The 50 most-cited articles in JAMA, 2023

Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range,…

Importance: Approximately 18.6 million people worldwide are affected by a diabetic foot ulcer each year, including 1.6 million people in the United States. These ulcers precede 80% of lower extremity amputations among people diagnosed with diabetes and are associated with an increased risk of death. Observations: Neurological, vascular, and biomechanical factors contribute to diabetic foot ulceration. Approximately 50% to 60% of ulcers become infected, and about 20% of moderate to severe infections lead to lower extremity amputations. The 5-year mortality rate for individuals with a diabetic foot ulcer is approximately 30%, exceeding 70% for those with a major amputation. The mortality rate for people with diabetic foot ulcers is 231 deaths per 1000 person-years, compared with 182 deaths per 1000 person-years in people with diabetes without foot ulcers. People who are Black, Hispanic, or Native American and people with low socioeconomic status have higher rates of diabetic foot ulcer and subsequent amputation compared with White people. Classifying ulcers based on the degree of…

Importance: Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals and increases with age. Five-year survival is approximately 36%. Observations: Approximately 49% of malignant brain tumors are glioblastomas, and 30% are diffusely infiltrating lower-grade gliomas. Other malignant brain tumors include primary central nervous system (CNS) lymphoma (7%) and malignant forms of ependymomas (3%) and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%), seizures (20%-50%), neurocognitive impairment (30%-40%), and focal neurologic deficits (10%-40%). Magnetic resonance imaging before and after a gadolinium-based contrast agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor biopsy with consideration of histopathological and molecular characteristics. Treatment varies by tumor type and often includes a combination of surgery, chemotherapy, and radiation. For patients with glioblastoma, the…

Importance: Autism spectrum disorder (ASD), characterized by deficits in social communication and the presence of restricted, repetitive behaviors or interests, is a neurodevelopmental disorder affecting approximately 2.3% children aged 8 years in the US and approximately 2.2% of adults. This review summarizes evidence on the diagnosis and treatment of ASD. Observations: The estimated prevalence of ASD has been increasing in the US, from 1.1% in 2008 to 2.3% in 2018, which is likely associated with changes in diagnostic criteria, improved performance of screening and diagnostic tools, and increased public awareness. No biomarkers specific to the diagnosis of ASD have been identified. Common early signs and symptoms of ASD in a child's first 2 years of life include no response to name when called, no or limited use of gestures in communication, and lack of imaginative play. The criterion standard for the diagnosis of ASD is a comprehensive evaluation with a multidisciplinary team of clinicians and is based on semistructured direct observation of the child's behavior and…

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44…

Importance: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. Objective: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. Design, Setting, and Participants: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. Interventions: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. Main Outcomes and Measures: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key…

Importance: Obesity affects approximately 42% of US adults and is associated with increased rates of type 2 diabetes, hypertension, cardiovascular disease, sleep disorders, osteoarthritis, and premature death. Observations: A body mass index (BMI) of 25 or greater is commonly used to define overweight, and a BMI of 30 or greater to define obesity, with lower thresholds for Asian populations (BMI ≥25-27.5), although use of BMI alone is not recommended to determine individual risk. Individuals with obesity have higher rates of incident cardiovascular disease. In men with a BMI of 30 to 39, cardiovascular event rates are 20.21 per 1000 person-years compared with 13.72 per 1000 person-years in men with a normal BMI. In women with a BMI of 30 to 39.9, cardiovascular event rates are 9.97 per 1000 person-years compared with 6.37 per 1000 person-years in women with a normal BMI. Among people with obesity, 5% to 10% weight loss improves systolic blood pressure by about 3 mm Hg for those with hypertension, and may decrease hemoglobin A1c by 0.6% to 1% for those with type 2 diabetes.…

Importance: Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, with a prevalence exceeding 400 per 100 000 in North America. Individuals with UC have a lower life expectancy and are at increased risk for colectomy and colorectal cancer. Observations: UC impairs quality of life secondary to inflammation of the colon causing chronic diarrhea and rectal bleeding. Extraintestinal manifestations, such as primary sclerosing cholangitis, occur in approximately 27% of patients with UC. People with UC require monitoring of symptoms and biomarkers of inflammation (eg, fecal calprotectin), and require colonoscopy at 8 years from diagnosis for surveillance of dysplasia. Risk stratification by disease location (eg, Montreal Classification) and disease activity (eg, Mayo Score) can guide management of UC. First-line therapy for induction and maintenance of remission of mild to moderate UC is 5-aminosalicylic acid. Moderate to severe UC may require oral corticosteroids for induction of remission as a bridge to medications that sustain remission (biologic monoclonal…

Importance: Heart failure with preserved ejection fraction (HFpEF), defined as HF with an EF of 50% or higher at diagnosis, affects approximately 3 million people in the US and up to 32 million people worldwide. Patients with HFpEF are hospitalized approximately 1.4 times per year and have an annual mortality rate of approximately 15%. Observations: Risk factors for HFpEF include older age, hypertension, diabetes, dyslipidemia, and obesity. Approximately 65% of patients with HFpEF present with dyspnea and physical examination, chest radiographic, echocardiographic, or invasive hemodynamic evidence of HF with overt congestion (volume overload) at rest. Approximately 35% of patients with HFpEF present with "unexplained" dyspnea on exertion, meaning they do not have clear physical, radiographic, or echocardiographic signs of HF. These patients have elevated atrial pressures with exercise as measured with invasive hemodynamic stress testing or estimated with Doppler echocardiography stress testing. In unselected patients presenting with unexplained dyspnea, the H2FPEF score…

Importance: Approximately 0.5% to 3% of patients undergoing surgery will experience infection at or adjacent to the surgical incision site. Compared with patients undergoing surgery who do not have a surgical site infection, those with a surgical site infection are hospitalized approximately 7 to 11 days longer. Observations: Most surgical site infections can be prevented if appropriate strategies are implemented. These infections are typically caused when bacteria from the patient's endogenous flora are inoculated into the surgical site at the time of surgery. Development of an infection depends on various factors such as the health of the patient's immune system, presence of foreign material, degree of bacterial wound contamination, and use of antibiotic prophylaxis. Although numerous strategies are recommended by international organizations to decrease surgical site infection, only 6 general strategies are supported by randomized trials. Interventions that are associated with lower rates of infection include avoiding razors for hair removal (4.4% with razors vs 2.5% with…

Importance: Psilocybin shows promise as a treatment for major depressive disorder (MDD). Objective: To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. Design, Setting, and Participants: In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days…

Importance: Each year in the US, approximately 100 000 people are treated for cervical precancer, 14 000 people are diagnosed with cervical cancer, and 4000 die of cervical cancer. Observations: Essentially all cervical cancers worldwide are caused by persistent infections with one of 13 carcinogenic human papillomavirus (HPV) genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. HPV vaccination at ages 9 through 12 years will likely prevent more than 90% of cervical precancers and cancers. In people with a cervix aged 21 through 65 years, cervical cancer is prevented by screening for and treating cervical precancer, defined as high-grade squamous intraepithelial lesions of the cervix. High-grade lesions can progress to cervical cancer if not treated. Cervicovaginal HPV testing is 90% sensitive for detecting precancer. In the general population, the risk of precancer is less than 0.15% over 5 years following a negative HPV test result. Among people with a positive HPV test result, a combination of HPV genotyping and cervical cytology (Papanicolaou testing) can identify…

Importance: Prediabetes, an intermediate stage between normal glucose regulation and diabetes, affects 1 in 3 adults in the US and approximately 720 million individuals worldwide. Observations: Prediabetes is defined by a fasting glucose level of 100 to 125 mg/dL, a glucose level of 140 to 199 mg/dL measured 2 hours after a 75-g oral glucose load, or glycated hemoglobin level (HbA1C) of 5.7% to 6.4% or 6.0% to 6.4%. In the US, approximately 10% of people with prediabetes progress to having diabetes each year. A meta-analysis found that prediabetes at baseline was associated with increased mortality and increased cardiovascular event rates (excess absolute risk, 7.36 per 10 000 person-years for mortality and 8.75 per 10 000 person-years for cardiovascular disease during 6.6 years). Intensive lifestyle modification, consisting of calorie restriction, increased physical activity (≥150 min/wk), self-monitoring, and motivational support, decreased the incidence of diabetes by 6.2 cases per 100 person-years during a 3-year period. Metformin decreased the risk of diabetes among individuals…

This database study examines the association between glucagon-like peptide 1 agonists (eg, semaglutide, liraglutide) used for weight loss and reports of gastrointestinal adverse events.

Importance: Pulmonary vein isolation (PVI) alone is less effective in patients with persistent atrial fibrillation (AF) compared with paroxysmal AF. The left atrial posterior wall may contribute to maintenance of persistent AF, and posterior wall isolation (PWI) is a common PVI adjunct. However, PWI has not been subjected to randomized comparison. Objective: To compare PVI with PWI vs PVI alone in patients with persistent AF undergoing first-time catheter ablation. Design, Setting, and Participants: Investigator initiated, multicenter, randomized clinical trial involving 11 centers in 3 countries (Australia, Canada, UK). Symptomatic patients with persistent AF were randomized 1:1 to either PVI with PWI or PVI alone. Patients were enrolled July 2018-March 2021, with 1-year follow-up completed March 2022. Interventions: The PVI with PWI group (n = 170) underwent wide antral pulmonary vein isolation followed by posterior wall isolation involving linear ablation at the roof and floor to achieve electrical isolation. The PVI-alone group (n = 168) underwent wide antral pulmonary vein…

This study examines the appropriateness of artificial intelligence model responses to fundamental cardiovascular disease prevention questions.

Importance: Red blood cell transfusion is a common medical intervention with benefits and harms. Objective: To provide recommendations for use of red blood cell transfusion in adults and children. Evidence Review: Standards for trustworthy guidelines were followed, including using Grading of Recommendations Assessment, Development and Evaluation methods, managing conflicts of interest, and making values and preferences explicit. Evidence from systematic reviews of randomized controlled trials was reviewed. Findings: For adults, 45 randomized controlled trials with 20 599 participants compared restrictive hemoglobin-based transfusion thresholds, typically 7 to 8 g/dL, with liberal transfusion thresholds of 9 to 10 g/dL. For pediatric patients, 7 randomized controlled trials with 2730 participants compared a variety of restrictive and liberal transfusion thresholds. For most patient populations, results provided moderate quality evidence that restrictive transfusion thresholds did not adversely affect patient-important outcomes. Recommendation 1: for hospitalized adult patients who…

This study assesses the diagnostic accuracy of the Generative Pre-trained Transformer 4 (GPT-4) artificial intelligence (AI) model in a series of challenging cases.

Importance: There is increased interest in and potential benefits from using large language models (LLMs) in medicine. However, by simply wondering how the LLMs and the applications powered by them will reshape medicine instead of getting actively involved, the agency in shaping how these tools can be used in medicine is lost. Observations: Applications powered by LLMs are increasingly used to perform medical tasks without the underlying language model being trained on medical records and without verifying their purported benefit in performing those tasks. Conclusions and Relevance: The creation and use of LLMs in medicine need to be actively shaped by provisioning relevant training data, specifying the desired benefits, and evaluating the benefits via testing in real-world deployments.

Importance: Nonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates. Objective: To emulate the design of 30 completed and 2 ongoing randomized clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters (population, intervention, comparator, outcome, time [PICOT]) and to quantify agreement in RCT-database study pairs. Design, Setting, and Participants: New-user cohort studies with propensity score matching using 3 US claims databases (Optum Clinformatics, MarketScan, and Medicare). Inclusion-exclusion criteria for each database study were prespecified to emulate the corresponding RCT. RCTs were explicitly selected based on feasibility, including power, key confounders, and end points more likely to be emulated with real-world data. All 32 protocols were registered on ClinicalTrials.gov…

Artificial intelligence (AI) technologies to help authors improve the preparation and quality of their manuscripts and published articles are rapidly increasing in number and sophistication.These include tools to assist with writing, grammar, language, references, statistical analysis, and reporting standards.Editors and publishers also use AI-assisted tools for myriad purposes, including to screen submissions for problems (eg, plagiarism, image manipulation, ethical issues), triage submissions, validate references, edit, and code content for publication in different media and to facilitate postpublication search and discoverability. 1 In November 2022, OpenAI released a new open source, natural language processing tool called ChatGPT. 2,3ChatGPT is an evolution of a chatbot that is designed to simulate human conversation in response to prompts or questions (GPT stands for "generative pretrained transformer").The release has prompted immediate excitement about its many potential uses 4 but also trepidation about potential misuse, such as concerns about using the language model to…

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to…

Importance: Bipolar disorder affects approximately 8 million adults in the US and approximately 40 million individuals worldwide. Observations: Bipolar disorder is characterized by recurrent episodes of depression and mania or hypomania. Bipolar depressive episodes are similar to major depressive episodes. Manic and hypomanic episodes are characterized by a distinct change in mood and behavior during discrete time periods. The age of onset is usually between 15 and 25 years, and depression is the most frequent initial presentation. Approximately 75% of symptomatic time consists of depressive episodes or symptoms. Early diagnosis and treatment are associated with a more favorable prognosis. Diagnosis and optimal treatment are often delayed by a mean of approximately 9 years following an initial depressive episode. Long-term treatment consists of mood stabilizers, such as lithium, valproate, and lamotrigine. Antipsychotic agents, such as quetiapine, aripiprazole, asenapine, lurasidone, and cariprazine, are recommended, but some are associated with weight gain. Antidepressants are not…

Importance: Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people. Observations: The most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with…

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any…

Importance: Acute myocarditis, defined as a sudden inflammatory injury to the myocardium, affects approximately 4 to 14 people per 100 000 each year globally and is associated with a mortality rate of approximately 1% to 7%. Observations: The most common causes of myocarditis are viruses, such as influenza and coronavirus; systemic autoimmune disorders, such as systemic lupus erythematosus; drugs, such as immune checkpoint inhibitors; and vaccines, including smallpox and mRNA COVID-19 vaccines. Approximately 82% to 95% of adult patients with acute myocarditis present with chest pain, while 19% to 49% present with dyspnea, and 5% to 7% with syncope. The diagnosis of myocarditis can be suggested by presenting symptoms, elevated biomarkers such as troponins, electrocardiographic changes of ST segments, and echocardiographic wall motion abnormalities or wall thickening. Cardiac magnetic resonance imaging or endomyocardial biopsy are required for definitive diagnosis. Treatment depends on acuity, severity, clinical presentation, and etiology. Approximately 75% of patients admitted with…

This Viewpoint describes medical applications of generative pretrained transformers (GPTs) and related artificial intelligence (AI) technologies and considers whether new forms of regulation are necessary to minimize safety and legal risks to patients and clinicians.

Importance: There has been increasing concern about the burden of mental health problems among youth, especially since the COVID-19 pandemic. Trends in mental health-related emergency department (ED) visits are an important indicator of unmet outpatient mental health needs. Objective: To estimate annual trends in mental health-related ED visits among US children, adolescents, and young adults between 2011 and 2020. Design, Setting, and Participants: Data from 2011 to 2020 in the National Hospital Ambulatory Medical Care Survey, an annual cross-sectional national probability sample survey of EDs, was used to examine mental health-related visits for youths aged 6 to 24 years (unweighted = 49 515). Main Outcomes and Measures: Mental health-related ED visits included visits associated with psychiatric or substance use disorders and were identified by International Classification of Diseases-Ninth Revision, Clinical Modification (ICD-9-CM; 2011-2015) and ICD-10-CM (2016-2020) discharge diagnosis codes or by reason-for-visit (RFV) codes. We estimated the annual proportion of mental…

Importance: Approximately 5% of all primary care visits in adults are related to knee pain. Osteoarthritis (OA), patellofemoral pain, and meniscal tears are among the most common causes of knee pain. Observations: Knee OA, affecting an estimated 654 million people worldwide, is the most likely diagnosis of knee pain in patients aged 45 years or older who present with activity-related knee joint pain with no or less than 30 minutes of morning stiffness (95% sensitivity; 69% specificity). Patellofemoral pain typically affects people younger than 40 years who are physically active and has a lifetime prevalence of approximately 25%. The presence of anterior knee pain during a squat is approximately 91% sensitive and 50% specific for patellofemoral pain. Meniscal tears affect an estimated 12% of the adult population and can occur following acute trauma (eg, twisting injury) in people younger than 40 years. Alternatively, a meniscal tear may be a degenerative condition present in patients with knee OA who are aged 40 years or older. The McMurray test, consisting of concurrent knee…

Importance: Pituitary adenomas are neoplasms of the pituitary adenohypophyseal cell lineage and include functioning tumors, characterized by the secretion of pituitary hormones, and nonfunctioning tumors. Clinically evident pituitary adenomas occur in approximately 1 in 1100 persons. Observations: Pituitary adenomas are classified as either macroadenomas (≥10 mm) (48% of tumors) or microadenomas (<10 mm). Macroadenomas may cause mass effect, such as visual field defects, headache, and/or hypopituitarism, which occur in about 18% to 78%, 17% to 75%, and 34% to 89% of patients, respectively. Thirty percent of pituitary adenomas are nonfunctioning adenomas, which do not produce hormones. Functioning tumors are those that produce an excess of normally produced hormones and include prolactinomas, somatotropinomas, corticotropinomas, and thyrotropinomas, which produce prolactin, growth hormone, corticotropin, and thyrotropin, respectively. Approximately 53% of pituitary adenomas are prolactinomas, which can cause hypogonadism, infertility, and/or galactorrhea. Twelve percent are…

Importance: Cystic fibrosis, a genetic disorder defined by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects more than 30 000 individuals in the US and approximately 89 000 worldwide. Absent or decreased function of the CFTR protein is associated with multiorgan dysfunction and shortened life expectancy. Observations: CFTR is an anion channel in the apical membrane of epithelial cells. Loss of function leads to obstructed exocrine glands. Of people with cystic fibrosis in the US, approximately 85.5% have the gene variant F508del. Manifestations of cystic fibrosis in patients with the F508del gene variant begin in infancy with steatorrhea, poor weight gain, and respiratory symptoms (coughing, wheezing). As people with cystic fibrosis age, chronic respiratory bacterial infections cause loss of lung function and bronchiectasis. With the availability of universal newborn screening in multiple countries including the US, many people with cystic fibrosis are asymptomatic at diagnosis. With multidisciplinary care teams that included dietitians,…

Importance: Menopause, due to loss of ovarian follicular activity without another pathological or physiological cause, typically occurs between the ages of 45 years and 56 years. During the menopausal transition, approximately 50% to 75% of women have hot flashes, night sweats, or both (vasomotor symptoms) and more than 50% have genitourinary symptoms (genitourinary syndrome of menopause [GSM]). Observations: Vasomotor symptoms typically last more than 7 years and GSM is often chronic. Efficacious treatments for women with bothersome vasomotor symptoms or GSM symptoms include hormonal and nonhormonal options. Systemic estrogen alone or combined with a progestogen reduces the frequency of vasomotor symptoms by approximately 75%. Oral and transdermal estrogen have similar efficacy. Conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) were the only hormonal treatments for which clinical trials were designed to examine cardiovascular events, venous thromboembolism, and breast cancer risk. Compared with placebo, the increased risk of stroke and venous…

Importance: Overt hyperthyroidism, defined as suppressed thyrotropin (previously thyroid-stimulating hormone) and high concentration of triiodothyronine (T3) and/or free thyroxine (FT4), affects approximately 0.2% to 1.4% of people worldwide. Subclinical hyperthyroidism, defined as low concentrations of thyrotropin and normal concentrations of T3 and FT4, affects approximately 0.7% to 1.4% of people worldwide. Untreated hyperthyroidism can cause cardiac arrhythmias, heart failure, osteoporosis, and adverse pregnancy outcomes. It may lead to unintentional weight loss and is associated with increased mortality. Observations: The most common cause of hyperthyroidism is Graves disease, with a global prevalence of 2% in women and 0.5% in men. Other causes of hyperthyroidism and thyrotoxicosis include toxic nodules and the thyrotoxic phase of thyroiditis. Common symptoms of thyrotoxicosis include anxiety, insomnia, palpitations, unintentional weight loss, diarrhea, and heat intolerance. Patients with Graves disease may have a diffusely enlarged thyroid gland, stare, or exophthalmos on…

Importance: Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality. Objective: To compare efficacy and comparative efficacy of therapies for alcohol use disorder. Data Sources: PubMed, the Cochrane Library, the Cochrane Central Trials Registry, PsycINFO, CINAHL, and EMBASE were searched from November 2012 to September 9, 2022 Literature was subsequently systematically monitored to identify relevant articles up to August 14, 2023, and the PubMed search was updated on August 14, 2023. Study Selection: For efficacy outcomes, randomized clinical trials of at least 12 weeks' duration were included. For adverse effects, randomized clinical trials and prospective cohort studies that compared drug therapies and reported health outcomes or harms were included. Data Extraction and Synthesis: Two reviewers evaluated each study, assessed risk of bias, and graded strength of evidence. Meta-analyses used random-effects models. Numbers needed to treat were calculated for medications with at least moderate…

Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. Design, Setting, and Participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease…

Importance: Major depressive disorder (MDD), a common mental disorder in the US, may have substantial impact on the lives of affected individuals. If left untreated, MDD can interfere with daily functioning and can also be associated with an increased risk of cardiovascular events, exacerbation of comorbid conditions, or increased mortality. Objective: The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate benefits and harms of screening, accuracy of screening, and benefits and harms of treatment of MDD and suicide risk in asymptomatic adults that would be applicable to primary care settings. Population: Asymptomatic adults 19 years or older, including pregnant and postpartum persons. Older adults are defined as those 65 years or older. Evidence Assessment: The USPSTF concludes with moderate certainty that screening for MDD in adults, including pregnant and postpartum persons and older adults, has a moderate net benefit. The USPSTF concludes that the evidence is insufficient on the benefit and harms of screening for suicide risk in adults,…

Importance: Health inequities exist for racial and ethnic minorities and persons with lower educational attainment due to differential exposure to economic, social, structural, and environmental health risks and limited access to health care. Objective: To estimate the economic burden of health inequities for racial and ethnic minority populations (American Indian and Alaska Native, Asian, Black, Latino, and Native Hawaiian and Other Pacific Islander) and adults 25 years and older with less than a 4-year college degree in the US. Outcomes include the sum of excess medical care expenditures, lost labor market productivity, and the value of excess premature death (younger than 78 years) by race and ethnicity and the highest level of educational attainment compared with health equity goals. Evidence Review: Analysis of 2016-2019 data from the Medical Expenditure Panel Survey (MEPS) and state-level Behavioral Risk Factor Surveillance System (BRFSS) and 2016-2018 mortality data from the National Vital Statistics System and 2018 IPUMS American Community Survey. There were 87 855 survey…

Importance: For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined. Objective: To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer. Design, Setting, and Participants: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022). Interventions: Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days. Main Outcomes and Measures: The primary end point, overall survival, was tested first in participants with left-sided tumors,…

Importance: Declines in cardiovascular mortality have stagnated in the US over the past decade, in part related to worsening risk factor control in older adults. Little is known about how the prevalence, treatment, and control of cardiovascular risk factors have changed among young adults aged 20 to 44 years. Objective: To determine if the prevalence of cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, obesity, and tobacco use), treatment rates, and control changed among adults aged 20 to 44 years from 2009 through March 2020, overall and by sex and race and ethnicity. Design, Setting, and Participants: Serial cross-sectional analysis of adults aged 20 to 44 years in the US participating in the National Health and Nutrition Examination Survey (2009-2010 to 2017-March 2020). Main Outcomes and Measures: National trends in the prevalence of hypertension, diabetes, hyperlipidemia, obesity, and smoking history; treatment rates for hypertension and diabetes; and blood pressure and glycemic control in those receiving treatment. Results: Among 12 924 US adults aged 20 to…

Importance: Cushing syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology. Although the most frequent cause of Cushing syndrome is exogenous steroid use, the estimated incidence of Cushing syndrome due to endogenous overproduction of cortisol ranges from 2 to 8 per million people annually. Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders. Observations: Cushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae and with metabolic manifestations such as hyperglycemia, hypertension, and excess fat deposition in the face, back of the neck, and visceral organs. Cushing disease, in which corticotropin excess is produced by a benign pituitary tumor, occurs in approximately 60% to 70% of patients with Cushing syndrome due to endogenous cortisol production. Evaluation of patients with possible Cushing syndrome begins with ruling out exogenous steroid use.…

Importance: Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome. Objective: To test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement. Design, Setting, and Participants: This case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity. Exposure: Prior to treatment with CD19-targeting CAR T cells, the…

Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group. Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration,…

This Medical News feature discusses how implementation science seeks to narrow the often yearslong gap between the development of evidence-based practices and their routine use in the real world.

Importance: VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. Objective: To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach. Design, Setting, and Participants: This retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022. Exposures: Exome sequencing was performed. Main Outcomes and Measures: Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic,…

Importance: Chronic lymphocytic leukemia (CLL), defined by a minimum of 5 × 109/L monoclonal B cells in the blood, affects more than 200 000 people and is associated with approximately 4410 deaths in the US annually. CLL is associated with an immunocompromised state and an increased rate of complications from infections. Observations: At the time of diagnosis, the median age of patients with CLL is 70 years, and an estimated 95% of patients have at least 1 medical comorbidity. Approximately 70% to 80% of patients with CLL are asymptomatic at the time of diagnosis, and one-third will never require treatment for CLL. Prognostic models have been developed to estimate the time to first treatment and the overall survival, but for patients who are asymptomatic, irrespective of disease risk category, clinical observation is the standard of care. Patients with symptomatic disease who have bulky or progressive lymphadenopathy or hepatosplenomegaly and those with a low neutrophil count, anemia, or thrombocytopenia and/or symptoms of fever, drenching night sweats, and weight loss (B symptoms)…

Importance: Artificial intelligence (AI) could support clinicians when diagnosing hospitalized patients; however, systematic bias in AI models could worsen clinician diagnostic accuracy. Recent regulatory guidance has called for AI models to include explanations to mitigate errors made by models, but the effectiveness of this strategy has not been established. Objectives: To evaluate the impact of systematically biased AI on clinician diagnostic accuracy and to determine if image-based AI model explanations can mitigate model errors. Design, Setting, and Participants: Randomized clinical vignette survey study administered between April 2022 and January 2023 across 13 US states involving hospitalist physicians, nurse practitioners, and physician assistants. Interventions: Clinicians were shown 9 clinical vignettes of patients hospitalized with acute respiratory failure, including their presenting symptoms, physical examination, laboratory results, and chest radiographs. Clinicians were then asked to determine the likelihood of pneumonia, heart failure, or chronic obstructive…

Importance: Epidemiological and genetic data have implicated lipoprotein(a) as a potentially modifiable risk factor for atherosclerotic disease and aortic stenosis, but there are no approved pharmacological treatments. Objectives: To assess the safety, tolerability, pharmacokinetics, and effects of lepodisiran on lipoprotein(a) concentrations after single doses of the drug; lepodisiran is a short interfering RNA directed at hepatic synthesis of apolipoprotein(a), an essential component necessary for assembly of lipoprotein(a) particles. Design, Setting, and Participants: A single ascending-dose trial conducted at 5 clinical research sites in the US and Singapore that enrolled 48 adults without cardiovascular disease and with lipoprotein(a) serum concentrations of 75 nmol/L or greater (or ≥30 mg/dL) between November 18, 2020, and December 7, 2021; the last follow-up visit occurred on November 9, 2022. Interventions: Participants were randomized to receive placebo or a single dose of lepodisiran (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, or 608 mg) administered subcutaneously. Main Outcomes…

Importance: Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. Objective: To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022. Interventions: Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based…

Importance: Airway mucus plugs are common in patients with chronic obstructive pulmonary disease (COPD); however, the association of airway mucus plugging and mortality in patients with COPD is unknown. Objective: To determine whether airway mucus plugs identified on chest computed tomography (CT) were associated with increased all-cause mortality. Design, Setting, and Participants: Observational retrospective analysis of prospectively collected data of patients with a diagnosis of COPD in the Genetic Epidemiology of COPD cohort. Participants were non-Hispanic Black or White individuals, aged 45 to 80 years, who smoked at least 10 pack-years. Participants were enrolled at 21 centers across the US between November 2007 and April 2011 and were followed up through August 31, 2022. Exposures: Mucus plugs that completely occluded airways on chest CT scans, identified in medium- to large-sized airways (ie, approximately 2- to 10-mm lumen diameter) and categorized as affecting 0, 1 to 2, or 3 or more lung segments. Main Outcomes and Measures: The primary outcome was all-cause mortality,…

Importance: Early onset of myopia is associated with high myopia later in life, and myopia is irreversible once developed. Objective: To evaluate the efficacy of low-concentration atropine eyedrops at 0.05% and 0.01% concentration for delaying the onset of myopia. Design, Setting, and Participants: This randomized, placebo-controlled, double-masked trial conducted at the Chinese University of Hong Kong Eye Centre enrolled 474 nonmyopic children aged 4 through 9 years with cycloplegic spherical equivalent between +1.00 D to 0.00 D and astigmatism less than -1.00 D. The first recruited participant started treatment on July 11, 2017, and the last participant was enrolled on June 4, 2020; the date of the final follow-up session was June 4, 2022. Interventions: Participants were assigned at random to the 0.05% atropine (n = 160), 0.01% atropine (n = 159), and placebo (n = 155) groups and had eyedrops applied once nightly in both eyes over 2 years. Main Outcomes and Measures: The primary outcomes were the 2-year cumulative incidence rate of myopia (cycloplegic spherical equivalent of at…