SEARCH RESULTS FOR: 2025

Salter Harris Fracture

Salter-Harris Fracture: Mechanisms, Classifications, and Findings Authors: Annmarie Lang-Hodge Reviewers: Mankirat Bhogal Michelle J. Chen Gerhard Kiefer* * MD at time of publication Longitudinal compressive force applied directly on physis Damage to hypertrophic zone, germinal matrix, & vascular supply of the physis Type V (<1%): Crushing of physeal cells & premature closure of physis No visible initial finding on imaging Incomplete calcification of cartilage to bone in the zone of provisional calcification of the physis (growth plate) The zone of provisional calcification is weak and connecting ligaments are stronger than the physis in pre-pubertal children Trauma in a pediatric patient Damage occurs to the physis (growth plate) Salter Harris Fracture Rotational, shear, +/- longitudinal forces applied to the physis Intra-articular damage Longitudinal or shear force applied to the physis Epiphysis splits from the metaphysis Type I (5%): Complete or incomplete fracture through the physis only Angular & longitudinal force exerted on the physis Type II (75%): Partial fracture through physis continuing into the metaphysis Creation of a Thurston- Holland fragment (metaphyseal fragment that is still connected to the epiphysis) Thurston-Holland fragment is visible & palpable Type III (10%): Fracture through the physis extending into the epiphysis Palpable step- off over the epiphysis only Type IV (10%): Fracture involving the epiphysis, physis, & metaphysis Swelling around joint Focal tenderness over the physis Palpable step-off over the epiphysis & metaphysis Risk of transphyseal vascularity development Recruitment of osteoprogenitor cells Bone bridge formation between the epiphysis & metaphysis Widening & separation of epiphysis from metaphysis on imaging Bone growth arrest Limb length discrepancy Asymmetric growth Post-traumatic Altered joint arthritis mechanics Growth arrest risk if the displacement is > 3mm Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 5, 2025 on www.thecalgaryguide.com

Pituitary Tumour Classification and Clinical Outcomes

Pituitary Tumour: Classification and clinical outcomes Functional tumour: Secretes excess Non-functional tumour (30%) (lack of hormone-producing cells or due to gene mutations) Authors: Chris Oleynick Caroline Kokorudz Reviewers: Amyna Fidai Laura Byford- Richardson Joseph Tropiano Julia Gospodinov Luiza Radu Hanan Bassyouni* * MD at time of publication hormones (70%) Relative abundance & predisposition for lactotroph (prolactin-producing), somatotroph (growth hormone – producing), thyrotroph (TSH producing) & corticotroph (adrenocorticotropic hormone – producing) cells to form adenomas (epithelial cell tumours) ↑ Lactotroph cells ↑ Prolactin (PRL) (most common) Hyper- prolactinemia (high prolactin blood levels) ↑ Somatotroph cells ↑ Growth hormone (GH) Acromegaly* (excess tissue growth & metabolic dysfunction) ↑ Corticotroph cells ↑ Adrenocortico- tropic hormone (ACTH) Cushing disease* (prolonged exposure to excess cortisol) ↑ Thyrotroph cells ↑ Thyroid stimulating hormone (TSH) Central hyper- thyroidism (↑ T4 & T3) Large size (macro) (>10mm on MRI) may cause mass effect (tissue compression from mass) Small size (micro) (<10mm on MRI) unlikely to cause mass effect (compression to surrounding structures) Asymptomatic Headache Nausea & vomiting Compresses pituitary gland & impairs blood supply & function of pituitary cells Impinges pituitary stalk & disrupts hormone transport from hypothalamus to the anterior and posterior pituitary Compresses surrounding structures ↑ Pressure & stretching of dural mater Stretching of the meninges activates mechanoreceptors (stretch receptors) in GI tract Pituitary hormone deficiency (typically in left-right order with mass effect): Dopamine release obstruction ↓ Inhibition of prolactin secretion Antidiuretic hormone (ADH) obstruction Inferior tumour growth Growth into sphenoid sinus Lateral growth of the tumor compresses surrounding cranial nerves Superior tumour growth ↓ GH ↓ Protein production & muscle cell proliferation ↓ Luteinizing hormone (LH) (triggers ovulation & sex hormone synthesis) & follicle stimulating hormone (FSH) (stimulates ovarian follicles & sperm growth) ↓ (TSH) ↓ ACTH (stimulates cortisol & androgen release) Cranial nerve (CN) II (optic) ↓ Visual acuity Diplopia (double vision) CN III, (oculomotor) IV (trochlear), or VI (abducens) Ptosis* (drooping upper eyelid) CN V (trigeminal) branches V1 & V2 Facial numbness Ophthalmoplegia (eye muscle paralysis) Compresses optic chiasma Bitemporal hemianopsia (decreased lateral peripheral vision) Tumour extends into hypothalamus Hypothalamic dysfunction due to damage to hypothalamic cells Disruption of multiple regulatory systems (i.e. sleep-wake cycles, appetite, temperature) Tumour occludes ventricles Tumour obstructs CSF flow ↑ Intracranial pressure Hydrocephalus* (abnormal buildup of CSF in ventricles of the brain) and papilledema Bacteria migrates from sinus flora into sphenoid sinus Cerebrospinal fluid (CSF) leaks into throat Post-nasal drip and nasopharyngeal mass Stunted growth and short stature in children ↓ Muscle mass & fatigue Diabetes insipidus* (excessive urination & extreme thirst) Central hypothyroidism* (↓ T4 & T3) Hyperprolactinemia Meningitis* (inflammation of the meningeal layers of central nervous system) *See relevant Calgary Guide slide Hypogonadotropic hypogonadism (↓ Sex hormones) Adrenal insufficiency* (↓ 8 AM cortisol) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 1, 2027; updated Jan 5, 2025 on www.thecalgaryguide.com

Opioid Use Disorder

Opioid Use Disorder: Clinical Findings and Complications Opioids act on mu, kappa & delta opioid receptors Widespread accumulation of opioids Excessive glutamate exposure Overstimulation of membrane receptors (i.e., Neuronal excitotoxicity) Neuronal injury or death Myoclonus (involuntary muscle twitches/jerks) In brain & brain stem Parasympathetic stimulation of oculomotor nerve (cranial nerve 3) Suppression of reticular activating system neurons Cessation of respiration Contraction of pupillary sphincter ↓ Excitatory input to the cortices ↓ Arousal Lack of oxygen in the brain & other organs Miosis (pupil constriction) ↓ Level of Consciousness Death ↓ GABA release in ventral tegmental area Activation of mesolimbic dopaminergic pathway Release of dopamine in nucleus accumbens ↓ Traumatic memories ↓ Acetylcholine release in GI tract ↓ Peristalsis in GI tract ↓ GI transit & motility ↑ Time for colonic absorption of water Constipation Activation of mu & delta receptors in medulla’s chemoreceptor trigger zone Nausea Activation of mu receptors in the pons & medulla ↓ Neural drive for breathing ↓ Respiration Euphoria Analgesia Craving, strong desire to use More frequent opioid use Authors: Keira Britto Kayla Marritt Meera Grover* Reviewers: Erik Fraunberger Sara Cho, Luiza Radu Spencer Krahn * * MD at time of publication Opioid Use Disorder: Pattern of opioid use leading to clinically significant impairment or distress Performing any given behaviour while intoxicated cAMP Mechanism upregulation unknown Mu opioid receptor desensitization Physical dependence reinforces opioid use Opioid withdrawal with cessation** Unable to ↓ or stop opioid usage With chronic use, ↓ response to opioids Behaviour tolerance ↑ Opioid required to achieve euphoria & analgesia (i.e., tolerance) ↑ Quantity & prolonged opioid consumption ↑ Time spent obtaining, using, & recovering from opioids Recurrent opioid use in physically hazardous situations despite physical, psychological, social & interpersonal consequences ↓ Participation in occupational social & recreational activities ↓ Fulfillment of work, school & personal obligations **See relevant Calgary Guide slide Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 28, 2025 on www.thecalgaryguide.com

Central Precocious Puberty

Central Precocious Puberty: Pathophysiology in females Environmental/social causes Genetic conditions/mutation Neurocutaneous syndromes (multisystem conditions Neoplasms (including hamartomas), trauma, infection, ischemia Damage to hypothalamic & pituitary structures (i.e. infarct or traumatic sheering forces often causing inflammation and ultimately cell death) Septo-optic dysplasia (early brain development disorder) Abnormal pituitary & hypothalamus development (unknown pathogenesis) Psychosocial stress International adoption from developing countries Rapid increase in nutrition Rapid catch-up growth Hormonal and metabolic changes Endocrine disrupting chemicals (ex. Phthalates, bisphenol A) Hypothalamic inflammation Suppression of inhibitory and activation of stimulatory elements of the GnRH production pathway Idiopathic familial central precocious puberty from different genetic mutations primarily impacting tissues derived from ectoderm) Makorin RING- finger protein 3( MKRN3) mutation (repressor of GnRH secretion) Kisspeptin protein and/or receptor mutation (regulates puberty & reproductive function) Extended Kisspeptin protein availability and/or ↑ production Kisspeptin receptors signal directly to gonadotropin releasing hormone (GnRH) neurons to release GnRH into portal system Early ↑ or inappropriate GnRH pulses Neurofibromatos is T1 (NF1) (causes benign tumors to grow in the brain along nerves)* Tumor development involving the optic chiasm (>15% of individuals with NF1) may impact hypothalamic function Damage to and/or disruption of normal hypothalamic & pituitary function Tuberous sclerosis autosomal dominant disorder (rare genetic disease that causes growth of benign tumors in brain & body) Dysregulated cell division & growth Hamartomas form as benign mass composed of cells similar to those surrounding it, occurs in many areas including hypothalamic hamartoma (HH) HH acts as an accessory, unregulated hypothalamus Autonomous (unregulated) pulsatile GnRH release Sturge-Weber Syndrome (vascular disorder causing capillary-venus malformations impacting the face, brain, eyes) Vascular malformation throughout the brain including the hypothalamus Impaired blood flow to the hypothalamus Hypothalamic ischemia Hypothalamus dysregulation and premature activation of GnRH release Disruption of excitation and inhibition balance in the CNS Hypothalamic- pituitary dysregulation Reduced inhibition of GnRH secretion Increased corticotropin- releasing hormone Adrenal gland production & release of androgens by unknown mechanism that play a role in maturation of the HPG axis Adrenarche (start of androgen production). Including: acne, body odor, & pubarche (pubic hair growth) Dysregulated GnRH pulses Dysregulated luteinizing hormone (LH) & follicle simulating hormone (FSH) release Early GnRH release Early FSH secretion from pituitary gland ↑ Uterine volume & growth of ovarian follicles Cyclical ovulation Premature menarche (first menses < 7 years) Early LH secretion from pituitary ↑ Gonadal androgen production ↑ Estrogen release from ovaries gland **See Calgary Guide slide - “Brain Neoplasms” ↑ Skeletal growth ↑ Bone mineral density Thelarche (breast development) Authors: Joanna Keough Reviewers: Run Xuan (Karen) Zeng Luiza Radu Samuel Fineblit* *MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 28, 2025 on www.thecalgaryguide.com

Vasoconstrictors in the OR

Vasoconstrictors in the Operating Room (OR): Mechanisms of action and clinical findings Indirect effects of ephedrine Ephedrine Intraoperative use if patient becomes: -Hypotensive -Bradycardic Inhibits reuptake of neuronal norepinephrine Bind to alpha-1 receptors in peripheral vasculature Bind to beta-1 receptors in cardiac tissue Bind to beta-2 receptors in pulmonary tissue Bind to alpha-1 receptors in peripheral vasculature Bind to alpha-1 receptors in iris dilator muscle (for opthalmic administration) Norepinephrine remains in synapse longer ↑ Norepinephrine release from storage vesicles Peripheral vein vasoconstriction ↑ Sinoatrial & atrioventricular nodal firing & inotropy (force of heart’s muscle contractions) Relaxes airway smooth muscle Vasoconstricts peripheral veins & arteries Iris dilator (smooth muscle) contraction Binds to alpha-1 receptors in peripheral vasculature Binds to beta-1 receptors in cardiac tissue Binds to beta-2 receptors in pulmonary tissue ↑ Blood pressure ↑ Systemic vascular resistance ↑ Heart rate ↑ Cardiac contractility ↑ Cardiac output Bronchodilation ↑ Blood pressure ↑ Preload ↑ Afterload ↑ Systemic vascular ↑ Blood pressure ↑ Heart rate ↑ Cardiac contractility Bronchodilation Sustained tachycardia (Heart rate >100 beats per minute) Arrhythmias (abnormal heart rhythms) Palpitations Baroreceptor mediated reflex bradycardia (Heart rate <60 beats per minute) ↓ Reduced cardiac output (when afterload > preload) Direct effects ephedrine of Phenylephrine Intraoperative use patient becomes: -Hypotensive if resistance Pupil dilation Authors: Rebecca Sugars Reviewers: Run Xuan (Karen) Zeng, Luiza Radu, Leyla Baghirzada* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 28, 2025 on www.thecalgaryguide.com

Dopamine Antagonists Metoclopramide & Domperidone

Dopamine Antagonists Metoclopramide & Domperidone: Mechanism of Action and Adverse Effects Authors: Ishjot Litt Naima Riaz Reviewers: Run Xuan (Karen) Zeng Luiza Radu Esther Ho* * MD at time of publication Binds to & blocks dopamine D2 receptors in the chemoreceptor trigger zone (CTZ) in medulla oblongata Binds to & blocks serotonin (5-HT3) receptors in the CTZ in medulla oblongata Binds to & blocks dopamine D1 & D2 receptors in the nucleus accumbens of the basal forebrain Binds to & blocks dopamine D2 receptors in the substantia nigra of the basal ganglia Binds to & blocks dopamine D2 receptors in the anterior pituitary Binds to & blocks dopamine D2 receptors in myenteric plexuses of the proximal gut Binds to & blocks dopamine D2 receptors in the myocardium Incoming vagal afferents (sensory nerve signals) reduce dopamine release at the CTZ Incoming vagal afferents (sensory nerve signals) reduce serotonin release at the CTZ ↓ Binding of dopamine released by neurons in the ventral tegmental area (VTA) of the midbrain ↓ Dopamine’s inhibitory effect on neurons in the ventrolateral (VL) nucleus of the thalamus ↓ Binding of dopamine released by neurons in the hypothalamus ↑ Acetylcholine (Ach) release from parasympathetic neuronal nerve endings ↓ Dopamine binding at the CTZ ↓ Serotonin binding at CTZ ↓ Activation of wake-promoting VTA neurons ↑ Excitatory activity of neurons in the VL nucleus of the thalamus ↓ Dopamine’s inhibitory effect on prolactin secretion Influx of calcium ions into smooth muscle ↓ Dorsal motor nucleus activity of the vagus nerve in the medulla oblongata ↓ Nucleus solitary tract activity (processes sensory signals from body) ↓ Vomiting center activity Suppressed vomiting reflex ↓ Vomiting Central Actions ↓ Excitatory signals to promote wakefulness Drowsiness Extrapyramidal symptoms (EPS; impaired motor control) Dystonia (sustained muscle spasm & abnormal posture), akathisia (restlessness), chorea (rapid, irregular movement), parkinsonism (tremors, rigidity) EPS symptoms occur mostly with metoclopramide. Domperidone does not readily cross CNS and is less likely to produce EPS symptoms. Continuous activation signal to corticospinal motor control system Hyperprolactinemia (↑ prolactin secretion) ↑ Involuntary movements Peripheral Actions Torsade de Pointes (polymorphic ventricular tachycardia; rapid & irregular heart rhythm on ECG) Membrane depolarization ↑ Velocity of excitatory waves on smooth muscle walls ↑ Gut tone & rhythm of contraction ↑ Gastric and small intestinal motility & ↑ lower esophageal sphincter tone Blocks potassium channel Inhibits potassium ion outflow Delayed ventricular repolarization (>440 milliseconds in men & >460 milliseconds in women) Myocardium unable to compensate for arrhythmia Ventricular fibrillation Cardiac Arrest Death Bradycardia (Slow than normal heart rate) Long QT Syndrome Extended QT interval seen on electrocardiogram (ECG) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 28, 2025 on www.thecalgaryguide.com

Osgood Schlatter Disease

Osgood-Schlatter Disease: Pathogenesis and clinical findings Growth-related factors Anatomical variations that may ↑ risk Tibial tubercle develops as a secondary ossification centre, starting with a cartilaginous outgrowth Developing cartilaginous tibial apophysis has ↓ resistance to mechanical stress ↑ Susceptibility to injury prior to tibial apophysis and epiphysis fusion Adolescent growth spurt Longitudinal growth of tibia exceeds ability of quadriceps-patellar tendon unit to stretch ↓ Quadriceps flexibility Repetitive knee extensor mechanism activities during adolescence (eg. jumping, running) Patellar tendon inserts more proximally or broadly on tibia ↓ Patellar tendon moment arm length causes ↑ biomechanical forces on tibial tubercle Patella alta (superior displacement of the patella within the trochlear groove) *temporal relationship uncertain Quadriceps require ↑ forces to achieve full extension Patellar tendon overuse ↑ Patellar tendon tension ↑ Traction stress on the patellar tendon insertion at the cartilaginous tibial tubercle apophysis in one or both knees Osgood-Schlatter Disease Self-limiting osteochondrosis or traction apophysitis (inflammation of the growth plate) of the proximal tibial tubercle at the insertion of the patellar tendon Tibial tubercle apophysis hypertrophies & develops chronic micro-avulsions (tibial apophyseal ossification centers & cartilage is pulled off the tibial metaphysis) ↑ Inflammation at injury site Proximal patellar tendon micro- Repetitive strain/forces on the proximal tibial apophysis Tibial apophysis undergoes partial arrest Asymmetric proximal tibial epiphyseal growth abnormality (posterior > anterior) Genu recurvatum (knee hyperextension) (rare) due to traction apophysitis avulses from the tibial apophysis overcomes bone-tendon attachment strength Activated immune cells release cytokines at injury site Sensitization of nociceptors in periosteum and surrounding tissues Tenderness and Antalgic swelling of gait patellar tendon Proximal tibial apophyseal fragmentation (visible on X-ray) Avulsion fracture of tibial tubercle Calcium is abnormally deposited in the tendon Calcific tendinopathy in patellar tendon (visible on X-ray) Anterior knee pain that worsens with exercise Inflammatory mediators recruit osteoblast precursors to stabilize injury site ↑ Osteoblast activity drives bone remodeling and formation of ossicles (small pieces of bone) Bone remodeling causes united ossicles (ossicle fusion with tibial tuberosity) Ununited ossicle imbedded within patellar tendon (visible on X-ray) Bony prominence of tibial tubercle (visible on X-ray) Residual ununited ossicle remains after apophysis fuses with proximal tibial metaphysis Persistent visible prominence after proximal tibial apophyseal closure Authors: Emily J. Doucette Reviewers: Michelle J. Chan Yan Yu* Gerhard Kiefer* * MD at time of publication Persistent pain & discomfort with ↓ strength & function Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 16, 2025 on www.thecalgaryguide.com

Polycythemia Vera Pathogenesis

Polycythemia Vera (PV): Pathogenesis and Clinical Findings Authors: Caitlin Bittman Noriyah Al Awadhi Yan Yu Peter Duggan* Reviewers: Maharshi Gandhi Kevin Zhan Michelle J. Chen Paul Ratti Merna Adly Crystal Liu Kareem Jamani* Man-Chiu Poon* Lynn Savoie* * MD at time of publication Familial PV inherited as autosomal dominant incomplete penetrance (5% of PV cases) Predisposition to acquire a second somatic mutation Hematopoietic cells with no known mutations in their DNA Acquired JAK2 (Janus kinase 2) mutation in a single hematopoietic pluripotent stem cell in the bone marrow JAK2 mutated cells in the bone marrow ↑ production of hematopoietic cells (RBCs, WBCs, platelets) and cytokines DNA changes leads to continuous replication of the mutated cell Abnormal cell becomes the predominant hematopoietic stem cell in the bone marrow ↑ RBC production independent of erythropoietin (EPO) ↑ Mast cell production ↑ Leukocyte production (basophils, neutrophils, eosinophils, monocytes ↑ Platelet production (thrombocytosis) Overproduced platelets often have abnormal function of activation and aggregation Hypercellular bone marrow on biopsy with trilineage growth (erythroid, granulocytic, and megakaryocytic cell lines) ↑ Hemoglobin concentration ↑ Hematocrit (proportion of blood volume occupied by RBCs) ↑ RBC leads to down-regulation of EPO by kidneys ↓ Serum EPO ↑ Levels of histamine, which is stored in granules within basophils & mast cells Contact with water causes degranulation and subsequent histamine release from mast cells & basophils Aquagenic pruritis (itchy skin after contact with water) Histamines released from mast cells in the stomach causes hypersecretion of gastric acid Stomach ulcers Acquired Von Willebrand syndrome (with platelets >1,000,000/microL) Despite thrombocytosis, there is an ↑ risk of bleeding due to platelet dysfunction ↑ Risk of hemorrhage & abnormal bleeding (e.g. GI and mucosal bleeding) Easy bruising, purpura, petechiae, dental bleeds, epistaxis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 7, 2012; updated Feb 22, 2025 on www.thecalgaryguide.com

Polycythemia Vera Complications

Polycythemia Vera (PV): Complications High numbers of cells & platelets ↑ blood viscosity Polycythemia Vera Hematological disorder in which JAK2 mutations in hematopoietic cells result in increased RBC production. See corresponding Calgary Guide slide “Polycythemia Vera: Pathogenesis” ↑ Blood cell volume Presence of increased numbers of platelets creates a hypercoagulable and prothrombotic state ↑ Risk of venous & arterial thrombosis ↑ Systemic vascular resistance Impaired/“sluggish” blood flow ↓ Perfusion to small vessels and ↓ oxygen delivery to throughout body Arterial clots in arms and legs or in vessels leading to brain prevent oxygen delivery to cells Systemic hypertension ↑ Turnover of hematopoietic cells (RBCs, WBCs, platelets) Fatigue Transient visual disturbances Neurological symptoms (e.g. headache, dizziness, tinnitus, concentration problems) Breakdown of nucleic acids during cell turnover ↑ uric acid levels in blood Lysing cells release lactate dehydrogenase (LDH) into bloodstream ↑ Spleen activity to filter and dispose of old blood cells Splenomegaly Authors: Caitlin Bittman Noriyah Al Awadhi Yan Yu Peter Duggan* Reviewers: Maharshi Gandhi Kevin Zhan Michelle J. Chen Paul Ratti Merna Adly Crystal Liu Kareem Jamani* Man-Chiu Poon* Lynn Savoie* * MD at time of publication Extramedullary hematopoiesis Pancytopenia Clots in the portal vein, splenic vein, & mesenteric vein are unusual & highly suggestive of PV Clots in cardiac arteries prevent O2 delivery to cardiac tissue Myocardial infarction Venous blood moves more slowly and is less pressurized compared to arterial blood. Combined with hypercoagulable state, clots are likely to form in deep veins (usually of the legs) Deep vein thrombosis Clot breaks off and travels through the inferior vena cava & right heart into the pulmonary arteries Pulmonary embolism Stimulation fibroblasts in the bone marrow Uric acid accumulates & precipitates in blood Hyperuricemia ↑ Serum LDH Limb ischemia Ischemic stroke & transient ischemic attacks Erythromelalgias (burning pain in the extremities and erythema due to poor perfusion and transient microvascular occlusion) Compensatory vasodilation in the capillaries of the skin Plethora/rusted or “ruddy” complexion, particularly noticeable on the face, palms, nailbeds, & mucous membranes Gout Uric acid stones Advanced Disease Progression Abnormal blood cells produced in PV release various growth factors and cytokines Production of excess collagen and other fibrous materials Hematopoietic cells in bone marrow replaced with fibrous tissue over time Bone marrow increasingly unable to produce healthy blood cells Myelofibrosis (rare type of chronic blood cancer; considered late-stage progression of PV characterized by bone marrow fibrosis) Bone marrow failure Chronic bone marrow hyperactivity leads to exhaustion and/or damage of hematopoietic cells Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 7, 2012, updated Feb 22, 2025 on www.thecalgaryguide.com

Neuraxial anesthesia

Neuraxial anesthesia: Mechanism of action and complications Spinal anesthesia Epidural anesthesia Anesthetic injected into epidural space (surrounding spinal cord) Blood vessel punctured Blood accumulates in epidural space Epidural hematoma Inhibits motor nerve conduction (least sensitive nerve fibers to anesthetics) Anesthetic injected into cerebrospinal fluid (CSF) in the subarachnoid space Punctured dura mater Cerebrospinal fluid leak Decrease cerebrospinal fluid pressure Vasodilation of cerebral blood vessels Post-dural puncture headache Inhibits sympathetic nerve conduction (most sensitive nerve fibers to anesthetics) Anesthetics diffuse across axon membranes & blocks voltage-gated sodium channel in nerve fibers ↓ Sodium ion flow into neuron Nerve fibers unable to depolarize & reach threshold to trigger action potential Inhibits sensory nerve conduction Cardiac sympathetic nerve fibers inhibited ↓ Norepinephrine release Unopposed parasympathetic (rest and digest) activity Parasympathetic nerves release acetylcholine (Ach) ACh binds to muscarinic receptors on smooth muscle ↑ Peristalsis ↑ Bowel motility C-fibre nerve fibers (unmyelinated) inhibited Loss of pain & temperature sensation A-delta nerve fibers (thinly myelinated) inhibited Loss of pinprick, pain & temperature sensation A-beta nerve fibers (myelinated) inhibited Loss of vibration, touch & pressure sensation A-alpha nerve fibers (heavily myelinated) inhibited Loss of proprioception Phrenic nerve fibers inhibited Diaphragm paralysis Impaired diaphragm contraction Apnea (temporary cessation of breathing) Loss of motor function ↓ Cardiac pacemaker activity Bradycardia (slow heart rate) Inhibits smooth muscle tone of blood vessels ↓ Systemic vascular resistance Authors: Shiva Ivaturi Reviewers: Run Xuan (Karen) Zeng, Luiza Radu, Julia Haber* *MD at time of publication Vasodilation Hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 24, 2025 on www.thecalgaryguide.com

Nitrous Oxide

Nitrous Oxide: Mechanism of action and clinical effects Binds to & activates γ- aminobutyric acid (GABAA) receptor ↑ Chloride ion influx into the neuron Possible activation of Calmodulin–Nictric Oxide Synthase–Cyclic Guanosine Monophosphate dependent Protein Kinase pathway (exact mechanism unclear) ↑ Neurotransmission Inhibition Minimal Sedation (Anxiolysis) Authors: Parthiv Amin Andre Skipper Tracey Rice Reviewers: Billy Sun, Joseph Tropiano Run Xuan (Karen) Zeng Luiza Radu Michael Chong* Leyla Baghirzada* * MD at time of publication N-methyl-D-aspartate (NMDA) receptor antagonist (inhibitor) Closes NDMA receptor channels Inhibit ionic currents ↓ Central nervous system excitability Analgesia Hyperhomocysteinemia (Excessive build-up of homocysteine due to lack of conversion to methionine) ↑ Reactive oxygen species (ROS) & endothelial damage ↑ Coagulation & endothelial adhesion ↑ Atherosclerosis & thrombosis ↑ Risk of perioperative cardiovascular complications (Myocardial ischemia & myocardial infarction) Pyramidal Cell Vacuole Reaction: Swelling of endoplasmic reticulum & mitochondria Rapidly reversible pyramidal cell neurotoxic vacuole reaction in posterior cingulate/retrosplenial cortex (PC/RSC) Neurotoxicity with prolonged use Lack of methionine impairs ability to produce S- adenosylmethionine (SAM) Lack of SAM (helps regulate folate production) causes diversion of folate to methionine production Lack of folate impairs thymidine production Lack of thymidine (crucial nucleotide in DNA synthesis) impairs DNA synthesis Megaloblastic Anemia Nociception modulation (Detection & transmission of harmful stimuli) Neurons stimulation in periaqueductal grey area (PAG) of midbrain Endogenous opioid peptides (EOPs) release EOP activates peripheral opioid receptors GABA-ergic nuclei of pons Inhibits activity of noradrenergic pathway (flight or flight response) Descending noradrenergic pathway activation in dorsal horn of spine Nitrous Oxide (N2O) irreversibly oxidizes (inactivates) vitamin B12 (cobalamin) Vitamin B12 no longer available as cofactor for methionine synthase Irreversible inhibition of methionine synthase (converts homocysteine to methionine) ↓ Pain signals between primary & second order afferent sensory neurons (direct pain inhibition) Upregulation of GABA interneurons (Indirect pain inhibition) GABA release further ↓ pain signals Analgesia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 20, 2017; updated Feb 24, 2025 on www.thecalgaryguide.com

Neonatal Seizures

Neonatal Seizures: Pathogenesis and clinical findings Hypoxic-Ischemic Encephalopathy Hemorrhage & intracerebral infarction Acute Trauma Infections (e.g. encephalitis, meningitis) ↑ Pro-inflammatory signaling Neurocutaneous syndromes (e.g. Tuberous sclerosis) Brain lesions disrupt cortical formation Metabolic disturbance (e.g. hypoglycemia, hyponatremia) Electrolyte imbalances alter osmolality Ion transport disruption Malformations of cerebral development Structural alteration in signal transmission Medication induced (e.g. anesthetics, opioids, alcohol) Direct toxicity or withdrawal symptom Benign neonatal seizures ↓ Blood flow to the brain Authors: Pauline de Jesus Reviewers: Annie Pham Emily J. Doucette Jean Mah* *MD at time of publication ↑ Neuronal excitability Non-Familial No specific underlying genetic etiology (likely environmental) Familial Autosomal dominant epileptic syndrome Derangement in the distribution of excitatory & inhibitory neurotransmitters and networks in the brain causes cortical dysfunction ↑ Influx of extracellular Ca2+ ↑ Opening of voltage dependent Na+ channels ↑ Influx of Na+ Voltage-gated K+ channels lose their function ↓ of K+ current Impaired repolarization of neuronal cell membranes Subtle Seizures Imitation of normal behaviours Clonic Seizures Alternating excitatory & inhibitory activity Tonic Seizures Excessive, widespread excitatory activity Myoclonic Seizures Rapid bursts of excitatory activity High frequency bursts of action potentials, hyper-synchronized depolarization in neuronal populations, & ↓inhibitory signaling in surrounding neurons Neonatal Seizures Sudden, paroxysmal, abnormal alteration of electrographic activity lasting from seconds to minutes from birth to the end of the first 4 weeks of life Paroxysmal alterations in behaviour Paroxysmal alterations in autonomic function (apnea) Focal: Altered activity in one neuronal population Multifocal: Asynchronous migration of depolarization Focal: Altered activity in one neuronal population Generalized (rare): Altered activity propagating to the cortex of both hemispheres Focal: Altered activity in one neuronal population Rapid jerks of upper extremity flexor muscles Multifocal: Asynchronous migration of depolarization Asynchronous twitching of multiple muscle groups Generalized (rare): Altered activity propagating to the cortex of both hemispheres Bilateral jerks of upper & sometimes lower limb flexors Paroxysmal alterations in motor function (ocular, oral-buccal-lingual) Slow, rhythmic jerks in muscles of the face, extremities, or axial structures unilaterally Time- synchronized EEG seizure activity Sustained limb posturing or asymmetric posturing of axial structures Sustained extension & flexion of upper extremities with extension of lower extremities ↑ Susceptibility to seizures later in life Neurodevelopmental dysfunction in learning, memory & cognition Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 14 2025 on www.thecalgaryguide.com

Tonsillitis Pathogenesis and clinical findings

Tonsillitis: Pathogenesis and clinical findings Authors: Taylor Krawec Amanda Marchak Reviewers: Nicola Adderley, Jim Rogers Emily J. Doucette, Danielle Nelson* James D. Kellner* * MD at time of publication Pathogen infiltrates tonsillar epithelium Microfold cells recognize pathogen & activate immune response Virus (most common) Group A Streptococci (GAS) (most common bacteria) Group B, C & G Strep, Fusobacterium necrophorum Age 5-15 (tonsils have ↑ role in immune function at this age) Tonsillitis Inflammation of the tonsils Infectious agent exposure Susceptible host Pathogen colonizes the oropharynx Acute suppurative disease Immune cells release proinflammatory cytokines & antibodies Inflammatory mediators ↑ vascular permeability of tonsils Leakage of protein & fluid into surrounding tissue Regional nodes receive ↑ lymph Enlarged anterior cervical nodes Sinusitis** Pharyngitis** Local spread of pathogen Acute otitis media** Pneumonia** Cervical lymphadenitis Bacteria spread from tonsils into lymphatic system & bloodstream Bacteremia F. necrophorum invades lateral pharyngeal space & soft tissue in neck Thrombosis forms in peritonsillar vein Thrombosis extends into internal jugular vein Lemierre’s syndrome Systemic inflammatory cytokines disrupt hypothalamic regulation Fever Additional immune cells are recruited to facilitate immune response Macrophages phagocytize pathogen Bacteria invade distant tissue & elicit local inflammatory response Hepatitis Osteomyelitis Infective endocarditis Bacteria illicit systemic response Sepsis Tonsillar tissue become swollen & irritated Tonsillar hypertrophy Localized collection of pus forms Immune cells cause inadvertent cellular injury & hemolysis Palatal petechiae Meningitis Products of immune response & cellular debris are deposited into tonsillar tissue Peritonsillar or Tonsillar retropharyngeal abscess** exudate ** See corresponding Calgary Guide slide Toxin-mediated disease Bacteria release exotoxins into bloodstream Inflammatory mediators & cytokines are overactivated (cytokine storm) Skin has local inflammatory response Toxic shock syndrome** Scarlet fever** Post-infectious disease Antibodies to GAS cross react with host tissue Acute rheumatic fever** Post-strep glomerulonephritis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 5, 2018; updated Mar 14, 2025 on www.thecalgaryguide.com

Febrile Seizures

Febrile Seizures: Pathogenesis and clinical findings Factors that ↓ seizure threshold Immunizations (DTaP, MMR) activate host immune system Immune cells release pro-inflammatory interleukin (IL)-1β, IL-6 & TNF-α cytokines that reach the central nervous system Viral infections (primarily HHV-6 & H1N1) activate host immune system Immature nervous system in children between 6 Family history of febrile seizures months & 5 years old (peak 12-18 months old) (genetic predisposition) Hypothalamus releases prostaglandin E2 (PGE2) to ↑ body temperature Fever reaches ≥380C ↑ Voltage gated Na+ & Ca2+ channel excitability ↑ Susceptibility to fevers Fever ↑ metabolic rate & ↑ oxygen demand ↑ Respiratory rate Hyperventilation ↑ volume of CO2 exhaled ↓ Serum CO2 leads to respiratory alkalosis Inherited mutations in genes encoding the GABAA receptor subunit ↓ GABAA receptor expression ↓ GABAergic inhibition Inherited mutations in genes encoding the Na+ channels IL-1β ↑ glutamate release & ↓ GABAergic inhibition Pro-inflammatory mediators ↑ sensitivity of N-methyl-D-aspartate (NMDA) (glutamate) receptors on medial temporal lobe neurons Imbalances between excitatory glutamate & inhibitory gamma- aminobutyric acid (GABA) neurotransmission ↑ Neuronal Na+ channel activity Neurons become more excitable & generate action potentials more readily Large groups of neurons fire simultaneously (synchronize) in the medial temporal lobe (hippocampus) Activity spreads to other subcortical or cortical brain regions via synapses & gap junctions Excessive excitatory signaling disrupts normal brain activity Authors: Merry Faye Graff Catherine Beyak, Dasha Mori Reviewers: Michelle J. Chen, Calvin Howard Emily J. Doucette, Gary Klein* Jean K. Mah* * MD at time of publication Simple Febrile Seizure Complex Febrile Seizure Focal seizure, associated with a fever, that lasts > 15 minutes or has multiple recurrences in a 24-hour period Generalized seizure, associated with a fever, that lasts < 15 minutes & does not recur in a 24-hour period Generalized (bilateral cortical involvement) tonic-clonic seizure Temporary post-ictal Temporary post-ictal weakness or ↓ Threshold for future febrile seizures Prolonged (> 30 mins) or recurrent seizures without full return to consciousness in between (Febrile status epilepticus) Focal (localized) seizures Damages to neuronal circuits in affected regions drowsiness or confusion **See corresponding Calgary Guide slide paralysis (Todd’s paralysis) Epilepsy** Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 21, 2019; updated Mar 20, 2025 on www.thecalgaryguide.com

Polymyalgia Rheumatica

Polymyalgia Rheuma>ca: Pathogenesis and Clinical Outcomes The pathophysiology of Polymyalgia Rheuma9ca (PMR) is s9ll poorly understood. PMR is a rheuma9c condi9on characterized Author: Anna Bobyn Reviewers: Anika Zaman, Kevin Zhan Luiza Radu, Emily J. Doucette Glen Hazlewood* *MD at time of publication by pain and s9ffness around the neck, shoulder, and pelvic girdle. Non-Modifiable factors Assigned female at birth: 3♀ : 1♂ Environmental factors Age-Related Changes: PMR almost exclusively affects people >50 Polymorphisms: (eg. HLA-DR1, Interleukin (IL)-1, IL-6, TNF⍺) Infectious Triggers: Epstein-Barr virus, Mycoplasma pneumoniae, parvovirus Link to Vaccina=ons: COVID-19, influenza, respiratory syncy=al virus Innate immunity involvement: Macrophages & dendri=c cells recognize & respond to unknown an=gen Immune cells ↑ production of cytokines (IL-6, IFN-γ, TNF-α) Adap=ve immunity involvement: No strong evidence of autoan=body role Early CD4+ T cell ac=va=on & infiltra=on of T cells into vascular =ssue Subclinical vascular inflammation, particularly of medium & large arteries ↑ Vascular Endothelial Growth Factor & micro-vasculariza=on Vascular dysfunction, ischemia, edema, & sensitization of pain receptors Systemic inflamma=on Local inflamma=on of synovial membrane, joint bursae, & tendon sheaths B cell dysregula=on (↓ naïve B cells, ↑ memory B cells) ↑ Serum inflammatory markers (CRP & ESR) ↑ Risk of cardiovascular events (heart attack, stroke) Low-grade fever (37.2- 38°C) ↓ Passive & ac>ve range of mo>on Bilateral morning stiffness lasting >30 minutes Fa>gue & malaise Muscle pain in proximal joints (shoulder & pelvic girdle) Development of Giant Cell Arteri>s** (15-20% of PMR pa>ents) **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complica=ons Published Mar 23, 2025 on www.thecalgaryguide.com

HIV Pathogenesis and Clinical Findings

Human Immunodeficiency Virus: Pathogenesis and clinical findings Blood transfusion with contaminated blood product Intravenous use of HIV contaminated needles Sexual intercourse with HIV positive partner (with sufficient viral load) Perinatal transmission during pregnancy, childbirth or breast feeding Direct contact of patient bloodstream or mucous membranes with HIV-1 infected blood, semen, rectal fluids, vaginal discharge or breast milk (HIV-2 is transmitted in similar fashion but is less common & more likely to be seen in West Africa) Authors: Taylor Krawec Ishjot Litt, Naima Riaz Reviewers: Candace Chan, Shahab Marzoughi Emily J. Doucette, Sarah Smith* * MD at time of publication Glycoproteins in HIV viral envelope bind to CD4 & chemokine receptors on CD4+ T-cells & other immune cells Viral & host cell membranes fuse Viral single-stranded RNA (ssRNA) genome & enzymes are released into the host cell Host CD4+ cells are destroyed via direct cytotoxic effects & immune cell-mediated cytotoxicity CD4+ cell count ↓ Virions are disseminated throughout host ↑ Viral load Viral proteins are transcribed & assembled into virions Virions bud off host cell membrane ssRNA is transcribed into proviral DNA by viral reverse transcriptase using host nucleotides Infected cells revert to memory state & establish latent HIV reservoir Chronic HIV infection Host is unable to keep up with loss of CD4+ cells Proviral DNA enters nucleus & integrates into host DNA Acute HIV infection Infected immune cells release proinflammatory cytokines Antibodies to HIV are generated in attempt to control infection (2-12 weeks post infection) Positive antibody-antigen immunoassay Cytokines disrupt hypothalamic temperature regulation Systemic immune system activation results in ↑ metabolic demand Cytokines extravasate to the dermis Fever Maculopapular Chills Fatigue rash Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Viral load ↓ & stabilizes around set-point viral load Oral hairy leukoplakia (oral infection with Epstein-Barr Virus) Complications Viral load ↑ & CD4+ cell count ↓ steadily over several years without treatment CD4+ cell count ↓ to 200-500 cells/μL Impaired host immune response ↑ risk of opportunistic infections Oropharyngeal or vulvovaginal candidiasis Severe manifestations of common infections (ex. herpes simplex, HPV) Published April 22, 2025 on www.thecalgaryguide.com Virus evades immune detection to allow ongoing viral replication, chronic immune activation & ↓ thymic function Vague viral symptoms (ex. fatigue, weight loss, lymphadenopathy) CD4+ count ↓ to < 200 cells/μL Acquired immunodeficiency syndrome (AIDS)

Varenicline

Varenicline: Mechanism and Side Effects Nicotine cessation monotherapy Adjuvant to nicotine replacement or behavioural therapy Varenicline Competitive partial agonist of α4β2 nicotinic receptors in the mesolimbic dopamine system which modulate reward signaling associated with nicotine use (E.g., cigarettes, e-cigarettes, vaping, smokeless tobacco) Activated α4β2 nicotinic receptors on cerebral blood vessels causes vasodilation Activation of gastrointestinal α4β2 nicotinic receptors Excessive vasodilation ↑ intracranial pressure Authors: Trevor Low Aliaksandr Savin Reviewers: Andrew Wu Luiza Radu Emily J. Doucette Joel Tappay* *MD at time of publication Headache Varenicline binds central α4β2 nicotinic acetylcholine receptors with higher affinity than exogenous nicotine ↓ Binding of exogenous nicotine to α4β2 nicotinic receptors Ventral tegmental area of midbrain releases ↓ dopamine Nucleus accumbens of ventral striatum receives ↓ dopaminergic signaling ↓ Sensations of pleasure or euphoria with nicotine use ↓ Satisfaction from nicotine consumption ↓ Positive reinforcement with nicotine use Legend: Selective activation of α4β2 nicotinic acetylcholine receptors Partial activation of central α4β2 nicotinic receptors Partial but sustained release of dopamine from ventral tegmental area at a level lower than nicotine Sustained partial release prevents phasic dopamine signaling to the nucleus accumbens Tonic dopamine relieves withdrawal symptoms ↓ Cravings & desire to consume nicotine to relieve withdrawal symptoms ↓ Nicotine use (nicotine cessation) Acetylcholine signaling to area postrema (vomiting center) ↑ Basal levels of dopamine disrupts signaling in nuclei responsible for arousal & sleep initiation ↑ Dopaminergic signaling in the limbic system during sleep ↑ Activation of amygdala (emotions) & hippocampus (memories) during sleep ↑ Intracranial pressure activates meningeal nociceptors Nausea & vomiting ↑ Wakefulness Delay in sleep onset Fragmentation of sleep cycles ↑ Activation causes premature or prolonged REM episodes Dopamine activates cholinergic neurons in nuclei responsible for rapid-eye- movement (REM) sleep Insomnia Abnormal, vivid & emotional dreams Pathophysiology Mechanism Pharmacologic effect Adverse effect Published April 22, 2025 on www.thecalgaryguide.com

Acute Infectious Mononucleosis

**See corresponding Calgary Guide slides Legend: Acute Infectious Mononucleosis: Pathogenesis & clinical findings Viral transmission (Epstein-Barr virus (EBV), Cytomegalovirus (CMV), human immunodeficiency virus (HIV), etc) through saliva (most commonly in adolescents & young adults aged 15-24) Virus infects epithelial cells of the oropharynx Virus infects & immortalizes circulating B lymphocytes Virus replicates in infected B-cells Immune cell proliferation in lymphatic system (primarily lymph nodes & spleen) Infected B-cells enter systemic circulation Systemic inflammatory response activated Inflammation & edema of sinuses Bilateral periorbital &/or palpebral edema Pharyngitis** (often with grey/white exudative secretions) Palatal petechiae Blood vessel damage in the soft palate Edema of soft palate & tonsils Airway obstruction ↑ Immunoglobulin M (IgM) antibodies to EBV viral capsid antigen (VCA) Positive IgM-VCA Immortalized B-cells produce ↑ antibodies Production of heterophile antibodies (weakly reactive & non-specific) Positive monospot (heterophile antibody) test (↓ sensitivity in children <4 years) Virus may remain dormant in B-cells Latent infection with periodic reactivation Generalized lymphadenopathy (enlarged lymph nodes) Massive cervical, mediastinal or hilar lymphadenopathy Posterior cervical lymphadenopathy Platelets sequestered (trapped) within spleen & overactive spleen (hypersplenism) discards ↑ platelets Thrombocytopenia (↓ platelets) Weak reticular tissue in the spleen stretches Splenomegaly Splenic rupture & becomes more susceptible to injury Inflammatory response ↑ energy demand Fatigue Longstanding impacts from unknown mechanism Chronic Fatigue Syndrome Inflammatory cytokines released into circulation ↑ Thermo-regulatory set-point at hypothalamus Fever Lymphocytosis (↑ lymphocytes) (markedly CD8+ T-cells & NK cells) Immune cells infiltrate the liver Hepatomegaly ↑ Aminotransferases Leukocytosis (↑ leukocytes) CD8+ T-cells & NK cells indirectly damage hepatocytes ↑ Bilirubin & jaundice** Systemic immune response &/or antibiotic hypersensitivity reaction CD8+ T-cells respond to virus Atypical lymphocytes on blood smear Generalized maculopapular rash Authors: Ayden Hansen, Griselle Leon Reviewers: Charissa Chen, Emily J. Doucette Danielle Nelson* * MD at time of publication Published Sept 3, 2015; updated Apr 22, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Trachoma

Trachoma: Pathogenesis and ocular manifestations Risk factors for infection Mode of transmission Authors: Palak Sharma, Helena Zakrzewski Reviewers: Prima Moinul, Riley Hartman Emily J. Doucette, Edsel Ing* * MD at time of publication Crowded living conditions Poor hygiene practices Limited access to sanitary facilities Direct contact with ocular & nasal secretions of infected individuals Indirect contact with fomites (contaminated objects or surfaces) Mechanical vectors: Eye-seeking flies (e.g. Musca sorbens) Chlamydia trachomatis infection (serotype A, B & C) Trachoma Chronic keratoconjunctivitis (inflammation of the conjunctiva & cornea) caused by recurrent infection with C. trachomatis Active Phase Bacteria infects the conjunctival epithelial cells Redness, irritation & mucopurulent discharge Immune response triggers inflammation of the upper tarsal conjunctiva Herbert’s pits (small, sunken scars at the limbus (border between cornea & sclera) from healed follicles Corneal lesions Pannus (invasion by superficial vessels) at the limbus Lymphoid follicles consisting mainly of B & T cells form in the upper tarsal conjunctiva Trachomatous inflammation - follicular: Presence of five or more white or yellow follicles, each 0.5 mm or bigger in size Inflammation leads to papillae formation with dilated blood vessels, infiltration of lymphocytes, plasma cells & neutrophils & proliferation of epithelial cells Small, raised bumps with a central blood vessel in the upper conjunctiva Papillary hypertrophy causes conjunctival thickening & opaqueness Trachomatous inflammation - intense: Papillae obscure deep tarsal blood vessels Repeated re-infection or untreated infections Cicatricial (scarring) Phase Proliferation of fibroblasts & deposition of collagen leads to scarring (fibrosis) Trachomatous scarring: White, horizontal lines or bands on upper tarsal conjunctiva Scarring blocks meibomian gland ducts Conjunctival epithelium atrophy & goblet cell destruction Subconjunctival fibrosis Entropion (eyelid turns inward) Cornea ulcers & scarring ↑ Tear evaporation ↓ Tear production Scar contraction distorts upper tarsal plate Dry eye Trachomatous trichiasis (eyelashes grow inward toward the eye) Corneal abrasion Corneal opacity & blindness Published Sept, 2 2015; updated May 7, 2025 on www.thecalgaryguide.com Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Wigger's Diagram

Wigger’s Diagram: Overview Diastole: Systole: Diastole: Sinoatrial node generates an electrical stimulus Atrial myocytes depolarize & contract (atrial systole) Atrial myocytes repolarize and relax Septum depolarizes Ventricular myocytes depolarize and contract (isovolumetric contraction) Ventricular myocytes repolarize and relax (isovolumetric relaxation) ↓ Left atrial pressure Left atrium squeezes blood into left ventricle through the open mitral valve ECG: P-wave** Left atria fills with blood from ECG: Q-wave ECG: R-wave ECG: T-wave ↑ Left pulmonary ventricular circulation pressure Atrial pressure: ‘x’ descent ↓ Left ventricular pressure ↑ Left atrial pressure ↑ Left atrial pressure ↑ Left ventricular volume Left ventricular pressure > left atrial pressure Mitral valve bulges into left atrium Left ventricular pressure > aortic pressure Atrial pressure: ‘v’ wave Atrial pressure: ‘a’ wave ↑ Left ventricular pressure Mitral valve closes Atrial pressure: ‘c’ wave Aortic valve opens First heart sound (S1) Left ventricle squeezes blood into aorta (ejection) ↑ Aortic pressure Legend: Pathophysiology Mechanism Left atrial pressure > left ventricular pressure Mitral valve opens Rapid inflow of blood into left ventricle from left atria ↓ Left ventricular volume ↑ Left ventricular volume ↓ Left atrial pressure ↓ Left ventricular pressure Atrial pressure: ‘y’ descent Aortic pressure > left ventricular pressure Aortic valve closes Second heart sound (S2) **See slide on PHYSIOLOGY OF THE NORMAL ECG WAVEFORM (LEAD II) Author: Nathan Archibald Reviewers: Stephanie Happ Emily Kuervers Sergio F. Sharif Angela Kealey* * MD at time of publication Sign/Symptom/Lab Finding Complications Published May 19, 2025 on www.thecalgaryguide.com

PROP1-Related Combined Pituitary Hormone Deficiency

↓ DNA-binding & transcriptional Impaired pituitary stem cell differentiation & anterior pituitary development ↓ Prolactin (PRL) from lactotrophs Impaired mammary gland stimulation prevents adequate milk production PROP1-Related Combined Pituitary Hormone Deficiency: Pathogenesis and clinical findings Consanguinity Inherited PROP1 mutation Family history of PROP1 mutation Sporadic PROP1 mutation Autosomal recessive or sporadic mutation of PROP1 on chromosome 5q35 (various mutations identified; ex. frameshift, insertion, deletion) activation ability of pituitary- specific transcription factor encoded by PROP1 gene PROP1-Related Combined Pituitary Hormone Deficiency Genetic disorder resulting in combined pituitary hormone deficiency (CPHD) characterized by a deficiency in growth hormone (GH) & ≥ 1 additional anterior pituitary hormone ↓ Follicle stimulating hormone (FSH) from somatotrophs ↓Luteinizing hormone (LH) from gonadotrophs ↓ GH from gonadotrophs ↓ Thyroid stimulating hormone (TSH) from thyrotrophs ↓ Adrenocorticotropic hormone (ACTH) from corticotrophs ↓ Gonad stimulation ↓ Sex hormone production Hypogonadotropic hypogonadism (hypogonadism due to problem at level of hypothalamus or pituitary) ↓ Secretion of insulin-like growth factor 1 (primarily ↓ Stimulation of growth at ↓ Thyroid stimulation ↓ Stimulation of adrenal glands epiphyseal plate of long bones ↓ Thyroid by liver) ↓ Serum hormone levels cortisol Absent secondary sexual characteristics Delayed or absent puberty Short stature Secondary/central hypothyroidism** Secondary/central adrenal insufficiency** Postpartum lactation failure Authors: Juliette Eshleman Taylor Krawec Reviewers: Annie Pham Emily J. Doucette Danielle Nelson* *MD at time of publication Impaired glucose regulation (↓ gluconeogenesis, ↓ glycogenolysis & ↓ lipolysis) Altered stress response to illness or injury ↓ Vascular tone & catecholamine response (fight-or-flight response) Impaired glucose metabolism Neonatal hypoglycemia** Adrenal crisis Hypotension Weakness Fatigue **See corresponding Calgary Guide slide Legend: Pathophysiology Published May 19, 2025 on www.thecalgaryguide.com Infertility Mechanism Sign/Symptom/Lab Finding Complications

Brachial Plexus Injury

**See corresponding Calgary Guide slide Legend: Brachial Plexus Injury: Pathophysiology and clinical findings High impact collision (ex. motorcycle accidents, sports) Fetal complications during labor & delivery** (ex. shoulder dystocia) Author: Merry Faye Graff Reviewers: Taylor Krawec Emily J. Doucette Jean K. Mah* *Indicates MD at time of publication Upward traction of arm with forced widening of scapulohumeral angle (lower brachial plexus injured first) Downward traction of arm with forced widening of shoulder-neck angle (upper brachial plexus injured first) Surgical trauma Direct trauma (i.e. gunshot wound, penetrating injuries) Pancoast tumour** Nerves are stretched or torn Nerves are severed or crushed Brachial Plexus Injury Damage to brachial plexus nerves that may cause weakness, decreased sensation or loss of movement in the shoulder, arm or hand Injury or compression demyelinates nerves without causing axonal injury (neuropraxia) Injury demyelinates nerves & severs axons (axonotmesis) Injury completely transects nerves (neurotmesis) Demyelination slows & disrupts nerve signal conduction Basal lamina tubes (axon scaffolds) are preserved Basal lamina tubes are severed Nerves are torn proximal to attachment at spine (post-ganglionic rupture) Nerve roots are torn from spinal cord (pre-ganglionic avulsion) ↓ Efferent signals (motor) ↓ Afferent signals (sensory) Inflammatory mediators sensitize primary afferent neurons Abnormal ectopic firing of nerves at or near nerve lesion Neuroma (benign growth or thickening of nerve tissue at lesion) during healing Breakdown of axon(s) & myelin distal to nerve lesion (Wallerian degeneration) Connection to central nervous system (CNS) lost Muscle weakness or loss of function in affected myotomes Paresthesia (numbness or tingling) in affected dermatomes Hyperalgesia (extreme sensitivity to touch) Neuropathic pain (burning, stabbing, electric-like pain) Neuroma blocks distal nerve conduction No conduction in affected nerves or nerve roots Repeated pain signals sensitize CNS Afferent signals are not transduced Efferent signals are not transduced Paravertebral sympathetic chain is disrupted (if C8 & T1 involved) Central sensitization Numbness Paralysis Horner’s syndrome** Shortening & hardening of muscles & tendons ↓ Muscle use Widespread pain Allodynia (normal touch perceived as painful) Contractures Muscle atrophy Note: Specific signs & symptoms vary based on nerves affected. Complications Published May 14, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding

Acetylcholinesterase inhibitors

Authors: Trevor Low Sunny Fong Reviewers: Billy Sun* Melinda Davis* * MD at time of publication Overstimulation of nicotinic acetylcholine receptors Overstimulation of muscarinic acetylcholine receptors Involuntary muscle twitches ↑Activity of respiratory smooth muscle & glands Acetylcholinesterase inhibitors: Mechanism of action and side effects Administration of acetylcholinesterase inhibitor (e.g., neostigmine or pyridostigmine) Reversible inhibition of acetylcholinesterase activity Cholinergic effects ↓ Breakdown of acetylcholine in the synaptic cleft Acetylcholine accumulates in the synaptic cleft Excessive accumulation of acetylcholine in synapses Acetylcholine competitively displaces non-depolarizing neuromuscular blockers** from nicotinic receptors in the neuromuscular junction ↑ Acetylcholine binding to pre-synaptic nicotinic receptors on neurons ↑ acetylcholine binding to post-synaptic nicotinic receptors on muscles Pre-synaptic nicotinic receptor depolarizes terminal membrane Post-synaptic nicotinic receptor activation results in action potential in muscle ↑ Vesicular release of acetylcholine by voltage- gated calcium signaling Muscle contraction occurs via excitation- contraction coupling Legend: Neurotransmission is sustained during Reversal of neuromuscular block repeated stimulation **See corresponding Calgary Guide slide Mechanism ↑ Activation of muscarinic receptors in myocardium ↑ Activation of muscarinic receptors in endothelial tissue Endothelial cells release nitric oxide Acetylcholine- activated potassium channels open Nitrous oxide causes vascular smooth muscle relaxation Sinoatrial node of the heart becomes hyperpolarized Vasodilation ↓ Vascular resistance Bradycardia Hypotension Depolarization block of nicotinic receptors in muscles Flaccid skeletal muscle paralysis Respiratory muscle paralysis & failure Bronchospasm & excess secretions Prolonged period of inadequate respiration ↓ Oxygen saturation ↑ Carbon dioxide ↑ Activation of gastrointestinal muscarinic receptors Stimulation of gastrointestinal muscles Activation of salivary muscarinic receptors ↑ Amplitude & duration of gut peristalsis ↑ Activity of salivary glands Overstimulation of the enteric nervous system Nausea ± vomiting ↑ Salivation Pathophysiology Sign/Symptom/Lab Finding Complications Published May 31, 2025 on www.thecalgaryguide.com

Meckels Diverticulum

Meckel’s Diverticulum: Pathogenesis and Clinical Findings No clear predisposition Stercolith (hard fecal mass) forms & is trapped in diverticulum Foreign body enters diverticulum & becomes trapped inside Incomplete vitelline duct obliteration (~5-7 weeks gestation) Diverticulum sags into Intussusception (section bowel lumen & acts as lead of intestine slides into Meckel’s Diverticulum point for intussusception adjacent region) Persistent remnant of vitelline duct containing all 3 layers of ileal mucosa (asymptomatic in 96-98% of cases) Diverticulum remains attached to umbilicus by persistent fibrous band Volvulus (loop of ileum twists around diverticulum) Ectopic tissue present within diverticulum Diverticulum goes through abdominal wall defect Littre’s Hernia (diverticulum in hernial sac) Diverticulum becomes incarcerated Ectopic gastric mucosa produces acid secretions Ectopic pancreatic tissue secretes digestive enzymes Ileal mucosa adjacent to diverticulum become ulcerated Inflammatory mediators disrupt hypothalamic regulation Small bowel becomes obstructed Perforation of diverticulum Brisk painless bleeding from small bowel Chronic inflammation & ulceration Fever Nausea/ vomiting Small bowel necrosis Hematochezia (bright red blood per rectum) ↓ Effective arterial blood volume Mucosa undergoes dysplastic & neoplastic transformation Complete erosion through ileal mucosa Small bowel perforation Hypotension Neuroendocrine tumour or other cancer Diverticulum becomes blocked & triggers local inflammatory response Meckel’s Diverticulitis Inflammation of Meckel’s Diverticulum Diverticulum is distended due to inflammation Visceral afferent nerves are stimulated by intestinal stretch Abdominal pain Chronic painless bleeding from small bowel Melena (partially digested blood in stool) Iron-deficiency anemia Authors: Taylor Krawec, Merry Faye Graff Reviewers: Emily J. Doucette, Sylvain Coderre* * Indicates MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Intestinal contents leak into peritoneum Peritonitis Systemic inflammatory response to peritonitis Published May 31, 2025 on www.thecalgaryguide.com Sepsis

Vaccine Mediated Immunity Comparing Vaccine Subtypes

Vaccine-Mediated Immunity: Comparing Vaccine Subtypes Live Attenuated Vaccines mRNA Vaccines Inactivated Component, Recombinant, Toxoid, Polysaccharide-Protein Conjugate Vaccines Measles/Mumps/Rubella (MMR), Varicella, Rotavirus, Influenza COVID-19 Serial passage in sub-optimal culture conditions weaken pathogen Pathogen maintains ability to slowly replicate (attenuated) Vaccine components (live attenuated pathogen, adjuvants, stabilizers, preservatives) are formulated & administered Attenuated pathogen enters host cells & replicates, mimicking natural infection Identify target protein of specific pathogen RNA polymerase transcribes DNA for target protein into mRNA (in vitro transcription) mRNA is purified & concentrated mRNA is encapsulated in lipid nanoparticles to prevent degradation Vaccine components (mRNA, lipid nanoparticles, adjuvants, preservatives) are formulated & administered Host cells take up mRNA & synthesize the antigenic protein Diphtheria, Tetanus, Pertussis, Pneumococcus, Meningococcus, Haemophilus influenzae type b, Influenza, Hepatitis B, Human Papilloma Virus Polio (IPV), Hepatitis A Antigen-presenting cells (APCs) take up intracellular & extracellular antigens Infected cells & APCs present intracellular antigens to CD8+ T cells via major histocompatibility complex-I (MHC-I) molecules Robust cell-mediated immunity ↑ Lymphocyte counts Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Authors: Tanis Orsetti Reviewers: Jessica Hammal Emily J. Doucette James D. Kellner* * MD at time of publication Inactivated Whole Virus Vaccines Identify target protein of specific pathogen (antigenic protein) Pathogen is inactivated using chemicals/detergents/heat Large quantity of antigenic protein produced in a laboratory setting Pathogen is unable to replicate Vaccine components (pathogen, adjuvants, stabilizers, preservatives) are formulated & administered APCs take up extracellular antigens APCs present extracellular antigens to CD4+ cells via major histocompatibility complex-II (MHC-II) molecules Activated CD4+ T helper cells stimulate B lymphocytes B lymphocytes produce antibodies specific to pathogen Robust humoral immunity ↑ Pathogen-specific antibody titers Published May 31, 2025 on www.thecalgaryguide.com

Chronic Mesenteric Ischemia

Chronic Mesenteric Ischemia: Pathogenesis and clinical findings Age Diabetes Smoking Genetic & environmental factors (etiology largely unknown) HLA-B52 allele & other genetic factors Dyslipidemia (abnormal blood lipid levels) Various etiologies (trauma, coagulopathies, inflammatory bowel disease, paraneoplastic syndrome, surgery, portal hypertension, cardiac) High blood pressure Fibromuscular dysplasia (systemic vascular disease) Takayasu’s arteritis (systemic inflammatory artery disease) Median arcuate ligament syndrome Atherosclerosis (plaque deposition in the subendothelium; cause of 90% of chronic mesenteric ischemia cases) Arterial wall thickening Growth & hardening of arterial wall Compression of celiac trunk by the median arcuate ligament Thromboembolism (clot formation) Turbulent blood flow at the level of the lesion Mesenteric artery stenosis (narrowing) Abdominal bruit (audible whoosh due to artery narrowing) Mucosal and submucosal injury & inflammation Insufficient blood supply to the gastrointestinal tract to meet demand (i.e., “intestinal angina”) Diarrhea ± constipation Gut motility dysfunction Activation of the vomiting centre in the brain Chronic Mesenteric Ischemia Chronic hypoperfusion of the bowel due to (typically) multivessel mesenteric artery stenosis or occlusion for >3 months Aortic dissection (tear) Radiation exposure Vascular injury Exposure of subendothelium & disruption of blood flow Mesenteric artery occlusion (blockage) Compensation by the mesenteric vasculature through expansion of collateral circulation Majority of patients are asymptomatic Nausea & vomiting Detectable stenosis/occlusion of mesenteric arteries Intake of food increases metabolic demand of bowel beyond levels accommodated by strained blood supply Mesenteric artery stenosis/ occlusion with medical imaging (ie. CT Angiogram) Postprandial abdominal discomfort (typically epigastric pain ~30 minutes following a meal, lasting for 1-4 hours) Published May 19, 2025 on www.thecalgaryguide.com Author: Liam Fitzgerald Reviewers: Sophia Khan Shahab Marzoughi Sergio F. Sharif Sylvain P. Coderre* * MD at time of publication Tobacco use Buerger’s disease (inflammatory artery disease) Formation of focal inflammatory blood clots Weight loss (>20 lbs) Food aversion, smaller meals, avoidance of fatty foods (caloric restriction) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Tetralogy of Fallot

Tetralogy of Fallot: Pathogenesis & Clinical Findings Authors: Genetic mutations Microdeletions Charissa Chen on chromosomes of q11 on Trisomies Akanksha Bhargava 20p12, 8q23, 5q34 chromosome 22 13, 18, 21 Sergio F. Sharif Reviewers: Julena Foglia Sunawer Aujla George S. Tadros Andrew Grant* Kim Myers* * MD at time of publication Maternal diabetes or phenylketonuria (PKU) Maternal exposure to alcohol or anticonvulsants Maternal infections (e.g., hepatitis B virus, coxsackievirus-B, human cytomegalovirus virus, rubella) Variable interaction between genetic associations and environmental risk factors Antero-cephalad deviation of conal septum (muscular structure that forms the boundary between right & left ventricular outflow tract during embryological development) Tetralogy of Fallot Cyanotic congenital heart disease with a combination of four cardiac defects Ventricular septal defect (VSD)** Overriding aortic root (aorta above VSD rather than left ventricle) Right ventricular outflow tract obstruction (RVOTO) Right Ventricular Hypertrophy Hole in septum Absent or reduced Stressors (eg., crying, between ventricles Right ventricle of Oxygenated blood from the left pulmonary valve defecation, fever, heart pumps ventricle and deoxygenated blood closure (P2) dehydration) trigger acute harder to push from right ventricle flows into aorta ↑ Left ventricular pressure infundibular spasm (spasm of blood through conus arteriosus) RVOTO Chronic volume overload L-R ventricular shunting Single, loud S2 Spasm ↓ blood flow through right ventricular outflow tract Aortic Dilated aortic root regurgitation** Hypercyanois or “tet” spells Turbulent blood flow from left ventricle through the hole in septum to right ventricle Turbulent diastolic backflow through incompetent aortic valve Deoxygenated blood flows through aorta to systemic circulation ↓ O2 Saturation Chemoreceptors in the carotid & aortic bodies stimulate respiratory centre in the medulla oblongata Harsh, holosystolic murmur Diastolic decrescendo murmur ↑ Deoxygenated blood entering systemic circulation ↑ Catecholamine release from adrenal medulla stimulating ↑ contractility of heart ↓ Blood flow across VSD ↑ contraction against outflow obstruction ↑ pulmonary vascular resistance ↓ Intensity or disappearance of holosystolic murmur Peripheral & central chemoreceptors detect ↓ arterial O2 content, triggering brainstem respiratory centre to stimulate ↑ work & rate of breathing ↓ Pulmonary blood flow ↑ Turbulence of blood flow through RVOTO ↑ R-L shunting ↑ Deoxygenated hemoglobin (dark red) relative to oxygenated hemoglobin (bright red), reflecting more blue light Cyanosis (blue discoloration of the mucous membranes, nail beds, skin) Paroxysmal hyperpnea (rapid and deep respirations) Irritability and crying Dyspnea (shortness of breath) Poor feeding Accentuation of systolic crescendo/decrescendo murmur with harsh ejection **See corresponding Calgary Guide slides Legend: Mechanism Published Jul 8, 2015; updated Jun 16, 2025 on www.thecalgaryguide.com Pathophysiology Sign/Symptom/Lab Finding Complications

Heparin-Induced Thrombocytopenia

Non-Immune Mediated: Type 1 (within two days of heparin administration) Platelets aggregate within the bloodstream ↓ Free unbound platelets in bloodstream Mild Thrombocytopenia: platelet count between 100 x 109/L - 150 x 109/L Fewer platelets available for thrombosis (formation of a pathological blood clot) Self limiting with no thrombotic risk Legend: Heparin-Induced Thrombocytopenia (HIT): Pathogenesis and clinical findings Obesity Hypertension Macrovascular disease Hyperlipidemia Heparin (often unfractionated) complexes with platelet factor 4 (PF4) on the platelet surface, due to heparin’s negative charge & PF4’s affinity for long-chain polysaccharides Immune-Mediated: Type 2 (within 5-15 days of heparin administration) Anti-heparin/PF4 Immunoglobulin G antibodies binds to the heparin-PF4 complex in the blood Splenic macrophages remove platelet- immunoglobulin G complexes in the spleen Thrombocytopenia: Platelet count < 100 x 109/L (though < 20 x 109/L should prompt consideration of other diagnoses) ↑ Vascular inflammation & endothelial dysfunction activate platelets Authors: Kelle Edgar, Hadi Hassan Sergio F. Sharif Reviewers: Haotian Wang, Jessica Asgarpour Yan Yu*, Lynn Savoie* Kareem Jamani* * MD at time of publication Activated platelets release PF4 Anti-heparin/PF4 antibodies activate adjacent platelets Activated platelets release inflammatory mediators Circulating anti- heparin/PF4 antibodies bind adjacent cellular targets Anti-heparin/PF4 antibodies bind endogenous heparan sulfate on endothelium Activated endothelium releases procoagulants thrombin & tissue factor Activated platelets release procoagulants (factors promoting blood clotting) Free platelets are consumed from formation of thrombi Hypercoagulable state (↑ risk of thrombosis) ↓ Platelets available to clot at different area of the body Thrombosis in coronary, peripheral or cerebral arteries Bleeding (rare) Myocardial infarction Acute ischemia Stroke Inflammatory mediators disrupt hypothalamic body thermoregulation Fever/ chills Inflammatory mediators promote vasodilation of arterioles under the skin ↑ Blood to surface of skin Flushing of skin Venous thrombosis in lower leg or lung Deep vein thrombosis Pulmonary embolism Microthrombi occlude vessels surrounding injection site, limiting nutrient supply Necrosis (tissue death) at heparin injection site Published Aug 29, 2014; updated Jun 16, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Obesity Hypoventilation Syndrome

Obesity Hypoventilation Syndrome: Pathogenesis and clinical findings Obesity (BMI ≥ 30 kg/m2) risk factors: Poor eating patterns, sedentary lifestyle, genetic predisposition, hypothyroidism, Cushing’s syndrome, socio-economic factors, age Sleep-disordered breathing risk factors: Family history, tonsillar or adenoidal hypertrophy, ↑ neck circumference, type 2 diabetes, HTN Authors: Mohammad Omer Mujtaba Siddique Reviewers: Ali Babwani Luiza Radu Jonathan Liu* MD at time of publication* ↑ Adipose deposition in abdomen Abdominal fat pushes against diaphragm ↑ Diaphragmatic displacement ↑ Resistance to chest wall expansion ↑Leptin resistance High pressure Pharyngeal on upper airway dilations unable Secondary depression ↓ Chest wall ↓ Leptins ability to stimulate ↑ lung to compensate Narrowing of (compromised function) of Poor ventilation to expansion ventilation (mechanism unknown) collapsibility for weight upper airways respiratory system lower lobes of lungs ↓ Tidal volume (air that moves in/out of lungs in a respiratory cycle) ↑ Respiratory rate ↑ Chest wall thickness ↑ Leptin (a hormone released by adipose tissues that controls hunger by signaling fullness) ↑ Adipose deposition near upper airways ↑ Buildup of edema in lower extremities ↑ Respiratory workload ↓ Chest wall compliance (ability to stretch) ↓ Leptin receptor expression ↓ Leptin through blood-brain barrier ↓ Pharyngeal space Respiratory system is unable to compensate to ↑ Fluid shifts from demands legs to neck during sleep Hypoventilation in sleep ↓ Ventilation (air exchange in lungs) ↑ PaCO₂ (partial pressure of arterial carbon dioxide) ↑ Serum [H+] ↑ Serum [HCO3 -] by renal reabsorption buffers [H+] rise ↓ PaO₂ (partial pressure of arterial oxygen) Hypoxia (low O₂ in tissue) Higher PaCO₂ required to reduce pH ↓ O₂ levels in alveoli triggers pulmonary vessel vasoconstriction PaCO₂ > 45 mmHG Respiratory acidosis ↓ response to CO₂ in central chemoreceptors in brain Pulmonary hypertension (high pressure in pulmonary arteries) ↓ Neural drive ↓ Ventilatory responsiveness ) Right heart pumps against higher pulmonary pressure leading to cardiomyocyte hypertrophy Cor pulmonale (right-sided heart failure) Fatigue Chronic hypercapnia (↑ CO2 retention) Pathophysiology Legend: Mechanism Sign/Symptom/Lab Finding Complications Morning headaches Daytime lethargy Published Jun 16, 2025 on www.thecalgaryguide.com

Varicella Zoster Virus

Varicella Zoster Virus (VZV) - Chicken Pox: Pathogenesis and clinical findings Exposure to individual with VZV infection VZV enters respiratory tract & conjunctiva VZV enters dendritic cells (DC) DCs travel to regional lymph nodes Primary viremia Authors: Morgan Garland, Sean Spence VZV replicates VZV proteins ↑ major ↓ MHCI Reviewers: in nasopharynx histocompatibility expression Yan Yu, Danny Guo, & CD4+ T cells complex class I on CD4+ T Emily J. Doucette, (MHCI) degradation cell surface Laurie Parsons*, James D. Kellner* *MD at time of publication Acute phase VZV evades the immune system VZV travels through the blood in CD4+ T cells Immune cells release cytokines to fight the virus (stronger in adults) Fluid & cellular debris accumulate between epidermal layers Generalized pruritic (itchy) vesicular rash at different stages of development (macule, papule, vesicle) Immune system activates & releases inflammatory compounds VZV replicates in liver, spleen & lymph nodes Erythema (redness) & pain Scratching lesions introduces bacteria Fibroblasts lay down collagen to heal skin lesions Resets thermostat in hypothalamus Systemic response Tissue damage in oropharynx Direct inflammation in neural tissues Cerebellar ataxia (more common in children) Bacterial superinfection from S. aureus & Streptococcus pyogenes (more common in children) Scarring Fever (prodromal) Malaise (prodromal) Sore throat (prodromal) Encephalitis (more common in adults) Abscess Cellulitis Toxic shock syndrome (TSS) Secondary viremia Immune cells release cytokines to fight infection (stronger in adults) Inflammation & fluid build up in lungs VZV travels through the blood in CD4+ T cells expressing skin homing receptors Fluid & cellular debris accumulate in damaged alveoli Lungs more susceptible to secondary bacterial infection Pneumonia** (more common in adults) VZV colonizes keratinocytes over several days VZV colonizes neurons & glial cells in the brain VZV colonizes alveolar epithelial cells Resolution & latency VZV tracks along neurons from sites of infection to dorsal root ganglia & cranial nerves ↓ MHCI expression in sensory ganglia Adaptive immune system controls viremia ↓ Viral gene expression Resolution of VZV infection & development of lifelong immunity Direct viral toxicity (DNA damage, mitochondrial dysfunction, & protein misfolds in infected cells) Apoptosis & dysfunction of infected cells Latent infection Stress or immune suppression may precipitate reactivation of VZV later in life Shingles** **See corresponding Calgary Guide slide Pathophysiology Mechanism Published Nov 12, 2012; updated Jun 22, 2025 on www.thecalgaryguide.com Legend: Sign/Symptom/Lab Finding Complications

Fluoroquinolones

Inhibition of cardiac voltage-gated potassium channels Delayed cardiac repolarization Fluoroquinolones: Mechanism of action & side effects Fluoroquinolones (FQs) Bactericidal antibiotics that inhibit bacterial DNA synthesis. Coverage depends on specific agent but includes gram-negatives (e.g., E. coli, H. influenzae), atypicals (e.g., Legionella, Mycoplasma), anaerobes & selected gram-positives (e.g., Streptococcus) High affinity for connective tissue FQ metabolism forms toxic metabolites & free radicals ↑ Concentration of FQ in tendons & connective tissue Toxic metabolites & free radicals accumulate in nerve tissue (mechanism poorly understood) ↑ Metalloprotease (MMP) activity & magnesium chelation (mechanism poorly understood) ↑ Inflammation & oxidative stress causes neuronal dysfunction & cell death Tendinopathy & tendon rupture Peripheral neuropathy (pain, numbness, weakness, tingling) Fluoroquinolones can cross placental membrane Collagenolytic effect of ↑ MMP-9 & MMP-2 disrupts aortic wall (mechanism poorly understood) Cartilage & bone toxicity in fetus Aortic dissection** & aortic aneurysm** **See corresponding Calgary Guide slide Pathophysiology FQ targets bacterial enzymes DNA gyrase & topoisomerase IV Structural similarity to gamma-aminobutyric acid (GABA) Broad-spectrum antibiotic FQ-DNA-enzyme complexes form & become irreversibly bound DNA replication fork movement is blocked causing DNA strand breakage DNA replication inhibition & bacterial cell death Bacterial clearance on microbiological culture Legend: Possible GABA antagonist (mechanism unclear) GABA binds less effectively to neurons in central nervous system (CNS) & exerts a weaker inhibitory effect ↑ Neuronal excitability & CNS stimulation ↓ Microbiome diversity ↑ Antibiotic- resistant strains ↑ Pathogenic & ↓ protective bacteria (gut dysbiosis) Gastritis (inflammation of the stomach lining) Clostridium difficile overgrowth & infection ↓ Seizure threshold Headache Insomnia Confusion Mechanism Sign/Symptom/Lab Finding Published Jun 22, 2025 on www.thecalgaryguide.com QT interval prolongation Torsades de Pointes** Blockage of ATP- sensitive potassium channels in pancreatic β cells ↑ β-cell membrane depolarization ↑ Insulin secretion Hypoglycemia** Authors: Ben Jackson Reviewers: Rafael Sanguinetti Luiza Radu Emily J. Doucette Meagan Deviaene* * MD at time of publication Complications

Unconjugated Hyperbilirubinemia

Pre-hepatic causes of ↑ bilirubin production Pathologic Unconjugated Neonatal Hyperbilirubinemia: Pathogenesis and clinical findings Hemolytic disease of the newborn** Isoimmune- mediated hemolysis Rhesus (Rh) factor incompatibility Maternal sensitization against Rh-positive fetal cells Maternal antibodies against Rh factor attack fetal RBCs ABO incompatibility Native maternal antibodies against non- native blood types attack fetal RBCs Sepsis** Widespread systemic inflammation Cytokines & complement factors damage RBC membranes Disseminated intravascular coagulation** (clotting proteins become overactive) Clots form in systemic circulation Small clots shear & damage RBCs in circulation Red blood cell (RBC) enzyme defects Glucose-6 phosphatase dehydrogenase (G6PD) deficiency** G6PD protects RBCs against oxidative damage ↑ RBC sensitivity to oxidative stress (during acute stressors) Pyruvate kinase deficiency (PKD) Abnormal glycolysis & cellular energy production ↓ RBCs life spans RBC membrane defects Hereditary spherocytosis RBCs are abnormally round (spherocytes) RBC membranes easily damaged in circulation Bilverdin reductase Hereditary elliptocytosis RBCs are abnormally elongated or oval converts bilverdin to Sickle cell Abnormal hemoglobin (HbS) RBCs become abnormally unconjugated bilirubin disease** polymerizes under ↓ O2 sickle shaped Hemoglobinopathies Thalassemia's** Defective hemoglobin chains in RBCs Irregularly shaped RBCs trapped in spleen RBC sequestration ↑ Production of RBCs (Polycythemia**) Accumulation of blood (i.e. Cephalohematoma, hemorrhage) ↑ RBC load & turnover Causes of ↓ hepatocellular bilirubin clearance Genetic defects in uridine diphosphate glucuronosyltransfe rase (UGT) enzyme (conjugates bilirubin in liver) Gilbert syndrome Unconjugated bilirubin ↓ UGT production remains insoluble & cannot Crigler–Najjar be excreted in bile syndrome Type II Crigler–Najjar syndrome Type I No UGT production Breast milk jaundice Breast milk contains β-glucuronidase Causes of ↑ entero-hepatic bilirubin circulation Intestinal obstruction Obstruction blocks bile flow from liver to intestines Breastfeeding jaundice Inadequate milk intake (volume depletion/dehydration) ↑ Reabsorption of bilirubin in the intestines **See corresponding Calgary Guide slide Legend: Macrophages engulf old or damaged RBCs in spleen & liver ↑ Hemolysis (RBC breakdown) RBCs release cellular contents including heme (from hemoglobin) Heme oxygenase converts heme to bilverdin ↑ Unconjugated (indirect) bilirubin accumulation in blood ↑ Total serum bilirubin levels Excess bilirubin deposition into elastin- rich tissues (eg. skin, sclera) due to ↑ affinity for elastin Pathologic neonatal jaundice (yellow discoloration of skin within first 24 hours of life) Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 13, 2025 on www.thecalgaryguide.com Authors: Merry Faye Graff Khushi Arora Reviewers: Annie Pham Emily J. Doucette Danielle Nelson* * MD at time of publication Hemolytic anemia** ↓ Bilirubin conjugation β-glucuronidase deconjugates bilirubin Bilirubin builds up in hepatic system Unconjugated bilirubin crosses blood-brain barrier Bilirubin-induced neurologic dysfunction (BIND) Kernicterus (bilirubin- induced neurological damage) Scleral icterus (yellowing of sclera in eyes)

Neuroanatomy and Physiology of Fear

Neuroanatomy and Physiology of Fear Sensory receptors detect an environmental stimulus (e.g., photoreceptors detect a snake-like image) Olfaction: olfactory bulb sends direct input to subcortical & cortical pathways Sight, sound, touch, & taste: thalamus† pre-processes & relays sensory information to subcortical & cortical pathways Authors: Taryn Stokowski Andrea Moir Reviewers: Erika Russell Usama Malik Emily J. Doucette Brienne McLane* * MD at time of publication Subcortical pathway (12 ms) Amygdala† initiates defensive response Nucleus accumbens (ventral basal ganglia) integrates input to bias selection of active (fight/flight) or passive (freeze) responses via ventral pallidum Periaqueductal gray (PAG) coordinates motor response Hypothalamus† coordinates the corresponding autonomic & hormonal responses Somatic motor system Medulla oblongata relays stimulation Endocrine system PAG activates brainstem motor nuclei & spinal cord Autonomic system Active only: hypothalamus† secretes corticotropin- releasing hormone Pituitary gland If active or releases If active early passive If passive adrenocorticotropic (dorsal If passive (sympathetic): (para- hormone** PAG): (ventral adrenal gland sympathetic): rapid, PAG): releases vagus nerve muscle whole- adrenaline releases Adrenal cortex releases cortisol activation body acetylcholine muscle tension Energy sustained (e.g, ↑ blood glucose) Defensive movement (e.g, startle or flee) Systemic physical response (e.g, ↑ heart rate) Cortical pathway (300 ms) Sensory cortices analyze the stimulus in detail (e.g., visual cortex determines that a coiled object is in view) Association areas in the parietal, temporal, and frontal lobes categorize the object based on previous knowledge (e.g., could this be a garden snake?) Insular cortex detects interoceptive information (e.g., awareness of racing heart) Hippocampus† uses memory to assign contextual meaning (e.g., has this type of snake harmed me before?) Prefrontal cortex (PFC) integrates interoceptive, sensory, & memory information to respond to stimulus Ventromedial PFC & anterior cingulate cortex† assess emotional salience & modulate subcortical response (e.g., ↓ arousal) Subjective experience of fear (e.g., I feel scared by that garden snake!) Emotion is regulated (e.g., body relaxes) †Part of the Limbic System **See corresponding Calgary Guide slide Note: This slide is based on the Two-System Framework by LeDoux & Pine (2016) Legend: Complications Published July 19, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding

Bilirubin Metabolism

Bilirubin Metabolism: Physiology Pre-Hepatic Macrophages in bloodstream & spleen phagocytize aging & damaged red blood cells (RBCs) Hemoglobin (Hb) is separated from RBC during phagocytosis & released into cytoplasm of macrophage Hb is broken down into heme & globin Circulating macrophages break down heme-containing proteins present in bloodstream (eg. myoglobin, cytochrome enzymes) Heme-oxygenase enzyme cleaves heme into biliverdin, Fe²⁺ & carbon monoxide Biliverdin reductase converts biliverdin to hydrophobic unconjugated bilirubin (UCB) Hepatic Albumin binds UCB in bloodstream & transports it to liver sinusoids (leaky capillaries allow for exchange of substances between blood & liver) UGT1A1 enzyme facilitates conjugation of UCB with glucuronic acid Conjugated bilirubin (CB) is water soluble & becomes component of bile A portion of urobilinogen returns to liver & becomes component of bile Bile is stored in gallbladder or secreted into small intestine through common bile duct Post-Hepatic Gut bacteria proteases process CB into urobilinogen ~20% of urobilinogen is absorbed & transported back to liver via portal system ~80% of urobilinogen is processed into urobilin & stercobilin by gut bacteria A portion of re-absorbed urobilinogen bypasses liver & enters systemic circulation Urobilin & stercobilin is excreted in feces Authors: Ethan Pichlyk* Taylor Krawec Reviewers: Annie Pham Emily J. Doucette Sarah Smith* *MD at time of publication Legend: Pathophysiology Urobilinogen is oxidized into urobilin in the kidneys Urobilin is excreted in urine Yellow urine Brown stool Mechanism Sign/Symptom/Lab Finding Complications Published July 24, 2025 on www.thecalgaryguide.com

Retropharyngeal Abscess

Retropharyngeal Abscess: Pathogenesis and clinical findings Viral upper respiratory tract infection (URTI) Secondary bacterial infection Bacterial URTI Dental infection Spinal discitis or osteomyelitis Retropharyngeal lymph nodes drain bacteria & debris from nasopharynx, adenoids, posterior paranasal sinuses & middle ear (these lymph nodes involute before puberty) Direct expansion into retropharyngeal space Microorganisms (classically polymicrobial), leukocytes & tissue debris secondary to infection accumulate in retropharyngeal space Retropharyngeal Abscess Collection of pus that develops in the retropharyngeal space between the buccopharyngeal fascia (anterior) & alar fascia (posterior) Inflammatory response Local tissue edema Worsening of mass effect Mass effect of abscess results in displacement or compression of trachea, esophagus or larynx Anterior & posterior cervical lymph nodes become inflamed Cervical lymphadenopathy Narrowing of airway lumen Compression of larynx &/or laryngeal nerves Neck swelling Neck extensor muscles become inflamed Partial Complete Pain with neck obstruction obstruction extension Dysphonia (hoarseness) Systemic cytokine release disrupts hypothalamic thermoregulation Asphyxiation Fever Narrowing of esophageal lumen Turbulent airflow through narrowed upper respiratory tract Insufficient tissue perfusion promotes compensatory ↑ respiratory rate ↓ Intrathoracic pressure Dysphagia (difficulty swallowing) Odynophagia (pain with swallowing) Difficulty swallowing oral secretions Stridor Tachypnea Intercostal retractions Drooling Legend: Oropharyngeal trauma Retropharyngeal space is inoculated with bacteria during traumatic injury Author: Stephanie de Waal* Reviewers: Annie Pham Taylor Krawec Michelle J. Chen Emily J. Doucette Danielle Nelson* *MD at time of publication Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Disruption of abscess results in rupture Mass effect partially relieved positionally Bacteria enters bloodstream Abscess contents drain into lower respiratory tract Sniffing position Sepsis (leaning forwards Aspiration pneumonia with slight neck extension) Spread of infection through alar fascia into “danger space” (region posterior to retropharyngeal space connecting to mediastinum) Spread of infection into mediastinum Descending necrotizing mediastinitis Published Aug 4, 2025 on www.thecalgaryguide.com

Autonomic Nervous System Overview

Autonomic Nervous System: Sympathetic vs Parasympathetic Physiology Sympathetic Nervous System (SNS) Parasympathetic Nervous System (PNS) Short preganglionic SNS neurons originate in thoracolumbar spinal cord (T1-L2) Long preganglionic PNS neurons originate in brainstem & sacral spinal cord (S2-S4) Authors: Aradhana Jacob Reviewers Allesha Eman Emily J. Doucette Jean Mah* * MD at time of publication Preganglionic neurons release excitatory neurotransmitter Acetylcholine (ACh) ACh binds nicotinic receptors on long postganglionic SNS neurons at the prevertebral ganglia (midline) or paravertebral ganglia (sympathetic chain) Postganglionic SNS neurons release norepinephrine (NE) NE binds α1- & β-adrenergic receptors in target organs NE binds α1 receptors on apocrine sweat glands Emotional sweating NE binds α1 receptors on radial muscle of the iris Contraction of radial muscle (dilator pupillae) Mydriasis (pupil dilation) NE binds α1 & β receptors on salivary gland acinar cells ↓ Saliva volume & ↑ protein content Xerostomia (dry mouth) NE binds β2 receptors on bronchial smooth muscle Inhibition of smooth muscle contraction Bronchodilation NE binds α1 & β2 receptors on hepatocytes ↑ Gluconeogenesis & ↑ glycogenolysis ↑ Blood glucose NE binds β1 receptors on the sinoatrial node in the heart ↑ Action potential frequency ↑ Heart rate NE binds α1 receptors on vascular smooth muscle Vascular smooth muscle contraction Vasoconstriction NE binds α1 receptors on smooth muscle of vas deferens, seminal vesicles, prostate, & internal urethral sphincter Smooth muscle contraction Seminal emission NE binds β2 receptors on GI smooth muscle GI smooth muscle relaxation ↓ GI motility ACh binds nicotinic receptors on short postganglionic PNS neurons located near or within target organs Postganglionic PNS neurons release ACh ACh binds muscarinic receptors in target organs ACh binds M3 receptors on sphincter pupillae muscle of iris Contraction of iris sphincter Myosis (pupil constriction) ACh binds M3 receptors on salivary gland acinar cells ↑ Saliva volume & ↑ salivary amylase ↑ Watery saliva ACh binds M3 receptors on Activation of smooth bronchial smooth muscle Bronchoconstriction muscle contraction ACh binds M3 receptors on Pancreatic β-cells ↑ Insulin secretion ↓ Blood glucose ACh binds M2 muscarinic receptors on the sinoatrial node in the heart ↓ Action potential frequency ↓ Heart rate ACh binds endothelial M3 receptors on blood vessels Vascular smooth muscle relaxation Vasodilation ↑ Nitric oxide production Smooth muscle relaxation in corpora cavernosa & vasodilation penile arteries Tumescence (penile erection) ACh binds M3 receptors on GI smooth muscle & glands ↑ Peristalsis (wave-like smooth muscle contractions) ↑GI motility Legend: Complications Published Aug 4, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding

Spina Bifida

↓ maternal dietary folate Spina Bifida: Pathogenesis and clinical findings Maternal obesity Maternal diabetes mellitus Maternal fungal fumonisin toxin exposure Metabolic syndrome Hyperglycemia Ceramide synthase inhibition Polymorphism of genes encoding MTHFR (methylene tetrahydrofolate reductase) Maternal valproic acid exposure Genetic factors (associated but not causative of NTDs) Potent histone deacetylase (HDAC) inhibition Disruption of genes of planar cell polarity pathway Trisomy 13 & 18 (mechanism unknown) Aberrant glucose control Reduced cell membrane folate-binding protein ↓ folate availability Disruption of Wnt signaling cascade MTHFR disfunction Mechanism unknown Suggested mechanism: disrupted Pax3 gene expression (mouse models) ↓ thymidine synthase activity Dihydrofolate reductase inhibition Disruption in gene expression DNA synthesis failure Aberrant cell migration during embryogenesis Primary neurulation failure (failed embryonic neural tube closure in the rostral–caudal axis) Neurulation failure (failed embryonic neural tube closure 4 weeks post-fertilization) Secondary neurulation failure (failed sacral and coccygeal spinal canalization) Meningeal and neuronal extrusion through incomplete vertebral arches without overlying skin Open spinal dysraphism Spina bifida aperta Failure of neural and mesodermal tissues to become distinct and spatially separated Myelomeningocele (bulging placode) Myelocele (placode flush with skin) Chiari II malformation (congenital posterior fossa malformation) Fetal protein leak into amniotic fluid and maternal circulation Neurodegeneration in utero due to amniotic fluid toxicity Skin overlying anomaly at the level of incomplete vertebral arch Closed spinal dysraphism Spina bifida occulta Tethered cord syndrome Adhered spinal cord subject to traction forces due to abnormal attachment Hydrocephalus ↑ Serum maternal alpha fetoprotein Findings at the level of the lesion ↑ fluid pressure on brain tissue Loss of motor & sensory function below level of dysraphism Ventriculomegaly Intellectual deficits Lipomyelocele (placode-lipoma interface within spinal canal) Lipomyelomeningocele (placode-lipoma interface outside spinal canal) Fatty filum (adipose infiltration of filum terminal) Split cord malformation (failed midline notochordal integration) Terminal myelocystocele (CSF filled cyst expanding spinal cord central canal) Meningocele (protrusion of meninges through vertebral arch deformity) Urinary & fecal Inability to walk incontinence Orthopedic sequelae: talipes (club foot), contractures, hip dislocation, scoliosis and kyphosis Lipomatous extrusion Sacral dimple Hairy patch Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 4, 2025 on www.thecalgaryguide.com Authors: Aryan Zawari Reviewers: Nojan Mannani, Shahab Marzoughi, Dr. Jay Riva-Cambrin* *MD at time of publication

Perioperative Aspiration Syndrome

Perioperative Aspiration: Pathogenesis and clinical findings ↑Intracranial Pressure Head trauma Drug or alcohol overdose Poorly managed perioperative and intraoperative pain Poorly managed gastroesophageal reflux disease History of upper or lower gastrointestinal surgery or obstruction, recent trauma Structural abnormalities (ie: hiatus hernia, incompetent lower esophageal sphincter) Authors: Punit Bhatt Reviewers: Priyanka Grewal Luiza Radu Leyla Baghirzada* *MD at time of publication Changing blood flow/stimulation of nucleus tractus solitarius Insufficient suppression of pain and reflexes Improper positive pressure ventilation Body habitus (pregnant, ascites, obesity, large abdominal tumors) Active labour Initiation of vomiting reflex by nucleus tractus solitarius Altered anatomy Emergency surgery Improper medication cessation (ie: opioid use or continuation of GLP-1 agonists History of gastroparesis Inadequate perioperative fasting Increased intraabdominal and intrathoracic pressure Inadequate gastric emptying and possible regurgitation into upper gastrointestinal tract Neurological or neuromuscular deficits Medication use (ie: local anesthetics) Decreased level of consciousness Air enters the stomach Inadequate anti-emetic and prophylactic therapy Difficulty swallowing or inadequate protective airway reflexes Regurgitation of stomach contents into the airway Fluids or secretions enter the airway Aspiration Inhalation of foreign material into respiratory tract Upper airway obstruction: From pharynx to larynx Fluid aspiration Lower airway obstruction: From trachea to alveoli Destruction of respiratory surfactant Complete airway obstruction No air exchange, no airflow into the lungs (↓ O2 and CO2 exchange) Partial airway obstruction Limited air exchange, some airflow into the lungs ↓ Air entry Narrowed airway Alveolar collapse Bronchodilation on inspiration allows air to enter, despite obstruction ↓ O2 and CO2 exchange Turbulent airflow Mismatch in O2 Hypoxia Turbulent airflow supply & due to narrowed myocardial O2 airway demand Cardiac Arrest Laryngeal Irritation (hoarseness of voice) Acute Respiratory Distress Syndrome ↑ Respiratory drive from brainstem Higher pitch sound ↑ Air velocity ↓ Air entry and incomplete ventilation of lungs Impaired vocal cord function Hypoxia Bronchospasm Hypoxia ↑ Air velocity Bronchoconstriction on expiration seals airway around obstruction Development of one-way valve: air can enter but not escape Higher pitch sound Tachypnea ↑ Work of breathing Expiratory wheeze ↓ Breath sounds Unilateral hyperinflation Inspiratory Stridor ↑ Work of breathing Acute Respiratory Distress Syndrome Diaphragm flattening Increased retrosternal airspace on chest X-Ray Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 12, 2025 on www.thecalgaryguide.com

Volatile Gases

Volatile Gases (e.g. desflurane, sevoflurane, isoflurane): Physiology & clinical findings Volatile agent (gas) delivered to the lungs Mean alveolar concentration of gas increases Gas enters the bloodstream via alveolar gas exchange Gas dissolves into lipid membranes within the central nervous system ↓ Pre-synaptic release of excitatory neurotransmitters (N- methyl-D-aspartate (NMDA), acetylcholine, serotonin, & glutamate) Inhibition of post- synaptic excitatory neurotransmitter receptors (NMDA, acetylcholine, serotonin, & glutamate) Distortion of electrophysiology of post-synaptic sodium channels Activation of post- synaptic potassium channels ↑ Presynaptic release of gamma- aminobutyric Post-synaptic cell acid (GABA) hyperpolarization Impaired neuronal depolarization ↓ Excitatory post- synaptic input ↑ Inhibitory post- synaptic input Disruption of synaptic transmission in cerebral cortex, basolateral amygdala, hippocampus, etc. Cerebral vasodilation & ↑ cerebral blood flow Authors: Punit Bhatt Billy Sun Reviewers: Priyanka Grewal Luiza Radu Melinda Davis* *MD at time of publication ↓ Pre-synaptic reuptake of GABA Activation of post- synaptic GABA receptors Amnesia Loss of consciousness ↑ Intracranial pressure Compression of brainstem resulting in stimulation of the vomiting region Nausea & Vomiting Legend: Disruption of potassium signaling in cerebral & systemic vasculature Decreased systemic vascular resistance Disruption of calcium signaling in cardiac myocytes Induction of Anesthesia Impaired smooth muscle contractility Negative inotropic effect Hypotension ↓ Stroke volume & consequently decreased cardiac output Tachycardia Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Disruption of synaptic transmission in medullary, respiratory, & phrenic motor neurons Neuromuscular blockade QT Prolongation Torsades de Pointes (Polymorphic Ventricular Tachycardia) Respiratory depression Hypercapnia (Elevated CO2 concentration in the blood) Muscle relaxation Unregulated release of calcium in susceptible patients Malignant hyperthermia (a life-threatening reaction to certain anesthetics)** ** See malignant hyperthermia slide Published Aug 12, 2025 on www.thecalgaryguide.com

Lupus Muco-cutaneous Manifestations

Lupus: Muco-cutaneous Manifestations Drugs (procainamide, hydralazine, sulfa antibiotics) Environmental factors (ultraviolet radiation, chemicals, Epstein Barr virus infection) Estrogen and prolactin hormones at birth Cell damage reduces clearance of intracellular contents and disrupts tolerance of immune cells towards self-tissue Genetic predisposition (HLA-DR2 & HLA-DR3): Increased autoimmune disorders Authors: Heena Singh Kevin Zhan Reviewers: Bill Ressl Matthew Harding Luiza Radu Liam Martin* Glen Hazlewood* *MD at time of publication Other autoimmune diseases such as thyroid disorders and Sjorgen’s disease Scaring alopecia (hair loss with scarring) Antibodies bind self-antigens & form soluble immune complexes (ICx) that deposit and promote inflammation in joints, skin & kidney Circulating ICx cause vascular/muco- membranous changes ICx activate and use up complement to induce tissue damage ↓ Complement levels (C3/C4) in blood (proteins involved in immune response) **See corresponding Calgary Guide slide Legend: Mechanism B cells are activated to produce autoantibodies towards intracellular contents ↑ Anti-DNA antibodies (anti-Ro, anti-La, anti- Sm, anti-RNP) ICx stimulate Langerhan cells and keratinocytes to release cytokines which induce localized inflammatory response Subacute cutaneous lupus: scaly annular lesions and plaques form in sun exposed areas Red plaques with keratotic scaling that extend inflammation onto hair follicles resulting in follicular plugging Discoid rash (chronic, scaring) Ultraviolet light ↑ cell death of keratinocytes within the skin Abnormal removal by phagocytes ↑ local inflammation on skin ICx & immunoglobulin deposit at the dermal-epidermal junction (not restricted to mucous membranes) Mouth/nasal ulcers Inflammation destroys hair follicles through complex mechanism Alopecia** Vasospasm of blood vessels in skin dermal layer (↓ release and activity of nitric oxide on endothelium as a vasodilator ) & ↓ venous circulation Malar (butterfly) rash Photosensitivity Livedo reticularis (net-like blue skin discoloration) Vasculitis Raynaud’s phenomenon: white/blue/red discoloration of toes and fingers induced by stress and cold Pathophysiology Sign/Symptom/Lab Finding Complications Published May 23, 2013; updated Aug 12, 2025 on www.thecalgaryguide.com

Chronic Thromboembolic Pulmonary Hypertension CTEPH Pathogenesis

Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Pathogenesis History of ↑ hypercoagulability from ↑ plasma clotting factor VIII Impaired clot breakdown from fibrin being resistant to plasmin-mediated lysis Impaired angiogenesis from improper vascular endothelial growth factor function Inflammation from chronic conditions or infected medical implants Legend: ↑ Incidence & persistence of clots Splenectomy (etiology unknown) Pro-thrombotic & impaired healing state Fibrin clots embed into blood vessel walls of pulmonary vasculature Pulmonary vasculature undergoes cellular remodeling in response to remnant clots Hypoxia & growth factors drives smooth muscle proliferation Chronic growth factors trigger faulty angiogenesis in pulmonary vasculature Clots activate platelets to release platelet derived & vascular endothelial growth factors Clots activate T cells to release pro-inflammatory cytokines Interleukin-6 & tissue necrosis factor-α Cytokines activate macrophages to release transforming growth factor-β (TGF-β) TGF-β triggers fibroblasts to deposit extra cellular matrix (ECM) Abnormal cell proliferation narrows lumen & impairs vasodilation Chronic inflammation & ECM deposits cause vessel thickening & fibrosis Vascular obstruction & fibrosis ↓ pulmonary arterial cross-sectional area & ↑ vascular resistance CT pulmonary angiography shows pulmonary artery occlusions with clots, webs, & stenotic lesions ↑ Blood pressure in unoccluded vessels of the pulmonary vasculature causes pulmonary hypertension** ↑ Pulmonary vascular resistance reduces cardiac output, especially during exertion CTEPH (Chronic Thromboembolic pulmonary hypertension): Prolonged occlusion of the pulmonary arteries due to intraluminal fibrosis of thromboembolic material from unresolved PE clots Exertional dyspnea** (difficulty breathing with physical activity) Progressive ↑ right ventricular pressure causes right atrial dilation & right ventricle hypertrophy Echocardiogram shows enlarged right atrium & right ventricle Right heart failure** **See corresponding Calgary Guide Slide(s) Authors: Dinusha T. Senaratne Devansh Bhatt Reviewers: Midas (Kening) Kang Usama Malik Sergio Sharif Natalie Morgunov* Lian Szabo* Jonathan Liu* * MD at time of publication Published Feb 7, 2018; updated Aug 13, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI): Pathogenesis and clinical findings Autosomal dominant (or less commonly autosomal recessive or de novo) mutation in COL1A1 or COL1A2 genes (collagen, type I, alpha 1 or 2) Loss of function of one copy of COL1A1 (collagen, type 1, alpha 1) OI Type I (mildest form) Osteogenesis Imperfecta Group of genetic disorders in which mutations impair the production or structure of type I collagen ↓ Synthesis of structurally normal type I collagen Mildly short stature ↓ Collagen in sclera of eyes Thin & translucent sclera Blue-colored choroid layer underneath the sclera is more visible ↑ Risk of scleral rupture Blue sclerae ↑ Bone fragility Fractures in infancy & adulthood Ossicles are brittle & misshapen Cubitus varus (elbow bends in towards body) Conductive hearing impairment Legend: Abnormal dentin (layer underneath enamel) development Dentinogenesis imperfecta (opalescent teeth) ↑ Tooth fractures & dental caries Extremely fragile & weak bones & connective tissue Progressive fracturing of ribs & underdevelopment of thoracic cavity (pectus deformities) Bowing &/or angulation deformities of long bones in- utero Heterozygous glycine substitution mutation in COL1A1 or COL1A2 OI Type II Synthesis of abnormal quality & ↓ quantity of type I collagen Improper bone mineralization Minimal calvarial (bones of skull) mineralization Multiple prenatal fractures Translucent skull on prenatal ultrasound Degeneration of cochlear structures Sensorineural hearing impairment Restricted lung growth Inadequate alveolar development & impaired gas exchange Severe respiratory insufficiency Beaded appearance of ribs on prenatal imaging Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Perinatal death or death by 4 weeks of age (90%) Authors: Berna Ilchi Reviewers: Annie Pham Emily J. Doucette Taylor Krawec Danielle Nelson* * MD at time of publication Published Aug 16 2025 on www.thecalgaryguide.com

Cystic Fibrosis

Authors: Navdeep Goraya, Spencer Montgomery Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery*, Danielle Nelson* *MD at time of publication Reproductive Manifestations Incomplete development of Wolffian duct derivatives (vas deferens, epididymis, & seminal vesicles) Cystic Fibrosis (CF): Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (transmembrane chloride ion channel found in exocrine tissue) dysfunction Mutated CFTR proteins prevent Cl- reabsorption in sweat glands ↑ Secretion of Cl- into sweat ↑ Sweat Cl- concentration Mutated CFTR proteins in duct epithelial tissue of other parts of the body prevent diffusion of Cl- into secretions ↓ Cl- diffusion into peri-ciliary fluid ↓ Water composition of peri-ciliary fluid ↓ Clearance of mucociliary secretions Secretions accumulate in secretory passages throughout the body Inhibition of sperm transport (obstructive azoospermia) Male infertility Upper Respiratory Tract Manifestations Retained secretions in sinuses Failure to clear bacteria in sinuses Persistent neutrophilic inflammation triggers tissue remodeling & mucosal overgrowth Bacterial proliferation Nasal polyps Chronic sinusitis Pancreatic Manifestations Trapped digestive enzymes degrade pancreatic tissue Pancreatic tissue damage triggers inflammation, scarring & fatty tissue replacement Islet cell damage & destruction Cystic-fibrosis related diabetes (CFRD) Lower Respiratory Tract Manifestations Retained secretions in airways Bacterial proliferation in lower airway Airway infection & inflammation Chronic productive cough Signs of obstructive lung disease (lung hyperinflation on x-ray & abnormal pulmonary function tests) Bronchitis ± bronchiectasis** ↓ Production & secretion of pancreatic enzymes into GI tract (pancreatic insufficiency) Fat & protein malabsorption Failure to thrive ↓ Absorption of fat-soluble vitamins Steatorrhea (↑ fat in stool) Vitamin D deficiency Vitamin K deficiency** Rickets** Osteoporosis** Coagulopathies Hepatic Manifestations Delayed passage of bile through biliary tree ↑ Loss of bile acids in stool Inflammatory hepatic response ↑ Production of lithogenic bile (bile supersaturated with cholesterol) Biliary cirrhosis with portal hypertension Cholelithiasis** Gastrointestinal (GI) Manifestations ↓ Movement of intestinal contents In newborns: Meconium ileus In children/adults: Distal ileal obstruction syndrome (DIOS) ↑ Retention of meconium ↑ Reabsorption of bilirubin Prolonged jaundice in neonates **See corresponding Calgary Guide slide Legend: Sign/Symptom/Lab Finding Complications Pathophysiology Mechanism Published Jan 21, 2013; updated Aug 20, 2025 on www.thecalgaryguide.com Reproductive Manifestations Degeneration of Wolffian duct derivatives (vas deferens, epididymis, & seminal vesicles) Inhibition of sperm transport (obstructive azoospermia) Male infertility Cystic Fibrosis (CF): Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) dysfunction Authors: Navdeep Goraya, Spencer Montgomery Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery*, Danielle Nelson* *MD at time of publication Mutated CFTR proteins prevent Cl- reabsorption in sweat glands ↑ Secretion of Cl- into sweat ↑ Sweat Cl- concentration Mutated CFTR proteins in duct epithelial tissue of other parts of the body prevent diffusion of Cl- into secretions ↓ Cl- diffusion into peri-ciliary fluid ↓ Water composition of peri-ciliary fluid ↓ Clearance of mucociliary secretions Secretions accumulate in secretory passages throughout the body Upper Respiratory Tract Manifestations Retained secretions in sinuses Failure to clear bacteria in sinuses Persistent neutrophilic inflammation triggers tissue remodeling & mucosal overgrowth Bacterial proliferation Nasal polyps Chronic sinusitis Lower Respiratory Tract Manifestations Retained secretions in airways Bacterial proliferation in lower airway Airway infection & inflammation Chronic productive cough Signs of obstructive lung disease (lung hyperinflation on x-ray & abnormal pulmonary function tests) Bronchitis ± bronchiectasis** Pancreatic Manifestations Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat & protein malabsorption ↓ Absorption of fat-soluble vitamins Failure to thrive ↓ Serum Vitamin D Osteoporosis** Trapped digestive enzymes degrade pancreatic tissue Tissue damage triggers inflammation, scarring & fatty tissue replacement Islet cell destruction Cystic-fibrosis related diabetes (CFRD) Hepatic Manifestations Delayed passage of bile through biliary tree Inflammatory hepatic response Cirrhosis** & portal hypertension Gastrointestinal Manifestations ↓ Movement of intestinal contents In newborns: Meconium ileus In children/adults: Distal ileal obstruction syndrome (DIOS) ↑ Retention of meconium ↑ Reabsorption of bilirubin Prolonged jaundice in neonates Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications **See corresponding Calgary Guide slide Published January 21, 2013 on www.thecalgaryguide.com Please only review slide 1 – slides 3-7 are previous draft versions. Thank you! Authors: Spencer Montgomery, Navdeep Goraya Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery*, Name Name* *MD at time of publication In the vas deferens in utero Cystic Fibrosis: Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) dysfunction Mutated CFTR proteins prevent Cl- reabsorption in sweat glands ↑ Secretion of Cl- into sweat ↑ Sweat Cl- concentration Mutated CFTR proteins in duct epithelial tissue of other parts of the body prevent diffusion of Cl- into secretions ↓ Cl- diffusion into peri-ciliary fluid ↓ Water composition of peri-ciliary fluid ↓ Clearance of mucociliary secretions Secretions accumulate in secretory passages throughout the body Degeneration of vas deferens, Wolffian ducts & associated structures Infertility in affected males In upper respiratory tract Retained secretions in sinuses Failure to clear bacteria in airways Persistent neutrophilic inflammation triggers tissue remodeling & mucosal overgrowth Bacterial proliferation Chronic sinusitis Nasal polyps In lower respiratory tract Chronic productive cough Retained secretions in airways Bacterial proliferation Airway infection & inflammation Signs of obstructive lung disease (lung hyperinflation on x-ray & abnormal pulmonary function tests) Bronchitis ± bronchiectasis** In pancreas Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat & protein malabsorption ↓ Absorption of fat- soluble vitamins Failure to thrive ↓ Serum Vitamin D Osteoporosis** Trapped digestive enzymes degrade pancreatic tissue Tissue damage triggers inflammation, scarring & fatty tissue replacement Islet cell destruction Cystic-fibrosis related diabetes (CFRD) In biliary tree Delayed passage of bile Inflammatory hepatic response Cirrhosis** & portal hypertension In GI tract ↓ Movement of intestinal contents In children/adults: Distal ileal obstruction syndrome (DIOS) In newborns: Meconium ileus ↑ Retention of meconium ↑ Reabsorption of bilirubin Prolonged jaundice in neonates Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 21, 2013 on www.thecalgaryguide.com Authors: Spencer Montgomery, Navdeep Goraya Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery*, Name Name* *MD at time of publication In the vas deferens in utero Cystic Fibrosis: Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) dysfunction Mutated CFTR proteins prevent Cl- reabsorption in sweat glands ↑ Secretion of Cl- into sweat ↑ Sweat Cl- concentration Mutated CFTR proteins in duct epithelial tissue of other parts of the body prevent diffusion of Cl- into secretions ↓ Cl- diffusion into peri-ciliary fluid ↓ Water composition of peri-ciliary fluid ↓ Clearance of mucociliary secretions Secretions accumulate in secretory passages throughout the body Degeneration of vas deferens, Wolffian ducts & associated structures Infertility in affected males In upper respiratory tract Retained secretions in sinuses Failure to clear bacteria in airways Persistent neutrophilic inflammation triggers tissue remodeling & mucosal overgrowth Bacterial proliferation Chronic sinusitis Nasal polyps In lower respiratory tract Chronic productive cough Retained secretions in airways Bacterial proliferation Airway infection & inflammation Signs of obstructive lung disease (lung hyperinflation on x-ray & abnormal pulmonary function tests) Bronchitis ± bronchiectasis** Trapped digestive enzymes degrade pancreatic tissue Inflammation Scarring & fatty tissue infiltration Islet cell destruction Type II Diabetes Mellitus** In pancreas Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat & protein malabsorption ↓ Absorption of fat- soluble vitamins Failure to thrive ↓ Serum Vitamin D Osteoporosis** In biliary tree Delayed passage of bile Inflammatory hepatic response Cirrhosis** & portal hypertension In GI tract ↓ Movement of intestinal contents In children/adults: Distal ileal obstruction syndrome (DIOS) In newborns: Meconium ileus ↑ Retention of meconium ↑ Reabsorption of bilirubin Prolonged jaundice in neonates Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 21, 2013 on www.thecalgaryguide.com In the vas deferens in utero Retained secretions in sinuses Cystic Fibrosis: Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) dysfunction Mutated CFTR proteins prevent Cl- reabsorption in sweat glands ↑ Secretion of Cl- into sweat ↑ Sweat Cl- concentration Mutated CFTR proteins in duct epithelial tissue of other parts of the body prevent diffusion of Cl- into secretions ↓ Cl- diffusion into peri-ciliary fluid ↓ Water composition of peri-ciliary fluid ↓ Clearance of mucociliary secretions Accumulation of secretions in secretory passages throughout the body obstructing these passages Authors: Spencer Montgomery, Navdeep Goraya Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery* *MD at time of publication Degeneration of vas deferens, Wolffian ducts & associated structures Infertility in affected males In upper respiratory tract Failure to clear bacteria in airways Bacterial proliferation Chronic sinusitis Nasal polyps In lower respiratory tract Chronic productive cough Retained secretions in airways Bacterial proliferation Airway infection & inflammation Signs of obstructive lung disease i.e. lung hyperinflation on x-ray & abnormal pulmonary function tests Bronchitis ± bronchiectasis Trapped digestive enzymes degrade pancreatic tissue Inflammation Scarring & fatty tissue infiltration Islet cell destruction Type II Diabetes Mellitus In pancreas Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat and protein malabsorption ↓ Absorption of fat- soluble vitamins Failure to thrive ↓Serum Vitamin D Osteoporosis In biliary tree Delayed passage of bile Inflammatory hepatic response Cirrhosis & portal hypertension In GI tract ↓ Movement of intestinal contents In children/adults: Distal ileal obstruction syndrome (DIOS) In newborns: Meconium ileus ↑ Retention of meconium ↑ Reabsorption of bilirubin Prolonged jaundice in neonates Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 21, 2013 on www.thecalgaryguide.com In the vas deferens in utero Cystic Fibrosis: Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) dysfunction Chloride channel no longer allows Cl- transport CFTR proteins in sweat glands reabsorb Cl- CFTR proteins in duct epithelial tissue of other parts of the body facilitate diffusion of Cl- into secretions ↓Reabsorption ↓Cl- diffusion into peri-ciliary fluid ↓Water composition of peri-ciliary fluid ↑Secretion of Cl- into sweat ↓Clearance of mucociliary secretions ↑Sweat Cl- concentration Accumulation of secretions in secretory passages throughout the body obstructing these passages Degeneration of vas deferens, Wolffian ducts & associated structures Authors: Spencer Montgomery, Navdeep Goraya Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery* *MD at time of publication Infertility in affected males In upper respiratory tract Retained secretions in sinuses Nasal polyps Bacterial proliferation Chronic sinusitis In lower respiratory tract Chronic productive cough Retained secretions in airways Bacterial proliferation Signs of obstructive lung disease i.e. lung hyperinflation on x-ray & abnormal pulmonary function tests Airway infection & inflammation Bronchitis ± bronchiectasis Trapped digestive enzymes degrade pancreatic tissue Inflammation Scarring & fatty tissue infiltration Islet cell destruction Type II Diabetes Mellitus In pancreas Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat and protein malabsorption ↓Absorption of fat- soluble vitamins Failure to thrive ↓Serum Vitamin D Osteoporosis In biliary tree Delayed passage of bile Inflammatory hepatic response Cirrhosis & portal hypertension In GI tract ↓Movement of intestinal contents In children/adults: Distal ileal obstruction syndrome (DIOS) In newborns: Meconium ileus ↑Retention of meconium ↑Reabsorption of bilirubin Prolonged jaundice in neonates Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 21, 2013 on www.thecalgaryguide.com In the vas deferens in utero Degeneration of vas deferens, Wolffian ducts and associated structures Infertility in affected males Legend: Cystic Fibrosis: Pathogenesis, clinical findings, and complications Mutation of Cystic Fibrosis Transmembrane Regulator (CFTR) gene on chromosome 7 à Dysfunction of the CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) Author: Spencer Montgomery Reviewers: Yan Yu, Kayla Nelson, Mark Montgomery* * MD at time of publication Chloride channel no longer allows Cl- transport In sweat glands, CFTR proteins are responsible for the reabsorption of Cl- In duct epithelial tissue of other parts of the body, CFTR proteins facilitate diffusion of Cl- into secretions Notes: • The CFTR mutation exhibits an autosomal recessive inheritance pattern • > 1700 different CFTR gene mutations are identified, ∆F508 mutation accounts for ~67% of cases in Caucasians. • Cystic fibrosis is diagnosed based presence of ↑ sweat chloride concentration, disease causing CFTR mutations, & symptoms of ≥ 1 associated organ system ↓ Cl- diffusion into peri-ciliary fluid → ↓water composition of peri-ciliary fluid In children/adults: Distal ileal obstruction syndrome (DIOS) ↓ reabsorption = ↑secretion of Cl- into sweat In GI tract ↓movement of intestinal contents ↓ clearance of mucociliary secretions In newborns: Meconium ileus ↑ retention of meconium → ↑ reabsorption of bilirubin Prolonged jaundice in neonates ↑ Sweat chloride concentration Accumulation of secretions in secretory passages throughout the body, obstructing these passages In biliary tree Delayed passage of bile → inflammatory hepatic response Cirrhosis & portal hypertension In upper respiratory tract In pancreas Trapped digestive enzymes degrade pancreatic tissue Nasal polyps Retained secretions in sinuses → bacterial proliferation Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat and protein mal- absorption ↓ absorption of fat soluble vitamins Inflammation → scarring & fatty tissue infiltration → islet cell destruction Chronic sinusitis ↓ serum Vit. D Type II Diabetes Mellitus Failure to thrive Osteoporosis Published January 21, 2013 on www.thecalgaryguide.com In lower respiratory tract Chronic productive cough Retained secretions in airways → bacterial proliferation à Airway infection & inflammation Persistent respiratory tract infections Can progress to chronic bronchitis ± bronchiectasis (This is the biggest cause of death in CF) Pathophysiology Signs of obstructive lung dx: i.e. Lung hyperinflation (on x-ray), Abnormal pulmonary function tests Mechanism Sign/Symptom/Lab Finding Complications

Propofol

Propofol: Mechanism of Action & Side Effects Primary Process ↑ Allosteric binding affinity (binds to a site other than the active site on the receptor to induce conformational changes) of Gamma- aminobutyric acid (GABA) to GABAA receptor in brain (ionotropic receptor) GABA remains bound to GABAA receptor Prolonged opening of chloride channels in neuronal cell membrane Influx of negatively charged chloride into neuron Hyper- polarization of nerve cell membrane ↑ Difficulty reaching threshold for action potential ↓ Number of successful action potentials Inhibition of central nervous system Central Nervous System ↓ Neuronal activity ↓ Level of consciousness, achieving sedation or general anesthesia (dose-dependent effect) ↓ Cerebral metabolic activity ↓ Cerebral blood flow ↓ Intracranial pressure Respiratory System Inhibition of central respiratory centers in brainstem Relaxation of upper airway muscles ↓ Hypercapnic & hypoxic ventilatory drive Airway obstruction ↓ Respiratory rate ↓ Tidal volume Hypoxemia Hypercapnia Apnea Cardiovascular System Inhibition of sympathetic cardiovascular activity Inhibition of cardiac smooth & striated muscle activity ↓ Baroreceptor response to decrease in blood pressure Vasodilation ↓ Myocardial contractility ↓ Systemic (minor effect) vascular resistance Diminished reflex tachycardia Diminished vasoconstrictor response Hypotension Authors: Caitlin Bittman Ryden Armstrong Reviewers: Billy Sun, Joseph Tropiano Priyanka Grewal Luiza Radu Melinda Davis* * MD at time of publication Secondary Process Direct interaction with α1 subunit of L-type calcium channels Alteration of calcium channel conformation Inhibition of voltage-gated calcium channels ↓ Response to depolarization signals Smooth & striated muscle relaxation throughout body ↓ Calcium ion influx into smooth & striated muscle cells, & ↓ cell depolarization Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 3, 2018; updated Aug 28, 2025 on www.thecalgaryguide.com

Genital Prolapse

Instrument-assisted vaginal deliveries (especially forceps) ↑ risk of levator muscle avulsion Pelvis widens during Valsalva maneuver (straining downwards to ↑ intra-abdominal pressure) ↑ Support needed to hold pelvic organs, which may eventually fail Genital Prolapse: Pathogenesis, clinical findings, & complications Pregnancy Levator ani muscle is injured or denervated due to overstretching & or compression during labour Levator ani muscle loses tone Genital hiatus opening enlarges Pelvic diaphragm descends & forms a funnel shape Ligamentous & connective tissue (e.g., arcus tendineus fascia pelvis, arcus tendineus levator ani, uterosacral ligaments) bear the ↑ abdominal pressure load Ligamentous & connective tissue stretch & may eventually fail with time ↑ Internal pressure from pelvic organ tissues pushes against pelvic muscles Hysterectomy Disruption to pelvic structural supports (particularly uterosacral ligament), pelvic blood supply, & or innervation during operation ↓ Pelvic organ support, which may fail with time Authors: Sara Cho Reviewers: Michelle J. Chen Jessica Revington Rachel Wang* * MD at time of publication Unclear mechanism Pelvic & or low back pain Dyspareunia (pain during intercourse) Legend: Pathophysiology Mechanism Conditions with impaired collagen quality (e.g. Ehlers-Danlos syndrome, Marfan syndrome) Alterations in collagen & elastin synthesis Dysfunction of pelvic connective tissue Aging/menopause ↓ Systemic estrogen concentrations ↓ Smooth muscle cell proliferation & collagen synthesis in tissues with estrogen receptors (e.g., endopelvic fascia, arcus tendineus, levator ani, uterosacral ligament) Chronic cough Frequent contraction of abdominal & pelvic muscles Chronic constipation Patient constantly bears down, contracting abdominal & pelvic muscles Genetic factors (e.g., family history of prolapse, urinary incontinence, abdominal or inguinal hernia) Obesity Surrounding adipose tissue ↑ intra-abdominal pressure ↑ Stress on pelvic supporting structures Repeated ↑ in intra- abdominal pressure Combination of risk factors that contribute to, predispose, promote, or worsen prolapse Sign/Symptom/Lab Finding ↓ Pelvic organ support, which may fail with time Genital Prolapse Vaginal or uterine descent through the introitus (genital opening) Rectum pushes against the vaginal wall & widens the anorectal angle (angle between anal canal & rectum) Fecal incontinence Published Aug 25, 2025 on www.thecalgaryguide.com Weakened pelvic floor muscles provide ↓ structural support & ↑ hypermobility of the urethra & bladder neck Urinary incontinence Complications

Hypocalcemia Physiology

Hypocalcemia: Physiology Hypomagnesemia** Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis** or severe illness Authors: Serra Thai, Ryan Dion Reviewers: Jessica Hammal, Michelle J. Chen, Emily J. Doucette, Hanan Bassyouni* * MD at time of publication Parathyroid gland hypofunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge Syndrome) Impaired Mg-dependent generation of cyclic adenosine monophosphate ↑ Systemic inflammation ↑ Calcium sequestration into cells (mechanism of action unknown) ↓ Liver function & albumin synthesis ↓ Or inappropriately normal parathyroid hormone (PTH) in circulation ↓ PTH receptor (PTHR) sensitivity ↓ Albumin-bound calcium in blood ↓ PTHR signaling in kidneys ↓ PTHR signaling in osteoblastic lineage Vitamin D deficiency** (e.g. cells within bones ↓ intake, malabsorption) False hypocalcemia (↓ total serum calcium with normal Ca2+ levels) Acute pancreatitis** ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule Chronic kidney disease (CKD)** ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to active form) activity in kidneys ↑ Claudin14 (tight junction membrane proteins) expression in thick ascending limb (TAL) of the loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in distal convoluted tubule ↓ Nuclear factor kappa B ligand (RANKL) expression & binding to receptors on osteoclast precursor cells Pancreatic enzymes are prematurely activated ↓ Sodium reabsorption triggers electrochemical gradient changes ↓ Glomerular filtration due to ↓ kidney function ↓ Activated vitamin D (calcitriol) synthesis Claudin14 binds cation channels composed of Claudin16 & 19 in TAL tight junctions Lipase released from pancreatic autodigestion breaks down peripancreatic fat ↓ Renal phosphate filtration from blood ↓ Binding of vitamin D regulated calcium transporters in duodenum & jejunum Binding blocks paracellular Ca & Mg transport from tubule into vasculature through tight junctions ↓ Probability of calcium transport channels opening ↓ Osteoclast differentiation (responsible for breaking down bone) Free fatty acids bind ionized Ca2+ to form insoluble calcium soaps (saponification) ↓ Circulating ionized calcium in blood ↑ Phosphate-calcium crystal formation ↓ Gastrointestinal ↓ Renal reabsorption ↓ Bone resorption of calcium of calcium reabsorption of calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 23, 2025 on www.thecalgaryguide.com Hypocalcemia: Physiology Authors: Serra Thai Ryan Dion Reviewers: Jessica Hammal Michelle J. Chen Emily J. Doucette Hanan Bassyouni* * MD at time of publication Parathyroid gland dysfunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge) ↓ Parathyroid hormone (PTH) in circulation ↓ PTHR signaling in kidneys Chronic kidney disease (CKD) ↓ Renal blood flow ↓ Glomerular filtration ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate-calcium complex formation **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Hypomagnesemia** Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis** or severe illness Impaired Mg-dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ PTH receptor (PTHR) sensitivity ↑ Calcium sequestration into cells (unknown mechanism of action) ↓ Liver function Vitamin D deficiency (e.g. ↓ intake, malabsorption) ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to active form) activity in kidneys ↑ Claudin14 (tight junction membrane protein) proteins are expressed in the thick ascending loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule ↓ Synthesis of activated vitamin D (calcitriol) Claudin14 binds to cation channels composed of Claudin16 & 19 found ↓ Binding of vitamin D in TAL tight junctions regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum Binding blocks paracellular Ca & Mg transport from tubule into vasculature through tight junctions between cells ↓ Probability of calcium transport channels opening ↓ Gastrointestinal reabsorption of Ca ↓ Renal reabsorption of calcium ↓ Synthesis of albumin ↓ PTHR signaling in osteoblastic lineage cells in bones ↓ Nuclear factor kappa B ligand (RANKL) expression & binding to receptors on osteoclast precursor cells ↓ Osteoclast differentiation (responsible for breaking down bone) ↓ Bone resorption ↓ Albumin- bound calcium with normal free (biologically active) Ca levels False hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) Published MONTH, DAY, YEAR on www.thecalgaryguide.com Sign/Symptom/Lab Finding Complications Hypomagnesemia* Impaired magnesium- dependent generation of cyclic adenosine monophosphate ↓ PTH receptor (PTHR) sensitivity Hypocalcemia: Physiology Authors: Serra Thai Ryan Dion Reviewers: Jessica Hammal Michelle J. Chen * MD at time of publication Parathyroid gland dysfunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge) Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis or severe illness ↓ Parathyroid hormone (PTH) in circulation ↓ PTHR signaling in kidneys Vitamin D deficiency (e.g. ↓ intake, malabsorption) ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to its active form) activity in the kidneys ↑ Claudin14 (tight junction membrane protein) proteins are expressed in the thick ascending loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule Chronic kidney disease ↓ Sodium reabsorption ↓ Synthesis of activated vitamin D (calcitriol) ↓ Renal blood flow Electrochemical gradient changes Claudin14 binds to cation channels composed of Claudin16 & 19 found in TAL tight junctions ↓ Glomerular filtration ↓ Phosphate excretion ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum Binding blocks paracellular Ca (and Mg) transport from the tubule into vasculature through tight junctions between cells ↓ Probability of calcium transport channels opening ↑ Phosphate-calcium complex formation ↓ Gastrointestinal reabsorption of Ca ↓ Renal reabsorption of calcium *See corresponding Calgary Guide slide: “Hypomagnesemia: Physiology” ** See corresponding Calgary Guide slide: “Hypoca;cemia: Clinical Findings” Legend: ↑ Inflammation ↑ Ca sequestration into cells (unknown mechanism of action) ↓ Liver function ↓ Synthesis of albumin ↓ PTHR signaling in osteoblastic lineage cells in bones ↓ Nuclear factor kappa B ligand (RANKL) expression and binding to its receptors on osteoclast precursor cells ↓ Differentiation of osteoclasts which are responsible for breaking down (resorbing) bone ↓ Bone resorption ↓ Albumin- bound calcium with normal free (biologically active) Ca levels False hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Hypocalcemia: Physiology Authors: Serra Thai Reviewers: Jessica Hammal Michelle J. Chen * MD at time of publication Parathyroid gland dysfunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge) Hypomagnesemia** Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis or severe illness Impaired magnesium- dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ Parathyroid hormone (PTH) in circulation ↓ PTH receptor (PTHR) sensitivity ↑ Ca sequestration into cells (unknown mechanism of action) ↓ Liver function ↓ Synthesis of albumin ↓ PTHR signaling in kidneys Vitamin D deficiency (e.g. ↓ intake, malabsorption) ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to its active form) activity in the kidneys ↑ Claudin14 (tight junction membrane protein) proteins are expressed in the thick ascending loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule Chronic kidney disease ↓ Sodium reabsorption ↓ Synthesis of activated vitamin D (calcitriol) ↓ Renal blood flow Electrochemical gradient changes Claudin14 binds to cation channels composed of Claudin16 & 19 found in TAL tight junctions ↓ Glomerular filtration ↓ Phosphate excretion ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum Binding blocks paracellular Ca (and Mg) transport from the tubule into vasculature through tight junctions between cells ↓ Probability of calcium transport channels opening ↑ Phosphate-calcium complex formation ↓ Gastrointestinal reabsorption of Ca ↓ Renal reabsorption of calcium ↓ PTHR signaling in osteoblastic lineage cells in bones ↓ Nuclear factor kappa B ligand (RANKL) expression and binding to its receptors on osteoclast precursor cells ↓ Differentiation of osteoclasts which are responsible for breaking down (resorbing) bone ↓ Bone resorption ↓ Albumin- bound calcium with normal free Ca levels due to homeostatic mechanisms False hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) Published MONTH, DAY, YEAR on www.thecalgaryguide.com **See corresponding Calgary Guide slide: “Hypomagnesemia: Physiology” Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Hypocalcemia: Physiology Hypomagnesemia** Authors: Serra Thai Reviewers: Jessica Hammal * MD at time of publication Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Vitamin D deficiency: ↓intake, malabsorption Pseudohypoparathyroidism Sepsis/severe illness ↓PTHR activation in kidneys CKD ↓ Renal blood flow ↓ Glomerular filtration ↓ Sodium- hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation **See corresponding Calgary Guide slide(s) Legend: ↓ 1-alpha hydroxylase enzyme activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Pathophysiology Mechanism Sign/Symptom/Lab Finding Impaired magnesium dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ Parathyroid hormone (PTH) ↑ Claudin14 (tight junction membrane protein) activity in the thick ascending loop of Henle ↑ Binding of claudin14 to claudin16 Inhibition of claudin 16 & 19 from forming cation permeable pores in the tight junctions ↑ Calcium sequestration ↓ Liver function into cells (mechanism of action ↓ Synthesis of albumin ↓ PTH receptor remains (PTHR) sensitivity ↓ Albumin- unknown) bound calcium with normal ↓ PTHR activation in bones free Ca levels due to homeostatic mechanisms ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule ↓ Probability of calcium transport channels opening ↓ Renal reabsorption of calcium ↓ Osteoblast stimulation ↓ Nuclear factor kappa b ligand (RANKL) secretion ↓ Nuclear factor kappa b receptor (RANK) binding on osteoclast precursors cells ↓Osteoclast production ↓ Bone resorption False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2 <2.1mmol/L+]) Published MONTH, DAY, YEAR on www.thecalgaryguide.com Complications Hypocalcemia: Physiology Hypomagnesemia** Authors: Serra Thai Pseudohypoparathyroidism Reviewers: Jessica Hammal * MD at time of publication Vitamin D deficiency: ↓ intake, malabsorption ↓ 1-alpha hydroxylase enzyme activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) CKD ↓ Renal blood flow ↓ Glomerular filtration **See corresponding Calgary Guide slide(s) Legend: Sepsis/severe illness Impaired magnesium dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ Signaling proteins ↓ Parathyroid hormone (PTH) ↓ PTH receptor (PTHR) sensitivity ↑ Calcium sequestration into cells (mechanism of action remains unknown) Pathophysiology Mechanism ↓PTHR1 activation in kidneys ↓ Activation of G- coupled protein signaling pathways ↑ Expression of sodium-phosphate co-transporters (NaPiIIa & NaPIIc) in proximal tubule ↓ Expression & phosphorylation of transient receptor potential vanilloid (TRPV5, calcium transporter channel) in distal convoluted tubule ↓ PTHR1 activation in bones ↓ Osteoblast ↑ Claudin14 (tight stimulation junction membrane protein) activity in the thick ascending loop of Henle ↓ Nuclear factor kappa b ligand (RANKL) secretion ↑ Binding of claudin14 to claudin16 ↓ Nuclear factor kappa b receptor Inhibition of (RANK) binding on osteoclast ↓ Phosphate excretion Electrochemical ↓ Amount of claudin 16 & 19 gradient TRPV5 & ↓ from forming precursors cells changes probability of cation-permeable channels pores in the tight ↑ Phosphate opening junctions calcium ↓Osteoclast production complex formation ↓ Paracellular transport of calcium ↓ Renal reabsorption of calcium ↓ Bone resorption Published MONTH, DAY, YEAR on www.thecalgaryguide.com ↓ Liver function ↓ Synthesis of albumin ↓ Albumin- bound calcium with normal free calcium levels due to homeostatic mechanisms False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2 <2.1mmol/L+]) Sign/Symptom/Lab Finding Complications Hypocalcemia: Physiology Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Hypomagnesemia** Impaired magnesium dependent generation of cyclic adenosine monophosphate ↓ Parathyroid hormone (PTH) ↓ PTH sensitivity Vitamin D deficiency: ↓intake, malabsorption ↓ Enzyme 1-alpha hydroxylase activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Legend: ↓PTH receptor activation in kidneys ↑ Claudin14 activity in the thick ascending loop of Henle Inhibition of claudin 16 & 19 from forming cation permeable pores in the tight junctions ↓ Transcription of calcium transporter genes in the distal convoluted tubule ↓ Probability of calcium transport channels opening ↓ Renal reabsorption of calcium ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications ↑ Inflammation Authors: Serra Thai Reviewers: Jessica Hammal * MD at time of publication Sepsis/severe illness ↑ Calcium sequestration into cells ↓ Liver synthesis of albumin ↓ Albumin- calcium binding False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Levels of undigested fats in small intestine Free fatty acids percipitate calcium ↓ PTH receptor activation in bones ↓ Osteoblast stimulation ↓ RANKL ligand secretion ↓ RAANK receptor binding ↓Osteoclast production ↓ Bone resorption Hypocalcemia (serum [Ca2+] <2.1mmol/L) Published MONTH, DAY, YEAR on www.thecalgaryguide.com Hypocalcemia: Physiology Vitamin D deficiency: ↓intake, malabsorption Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Hypomagnesemia** Impaired magnesium dependent generation of cyclic adenosine monophosphate ↓ Parathyroid hormone (PTH) ↓ PTH sensitivity ↓ Enzyme 1-alpha hydroxylase activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Legend: ↓PTH receptor activation in kidneys ↑ Claudin14 activity in the thick ascending loop of Henle Inhibition of claudin 16 & 19 from forming cation permeable pores in the tight junctions ↓ Transcription of calcium transporter genes in the distal convoluted tubule ↓ Probability of calcium transport channels opening ↓ Renal reabsorption of calcium ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications ↑ Inflammation Sepsis/severe illness ↑ Calcium sequestration into cells ↓ Liver synthesis of albumin ↓ Albumin- calcium binding False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Levels of undigested fats in small intestine Free fatty acids percipitate calcium ↓ PTH receptor activation in bones ↓ Osteoblast stimulation ↓ RANKL ligand secretion ↓ RAANK receptor binding ↓Osteoclast production ↓ Bone resorption Hypocalcemia (serum [Ca2+] <2.1mmol/L) Authors: Name Name Name Name* Reviewers: Name Name Name Name* * MD at time of publication Published MONTH, DAY, YEAR on www.thecalgaryguide.com Hypocalcemia: Physiology Chronic kidney disease ↓ Renal blood flow ↓ Glomerular filtration Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Vitamin D deficiency: ↓intake, malabsorption Sepsis/severe illness ↓ NHE3 activity and expression in proximal tubule ↓PTH receptor activation in kidneys ↑ Claudin14 activity in the thick ascending loop of Henle ↓ Parathyroid hormone (PTH) ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule ↓ Enzyme 1-alpha hydroxylase activity ↓ PTH receptor activation in bones ↓ osteoblast stimulation ↓ RANKL ligand secretion ↑ Inflammation ↓ PTH sensitivity ↓ Glomerular filtration ↓ Liver synthesis of serum albumin False Hypocalcemia ↑ Calcium sequestration into cells** ↓ Lipase secretion from pancreas Acute pancreatitis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding ↓ Albumin- bound calcium Current mechanism is unknown ↑ levels of undigested fats in small intestine Complications Hypomagnesemia Multiple blood transfusions ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation Inhibits claudin16 and 19 from forming cation permeable pores in the tight junctions ↓Probability of calcium transport channels opening ↓ Synthesis of activated vitamin D (calcitriol) ↓ RAANK receptor binding ↓ Calcium reabsorption ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9K, PMCa2B, NCX2) in the duodenum and jejunum ↓osteoclast production ↓ Bone resorption ↓ Serum calcium Hypocalcemia <2.1 mmol/L ↑ Precipitation of calcium by free fatty acids Authors: Name Name Name Name* Reviewers: Name Name Name Name* * MD at time of publication Published MONTH, DAY, YEAR on www.thecalgaryguide.com https://journals.physiology.org/doi/full/10.1152/physrev.00003.2004?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88- 2003&rfr_id=ori%3Arid%3Acrossref.org – Calcium Absoprtion across Epithelia https://academic.oup.com/endo/article-abstract/137/1/13/2498579 - PTH and Calcium Signaling Pathways https://www.pnas.org/doi/10.1073/pnas.1616733114 - Information on Claudin 14 https://onlinelibrary-wiley-com.ezproxy.lib.ucalgary.ca/doi/full/10.1111/apha.13959 - effects of PTH on renal calcium and phosphate handling https://www.ncbi.nlm.nih.gov/books/NBK430912/ - Hypocalcemia overview + causes + pathophys https://www.orthobullets.com/basic-science/9010/bone-signaling-and-rankl - information about bone signaling https://www.sciencedirect.com/science/article/abs/pii/S0889852921000682?via%3Dihub – Calcium homeostasis article https://pubmed.ncbi.nlm.nih.gov/3012979/#:~:text=Abstract,intestine%2C%20require%20the%20parathyroid%20hormone. vitamin D metabolism and function – https://pmc.ncbi.nlm.nih.gov/articles/PMC2669834/#:~:text=Calcium%20is%20actively%20absorbed%20from,for%20proper %20mineralization%20of%20bone. – more vitamin D metabolism and specific receptors https://jidc.org/index.php/journal/article/view/32903236/2331 - sepsis + hypocalcemia

Anemia of Prematurity

Anemia of Prematurity: Pathogenesis and clinical findings Premature infants grow rapidly after birth to compensate for shortened gestation Neonatal erythropoietin (EPO) is produced in liver (rather than kidneys after neonatal period) Premature birth shortens 3rd trimester duration ↑ Red blood cell (RBC) demand consumes available iron Blood volume rapidly ↑ ↑ Risk of complications in preterm infants Immature liver has ↓ response to hypoxia ↓ Placental iron transfer to fetus ↓ Available iron stores Repeated blood draws for monitoring ↓ Plasma EPO ↓ RBC production Hemodilution ↑ Relative blood loss Anemia of Prematurity Hemoglobin nadir (lowest point) of 70-80g/L in preterm infants <32 weeks gestation at 4-6 weeks of age ↓ Hgb available for O2 transport to tissues Compensatory mechanisms triggered in response to ↓ tissue perfusion ↓ Cerebral perfusion ↓ Function of intestinal mucosa ↓ Metabolic rate ↑ Cardiac output to ↑ O2 delivery Immature respiratory centers in brainstem have paradoxical response to hypoxia ↓ Iron delivery to cerebrum ↓ Nutrient absorption ↑ Fatigue & ↓ endurance ↓ Neuronal metabolism, neurotransmitter production & myelination Poor growth ↓ Nutrient consumption Poor feeding Lethargy Tachycardia Apnea of prematurity** Impaired neurodevelopment Legend: Authors: Katelyn du Plessis Reviewers: Taylor Krawec Emily J. Doucette Lindsay Stockdale* * MD at time of publication Immature RBCs are more susceptible to oxidative injury ↑ Proportion of fetal hemoglobin (Hgb) compared to term infant ↓ RBC life span ↑ RBC destruction Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications ↓ Circulating RBCs Pallor Destroyed RBCs release Hgb into bloodstream Liver converts heme into bilirubin ↑ Unconjugated bilirubin Physiologic neonatal jaundice** **See corresponding Calgary Guide slide Published Aug 28, 2025 on www.thecalgaryguide.com

Hemodynamic Changes in Pregnancy

Hemodynamic Changes in Pregnancy: Pathogenesis & clinical findings Hormonal & physical changes in the body occur during pregnancy ↑ Estrogen & progesterone levels activate the renin-angiotensin-aldosterone system** to ↑ aldosterone levels Aldosterone promotes sodium & water retention to ↑ blood volume Estrogen ↑ peripheral vasodilation which ↓ vascular resistance Baroreceptors detect a ↓ in blood pressure & send sympathetic signals to the heart to ↑ cardiac output Blood pressure ↓ between 0-24 weeks gestation Estrogen, progesterone, & relaxin circulate systemically & ↓ systemic vascular resistance ↑ Estrogen stimulates liver to ↑ fibrinogen production & clotting factors I, II, VII, VIII, IX & XII Estrogen inhibits hepatic production of antithrombotic factor S & antithrombin to ↓ fibrinolysis Blood becomes hypercoagulable & ↑ risk of thrombus (clot) formation ↑ Risk of disseminated intravascular coagulation** Thrombus forms in deep vein of leg, calf, or pelvis ↑ Plasma volume ↑ Hydrostatic pressure in peripheral vessels pushes fluid into extravascular spaces ↑ Water in vessels ↓ red blood cell (RBC) concentration (↓ hematocrit) ↑ Risk of blood loss during Peripheral edema ↑ Blood flow to uterus delivery Mild tachycardia to supply fetus with oxygen & nutrients Anemia early in pregnancy (first trimester) Kidneys detect ↓ oxygen levels from ↓ hematocrit & upregulate erythropoietin production Erythropoietin stimulates ↑ RBC production in bone marrow Gestational hypertension (new onset hypertension after 20 weeks gestation) ↑ Hematocrit later in pregnancy Deep vein thrombosis** Authors: Orly Aziza Alam Randhawa Reviewers: Riya Prajapati Michelle J. Chen Jessica Revington Rachel Wang* * MD at time of publication ** See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism ↑ Risk of developing preeclampsia** Sign/Symptom/Lab Finding Complications Pale or Cold Dizziness clammy skin Fatigue ↑ Risk of shock ↑ Risk of organ damage ↑ Risk of syncope Published Aug 25, 2025 on www.thecalgaryguide.com Thrombus travels through venous circulation to the heart & into the pulmonary arteries Pulmonary embolism

Hemophilia

Hemophilia A & B: Pathogenesis and clinical findings X-Linked recessive mode of inheritance Sporadic mutation Genetic defect on the X chromosome Authors: Julia Fox, Sean Spence Reviewers: Jennifer Au, Yan Yu, Erin Stephenson, Emily J. Doucette Lynn Savoie*, Dawn Goodyear* * MD at time of publication Defective factor VIII gene Defective factor IX gene Deficiency of functional factor VIII (Hemophilia A) in blood (~85% cases) Deficiency of functional factor IX (Hemophilia B) in blood (~15% cases) 5-40% factor levels (mild disease) 1-5% factor levels (moderate disease) Hemophilia A & B <1% factor levels (severe disease) Impaired intrinsic clotting pathway** Impaired thrombin generation causes inadequate clot formation when the body faces a bleeding challenge ↑ Partial thromboplastin time (PTT) Prolonged &/or excessive bleeding after trauma or surgery Easy bruising Epistaxis Oropharyngeal bleeding Hemarthrosis (bleeding into joints) Hematuria Gastrointestinal bleeds Intracranial hemorrhage Intramuscular hemorrhage Extensive muscle bleeding compromises neurovascular structures Recurrent bleeding triggers inflammation & synovial hypertrophy Hemophilic arthropathies Blood accumulates in muscle or soft tissue compartments Compartment syndrome (↑ pressure in muscle compartment) Localized swelling, bleeding, &/or nerve compression Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications **See corresponding Calgary Guide slide on the Coagulation Cascade Re-Published Aug 31, 2025 on www.thecalgaryguide.com

Malignant Renal Mass

Malignant Renal Mass: Pathogenesis & clinical findings ↑ Central Chronic renal adiposity Smoking Hypertension failure ↑ Glomerular blood flow in nephron of ↑ Insulin Accumulation Induction of Formation of kidney ↑ Adipokines ↑ Cytokines ↑ Oxidative state resistance of heavy metals metabolic changes renal cysts ↑ Availability of insulin-like growth factor promotes cellular proliferation Aberrant proliferation causes mass effect Mass compresses various structures Obstructs the collecting system of the kidney (including ureter, ureteropelvic junction, renal pelvis, renal calyces) & prevents flow of urine ↑ Leptin & vasfatin promote cellular metabolism to attempt to meet energy demands of proliferating cells ↑ IL-15 & VEGF promote inflammation ↑ VEGF in response to energy demands causes ↑ angiogenesis (blood vessel growth) causing cellular damage & ↑ angiogenesis Cadmium & arsenic in renal tissue disrupt metal & ion homeostasis causing cell damage which initiates injury- repair cycle Generation of reactive oxygen species causes oxidative damage to genes regulating cell cycle ↓ Oxidative phosphorylation promotes glycolysis/ survival in hypoxic conditions typical of tumor microenvironment Altered amino acid metabolism in cells enhances biosynthetic capabilities & promotes cell proliferation ↑ Pressure causes hypoxic conditions as tubular electrolyte load is ↑ & ↑ Atypical energy demand on renal epithelial cell tubular cells is ↑ proliferation promotes tumor suppressor gene mutations Hypoxia stimulates VEGF to ↑ angiogenesis ↑ Blood flow damages endothelial cells & initiates the injury-repair cycle which ↑ the risk of cell mutations ↑ Angiogenesis ↑ Cellular metabolism ↓ Fidelity of DNA repair mechanisms ↑ Cellular damage results in DNA mutations Altered metabolism promotes survival in tumor microenvironment ↑ Proliferation of cancer cells (typically from proximal tubular epithelial cells, as in clear cell renal cell carcinoma) Malignant Renal Mass Metastasis to distal sites (most commonly bone, lungs, liver, brain) Cancer cells release proteolytic (protein degrading) enzymes including MMPs, cathepsins, & uPA Degradation of healthy renal tissue & vasculature surrounding collecting system of kidneys impairing flow of urine and causing blood loss into collecting system Inactivation of VHL gene ↑ VEGF expression & causes ↑ angiogenesis ↑ Vascular permeability due to uninhibited growth ↑ Muscle & fat wasting from ↑ inflammatory cytokines activates JAK/STAT & NF-κB pathways Gain of function mutations to PI3K/AKT/mTOR cause ↑ glucose uptake & drive insulin resistance without hyperinsulinemia (↑ blood insulin Cancer cells release of adipose triglyceride lipase & hormone- sensitive lipase Tumor-generated ↑Secretion of Tumor- cell death releases parathyroid generated cell proinflammatory hormone- death ↑ IL-6 cytokines & ↓ renal related protein levels & cell production of (PTHrP) initiates ↑ erythropoietin (EPO) production of ↑ lipolysis & browning (protein regulating PTHrP is thrombopoietin of white adipose tissue red blood cell Weaker vessels form (conversion to homologous to (protein production) Hydronephrosis within the kidney metabolically active parathyroid regulating ↑ Creatinine (hydrostatic collecting system & state by ↑ UCP1 hormone (PTH) platelet dilation of the subsequently rupture expression) & competes production) renal pelvis & ↓ Erythropoiesis (red with PTH to calyces) blood cell production) bind to PTH from ↓ EPO receptors Thrombocytosis (↑ platelets) Compresses posterior abdominal wall nerves Imbalance of anabolic & catabolic metabolism, reducing body mass due to ↑ catabolism Brown adipose tissue thermogenic properties ↑ body temperature Flank pain Hematuria (presence of blood in urine) Anemia Bleeding at site of metastasis Weight loss Drenching night sweats PTH receptor activation promotes ↑ bone resorption & renal Ca2+ reabsorption ↑ Ca2+ Published Aug 31, 2025 on www.thecalgaryguide.com Familial Renal Carcinoma Syndrome Genetic mutations conferred from birth Authors: Kaiden Jobin Sergio F. Sharif Reviewers: Jessica Revington Nimira Alimohamed* *MD at time of publication Gain of function for proto- oncogenes Loss of function for tumor suppressor genes Compresses stomach/ esophagus Compresses bladder Compresses diaphragm ↑ Urinary Early satiety Cough frequency Legend: Malignant renal cells produce ↑ EPO & subsequently ↑ erythropoiesis Polycythemia (↑ red blood cells) Neoplastic proximal tubule cells secrete ↑ renin Intrarenal ischemia (reduced blood flow) due to tumor growth compressing renal blood supply Hypertension ↑ Tumor cell secretion of hepatotoxins, lysosomal enzymes, & IL-6 Secreted products hepatocellular injury, releasing cell contents IL-6 triggers immune response against hepatocellular cell contents in response to injury ↑ ALT ↑ AST ↑ ALP ↑ Prothrombin time ↑ Bilirubin Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Apert Syndrome

Apert Syndrome: Pathogenesis and clinical findings Gain of function mutation in fibroblast growth factor 2 receptor (FGFR2) on chromosome 10q Mutated FGFR2 protein has ↑ ligand binding & signalling activity Osteoblasts undergo early differentiation & maturation in response to ↑ FGFR2 ↑ Bone deposition & ossification Osteoblast progenitors proliferate at ↑ rate Abnormal mesenchymal differentiation in response to ↑ FGFR2 Authors: Merry Faye Graff, Taylor Krawec Reviewers: Emily J. Doucette, Ryan Frank* * Indicates MD at time of publication Apert Syndrome (Acrocephalosyndactyly Type I) A rare genetic disorder characterized by multisuture craniosynostosis, midface retrusion, & syndactyly of the hands & feet Craniofacial Abnormalities Premature differentiation of neural crest-derived mesenchyme in face Underdevelopment of midfacial bones (e.g. maxilla, zygoma) Orbit growth is rotated outward Extraocular muscles insert anomalously ↓ Control of eye movement Mesenchymal cells at palatal shelf undergo abnormal differentiation Palatal midline epithelial seam fails to undergo apoptosis Premature osteoblast maturation in suture mesenchyme Midface hypoplasia Hypertelorism (widely separated orbits) V-pattern exotropia (“V” shaped eye movement) ↓ Palatal shelf outgrowth & misalignment Bicoronal synostosis (premature fusion of coronal sutures) Shallow orbits displace globes forward Depressed nasal bridge ↓ Length of hard palate Abnormal eustachian tube development ↓ Anteroposterior growth of nasal cavity Cleft palate** Fusion of coronal sutures restricts anteroposterior skull growth Exorbitism (protruding eyes) Beaked nose ↓ Drainage of middle ear Choanal stenosis (narrowed nasal passages) Skull grows vertically as brain develops Cerebral spinal fluid accumulates in ventricles Incomplete eyelid closure ↑ corneal exposure & damage Class III malocclusion (underbite) V shaped dental arch High arched palate Recurrent ear effusions ↑ Nasal canal obstruction Breathing difficulty Turribrachycephaly (tower shaped skull) Ventriculomegaly (↑ ventricular size) Corneal scarring Exposure keratopathy Impaired ossicle function Conductive hearing loss Brain growth is restricted Developmental delay Limb & Skeletal Abnormalities Phalanges of fingers &/or toes undergo premature ossification ↑ Proliferation in apical ectodermal ridge at distal limb bud during embryonic development ↓ Regression of interdigital mesenchyme allow persistence of interdigital soft tissue bridges Other Abnormalities FGFR2 mutation leads to sebaceous gland hyperplasia & follicular keratinization Excess sebum production & follicular blockage Osseus syndactyly Legend: ↑ FGFR2 alters BMP & SHH signaling balance Pathophysiology Mechanism Sign/Symptom/Lab Finding Cutaneous syndactyly (may include nailbed) Severe acne Published Sept 16, 2025 on www.thecalgaryguide.com Complications

Antibiotics Classes and Mechanisms

Antibiotics: Overview of classes and mechanisms of action Nucleic acid synthesis inhibitors Cell wall synthesis inhibitors Protein synthesis inhibitors Nitroimidazoles (e.g. metronidazole) Antibiotic is activated by bacterial pyruvate:ferredoxin oxidoreductase system (only active in anaerobic bacteria) Fluoroquinolones** (e.g. ciprofloxacin) Drug binds & inhibits bacterial DNA topoisomerases (enzymes that cut & re-ligate DNA to stabilize helix) β-lactam antibiotics Penicillins (e.g. amoxicillin) Cephalosporins (e.g cefazolin) Carbapenems (e.g meropenem) Drug binds & inhibits penicillin binding proteins (enzymes involved in peptidoglycan cross-linking & cell wall synthesis) β-lactam with β- lactamase inhibitor (e.g. amoxicillin- clavulanate) β-lactamase inhibitor irreversibly binds bacterial β-lactamases (enzymes that break β-lactam rings & contribute to β-lactam resistance) Glycopeptides (e.g. vancomycin) Drug binds to bacterial cell wall peptidoglycan precursors, interrupting cell wall synthesis Aminoglycosides (e.g. gentamicin) Drug irreversibly binds bacterial 30S ribosomal subunit Binding interferes with proofreading process in mRNA translation Macrolides (e.g. azithromycin) Lincosamides (e.g. clindamycin) Tetracyclines (e.g. doxycycline) Sulfonamides (e.g trimethoprim- sulfamethoxazole) Reactive nitrogen free radicals generated Single- & double- stranded DNA breaks form without re-ligation ↓ Bacterial cell wall cross-linkage Free radicals interact with and destroy bacterial DNA DNA fragments released into cell Autolysins weaken & lyse bacterial cell wall Author: Steven Quan Reviewers: Julia Fox, Emily J. Doucette, Brandon Christensen* *MD at time of publication Bactericidal (bacterial cell death) β-lactamases are unable to break β-lactam rings, allowing for β-lactam function Bacterial cell wall is incomplete & weakened Incorrect amino acids accepted into protein chain Bacteria undergoes lysis Nonfunctional proteins produced Metabolic pathway inhibitors Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Drug reversibly binds bacterial 50S ribosomal subunit Drug reversibly binds bacterial 30s ribosomal subunit Drug binds & inhibits bacterial dihydropteroate synthetases (enzymes involved in folate synthesis) Complications Binding physically inhibits addition of amino acids, preventing peptide elongation Binding inhibits tRNA from adding amino acids to protein chain Bacteria cannot produce folate (cofactor required for nucleotide synthesis) Protein synthesis not completed ↓ Nucleotide production Bacteriostatic (inhibition of bacterial growth & replication) **See corresponding Calgary Guide slide Published Sept 16, 2025 on www.thecalgaryguide.com

Tricyclic Antidepressants

Tricyclic Antidepressants: Mechanism of action and side effects Tricyclic Antidepressants (TCAs) -tryptylines (e.g. amitriptyline, nortriptyline), -pramines (e.g. clomipramine, imipramine), doxepin Competitive inhibition of excitatory muscarinic acetylcholine (ACh) receptors (primary neurotransmitter at neuromuscular junctions) Blockage of sodium channels in cardiac muscle cells ↓ Cortical neuronal firing ↓ Parasympathetic activity ↓ Depolarization of cardiac cells Exact mechanism unknown ↓ Smooth muscle contractions QT interval prolongation Arrythmias ↓ Bladder contractions Urinary retention Competitive inhibition of alpha-1 receptors on vascular smooth muscle throughout the body Blockage of serotonin (5-HT) & norepinephrine (NE) transporters on presynaptic neurons Competitive inhibition of histamine (H1) receptors throughout the body, especially in sleep-wake regions of the CNS (eg. thalamus & cortex) Exact mechanism unknown ↓ Blood vessel constriction Orthostatic hypotension ↓ Regulation of sympathetic activity Transient cerebral hypoperfusion ↑ Heart rate & cardiac contractility Dizziness ↓ Gut motility ↓ Saliva production Constipation Xerostomia (dry mouth) ↑ Levels of 5-HT & NE at synaptic cleft ↓ H1-induced depolarization in cerebral cortex ↓ Regulation of food intake (exact mechanism unknown) Diaphoresis (excessive sweating) Sedation ↓ Satiety signalling ↑ Neurotransmission in mood-regulating brain areas (e.g., limbic system) ↓ N-methyl-D-aspartate (NMDA) receptor depolarization of cortical neurons Weight gain ↑ Appetite Antidepressant effect (eg. ↑ mood & ↑ self worthiness) Author: Emily Cox Reviewers: Sara Cho, Luiza Radu, Emily J. Doucette, Susan Poon* Confusion * MD at time of publication Published Sept 16, 2025 on www.thecalgaryguide.com Legend: Exact mechanism unknown ↓ Pupillary dilation Paradoxical sweating Blurred vision Anticholinergic side effects Pathophysiology Mechanism Pharmacologic effect Adverse effect

Obstructive Shock

Obstructive Shock: Pathogenesis, complications & clinical findings Cardiac tamponade** ↑ Pericardial cavity pressure due to fluid filling potential space Pericardial pressure exceeds cardiac venous filling pressure & compresses heart chambers ↓ Venous return to right atrium & left atrium Pulmonary embolism** Obstruction of pulmonary blood flow ↑ Right ventricle afterload (pressure the ventricle contracts against) ↓ Right ventricle stroke volume (blood volume ejected per beat) ↓ Blood return to left atrium Underfilled left ventricle Obstructive shock ↓ systemic blood flow due to a physical obstruction of the heart’s pumping function Insufficient organ perfusion Tension pneumothorax** ↑ Pressure in the pleural cavity Intrathoracic pressure exceeds venous filling pressures & compresses heart chambers ↓ Venous return to right atrium & left atrium Author: Ryan Dion Sergio F. Sharif Dean Percy Reviewers: Yan Yu Tristan Jones Jason Waechter* * MD at time of publication ** See corresponding Calgary Guide slides ↓ Preload (degree of left ventricular filling) as left ventricle receives low levels of blood ↓ Cardiac output (volume of blood ejected from the ↓ Blood pressure (BP) heart/min) Baroreceptors in carotid sinus & aortic arch detect low blood pressure Skin Reflexive release of catecholamines via sympathetic nervous system Blood supply diverted away from peripheral tissues to vital organs Tachycardia Hypotension Cold extremities Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Brain ↓ Cerebral blood flow causes cerebral hypoxia Altered consciousness Heart ↓ Coronary artery perfusion Myocardial ischemia** Complications Blood backs up into venous system Kidneys ↓ Blood flow to kidneys Prerenal acute kidney injury ** ↑ Pressure distends veins ↑ Jugular venous pressure Pressurized fluid leaks out of veins into tissue Fluid enters pulmonary perivascular spaces Fluid impedes normal gas exchange in lungs Tachypnea (↑ respiratory rate) Dyspnea Published July 7, 2013; updated Sept 28, 2025 on www.thecalgaryguide.com

Endometriosis

Endometriosis: Pathogenesis, clinical findings, & complications Risk factors Theories of endometrial tissue migration Genetic causes (family history & specific gene loci) Transfer of endometrial tissue away from the uterus during pelvic surgery, vaginal delivery, or cesarean section Sampson’s theory: Retrograde flow of endometrial tissue through fallopian tubes Long menstrual flows (↑ retrograde menstruation) Coelomic metaplasia theory: Undifferentiated mesothelial cells from the peritoneal cavity differentiate into endometrial cells during fetal development. May also occur in patients with testes Implantation theory: Menstrual endometrium implants onto pelvic structures ↓ Cellular antioxidant capacity (↑ cell damage) Alcohol use (mechanism unclear) Early menarche (↑ estrogen exposure) Stem cell theory: Endometrial stem/ Embryonic rest theory: Residual progenitor cells from menstrual embryonic cells from Müllerian Dissemination theory: Endometrial blood or neonatal uterine bleeding or Wolffian ducts are misplaced tissue transported through bloodstream implant in the pelvic cavity during organogenesis or lymphatics to extrauterine structures (e.g., brain, pericardium) Cells differentiate into endometrial-like tissue Ovary releases estrogen & progesterone Endometriosis Endometrial glands & stroma (structural support tissue) found outside the uterus Ectopic endometrial-like tissue on bladder Ectopic endometrial-like tissue in posterior cul-de-sac Monthly proliferation (by estrogen) and stabilization (by progesterone) of endometrial tissue Chronic inflammation of surrounding tissues & fibrosis/adhesion formation Tissue inflammation & fibrosis/adhesions push on & displace pelvic organs Ectopic tissue abnormally activates nerve signaling pathways responsible for bladder contraction Bladder wall contractions activate nociceptors (pain sensors) Penetrative intercourse involving the posterior vagina applies ↑ pressure to tethered & immobile pelvic structures Feces moves down colon into rectum & applies pressure to the tethered rectum Monthly progesterone withdrawal Dyspareunia (pain with deep intercourse) Dyschezia (pain with bowel movements) ↑ Urinary frequency & urgency Pain with micturition (urination) Endometrial tissue sloughs off from a basal tissue layer (menstruation**) Extra-uterine endometrial- like tissue cannot evacuate the implantation site Retrograde menstruation in ovary ↑ the presence of ectopic endometrial-like tissue & blood (mechanism poorly understood) Old blood fills endometrial-like tissue on ovary Endometrioma (chocolate cyst) Chronic cyclical local inflammation (release of pro-inflammatory chemicals) Nociceptors near ectopic endometrial-like tissue activate Pain signals & release of inflammatory mediators subsides over time Cyclic dysmenorrhea (menstrual pain) Repair of inflammation Ectopic endometrial-like tissue becomes fibrotic (scarred) Significant ↑ scar tissue Nodule formation ↓ Hormone levels post-menopause Accumulation of inflammatory fluid within scar tissue ↑ Risk of scar tissue obstructing or kinking fallopian tubes Endometrial tissue stops proliferating Hormone-dependent symptoms (e.g., dysmenorrhea) cease Cyst formation Embryos unable to pass through fallopian tube to uterus Author: Joshua Seto Kayla Nelson Reviewers: Yan Yu Sean Spence Jessica Revington Infertility Colin Birch*, Rachel Wang* * MD at time of publication **See corresponding Calgary Guide slide Legend: Published December 20, 2013, revised September 24, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Hydrocephalus in pediatrics

Aqueduct stenosis (channel between 3rd & 4th ventricle narrows) Narrowing blocks CSF flow from 3rd to 4th ventricle Congenital anomalies blocking CSF flow Atresia of foramen of Monro (channels connecting paired lateral ventricles & 3rd ventricle narrow) Narrowing blocks CSF flow from lateral ventricles to 3rd ventricle Posterior fossa malformations (4th ventricle closure failure) (e.g. Dandy-Walker Malformations) Persistence of Blake's pouch (cyst in 4th ventricle) obstructs CSF outflow from 4th ventricle Brain mass/tumor (e.g. medulloblastoma, pinealoma) Obstructs the passage of CSF from ventricles to subarachnoid space Hydrocephalus in Pediatrics: Pathogenesis and complications Intracranial or subarachnoid hemorrhage (brain bleed) Blood accumulates in ventricles or subarachnoid space Accumulated red blood cells break down over time & release hemoglobin, bilirubin, etc. Blood clots form in subarachnoid spaces & around ventricular outlets Developmental cysts (CSF filled sacs located between the brain & arachnoid Infection in brain membrane – e.g. tissue or meninges Arachnoid Cysts) (e.g., meningitis) Breakdown products trigger inflammation of ependymal lining & arachnoid membranes Immune cells respond to infection & accumulate Inflammation stimulates transforming growth factor- beta (TGF-β) & neutrophil extracellular traps (NETs) Exudate & pus form in subarachnoid spaces & around ventricular outlets TGF-β promotes fibrosis in subarachnoid space NETs obstruct meningeal lymphatic vessels Scarring & obliteration of arachnoid villi Obstruction impairs cerebrospinal fluid (CSF) drainage through lymphatics Choroid plexus tumors Choroid plexus epithelial cells are overactive Sacs compress or obstruct interventricular foramina, 3rd or 4th ventricle, aqueduct of Sylvius, etc. (location dependent) Congenital absence of arachnoid villi Impaired CSF resorption Normal flow of CSF is physically blocked Overactivity produces excessive CSF Communicating hydrocephalus (CSF accumulation due to impaired absorption or increased production in the subarachnoid spaces) Obstructive hydrocephalus (CSF accumulation due to structural blockage of CSF flow within the ventricular system) Hydrocephalus Active distension of the ventricles in the brain due to excessive accumulation of CSF Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 29, 2025 on www.thecalgaryguide.com Chiari II malformation (downward herniation of cerebellum, brainstem, & 4th ventricle through foramen magnum) Herniated structures block CSF outflow to spinal cord Authors: Abisola Adegbulugbe, Lexyn Iliscupidez Reviewers: Annie Pham, Merry Faye Graff, Emily J. Doucette, Jean Mah* *MD at time of publication Legend:

Sturge-Weber Syndrome

Sturge-Weber Syndrome (SWS): Pathogenesis, mechanisms & clinical findings Somatic mosaic mutations (embryonic development mutations producing multiple cell lines) occur in the GNAQ gene Abnormal regulation of intracellular signaling pathways during early embryogenesis Mechanism unclear. Attributed to primary defect(s) in a subset of angioblasts (precursor embryonic cells for the endothelial cells lining blood vessels) or in other cells supporting vascular function Authors: Dylan Hollman* Reviewers: Mina Youakim Jessica Revington Fatemeh Jafarian* * MD at time of publication **See corresponding Calgary Guide slide Localized abnormal vasculogenesis (initial creation of blood vessels during embryonic development) & vascular function Facial vascular malformations Intracranial vascular malformations Ocular vascular malformations Nevus flammeus (port-wine stain birthmark) along skin in the distribution of the trigeminal nerve (ophthalmic/maxillary branches) Leptomeningeal capillary-venous malformation (abnormal blood vessel cluster in the brain/spinal covering) Heterochromia (different colored eyes) Episcleral & conjunctival VMs (abnormal blood vessels on the eye surface) Corresponding overgrowth of cutaneous (skin) vasculature Corresponding overgrowth of underlying soft tissues & facial bones Impaired venous drainage ↓ normal blood flow in the brain & ↑ overall venous pressure, causing venous hypertension Mechanism unclear. Associated with disruption of the hypothalamic-pituitary axis Choroidal hemangioma (benign blood vessel tumor in the choroid layer of the eye) Growth hormone deficiency Nodularity (nodule growths on skin) ↑ Venous pressure & ↓ venous blood flow cause venous stasis (blood pooling in veins) ↑ Accumulation of coagulation factors in the veins contributes to an ↑ risk of thrombosis (blood clots) ↑ Venous pressure in the episclera (outer layer of the eye) contributes to ↑ intraocular pressure Hypothyroidism** ↓ Venous blood flow impairs overall circulation & ↓ tissue oxygenation (chronic tissue ischemia) Thrombi (blood clots) travel through vasculature & can further ↓ or block blood flow ↑ Intraocular pressure gradually damages the optic nerve & contributes to vision loss Stroke-like events Glaucoma Interruption of blood flow & oxygen delivery to the brain damages key areas of brain tissue & ↓ clearance of waste products Hemiparesis (weakness on one side of the body) Cerebral hemiatrophy (loss of tissue or shrinkage of one side of the brain) ↑ Risk of focal cortical dysplasia (abnormal organization of brain cells in specific brain locations) ↑ Risk of brain atrophy ↑ Intraparenchymal calcification (calcium deposits in brain tissue) Chronic damage to brain tissue & continued impairment of key neurological functions Visual field defects Seizures Intellectual disability Behavioral problems Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 20, 2025 on www.thecalgaryguide.com Gingival/palatal angiomatosis (abnormal blood vessel growth in gum tissue & palate) Gingival hyperplasia (overgrowth of gum tissue) Legend: Sturge-Weber syndrome (SWS): Pathogenesis and clinical findings Somatic mosaic mutations in the GNAQ gene Authors: Dylan Hollman* Reviewers: Mina Youakim Fatemeh Jafarian* * MD at time of publication Abnormal regulation of intracellular signalling pathway in early embryogenesis Unclear mechanism → Primary defect in subset of angioblasts or other vascular supporting cells Facial vascular malformations (VMs) Localized abnormal vasculogenesis & vascular function Ocular vascular malformations (VMs) Port-wine stain (flat, red or purple birthmark caused by dilated blood vessels) → commonly affects trigeminal nerve (ophthalmic/maxillary) Intracranial vascular malformations (VMs) Choroidal Heterochromi Episcleral & hemangioma a conjunctival VMs (benign tumor (different (abnormal blood Leptomeningeal of blood vessels colored eyes) vessels on the capillary-venous in the choroid eye's surface) Overgrowth of Overgrowth of malformation layer of the eye) underlying soft cutaneous (abnormal blood tissue & bone vasculature vessel cluster in the ↑ episcleral brain/spinal (eye’s outer Nodularity Gingival/palatal covering) layer) venous angiomatosis pressure (abnormal blood Gingival Glaucoma vessel growth in hyperplasia Venous hypertension gum tissue & (overgrowth of gum palate) tissue) Chronic tissue ischemia Thrombosis Hemiparesis (weakness on one side of body) Venous stasis Unclear mechanism → disruption of hypothalamic-pituitary axis Focal cortical dysplasia (abnormal brain tissue in specific areas) Intraparenchymal calcification (calcium deposits in brain tissue) Stroke-like events Hemiatrophy (loss of tissue or shrinkage on one side of body) Hypothyroidism Growth hormone deficiency Seizures Visual field defects Intellectual disability Behavioral problems Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com Brain atrophy

Ventricular Fibrillation

Ventricular Fibrillation: Pathogenesis and clinical findings Channelopathies (diseases of ion channels such as Brugada syndrome) Abnormalities in ion channel (Na+ , K+, Ca2+) permeability & channel opening/closing Impaired cardiomyocyte depolarization & repolarization Replacement of cardiac tissue with nonconductive fibrous tissue Structural damage (cardiac surgery or genetic conditions like arrhythmogenic dysplasia) Authors: Jared McCormick, Shuvam Prasai, Sergio F. Sharif Reviewers: Brett Edwards, Dave Nicholl, Angela Kealey*, Jason Waechter*, Vikas Kuriachan* * MD at time of publication Hypoglycemia Impairment in ATP- dependent processes Disruption in cardiomyocyte action potential propagation ↓ Oxygen delivery & ischemia Cardiac hypoperfusion Drugs (antiarrhythmics, QT prolonging antipsychotics, etc.) Direct alteration of ion channel function Disruption in the ion gradients of cardiac cells At-risk patient (altered impulse conduction) Impairment & damage to cardiac tissue ↓metabolic activity & blood flow Hypothermia Electrolyte imbalances (K+ , Mg2+, Ca2+ etc.) Abnormal extracellular ion concentrations ↑ ectopic activity & self-sustaining conduction loops further disrupt normal pathways Major ischemia & necrosis of cardiac tissue Myocardial infarction** (one of the most common causes of V-Fib) Abnormal rhythm Impairment in ion channel activation & recovery Ventricular fibers contract erratically instead of in unison Atrial fibrillation** & rapid conduction to ventricles Accessory pathway (pathways bypassing normal conduction pathways in the heart) ECG shows disorganized activity without identifiable QRS/T waves & obscured P waves* Ventricular Fibrillation (V-fib) Heart rhythm disorder where the ventricles fibrillate (quiver) & fail to contract effectively *Obscured P waves No heart rate ↓ATP & disruption in Na⁺/K⁺-ATPase Pump Cerebral hypoxia (ischemia driven brain injury) Uncoordinated contraction & no cardiac output (V-fib is non-perfusing) No blood pressure ↑ Creatinine kinase indicating cell damage Ion imbalances & intracellular Ca2+ influx Depolarization induced glutamate release Global hypoperfusion (widespread ↓ in blood flow to tissues & organs) Ca2+ toxicity & widespread neuronal cell damage & death Death Multi-system organ failure due to ↓ perfusion Clinical cardiac arrest (cessation of cardiac activity)** Inadequate blood flow & widespread ischemic injury** ↑ Lactate dehydrogenase indicating ischemia **See corresponding Calgary Guide slides ↑ Troponin indicating myocardial injury Legend: Published Feb 10, 2014; updated Oct 19, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Fecal Incontinence

Authors: Britney Wong Timothy Fu Reviewers: Shahab Marzoughi Jake Thorsteinson Jessica Revington Yan Yu* Erika Dempsey* * MD at time of publication **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Fecal Incontinence: Pathogenesis, mechanisms, & complications Chronic bowel straining Complex vaginal delivery Stretch injury of pudendal nerve (innervates the pelvic muscles & external anal sphincter) Rectal or genital prolapse** Pelvic surgery Local neuronal damage Direct impairment of internal anal sphincter which controls approximately 70% of anal resting tone Pelvic trauma Impaired motor control of pelvic muscles & the external anal sphincter Direct impairment of external anal sphincter ↓ Resting tone in internal anal sphincter Voluntary external anal sphincter contraction is no longer sufficient to close the anus Continence (voluntary ability to control release of stool) mechanisms are impaired ↓ Control over an essential bodily function ↑ Assistance required with toileting & basic hygiene Colon inflammation (e.g., ulcerative colitis, radiation proctitis) ↓ Stretch capacity of rectal smooth muscle ↓ Stool storage capacity in rectum ↑ Defecation urgency Internal anal sphincter reflex relaxes ↑ Caretaker burden ↑ Perception of & exposure to various social stigmas associated with poor hygiene practices ↑ Feelings of shame or significant embarrassment ↑ Stress & anxiety ↓ Confidence & sense of agency ↓ Engagement in social activities or work Complications Sign/Symptom/Lab Finding Diarrhea- predominant irritable bowel syndrome Movement disorders (e.g., arthritis, Parkinson’s) Age-related ↓ in mobility Sensory neuropathy (e.g., diabetic neuropathy) Conditions altering mental status (e.g., stroke, dementia) Chronic constipation Chronic diarrhea Solid & immobile mass of stool builds up in the rectum Laxatives ↓ Mobility can impact timely toileting access & habits Rectal hyposensitivity (↓ perception of rectal distension) ↑ Stool volume ↑ Loose stools Loose stool is more prone to escape through the anal canal, compared to solid stool Failure to sense rectal fullness leads to voluntary relaxation of the external anal sphincter Loose stool can flow around impacted stool mass & exit the anal canal (overflow diarrhea) Continence mechanisms are intact. Mechanisms are subsequently overwhelmed or bypassed Fecal Incontinence Unintentional loss of solid or liquid stool ↑ Prolonged skin contact with an irritant (stool) Prolonged skin exposure to digestive enzymes (e.g., proteases, lipases) in stool ↑ Skin pH, repeated mechanical abrasion (wiping) & excessive moisture degrade built-in protective barriers in the skin ↑ Skin inflammation ↑ Skin erythema (redness) Incontinence-associated dermatitis (degradation & loss of protective skin layers) ↑ Pain & skin irritation Bacteria from residual stool can colonize eroded & damaged tissue ↑ Risk of skin infection ↓ Help-seeking behaviours ↓ Access to & pursuit of treatment Published May 2, 2020; updated October 19, 2025 on www.thecalgaryguide.com

GLP-1 Receptor Agonists

Glucagon-like Peptide-1 (GLP-1) Receptor Agonists: Mechanism of action and side effects Management of Type 2 Diabetes Mellitus** Weight management Authors: Saania Tariq, Trevor Low Reviewers: Rafael Sanguinetti Luiza Radu, Emily J. Doucette Activated GLP-1 receptors in Activated GLP-1 Hanan Bassyouni* * MD at time of publication the myenteric plexus inhibit receptors stimulate gastric motor neurons pancreatic islet cells GLP-1 Receptor Agonists Synthetic analogs (e.g., Semaglutide) of GLP-1 peptide hormone endogenously produced by intestinal enteroendocrine L cells directly activate GLP-1 receptors to modulate food intake & glucose metabolism ↓ Gastric motility ↑ Pyloric sphincter tone via disinhibition ↓ Glucagon release from α-cells ↑ Regeneration, ↑ growth & ↓ apoptosis of β-cells Slowed gastric emptying Subcutaneous injection or oral ingestion prolongs GLP-1 receptor activation ↑ β-cell function & glucose- dependent insulin production GLP-1 receptor activation on neurons in the arcuate nucleus of the hypothalamus modulates appetite & satiety Activation of GLP-1 receptors in the gastrointestinal system regulates metabolism Prolonged gastric distension & stasis activates chemoreceptors & mechanoreceptors Delayed digestion of gastric contents ↓ glucose spikes after meals ↑ Glycogen synthesis & glucose uptake in liver & skeletal muscles Neuropeptide Y & agouti-related protein expressing neurons are hyperpolarized Pro-opiomelanocortin expressing neurons become ↑ excitable Activated GLP-1 receptors signal to hypothalamus via vagus nerve afferents ↑ Vagal afferent signaling to area postrema (vomiting centre) Nausea & vomiting ↓ Release of neuropeptide Y & agouti-related protein ↑ Anorexigenic signalling ↑ Parasympathetic output via dorsal motor nucleus of vagus nerve GLP-1 agonists directly activate receptors in area postrema ↑ Satiety (feeling of fullness) ↓ Adiposity (weight loss) ↓ Orexigenic drive ↓ Inflammatory stress in pancreatic β-cells ↑ β-cell function improves insulin secretion ↓ Appetite ↓ Caloric intake ↓ Inflammatory cytokines & lipotoxicity ↓ Systemic inflammation ↑ Insulin sensitivity in skeletal muscle & liver **See corresponding Calgary Guide slide Legend: Sign/Symptom/Lab Finding Pathophysiology Mechanism Complications ↓ Hepatic glucose production (glycogenolysis) ↓ Fasting & postprandial blood glucose ↓ Red blood cell (RBC) glycation (glucose irreversibly binds to hemoglobin in RBCs) ↓ Production of glycated proteins and lipids ↓ % of glycated RBCs over time ↓ Vascular endothelial damage and atherosclerosis ↓ Endothelial damage to glomeruli ↓ Hemoglobin A1c ↓ Risk of cardiovascular complications ↓ Risk of renal complications Published Jun 22, 2025 on www.thecalgaryguide.com

Triptans

Triptans: Mechanism of action and side effects Triptans Selective competitive agonists of trigeminovascular serotonin (5-HT) receptors that cause constriction of cranial blood vessels & inhibition of trigeminal pain signaling to abort migraines & cluster headaches Activation of 5-HT₁B receptors on peripheral & visceral blood vessels ↑ Vascular tone Deformation of vessel walls Activation of mechano- sensitive nerve endings in coronary vessels Activation of mechano- sensitive nerve endings in peripheral vessels Transmission of signals via T1- T4 sympathetic fibres Continued use of triptans ↓ activation threshold Central interpretation of signals as painful ↑ Abnormal signaling to CNS Chest tightness Paresthesias Legend: Activation of 5-HT₁B receptors on meningeal artery smooth muscle ↑ Vasoconstriction of dilated meningeal vessels ↓ Mechanical distension ↓ Activation of meningeal nociceptors ↓ Throbbing sensation Activation of 5-HT₁D receptors on V1 segment of the trigeminal nerve ↓ Calcitonin gene- related peptide (CGRP) & other vasoactive neuropeptides ↓ Vasodilation ↓ Neurogenic inflammation ↓ Plasma leakage into tissues ↓ 1st order neuron signaling to trigeminal nucleus caudalis & thalamus 5-HT₁B/₁D (±₁F) receptor agonism directly on trigeminal nucleus caudalis & brainstem ↓ Glutamatergic signaling Transient changes in central excitability Suppression of excessive excitably in thalamus ↓ Integration of retinal & cochlear inputs ↓ Photophobia & phonophobia Authors: Sarah Johns Reviewers: Trevor Low Emily J. Doucette Jean Mah* * MD at time of publication Suppression of excitably in dorsal raphe nucleus ↓ Arousal Fatigue & drowsiness Pathophysiology Mechanism Pharmacologic Effect Side Effects ↓ 2nd order neuron firing ↓ Input to vestibular nuclei ↓ Neuronal activity in nucleus tractus solitarus ↓ Nausea Published Oct 19, 2025 on www.thecalgaryguide.com ↓ Integration of balance & spatial orientation Dizziness & unsteadiness

Rickets and Osteomalacia Pathogenesis and Clinical Findings

Nutritional PO₄³⁻ deficiency Rickets and Osteomalacia: Pathogenesis and clinical findings **See corresponding Calgary Guide slide Direct inhibition of bone mineralization Phosphopenic rickets (insufficient phosphate (PO₄³⁻)) Medications (i.e., bisphosphonates) Hereditary hypophosphatasia Medication act as pyrophosphate (PPi) analogue Renal tubular defects (e.g., Faconi syndrome, distal renal tubular acidosis) Chronic use of Tumor- phosphate binders induced (e.g., calcium osteomalacia carbonate) Hereditary hypophosphatemic rickets Calcipenic rickets (insufficient calcium (Ca2+)) ↓ Sunlight exposure ↓ Intestinal absorption of fat- soluble vitamins (A, D, E & K) (e.g., in GI or liver disease) ↓ Intake through food Vitamin D- dependent rickets type 1 Vitamin D- dependent rickets type 2 Osteoblasts secrete ↓ alkaline phosphatase (ALP) (cleaves PPi to create sites forCa2+ & PO₄³⁻ deposition) ↑ Fibroblast growth factor 23 (FGF23) Mutation in CYP27B1 or CYP2R1 gene Mutation in vitamin D receptor gene ↑ PPi binds to growing hydroxyapatite crystals in bone & prevents further deposition of Ca2+ & PO₄³⁻ ↑ Renal losses of PO₄³⁻ FGF23 ↑ breakdown of FGF23 ↑ 24- 1α-hydroxylase (converts Hydroxylase Vitamin D deficiency (most common cause) calcidiol (inactive vitamin activity D) to calcitriol (active (catabolizes calcitriol) vitamin D) ↓ Calcidiol Mutations prevent conversion of calcidiol to calcitriol End-organ resistance to calcitriol ↓ Cleavage of PPi ↓ Calcitriol ↓ PO₄³⁻ released from PPi ↓ PO₄³⁻ absorption in intestines ↓ Ca2+ absorption from intestines & kidneys Hypophosphatemia (↓ Serum PO₄³⁻) Hypocalcemia** (↓ Serum Ca2+) Ca2+ deficiency ↓ Availability of PO₄³⁻ & Ca2+ impairs formation of hydroxyapatite ((Ca10(PO4)6(OH)2) crystals (deposition of crystals hardens bone) Parathyroid gland releases PTH (secondary hyperparathyroidism) to maintain serum Ca2+ Impaired mineralization of osteoid ↑ Parathyroid hormone** (PTH) Rickets Defective mineralization of new bone formation at growth plate (only occurs in children with open growth plates) Defective mineralization of preformed osteoid Osteomalacia Defective mineralization of existing bone (can occur in individuals with open or closed growth plates) Unmineralized cartilage overgrows at growth plates ↓ Mineralization impairs structural integrity of bone ↓ Calcitriol & PO₄³⁻ impairs dentin & enamel mineralization Unmineralized cartilage overgrows at costochondral junctions ↓ Mineralization of skull bones ↓ Structural integrity & ↓ bone density ↓ PO₄³⁻ disrupts ATP production in muscles Osteoblasts secrete ↑ ALP to compensate for ↓ mineralization ↑ Diameter of growth plate & metaphysis Shear forces bend osteopenic bone during ambulation Delayed dental eruption & enamel hypoplasia Rachitic rosary (palpable bead-like nodules along ribs) ↑ Stress on poorly mineralized bone ↑ Stimulation of periosteal nociceptors Muscle weakness &/or poor tone ↑ALP Metaphyseal cupping on X-ray Widened wrists & ankles Progressive lateral bowing of femur & tibia Abnormal gait Genu varum/valgum Delayed fontanelle closure Craniotabes (softening of skull bones) Fractures &/or pseudofractures Localized bone pain or tenderness ↓ Bone mineral density Authors: Olivia Yung, Payam Pournazari Reviewers: Merry Faye Graff, Yan Yu, Spencer Montgomery, Emily J. Doucette, David Hanley*, Danielle Nelson* * MD at time of publication Sign/Symptom/Lab Finding Complications Published Nov 26, 2012; updated Nov 2, 2025 on www.thecalgaryguide.com ↓ Mineralization impairs growth plate fusion ↓ Linear bone growth Short stature Legend: Pathophysiology Mechanism

Brachial Plexus

Brachial Plexus: Anatomy and physiology Elevates, retracts & inferiorly rotates scapula Innervates supraspinatus & infraspinatus Stabilizes, abducts & laterally rotates at glenohumeral joint Inferiorly rotates & protracts scapula Innervates rhomboids & levator scapulae Dorsal scapular nerve Suprascapular nerve C5 Superior C6 Nerve to subclavius Innervates subclavius Anchors & depresses clavicle Middle C7 Long thoracic nerve Innervates serratus anterior Protracts scapula C8 Inferior T1 Innervates pectoralis minor Innervates acromioclavicular & glenohumeral joints Lateral pectoral nerve Lateral Stabilizes & medially rotates at glenohumeral joint Extends, adducts & medially rotates at glenohumeral joint Innervates subscapularis Innervates teres major Superior subscapular nerve Inferior subscapular nerve Posterior Thoracodorsal nerve Innervates latissimus dorsi Extends, adducts & medially rotates at glenohumeral joint Innervates skin of inferior portion of medial side of arm Innervates skin of arm overlying biceps brachii, & medial side of forearm Medial brachial cutaneous nerve Medial antebrachial cutaneous nerve Medial Adducts & medially rotates at glenohumeral joint, inferiorly rotates, protracts & draws scapula anteriorly Innervates pectoralis major & minor Medial pectoral nerves Innervates adductor pollicis Innervates interossei of hand Adducts thumb Abducts & adducts digits 2-5 Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Author: Merry Faye Graff Reviewers: Mitchell Chorney, Ryan Dion, Emily J. Doucette, Jean Mah* * MD at time of publication Roots à Trunks à Anterior & Posterior Divisions à Cords à Terminal Branches Innervates anterior compartment of arm Supinates at radioulnar joint, flexes at elbow & flexes & adducts at glenohumeral joint Musculocutaneous nerve Lateral cutaneous nerve of forearm Innervates skin of lateral forearm Innervates teres minor & deltoid Stabilizes, laterally & medially rotates, adducts, abduct & flexes at glenohumeral joint Axillary nerve Innervates skin of lateral shoulder Innervates most of anterior compartment of forearm Flexes, adducts & abducts at wrist, flexes digits 1-5 & pronates forearm Innervates thenar compartment of hand Opposes, abducts & flexes the thumb Median nerve Innervates radial 2 lumbricals of hand Flexes at MCP joints & extends at IP joints Innervates skin of radial ½ of palm, palmar aspect of radial 3½ digits, dorsal aspect of radial 2½ fingertips Innervates skin of posterior arm, forearm, & dorsum of radial 2½ digits (excluding fingertips) Radial nerve Innervates posterior compartment of arm Innervates posterior compartment of forearm Extends at elbow Extends, abducts & adducts at wrist, extends digits 2-5, & supinates at radioulnar joint Ulnar nerve Innervates skin of ulnar ½ of palm & dorsum of hand, ulnar 1½ digits Innervates hypothenar compartment of hand Innervates ulnar 2 lumbricals of hand Innervates some of anterior compartment of forearm Abducts & flexes 5th digit Flexes at metacarpophalangeal (MCP) joints & extends at interphalangeal (IP) joints Flexes & adducts at wrist, flexes 4th & 5th digit Published Nov 2, 2025 on www.thecalgaryguide.com

Lithium

Lithium: Mechanism of action and side effects Bipolar (I & II) Treatment-resistant depression Accumulated Li inhibits adenylyl cyclase Suicidality Schizoaffective Disorder Li passively enters cells in kidney, thyroid, & area postrema via sodium channels Li’s small size prevents active transport out of cells ↓ cAMP ↓ PKA phosphorylation Lithium (Li) Magnesium (Mg²⁺) analog which inhibits Mg²⁺-dependent enzymes such as glycogen synthase kinase-3β (GSK-3β) & inositol monophosphatase (IMPase). This activity modulates neuroplasticity, inflammation, & mood regulation. ↓ T3/T4 synthesis & release from thyroid Authors: Rida Mahmood, Hadi Hassan Reviewers: Taryn Stokowski, Emily J. Doucette, Rohit Ghate* * MD at time of publication ↓ T3/T4 ↑ TSH ↓ Aquaporin insertion in principal cells of collecting ducts of kidneys ↓ Water reabsorption Nephrogenic diabetes insipidus** Li carbonate (an inorganic salt) irritates gastric mucosa Li stimulates chemoreceptor trigger zone Subclinical or overt hypothyroidism Li competes with Mg2+ at cofactor site of IMPase & GSK-3β Enterochromaffin cells ↑ serotonin release ↑ Gut motility & vagal afferent nerve activation Activation of vomiting center in area postrema Nausea & vomiting** ↓ GSK-3β activity throughout brain IMPase & inositol polyphosphate phosphatase (IPP) inhibition prevents hydrolysis of inositol monophosphate to free inositol within neurons Inhibited IRS & ↓ Phosphorylation of transcription factors, PI3K/Akt signaling signaling proteins, & metabolic enzymes ↓ GLUT4 translocation & ↓ glucose uptake in muscle & adipose tissue ↓ Systemic insulin sensitivity Weight gain ↓ Downstream dopamine release in mesolimbic, mesocortical, & nigrostriatal pathways ↓ Conversion of inositol into phosphatidylinositol 4,5-bisphosphate (PIP2) ↓ Pro-apoptotic signaling (Bax, p53, & caspases) ↓ neural apoptosis ↑ Neurotrophic signaling (Akt & MAPK/ERK) ↓ D2 receptor stimulation in nucleus accumbens, prefrontal cortex, & striatum Sustained cAMP Response Element- Binding Protein activity promotes gene transcription ↑ Circadian clock proteins & transcription factor (CLOCK, BMAL1, CRY1, & PER2) stabilization in suprachiasmatic nucleus ↓ PIP2 available for cleavage into second messengers inositol triphosphate (IP3) & diacylglycerol (DAG) during G Protein activation ↓ Dopaminergic inhibition of GABAergic interneurons ↓ Availability of IP3 & DAG ↓ Reward drive in nucleus accumbens ↓ Drive & arousal in prefrontal cortex Dopamine & acetylcholine imbalance in striatum ↑ Circadian rhythm stabilization Thalamocortical motor circuit instability ↑ Brain-Derived Neurotrophic Factor expression in hippocampus & prefrontal cortex Improved sleep timing & stability ↓ Impulsivity Glutamatergic signalling stabilizes (↓ release, ↑ reuptake, ↓ NMDA activity) ↓ Aggression ↑ Involuntary rhythmic muscle activity ↑ Neuronal survival, synaptogenesis, & dendritic growth ↓ Tau hyper- phosphorylation ↑ GABAergic inhibition Excitatory–inhibitory balance in cortical & limbic regions normalizes ↓ Psychomotor agitation Upper extremity postural tremor ↑ Gray matter volume & prefrontal cortex– hippocampus connectivity Neuroprotection & ↓ dementia risk Prefrontal cortex exerts better top-down control ↓ Amygdala hyper-responsivity ↑ Hippocampal regulation of thought loops Improved ↓ Irritability ↓ Mood lability decision-making ↑ Working memory ↓ Distractibility ↓ Racing thoughts Mood stabilization (↓ frequency & severity of manic & depressive episodes) ** See Corresponding Calgary Guide slides Legend: Pathophysiology Mechanism Pharmacologic Effect Side Effects Published Nov 2, 2025 on www.thecalgaryguide.com

Systemic Juvenile Idiopathic Arthritis

Systemic Juvenile Idiopathic Arthritis: Pathogenesis and clinical findings Genetic predisposition (eg. HLA-DRB1*11; IL1, IL6, IL10 & MIF polymorphism, others) Unknown environmental trigger (eg. infection, medications, other environmental stimuli) Systemic Juvenile Idiopathic Arthritis (sJIA) A subtype of JIA occurring in children < 16 y.o. that presents with at least 2 weeks of fever (quotidian for ≥3 consecutive days) along with other symptoms (eg. arthritis, evanescent rash, generalized lymphadenopathy, hepatomegaly, splenomegaly, serositis) Author: Eryn Bugbee Reviewers: Taylor Krawec Annie Pham Michelle J. Chen Emily J. Doucette Danielle Nelson* * MD at time of publication Idiopathic innate immune cell activation (eg. via Toll-like receptor (TLR) signaling) Splenomegaly TLR signaling induces innate immune cell activation & proliferation Leukocytosis (>15,000/mm3) with neutrophilia Positive feedback on inflammatory cascade Activated innate immune cells ↑ inflammatory cytokine production Secondary activation & proliferation of lymphocytes Lymphadenopathy ↑ Interleukin-18 ↑ Interleukin-1β ↑ Interleukin-6 ↑ Ferritin production & secretion by macrophages & hepatocytes ↑ Synthesis & activation of proinflammatory S100 proteins in epithelial cells & keratinocytes ↑ Synovial inflammation & hyperplasia Megakaryocyte stimulation in bone marrow ↑ Prostaglandin synthesis in CNS Enzymatic degradation of bone/cartilage ↑↑ Ferritin Evanescent (<24hrs) erythematous rash (hallmark feature) Arthritis in ≥ 1 joint(s) ↑ C-reactive protein & ferritin Thrombocytosis Quotidian fever (reaches ≥39˚C daily & returns to ≤37˚C between fever peaks) Possible environmental trigger (eg. EBV, CMV, influenza) Genetic predisposition (eg. mutations affecting cytolytic functioning to NK cells & CD8+ T cells, others) Sustained pro-inflammatory state & overproduction of cytokines (cytokine storm) Macrophage activation syndrome (characterized by sustained fever & laboratory findings consistent with hyperinflammatory state (eg. hyperferritinemia, coagulopathy, pancytopenia, hepatic dysfunction)) Mechanism Sign/Symptom/Lab Finding Complications Published Nov 2, 2025 on www.thecalgaryguide.com Hepatocyte stimulation in liver Acute phase protein production Hepatomegaly Legend: Pathophysiology

Non-Depolarizing neuromuscular blocks ndnmbs

Non-Depolarizing Neuromuscular Blockers: Mechanism of action and side effects Facilitation of tracheal intubation Facilitation of mechanical ventilation Improvement in operating conditions Non-depolarizing neuromuscular blocker (NDNMB) Agents that cause muscle paralysis primarily by competitive antagonism of acetylcholine (e.g., Rocuronium, Pancuronium, Atracurium, Cisatracurium) Authors: Simi Gill Sunny Fong Reviewers: Trevor Low Sergio Sherif Billy Sun* Alan Chu* * MD at time of publication Hypersensitivity Reaction Non-immunologic mast cell degranulation (anaphylactoid) Immunoglobulin E-mediated allergic reaction to NDNMB agent (anaphylaxis) Mass histamine release Stimulates H1 receptors on airway smooth muscle Airway smooth Muscle contraction Bronchospasm ↑ Release of nitric oxide Vasodilation ↓ Peripheral vascular resistance Hypotension Stimulates H1 & H2 receptors on vascular endothelium & smooth muscle ↑ Vascular fluid permeability ↑ Superficial dermal arteriole supply Plasma leakage into superficial dermis Red flare on skin Welts on skin Urticaria Competitive antagonism of acetylcholine Blocks neuronal nicotinic acetylcholine receptors on pre-synaptic neuron ↓ Activation of pre- synaptic nicotinic receptors ↓ Neuronal acetylcholine production and release Declining muscle contractility with repeat stimulation Twitch suppression on muscle monitoring (e.g Train-of-Four) indicating adequate paralysis Blocks muscular nicotinic acetylcholine receptors on motor end plate ↓ Activation of post- synaptic nicotinic receptors ↓ Muscle cell depolarization and contraction Skeletal muscle paralysis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 2, 2025 on www.thecalgaryguide.com

Reactive infectious mucocutaneous eruption

Reactive Infectious Mucocutaneous Eruption (RIME): Pathogenesis & clinical findings Bacterial or viral respiratory infection (most common infectious agent is Mycoplasma pneumoniae) ↑ Proliferation of polyclonal B cells (antibodies secreted by different B cell lines) & ↑ antibody production Antibodies cross-react (react to multiple antigens) with antigens in host tissue causing inflammation & tissue damage Systemic & local inflammatory response targets infectious agent RIME prodrome (early symptoms indicating a forthcoming illness) Fever Malaise Cough Dyspnea Inflammation & tissue damage activate inappropriate immune responses at distal sites Authors: Sonia Czyz Reviewers: Shahab Marzoughi Jessica Revington Michele Ramien* * MD at time of publication Normal Mucosa Complement system activates as part of the immune response & produces various complement proteins Epithelium Lamina propria Complement proteins C3a & C5a attract other immune cells to the site of infection & initiate ↑ inflammatory responses Complement protein C3b tags pathogens & infectious agents to help immune cells identify them ↑ Leukocyte infiltrate (accumulation) in tissue & ↑ vascular permeability of surrounding tissues Skin tissue experiences immune-mediated damage from immune cells & active complement proteins Cutaneous lesions (abnormal surface skin growths or skin changes) Mucositis in RIME Legend: Pathophysiology Mechanism Antibodies bind to antigens & form active immune complexes to attack infectious agents Immune complexes circulate in the body to target infectious agents. Antigen excess forms additional immune complexes Immunoglobulin G antibodies specific to the infectious agent cross- react with antigens on keratinocytes (keratin- producing skin cells) & mucosal cells in the epidermis (outermost skin layer) Additional immune complexes continue circulating in the absence of an infectious agent & subsequently deposit in skin tissue & mucous membranes Antibodies & immune complexes Leukocyte infiltrate Destructive inflammatory response induced at mucosal & skin sites with no target pathogen or infectious agent Complement activation Mucosal sites experience localized intense inflammation & ongoing immune-mediated damage from active complement proteins Severe mucositis (inflammation & ulceration of the mucous membranes) Acute hemorrhagic (excessively bleeding) crusts & erosions, ulcers, or vesiculobullous lesions (fluid-filled blisters) in multiple mucosal sites Published Nov 8, 2025 on www.thecalgaryguide.com Full-thickness epithelium necrosis (tissue death) Lamina propria Sign/Symptom/Lab Finding Complications Mucositis in RIME Reactive Infectious Mucocutaneous Eruption (RIME): Pathogenesis and clinical findings Normal Mucosa Epithelium Bacterial or viral respiratory infection; most common infection is Mycoplasma pneumoniae Systemic and local inflammatory response towards invading microbe Lamina propria Polyclonal B cell proliferation and antibody production Full-thickness epithelium necrosis Prodrome: cough, dyspnea, malaise, fever ~1 week prior to mucocutaneous eruption The antibodies cross-react with host tissue causing inflammation and tissue damage Lamina propria Authors: Sonia Czyz Reviewers: Shahab Marzoughi * MD at time of publication Inappropriate immune responses at distal sites Molecular mimicry Immune complex activation Complement activation I would remove all of this Immunoglobulin G antibodies specific for invading microbe cross- react with antigens on keratinocytes and mucosal cells in the epidermis Circulating immune complexes form in antigen excess C3a, C5a, and C3b produced Deposition in skin and mucous membrane ↑ Leukocyte infiltrate and vascular permeability Severe mucositis (inflammation and ulceration of the mucous membranes Destructive inflammatory response at mucosal and skin sites Antibodies & immune complexes Leukocyte infiltrate Complement activation Acute occurrence of hemorrhagic crusts and erosions, ulcers, or vesiculobullous lesions in 2 or more mucosal sites Localized inflammation and immune response activate complement system which damage mucosal tissues Immune response leads to painful, red nodules typically on the shins Triggering localized, intense inflammation and immune- mediated damage in these specific mucosal sites. Legend: Widespread systemic immune response Erythema nodosum Urticaria Immune response results in hives or itchy welts on the skin. Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Cutaneous lesions Published MONTH, DAY, YEAR on www.thecalgaryguide.com

Acute Tubular Necrosis

Acute Tubular Necrosis: Pathogenesis & clinical findings Severe systemic volume depletion (e.g., vomiting, diarrhea) Septic shock** Cardiogenic shock** Cholesterol embolization syndrome (rare) Severe hypotension ↓ Mean arterial pressure reduces renal perfusion pressure which ↓ renal blood flow Renal vascular autoregulation fails to maintain renal perfusion Tubular cell hypoxia & depletion of adenosine triphosphate (ATP) (primary energy carrier in cells) Cell ion pump failure, cell swelling, & cell membrane disruption Ischemic tubular necrosis (renal tubular cell injury secondary to ↓ blood flow) Myoglobinuria Hemoglobinuria Aminoglycosides Ethylene glycol Amphotericin Cisplatin ↓ Efficiency of kidney reabsorption & excretion Kidney removes ↓ potassium (K+) from the blood volume Hyperkalemia** (high K+ concentration in the blood) ↑ Serum K+ levels induce abnormal cardiac electrical conduction patterns & excessive cardiac excitability Fatal cardiac dysrhythmia (irregular heartbeat pattern) Kidney removes ↓ urea from the blood volume Kidney removes ↓ creatinine from the blood volume Azotemia (↑ serum urea & creatinine) Uremic toxins systemically impair neutrophil function Uremic toxins (indoxyl sulfate or paracresyl sulfate) induce oxidative stress in the brain through accumulation of reactive oxygen species (ROS) ↑ Risk of infection ROS damage neuronal membranes & ion channels & induce dysfunctional mitochondria in the brain Authors: Adam Bubelenyi Reviewers: Britney Wong Luiza Radu Jessica Revington Veronica Hammer* Braden Manns* * MD at time of publication **See corresponding Calgary Guide slide Dysfunctional brain mitochondria cannot properly metabolize purines & urea Brain cannot use any metabolic or cellular pathways requiring ATP ↓ Cerebral neuronal signaling Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Intravenous (IV) administration of iodinated contrast medium Tumor lysis syndrome Cancer cell apoptosis (cell death) releases ↑ uric acid & phosphate Heme-containing pigments Medications Uric acid & calcium phosphate crystals precipitate in renal tubules Nephrotoxic substances damage renal tubular cells through unique mechanisms Lipid peroxidation (oxidative degradation) of lipid bilayer weakens renal tubular cell membranes Damage to mitochondria in tubular cells causes depletion of ATP Formation of oxygen free radicals in renal tubular cells Impairment of ATP- dependent processes Activation of pro-inflammatory cytokines & enzymes in the kidney ↑ Renal tubular cell permeability Disruption of protein synthesis & enzyme function in renal tubular cells Degradation of tubular cell membrane lipids & proteins Free radicals oxidize tubular cell proteins & impair structure & function Toxic tubular necrosis (renal tubular injury due to nephrotoxic substances) Acute Tubular Necrosis Acute kidney injury via renal tubular cell damage & cell death Denudation (removal of surface tissue layers) & erosion of the tubular basement membrane Kidney removes ↓ sodium (Na+) & water from the blood volume ↓ Bicarbonate reabsorption from the proximal tubule of the kidney Necrotic tubular cells fall into tubular lumen Ongoing tubule damage ↓ ability to concentrate urine solutes ↓ Bicarbonate neutralization of acids in the blood Necrotic tubular cells release intracellular contents Obstruction of tubular lumen impedes glomerular filtration ↓ Urine osmolality (low urine solute concentration) ↑ Water in blood volume dilutes Na+ serum concentration Metabolic acidosis (blood pH <7.35) Muddy brown granular casts ↓ Glomerular filtration rate (GFR) Hyponatremia** (low Na+ concentration in the blood) ↑ Na+ retention in the circulatory blood volume & ↓ Na+ excretion in the urine ↓ Urine output Accumulation of ROS activates microglia & releases pro-inflammatory cytokines ↑ Fluid retention in the circulatory system Aggressive IV fluid rehydration in septic shock or cardiogenic shock patients Cerebral inflammation ↑ oxidative damage to neurons & glial cells Fluid overload Uremic encephalopathy Pulmonary edema (excess fluid accumulation in lung alveoli & interstitium) Published November 15, 2025 on www.thecalgaryguide.com Complications Disruption of DNA & RNA synthesis within renal tubular cells Tubular epithelial cells in urine Epithelial cell casts in urine (cast composed of epithelial cells embedded in a matrix) ↓ Ability to clear bacteria in urine ↑ Risk of urinary tract infection

Infection-Related Glomerulonephritis

Infection-Related Glomerulonephritis: Pathogenesis & clinical findings Viral or bacterial infections (most commonly streptococcus & staphylococcus) trigger the inflammatory cascade Common infection sites include pharyngitis (infection of the mucous membranes in the oropharynx) & endocarditis (inflammation of the endocardium) but bacterial infections can originate anywhere in the body In streptococcal infections, bacteria release nephritis (inflammation of the kidney) associated plasmin receptor antigens (NAPlr) & streptococcal pyrogenic exotoxin B antigens (SPeB) into the systemic circulation from the infection site. Other bacterial infections may have different pathophysiology Immune response generated against circulating NAPlr & SPeB antigens includes ↑ production of IgG antibodies (critical for immune response & memory) IgG antibodies bind with self-antigens (molecules recognized by the immune system as belonging to the host) including plasmin & glomerular proteins (proteins found in the kidney’s filtering unit, the glomerulus) IgG antibodies activate plasmin (enzyme responsible for breaking down protein in the kidneys) Plasmin degrades protein in the kidneys IgG antibodies bind to glomerular proteins in the kidney & form immune complexes in glomeruli basement membrane & sub- epithelial podocytes (highly specialized cells in the glomerular filtration barrier) Degradation of key glomerulus components, including the glomerular basement membrane (GBM) & mesangial matrix Damage to key glomerulus components leads to abnormal regulation of blood filtration ↓ Selective permeability of the glomerular membrane IgG antibodies bind with NAPIr & SPeB antigens & form immune complexes (antibody & antigen combinations involved in immune system signalling) Immune complexes circulate & deposit in glomeruli basement membrane & sub-epithelial podocytes RBCs escape through the glomerulus into renal tubules & progress into the urine Dysmorphic hematuria (blood in the urine characterized by misshapen RBCs) Author: Joanna Keough Reviewers: Britney Wong Luiza Radu Jessica Revington Veronica Hammer* Louis Girard* *MD at time of publication **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Immune complexes activate complement (C3, oxidizing agents, proteases) Complement activation helps ↑ proliferation of glomerular mesangial cells (cells with specialized proteins capable of producing motile forces) Mesangial cells produce extracellular matrix in the glomerulus Excess extracellular matrix blocks glomerular capillaries Mesangial cells release chemoattractants (signalling molecules) into the glomerulus & attract various immune cells Lymphocytes follow chemoattractants to the glomerulus & activate Neutrophils follow chemoattractants to the glomerulus & release lysosomal enzymes Lymphocytes accumulate in the glomerulus & obstruct glomerular capillaries Impaired blood flow through glomerular capillaries Capillary injury Podocyte injury or death Infection-Related Glomerulonephritis Glomerular kidney damage sustained after a bacterial or viral infection ↓ Glomerular filtration rate (GFR) Creatinine builds up in the blood ↑ Glomerular membrane permeability allows large molecules to pass through the membrane (e.g., red blood cells (RBCs), protein) ↓ GFR impairs the kidney’s ability to filter & excrete fluid ↓ Estimated GFR Prolonged (eGFR) renal damage Protein escapes into renal tubules & progresses into the urine Chronic kidney disease Proteinuria (loss of protein through the urine) ↑ Fluid retention in systemic circulation & ↓ renal blood flow Impaired potassium excretion ↓ Urine output Impaired acid waste product excretion Urine contains ↑ large proteins (e.g., albumin) Activation of the intrarenal renin- angiotensin-aldosterone system (RAAS)** Hyperkalemia (↑ serum potassium) Oliguria (↓ urine volume) Metabolic acidosis** Albuminuria (loss of albumin through the urine) Intrarenal RAAS activation leads to ↑ angiotensin II (Ang II) production ↑ Sodium & water retention in systemic circulation & ↓ excretion in urine (↓ GFR) Hypertension** Edema (swelling due to ↑ fluid in body tissues) Circulating blood volume exerts ↑ pressure on blood vessels & forces the heart to pump harder Left ventricle thickens & enlarges over time & demonstrates progressive cardiac injury (e.g., fibrosis, loss of cardiac muscle cells) Impaired cardiac output Heart failure Sign/Symptom/Lab Finding Complications Published November 15, 2025 on www.thecalgaryguide.com

Pediatric Asthma Exacerbations

Pediatric Asthma Exacerbations: Pathogenesis and clinical findings Non-allergic asthma (not triggered by allergens) Allergic asthma (triggered by allergens) (e.g., pollen, animal dander, dust mites) Viral respiratory tract infections Extreme weather Physical exertion Pollutants (e.g. cigarette smoke) Allergen inhalation activates IgE on mast cells Virus invades epithelial cells in airway Inhalation of cold ↑ Minute ventilation or dry air dries ↑ Air flow irritates & dries airway mucosa airway mucosa Inhaled irritants damage airway Epithelial barrier breakdown releases inflammatory mediators epithelium & activate immune cells Immune system releases inflammatory mediators (e.g., histamine, leukotrienes, prostaglandins, cytokines) into airway Histamine & leukotrienes stimulate smooth muscle cells in the airway to constrict Cytokines attract white blood cells (e.g., eosinophils, neutrophils, monocytes) Inflammatory mediators stimulate epithelial goblet cells Inflammatory mediators ↑ vascular permeability in airway mucosa Bronchoconstriction (bronchioles narrow) Airway inflammation persists & intensifies Goblet cells produce excess mucus plugs & obstruct small airways Airway wall swells (mucosal edema) Asthma Exacerbation Acute or sub-acute episode marked by a progressive ↑ in asthma symptoms & a measurable ↓ in lung function compared to patient’s baseline Bronchial hyperresponsiveness (an exaggerated & easily triggered constricting response of the airways to various stimuli) Narrowed bronchioles mechanically obstructs air flow & ↓ ventilation ↓ Ventilation impairs elimination of carbon dioxide (CO₂) from blood More force is required to expel air Turbulent airflow through narrowed bronchioles during expiration Severe airflow obstruction prevents airflow into distal lung regions ↓ Ventilation traps air in alveoli Prolonged expiratory phase Inflammatory mediators & mucous hypersecretion sensitize afferent nerves in airway ↑ Arterial partial pressure of CO2 (PaCO2)) triggers hyperventilation ↑ Work of breathing Expiratory wheeze ↓ Breath sounds Afferents activate cough reflex via Trapped air ↑ intra- Air trapping alveolar pressure overinflates vagus nerve above pleural pressure lungs Cough ↓ PaCO2 ↑ blood pH Tachypnea (↑ respiratory rate) Exhaustion of respiratory muscles ↓ strength & respiratory rate Air trapping limits oxygen (O2) exchange in alveoli ↑ Pressure ruptures alveoli ↓ Diaphragmatic excursion Hyperinflation on chest X-ray Pneumothorax (air collects in pleural space) ↓ Oxygenation of blood (hypoxemia) Respiratory alkalosis Normocapnia, can progress to hypercapnia (↑ PaCO2) Engagement of accessory respiratory muscles Respiratory failure ↓ O2 delivery to peripheral tissues Legend: Authors: Fares Senjar, Jody Platt Hypoxemic hypoxia (SpO2 < 90% on room air) Reviewers: Merry Faye Graff, Emily J. Doucette, Central cyanosis (bluish discoloration of skin & mucous membranes) Elizabeth De Klerk, Yan Yu, Alexander Arnold, Naminder Sandhu*, Jonathan Liu* Tachycardia (↑ heart rate) *MD at time of publication Complications Published Dec 2, 2013; updated Nov 15 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding

Suppurative Tenosynovitis

Legend: Suppurative Tenosynovitis: Pathogenesis & clinical findings Penetrating trauma involving the tendon sheath (e.g., puncture wounds, human or animal bite, intravenous drug use, other trauma sources) Bacteria spread into the tendon sheath from a nearby infected joint or deep space (less common) Hematogenous spread (bacterial infection travels through the bloodstream to other parts of the body, rare) Authors: Stephen Langor Reviewers: Nojan Mannani Mankirat Bhogal Jessica Revington Kate Elzinga* * MD at time of publication Bacterial infection of the tendon sheath (most commonly Staphylococcus aureus) Bacterial infection of the tendon sheath (e.g., Neisseria gonorrhoeae, mycobacteria) Suppurative Tenosynovitis Severe bacterial infection of the flexor tendon sheath Bacterial infection causes an immune response & subsequently activates macrophages & neutrophils Immune cells & mast cells release vasoactive cytokines (molecules capable of dilating or constricting blood vessels) Immune cells produce pyrogens (fever- inducing substances) & inflammatory cytokines (e.g.,IL-1, IL-6, TNF⍺) ↑ White blood cell count Vasoactive cytokines ↑ vascular permeability during capillary dilation & allow for the outflow of fluid, immune cells, & plasma into surrounding tissues Systemic cytokines (immune messenger proteins) produce ↑ concentrations of non- specific acute-phase reactants (inflammatory markers) Pyrogens stimulate prostaglandin E2 production in the hypothalamus Fluid outflow reaches the synovial space (a fluid-filled sac surrounding tendons). The synovial space is between the visceral epitenon layer (connective tissue sheath immediately covering the tendon) & outer parietal layer of the tendon Infection & corresponding immune response spread from the thumb to the little finger (or vice versa) through the radial & ulnar bursae (fluid-filled sacs surrounding hand flexor tendons) ↑ Serum C- reactive protein ↑ Prostaglandin E2 production disrupts thermoregulation in the hypothalamus & forces body temperature elevation Chills (rare) Fever (rare) Exudate (fluid leaking from nearby blood vessels) continues accumulating in the flexor tendon sheath’s synovial space Dead inflammatory cells also begin accumulating & fill the synovial space with purulent fluid (pus) Fluid accumulation can ↑ pressure in the synovial space & compromise blood flow to the sheath, tendon, & adjacent structures Erythema (redness), swelling, & pain in both the thumb & little finger Tendon necrosis (tissue death) Tendon ischemia (↓ blood flow) Hand horseshoe abscess Fluid leaks into the surrounding tissue & causes swelling. Swelling is more prominent on the ventral (front) side of the affected digit(s) ↑ Synovial space content applies ↑ pressure on the visceral & parietal layers of the tendon sheath ↑ Pressure disrupts tendon blood flow & nutrient supply ↑ Risk of tendon damage & scarring, which may ↑ fibrotic tissue deposition along the tendon ↑ Swelling & pressure cause passive mechanical stretching of digit tissue. Stretch is ↑ in the ventral direction ↑ Pressure activates nociceptors (sensory receptors detecting harmful stimuli) Fibrotic tissue may cause tendon adhesion, thicken joint capsules, & damage the flexor pulley system Fibrotic tissue is stiff & may ↓ tendon elasticity Symmetric enlargement of affected digit(s) Digit slightly flexed at rest ↑ Pain along the tendon with passive extension Kanavel Criteria ↑ Tenderness along the tendon sheath ↓ Range of motion Chronic stiffness Tendon rupture Published November 20, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Pyelonephritis

Acute Pyelonephritis: Pathogenesis and clinical findings Female sex Indwelling Diabetes (especially post- urinary catheter mellitus menopausal due to loss of protective Lactobacillus species) Obstruction of bladder outlet (congenital/acquired) High blood glucose damages nerves controlling the bladder, as well as blood vessels supplying bladder nerves Glycosuria (elevated levels of glucose in urine) create nutritive environment for bacterial growth Excessive urine buildup increases pressure exerted against the bladder, pushing urine from bladder up to ureters Authors: Sergio F. Sharif Reviewers: Michelle J. Chen Jessica Revington Yan Yu* Juliya Hemmett* Brandon Christensen* * MD at time of publication Shorter urethra allows for fecal microbes to more readily enter the urinary tract Catheter inoculates deep urinary tract with bacteria & facilitates organisms to enter bladder Neurogenic bladder (decreased bladder control due to nerve damage) is unable to appropriately release urine, leading to urinary retention & failure to clear residing bacteria Bacteremia (bacterial infection in bloodstream) Bacteria initially colonize the lower urinary tract, then migrate up the tract towards one or both kidneys (most commonly Gram-negative rods, e.g., Escherichia coli) Bacteria, such as Staphylococcus species, spread from another site of infection to kidneys via bloodstream Acute Pyelonephritis Inflammation of the kidney interstitium due to upper urinary tract infection, usually bacterial Collective contribution of mechanisms stated below, if severe Sepsis** Concurrent cystitis irritates urinary tract (see lower UTI slide)** Bacteria expressing virulence factors (e.g., P fimbriae in Escherichia coli) exploit host susceptibility & infect upper urinary tract (ureters & kidneys) Positive urine culture Dysuria (pain & burning while urinating) Bacteria trigger IL-8 release by local immune cells in the upper urinary tract, triggering recruitment of neutrophils to renal tubules & interstitium Neutrophils degranulate in the infected tissue, phagocytose bacteria & form sacrificial neutrophil extracellular traps (resulting in neutrophil death) in attempt to clear infection Neutrophil-mediated immune response damages surrounding kidney tissue (tubular injury) Acute kidney injury** Immune cells at the site of infection release cytokines (e.g., IL-1, TNF), which disseminate systemically Cytokines act in the brain in concert with unclear mechanisms relating to tissue injury & inflammation triggered by infection (see Neurotransmitters & Pharmacology behind Nausea and Vomiting slide**) Cytokines bind receptors in the anterior hypothalamus, triggering pathways ultimately leading to heat-generating responses (e.g., shivering) Cytokines promote the growth & release of white blood cells from bone marrow into bloodstream Dead neutrophils collect in renal tubules near infection & attach to assemblies of mucoprotein (a renal tubular epithelium protein secreted into tubules) Pyuria (WBCs in urine) Nausea/vomiting Fever Leukocytosis (↑ WBCs) Urine white blood cell (WBC) casts (cylindrical particles with WBCs seen on microscopy) Costovertebral Flank pain CT KUB - angle tenderness findings may include focal or diffuse involvement, fat stranding, gas formation, &/or other complications including renal scarring **See corresponding and abscesses Calgary Guide slide(s) Complications Published November 23, 2025 on www.thecalgaryguide.com Unclear mechanism involving systemic inflammation worsens mental status in susceptible individuals Altered level of consciousness (especially in elderly) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding

Hypothyroidism

Hypothyroidism: Pathogenesis & Clinical Findings Hashimoto’s thyroiditis Transient congenital hypothyroidism Congenital deficiency of thyroid hormone (TH) Iodine deficiency Infiltrative disease affecting thyroid gland cells Iatrogenic or medication- related thyroid dysfunction Hypothyroid phase of thyroiditis (inflammation of the thyroid) Pituitary gland dysfunction (central hypothyroidism) Progressive autoimmune destruction of thyroid gland cells ↓ T3/T4 levels activate the hypothalamus- pituitary-thyroid axis & ↑ TSH release by the pituitary gland Primary hypothyroidism (↑ TSH and ↓ T3/T4) ↓ T3/T4 levels cause ↓ expression of TH-dependent myocardial enzymes essential for cardiac contractility Cardiac myocytes (cardiac muscle cells) experience ↓ contractility ↓ Heart rate ↑ Bleeding Impaired function of the thyroid gland & ↓ thyroid hormone (TH) secretion Pituitary gland secretes ↓ levels of thyroid stimulating hormone (TSH) Hypothyroidism Low or significantly ↓ secretion of triiodothyronine (T3) & thyroxine (T4) from the thyroid gland ↓ T3/T4 levels ↓ production of nitric oxide (vasodilator) & cause systemic vasoconstriction of blood vessels Systemic vaso- constriction ↑ systemic vascular resistance ↑ Systemic vascular resistance à ↑ intrarenal vascular resistance & contributes to ↓ renal perfusion ↓ T3/T4 levels reduce the rate of metabolic reactions in the body including ↓ rates of carbohydrate, fat, & protein metabolism ↓ T3 levels allow fibroblasts (connective tissue cells) to synthesize ↑ glycosaminoglycans (GAGs – structural cell molecules capable of attracting large amounts of water) ↓ Basal metabolic rate (base energy required to sustain bodily functions) ↑ Diastolic blood pressure (diastolic hypertension) ↓ Renal blood flow à ↓ glomerular filtration rate (GFR) ↓ GFR impairs renal clearance of excess GAGs ↑ GAG deposits & water retention in body tissues ↓ Energy to support physiological function Narrowed pulse pressure (↓ difference between systolic & diastolic blood pressure) Compensatory mechanisms to manage blood volume & circulation during ↓ T3/T4 levels are overwhelmed in the presence of an infection or systemic trauma (e.g., heart attack, stroke) ↓ GFR impairs removal of excess free water from the blood volume by the kidneys ↑ GAG deposits & swelling in skin tissue ↑ GAG deposits in the larynx swell & stiffen vocal cords ↓ Skin gland activity & ↓ sebum (oil) & sweat production ↑ Fatigue ↓ Motility of the gastrointestinal (GI) tract causes ↓ movement of digested food & ↓ rate of waste excretion ↓ TH levels & ↓ metabolic rate impair neurologic function (e.g., neurotransmitter signaling & neuron functioning) Thickened skin Hoarse speech Dry skin ↑ Sodium (Na+) & water retention in blood volume ↓ Perspiration (sweating) Constipation Neurologic symptoms (e.g. depression, somnolence) Abnormally heavy menses Excessive water retention dilutes serum Na+ levels in severe hypothyroidism ↓ Caloric expenditure at rest & with activity ↑ Risk of infertility Myxedema coma** (extreme manifestation of hypothyroidism) Hyponatremia (↓ Na+) ↑ Fluid retention in body tissues Weight gain Musculoskeletal symptoms (e.g., muscle cramps, joint pain & ↓ muscle tone) Published June 19, 2013, revised November 23, 2025 on www.thecalgaryguide.com Normal or ↓ TSH levels when T3/T4 levels are low Authors: Sophia Khan, Ayden Hansen, Jessica Revington, Rupali Manek, Jaye Platnich Reviewers: Shahab Marzoughi, Gurreet Bhandal, Raafi Ali, Matthew Harding, Mark Elliott, Hanan Bassyouni*, Breanna McSweeney* * MD at time of publication **See corresponding Calgary Guide slides ↓ T3 levels lead to ↓ lipoprotein lipase (lipid metabolism enzyme) activity ↑ Triglyceride levels in blood ↓ TH levels & ↓ metabolic rate impair cold tolerance & thermogenesis (heat production) mechanisms Cold extremities (e.g. hands, feet) ↓ Cold tolerance ↓ Activation of the T3- mediated low- density lipoprotein (LDL) receptor gene ↓ LDL receptor expression for LDL clearance ↑ LDL cholesterol levels in the blood ↓ T3/T4 levels ↓ coagulation factor synthesis by the liver ↓ T3/T4 levels disrupt the menstrual cycle & cause anovulation (absence of ovulation) Legend: Hyperlipidemia Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Diverticulosis and Angiodysplasia

Diverticulosis and Angiodysplasia: Pathogenesis and clinical features Diverticulosis Angiodysplasia Disturbances in enteric nervous system regulation leading to uncoordinated or exaggerated peristaltic waves Older age Renal failure Constipation from low fiber diets Parts of colon susceptible to obstruction leading to leading to vessel alterations in weakening and vascular blood dilation flow Autoimmune diseases cause inflammatory vascular damage Abnormal angiogenesis (vessel formation) from idiopathic causes von Willebrand Deficiency (lack of vWF) aggravates bleeding tendency Aging weakens the circular muscles strutting the colon High intracolonic pressure primarily in the sigmoid colon (e.g., from peristalsis pushing against colonic waste that is low in fiber & harder to move) Muscular hypertrophy of the colon in response to repeated high- pressure contractions of the smooth muscle as a compensatory mechanism to move stool in high resistance areas Arterial-venous malformations (AVMs; abnormal connections between arteries & veins) bypass capillary beds and rise to the mucosa of the lower GI tract Flat cherry-red vessels originating from a central artery as seen on upper GI endoscopy or colonoscopy Colon wall forms little outpouchings (diverticuli) that span around 3-10mm Gradual & repetitive expansion thins the diverticular wall Stretching of colonic serosa stimulates somatic sensory nerves innervating the colon Colonic diverticuli trap feces Venous rupture of submucosal veins in the High pressure arterial blood flows colon directly into veins, causing venous dilation & weakening of vascular walls Overlap with other vascular lesions such as Dieulafoy’s Capillaries within diverticuli burst and leak blood into the colon lumen Stretching of nociceptors that are primarily sensitive to mechanical stimuli such as distension of the colonic wall Bacteria have more time to metabolize the undigested materials, producing gas Irregular defecation (constipation, increased frequency) GI tract lumen bleeding due to irritation of these malformations Large volume blood loss Iron deficiency anemia Lower GI bleed (usually stops by itself) Bloating & cramping (most often painless) Flatulence (accumulation of gas) Lower GI bleed (occult, slow, asymptomatic) Author: Yan Yu Ali Babwani Reviewers: Jason Baserman Jennifer Au Paige Sheleme Tony Gu Luiza Radu Sergio F. Sharif Kerri Novak* Sylvain Coderre* * MD at time of publication Legend: Re-Published Aug 4, 2019 and Nov 23, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Infectious Large Bowel Diarrhea

Infectious large bowel diarrhea: Pathogenesis and clinical findings Bodily fluids, organ transplantation (active in immuno- compromised hosts) Contaminated food, water, poor sanitation Eggs, contaminated Undercooked poultry Undercooked pork Contaminated food, water produce, undercooked poultry Unpasteurized milk Undercooked beef, contaminated vegetables Antibiotic use, healthcare associated infection Cytomegalovirus S. enteritidis, S. Enteroinvasive Enterohemorrhagic typhimurium E. histolytica Y. enterocolitica E. coli (EIEC) Shigella E. coli (EHEC) C. jejuni C. difficile Individual ingests an adequate amount of organism Bacteria employ protective mechanisms to survive gastric acid Organism adheres to colonic wall & colonizes the large bowel Organism releases a toxin that disrupts the colon (enterotoxin) Invading organisms activate local immune surveillance Toxins A & B (from C. diff) disrupt tight junctions between colonocytes Toxin enters bloodstream Release of pro-inflammatory cytokines triggers colonic inflammation Cytokines Inflammation &/or toxins stimulates act on nerve endings hypothalamus in rectal wall to trigger temperature change (pyrogens) Inflammation dysregulates enteric nervous system Inflammation spreads to visceral peritoneum Inflammation & invading bacteria breaks down colonic mucosa Triggers apoptosis of colonocytes Massive neutrophilic infiltration Toxin reaches the chemoreceptor trigger zone in medulla Shiga toxins (from Shigella or EHEC) bind to Gb3 receptors on endothelial cells Pseudomembranous colitis on endoscopy Abnormal peristalsis & spasms Diffuse abdominal pain & cramping Nausea & vomiting Toxin enters cells via endocytosis Fever Colonic epithelium loses Na⁺ resorptive channels Colonic epithelial cells secrete ↑ Cl⁻ into lumen ↑ Sense of urgency & incomplete evacuation (Tenesmus) Inflammation & organisms disrupts blood vessels & mucosa develops ulcers Intestine absorbs ↓ fluid from lumen Intestine secretes ↑ fluid into lumen Shiga toxin activates platelets (mechanism unclear) Toxin inhibits protein synthesis & induces apoptosis Authors: Merry Faye Graff, Noriyah Al Awadhi, Yan Yu Reviewers: Paul Ratti, Jason Baserman, Sergio F. Sharif Kerri Novak*, Sylvain Coderre* *Indicates MD at time of publication **See corresponding Calgary Guide slide Small volume diarrhea Ulcers bleed into colonic lumen Volume depletion Platelet activation & endothelial cell damage promote microthrombi formation within systemic vasculature Dehydration Hypotension Bloody stool (can be nocturnal) Hemolytic uremic syndrome** Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 7, 2012; updated Nov 23, 2025 on www.thecalgaryguide.com

Heart Transplant Indications and Benefits

Failed existing transplant Cardiogenic Shock** Circulatory failure secondary to ↓ CO Untreatable Arrythmias** Irregular heart rate or rhythm Ventricular Assist Devices (VAD) Used as bridge to transplant Failure of treatment with conventional heart failure therapies Cardiac transplant recommended Major systemic diseases, including cancer Assess surgical readiness and comorbidities with evaluation by cardiac surgeon & cardiologist Psychological Instability Active or recent substance abuse Bridge to transplant with inotropes or mechanical circulatory support devices (VAD, ECMO, IABP) Cardiac Transplant Surgery to replace dysfunctional heart with a functional donor heart **See corresponding Calgary Guide slide(s) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Heart Transplant: Indications & Benefits Indications Kate Fougere Authors: Reviewers: Emily Kuervers Sergio F. Sharif Dr. Robert Miller* Severe cardiomyopathy Myocardial dysfunction * MD at time of publication Disease of the cardiac Pump Failure ↓ Stroke volume (SV), muscle (Dilated, ↓ Forward flow, ↓ cardiac output (CO), hypertrophic, restrictive backup into lungs ↓ blood pressure (BP) cardiomyopathies**) Acyanotic heart disease Normal concentration of oxygenated Hb ↓ Perfusion of organs with ↑ pulmonary congestion Congenital Heart Disease** Disruption of normal cardiac formation that is unsuccessfully treated with surgical repair Cyanotic heart disease ↑ Concentration of deoxygenated hemoglobin (Hb) Cyanosis (dusky, blue skin discoloration) Cardiac Allograph Vasculopathy (CAV) Diffuse concentric narrowing of coronary arteries Antibody mediated graft rejection & fibrosis Symptoms of heart failure ** Cardiovascular risk factors exacerbated by immunosuppressive drugs ↓ BP Reduced SV with no response to medical therapy Pump Failure ↓ Forward flow, backup into lungs ↓ Perfusion of organs ↓ Level of consciousness End organ damage Abnormal electrical activity does not respond to pharmacological agents, cardiac ablation or electrophysiological interventions (ICD) Refractory arrythmias (ventricular tachycardia, ventricular fibrillation) & subsequent cardiac death Device complications arise while awaiting transplantation Device infection Clotting or bleeding complications (stroke or hemorrhage) Abbreviations: • ICD - Implantable cardioverter defibrillators • ECMO- Extracorporeal membrane oxygenation • IABP - Intra-aortic balloon pump Low survival benefit from transplant ↓ Capacity to manage post transplant requirements Graft rejection ↑ Potential for relapse after transplant ↓ Symptoms of heart failure** Restoration of cardiac output & normalization of volume status ↑ Life expectancy ↑ Quality of life Published Nov 23, 2025 on www.thecalgaryguide.com

Esophageal Atresia & Tracheoesophageal Fistula

Congenital Esophageal Atresia & Tracheoesophageal Fistula: Pathogenesis and clinical findings Genetic risk factors Environmental risk factors Aneuploidies (e.g., trisomy 13, 18 & 21**) Associated syndromes (e.g., VACTERL, CHARGE, Feingold, Anophthalmia- Esophageal-Genital) De novo mutations (e.g., 10q25.3 duplications) Teratogenic exposure (e.g., alcohol, methimazole, mycophenolate) Advanced maternal age (>35 years) First trimester exposure to maternal diabetes Interaction between genetic & environmental risk factors disrupt signalling pathways essential for embryonic development of esophagus & trachea (exact mechanism unclear) Abnormal signalling pathways alter recanalization & elongation of esophagus Abnormal signalling disrupts septation (division) of the single-lumen fetal foregut into esophagus & trachea Abnormal epithelial-mesenchymal signalling in the embryonic lung bud Embryonic lung bud trifurcates Incomplete separation of developing esophagus from developing trachea Middle branch of tracheal trifurcation continues to grow caudally as an unbranched tube Interrupted continuity of esophagus Abnormal connection forms between esophagus & trachea Abnormal branch grows caudally until it fistulizes with esophagus or stomach Esophageal Atresia Congenital defect in which the esophagus fails to connect the upper & lower segments, leaving the upper pouch ending blindly Tracheoesophageal Fistula Fistula (abnormal connection) between trachea & esophagus that may be connected to proximal &/or distal esophageal segment Blind-end esophagus prevents food & secretions from reaching stomach Abnormal gut motility & altered esophageal length Fetus fails to swallow amniotic fluid Gastric contents reflux into trachea Tracheal cartilage is malformed Air passes from trachea to stomach Gastroesophageal reflux disease** Aspiration pneumonia** Coughing & choking Difficulty breathing Abnormal abdominal distention Free air under diaphragm on chest x-ray Excessive secretions & foaming at mouth Feeding tube cannot pass through esophagus Dehydration Regurgitation Tracheomalacia (abnormal collapsing of tracheal walls) Drooling Electrolyte imbalances (e.g., hyponatremia**, hypokalemia**) Polyhydramnios (accumulation of amniotic fluid in uterus) Respiratory distress Author: Skanda Kaushik Reviewers: Merry Faye Graff, Emily J. Doucette, Danielle Nelson* * MD at time of publication ** See corresponding Calgary Guide slide Published Nov 23, 2025 on www.thecalgaryguide.com Inadequate nutrition Malnutrition Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Peripheral Vestibular Dysfunction

Peripheral Vestibular Dysfunction: Pathogenesis, mechanisms, & clinical findings Preceding viral illness or bacterial infection Vestibular structure pathologies Impaired resorption of endolymph (inner ear fluid involved in hearing & balance) in the membranous labyrinth (fluid-filled chambers & ducts in the inner ear) ↑ Humoral & cellular immune responses in the inner ear cause nerve inflammation Otoconia (calcium carbonate crystals in the inner ear) dislodge & migrate into the ear’s semicircular canals Direct entry of pathogens via oval or round window (membrane-covered openings between the middle & inner ear) Hematogenous (through blood) or subarachnoid space infection ↑ Accumulation of endolymph distends the membranous labyrinth & produces ↑ pressure on inner ear structures Dislodged otoconia cause differences in endolymph flow & subsequent asymmetric hair cell movement Ménière’s disease Endolymphatic hydrops (abnormal endolymph buildup in the inner ear) Vestibular hyperactivity & mismatched visual sensory input activates the histaminergic neuronal system in the hypothalamus Histaminergic neurons send activation signals to histamine H1 receptors in the brain’s vomiting centre Activation of H1 receptors stimulates the chemoreceptor trigger zone in the vomiting centre Nausea** Vomiting** Legend: ↑ Cytokines (immune chemical messengers) ICAM-1 & IL-1β recruit additional immune cells to the inner ear & further ↑ immune responses Activation of immune cells within inner ear Benign paroxysmal positional vertigo** Breakdown of the inner ear blood-labyrinth barrier Autoimmune inner ear disease (e.g., Cogan’s syndrome, granulomatosis with polyangiitis, systemic lupus erythematosus) Systemic manifestations of autoimmune disease (e.g., rash, joint pain, eye inflammation) Labyrinthitis (membranous labyrinth inflammation) Vestibular neuritis (inflammation of the vestibular nerve) Peripheral Vestibular Dysfunction Pathology of the inner ear & vestibular portion of the vestibulocochlear nerve Central nervous system receives dysregulated visual inputs, vestibular inputs, & proprioceptive (body positioning) inputs ↑ Damage to the hair cells (sensory receptors) in the inner ear ↑ Damage to the vestibulocochlear nerve Loss of nerve input from the vestibulocochlear nerve causes abnormal neuronal activity in the auditory cortex Asymmetric, mismatched, or contradictory sensory inputs cannot be properly interpreted by the brain Damaged hair cells cannot convert sound or movement into appropriate electrical signals for vestibulocochlear nerve transmission Brainstem & auditory cortex receive ↓ or no auditory signal input from the vestibulocochlear nerve Abnormal neuronal activity & nerve signals may be misinterpreted by the auditory cortex as sound Sensorineural hearing loss Dizziness Vertigo (abnormal sensation of spinning or movement) Subjective tinnitus** (continuous or intermittent perception of ringing or buzzing without an acoustic stimulus) Published November 23, 2025 on www.thecalgaryguide.com Vestibulocochlear nerve pathologies NF2 gene encodes for functional schwannomin (cell structure protein involved in suppressing tumour growth) Point mutations & loss of heterozygosity in the NF2 gene result in ↓ or absent schwannomin Schwann cells (cells protecting nerve fibres) form a protective myelin sheath on the vestibulocochlear nerve Schwann cells malfunction in the absence of schwannoma & the myelin sheath is compromised Vestibular schwannomas (benign tumours on the vestibulocochlear nerve) develop in the absence of functional schwannomin Asymmetric vestibular input disrupts the nerve inputs sent to the oculomotor nuclei (brainstem nerve cells responsible for muscles involved in eye movement) Triggers an abnormal vestibulo-ocular reflex (normal reflex keeps vision steady while the head moves) Authors: Nystagmus (repetitive & uncontrolled eye movements) Fariha Rahman Farah Ali Reviewers: Vaneeza Moosa Jessica Revington Gabrielle Juliet French* * MD at time of publication **See corresponding Calgary Guide slide Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Teen Brain Changes

Changes in the Teen Brain and their Behavioral Manifestations Mesolimbic Dopamine Pathways (Reward & Motivation) Sex hormones ↑ Early maturation of glutamatergic dopaminergic signaling (excitatory) pathways ↑ Dopamine receptor density in ventral striatum ↑ Phasic dopamine release by ventral tegmental area Exaggerated response to novelty & reward ↑ Risk taking ↑ Impulsivity ↑ Novelty seeking ↑ Vulnerability to substance use disorder ↑ Potential for unsafe behaviors (e.g. unprotected sex) until executive networks mature (later) Frontolimbic Pathways (Emotional Regulation & Impulse Control) Late maturation of GABAergic (inhibitory) pathways Early maturation of amygdala ↓ Top-down control over amygdala by immature prefrontal cortex (PFC) Difficulty regulating stress ↓ Emotional regulation & impulse control ↑ Sensitivity & excitability of amygdala ↑ Response to emotional stimuli (limbic > PFC control) Mood swings ↑ Reactive decisions ↑ Sensitivity to peer evaluation ↑ Memory of emotional events ↑ Vulnerability to anxiety & mood disorders Sleep-Wake Regulation Pathways Suprachiasmatic nucleus maturation shifts circadian rhythm later ↓ Accumulation of sleep pressure Melatonin secretion is ↓ & occurs later in evening Delayed sleep phase & altered circadian rhythm ↑ Length of time awake before feeling tired Evening chronotype (↑ evening wakefulness & difficulty with early waking) Conflict between early school start & delayed sleep phase Late sleeping ↓ Sleep Chronic sleep deprivation Irritability ↓ Concentration Frontoparietal Pathways (Executive Function) Grey matter synaptic pruning Androgens facilitate synthesis of myelin in oligodendrocytes Aberrant pruning Elimination of excess or weak connections Myelination ↑ speed & ↓ energy demand for impulse conduction ↑ Vulnerability to psychiatric disorders ↑ Efficiency of neural circuits (occurs “back-to front”; prefrontal cortex last) ↑ Learning capacity for frequently practiced activities ↑ Executive functioning & abstract thought (later) ↑ Performance with practice (eg. sports, language, instruments) ↑ Hypothetical reasoning & future planning Author: Katelyn du Plessis Reviewers: Taylor Krawec, Trevor Low, Emily J. Doucette, Jean K. Mah*, *MD at time of publication Legend: Default Mode Network (Social Cognition) ↑ Time with peers ↑ Sensitivity to social context & rewards ↑ Self-awareness & reflection ↑ Drive for peer acceptance Medial prefrontal cortex & posterior cingulate connections mature ↑ Ability to mentalize ↑ Ability to take another’s perspective (versus as a child) ↑ Ability to navigate social situations ↑ Sense of identity Hippocampus undergoes structural refinement & ↑ integration with prefrontal cortex & amygdala ↑ Encoding, retrieval & emotional contextualization of experiences ↑ Autobiographical memory Development of cohesive self narrative Pathophysiology Mechanism Behavioral Manifestations Consequences Published Nov 26, 2025 on www.thecalgaryguide.com

Hypoxic Ischemic Encephalopathy

Authors: Isabella Reis, Alam Randhawa Reviewers: Annie Pham, Taylor Krawec, Emily J. Doucette, Danielle Nelson* *MD at the time of publication **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Hypoxic Ischemic Encephalopathy: Pathogenesis and clinical findings Intrauterine growth restriction** (most important) ↑ Maternal age Gestational hypertension** Chorioamnionitis** Oligohydramnios Antepartum risk factors Intrapartum risk factors Antenatal trauma Maternal illness Maternal thyroid disease Gestational age > 41 weeks Preeclampsia** Hypoxic Ischemic Encephalopathy (HIE) Brain injury resulting from disrupted cerebral oxygen (hypoxia) & blood flow (ischemia) before, during or shortly after birth 1. Primary Energy Failure (within minutes to hours) Insufficient cerebral perfusion triggers anaerobic metabolism 2. Latent Phase (within hours) 3. Secondary Energy Failure (within days) ↑ Lactic acid ↓ ATP production High anion gap metabolic acidosis** ATP-dependent pumps fail (i.e., Na+/K+ -ATPase, Ca2+ -ATPase) in areas with ↑ demand Return of O2 supply allows transient recovery of oxidative metabolism Prolonged reaction to primary insult Intracellular acidosis ↓ enzyme, mitochondria & membrane function ↑ Na+ & Ca2+ influx & K+ efflux Reperfusion Ion imbalance Widespread of surviving ↓ Umbilical drives H2O influx depolarization brain cells cord blood gas (pH ≤7.0 mEq/L, base excess ≥-16 Cellular swelling & edema Glutamate release mEq/L) Cell lysis ↑↑ Ca2+ influx Early necrotic injury Transient improvement after initial event Delayed necrosis Need for prolonged resuscitation Diffuse brain injury Diffuse neurological deficits (e.g., coma, generalized seizure) Focal brain injury Focal neurological deficits (e.g., focal seizure, hemiparesis) Complications Reperfusion generates reactive O2 species Apoptotic cascade is activated Shoulder dystocia** Operative vaginal delivery Uterine rupture Placental abruption** Prolonged ruptured membranes &/or active labour Cord prolapse** Prematurity Nuchal cord DNA, cell & mitochondria damage 4. Tertiary Energy Failure (within weeks to months) Persistent glial cell activation Gliosis & glial scar formation Chronic inflammation Impaired oligodendrocyte maturation ↓ Neuronal myelination by oligodendrocytes Impaired synaptogenesis & abnormal pruning Motor & sensory deficits Ongoing synaptic dysfunction Ongoing white matter loss Sign/Symptom/Lab Finding Global deficits persist Focal deficits persist Global/systemic complications (e.g., global developmental delay, quadriplegic cerebral palsy) Focal complications (e.g., focal epilepsy, visual impairment, hemiplegic cerebral palsy) Published Dec 7, 2025 on www.thecalgaryguide.com

Ventricular Septal Defect

Authors: Merry Faye Graff, Ryan Wilkie Reviewers: Julena Foglia, Dave Nicholl, Taylor Krawec, Emily J. Doucette, Andrew Grant* Danielle Nelson* * MD at time of publication Legend: Ventricular Septal Defect (VSD): Pathogenesis and clinical findings Variants in genes involved in cardiac development (e.g., GATA4) DiGeorge syndrome** (deletion on chromosome 22q11) Holt-Oram syndrome (TBX5 mutations) Down syndrome** (Trisomy 21) (more commonly AVSD) CHARGE syndrome Infection Medication (e.g., isoretinoin) Uncontrolled metabolic conditions (e.g., diabetes**) Environmental exposures (e.g., alcohol) Genetic factors that ↑ susceptibility Complex interplay between genetic susceptibility & environmental factors Maternal factors during pregnancy that ↑ risk Disruption in formation of interventricular septum during fetal heart development Ventricular Septal Defect (VSD) Defect in interventricular septum that allows blood to shunt from the left ventricle (LV) to the right ventricle (RV) LV pumps against high systemic vascular resistance (SVR) & RV pumps against lower pulmonary vascular resistance (↓ after birth) Blood flows through VSD from LV to RV during systole (left-to-right shunt) Small defect (<4 mm) between ventricles Moderate (4-6 mm) to large defect (>6 mm) between ventricles Narrow (restrictive) defect between ventricles provides intrinsic resistance to flow Wide (unrestrictive) defect between ventricles offers little resistance to blood flow ↑ Volume of blood in pulmonary circulation ↑ Turbulent blood flow through small defect ↓ Turbulent blood through large defect Pulmonary arterial hypertension (PAH)** ↑ Pulmonary venous return to left heart Grade 3 to 5/6 harsh holosystolic murmur Grade 1 to 2/6, mid-frequency, holosystolic murmur Loud pulmonic S2 on auscultation ↑ Pulmonary vascular markings on x-ray LV undergoes eccentric hypertrophy to accommodate chronic ↑ volume ↑ Left atrial pressure Dilation of tricuspid annulus LV dilation & myocardial stretch impairs contractile function Lateral displacement of cardiac apex on x-ray Mitral regurgitation Impaired ejection (systolic dysfunction) results in ↓ stroke volume & ejection fraction ↑ LV end-diastolic pressure ↑ Pulmonary venous pressure Mid-diastolic murmur ↓ Cardiac output (CO) Left heart failure** Pulmonary edema (fluid accumulation in pulmonary interstitium & alveoli) Sympathetic nervous system is activated Systemic venous congestion Renin-angiotensin aldosterone system** is activated ↑ Work of breathing Diaphoresis Pallor ↑ Heart (excessive rate sweating) Peripheral edema Hepatomegaly Na+ & fluid retention Shortness of breath ↑ Respiratory rate **See corresponding Calgary Guide slide Complications Published Oct 17, 2015; updated Dec 7, 2025 on www.thecalgaryguide.com Prolonged PAH drives reactive constriction & permanent remodeling of pulmonary vessels Chronic ↑ RV afterload Irreversible PAH RV hypertrophy & dilation to overcome ↑ afterload Dilation ↑ RV wall stress ↑ RV stretch impairs ability to eject blood ↑ RV end-diastolic pressure RV pressure > LV pressure Right heart failure** Eisenmenger syndrome** (shunt reversal, right-to-left shunt) Pathophysiology Mechanism Sign/Symptom/Lab Finding

Vancomycin

Vancomycin: Mechanism of action and side effects Vancomycin Glycopeptide antibiotic that inhibits bacterial cell wall synthesis. Active against gram-positive organisms, such as Staphylococcus aureus (including MRSA), coagulase-negative Staphylococcus spp., Streptococcus spp., Enterococcus spp. (including E. faecium), & Clostridium difficile (when given orally). Often requires therapeutic drug monitoring due to risk of toxicity. Blocks cross-linking of peptidoglycan strands Drug binds to D-alanyl-D- alanine (D-Ala-D-Ala) terminal of peptidoglycan precursors Acquisition of van gene clusters (vanA/vanB) Transglycosylation & transpeptidation reactions are inhibited Target site changes from D-Ala-D-Ala to D-Ala-D-Lac or D-Ala-D-Ser Bacterial cell wall becomes osmotically unstable ↓ Binding affinity of drug to bacteria Bacterial cell lysis Development of vancomycin resistance Bacterial clearance on microbiological culture Legend: Primarily eliminated by glomerular filtration Presence of renal dysfunction impairs drug clearance ↑ Serum drug levels Oxidative stress & mitochondrial dysfunction of proximal tubular epithelium Direct proximal tubular cell injury Acute tubular necrosis** or acute interstitial nephritis ↓ Kidney function ↑ Serum creatinine & ↓ glomerular filtration rate (GFR) Prolonged therapy or prior exposure Rapid infusion, high dose or co- administration with anesthetics Possible direct damage to auditory branch of cranial nerve VIII (mechanism not well understood) Sensorineural hearing loss, tinnitus**, &/or balance disturbance Vancomycin- dependent antibodies are produced Antibodies bind to platelets &/or neutrophils Reversible cytopenia +/- bleeding Platelet &/or neutrophil destruction ↓ Platelets &/or ↓ neutrophils Activation of mast cells & basophils (non-IgE) Self-limited infusion reaction (not an allergy) Mast cell degranulation releases histamine & other vasoactive mediators Erythema of face, neck & torso ↓ Blood pressure Pruritus (itching) Author: Oleksandr Baran Reviewers: Trevor Low, Emily J. Doucette, Brandon Christensen* *MD at time of publication **See corresponding Calgary Guide slide Published Dec 7, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Pharmacologic Effects Side Effects

Kawasaki Disease

Kawasaki Disease: Pathogenesis and clinical findings Mutations that ↑ genetic susceptibility (e.g., FCGR2A, CASP3) External trigger such as infection or environmental factor (particulate matter, seasonal airborne antigenic triggers possible) Kawasaki Disease (KD) Acute systemic, inflammatory illness affecting medium-sized arteries (especially coronary arteries), diagnosed clinically with presence of fever & 4/5 of: conjunctivitis, polymorphous rash, cervical lymphadenopathy, mucosal involvement, edema/erythema on hands/feet. KD is the most common cause of acquired heart disease in children in developed countries. Authors: Taylor Krawec, Sunni Ho, Zarrukh Baig, Nissi Wei Reviewers: Merry Faye Graff, Emily J. Doucette, Zaini Sarwar, Mandy Ang, Charissa Chen, Taj Jadavji*, Susanne Benseler*, Danielle Nelson* * MD at time of publication Acute Phase Cytokines disrupt hypothalamic thermoregulation Fever Innate immune cells around medium-sized vessels (especially coronary arteries) are inappropriately activated Neutrophils infiltrate tunica adventitia (outer vessel wall) Coronary arteritis Cytokines enter circulation & mediate systemic inflammation Cervical lymphadenopathy Immune cells infiltrate additional tissue (e.g., lymph nodes, myocardium, pericardium) Myocarditis Pericarditis Local cytokine release Inflammation of tunica media & intima (middle & inner vessel walls) Endothelial activation in small vessels ↑ vasodilation & vessel permeability ↑ Blood flow, plasma leakage & perivascular infiltration of skin & mucosa Strawberry tongue Cracked lips Edema & erythema of hands/feet Bilateral non-exudative conjunctivitis Non-vesicular rash Uveitis Patchy destruction all 3 vessel layers (necrotizing arteritis) but with vessel wall remaining intact Early coronary changes on echocardiogram Subacute Phase / Chronic Vasculitis Vessel walls lose structural integrity Coronary artery aneurysm (rarely other aneurysms) Extensive adaptive immune-mediated destruction of intima, media, elastic lamina & smooth muscle Adaptive immune cells (e.g., eosinophils, plasma cells, lymphocytes) drive ongoing inflammation Damaged vessels disrupt blood flow Thrombus formation Acute myocardial infarction** Systemic inflammation stimulates megakaryocyte proliferation in bone marrow ↑ Platelet production Thrombocytosis Inflammation damages dermis & epidermis Gradual resolution of edema from acute phase & initiation of dermal/epidermal repair Periungal desquamation (peeling of skin around nails) Luminal Myofibroblast Infiltration ↓ Baseline coronary perfusion Coronary flow cannot ↑ to match myocardial O2 demand when needed (demand ischemia) Exertional chest pain or dyspnea Myofibroblasts replace inflammatory infiltrates in vessel walls during chronic healing phase Myofibroblast proliferation thickens intima Affected arteries become narrowed (coronary arteries most common) Exercise intolerance Ischemic myocardium Coronary artery stenosis Arrhythmias is electrically unstable Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 10, 2014; updated Dec 12 2025 on www.thecalgaryguide.com

Hereditary Spherocytosis

Hereditary Spherocytosis: Pathogenesis and clinical findings Gene mutation of SLC4A1 (Band 3: Transmembrane anchor protein) Gene mutation of ANK1 (Ankyrin-1: Adaptor protein binding a & b Spectrin to cell membrane) Gene mutation of SPTB (b Spectrin: Scaffold protein) Gene mutation of SPTA1 (a Spectrin: Scaffold protein) Gene mutation of EPB42 (Protein 4.2: Band 3 & Ankyrin linker protein) Authors: Catherine R Jarvis Reviewers: Sergio Sharif, Yan Yu*, Kareem Jamani* * MD at time of publication Mutation is inherited via autosomal dominant pattern (inherits 1 copy from an affected parent) Mutation is inherited via autosomal recessive pattern (inherits 1 copy from both affected or carrier parents) Gene mutation limits adequate production of associated RBC (red blood cell) structural protein Structural protein deficiency hinders RBC from maintaining good adherence between outer bilipid cell membrane & spectrin cytoskeleton (inner scaffolding) ↓ RBC membrane stability results in cell losing portions of its cell membrane in circulation à ↓ RBC surface area in relation to its volume Normally discoid-shaped RBCs become non-flexible, smaller than usual spherically shaped cells (spherocytes) Hereditary Spherocytosis Rigid spherocytes cannot adequately deform to pass through spleen microcirculation for clearance (removal) Splenic red pulp macrophages phagocytose & intracellularly hemolyze (breakdown) trapped spherocytes Hemolyzed spherocytes release hemoglobin inside macrophages ↓ Circulating number of RBCs Spleen cannot clear spherocytes with sufficient speed Routine cellular processes convert the heme group inside hemoglobin molecules into bilirubin, which is then released into circulation Hemolytic anemia (↓ hemoglobin from hemolysis) Spherocyte overload physically expands size of spleen Splenomegaly (enlarged spleen) ↓ ability to carry O2 (oxygen) in circulation Liver normally conjugates bilirubin for excretion. ↑ Bilirubin levels in circulation overwhelm the liver’s ability to conjugate all available bilirubin molecules Kidneys sense ↓ O2 Kidneys release erythropoietin (EPO) ↑ Unconjugated bilirubin in circulation ↑ Unconjugated bilirubin in bile Bilirubin deposits in skin & eyes EPO stimulates bone marrow to ↑ reticulocytes Jaundice (yellow skin & eyes) Cholelithiasis (gallstones)** Reticulocytosis (>2.5%) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Body cannot efficiently carry out cellular respiration Fatigue Body restricts blood flow to less critical areas like skin Pallor (pale skin) Chemoreceptors detecting low oxygen trigger sympathetic nervous system Tachycardia (fast heart rate) Tachypnea (fast breathing rate) **See corresponding Calgary Guide slide(s) Published Dec 17, 2025 on www.thecalgaryguide.com

Diphtheria

Diphtheria: Pathogenesis and clinical findings Travel to endemic areas Immunity (primarily acquired through vaccination) is incomplete, absent, or waning Poor hygiene environments Exposure to respiratory droplets or direct contact with infected surface Colonization of the pharynx or cutaneous sites with corynebacterium diphtheriae (C. diphtheriae) C. diphtheriae proliferate locally & secrete diphtheria exotoxin Exotoxin enters nearby host cells & inhibits host cell protein synthesis Local epithelial tissue necrosis & activation of inflammatory response Accumulation of dead cells, fibrin, bacteria & inflammatory cells Lymphatic & hematogenous spread of exotoxin to distant tissues (preferentially tissues with ↑ metabolic activity) Author: Julia Fox Reviewers: Steven Quan, Emily J. Doucette, James D. Kellner* *MD at time of publication **See corresponding Calgary Guide slide Cutaneous Diphtheria Cutaneous skin breakdown Vesicle/pustule formation Superficial, non-healing ulcers with grey pseudomembrane Respiratory Diphtheria Presence of inflammatory mediators in the pharynx Mucosal edema & sensitization of nociceptors Dense necrotic pseudomembrane forms & adheres to larynx, pharynx, or tonsils Pseudomembrane dislodgment or extension into the airway Diphtheria antigens drain to cervical lymph nodes Cervical lymphadenitis Pain & inflammatory response at infection site (eg. pharyngitis, tonsillitis, etc.) Diphtheritic membrane (grey mucous membranes) Localized airway obstruction (severe laryngeal cases) Bull neck appearance Systemic Manifestations Protein synthesis inhibition in myocardial cells Protein synthesis inhibition in neurons & Schwann cells Focal myocardiocyte necrosis, inflammation, & fibrosis Demyelination, ↓ myelin regeneration, & axonal injury Myocarditis** Damaged myocardium disrupts conduction pathways & contractility Cranial nerve conduction impaired first (especially CN IX, X, III) due to ↓ length, ↑ metabolic activity & proximity to mucosal infection sites ECG changes (arrhythmias & heart block) Palatal & pharyngeal paralysis Oculomotor palsy Dysphonia, dysphagia, & loss of gag reflex Protein synthesis inhibition in glomeruli & renal tubular epithelial cells Tubular necrosis & interstitial inflammation Renal failure Endothelial injury ↑ glomerular permeability Long peripheral nerve conduction impaired later (2-6 weeks after initial infection) Ascending muscle weakness Paresthesia & numbness Acute tubular necrosis Granular casts in urine Proteinuria Microscopic hematuria Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 18, 2025 on www.thecalgaryguide.com

Childhood Immunization Schedule

Alberta Health Services Childhood Immunization Schedule: Why we immunize Diphtheria** toxin Bacteria colonize upper respiratory epithelium & secrete exotoxin that enters local cells Sore throat, low grade fever, lymphadenopathy, stridor or wheeze, gray pseudomembrane in the airway ↑ Mortality from CNS, respiratory & cardiac disease Tetanus** toxin Pertussis** metabolites Polio virus Haemophilus influenzae type B Hepatitis B virus Streptococcus pneumoniae Rotavirus Neisseria meningitidis Measles** virus Mumps virus Rubella virus Varicella zoster virus** Human papillomavirus (HPV) Spores enter contaminated wounds & bacteria produce tetanospasmin to invade central nervous system (CNS) Muscle rigidity spasms, hyperreflexia, autonomic dysfunction, laryngeal spasms ↑ Mortality from respiratory obstruction & failure Bacteria attach to ciliated respiratory epithelial cells & release toxins Prolonged paroxysmal cough, inspiratory “whoop” sound, emesis, apnea, cyanosis, leukocytosis ↑ Risk of pneumonia, seizures & encephalopathy Virus invades oropharynx/GI tract & replicates in lymphoid tissue before hematogenous spread to motor neurons ↑ Risk of paralytic poliomyelitis & respiratory failure Bacteria colonize the nasopharynx & invade the bloodstream & CNS Virus invades hepatocytes via specific receptors & replicates within liver cells Bacteria colonize the nasopharynx & may invade the lungs, bloodstream, or meninges Virus invades mature enterocytes in the small intestine Bacteria colonize the nasopharynx & enter the bloodstream to cross the blood–brain barrier Virus invades respiratory epithelium & spreads to regional lymphoid tissue & bloodstream Virus infects upper respiratory tract (URT) & disseminates via viremia to salivary glands & other organs Virus invades URT & enters the bloodstream & regional lymphoid tissue Virus infects URT & lymphoid tissue before invading neural tissue Virus infects anogenital & oropharyngeal basal layer epithelium tissue Influenza virus Virus invades upper & lower respiratory epithelium Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)** Viral invasion of mucous membranes & may invade extrapulmonary tissues Legend: Muscle weakness, asymmetric reduction in tone, quadriplegia Fever, fatigue, shortness of breath, nausea, emesis, headache, stiff neck, altered mental status, otitis media** Fatigue, anorexia, nausea, jaundice, arthralgia, right upper quadrant pain Otitis media**, sinusitis, pneumonia**, meningitis**, bacteremia Gastroenteritis with emesis, fever, diarrhea, malaise & dehydration Fever, headache, neck stiffness, altered level of consciousness, purpuric rash Koplik spots, conjunctivitis, fever, rhinorrhea, cough, diarrhea, otitis media, pneumonia Parotitis, headache, fever, malaise, sensorineural hearing loss, orchitis, mastitis, oophoritis, pancreatitis Fever, lymphadenopathy, rash, congenital anomalies such as hearing loss, cataracts & cardiac defects ↑ Mortality from meningitis, pneumonia & sepsis ↑ Risk of cirrhosis, hepatic malignancy, & liver failure ↑ Mortality from respiratory, CNS & cardiac dysfunction ↑ Mortality from hypovolemic shock & CNS infection ↑ Mortality from sepsis, multiorgan failure & necrosis ↑ Mortality from pneumonia & encephalitis ↑ Mortality from meningitis & encephalitis ↑ Mortality from congenital rubella Vesicular & pruritic rash, fever, malaise, pneumonia, encephalitis, cellulitis ↑ Morbidity from necrotizing fasciitis, CNS, soft tissue & respiratory infections Often asymptomatic, or may present with painless anogenital warts ↑ Risk of anogenital & head & neck malignancy Fever, cough, myalgia, malaise, cough, headache, emesis, diarrhea, abdominal pain, febrile seizures ↑ Mortality from widespread multiorgan infection Fever, cough, fatigue, shortness of breath, anosmia, ageusia, pneumonia, multiorgan dysfunction ↑ Mortality from respiratory distress & multiorgan failure DTaP-IPV-Hib-HB vaccine Given at 2, 4 & 6 months old Protects against diphtheria, Tetanus, Pertussis, Polio, Haemophilus influenzae type B, & Hepatitis B DTaP-IPV-Hib vaccine Given at 18 months old Protects against diphtheria, Tetanus, Pertussis, Polio, & Haemophilus influenzae type B Pneumococcal conjugate vaccine Given at 2, 4 & 12 months old (additional 4th dose given at 6 months if at ↑ risk of invasive pneumococcal disease) Authors: McKayla Kirkpatrick, Stacey Holbrook Reviewers: Merry Faye Graff, Emily J. Doucette, Charissa Chen, Amanda Ang, Danielle Nelson* * MD at time of publication Tdap-IPV vaccine Given at 4 years old Tdap vaccine Given in Grade 9 Protects against diphtheria, Tetanus, Pertussis, & Polio Protects against diphtheria, Tetanus, & Pertussis HB vaccine Given in Grade 6 Protects against Hepatitis B virus Protects against Streptococcus pneumoniae Rotavirus vaccine Given at 2 & 4 months old Protects against rotavirus Meningococcal conjugate (MenconC) Given at 4 & 12 months old MenC-ACYW (Meningococcal type A, C, Y, W-135) in Grade 9 Protects against Neisseria meningitidis MMR-Var vaccine (e.g., Priorix-Tetra) Given at 12 & 18 months old Protects against measles, mumps, rubella & varicella Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications HPV vaccine Given in Grade 6 (2-3 doses over 6 months) Seasonal influenza vaccine Given annually starting at 6 months or older COVID-19 vaccine Given at 6 months or older Published Aug 19, 2015; updated Dec 31, 2025 on www.thecalgaryguide.com Protects against HPV Protects against influenza viruses predicted to circulate each fall & winter Protects against SARS-CoV2