USMLE Step 1
USMLE Step 1 study notes
Free, full-length USMLE Step 1 study notes from Examrix — acid–base regulation, hypersensitivity, immunodeficiencies, tumour genetics, vitamins and neuroanatomy, mapped to the official content outline.
Renal and Urinary System
Reproductive Systems, Pregnancy, Childbirth and Breast
- Amenorrhea, Dysmenorrhea and Abnormal Uterine BleedingThe pathology of amenorrhea, dysmenorrhea, and abnormal uterine bleeding hinges on the endocrine, cellular, and structural integrity of the female reproductive system. Primary amenorrhea workup divides patients by the presence/absence of secondary sex characteristics (estrogen exposure) and uterine presence. Secondary amenorrhea always requires looking for pregnancy first, followed by assessing the HPO axis (e.g., hypothalamic amenorrhea, hyperprolactinemia, primary ovarian insufficiency) and outflow tract anatomy (e.g., Asherman syndrome). Dysmenorrhea is categorized into primary (excessive PGF2-alpha causing uterine ischemia) and secondary (structural conditions such as endometriosis or adenomyosis). Finally, abnormal uterine bleeding assessment is classified under the FIGO PALM-COEIN structured system, bridging the gap between basic pathophysiological mechanisms and therapeutic targets. Free to read 30 min read
- Placental Development & Physiology Free to read 30 min read
Cardiovascular System
- ArrhythmiasArrhythmias encompass a spectrum of cardiac electrical abnormalities ranging from benign physiological variations to lethal ventricular disruptions. Sinus arrhythmia represents a normal vagally-mediated response to respiration. Atrial fibrillation, driven by ectopic pulmonary vein triggers, leads to an irregular rhythm and high stroke risk. Reentrant tachycardias, such as SVT (AVNRT/AVRT), rely on dual conducting pathways or accessory connections (e.g., WPW). Congenital and acquired Long QT syndromes prolong the ventricular action potential, paving the way for early afterdepolarizations and Torsades de Pointes. Ultimately, severe ventricular disorganization from ischemia or structural heart diseases culminates in sudden cardiac death, highlighting the vital importance of prompt identification and mechanistic-based pharmacological intervention. Free to read 30 min read
- Valve DiseaseValvular heart disease involves structural abnormalities that impair forward cardiac flow (stenosis) or permit retrograde leakage (regurgitation). Pathologies are characterized by distinctive murmurs, characteristic alterations in ventricular geometry (eccentric vs. concentric hypertrophy), and classic physical exam findings like the wide pulse pressure of aortic regurgitation or the opening snap of mitral stenosis. Rheumatic heart disease remains a key high-yield etiology, demonstrating a type II hypersensitivity reaction triggered by molecular mimicry with Group A streptococcal M protein. Understanding these valvular pathologies through the lens of basic hemodynamics, dynamic auscultation maneuvers, and systemic manifestations is a cornerstone of success on the USMLE Step 1 exam. Free to read 30 min read
Multisystem Processes and Disorders
- Asbestos Exposure and Radiation Exposure Free to read 30 min read
- Cancer Metastasis & Tumour Markers Free to read 30 min read
- Macronutrients, Micronutrients, Vitamin Deficiencies & Vitamin ToxicitiesMicronutrients and macronutrients serve as the essential biochemical machinery of cellular metabolism. Fat-soluble vitamins (A, D, E, K) integrate closely with lipid pathways and depend on micelle formation for absorption, making them highly susceptible to malabsorption syndromes and prone to toxicity due to tissue storage. Water-soluble vitamins (B-complex and C) function primarily as critical coenzymes in central energy-producing pathways, including glycolysis, the TCA cycle, and the pentose phosphate pathway; their deficiencies manifest rapidly in highly metabolic tissues, presenting as dermatitis, glossitis, diarrhea, and peripheral neuropathies. A deep, mechanistically grounded understanding of these nutritional components is indispensable for identifying classic clinical syndromes on the USMLE Step 1 and safeguarding patient health in diverse clinical environments. Free to read 30 min read
Basic Sciences
- Cell Cycle, Cell Death and Cellular AdaptationCellular homeostasis relies on a delicate balance between cell cycle progression, programmed cell death, and adaptive responses to physiological or pathological stress. The cell cycle is highly regulated by cyclin-CDK complexes and monitored at crucial checkpoints by tumor suppressors like p53 and Rb to prevent genomic instability. When cells face irreversible damage, they undergo cell death via either apoptosis (an organized, non-inflammatory programmed pathway) or necrosis (a chaotic, inflammatory, accidental pathway). When faced with chronic but sublethal stress, tissues dynamically adapt using hypertrophy, hyperplasia, atrophy, or metaplasia; however, persistent stress can trigger a transition to dysplasia, a pre-neoplastic state requiring close clinical surveillance. Free to read 30 min read
- Foundations of Innate and Adaptive ImmunityThe immune system is divided into innate and adaptive components that work in tandem to protect the host. The innate system provides rapid, non-specific defenses utilizing phagocytes, complement pathways, and cytokines like IL-1, TNF-α, and IL-6 to orchestrate systemic inflammation. The adaptive system provides antigen-specific, long-term memory mediated by T cells (cell-mediated immunity) and B cells (humoral immunity). Major Histocompatibility Complex (MHC) molecules act as the critical bridge, presenting digested antigens to T-cell receptors. Precise execution of lymphocyte development, selection, and activation prevents both immunodeficiency and autoimmune pathology. Free to read 30 min read
- Hypersensitivity and Transplant ImmunologyHypersensitivity reactions represent exaggerated or inappropriate immune responses classified into four distinct types based on their underlying immunopathologic mechanisms. Type I is IgE-mediated and immediate; Type II involves IgG/IgM targeting cell-surface antigens; Type III is driven by circulating immune complex deposition; and Type IV is a delayed, T-cell-mediated process. These same immunologic principles govern transplant medicine. Hyperacute rejection mimics a Type II reaction due to pre-existing anti-donor antibodies. Acute rejection is predominantly a Type IV cellular response with potential humoral contributions, and chronic rejection is a slow, indirect T-cell-driven process resulting in vascular occlusion and graft fibrosis. Conversely, Graft-Versus-Host Disease occurs when immunocompetent donor T cells in a graft attack an immunocompromised host's tissues, highlighting the critical nature of HLA matching and targeted post-transplant immunosuppression. Free to read 30 min read
- Tumor Genetics: Oncogenes, Tumor Suppressor Genes, DNA Repair Defects, Microsatellite InstabilityTumor genetics comprises a delicate balance between proto-oncogenes, which drive cell survival and proliferation when mutated (resembling an accelerator stuck down), and tumor suppressor genes, which arrest aberrant growth (acting as damaged brakes). Deficiencies in DNA repair pathways, such as double-strand homologous recombination (BRCA1/2), nucleotide excision repair (XP genes), and mismatch repair (MSH2/MLH1), critically compromise genomic integrity. This genomic instability accelerates the acquisition of driver mutations, giving rise to classic hereditary cancer syndromes like Lynch, Li-Fraumeni, and Familial Adenomatous Polyposis, each highly testable on the USMLE Step 1. Free to read 30 min read
- VirologyUSMLE Step 1 virology emphasizes structural classification, replication mechanisms, latency, and oncogenesis. DNA viruses generally have double-stranded, linear genomes and replicate in the nucleus, with key exceptions like Parvovirus (ssDNA) and Poxvirus (cytoplasmic replication). RNA viruses are highly diverse and rely on error-prone RNA-dependent RNA polymerases, leading to antigenic drift. Retroviruses incorporate their genetic material directly into the host genome, establishing permanent infection. Latency allows viruses to evade the immune response in immunologically privileged sites, such as sensory ganglia or memory B cells, until reactivation occurs. Finally, viral oncogenesis involves targeted subversion of host cell cycle regulatory checkpoints, primarily through the inhibition of tumor suppressors p53 and Rb, driving unregulated cellular proliferation. Free to read 30 min read
Social Sciences, Ethics and Communication
- ConfidentialityConfidentiality is a cornerstone of medical ethics, protecting patient privacy and fostering clinical trust. Under USMLE Step 1 standards, you must prioritize patient autonomy and avoid disclosing information to anyone—including family members—without explicit consent. However, you must recognize when the duty to protect the public or vulnerable individuals legally supersedes confidentiality, specifically in cases of suspected child or elder abuse, reportable infectious diseases, suicidal intent, and explicit homicidal threats to identifiable third parties. Free to read 30 min read
- End-Of-Life Care and Advance DirectivesEnd-of-life care is structurally anchored in the principle of patient autonomy. When a patient loses decision-making capacity, clinicians must look to advance directives, including living wills and durable powers of attorney. In their absence, surrogate decision-makers are identified to make decisions using the substituted judgment standard. When a patient's wishes are entirely unknown, the best interest standard is applied. Comfort measures and symptom alleviation must always be maintained, ethically protected by the principle of double effect, which permits the aggressive titration of palliative analgesics even if it might foreseeably hasten death. Free to read 30 min read
Biostatistics, Epidemiology, Population Health and Interpretation of Medical Literature
- Correlation and RegressionCorrelation (r) quantifies the strength and direction of the linear association between two variables, ranging from -1 to +1, while its square (r²) represents the proportion of variance explained. Regression analysis goes a step further by predicting outcomes: linear regression is utilized for continuous dependent outcomes, whereas logistic regression is utilized for binary, qualitative outcomes. Distinguishing between these methods and remembering that correlation does not equal causation are high-yield principles for success on the USMLE Step 1 exam. Free to read 30 min read
- Sensitivity and SpecificitySensitivity and specificity are fundamental epidemiologic metrics used to quantify the accuracy of diagnostic tests. Calculated vertically using a standard 2x2 table, sensitivity represents the test's ability to identify true diseased individuals, while specificity represents its ability to correctly identify healthy cohorts. Because these metrics are intrinsic to the test itself, they do not change with disease prevalence. Understanding the trade-offs between sensitivity and specificity when adjusting diagnostic thresholds is vital for interpretation of clinical trials and medical board exam vignettes. Free to read 30 min read
Behavioral Health, Psychiatry, Nervous System and Special Senses
- Demyelinating, Peripheral Nerve and Neuromuscular Junction DisordersThis tutorial covers critical neuropathologies spanning the central and peripheral nervous systems, with a focus on demyelinating conditions and neuromuscular junction disorders. By evaluating the cellular targets (oligodendrocytes in MS/ADEM vs. Schwann cells in GBS/CMT) and the molecular mechanisms of synaptic dysfunction (postsynaptic AChR in MG vs. presynaptic VGCC in LEMS), students can build a systematic framework to correctly diagnose, localize, and understand these high-yield pathologies on the USMLE Step 1 exam. Free to read 30 min read
- Neurodegenerative DisordersNeurodegenerative disorders are characterized by the progressive loss of specific subsets of neurons associated with abnormal protein aggregation. Alzheimer disease causes generalized cortical atrophy (prominent in the temporal and parietal lobes) due to extracellular Aβ amyloid plaques and intracellular tau tangles, presenting with gradual memory loss. Parkinson disease targets dopaminergic neurons in the substantia nigra, manifesting as a hypokinetic movement disorder with α-synuclein Lewy bodies. Huntington disease causes chorea and dementia via caudate and putamen atrophy, driven by a toxic gain-of-function CAG repeat expansion. ALS selectively damages both upper and lower motor neurons, leaving sensory and extraocular motor systems intact, while Frontotemporal Dementia affects the frontal and temporal lobes early, causing profound personality and behavioral alterations with preserved memory in its initial stages. Free to read 30 min read
- Peripheral and Autonomic Neuroanatomy Free to read 30 min read
Blood, Lymphoreticular and Immune Systems
- Haemolytic Anaemias and HaemoglobinopathiesHaemolytic anaemias are broadly classified into intrinsic (congenital) defects—including qualitative hemoglobinopathies (Sickle Cell), quantitative globin defects (Thalassaemias), membrane defects (Hereditary Spherocytosis), and metabolic enzyme deficiencies (G6PD and Pyruvate Kinase deficiencies)—and extrinsic (acquired) defects, notably autoimmune haemolytic anaemias (Warm IgG and Cold IgM subtypes). Diagnosing these disorders relies on combining clinical presentations (jaundice, splenomegaly, gallstones) with classic laboratory findings, including blood smear morphologies (target cells, spherocytes, bite cells, sickle cells), reticulocyte counts, and specific diagnostic assays like haemoglobin electrophoresis, the osmotic fragility test, and the Direct Antiglobulin Test. Free to read 30 min read
- Primary and Secondary ImmunodeficiencyImmunodeficiencies are categorized into primary (congenital genetic anomalies) and secondary (acquired due to drugs, nutrition, or infections). Primary immunodeficiencies affect humoral immunity (B-cell defects like XLA and CVID presenting with encapsulated bacterial infections), cellular immunity (T-cell defects like DiGeorge presenting with opportunistic viral and fungal infections), or innate/phagocytic pathways (like CGD and LAD). Secondary immunodeficiencies are far more common globally, with HIV being the classic viral prototype. HIV targets CD4+ helper T cells, leading to severe cellular immunodeficiency. When the helper T-cell count falls below specific thresholds, patients become susceptible to life-threatening opportunistic infections, highlighting the clinical necessity of prophylactic antimicrobial therapy and targeted antiretroviral management. Free to read 30 min read
- Thrombocytopenia and Thrombotic MicroangiopathiesThrombocytopenias and thrombotic microangiopathies represent a spectrum of hematologic disorders presenting with low platelet counts but differing fundamentally in their pathophysiology. ITP is an autoimmune, isolated platelet destruction disorder with normal coagulation times. HIT is an antibody-mediated, prothrombotic drug reaction triggered by heparin-PF4 complexes. TTP and HUS are microangiopathic hemolytic anemias (MAHAs) characterized by microvascular platelet aggregation, schistocytes, and normal PT/PTT, driven by ADAMTS13 deficiency or Shiga toxin-mediated endothelial injury, respectively. DIC stands apart as a severe, systemic consumptive coagulopathy driven by widespread tissue factor exposure, resulting in both microvascular thrombosis and hemorrhagic depletion of clotting factors, marked by prolonged PT/PTT and elevated D-dimer. Free to read 30 min read
Skin and Subcutaneous Tissue
- Hair and Pigmentation DisordersThis tutorial reviews the essential pathophysiology, clinical features, and pharmacological management of key hair and pigmentation disorders. Pigmentary disorders are classified by cellular mechanics: Vitiligo involves the autoimmune destruction of melanocytes, whereas Albinism represents an autosomal recessive defect in melanin synthesis (typically tyrosinase deficiency) with a normal melanocyte count. Melasma is a hyperpigmentation disorder driven by UV light and estrogen/progesterone exposure. Hair disorders are split into autoimmune-mediated (Alopecia Areata, a non-scarring T-cell attack) and androgen-mediated processes. The latter includes Androgenic Alopecia (DHT-induced follicle miniaturization treated with finasteride) and Hirsutism (excess terminal male-pattern hair in females, frequently indicating PCOS). Free to read 30 min read
- Viral, Fungal and Parasitic Skin InfectionsViral, fungal, and parasitic skin infections represent highly testable clinical scenarios on the USMLE Step 1 exam. Diagnostic mastery relies on identifying specific histopathological and microscopic hallmarks, such as multinucleated giant cells for HSV/VZV, koilocytes for HPV, Henderson-Paterson bodies for Molluscum, germ tubes for Candida albicans , septate hyphae for dermatophytes, and microscopic mites or eggs for scabies. Understanding the basic science mechanisms of pathogenesis—such as the viral thymidine kinase target for acyclovir, the lipid-dependent growth of Malassezia , and the type IV hypersensitivity response to scabies mites—bridges preclinical knowledge with clinical diagnosis and treatment selection. Free to read 30 min read
Gastrointestinal System
- Hepatitis & IBD DrugsPharmacological management of Hepatitis and IBD hinges on targeting specific viral enzymes or immunomodulatory pathways. Hepatitis B is managed primarily with nucleoside/nucleotide reverse transcriptase inhibitors (like Tenofovir or Entecavir) or interferon-alpha, while Hepatitis C is cured using targeted DAA combinations (-previrs, -asvirs, and -buvirs) and occasionally Ribavirin. Inflammatory bowel disease (IBD) utilizes a escalating ladder of therapy starting with 5-ASA compounds (Sulfasalazine, Mesalamine) for colonic inflammation, progressing to corticosteroids for acute flares, and utilizing thiopurines (Azathioprine/6-MP), methotrexate, or anti-TNF-α agents (Infliximab, Adalimumab) for long-term maintenance of remission. Free to read 30 min read
- Pancreatic Cancer & Pancreatic Endocrine TumorsPancreatic neoplasms are broadly categorized into highly aggressive exocrine tumors (predominantly pancreatic ductal adenocarcinoma) and slower-growing, endocrine-derived neuroendocrine tumors (PanNETs). Adenocarcinoma typically arises in the pancreatic head, causing common bile duct obstruction and painless jaundice, driven by systematic mutations in KRAS , CDKN2A , TP53 , and SMAD4 . In contrast, PanNETs secrete active hormones leading to precise diagnostic syndromes: insulinomas cause hypoglycemia with elevated C-peptide; gastrinomas cause severe, recurrent peptic ulcers; VIPomas drive secretory diarrhea and hypokalemia; glucagonomas present with necrolytic migratory erythema; and somatostatinomas cause steatorrhea and cholelithiasis. Determining histological features—such as glandular, mucin-producing structures for adenocarcinoma versus "salt-and-pepper" chromatin with chromogranin positivity for PanNETs—remains key to diagnostic differentiation on the USMLE. Free to read 30 min read
Musculoskeletal System
- Inflammatory ArthritidesInflammatory arthritides represent a diverse clinical spectrum of systemic autoimmune conditions divided into seropositive (Rheumatoid Arthritis) and seronegative spondyloarthropathies (Ankylosing Spondylitis, Psoriatic Arthritis, Reactive Arthritis). Rheumatoid Arthritis is characterized by symmetric, erosive small-joint destruction driven by CD4+ T cells, synovial hyperplasia (pannus), and autoantibodies (anti-CCP and RF) with a strong HLA-DR4 association. Seronegative spondyloarthropathies share a strong HLA-B27 genetic association, lack autoantibodies, involve the axial skeleton and entheses, and manifest extra-articular pathologies such as anterior uveitis, dactylitis, and skin/mucosal lesions. Differential diagnosis relies heavily on the specific pattern of joint involvement, radiographic signatures, and preceding triggers. Free to read 30 min read
- SarcomaMusculoskeletal tumors represent a diverse group of neoplasms categorized by their tissue of origin: osteogenic (Osteosarcoma, Osteochondroma), chondrogenic (Chondrosarcoma), neuroectodermal (Ewing Sarcoma), osteoclastic (Giant Cell Tumor), lipogenic (Liposarcoma), or plasma-cell mediated (Multiple Myeloma bone disease). Distinguishing these tumors on USMLE Step 1 relies heavily on identifying the patient's age, the specific anatomical location within the long bone (epiphysis, metaphysis, or diaphysis), characteristic radiographic appearances (such as sunbursts, soap bubbles, or onion-skinning), and classic cytogenetic translocations (like t(11;22) in Ewing Sarcoma). Free to read 30 min read
- Upper Limb Anatomy and Brachial PlexusThe upper limb anatomy and brachial plexus are highly structured systems with clear, reproducible clinical correlations. Mastery of this topic for Step 1 requires connecting specific anatomical landmarks—such as the surgical neck of the humerus, the radial groove, the medial epicondyle, and the carpal tunnel—with their corresponding nerves, blood vessels, and motor/sensory deficits. Knowing the classic presentations of nerve injuries (e.g., wrist drop, claw hand, waiter's tip) and the distinct mechanisms of injury (trauma, compression, stretching) allows for rapid and accurate diagnosis on exam day. Free to read 30 min read