Concomitant use of oral organic nitrates (nitrates) and phosphodiesterase type 5 (PDE5) inhibitors is contraindicated.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder associated with increased risk for fractures, cardiovascular disease, kidney disease, and cancer and increased mortality. In mild PHPT with modest hypercalcemia and without known morbidities, parathyroidectomy (PTX) is debated because no long-term randomized trials have been performed.

Genomic tests expand diagnostic and screening opportunities but also identify genetic variants of uncertain clinical significance (VUSs). Only a minority of VUSs are likely to prove pathogenic when later reassessed, but resolution of the uncertainty is rarely timely. That uncertainty adds complexity to clinical decision making and can result in harms and costs to patients and the health care system, including the time-consuming analysis required to interpret a VUS and the potential for unnecessary treatment and adverse psychological effects. Current efforts to improve variant interpretation will help reduce the scope of the problem, but the high prevalence of rare and novel variants in the human genome points to VUSs as an ongoing challenge. Additional strategies can help mitigate the potential harms of VUSs, including testing protocols that limit identification or reporting of VUSs, subclassification of VUSs according to the likelihood of pathogenicity, routine family-based evaluation of variants, and enhanced counseling efforts. All involve tradeoffs, and the appropriate balance of measures is likely to vary for different test uses and clinical settings. Cross-specialty deliberation and public input could contribute to systematic and broadly supported policies for managing VUSs.

Community-acquired pneumonia is an important cause of morbidity and mortality. It can be caused by bacteria, viruses, or fungi and can be prevented through vaccination with pneumococcal, influenza, and COVID-19 vaccines. Diagnosis requires suggestive history and physical findings in conjunction with radiographic evidence of infiltrates. Laboratory testing can help guide therapy. Important issues in treatment include choosing the proper venue, timely initiation of the appropriate antibiotic or antiviral, appropriate respiratory support, deescalation after negative culture results, switching to oral therapy, and short treatment duration.

Sickle cell disease is prevalent in large numbers of patients in the United States and has a significant global impact. Its complications span numerous organs and lead to reduced life expectancy. Acute and chronic sickle cell pain is a common cause of patient suffering. The American Society of Hematology published updated guidelines on management of acute and chronic pain from sickle cell disease in 2019. Several of the recommendations are conditional and leave specific decisions to the treating physician. These include conditional recommendations about the use of ketamine for acute pain and the initiation and discontinuation of long-term opioid therapy for chronic pain. Here, 2 hematologists discuss these guidelines and make contrasting recommendations for the management of acute and chronic pain for a patient with sickle cell disease.

Randomized controlled trials established the cardiac protection of sodium-glucose cotransporter-2 (SGLT2) inhibitors among adults with type 2 diabetes. New evidence suggests that these results could extend to people without diabetes.

On 8 December 2021, the U.S. Food and Drug Administration issued an emergency use authorization for AstraZeneca's Evusheld (tixagevimab copackaged with cilgavimab, administered as concomitant injections) for the prevention of COVID-19 in those who are moderately to severely compromised, are aged 12 years or older, and weigh more than 40 kg. This commentary discusses current appropriate use of this important preventive intervention.

Roaldsen MB, Lindekleiv H, Mathiesen EB. Intravenous thrombolytic treatment and endovascular thrombectomy for ischaemic wake-up stroke. Cochrane Database Syst Rev. 2021;12:CD010995. 34850380.

Ospina-Tascón GA, Calderón-Tapia LE, García AF, et al. Effect of high-flow oxygen therapy vs conventional oxygen therapy on invasive mechanical ventilation and clinical recovery in patients with severe COVID-19: a randomized clinical trial. JAMA. 2021;326:2161-71. 34874419.

Freund Y, Chauvin A, Jimenez S, et al. Effect of a diagnostic strategy using an elevated and age-adjusted D-dimer threshold on thromboembolic events in emergency department patients with suspected pulmonary embolism: a randomized clinical trial. JAMA. 2021;326:2141-9. 34874418.