Step 1 | 1 General Principles

1.1       Biochemistry and molecular biology

1.1.1    gene expression: DNA structure, replication, and exchange

1.1.1.1     DNA structure: single- and double-stranded DNA, stabilizing forces, supercoiling
1.1.1.2     analysis of DNA: sequencing, restriction analysis, PCR amplification, hybridization
1.1.1.3     DNA replication, mutation, repair, degradation, and inactivation
1.1.1.4     gene structure and organization; chromosomes; centromere, telomere
1.1.1.5     recombination, insertion sequences, transposons
1.1.1.6     mechanisms of genetic exchange, including transformation, transduction, conjugation, crossover, recombination, linkage
1.1.1.7     plasmids and bacteriophages

1.1.2    gene expression:  transcription, including defects

1.1.2.1     transcription of DNA into RNA, enzymatic reactions, RNA, RNA degradation
1.1.2.2     regulation:  cis-regulatory elements, transcription factors, enhancers, promoters, silencers, repressants, splicing

1.1.3    gene expression:  translation, including defects

1.1.3.1     the genetic code
1.1.3.2     structure and function of tRNA
1.1.3.3     structure and function of ribosomes
1.1.3.4     protein synthesis
1.1.3.5     regulation of translation
1.1.3.6     post-translational modifications, including phosphorylation, addition of CHO units
1.1.3.7     protein degradation

1.1.4    structure and function of proteins

1.1.4.1     principles of protein structure and folding
1.1.4.2     enzymes: kinetics, reaction mechanisms
1.1.4.3     structural and regulatory proteins: ligand binding, self-assembly
1.1.4.4     regulatory properties

1.1.5    energy metabolism, including metabolic sequences and regulation

1.1.5.1     generation of energy from carbohydrates, fatty acids, and essential amino acids; glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, ketogenesis, electron transport and oxidative phosphorylation, glycogenolysis
1.1.5.2     storage of energy: gluconeogenesis, glycogenesis, fatty acid and triglyceride synthesis
1.1.5.3     thermodynamics: free energy, chemical equilibria and group transfer potential, energetics of ATP and other high-energy compounds

1.1.6    metabolic pathways of small molecules and associated diseases

1.1.6.1     biosynthesis and degradation of amino acids (eg, homocystinuria; maple syrup urine disease)
1.1.6.2     biosynthesis and degradation of purine and pyrimidine nucleotides
1.1.6.3     biosynthesis and degradation of lipids (eg, dyslipidemias, carnitine deficiency)
1.1.6.4     biosynthesis and degradation of porphyrins
1.1.6.5     galactosemia and other small sugar disorders
1.1.6.6     biosynthesis and degradation of alcohols and other small molecules

1.1.7    biosynthesis and degradation of other macromolecules and associated abnormalities, complex carbohydrates (eg, lysosomal storage disease), glycoproteins, and proteoglycans (eg, type II glycogen storage disease)

1.2       Biology of cells

1.2.1    structure and function of cell components

1.2.1.1     endoplasmic reticulum
1.2.1.2     Golgi complex
1.2.1.3     mitochondria
1.2.1.4     lysosome, peroxisome, endosome
1.2.1.5     centriole, microtubule
1.2.1.6     ribosome, polysome
1.2.1.7     plasma membrane (eg, glycolipids, glycoproteins, glycosaminoglycans, membrane fluidity)
1.2.1.8     cytosol
1.2.1.9     cilia
1.2.1.10   nucleus, including chromatin, nucleolus, the nuclear envelope, and nuclear matrix
1.2.1.11   cytoskeleton (eg, actin filaments, intermediate filaments, microtubules)

1.2.2    signal transduction

1.2.2.1     basic principles: autocrine, paracrine, endocrine
1.2.2.2     receptors and channels
1.2.2.2.1     protein kinase receptors
1.2.2.2.2     non-protein kinase receptors
1.2.2.2.3     nuclear receptors
1.2.2.2.4     G protein-linked receptors
1.2.2.2.5     voltage-gated channels
1.2.2.2.6     ligand-gated channels
1.2.2.3     second messengers (eg, IP3, DAG, PKA, PKC)
1.2.2.4     signal transduction pathways (eg, MAPK, JNK, TGF-β)

1.2.3    cell-cell and cell-matrix adhesion

1.2.4    cell motility

1.2.5    intracellular sorting (eg, trafficking, endocytosis)

1.2.6    cellular homeostasis (eg, turnover, pH maintenance, proteasome, ions, soluble proteins)

1.2.7    cell cycle

1.2.7.1     mitosis
1.2.7.2     meiosis
1.2.7.3     structure of spindle apparatus
1.2.7.4     cell cycle regulation (eg, cyclins, cdks, cdk inhibitors)

1.2.8    structure and function of basic tissue components

1.2.8.1     epithelial cells
1.2.8.2     connective tissue cells (eg, fibroblasts)
1.2.8.3     muscle cells
1.2.8.4     nerve cells
1.2.8.5     extracellular matrix (eg, basement membranes)

1.2.9    adaptive cell response to injury

1.2.10  intracellular accumulations (eg, pigments, fats, proteins, carbohydrates, minerals, inclusions, vacuoles)

1.2.11  mechanisms of injury and necrosis

1.2.12  apoptosis

1.3       Human development and genetics

1.3.1    embryogenesis: programmed gene expression, tissue differentiation and morphogenesis, homeotic genes; developmental regulation of gene expression

1.3.2    congenital abnormalities: principles, patterns of anomalies, dysmorphogenesis

1.3.3    principles of pedigree analysis

1.3.3.1     inheritance patterns
1.3.3.2     occurrence and recurrence risk determination

1.3.4    population genetics: Hardy-Weinberg law, founder effects, mutation-selection equilibrium

1.3.5    genetic mechanisms

1.3.5.1     chromosomal abnormalities: translocations; deletions; duplications, including nucleotide repeats and inversions, mosaicism
1.3.5.2     mendelian inheritance
1.3.5.2.1     homozygosity, heterozygosity
1.3.5.2.2      phenotypic variation: pleiotropy, variable expression, delayed onset
1.3.5.2.3     imprinting
1.3.5.2.4     polymorphisms
1.3.5.3     multifactorial diseases

1.3.6    clinical genetics

1.3.6.1     genetic testing
1.3.6.2     prenatal diagnosis
1.3.6.3     newborn screening
1.3.6.4     genetic counseling: ethics
1.3.6.5     gene therapy

1.4       Biology of tissue response to disease

1.4.1    inflammation, including cells and mediators

1.4.1.1     acute inflammation and mediator systems
1.4.1.2     vascular response to injury, including mediators
1.4.1.3     inflammatory cell recruitment, including adherence and cell migration, and phagocytosis
1.4.1.4     bactericidal mechanisms and tissue injury
1.4.1.5     clinical manifestations (eg, pain, fever, leukocytosis, leukemoid reaction, chills)
1.4.1.6     chronic inflammation

1.4.2    reparative processes

1.4.2.1     wound healing, hemostasis, and repair: thrombosis, granulation tissue, angiogenesis, fibrosis, scar/keloid formation
1.4.2.2     regenerative processes

1.4.3    neoplasia

1.4.3.1     classification of neoplasms; histologic diagnosis of malignancy
1.4.3.2     grading and staging of neoplasms
1.4.3.3     cell biology, biochemistry, and molecular biology of neoplastic cells: transformation, oncogenes, altered cell differentiation and proliferation
1.4.3.4     hereditary neoplastic disorders
1.4.3.5     invasion and metastasis
1.4.3.6     tumor immunology
1.4.3.7     paraneoplastic manifestations of cancer
1.4.3.8     cancer epidemiology and prevention

1.5       Gender, ethnic, and behavioral considerations affecting disease treatment and prevention, including psychosocial, cultural, occupational, and environmental

1.5.1    progression through the life cycle, including birth through senescence

1.5.1.1     cognitive, language, motor skills, and social and interpersonal development
1.5.1.2     sexual development (eg, puberty, menopause)
1.5.1.3     influence of developmental stage on physician-patient interview

1.5.2    psychologic and social factors influencing patient behavior

1.5.2.1     personality traits or coping style, including coping mechanisms
1.5.2.2     psychodynamic and behavioral factors, related past experience
1.5.2.3     family and cultural factors, including socioeconomic status, ethnicity, and gender
1.5.2.4     adaptive behavioral responses to stress and illness
1.5.2.5     maladaptive behavioral responses to stress and illness (eg, drug- seeking behavior, sleep deprivation)
1.5.2.6     interactions between the patient and the physician or the health care system (eg, transference)
1.5.2.7     patient adherence

1.5.2.7.1     general
1.5.2.7.2     adolescent

1.5.3    patient interviewing, consultation, and interactions with the family

1.5.3.1     establishing and maintaining rapport
1.5.3.2     data gathering
1.5.3.3     approaches to patient education
1.5.3.4     enticing patients to make lifestyle changes
1.5.3.5     communicating bad news
1.5.3.6     “difficult” interviews (eg, anxious or angry patients)
1.5.3.7     multicultural ethnic characteristics

1.5.4    medical ethics, jurisprudence, and professional behavior

1.5.4.1     consent and informed consent to treatment
1.5.4.2     physician-patient relationships (eg, ethical conduct, confidentiality)
1.5.4.3     death and dying
1.5.4.4     birth-related issues
1.5.4.5     issues related to patient participation in research
1.5.4.6     interactions with other health professionals (eg, referral)
1.5.4.7     sexuality and the profession; other “boundary” issues
1.5.4.8     ethics of managed care
1.5.4.9     organization and cost of health care delivery

1.6       Multisystem processes

1.6.1    nutrition

1.6.1.1     generation, expenditure, and storage of energy at the whole-body level
1.6.1.2     assessment of nutritional status across the life span, including calories, protein, essential nutrients, hypoalimentation
1.6.1.3     functions of nutrients, including essential, trans-fatty acids, cholesterol
1.6.1.4     protein-calorie malnutrition
1.6.1.5     vitamin deficiencies and/or toxicities

1.6.1.5.1     vitamin A
1.6.1.5.2     vitamin B complex
1.6.1.5.3     vitamin C
1.6.1.5.4     vitamin D
1.6.1.5.5     vitamin E
1.6.1.5.6     vitamin K

1.6.1.6     mineral deficiencies and toxicities
1.6.1.7     eating disorders

1.6.1.7.1     obesity
1.6.1.7.2     anorexia and bulimia
1.6.1.7.3     alternative diets, nutritional supplements, and food fads
1.6.1.7.4     treatment of eating disorders

1.6.2    temperature regulation

1.6.3    adaptation to environmental extremes, including occupational exposures

1.6.3.1     physical and associated disorders

1.6.3.1.1     temperature
1.6.3.1.2     radiation
1.6.3.1.3     burns, including electrocution, lightning
1.6.3.1.4     decreased atmospheric pressure, high-altitude sickness
1.6.3.1.5     increased water pressure (eg, “bends”)

1.6.3.2     chemical

1.6.3.2.1     gases, vapors, smoke inhalation (eg, poison gases)
1.6.3.2.2     agricultural hazards (eg, insecticides)
1.6.3.2.3     volatile organic solvents (eg, chloroform)
1.6.3.2.4     heavy metals (eg, lead)
1.6.3.2.5     principles of poisoning and therapy

1.6.4    fluid, electrolyte, and acid-base balance and disorders (eg, dehydration, acidosis, alkalosis)

1.7       Pharmacodynamic and pharmacokinetic processes

1.7.1    general principles

1.7.1.1     pharmacokinetics: absorption, distribution, metabolism, excretion, dosage intervals
1.7.1.2     mechanisms of drug action, structure-activity relationships
1.7.1.3     concentration- and dose-effect relationships (eg, efficacy, potency), types of agonists (eg, full, partial, inverse) and antagonists and their actions
1.7.1.4     individual factors altering pharmacokinetics and pharmacodynamics (eg, age, gender, disease, tolerance, compliance, body weight, metabolic proficiency, pharmacogenetics)
1.7.1.5     drug side effects, overdosage, toxicology
1.7.1.6     drug interactions
1.7.1.7     regulatory issues (eg, drug development, approval, scheduling)

1.7.2    general properties of autacoids

1.7.2.1     peptides and analogs
1.7.2.2     biogenic amines
1.7.2.3     prostanoids and their inhibitors
1.7.2.4     smooth muscle/endothelial autacoids (eg, nitric oxide)

1.7.3    general principles of autonomic pharmacology

1.7.4    general properties of antimicrobials, including mechanisms of action and resistance

1.7.4.1     antibacterials

1.7.4A        aminoglycosides
1.7.4B        cephalosporins and penicillins
1.7.4C        quinolones and tetracyclines
1.7.4D        antituberculous
1.7.4E         other antibacterials

1.7.4.2     antivirals

1.7.4F         antiretrovirals
1.7.4G        other antivirals

1.7.4.3     antifungals

1.7.4H        antifungals

1.7.4.4     antiparasitics

1.7.4E         antiparasitics

1.7.5    general properties of antineoplastic agents and immunosuppressants, including drug effects on rapidly dividing mammalian cells

1.8       Microbial biology and infection

1.8.1    microbial classification and its basis

1.8.2    bacteria and bacterial diseases

1.8.2.1     structure and composition
1.8.2.2     metabolism, physiology, and regulation
1.8.2.3     genetics
1.8.2.4     nature and mechanisms of action of virulence factors
1.8.2.5     pathophysiology of infection
1.8.2.6     epidemiology and ecology
1.8.2.7     principles of cultivation, assay, and laboratory diagnosis

1.8.3    viruses and viral diseases

1.8.3.1     physical and chemical properties
1.8.3.2     replication
1.8.3.3     genetics
1.8.3.4     principles of cultivation, assay, and laboratory diagnosis
1.8.3.5     molecular basis of pathogenesis
1.8.3.6     pathophysiology of infection
1.8.3.7     latent and persistent infections
1.8.3.8     epidemiology
1.8.3.9     oncogenic viruses

1.8.4    fungi and fungal infections

1.8.4.1     structure, physiology, cultivation, and laboratory diagnosis
1.8.4.2     pathogenesis and epidemiology

1.8.5    parasites and parasitic diseases

1.8.5.1     structure, physiology, and laboratory diagnosis
1.8.5.2     pathogenesis and epidemiology

1.8.6    principles of sterilization and pure culture technique

1.9       Immune responses

1.9.1    production and function of granulocytes, natural killer cells, and macrophages

1.9.2    production and function of T lymphocytes, T-lymphocyte receptors

1.9.3    production and function of B lymphocytes and plasma cells; immunoglobulin and antibodies: structure and biologic properties

1.9.4    antigenicity and immunogenicity; antigen presentation; cell activation and regulation; tolerance and clonal deletion

1.9.5    immunologic mediators: chemistry, function, molecular biology, classic and alternative complement pathways, cytokines, chemokines

1.9.6    immunogenetics; MHC structure and function, class I, II molecules; erythrocyte antigens

1.9.7    immunizations: vaccines, protective immunity

1.9.8    alterations in immunologic function

1.9.8.1     T- or B-lymphocyte deficiencies (DiGeorge syndrome)
1.9.8.2     deficiencies of phagocytic cells
1.9.8.3     combined immunodeficiency disease
1.9.8.4     HIV infection/AIDS and other acquired disorders of immune responsiveness
1.9.8.5     drug-induced alterations in immune responses, immunopharmacology

1.9.9    immunologically mediated disorders

1.9.9.1     type I, type II, type III hypersensitivity
1.9.9.2     type IV hypersensitivity
1.9.9.3     transplant and transplant rejection
1.9.9.4     autoimmune disorders
1.9.9.5     risks of transplantation, transfusion (eg, graft-versus-host disease)
1.9.9.6     isoimmunization, hemolytic disease of the newborn
1.9.9.7     immunopathogenesis

1.9.10  immunologic principles underlying diagnostic laboratory tests (eg, ELISA, complement fixation, RIA, agglutination)

1.9.11  innate immunity

1.10     Quantitative methods

1.10.1  fundamental concepts of measurement

1.10.1.1   scales of measurement
1.10.1.2   distribution, central tendency, variability, probability
1.10.1.3   disease prevalence and incidence
1.10.1.4   disease outcomes (eg, fatality rates)
1.10.1.5   associations (eg, correlation and covariance)
1.10.1.6   health impact (eg, risk differences and ratios)
1.10.1.7   sensitivity, specificity, predictive values

1.10.2  fundamental concepts of study design

1.10.2.1   types of experimental studies (eg, clinical trials, community intervention trials)
1.10.2.2   types of observational studies (eg, cohort, case-control, cross- sectional, case series, community surveys)
1.10.2.3   sampling and sample size
1.10.2.4   subject selection and exposure allocation (eg, randomization, stratification, self-selection, systematic assignment)
1.10.2.5   outcome assessment
1.10.2.6   internal and external validity

1.10.3  fundamental concepts of hypothesis testing and statistical inference

1.10.3.1   confidence intervals
1.10.3.2   statistical significance and Type I error
1.10.3.3   statistical power and Type II error

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