367 changes. We went through the book page by page.

Important in repair of damage via oxidative stress, radiation, alkylating agents, or replication errors.

Bare lymphocyte syndrome: Autosomal recessive. Decreased MHC expression leads to T-cell dysfunction. Type I: TAP mutation causes decreased MHC I leading to decreased CD8+ T cells and chronic sinopulmonary infections. Type II: defective MHC II transcription factors cause decreased MHC II leading to decreased CD4+ T cells and susceptibility to intracellular pathogens.

Peripheral tolerance: Suppression/inactivation of self-reactive T/B cells (outside thymus/bone marrow) preserves self-tolerance; loss leads to autoimmunity. Mechanisms include: anergy (lack of co-stimulation), regulatory T cells (Tregs), and clonal deletion.

Complement pathway testing: CH50 (total hemolytic complement) tests classical pathway. Low CH50 + low C3 indicates alternative/classical pathway consumption. Low CH50 + normal C3 indicates terminal complement deficiency. C4 level distinguishes classical from alternative pathway defects.

Drug reactions — severe cutaneous adverse reactions (SCARs): acute generalized exanthematous pustulosis (AGEP) — widespread sterile pustules on erythematous base, fever, leukocytosis with eosinophilia. Caused by antibiotics (amoxicillin, ampicillin), antimalarials, Ca2+ channel blockers. Resolves within 2 weeks of stopping drug. Type IV hypersensitivity.

Dengue virus diagnosis: NAAT (nucleic acid amplification testing) — used in early infection (days 1-5, before antibody seroconversion); serology (IgM/IgG) — used after day 5 when antibodies have developed

NS5A inhibitors: key role in RNA replication, virion assembly, and release

Ferroptosis: Iron-dependent, regulated form of cell death. Characterized by accumulation of lipid peroxides. Regulated by glutathione peroxidase 4 (GPX4), which normally neutralizes lipid peroxides. GPX4 inactivation → lipid peroxide accumulation → ferroptosis. Distinct from apoptosis (no caspases), necrosis (not accidental), and pyroptosis (no inflammasome).

Inflammasome expanded: activated by DAMPs/PAMPs, role in pyroptosis, and NLRP3 identified as the canonical inflammasome example. Cytoplasmic complex that activates caspase-1 → cleavage of pro-IL-1β → active IL-1β.

Warburg effect: driven by altered metabolic enzymes (eg, pyruvate kinase isoform PKM2) that favor aerobic glycolysis over oxidative phosphorylation.

Pilocarpine: used for glaucoma, xerostomia, Sjogren syndrome

Warfarin: hepatic metabolism via CYP450 enzymes (primarily CYP2C9, also CYP3A4 and CYP1A2), narrow therapeutic index, many drug interactions

Example: If one MZ twin develops schizophrenia, the other twin has ~50% concordance (not 100%) — demonstrates genetic contribution but not genetic determinism.

Example: Adopted child has higher schizophrenia risk if biological parents have schizophrenia (not adoptive parents) — demonstrates genetic over environmental contribution.

Hazard ratio (HR): Ratio of hazard rates between two groups. Interpreted like relative risk in survival analysis. HR >1 = increased risk of event. HR <1 = decreased risk. Used in time-to-event analyses (Kaplan-Meier, Cox proportional hazards regression). Unlike RR, HR accounts for censoring and varying follow-up times.

Sudden cardiac death: unexpected death from cardiac arrhythmia within 1 hour of symptom onset.

Atrial fibrillation rhythm control options: cardioversion, catheter ablation, or pulse field ablation (emerging technique). Pulse field ablation uses brief high-voltage electrical pulses to create irreversible electroporation of cardiac tissue; tissue-selective (targets myocardium while sparing esophagus and phrenic nerve).

TTN mutation → shortened titin protein. Most common genetic cause of familial DCM (~25% of familial cases). Titin spans half the sarcomere (Z-disc to M-line); truncating mutations impair sarcomere assembly → systolic dysfunction → chamber dilation.

Somatostatin: GHIH (growth hormone release inhibiting hormone). Also called somatotropin release inhibiting factor (SRIF).

Diagnosis: Uosm > Posm, euvolemia

Parafollicular C cells produce calcitonin. Both calcitonin and CEA (carcinoembryonic antigen) are used as tumor markers for post-operative surveillance.

MEN 1: 3 P's (Pituitary, Pancreas, Parathyroid). Also includes GHRH-secreting hypothalamic tumors.

In pancreas divisum, the dorsal pancreatic duct (of Santorini) drains the majority of the pancreas through the minor papilla (dominant drainage), while the ventral duct (of Wirsung) drains only the uncinate process and inferior head through the major papilla. The minor papilla provides relatively inadequate drainage for the dominant dorsal duct, predisposing to recurrent pancreatitis.

In selective IgA deficiency, IgA-based celiac serologies (anti-tTG IgA, anti-endomysial IgA) will be falsely negative. Use IgG-based testing: IgG anti-tTG or IgG deamidated gliadin peptide (DGP) antibodies.

Lynch syndrome (HNPCC) associated malignancies now include stomach cancer. Updated list: Colorectal, Endometrial, Ovarian, Small bowel, Stomach.

For severe beta-thalassemia (transfusion-dependent), gene therapy via beta-globin gene addition or gene editing can restore functional beta-globin production. This represents a curative option, potentially eliminating lifelong transfusion dependence. Exagamglogene autotemcel (exa-cel) uses CRISPR-Cas9 to edit BCL11A enhancer, reactivating fetal hemoglobin. Betibeglogene autotemcel (beti-cel) adds functional beta-globin gene via lentiviral vector.

Shiga toxin (from EHEC O157:H7) causes: (1) Endothelial dysfunction — direct toxicity to glomerular endothelial cells, (2) Capillary microthrombi — platelet consumption at damaged endothelium, (3) Renal vascular occlusion — mechanical obstruction of glomerular capillaries. This produces the classic triad: thrombocytopenia + MAHA + acute renal failure. Key distinction from TTP: HUS = primary endothelial injury (toxin-mediated). TTP = ADAMTS13 deficiency leading to uncleaved vWF multimers.

The t(15;17) translocation in acute promyelocytic leukemia (APL) produces the PML-RARalpha fusion protein. This fusion protein blocks myeloid differentiation at the promyelocyte stage by repressing retinoic acid-responsive genes. All-trans retinoic acid (ATRA) overcomes the block by binding RARalpha at pharmacologic doses, forcing differentiation of promyelocytes into mature granulocytes.

Oncogenic signaling pathways in hematologic malignancies: BCR-ABL t(9;22) — constitutive tyrosine kinase — CML, Ph+ ALL — imatinib, dasatinib. JAK2 V617F — JAK-STAT signaling — polycythemia vera, essential thrombocythemia, primary myelofibrosis — ruxolitinib. FLT3-ITD — receptor tyrosine kinase — AML (poor prognosis) — midostaurin, gilteritinib. NPM1 — nucleolar protein shuttling — AML (favorable prognosis) — standard chemo (good response). Key concept: these represent gain-of-function mutations that drive proliferation independent of normal growth signals.

Klumpke palsy: lower trunk (C8-T1) injury causing hand intrinsic muscle weakness with claw hand deformity. +/- Horner syndrome (miosis, ptosis, anhidrosis) if T1 root or adjacent sympathetic chain is involved.

USPSTF guideline: One-time screening with DEXA scan recommended for all females aged 65 and older. Younger postmenopausal women should be screened if risk factors present (low body weight, prior fracture, family history, smoking, excess alcohol). FRAX score can guide decision-making in women aged 50-64.

Chronic systemic inflammation in RA leads to increased risk of aortic stenosis and premature cardiovascular disease. RA patients have 1.5-2x increased cardiovascular mortality compared to general population. Mechanism: chronic TNF-alpha, IL-6, and CRP elevation accelerate atherosclerosis and promote valvular calcification.

↓ Dopamine (Parkinson disease) → ↓ direct pathway activity, ↑ indirect pathway activity → ↑ inhibition of thalamus → ↓ movement (hypokinesia). ↑ Dopamine (Huntington disease, hemiballismus) → ↑ direct pathway, ↓ indirect pathway → ↓ thalamic inhibition → excessive involuntary movement (hyperkinesia).

Spinothalamic tract functional divisions: Anterior (ventral) spinothalamic tract = crude touch and pressure. Lateral spinothalamic tract = pain and temperature. Both decussate within 1–2 levels of entry at the anterior white commissure.

L5: dorsum of foot, great toe dorsiflexion (extensor hallucis longus), no reliable reflex. S1: lateral foot/sole, plantar flexion, Achilles (ankle jerk) reflex.

Normal bereavement involves sadness, crying, and preoccupation with the deceased that gradually resolves over time. Prolonged grief disorder (DSM-5-TR): persistent intense grief >12 months in adults (>6 months in children), preoccupation with the deceased, and functional impairment disproportionate to cultural norms.

Manic episode: distinct period of abnormally elevated, expansive, or irritable mood lasting at least 7 days. Exception: hospitalization OR psychotic features at any point qualifies as mania regardless of duration — do not require full 7 days if either is present.

Somatic symptom disorder: one or more prominent somatic symptoms with excessive thoughts, feelings, or behaviors. Illness anxiety disorder: minimal or NO somatic symptoms with excessive worry about having a serious disease. The single distinguishing feature is presence vs absence of prominent somatic symptoms.

ADHD: inattention, hyperactivity, impulsivity beginning before age 12. Adult presentation: predominantly inattentive symptoms; hyperactivity becomes less prominent with age. Presents with time management difficulties, disorganization, executive dysfunction. Often diagnosed later (especially in women) because hyperactivity — the most visible childhood symptom — fades.

Treatment of Type 1 (distal) RTA: sodium citrate or sodium bicarbonate. Corrects metabolic acidosis and reduces complications (nephrocalcinosis, kidney stones).

Treatment of Type 2 (proximal) RTA: sodium bicarbonate. Large doses may be required because supplemented bicarbonate is poorly reabsorbed and lost in urine.

Type 4 RTA: hyperkalemia causes decreased ammoniagenesis in the proximal tubule, reducing NH3/NH4+ available for distal H+ buffering. This impairs net acid excretion despite intact distal H+ secretion (urine pH < 5.5).

Neural crest cells are now marked as S100 positive. S100 is a calcium-binding protein used as an immunohistochemical marker for neural crest derivatives including schwannomas, neurofibromas, melanomas, and Langerhans cell histiocytosis.

GnRH pulsatility is a new FA 2026 topic. Pulsatile GnRH stimulates LH and FSH release (physiologic mechanism). Continuous GnRH (or GnRH agonist) administration causes initial stimulation (flare) followed by downregulation of GnRH receptors, resulting in LH/FSH suppression. Therapeutic applications of continuous GnRH agonists: precocious puberty, prostate cancer, endometriosis.

Compared to combined oral contraceptives, progestin-only pills are safe in breastfeeding women and those with estrogen contraindications (DVT history, migraines with aura, smokers >35 years old). Progestins do not increase thromboembolism risk and do not suppress lactation.

Anabolic androgenic steroids are testosterone derivatives used to increase muscle mass. Side effects include: testicular atrophy (due to HPG axis suppression), gynecomastia (peripheral aromatization of excess testosterone to estrogen), virilization in women, hepatotoxicity, dyslipidemia (decreased HDL, increased LDL), and aggression.

Pulmonary circulation: ↓ alveolar PO2 → pulmonary vasoconstriction (redirects blood to better-ventilated areas). This is the OPPOSITE of systemic circulation, where ↓ tissue PO2 → vasodilation to increase local oxygen delivery.

Methemoglobin: Fe3+ cannot bind O2, AND Fe3+ increases O2 affinity of remaining Fe2+ heme groups (O2 held tightly, cannot be released to tissues). This explains the LEFT shift on oxyhemoglobin dissociation curve + functional anemia despite normal total hemoglobin.

Connective tissue disease (RA, scleroderma, polymyositis/dermatomyositis) added as cause of interstitial lung disease. Scleroderma-ILD (NSIP pattern) is the most tested CTD-ILD association; anti-Scl-70 correlates with diffuse disease + ILD.

COPD triple therapy: LAMA + LABA + ICS combination. Indicated for moderate-severe COPD with frequent exacerbations despite dual bronchodilator therapy, especially with eosinophils ≥300 cells/μL. LAMA (tiotropium) blocks M3 → bronchodilation; LABA (formoterol) stimulates β2 → bronchodilation; ICS suppresses eosinophilic airway inflammation → reduces exacerbations.

Sotatercept: activin receptor ligand trap (fusion protein/decoy receptor). Binds activin ligands extracellularly → reduces TGF-β superfamily signaling → ↓ pulmonary vascular smooth muscle proliferation and remodeling → ↓ pulmonary vascular resistance. Used in pulmonary arterial hypertension (PAH) as add-on therapy.