USMLE Step 1
Practice Test 4 for USMLE Step 1: real questions and explanations from the Varsity Tutors practice-test pool.
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A 58-year-old woman who recently underwent hip replacement surgery develops acute-onset shortness of breath and pleuritic chest pain. Her heart rate is 110/min and respiratory rate is 28/min. A CT angiogram confirms a large pulmonary embolism in the right main pulmonary artery.
This patient's condition leads to hypoxemia primarily by causing a marked increase in which of the following?
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A 58-year-old woman who recently underwent hip replacement surgery develops acute-onset shortness of breath and pleuritic chest pain. Her heart rate is 110/min and respiratory rate is 28/min. A CT angiogram confirms a large pulmonary embolism in the right main pulmonary artery.
This patient's condition leads to hypoxemia primarily by causing a marked increase in which of the following?
Explanation: A pulmonary embolism obstructs blood flow to a region of the lung. This creates an area that is ventilated but not perfused (or underperfused). This is known as alveolar dead space. The sum of anatomic dead space (conducting airways) and alveolar dead space is physiologic dead space. The large increase in physiologic dead space represents wasted ventilation, leading to a severe ventilation/perfusion (V/Q) mismatch and hypoxemia.
A randomized controlled trial enrolls 210 adults (ages 19–55) with moderate persistent asthma and frequent nighttime symptoms despite inhaled corticosteroids. Investigators test the hypothesis that adding a new leukotriene antagonist reduces exacerbations over 24 weeks. Participants are randomized 1:1 using sealed, opaque envelopes prepared by an independent pharmacist; tablets are identical, and both patients and clinicians are blinded. Exacerbations are defined as need for systemic steroids or urgent visit. Results: 22/105 (21%) in treatment vs 35/105 (33%) in placebo have an exacerbation. However, 18% of participants correctly guess their assignment due to mild headache occurring more often in the active group (26% vs 10%).
What is the primary advantage of the study design described?
Explanation: This question tests understanding of study design and evidence types in biostatistics and epidemiology. Study design involves choosing the appropriate methodology to answer a research question while minimizing bias. In this vignette, the described study design is a randomized controlled trial, which is appropriate for evaluating the efficacy of a new leukotriene antagonist in reducing asthma exacerbations. The correct answer identifies the study design's advantage, such as reducing confounding through random assignment. A common misconception, as seen in choice C, is misidentifying the study design due to overestimating its efficiency for rare outcomes. Teaching strategies include emphasizing study design features and common biases, using real-world examples to illustrate abstract concepts, and practicing vignettes to identify design characteristics.
A 28-year-old woman is evaluated for palpitations. Auscultation reveals a mid-systolic click followed by a late systolic murmur at the cardiac apex. The click and murmur occur earlier in systole when she moves from a squatting to a standing position.
This patient's auscultatory findings are best explained by which of the following underlying valvular pathologies?
Explanation: The mid-systolic click and late systolic murmur are pathognomonic for mitral valve prolapse (MVP). The underlying pathology is myxomatous degeneration of the mitral valve leaflets and chordae tendineae, making them redundant and floppy. During systole, the leaflet billows back into the left atrium (the 'click' occurs when the chordae abruptly tense). If the prolapse is severe enough, mitral regurgitation occurs late in systole (the murmur). Standing decreases venous return and reduces left ventricular volume, causing the prolapse to occur earlier in systole and the murmur to lengthen.
A 29-year-old woman delivered a healthy infant 8 weeks ago. She exclusively breastfeeds and has not resumed menses. Physical examination is normal.
High prolactin levels in this patient most directly suppress which hypothalamic hormone, leading to her lactational amenorrhea?
Explanation: When you encounter lactational amenorrhea questions, focus on the hormonal cascade that maintains breastfeeding while suppressing ovulation. This is a classic example of how one reproductive state (lactation) temporarily shuts down another (ovulation). During breastfeeding, elevated prolactin levels directly inhibit the pulsatile release of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus in the hypothalamus. This pulsatile GnRH secretion is absolutely critical for normal reproductive function—it stimulates the anterior pituitary to release LH and FSH, which drive ovulation and menstruation. Without proper GnRH pulsatility, the entire reproductive axis shuts down, resulting in lactational amenorrhea. Choice A correctly identifies this mechanism. The arcuate nucleus is the specific hypothalamic region responsible for GnRH's pulsatile release pattern, and prolactin's suppression of this pulsatility is the direct cause of amenorrhea. Choice B is incorrect because corticotropin-releasing hormone (CRH) regulates the stress response and cortisol production, not reproductive function. Choice C is wrong because thyrotropin-releasing hormone (TRH) controls thyroid function through TSH release, which isn't the primary mechanism of lactational amenorrhea. Choice D is incorrect because somatostatin (growth hormone-inhibiting hormone) primarily regulates growth hormone release, not reproductive hormones. Remember that lactational amenorrhea questions almost always center on the prolactin-GnRH relationship. The key concept is that prolactin doesn't directly affect the ovaries—it works upstream by disrupting the hypothalamic pulsatile GnRH release that's essential for normal ovulation.
An agricultural worker is exposed to a pesticide containing high levels of arsenate. He presents to the emergency department with symptoms of nausea, vomiting, and confusion. Arsenate is known to interfere with glycolysis by acting as a phosphate analog.
Arsenate disrupts glycolysis by substituting for phosphate in the reaction catalyzed by which of the following enzymes, leading to no net production of ATP from the pathway?
Explanation: Arsenate is structurally similar to inorganic phosphate. It can substitute for phosphate in the reaction catalyzed by glyceraldehyde-3-phosphate dehydrogenase. This forms an unstable 1-arseno-3-phosphoglycerate intermediate, which spontaneously hydrolyzes to 3-phosphoglycerate. This bypasses the substrate-level phosphorylation step normally catalyzed by phosphoglycerate kinase, where ATP is generated. As a result, glycolysis can proceed, but the 2 ATP molecules normally generated at this step are lost, resulting in a net yield of 0 ATP for the entire pathway.
A 66-year-old woman with end-stage renal disease secondary to hypertension is evaluated for persistent fatigue and shortness of breath on exertion. She has been on hemodialysis for 3 years. Her blood pressure is 145/88 mm Hg and her weight is stable. A complete blood count reveals a hemoglobin of 8.5 g/dL and hematocrit of 26%. The mean corpuscular volume is 90 fL. Iron studies are within normal limits.
The patient's anemia is primarily caused by a deficiency in the production of a hormone synthesized by which of the following renal cells?
Explanation: Anemia of chronic kidney disease (CKD) is a normocytic, normochromic anemia primarily caused by decreased production of erythropoietin (EPO). In adults, EPO is synthesized mainly by the peritubular interstitial fibroblasts in the renal cortex in response to hypoxia. In ESRD, the number of these cells is greatly reduced due to fibrosis, leading to insufficient EPO production and subsequent anemia. A: Mesangial cells are intraglomerular contractile cells. B: Juxtaglomerular cells synthesize renin. D: Principal cells are involved in sodium and potassium balance in the collecting duct.
A large observational study in a seaside town finds a strong positive correlation (r = +0.85) between monthly ice cream sales and the number of drowning incidents.
Based on this information, which of the following is the most appropriate conclusion?
Explanation: Correlation does not imply causation. A strong correlation between two variables does not mean that one causes the other. In this classic example, a third factor, or confounding variable (e.g., warm weather), is likely responsible for the increase in both ice cream sales and swimming activities, which in turn leads to more drowning incidents. This is a much more plausible explanation than a direct causal link.
A phenotypically normal man has a history of two children with different partners, both of whom had multiple congenital anomalies and died in infancy. Karyotype analysis of the man reveals 46,XY,inv(3)(p25q21). His parents have normal karyotypes.
The chromosomal abnormality in this man increases the risk of abnormal offspring due to the potential for producing which of the following?
Explanation: The man has a pericentric inversion, which involves a segment of a chromosome that includes the centromere. During meiosis, if a crossover event occurs within the inverted segment, it can lead to the formation of recombinant chromosomes that have a duplication of one end and a deletion of the other. Fertilization with such a gamete results in an unbalanced karyotype and is often lethal or causes severe congenital anomalies.
A 5-year-old boy presents with pallor, easy bruising, and recurrent fever. A complete blood count shows pancytopenia with circulating blasts. A bone marrow aspirate is performed, and the sample is treated with fluorescently-labeled antibodies against various cell surface markers. The cells are then passed one-by-one through a laser beam to identify their lineage and maturation stage, which is crucial for diagnosis and classification of acute leukemia.
Which of the following laboratory techniques is described in this scenario?
Explanation: Flow cytometry is a technique used to analyze the characteristics of individual cells within a heterogeneous population. By using fluorescent antibodies against specific surface proteins (CD markers), it can identify and quantify cell populations, which is essential for the diagnosis and classification of hematologic malignancies like acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).
A 6-year-old child is diagnosed with a mitochondrial disorder. Subsequent genetic testing reveals that the causal mutation is in a nuclear gene that follows an autosomal recessive pattern of inheritance. The mutated gene codes for a protein essential for the assembly of Complex IV of the electron transport chain.
Where in the cell is the protein encoded by this mutated gene synthesized?
Explanation: Although mitochondria have their own DNA and ribosomes, they only produce 13 of the proteins required for oxidative phosphorylation. The vast majority (~99%) of mitochondrial proteins, including assembly factors and many ETC subunits, are encoded by nuclear DNA. These genes are transcribed in the nucleus, the mRNA is exported to the cytoplasm, and the proteins are synthesized on free cytoplasmic ribosomes. They are then targeted and imported into the mitochondria post-translationally.
A 25-year-old woman presents with hemoptysis and dyspnea 4 months after a suction curettage for a hydatidiform mole. Her serum β-hCG level is 200,000 mIU/mL. A chest radiograph reveals multiple, bilateral, well-circumscribed nodules.
The pulmonary findings in this patient are the result of a malignancy that has a strong propensity for which type of metastatic spread?
Explanation: This patient has developed choriocarcinoma, a malignant neoplasm of trophoblastic cells, as a complication of her molar pregnancy. Choriocarcinoma is characterized by its aggressive nature and tendency for early hematogenous spread. The malignant cells invade the uterine vasculature and embolize to distant sites, most commonly the lungs. This results in the characteristic 'cannonball' metastases seen on chest imaging and can cause symptoms like hemoptysis and dyspnea.
A 28-year-old woman receives the Tdap (Tetanus, Diphtheria, acellular Pertussis) vaccine during her third trimester of pregnancy. The goal is to provide her newborn with protection against pertussis (whooping cough) during the first few months of life.
The protection conferred upon the newborn is primarily mediated by which of the following mechanisms?
Explanation: Vaccinating a pregnant woman boosts her levels of antigen-specific IgG antibodies. IgG is the only immunoglobulin isotype that can actively be transported across the placenta into the fetal circulation. This provides the newborn with a high level of maternal IgG at birth, offering passive immunity against pathogens like Bordetella pertussis until the infant can receive its own primary vaccinations. While IgA is transferred via breast milk, the primary mechanism of protection from maternal Tdap vaccination is transplacental IgG.
A 70-year-old man is hospitalized for a pulmonary embolism and started on a continuous intravenous infusion of an anticoagulant. Five days later, his platelet count drops from 250,000/mm³ to 40,000/mm³. A new thrombus is noted in his right leg despite being on anticoagulation. The development of this condition is caused by antibodies directed against a complex of the anticoagulant and which of the following endogenous molecules?
The development of this condition is caused by antibodies directed against a complex of the anticoagulant and which of the following endogenous molecules?
Explanation: This patient has developed heparin-induced thrombocytopenia (HIT), an immune-mediated adverse drug reaction. HIT is caused by the formation of IgG antibodies against the heparin-platelet factor 4 (PF4) complex. The binding of these antibodies to platelets leads to their activation, aggregation, and clearance, causing thrombocytopenia. Paradoxically, this platelet activation also creates a prothrombotic state, leading to new or worsening thrombosis.
A 15-year-old boy is brought to the emergency department with a 3-hour history of sudden, severe left testicular pain that began during a soccer match. He also reports nausea. On examination, the left testis is swollen, exquisitely tender, and positioned high in the scrotum with a horizontal lie. The cremasteric reflex is absent on the left side.
This urologic emergency is most commonly predisposed by which of the following underlying abnormalities?
Explanation: Testicular torsion occurs when the spermatic cord twists, cutting off blood supply to the testis. The most common predisposing factor is a congenital anomaly known as the 'bell clapper' deformity, where the tunica vaginalis has an abnormally high attachment to the spermatic cord. This allows the testis to rotate freely within the tunica vaginalis, leading to torsion. A patent processus vaginalis leads to hydroceles or indirect inguinal hernias. Dilatation of the pampiniform plexus is a varicocele.
A 25-year-old man is hospitalized after a severe motor vehicle accident that resulted in a basilar skull fracture. Five days into his hospital course, his urine output increases dramatically to over 300 mL per hour. Laboratory studies show a serum sodium of 155 mEq/L and a urine specific gravity of 1.002. A water deprivation test shows continued production of dilute urine. However, administration of desmopressin results in a rapid increase in urine osmolality to 600 mOsm/kg.
This patient's polyuria is due to a deficiency in the secretion of a hormone from which of the following locations?
Explanation: The patient has developed central diabetes insipidus (DI) as a complication of head trauma. This condition is characterized by a deficiency of antidiuretic hormone (ADH), which is synthesized in the hypothalamus and released from the posterior pituitary. The lack of ADH prevents the insertion of aquaporin-2 channels in the renal collecting ducts, leading to an inability to concentrate urine and resulting in polyuria, hypernatremia, and low urine osmolality. The positive response to desmopressin (an ADH analog) confirms the diagnosis of central (as opposed to nephrogenic) DI.
A male infant is born with ambiguous genitalia. Physical examination reveals hypospadias and bilateral undescended testes. Karyotype analysis is 46,XY. Further investigation reveals a deletion on the short arm of the Y chromosome.
Deletion of which of the following genes is the most likely cause of this infant's failure to develop normal male external genitalia?
Explanation: The SRY (Sex-determining Region on Y) gene, located on the short arm of the Y chromosome, is the primary genetic switch for male development. It encodes a transcription factor that initiates the differentiation of the gonads into testes. A deletion or mutation in the SRY gene in a 46,XY individual leads to gonadal dysgenesis, where the gonads fail to develop properly into testes. Without functional testes, there is insufficient testosterone and anti-Müllerian hormone production, resulting in the development of female or ambiguous external genitalia.
To analyze global mRNA expression changes in melanoma cells treated with an experimental drug, investigators isolate total RNA, reverse transcribe it to cDNA, fluorescently label the sample, and hybridize it to an array containing thousands of oligonucleotide probes spotted on a glass slide. Which laboratory technique are they using?
Explanation: When you encounter questions about gene expression analysis techniques, focus on the key procedural details described - they're your clues to identifying the specific method being used. The described procedure perfectly matches DNA microarray analysis. The investigators isolate RNA, convert it to cDNA through reverse transcription, add fluorescent labels, then hybridize the sample to oligonucleotide probes spotted on a glass slide. This glass slide array setup is the hallmark of microarray technology, where gene expression is measured by comparing fluorescence intensity across thousands of probe spots - exactly what answer choice A describes. Let's examine why the other options don't fit: Choice B describes next-generation sequencing, which would involve creating sequencing libraries and reading individual DNA sequences rather than using probe hybridization on glass slides. Choice C refers to SAGE (Serial Analysis of Gene Expression), an older technique that creates short sequence tags from transcripts and doesn't involve fluorescent labeling or glass slide arrays. Choice D describes Northern blotting, which uses gel electrophoresis to separate RNA by size and typically employs radioactive rather than fluorescent detection - completely different from the array-based approach described. The key distinguishing features of microarrays are the glass slide format with spotted oligonucleotide probes and fluorescence-based detection through hybridization. When you see these elements together in a question stem, think microarray analysis. Remember that while newer RNA-seq techniques have largely replaced microarrays, understanding these classic molecular biology methods remains important for the USMLE.
A 40-year-old man is being treated for active tuberculosis with a multi-drug regimen that includes isoniazid. After several months of treatment, he develops a tingling sensation and numbness in his hands and feet, consistent with peripheral neuropathy. This adverse effect is known to be caused by the drug's interference with the metabolism of a specific vitamin. This vitamin, in its active form, is a crucial cofactor for the enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
Isoniazid is most likely interfering with the function of which of the following vitamins?
Explanation: Isoniazid can cause a functional deficiency of pyridoxine (vitamin B6) by increasing its excretion. The active form of B6, pyridoxal phosphate (PLP), is a critical coenzyme for transamination reactions, which are catalyzed by aminotransferases like ALT and AST. PLP is also required for decarboxylation and deamination reactions involved in the synthesis of neurotransmitters, and its deficiency can lead to peripheral neuropathy.
A 22-year-old man presents with a 2-day history of purulent urethral discharge and dysuria after unprotected sexual contact. A urethral swab is sent for culture. To isolate the fastidious gram-negative diplococcus responsible for his condition, the sample is plated on a selective medium containing vancomycin, colistin, nystatin, and trimethoprim.
What is the name of this selective medium?
Explanation: The clinical presentation is classic for gonorrhea, caused by Neisseria gonorrhoeae. This organism is fastidious and is often found in sites with normal flora. Thayer-Martin agar (or modified Thayer-Martin) is a selective medium used for its isolation. It is a chocolate agar base enriched with antibiotics: vancomycin to inhibit gram-positive bacteria, colistin to inhibit other gram-negative bacteria, nystatin to inhibit fungi, and trimethoprim to inhibit swarming Proteus.
In a molecular genetics laboratory, a technician is preparing a labeled, single-stranded DNA molecule. This molecule is designed to be complementary to a specific gene sequence on a chromosome. It will be used in an experiment to visualize the location of that gene within a cell nucleus.
The fundamental principle that allows this DNA 'probe' to bind specifically to its target sequence on the chromosome is known as which of the following?
Explanation: Hybridization is the process by which a single-stranded nucleic acid molecule (DNA or RNA) anneals to its complementary sequence through hydrogen bonds between the bases. This principle of specific base pairing (A with T, G with C) is the foundation for techniques like FISH, Southern blotting, Northern blotting, and microarrays, where a labeled probe is used to detect a target sequence.
Administration of an intravenous bolus of nitroprusside primarily decreases afterload. Which of the following immediate changes is most likely to occur in a normal left ventricle as afterload falls?
Explanation: When you encounter questions about afterload reduction, think about how the left ventricle responds to decreased resistance against which it must pump blood. Afterload represents the pressure the ventricle must overcome to eject blood into the systemic circulation. Nitroprusside reduces afterload by dilating arteries, making it easier for the left ventricle to eject blood. When afterload falls, the ventricle encounters less resistance during systole, allowing it to empty more completely. This results in a smaller end-systolic volume because more blood is ejected with each contraction. Choice A correctly identifies this mechanism - reduced afterload allows more complete ventricular emptying, decreasing end-systolic volume. This is a direct consequence of the pressure-volume relationship in cardiac mechanics. Choice B is incorrect because end-diastolic volume changes are primarily related to venous return and filling time, not afterload. Afterload affects ejection, not filling. Choice C misunderstands the relationship between afterload and ventricular pressure. When afterload decreases, the ventricle doesn't need to generate as high a pressure to eject blood, so maximum left ventricular pressure actually decreases, not increases. Choice D confuses the immediate mechanical effects with potential secondary hemodynamic changes. While reduced systemic vascular resistance may lower arterial pressure, the immediate effect on stroke volume is actually an increase due to more complete emptying, not a decrease. Remember: afterload primarily affects the ejection phase of the cardiac cycle. Reduced afterload = easier ejection = more complete emptying = decreased end-systolic volume.
A geneticist is studying a large family affected by a rare, autosomal dominant form of early-onset dementia. The causative gene is unknown. To identify the chromosomal location of the gene, the researcher genotypes all family members, both affected and unaffected, for hundreds of polymorphic DNA markers spread across the genome. The goal is to find markers that are consistently inherited along with the disease.
This research method, which tracks the co-segregation of a genetic marker and a disease phenotype within a family, is best described as which of the following?
Explanation: Linkage analysis is a method used to map a disease-causing gene to a specific chromosomal region by studying its inheritance pattern alongside known genetic markers in large families. Markers that are physically close to the disease gene on a chromosome tend to be inherited together (i.e., they are 'linked') and will not assort independently. GWAS is a population-based study to find common variants associated with common diseases, not for mapping rare single-gene disorders in families.
A university hospital follows a prospective cohort of 2,400 adults aged 50–75 without dementia at baseline (60% women; 30% with hypertension). Investigators test the hypothesis that chronic benzodiazepine use increases incidence of Alzheimer disease over 8 years. Exposure is defined from pharmacy refill records (≥90 days supplied per year). Annual cognitive screening and neurologist adjudication determine incident Alzheimer disease. Results: Alzheimer disease develops in 96/800 (12.0%) exposed vs 144/1,600 (9.0%) unexposed. Exposed participants have higher baseline anxiety and poorer sleep, and they attend follow-up visits less often. Investigators adjust for age, education, depression, and comorbidities, but they acknowledge persistent differences between groups.
Which bias is most likely to affect the results of this study?
Explanation: This question tests understanding of study design and evidence types in biostatistics and epidemiology. Study design involves choosing the appropriate methodology to answer a research question while minimizing bias. In this vignette, the described study design is a prospective cohort study, which is appropriate for measuring incident Alzheimer disease in relation to benzodiazepine exposure over time. The correct answer identifies selection bias from differential loss to follow-up, as exposed participants attend less often. A common misconception, as seen in choice C, is misidentifying the study design due to assuming recall bias in a prospective setup with records. Teaching strategies include emphasizing study design features and common biases, using real-world examples to illustrate abstract concepts, and practicing vignettes to identify design characteristics.
A newborn is diagnosed with a severe form of β-thalassemia, characterized by a profound deficiency of β-globin chain synthesis. DNA sequencing of the β-globin gene itself, including its exons, introns, and promoter, is found to be normal. Further analysis reveals a large deletion in a region of DNA located approximately 50,000 base pairs upstream of the β-globin gene. This region is known as the locus control region (LCR).
The deleted DNA segment in this patient most likely functions as which of the following?
Explanation: Enhancers are DNA regulatory elements that can be located far upstream, downstream, or within an intron of a gene they regulate. They bind specific transcription factors to dramatically increase the rate of transcription. The locus control region (LCR) for the β-globin cluster is a powerful enhancer element required for high-level, tissue-specific expression. Its deletion leads to severe thalassemia despite a normal gene sequence.
A 35-year-old woman presents to the emergency department with a 2-day history of high fever, confusion, diffuse sunburn-like rash, and profound hypotension with a blood pressure of 80/40 mm Hg. She reports using super-absorbent tampons for her current menstrual period. Laboratory studies show evidence of acute kidney and liver injury. This condition is caused by a bacterial toxin that acts as a superantigen.
What is the primary mechanism of action of a superantigen toxin?
Explanation: The patient has toxic shock syndrome (TSS), most commonly caused by Staphylococcus aureus producing TSST-1. This toxin is a superantigen, which binds directly to MHC class II molecules on antigen-presenting cells and the variable region of the T-cell receptor beta chain. This cross-linking causes nonspecific activation of a large fraction of T-cells, leading to a massive release of cytokines (e.g., IL-1, IL-2, TNF-α), resulting in systemic inflammation, hypotension, and shock.