Glucagon-like peptide-1 (GLP-1) receptor agonists are incretin analogues that promote glucose-mediated insulin release and are used to treat type 2 diabetes mellitus and obesity. GLP-1 receptor agonists and GLP-1 and glucose-dependent insulinotropic peptide agonists have several mechanisms of action, including reduction of gastric emptying, inhibition of glucagon secretion, beneficial changes in the intestinal microbiome, and direct effects on hypothalamic nuclei to enhance satiety (which promotes weight loss). Beyond the impressive effects of GLP-1 receptor agonists on blood glucose levels and body weight, large-scale randomized, controlled trials have shown that GLP-1 receptor agonists reduce cardiovascular risk and slow progression to renal failure in persons at high risk and those with type 2 diabetes. Adverse side effects from GLP-1 receptor agonists are mostly gastrointestinal but may also include loss of muscle and bone mass. Questions remain about long-term adherence, weight regain after discontinuation of treatment, and the functional implications of the loss of muscle and bone mass. Recent and ongoing targeted studies suggest the possibility of additional uses for GLP-1 receptor agonists.

Minipuberty refers to a specific period in early postnatal life with high activity of the hypothalamic-pituitary-gonadal (HPG) hormone axis. In infant boys 1 to 3 months of age, high concentrations of follicle-stimulating hormone and luteinizing hormone are released, which results in high levels of gonadal hormones from testicular Leydig cells (testosterone and insulin-like 3) and Sertoli cells (inhibin B and antimüllerian hormone). The HPG axis is also active in infant girls, who have adult levels of follicle-stimulating hormone and luteinizing hormone during this period. Immediately after minipuberty, the HPG axis is silenced for approximately 10 years and is reactivated only with the onset of puberty. Thus, minipuberty represents an early window for diagnosing disorders of sexual differentiation and rare endocrine disorders, such as congenital hypogonadotropic hypogonadism, and may help guide dosing of therapeutic interventions including gonadotropin therapy. Of note, minipuberty predicts adult reproductive capacity.

Investigations of the genetic basis of coronary artery disease have led to advances in mechanistic insights, therapeutics, prevention, and risk prediction. Indeed, most contemporary medicines for coronary artery disease target pathways that promote atherosclerosis due to underpinning genetic mechanisms. Monogenic causes of coronary artery disease occur in approximately 1 out of 250 people and mostly result in massively elevated lipid levels. At the population level, hundreds of common variants with small effect sizes have even greater influence. They can be combined in polygenic risk scores that depict genetic risk in a person relative to the average in the general population. The risk among persons in the highest 5% is 3 to 5 times that among persons with an average score; relative risk derived from the polygenic risk score can be used to multiply the absolute risk derived from a clinical risk score. Key questions remain regarding the clinical value, cost-effectiveness, and implementation strategies required to integrate coronary artery disease polygenic risk scores into clinical practice.

Polymyalgia rheumatica is an inflammatory condition that affects persons older than 50 years of age and is characterized by pain in both shoulders with or without hip or neck pain (or both) and with pronounced morning stiffness. The condition is typically diagnosed on the basis of these hallmark symptoms along with elevated inflammation markers (erythrocyte sedimentation rate and C-reactive protein level) and the ruling out of other conditions including giant-cell arteritis. Glucocorticoids are the primary treatment, which provide rapid symptom relief. The initial dose, usually 12.5 to 25 mg of prednisone equivalent daily, is gradually reduced, ideally over 12 months or less, although the disease course varies and polymyalgia rheumatica may persist for a longer duration. Relapses are common and sometimes warrant the use of interleukin-6 receptor inhibitors or methotrexate to minimize glucocorticoid exposure.

Radiotherapy is a key foundation of oncologic treatment that is used across the spectrum of cancer indications. Advances in imaging, treatment planning, and dose delivery have led to increasingly conformal and even ablative treatments, which have resulted in improved tumor control with no increase in the risk of side effects (or with a decrease in risk) as compared with previous treatments. These advances have facilitated the combined use of radiotherapy with efficacious systemic therapies, including targeted treatments and immunotherapies. Radiation-induced changes in normal tissue occur as a result of stem-cell senescence, inflammation, vascular changes, fibroblast activation, and loss of parenchymal cells. Research into the biologic underpinnings of radiation-induced changes in normal tissue, biomarkers of side effects of various irradiation regimens, and new treatment methods offers great promise for further increasing the efficacy of radiotherapy and improving the side-effect profile through personalized approaches.

Group B streptococcus commonly colonizes the human gastrointestinal and genitourinary tracts and is the single most common bacterial cause of invasive infection among newborns in the United States. Intrapartum antibiotic prophylaxis is currently used to reduce the risk of group B streptococcal disease among pregnant persons and newborns. No strategies are currently available to prevent disease in later infancy or among nonpregnant adults. Vaccines against group B streptococcal disease that consist of capsular polysaccharides linked to protein antigens are in development and may provide a means of prevention for all at-risk populations.

The risk of recurrent ischemic stroke can be reduced by managing modifiable risk factors and instituting a regimen of mechanism-specific secondary stroke prevention. Strategies for secondary prevention should be instituted as early as possible. Poststroke monitoring of risk metrics, lifestyle behaviors, and medication recommendations is of key importance.

Mucormycosis is a rapidly progressive, invasive fungal infection that affects patients who are severely immunocompromised, as well as patients with diabetes and persons with immunocompetence who have major trauma. Mucormycosis manifests in several clinical forms, including sino-orbital, rhinocerebral, sinopulmonary, gastrointestinal, cutaneous, musculoskeletal, osteoarticular, and disseminated mucormycosis, as well as single-organ disease. Although mucormycosis is often lethal, early intervention reduces mortality. Successful treatment depends on early detection and staging of the disease, timely initiation of antifungal therapy, surgical resection of infected tissue, reversal of immunodeficiencies, and correction of metabolic abnormalities. Liposomal amphotericin B is the preferred agent for initial antifungal therapy, with oral triazoles as alternative agents. Research on rapid molecular diagnostic strategies, new antifungal agents, host-directed immune augmentation, antivirulence immune therapeutics, and risk-based stratification to inform management of disease may substantially improve outcomes in patients with this highly destructive mycosis.

Peripheral artery disease affects approximately 236 million persons worldwide and is diagnosed with an ankle-brachial index of less than 0.90. Among older persons, 3.3% of those without peripheral artery disease, 18.1% with mild disease, and 52.0% with severe disease could not complete a 6-minute walk test without resting. To prevent cardiovascular events in persons with peripheral artery disease, intensive cholesterol-lowering medications (statins), antiplatelet medications or low-dose aspirin with rivaroxaban, blood-pressure lowering to less than 130/80 mm Hg, and semaglutide are recommended, along with sodium-glucose cotransporter 2 inhibitors in patients with diabetes. Supervised walking exercise and structured home-based walking exercise each improve walking ability in persons with peripheral artery disease. Revascularization in the legs should be reserved for those with persistent disease symptoms that do not respond to exercise.

Cardiac physiologic pacing, also known as cardiac resynchronization therapy, is indicated in patients with heart failure, reduced left ventricular ejection fraction (LVEF) of 50% or less, and either a high (or anticipated high) ventricular pacing burden or a wide QRS complex. Traditionally, physiologic pacing has been achieved with biventricular pacing with a right ventricular lead and a coronary sinus branch lead. Randomized trials involving more than 10,000 patients with heart failure have shown clinical, exercise, and quality-of-life benefits associated with biventricular pacing, as well as improved LVEF and reduced mitral regurgitation and ventricular volumes. These benefits are greatest in patients with left bundle-branch block and a QRS duration of 150 msec or longer. Recent studies support targeting the His bundle or left bundle branch as an alternative cardiac physiologic pacing strategy. Ongoing randomized trials are expected to more clearly define the comparative efficacy and safety of conduction system pacing as compared with biventricular pacing.

The incidence of sudden cardiac arrest in athletes varies according to age, race and ethnic group, sex, sport, and social determinants of health. The common causes of sudden cardiac arrest include cardiomyopathies, electrical disorders, coronary-artery anomalies, and other cardiac structural abnormalities. There has not been an increase in the incidence of sudden cardiac arrest in athletes during the time frame of the coronavirus disease 2019 (Covid-19) pandemic. Primary prevention is based on cardiovascular screening before participation, and secondary prevention on implementation of emergency action plans. Diagnostic evaluation of athletes who survive sudden cardiac arrest should mirror that of age-matched nonathletes, with additional sport-specific considerations, and should be performed by medical professionals with expertise in the interpretation of test results in the context of athletic adaptation. An increasing body of evidence indicates that many athletes can return to play after disease-specific treatment, without an increase in risk, and professional societies now consider return to participation in sports to be reasonable or appropriate through shared decision making for numerous cardiac conditions.

Functional dyspepsia is a common but serious medical syndrome that can induce weight loss and food aversion and may be associated with increased risks of hospitalization and death. It probably comprises several different and as yet incompletely characterized disorders. Patients with local mucosal microinflammation driven by an aberrant Th2 response may represent an important subgroup. There is overlap with other gastrointestinal syndromes, particularly irritable bowel syndrome and gastroesophageal reflux disease, and patients with overlap have more severe symptoms. There is no approved drug for functional dyspepsia. Treatment is empirical and directed at symptoms and consists of acid suppressants and low-dose tricyclic antidepressants (and other neuromodulators) along with appropriate nutritional and psychological support.

Cardiogenic shock is characterized by depression of cardiac function that leads to low blood pressure, coronary ischemia, and further decreased cardiac contractility resulting in tissue hypoxemia. The condition is associated with high early mortality, approaching 50%, which is largely influenced by the underlying etiologic factors. In infarct-related cardiogenic shock, rapid restoration of coronary blood flow substantially reduces mortality. Mechanical circulatory support devices offer hemodynamic stabilization and improved outcomes in carefully selected patients, although optimal patient selection and timing of initiation of mechanical circulatory support remain areas of active investigation. Although there have been advances in coronary revascularization techniques and mechanical circulatory support devices, overall survival in cardiogenic shock has improved only modestly. Therefore, future research should focus on refining treatment algorithms, optimizing device use, and developing new strategies to address the high mortality associated with cardiogenic shock.

The benefit of beta-blockers after myocardial infarction in patients with a preserved left ventricular ejection fraction (LVEF) is unclear.