattern distribution; altered proprioception Claw toe deformity Charcot Foot: weakening of bones, joints, soft tissues causes pain insensitivity Distal motor axonal loss ↓ Ability of axons to transmit signals to central nervous system to foot muscles ↓ Foot muscle strength, ↓ Coordination & imbalance between toe extensors & flexors Weight shift creates pressure points Fissures in skin of weight-bearing areas Infection & chronic ulceration Damage to nerves that control contractions of stomach muscles Gastroparesis: stomach muscles weakened, ↓ motility & delayed transit of contents Autonomic neuropathy Damage to nerves that control heart blood flow, contractions & contractility Damage to nerves that control blood flow and arousal responses for sexual function Erectile dysfunction Orthostatic or postural hypotension Exercise intolerance Resting tachycardia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 28, 2014; updated Nov 16, 2024 on www.thecalgaryguide.com Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Gurreet Bhandal Amanda Eslinger Reviewers: Raafi Ali Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia (↓ Intracellular insulin levels) ↓ Insulin induces expression of neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, insulin-like growth factor (IGF), & vascular endothelial growth factor (VEGF)) ↓ Stimulus for peripheral nerve maintenance & repair Impaired peripheral nerve repair Hyperglycemia (↑ Intracellular glucose levels) Protein Kinase C Pathway in endothelium, vascular smooth muscle, fibroblasts of blood vessels ↑ Inflammation Prothrombotic state with ↑ chance of blood clots, ↑ vasoconstriction & ↑ arterial stiffening Ischemia ↑ Glycolysis (breakdown of glucose) Advanced Glycation End Products (AGEs): end products of glycolysis that have carbohydrates attached AGEs bind cellular receptors Inflammation, vascular permeability, procoagulant activity & monocyte influx Immune cells generate toxic reactive oxygen species as part of their defense system ↑ Intermediates & products of glycolysis (i.e. Protein Kinase C, AGE, sorbitol & fructose, NADH) Polyol Pathway in kidney, retina, nerves Excess glucose converted to sorbitol & fructose Metabolism of sorbitol & fructose produces intermediates that undergo auto-oxidation ↑ Reactive oxygen species ↑ Leakage of electrons when NADH (reducing agent) overloads the electron transport chain ↑ Free radical formation (type of reactive oxygen species that is toxic to cells & tissues when in excess) ↑ Oxidative stress Diabetic Polyneuropathy (damage to & loss of peripheral nerve function due to nerve hypoxia & impaired repair mechanisms) Sensory axonal loss Damage to small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesia (pins & needles feeling), dysthesia (burning, tingling, itching) X-ray: destruction of weight-bearing foot joints Damage to large myelinated fibers Loss of vibratory sensation in glove & stocking pattern distribution; altered proprioception Claw toe deformity Charcot Foot: weakening of bones, joints, soft tissues causes pain insensitivity Distal motor axonal loss ↓ Ability of axons to transmit signals to central nervous system to foot muscles ↓ Foot muscle strength, ↓ Coordination & imbalance between toe extensors & flexors Weight shift creates pressure points Fissures in skin of weight-bearing areas Infection & chronic ulceration Damage to nerves that control contractions of stomach muscles Gastroparesis: stomach muscles weakened, ↓ motility & delayed transit of contents Autonomic neuropathy Damage to nerves that control heart blood flow, contractions & contractility Damage to nerves that control blood flow and arousal responses for sexual function Erectile dysfunction Orthostatic or postural hypotension Exercise intolerance Resting tachycardia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Gurreet Bhandal Amanda Eslinger Reviewers: Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia ↓ intracellular insulin levels ↓ Neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, IGF, & VEGF) ↓ stimulus for peripheral nerve maintenance and repair Impaired peripheral nerve repair Sensory axonal loss Small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesias or tingling and numbness, dysthesias where sense of touch is distorted Hyperglycemia ↑ Intracellular glucose levels This produces an excess of glycolysis intermediates & products of glycolysis (i.e. sorbitol & fructose; AGE; Protein Kinase C) PKC Pathway in endothelium, vascular smooth muscle, fibroblasts of blood vessels ↑ inflammation Prothrombotic state with ↑ chance of blood clots; vasoconstriction & arterial stiffening Ischemia Advanced Glycation End Products: The body “glycates” end products of glycolysis, which means that some end products have a carbohydrate added to them Polyol Pathway in kidney, retina, nerves Excess glucose is converted to sorbitol and fructose, which accumulates in cells ↑ Oxidative stress ↑ Free Radical Formation AGE’s bind cellular receptors inducing inflammation, vascular permeability, procoagulant activity & monocyte influx Abbreviations: AGE – Advanced Glycation End Products IGF - Insulin-like Growth Factor VEGF - Vascular Endothelial Growth Factor PKC – Protein Kinase C Autonomic neuropathy Nerve hypoxia & impaired repair mechanisms leading to dysfunction & loss of peripheral nerves Distal motor axonal loss Large myelinated fibers Atrophy of intrinsic foot muscles Fissures in skin of weight-bearing areas Imbalance between toe extensors & flexors Weight shift results in pressure points Infection & chronic ulceration Gastroparesis: stomach muscles weakened with ↓ motility Claw toe deformity Erectile dysfunction Altered proprioception X-ray: destruction of weight-bearing foot joints Loss of vibratory sensation in glove & stocking pattern distribution Charcot Foot: weakening of bones, joints, soft tissues causes pain insensitivity Cardiac: Resting tachycardia, exercise intolerance, orthostatic or postural hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Amanda Eslinger Reviewers: Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia ↓ Neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, IGF, & VEGF) ↓ stimulus for peripheral nerve maintenance and repair Impaired peripheral nerve repair Sensory axonal loss Small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesias, dysthesias Hyperglycemia ↑ Intracellular glucose levels This produces of glycolysis an excess of glycolysis intermediates & products (i.e. sorbitol & fructose; AGE; Protein Kinase C) PKC Pathway PKC pathway activation results in ↑ inflammation Prothrombotic state; vasoconstriction & arterial stiffening Ischemia Advanced Glycation End Products: The body “glycates” end products of glycolysis, which means that some end products have a carbohydrate added to them AGE’s bind cellular receptors inducing inflammation, vascular permeability, procoagulant activity & monocyte influx Polyol Pathway (i.e. sorbitol & fructose) Excess glucose is converted to sorbitol, which accumulates in cells ↑ Oxidative stress ↑ Free Radical Formation Nerve hypoxia & impaired repair mechanisms leading to dysfunction & loss of peripheral nerves Distal motor axonal loss Abbreviations: AGE – Advanced Glycation End Products IGF - Insulin-like Growth Factor VEGF - Vascular Endothelial Growth Factor PKC – Protein Kinase C Autonomic neuropathy Large myelinated fibers Altered proprioception Atrophy of intrinsic foot muscles Fissures in skin of weight-bearing areas Infection & chronic ulceration Imbalance between toe extensors & flexors Weight shift results in pressure points Gastroparesis Claw toe deformity Erectile dysfunction X-ray: destruction of weight-bearing foot joints Loss of vibratory sensation in glove & stocking pattern distribution Charcot Foot Cardiac: Resting tachycardia, exercise intolerance, orthostatic hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com

Rapid sequence induction and intubation

Rapid Sequence Induction & Intubation (RSII): Indications & considerations “Full stomach”: ↑ risk of regurgitation, vomiting, aspiration Life-threatening injury or illness requiring immediate or rapid airway control ↓ Gastro- esophageal sphincter competence (elderly, pregnancy, hiatus hernia, obesity) ↑ Intragastric pressure (pregnancy, obesity, bowel obstruction, large abdominal tumors) Delayed gastric emptying (narcotics, anticholinergics, pregnancy, renal failure, diabetes) ↓ Level of consciousness (drug/alcohol overdose, head injury, trauma or shock state) Respiratory & ventilatory compromise (i.e., hypoxic or hypercapnic respiratory failure) Achalasia (esophageal motility disorder resulting in impaired swallowing) Dynamically deteriorating clinical situation (i.e., trauma) GI bleed Impaired airway reflexes ↓ Muscle tone of structures in the airway (i.e., tongue, pharyngeal walls, & soft palate) Patients who did not stop GLP-1 agonist preoperatively as advised Impaired clearance of secretions or vomitus ↓ Safe apnea time before hemodynamic decompensation Unprotected airway Need for rapidly securing airway while avoiding aspiration & hemodynamic compromise Rapid sequence intubation (RSI): Simultaneous administration of induction agent (unconsciousness) & neuromuscular blocking agent (paralysis) to achieve intubation conditions (~45-60 seconds after IV push) for rapid control of an emergency airway Preoxygenation Deranged physiologic conditions (i.e., hypotension, acidosis, hypoxemia) Reduced tolerance for apnea (period with no ventilation or oxygenation) Pre-oxygenate with high flow O2 (15L) to create a large pulmonary & tissue reservoir of oxygen ↓ Significant oxygen desaturation during apnea ↑ Oxygen saturation on pulse oximetry Induction Laryngoscopy & intubation are a potent sympathetic nervous system stimulus Airway manipulation causes a surge in catecholamines Paralysis Visualization & passage of endotracheal tube requires relaxation of vocal cords & surrounding muscles Neuromuscular blocking agents facilitate paralysis Rescue Some induction agents (i.e., propofol) are vasodilators Hemodynamically unstable or patients in shock Hypotension Tachycardia ↑ Intracranial pressure (ICP) Hypertension Suppress cough & gag reflex Prevent laryngospasm (involuntary closure of vocal cords to airway manipulation) Minimize movement during procedure Vasoactive agents (i.e., ephedrine, phenylephrine) ↑ systemic vascular resistance Atropine & glycopyrrolate ↑ heart rate Lidocaine (Na+ channel blocker) & opioids (μ receptor agonist) ↓ transmission of pain ↓ Sympathetic response, myocardial demand & physiologic stress Anesthetics (i.e., propofol) achieve unconsciousness for paralysis & intubation ↓ Airway trauma & damage to vocal cords Bag mask ventilation typically avoided in this step to ↓ gastric insufflation & risk of aspiration Cricoid pressure (Sellick maneuver): posterior displacement of cricoid ring to compress esophagus against C-spine to prevent passive regurgitation of gastric contents to airway. Applied from start of induction, released when placement of endotracheal tube is confirmed by capnography. Intubation ↑ Blood pressure and/or cardiac output Authors: Jen Guo Reviewers: Priyanka Grewa Luiza Radu Leyla Baghirzada* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 18, 2024 on www.thecalgaryguide.com

Open Fractures

Open Fractures: Mechanisms, clinical features and complications Direct, high-energy force (e.g. vehicle collisions, gunshot) or low-energy force on diseased bone Force applied to bone exceeds strength of bone resulting in periosteal stripping and subsequent soft tissue and neurovascular destruction Open Fractures Also known as “compound fractures” and classified with the Gustilo-Anderson classification system (Types I, II, III), these are fractures in which the skin is penetrated and bone is exposed to the external environment. Comminuted fractures have ≥ 2 breaks in the bone. Inside-out (bone) or outside-in (external) penetration of skin to create a wound Skin tearing creates vacuum-like effect pulling debris into wound Minimal comminution Bone penetrates skin to create a wound < 1 cm in diameter (Type I) Smaller wound creates minimal opportunities for pathogen entry and contamination Moderate comminution Bone penetrates skin to create a wound 1-10 cm in diameter (Type II) Moderate wound creates some opportunity for pathogen entry and contamination Extensive comminution Bone penetrates skin to create a wound > 10 cm in diameter (Type III) Large wound creates ample opportunity for pathogen entry and extensive contamination Type IIIA (adequate soft tissue for bone coverage) Type IIIB (soft tissue damage with periosteal stripping) Type IIIC (vascular injuries, potential amputation) Displacement/shortening/ angulation/rotation of fracture fragment Improper bone healing Bone deformity Authors: Meaghan MacKenzie Holly Zahary Loreman Nojan Mannani Reviewers: Annalise Abbott Usama Malik Michelle J. Chen Dr. Prism Schneider* Dr. Jared Topham* * MD at time of publication Pain & lack of mechanical load bearing axis Inability to weight bear Decreased mobility promotes stasis of venous blood flow & intravascular vessel wall damage Deep vein thrombosis Potential progression to pulmonary embolism Bleeding or inflammation within fascia Muscle atrophy Compartment syndrome (↑ pressure in muscle) ** Open wound exposes bone Infiltration of debris & contaminants Infection of soft tissues or bone (osteomyelitis) Initial injury damages blood vessels Initial injury damages nerves ↓ Sensation distal to injury ↓ Limb function & proprioception ↓ Pulses distal to injury Amputation ↓ Blood flow to bone Avascular necrosis (bone tissue death) Limb ischemia ↓ Blood flow & oxygen delivery to tissues Compartment syndrome** Delayed union (bone healing) on serial radiographs Non-union (bone fails to heal) on serial radiographs **See corresponding Calgary Guide slide on Acute Compartment Syndrome Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 16, 2017; updated Nov 21, 2024 on www.thecalgaryguide.com

Calcium Channel Blockers

Calcium Channel Blockers: Mechanisms & side effects Authors: Caroline Kokorudz Reviewers: Rafael Sanguinetti Andrew Wu Luiza Radu Timothy Pollak* * MD at time of publication Calcium channel blocker medications inhibit Ca2+ channels in smooth muscle Reduction of Ca2+ influx into smooth muscle cells Inhibits calcium-dependent aldosterone synthesis reducing Na+ & H2O resorption in renal distal tubules Negative feedback to pituitary gland causing ↑ ACTH (adrenocorticotropic hormone) ↑ Androgens (testosterone) Testosterone acts on gingival cells (multiple cell types that support teeth) & connective tissue matrix Gingival hyperplasia (gum overgrowth) Non-dihydropyridines: (Phenylalkylamines [verapamil], Benzothiazepines [diltiazem]) less potent vasodilators & selective for heart muscle Prevents smooth muscle contraction Dihydropyridines: (amlodipine, felodipine, nifedipine) vasodilate vascular smooth muscle ↓ Arterial resistance and blood pressure in coronary & peripheral arteries Coronary artery vasodilation ↓ Pressure in coronary arteries ↑ Blood flow through coronary arteries Reduced ischemia relieves angina Inhibits L-type Ca2+ channels, preventing rapid nodal depolarization Reduces excitation of sinoatrial (SA) & atrioventricular (AV) nodal tissues ↓ Conduction speed of electrical impulses ↓ Contractile strength of cardiomyocytes (heart muscle cell) ↓ Systemic vascular resistance & cardiac afterload (heart pumping resistance) ↑ Blood volume flowing into significantly smaller vessels ↑ Capillary blood pressure ↑ Circulation to face Flushes (red & warm) ↓ Cardiac output ↓ Tissue perfusion & attempt to ↑ cardiac output Worsens heart failure ↓ Oxygen demand of heart muscle More favorable oxygen supply to demand ratio Relieves angina ↓ Blood pressure ↓ Cerebral perfusion Syncope (fainting) Relieves angina Capillary fluid leak increased to interstitial space Peripheral edema ↑ Intracranial pressure Compresses nerve endings Headache ↓ Heart rate Bradycardia Suppresses dysrhythmias (abnormal heart rhythm) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 21, 2024 on www.thecalgaryguide.com

Dexmedetomidine

Dexmedetomidine: Mechanism of Action and Adverse Side Effects Central Nervous System Dexmedetomidine is a highly-selective, direct α2-adrenoceptor agonist Peripheral Vascular System Binds to the pre and post junctional α2 receptors in the dorsal horn of the spinal cord Binds to transmembrane α2 receptors at the locus ceruleus in the brain stem Stimulation of arterial transmembrane α2 receptors Inhibits adenylate cyclase intracellularly ↓ Cell membrane protein phosphorylation Altered ion channel activity Hyperpolarization of neuronal cell membranes Termination of nociceptor (pain) signal propagation Analgesia ↑ Sedation Anxiety suppression ↓ Formation of cyclic AMP (cAMP) ↓ cAMP-dependent kinase activity Neuronal firing suppression, mimicking endogenous sleep ↓Cerebral blood flow ↓ Sympathetic tone Heart block and asystole Maintenance of seizure foci on EEG in seizure surgeries ↑ Smooth muscle contraction ↑ Vasoconstriction Transient hypertension and reflexive bradycardia on bolus administration ↓ Heart rate and systemic vascular resistance Bradycardia & hypotension Authors: Kayleigh Yang, Arzina Jaffer Reviewers: Priyanka Grewal, Luiza Radu Leyla Baghirzada * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 21, 2024 on www.thecalgaryguide.com

Pre-Eclampsia Pathogenesis

Pre-Eclampsia: Pathogenesis Pregnant person risk factors Fetal risk factors Imbalance of Th17/Treg cells and other inflammatory or immune factors Aberrant activation of innate immune cells creates a cytotoxic environment in utero (exact mechanism unclear) Primigravida (1st pregnancy) Advanced maternal age Genetic factors (e.g. sFLT1) Collagen vascular disease Previous preeclamptic pregnancies Multiple gestation Other unclear causes Dysregulated immune and non-immune decidual cells (specialized endometrial cells) promote abnormal placental trophoblast invasion and uterine spiral artery formation (exact mechanism unclear) Multiple unclear, complicated mechanisms Abnormal association of placental vasculature with uterine vasculature early in pregnancy (utero-placental mismatch) disrupts adequate blood perfusion from placenta to fetus (< 20 weeks gestation or early-onset) Fetus experiences under- perfusion, hypoxia, ischemia, and oxidative stress Placental cells release molecules toxic to vascular endothelium into the maternal circulation Damaged maternal blood vessels are less able to perfuse the placenta Systemic dysfunction of maternal blood vessel endothelium (endothelial cell activation) (>20 weeks gestation or late-onset) Inflammatory cells retain memory postpartum which increases risk for developing preeclampsia in subsequent pregnancies Hypoxia leads to placental cell death, which results in release of fetal antigens Authors: Yan Yu Jasmine Nguyen Reviewers: Kayla Nelson Radhmila Parmar Sean Spence Monica Kidd* Katrina Krakowski* Maryam Nasr-Esfahani* Riya Prajapati Michelle J. Chen Jadine Paw* * MD at time of publication Placental ischemia & injury Pre-existing maternal diseases damage endothelial cells (e.g. vasculitis, diabetes, renal diseases, chronic hypertension) Placenta is unable to supply sufficient O2 and nutrients to meet demands of growing fetus Maternal Clinical Findings and Complications** Fetal Clinical Findings and Complications** **See corresponding Calgary Guide slides Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 10, 2017; updated Nov 22, 2024 on www.thecalgaryguide.com

Loop diuretics

Loop Diuretics: Mechanism & side effects Inhibit Na+/K+/2Cl- (NKCC) symporter at thick ascending limb of Loop of Henle (aLOH) Authors: Andrew Wu, Rafael Sanguinetti Reviewers: Luiza Radu, Adam Bass* * MD at time of publication Over-inhibition of ion symporter in ear at high concentrations Damage to tight junctions in the blood vessel epithelium in the ear Disruption of the blood- cochlear barrier Hearing loss Opening of ATP-sensitive K+ channels on pancreatic β- cells causes efflux of K+ ↓ Intracellular K+ causes a negative intracellular charge ↓ Ability for pancreatic β- cells to depolarize & release insulin Hyperglycemia (rare) Stimulation of prostaglandin E2 (PGE2) synthesis in the cortical & medullary aLOH Stimulation of endothelial nitric oxide synthase releases nitric oxide Systemic venodilation (dilation of veins) ↓ Systemic vascular resistance ↓ Blood pressure ↓ Na+ in renal interstitium ↓ Water reabsorption (water follows Na+) Interstitial washout (↑ NaCl & water wasting in interstitium) ↓ Sodium (Na+) reabsorption ↑ Positive luminal charge at thick aLOH ↓ Electrochemical gradient reduces cellular transport of cations ↓ Ca2+ & Mg2+ reabsorption in the aLOH Hypocalcaemia & hypomagnesemia ↑ Na+ delivery to the distal convoluted tubule (DCT) ↑ Intracellular Na+ at collecting duct ↑ K+ efflux via renal outer medullary potassium channel (ROMK) ↓ Fluid status ↓ Serum Na+ ↓Serum Cl- ↑ Luminal K+ at alpha intercalated cell Chemical gradient ↑ K+/H+ antiporter activity ↑ K+ excretion Hypokalemia Chemical gradient shifts K+ into cells creating a charge gradient to shift H+ out Hyponatremia Hypovolemia Hypochloremia ↓ Volume status activates angiotensin II, which plays a role in sodium and volume retention ↑ Na+/H+ antiporter 3 (NHE3) activity in the proximal tubule Kidneys excrete & conserve ions to preserve intracellular charge gradient ↑ H+ loss in the urine ↓ Serum H+ ↑ Proximal Na+ reabsorption causes ↑ urate reabsorption via urate-hydroxyl exchangers Hyperuricemia Contraction alkalosis (loss of Na+-rich, HCO3- low fluid) & hypokalemia ↑ Serum HCO3- Metabolic alkalosis (systemic pH > 7.45 due to metabolic process) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 18, 2024 on www.thecalgaryguide.com

Statins Mechanisms and Side Effects

Statins: Mechanisms & side effects Activation of inducible nitric oxide synthase, in endothelial cells, systemically ↑ Nitric oxide ↑ Vasodilation Competitive inhibition of HMG-CoA reductase activity (rate controlling enzyme of cholesterol production) ↓ Mevalonate acid (cholesterol precursor) production in the mevalonate pathway (metabolic processes that produce cholesterol) ↓ Cholesterol ubiquinone (CoQ10) production ↓ Ubiquinone (protective of cellular oxidative effects) Impaired mitochondrial function ↓ Cyclooxygenase-2 (COX2) expression (enzyme involved in the production of prostaglandins) ↓ Availability of arachidonic acid (derivative of LDL cholesterol breakdown) ↓ Thromboxane A2 (lipid with prothrombotic properties) ↓ Platelet adhesion ↓ Thrombogenicity (tendency to generate blood clots) Improved endothelial function Improved myocardial blood flow ↓ Intrinsic cholesterol biosynthesis in the liver Compensatory mechanisms ↓ Isoprenoid production (electron & proton carriers) ↓ Isoprenoid intermediates ↓Inflammatory signaling proteins ↓Proliferation of macrophages ↓ Inflammation Upregulation of hepatic LDL receptors ↑ Hepatic LDL uptake ↓ Serum low-density lipoprotein (LDL) ↑ Apolipoprotein A1 (component of HDL) production ↑ High-density lipoprotein (HDL) Carries serum cholesterol back to liver ↓ Serum apolipoprotein B levels (acts as a tag for LDL, facilitating uptake by LDL receptors) ↑ Oxidative Stress Hepatocyte damage & inflammation ↑ Serum liver enzymes Hepatotoxicity ↓ ATP ↓ Serum cholesterol ↓ Muscle membrane stability Rhabdomyolysis (muscle breakdown) Author: Rupali Manek, Andrew Wu, Rafael Sanguinetti, Luiza Radu Reviewers: Joshua Dian, Laura Byford-Richardson, Alexander Ah-Chi Leung* * MD at time of publication Stabilization of plaques ↓ Atherosclerosis (plaque build-up in arteries) ↓ Coronary events & mortality Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Physiological outcome Published Jan 9, 2017; updated Nov 22, 2024 on www.thecalgaryguide.com

Fibromylagia

Fibromyalgia: Pathogenesis and clinical findings Authors: Modhawi Alqanaie Reviewers: Mao Ding Kevin Zhan Luiza Radu Gary Morris* *MD at time of publication ↑ Substance P (a potent pain mediator neuropeptide) in cerebrospinal fluid ↑ Glutamate (pro- nociceptive excitatory neurotransmitter) ↑ Nerve growth factor ↑ Propagation of pain signals ↓ Norepinephrine ↓ Serotonin Hyperactive nociceptors (nerve cell endings for pain sensation) ↓ Polarization of afferent sensory neurons ↓ Suppression of pain transmission at the nociceptive spinal cord Underactive inhibitory pathway Central sensitization (amplifying neural signal to perceive pain from a non-painful stimuli) Fibromyalgia Syndrome Hypersensitivity to pressure (tender points) Muscle spasm (involuntary contraction of a muscle) Allodynia (pain to a non-painful stimulus) Nocturnal awakening Sleep disturbance Chronic stress and tension Depression Prolonged cortisol elevation Diffuse hyperalgesia (increased pain to pressure) Persistent activation of peripheral pain receptors Ongoing tissue injury Chronic pain Possible metabolic changes Mitochondrial dysfunction Oxidative stress (imbalance between free radicals and antioxidants) Muscle fiber dysfunction Reduced muscle oxidative capacity Muscle fatigue Low energy Systemic production of eotaxin chemokines and IL-10 cytokines Disturbances in neural networks ↓ Attentional capacity Mood fluctuations ↑ Irritability Social isolation Dysesthesia (abnormal feelings of itching, stinging, tingling, or general tightening) Muscle and joint stiffness Changes in frontal cortex Deficits in cognitive functions Memory issues Hippocampal atrophy Brain fog Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 22, 2024 on www.thecalgaryguide.com

Hypocalcemia Pathogenesis

Hypocalcemia: Pathogenesis Malnutrition ↓ Oral intake Acquired (e.g. neck surgery) Autoimmune (e.g., autoimmune polyglandular syndrome) Infiltrative (e.g., hemochro matosis, Wilson’s disease) Congenital (e.g., DiGeorge) Hypomagnesemia Magnesium is needed to produce PTH Malabsorption ↓ Small bowel surface area ↓ Absorption of 25-OH Vitamin D (calcidiol) ↓ Conversion of calcidiol to 1-25 (OH)2 Vitamin D (calcitriol) by 1-α- hydroxylase ↓ Calcitriol (impacts GI absorption of calcium) Chronic Renal Failure ↓ Renal parenchymal mass (site of 1-α- hydroxylase production) Vitamin D Dependent Type 1 Rickets Mutation in the gene that encodes 1-α- hydroxylase ↓ Sun exposure ↓ 1-α-hydroxylase Pancreatitis Destruction or atrophy of parathyroid gland ↓ Parathyroid hormone (PTH) Calcitriol resistance (e.g., Vitamin D Type 2 rickets) Inflammation of pancreas ↑ Release of lipase enzyme into serum ↑ Breakdown of fat by lipase ↑ Free fatty acids in serum ↑ Ca2+ binding to negatively charged tail of free fatty acids ↑ Parathyroid hormone (PTH) PTH resistance Genetic mutation causes body to not respond to PTH ↓ Renal calcium reabsorption ↑ Calcium excretion ↓ Osteoclast activity ↓ Calcium release from bone ↓ Action of PTH on intestinal cells ↓ Absorption of calcium in the small intestine ↑ Serum phosphate (PO4) (e.g. tumor lysis, rhabdomyolysis) ↑ Ca2+ binding to negatively charged PO4 ↑ Serum pH ↓ H+ in serum binding to proteins ↑ Ca2+ binding to proteins Calcium sequestration ↓ Absorption of calcium in the small intestine Hypocalcemia Author: Breanna Fang Reviewers: Gurreet Bhandal, Raafi Ali, Luiza Radu Samuel Fineblit* * MD at time of publication Serum calcium levels below 2.10mmol/L Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 22, 2024 on www.thecalgaryguide.com

Acute Compartment Syndrome

Acute Compartment Syndrome: Pathogenesis and clinical findings Fracture (especially Authors: Nojan Mannani, Chris Sveen Reviewers: Michelle J. Chen, Spencer Montgomery, Yan Yu, Dr. Andrew Reed*, Dr. Gerhard Kiefer* * MD at time of publication of long bones) Penetrating injuries Crush injuries High volume IV transfusion or punctured vein Reperfusion syndrome Venomous animal bites Severe burns Burn eschar (rigid dead tissue) Prolonged limb compression Injury resulting in swelling Bleeding into muscle compartment ↑ Pressure compresses veins (thin walls make them easily compressible), preventing venous outflow from muscle compartment Buildup of venous blood in capillaries & venules further ↑ pressure in compartment Arterioles collapse as they are unable to withstand higher pressure ↑ Pressure in capillaries prevents/slows blood flow from arterioles to capillaries, reducing tissue perfusion ↓ Oxygen delivery to muscles Muscle & nerve necrosis Ability for somatic sensory fibres to transmit information to the brain is impaired Fluids intended for IV space leak into surrounding tissues Tissue damage triggers release of inflammatory mediators increasing vascular permeability Accumulation of fluids ↑ pressure within a muscle compartment Stimulation of nociceptors in muscle Pain out of proportion to injury Edema in muscle compartment Muscle feels hard on palpation Swelling Reduced arterial pulses (late finding) Pallor Muscle feels cold on palpation Muscle weakness Paresthesia Sensory deficits Rigid eschar prevents compartment expansion Ischemic muscle releases inflammatory mediators Constrictive bandage/cast applied before swelling subsides External compression prevents muscle compartment from expanding to accommodate intra-compartment swelling Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 4, 2014, Updated Nov 19, 2024 on www.thecalgaryguide.com

Pelvic Ring Fractures

Pelvic Ring Fractures: Classification, Mechanisms, Clinical Features and Complications Anteroposterior force on pelvic ring (e.g. motorcycle accident) Diastasis (separation) of pubic symphysis Anterior Posterior Compression (APC) Axial shear force (e.g. fall) Superior or inferior displacement of hemipelvis Vertical Shear (VS) Grade 3: APC 2 with additional disruption of posterior sacroiliac ligaments Lateral compression force (e.g. automobile collides with pedestrian) Internal rotation of hemipelvis Lateral Compression (LC) Authors: Meaghan Mackenzie Stephanie de Waal Nojan Mannani Reviewers: Annalise Abbott Usama Malik Sunawer Aujla Mankirat Bhogal Michelle J. Chen Dr. Prism Schneider* Dr. Alyssa Federico* * MD at time of publication Grade 1: pubic symphysis diastasis < 2.5 cm Grade 2: pubic symphysis diastasis >2.5 cm, anterior sacroiliac diastasis, disruption of sacrospinous and sacrotuberous ligaments Grade 1: pubic rami fracture with ipsilateral sacral compression fracture Grade 2: pubic rami fracture with ipsilateral sacral and ilium fractures Grade 3: ipsilateral LC 1 or 2 injury and contralateral APC injury (windswept pelvis) Young-Burgess Classification of Pelvic Ring Fractures (Combination of any of the three classes can also occur) Blood vessels surrounding the fracture site rupture during injury Pelvic has capacity of hold large volume of blood Supporting ligaments are stretched or ruptured Damage to adjacent urogenital structures Gross hematuria Posterior urethral tear or bladder rupture Scrotal, labial or perineal hematoma Displacement of hemipelvis Limb-length discrepancy Damage to adjacent neurological structures Flank hematoma Potential hemorrhagic shock Loss of rectal tone or perirectal sensation L5 or S1 dermatomal paresthesia Chronic instability Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 16, 2017; updated Nov 22, 2024 on www.thecalgaryguide.com

Vaccine-Mediated Immunity General Physiology

Vaccine-Mediated Immunity: General Physiology Pathogen-derived antigen Adjuvants boost the immune response Preservatives inhibit microbial growth Stabilizers prevent vaccine degradation Vaccine components are formulated and administered to patient Antigen Presenting Cells (APCs) phagocytose and process antigen Adjuvants in vaccines activate local immune response ↑ Production of pro-inflammatory signals (chemokines & cytokines) Chemokines & cytokines act as signaling molecules that attract APCs to draining lymph nodes APCs present antigen on MHC I molecules to CD8+ T cells APCs present antigen on major histocompatibility complex II (MHC-II) molecules to naïve CD4+ T helper cells Recognition of antigenic material activates naïve CD4+ T helper cells A subset of naïve B cells differentiate into short-lived plasma cells Plasma cells produce antibodies Antibodies cover the pathogen’s surface (neutralization) Antibody-coated pathogens are phagocytosed by macrophages/neutrophils (opsonization) ↑ Pathogen-specific antibody titers CD8+ T cells multiply to form an antigen- specific cytotoxic T cell population (clonal expansion) ↑ Lymphocyte counts Authors: Tanis Orsetti Reviewers: Allesha Eman Michelle J. Chen Dr. Russell Sterrett* Prevention of specific pathogen from causing severe disease upon subsequent exposure * MD at time of publication Some activated CD4+ T helper cells stimulate naïve B cells A subset of activated CD4+ T helper cells differentiate into memory CD4+ T cells A subset of CD8+ T cells differentiate into memory CD8+ T cells A subset of naïve B cells differentiate into memory B cells Memory B cells circulate the body and monitor for secondary exposure to the pathogen Memory T cells circulate the body and monitor for secondary exposure Memory T cells are activated upon secondary exposure to the pathogen Activated memory T cells differentiate into effector T cells Memory B cells differentiate into plasma cells when there is a secondary exposure to the pathogen Effector CD4+ T helper cells stimulate B lymphocytes CD8+ cytotoxic T cells induce apoptosis of infected cells Vaccine-Mediated Immunity Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 23, 2024 on www.thecalgaryguide.com

Anesthetic Considerations Laparoscopic Abdominal Surgery

Anesthetic Considerations: Laparoscopic abdominal surgery – healthy adult Authors: Madison Amyotte, Tracey Rice, Priyanka Grewal, Luiza Radu Reviewers: Jasleen Brar, Leyla Baghirzada* * MD at time of publication Hypercarbia (↑ CO2 in bloodstream) Cardiovascular Effects Positional Pneumoperitoneum (introduction of gas eg. CO2 in the abdominal cavity for easier access to organs during laparoscopy) Systemic vasodilation ↓ Systemic vascular resistance ↑ Systemic blood flow & oxygen delivery Respiratory acidosis Acidosis leads to ↓ cardiac contractility Arrhythmia Cardiac arrest Reverse Trendelenburg positioning of patient (patient supine with head of OR table ↑) ↑ Venous pooling (accumulation of blood in veins) ↓ Venous return (blood returning to the heart) ↓ Preload ↓ Blood pressure Trendelenburg positioning of patient (patient supine with head of OR table ↓) Low fluid status Compression of large abdominal vessels ↓ Preload ↓ Blood pressure High fluid status ↑ Venous return (blood returning to the heart) ↑ Preload (ventricle filling pressure prior to contraction) ↑ Blood pressure ↑ Venous return ↑ Preload ↑ Blood pressure Vagus nerve stimulation Bradyarrhythmia (slow and irregular heart rate) Asystole (absence of electrical activity and contractility of the heart) ↑ Cerebral blood flow Cephalad (upward) displacement of diaphragm & compression of thoracic cavity ↓ Functional residual capacity (volume remaining after expiration) & pulmonary compliance ↓ Tidal volumes (air inhaled per breath) Atelectasis (partial or full collapse of lung) V/Q mismatch (lung ventilation & perfusion imbalance) Respiratory Effects ↑ Intraocular pressure (e.g. papilledema) Ophthalmic compromise (visual system impairment) ↑ Intracranial pressure Compression of renal vessels à↓ Renal blood flow Release of catecholamines (norepinephrine & dopamine) Renin angiotensin aldosterone system activation Aldosterone & vasopressin release ↑ Blood pressure Renal System Effects Neurologic Effects Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 25, 2024on www.thecalgaryguide.com

Chronic Inflammatory Demyelinating Polyneuropathy

Chronic Inflammatory Demyelinating Polyneuropathy: Pathogenesis & clinical findings Unknown trigger (e.g., surgery, trauma, autoimmune disorder, environmental factors) Systemic illness (e.g., hepatitis B, Hepatitis C, HIV, thyroid Disease, nephrotic syndrome, irritable bowel syndrome) Authors: Andrea Soumbasis Reviewers: Braxton Phillips Shahab Marzoughi Sina Marzoughi* * MD at time of publication Autoimmune response initiation Lumbar Puncture: Cytoalbuminologic Dissociation CSF protein count elevated with normal cell count Cell-mediated response: Putative antigen (unidentified immune target) presents to auto-reactive T cells Activated T cells secrete inflammatory mediators (matrix metalloproteinases) Inflammatory response ↑ peripheral nerve permeability & T cells cross blood-nerve barrier Humoral Response: Immunoglobulin & complement deposits on compact myelin & nodal regions Autoantibodies target unknown epitope (antigen molecule recognized by antibody) on outer surface of Schwann cells IgG4 antibodies target axoglial junction (Contactin-1, Neurofascin 155) that maintain Node of Ranvier of myelinated axons ↑ Permeability of blood- nerve barrier allows large proteins to leak into CSF CD8+ T cells, CD4+ T cells & macrophages infiltrate peripheral nerves Macrophages form clusters around endoneurium, release proinflammatory cytokines & strip away myelin via phagocytosis Abnormal expression & distribution of Contactin-1 & Neurofascin 155 antibodies along axoglial junction Disrupted ion channel segregation & paranodal structure ↓ Saltatory conduction Nodopathy & Paranodopothy: Neurofascin 155 – Distal sensorimotor ataxia Contactin-1 – Sensorimotor ataxia Caspr-1 – Neuropathic pain & nephrotic syndrome Onion bulb formation: Nerve biopsy showing concentric, circular layers of cells surrounding the axon Segmental demyelination & remyelination of peripheral nerves ↑ Demyelination Chronic Inflammatory Demyelinating Polyneuropathy Progressive weakness & sensory loss over a period of greater than 8 weeks due to autoimmune dysfunction Peripheral nerve degeneration & conduction velocity Nerve Conduction Study: Partial nerve conduction block, conduction velocity slowing, prolonged distal motor latencies, delay or disappearance of CMAP (compound muscle action potential) Lesions of larger myelinated fibers in the dorsal columns for vibration & position sense Lesions of peripheral motor nerves in non-length dependent pattern (does not only affect longest nerves first) Motor Deficits ↓ Sensory input and/or ↓ motor output Abnormal Reflexes Globally ↓ reflexes Lesions affecting sympathetic & parasympathetic nerve fibers Autonomic Deficits Bladder & bowel dysfunction, heart rate irregularities, blood pressure fluctuation Sensory Deficits Gait ataxia Proximal weakness (muscles closer to the trunk or center of the body): Difficulty climbing stairs, rising from seated position, lifting objects overhead, frequent falls Distal weakness (muscles farther from the trunk or the extremities): Tripping due to foot drop, difficulty with fine motor tasks ↓ Vibration & proprioception Paraesthesias (e.g., tingling, numbness) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 29, 2024 on www.thecalgaryguide.com

Acquired Inguinal Hernias

Acquired Inguinal Hernias: Indirect & Direct Abdominal fluid or mass Constipation Pregnancy Chronic cough ↑ intraabdominal pressure Stretching of musculoaponeurotic structures & weakening of the abdominal fibromuscular tissue Direct Inguinal Hernia Authors: Adam Bubelenyi Jeffery Lindgren Peter Bishay Reviewers: Sophia Khan Shahab Marzoughi Brandon Hisey Vadim Iablokov Usama Malik Dr. Sylvain Coderre* * MD at time of publication Developmental Ehlers-Danlos & Marfan syndrome (genetic disorders characterized by impaired connective tissue development) Collagen deficiency ↑ Protease activity Smoking Aging Malnutrition Collagen breakdown Long-term glucocorticoid use Fibroblast (cells which produce collagen) suppression causing ↓ collagen production Thinning of skin & soft tissues Incomplete obliteration of the processus vaginalis (peritoneal tunnel through which the testes migrate toward the scrotum during embryological development) Failed closure leaves an opening for organs to herniate through Intestinal loops entrapped within herniation Weakening of connective tissues Indirect Inguinal Hernia Protrusion of abdominal and/or pelvic contents through deep inguinal ring Protrusion of abdominal and/or pelvic contents through the Hesselbach triangle (anatomic area defined by the rectus abdominis medially, inferior epigastric vessels laterally, and the inguinal ligament inferiorly) Herniated contents become entrapped Inguinal mass +/- pain that is worse with straining Abdominal distension & tenderness Rhythmic contractions of the intestine attempting to push contents past the blockage site Colicky pain Incarceration (Surgical Emergency) Reduced vascular supply to entrapped contents Strangulation (Surgical Emergency) Constriction & ischemia of hernial contents Gangrenous skin changes (swelling, blue/purple colour, ↑ temperature, ulceration, ↓ sensation) Inflammation of the herniated contents to larger than the hernial opening Irreducible hernia (a hernia which cannot be manually reduced) Bowel Obstruction (Surgical Emergency) Obstruction of intestinal lumen impairs passage of intestinal contents Stimulation of stretch receptors in the bowel wall Nausea +/- vomiting Herniated tissue undergoes necrosis (irreversible cell death), perforating the gastrointestinal wall Obstipation (complete inability to pass stool or gas) Bowel perforation (surgical emergency) Leakage of gastrointestinal contents allows bacteria to infect the abdominal cavity Sudden ↑ pain Abscess (localized collection of pus) Peritonitis (inflammation of the peritoneum) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jun 3, 2018; updated dec 29, 2024 on www.thecalgaryguide.com

Polycystic Ovarian Syndrome

Polycystic Ovarian Syndrome (PCOS): Pathogenesis and clinical findings Genetic Susceptibility: ↑ Expression of LH receptors in granulosa cells, and anterior pituitary ↑ production of luteinizing hormone (LH) ↑ Serum LH compared to FSHà higher levels of LH increasingly activate thecal cells Excess nutrients (from overeating and sedentary behavior) is stored as visceral fat ↑ Central adiposity (accumulation of fat around abdominal area) Adipose tissue ↑ secretion of estrogen, inflammatory mediators, adipokines, free fatty acids ̄ Hepatic synthesis of sex hormone-binding globulin Acne Hair loss on scalp, and less commonly eyebrows and eyelashes (alopecia) Excessive hair growth around mouth, chin, chest, abdomen, upper arms, thighs, and upper & lower back (hirsutism) Metabolic syndrome develops, including ↑ insulin resistance, obesity, dyslipidemia, liver disease, & cardiovascular disease Theca cells in ovaries ↑ androgen secretion ↑ Serum androgens State of hyperandrogenism Androgen and estrogen levels are elevated too early in menstrual cycle (estrogen has negative feedback inhibition on anterior pituitary hormone production) Early suppression of FSH Limited proliferation of follicles Relative reduction in secretion of progesterone Imbalance between progesterone and estrogen Unpredictable ovulation ↑ Circulating insulin- like growth factor Growth factor promote keratinocyte and dermal fibroblast proliferation Velvety, darkening of the skin fold areas such as back of neck, armpit area, groin (acanthosis nigricans) ↑ Risk of type 2 diabetes mellitus Since granulosa cells normally convert testosterone to estrogen, ̄ granulosa cell function means more testosterone exists Since follicle stimulating hormone (FSH) activates granulosa cells, ̄ FSH means ̄ granulosa cell function. Follicles arrested in development accumulate fluid, becoming cysts Polycystic ovaries visible on ultrasound Infertility Unpredictable uterine bleeding ↑ Risk of endometrial hyperplasia & endometrial cancer Irregular menstruation (amenorrhea/oligomenorrhea) Authors: Lauren Standerwick Claire Song Reviewers: Mackenzie Grisdale Amy Fowler Christina Schweitzer Michelle J. Chen Dr. Yan Yu* Dr. Bernard Corenblum* Dr. Sylvie Bowden* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 20, 2017; updated Dec 15, 2024 on www.thecalgaryguide.com

Barretts Esophagus

Barrett’s Esophagus: Pathogenesis, clinical findings and complications Gastroesophageal Reflux Disease (GERD) Authors: Sophia Khan Reviewers: Claire Song Shahab Marzoughi Sylvain Coderre* * MD at time of publication Reflux of stomach acid, bile salts + digestive enzymes through lower esophageal sphincter (located at junction between esophagus and stomach) Chronic reflux exposure to squamous epithelium (cells lining distal esophagus) Squamous epithelial cells release inflammatory cytokines: interleukin-8 and interleukin-1beta Inflammation of squamous epithelium Adaptive changes of squamous epithelium to prevent damage by acidic reflux Migration of stem cells in gastric cardia (proximal region of the stomach) into distal esophagus Replacement of esophageal squamous epithelium by gastric columnar epithelium Conversion (metaplasia) of normal esophageal squamous epithelium into abnormal gastric columnar epithelium with interspersed goblet cells Z line (the squamocolumnar junction between the esophagus and stomach) is irregular and displaced proximally on esophagus on endoscopy Heartburn (retrosternal burning sensation from stomach reflux) Regurgitation (involuntary expulsion of stomach content back into esophagus) Development of goblet cells (intestinal mucus-producing cells) within esophageal epithelium Abnormal presence of goblet cells on histology of distal esophagus Abnormal presence of columnar epithelial cells on histology of distal esophagus ↑ Atypical proliferation & ↓ apoptosis of Barrett’s epithelial cells Dysplasia (disordered growth of cells with the potential to develop into cancer) of Barrett’s epithelium Esophageal adenocarcinoma Improper division of nuclear chromatin (packaged DNA) Cellular nuclei increase in size due to retained chromatin from improper division Excess chromatin absorbs more stain during histology Double- stranded DNA breaks Nuclear enlargement on histology Continued acidic reflux causes oxidative DNA damage Hyperchromatic (darkly stained) nuclei on histology Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 15, 2024 on www.thecalgaryguide.com

Ptosis

Ptosis: Pathogenesis and Clinical Findings Neurogenic causes of low Mechanical causes of low eyelid position Mass lesion of the upper eyelid (Chalazion, hemangioma, malignancy, etc.) Gravitational effect from excess eyelid weight Traumatic causes of low eyelid position Direct injury limits function of LPS or conduction of generated force to the tarsal plate Laceration of the LPS limiting its function or transection of the levator aponeurosis Congenital causes of eyelid drooping Fibrofatty replacement of the LPS muscle at birth Reduced levator function eyelid position Insult to the oculomotor nerve (CNIII) (e.g., compressive, microvascular, demyelinating) CNIII innervates levator palpebrae superioris, the main muscle responsible for upper eyelid elevation Insult to the sympathetic innervation (e.g., Horner’s syndrome) Ocular sympathetic innervate the Muller muscle, which provides approximately 2mm of the upper eyelid’s height Neuromuscular or myogenic causes of low eyelid position (e.g., myasthenia gravis) LPS muscle myopathy or defect at its neuromuscular junction that limits the elevation of the eyelid Aponeurotic causes of low eyelid position Involutional change (disinsertion) of the levator aponeurosis which connects the LPS to the tarsal plate Ptosis (also called blepharoptosis) Abnormally low position of the upper eyelid ↓ distance between the central corneal light reflex (as produced by an examiner’s penlight) and the level of the center of the upper-eyelid margin ↓ Margin-Reflex Distance (Normal: 4-6mm) Obstruction of the pupil/visual axis Decreased or occluded superior visual field ↓ distance between the upper eyelid margin and the lower eyelid margin ↓ Palpebral Fissure Height (Normal: 10-12mm) Flattening of the peripheral cornea by eyelid pressure Induced with-the-rule astigmatism Authors: Mina Mina Reviewers: Aicha Djaoutkhanova Shahab Marzoughi Lucy Yang Mao Ding William Trask* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 29, 2024 on www.thecalgaryguide.com

Malignant Esophagitis

Malignant Esophagitis: Pathogenesis and Clinical Features Authors: Hamza Kamran Reviewers: Claire Song Shahab Marzoughi Sylvain Coderre* * MD at time of publication Barrett’s Esophagus (pre-malignant condition) Chronic gastric reflux (acidic partially- digested stomach contents) Conversion of normal esophageal squamous epithelium to metaplastic columnar epithelium Gastroesophageal Reflux Disease Recurrent regurgitation of gastric content Chronic Irritation & damage to the esophageal mucosa Lesions and plaques develop in distal esophagus Malignancy develops in the mucus-producing glandular cells in the lower esophagus Smoking Carcinogenic tobacco condensate is swallowed Irritation of the the esophageal lining Heavy alcohol consumption Mutation in alcohol- dehydrogenase, which breaks down ethanol ↓ Alcohol breakdown Irritation of the esophageal mucosa & lining ↑ Inflammation of the squamous epithelium located in the upper & middle esophagus Achalasia (Esophageal smooth muscle motility disorder) Food stasis in the esophagus ↑ Bacteria production Lactic acid production & fermentation damages esophageal mucosa Chronic inflammation in the esophageal epithelium Malignant cells invade the aorta & tracheobronchial region ↑ Spread & growth of cancer in other organ systems Metastatic invasion into the aorta, lungs, liver, bones, & kidneys through the lymph nodes ↑ Spread & growth of cancer in other organ systems ↑ Metabolic demand Unintentional weight loss Generalized chest pain Hoarseness Cough Esophageal adenocarcinoma (malignancy of the glandular cells of the esophagus) Esophageal squamous cell carcinoma (malignancy of the squamous epithelium of the esophagus) ↑ Metabolic demand ↑ Weight loss Chronic GI bleeding Iron-deficiency anemia ↑ Ulceration Exposure to stomach acid ↑ Tumor- induced inflammation ↑ Fibrosis Irregular stricture of the upper & middle esophagus Dysphagia Esophageal wall narrowing Abnormal reflexes of GI tract Dysphagia Indigestion Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 15, 2024 on www.thecalgaryguide.com

Pulsus Paradoxus

Pulsus Paradoxus: Pathogenesis and Clinical Findings Inspiration: Diaphragm and intercostal muscles contract Author: Yan Yu, Victória Silva, Layla Al-Yasiri Reviewers: Sean Spence, Laura Craig, Juliette Hall, Raafi Ali, George Tadros. Shahab Marzoughi Nanette Alvarez* * MD at time of publication Vascular pathology (rare) Thoracic cavity expands Lungs expand and intrathoracic pressure ↓ Physiologic: ↑ Venous return to right (R) heart ↑ R heart preload (volume of blood inside the ventricle right before it contracts) ↑ Blood pools in the right side of the heart Obstructive lung diseases (e.g., COPD**, asthma**) Hyperinflated lungs ↑ Stretching of pulmonary vessels at rest On inspiration, ↑↑ stretching of pulmonary vessels ↑↑ Blood pools within pulmonary vasculature ↓↓ Flow to L heart Pathologic: Constrictive pathologies (e.g., cardiac tamponade**, constrictive pericarditis**) Decreased pericardial compliance Constriction of ventricles On inspiration, ↑ venous return to R heart (normal) R ventricle unable to fully expand due to ↓ compliance Septum bows into L ventricle L ventricle unable to fully expand ↓↓ Filling of L heart ↓↓ L ventricular end diastolic volume ↓↓ L heart stroke volume ↓↓ Cardiac output Pulsus Paradoxus Exaggerated ↓in systolic BP on inspiration (>10mmHg) Air flows into the lungs Pulmonary vessels are physically stretched/pulled ↑ Blood pools in pulmonary vessels ↓ Return of blood to left (L) heart ↓ L heart preload ↓ L heart stroke volume ↓ Cardiac output Obstruction of superior or inferior vena cava (e.g., clot) ↓↓ Venous return to R heart at rest ↓↓ Right heart filling ↓↓ Blood flow to pulmonary arteries Pulmonary embolism** Clot occludes pulmonary arteries/ arterioles ↓↓ Flow to pulmonary veins At rest, ↓↓ flow to L heart On inspiration, ↓↓↓ flow to L heart ↓ Systolic blood pressure (BP) of < 10mmHg on inspiration BP = cardiac output x systemic vascular resistance **See corresponding Calgary Guide slides Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 21, 2013; updated Dec 3, 2024 on www.thecalgaryguide.com

Constipation in Children

Constipation in Children: Pathogenesis and clinical findings Neonate / Infant (≤1 years old) Older Child (>1 years old) Dietary (e.g., lack of fluids / fiber) Mechanical (e.g.,. intestinal Atresia, anal atresia) Congenital malformation (narrowing, absence, or malrotation) of structure of intestine / anus Interrupted flow of bowel contents Genetic (e.g., cystic Fibrosis) Mucous blocks pancreatic duct Inability of pancreatic enzymes to reach small intestine ↓ Digestion after a meal Large, thickened stool Neurologic (e.g., Hirschsprung's disease) Congenital disruption of the migration of neural crest cells to the distal colon Affected segment of the colon fails to relax Progressive secondary dilation of the healthy proximal colon Systemic (e.g., hypothyroidism) Thyroid hormone deficiency Reduction in the stimulation of gut tone & contractility by thyroid hormones ↓ Peristalsis (intestinal contractions) of the bowel Dietary (e.g., lack of fluids/ fiber) Mucosal (e.g., celiac disease) Inappropriate immune response against gluten Intestinal mucosal injury Malabsorpti on of water and other nutrients Functional (e.g., pain) Prolonged stool retention in bowel ↑ Time in bowel causing over- absorption of water from stool into the large intestine Mechanical (e.g., bowel obstruction) Mechanical obstruction in the intestines Interrupted flow of bowel contents Intestinal obstruction Neurologic (e.g., neglect, physical abuse) Disturbance in brain-intestine axis Mechanisms not fully understood Visceral hyper- sensitivity (increased pain sensation) Withholding behaviour Lack of soluble fiber ↓ Attractive forces between water & stool Prevention of secretion of water into stool Lack of insoluble fiber ↓ Stool bulk and laxation ↓ Secretion of water & mucous into stool Lack of soluble fiber ↓ Attractive forces between water & stool Prevention of secretion of water into stool Lack of insoluble fiber ↓ Stool bulk and laxation ↓ Secretion of water & mucous into stool Formation of dry & hard stool Formation of dry & hard stool Difficulty passing stool Difficulty passing stool Authors: Jennifer Wytsma Reviewers: Sophia Khan, Shahab Marzoughi, Sylvain Coderre* * MD at time of publication Intestinal obstruction Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 15, 2024 on www.thecalgaryguide.com

Avascular Necrosis of the Scaphoid

Osteonecrosis of the Scaphoid (Avascular Necrosis): Pathogenesis and clinical findings The radial artery provides the primary blood supply to the scaphoid bone Blood flows to the distal end of the scaphoid and travels “retrograde” back along the bone towards the proximal end Poor blood supply may lead to incomplete healing of the fracture High risk of progressing to a non-union (non- healing) fracture Further ↑ risk of developing osteonecrosis (previously known as avascular necrosis) Trauma or injury to the wrist or hand Scaphoid fracture, most commonly at the thin middle third of the bone, known as the waist Retrograde blood supply to the proximal part of the scaphoid becomes disrupted Poor blood supply to the proximal scaphoid The body breaks down and absorbs necrotic bone tissue, commonly at the proximal part of the scaphoid with poor blood supply Structural integrity of the scaphoid bone weakens The scaphoid becomes more prone to collapse during normal wrist movement and the natural alignment of the carpal bones may become disrupted Prolonged disruption in blood and oxygen supply Ischemia of bone tissue Bone tissue necrosis Osteonecrosis (AVN) of the Scaphoid Disease resulting in death of bone tissue due to insufficient blood supply** Authors: Sydney Guderyan Reviewers: Mankirat Bhogal Michelle J. Chen Dr. Gerhard Kiefer * MD at time of publication Abnormal stress on the radiocarpal and intercarpal joints Progressive degenerative changes Proximal row collapse (proximal row of carpal bones destabilize) Imaging shows bone collapse, sclerosis, or cystic changes Tenderness at the anatomical snuffbox Pain & swelling on the radial side of the wrist ↓ Range of motion at the wrist ↓ Grip strength & wrist function Stiffness ** See corresponding Calgary Guide slide “Avascular Necrosis: Pathogenesis and Clinical Findings” End-stage osteoarthritis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 30, 2024 on www.thecalgaryguide.com

Ankle Fracture

Ankle fracture: Pathogenesis and clinical findings High mechanical force to ankle Risk factors Age Post-menopause ↓ Osteoblast activity Twisting force (e.g. sports injury) Crushing force (e.g. limb Loading force entrapment beneath heavy object) (e.g. fall) Force exceeds mechanical strength of bone Ankle eversion or inversion Osteoporosis Compromised bone scaffolding & repair impairs the structural integrity of bone. Force required for fracture is lowered Ankle Fracture (Fracture of the talus and/or the distal 6 cm of the tibia and/or fibula) Fractured bone is displaced through the dermal layers Open Fracture Compromised dermal layers create an opportunity for pathogens to enter the wound site Infection Multiple malleoli are fractured within the ring of the ankle Lack of ligamentous & bone support makes ankle joint unstable Displacement of bone from fracture site Misalignment of bone segments prevents regeneration & union Malunion of unreduced fracture Ligamentous injury occurs concurrently from excessive tensile force Fractured bone disrupts surrounding vasculature Hyaline cartilage of the articulating surface is damaged Trauma induces synovitis, chondrocyte apoptosis, & necrosis Fractured bone disrupts surrounding peripheral nerves Numbness Localized Pain Pain is induced when the patient attempts to weight bear Inability to weight bear Authors: Ethan Smith Reviewers: Nojan Mannani Michelle J. Chen Dr. Gerhard Kiefer* * MD at time of publication Platelets are exposed to the extravascular environment, thereby releasing platelet derived factors & complement factors Plasma coagulation cascade is activated Chondrocyte dysfunction in proliferation Reduced synovial functioning ↑Vascular permeability from inflammatory cytokines Protective hematoma forms in the joint space Hyaline cartilage loss Lost cartilage over time degrades proper articulation & causes joint narrowing, osteophytes, subchondral sclerosis Post traumatic osteoarthritis Edema Fluid in the joint space changes position of bony articulations Bruising Restricted range of movement Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 30, 2024 on www.thecalgaryguide.com

Ewing Sarcoma

Ewing Sarcoma: Pathogenesis and clinical findings Demographic risk factors 85% of cases have de novo translocation mutation of EWSR1 gene on chromosome 22 to FLI1 gene on chromosome 11 Age < 30 White ethnicity Male to female 1.5-3:1 predominance EWSR1-FLI1 fusion product functions as an oncogene Tumorigenesis Ewing Sarcoma Translocation t(11;22)(q24;q12) detectable with a genetic molecular study called FISH Authors: Curtis Ostertag Nojan Mannani Reviewers: Mankirat Bhogal Michelle J. Chen Dr. Michael Monument* * MD at time of publication Well-defined histopathology Biopsy: sheets of monotonous small round blue cells with increased nuclear to cytoplasmic ratio Immunohistochemistry staining positive for CD99 (80% of cases) Diagnostic confirmation by histopathology Diagnostic confirmation by molecular genetics X-Ray findings: moth-eaten lesions, Codman triangle of elevated periosteum, or onion- skin periosteal reaction MRI findings: solid mass in bone, low T1 intensity, high T2, gadolinium enhancement, surrounding edema & soft tissue mass Malignant small round cell tumor; the second most common malignant bone tumor in adolescents and young adults. Most common in the axial skeleton (pelvis, shoulder girdle, and ribs) and diaphysis of long bones. Rapid cell turnover Tumor expansion in bone, disrupting normal tissue Possible metastasis to surrounding soft tissue Possible metastasis to lung/pleura Nodule/malignant pleural effusion Absent breath sounds, pleural signs, crackles/rales Possible metastasis to bone marrow Replacement of normal hematopoietic tissue, including megakaryocytes (source of platelets) Thrombocytopenia Petechiae/purpura Peritumoral edema Swelling Stiffness Invasion of cancer cells to distant tissues via bloodstream Tumor expands toward skin surface Palpable lump Tumor secretes ↑ vascular endothelial growth factor (VEGF) ↑ Generation of immature blood vessels which have ↑ permeability ↑ Expression of inflammatory cytokines (i.e. IL-6) Massive metabolic demand from cancer cells Energy starved state Systemic constitutional symptoms including fevers, chills, weight loss, night sweats, fatigue ↓ Distractions at night brings ↑ attention to pain Adrenal glands naturally release ↓ cortisol throughout the day with the lowest levels at night. Lack of anti- inflammatory properties from cortisol ↑ pain Potential gravity- related ↑ in tumor- related pressure & ↑ in active bone remodeling Tumour growth stretches periosteum (connective tissue around bone) causing osteolysis, inflammation, nerve infiltration, edema, structural weakening (microfractures) Pain that worsens at night Limp Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 30, 2024 on www.thecalgaryguide.com