NEJM evidence最新文献

Background: More individuals work early-morning shifts than night shifts, yet investigations into the treatment of shift work disorder (SWD) in this population are lacking.

Methods: This randomized, double-blind, placebo-controlled trial evaluated the efficacy of solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor, for treating excessive sleepiness in 78 early-morning shift workers (shift starting between 3 and 7 a.m.) with excessive sleepiness associated with SWD. The primary outcome was change in objective sleepiness, as measured by sleep latency on the Maintenance of Wakefulness Test (longer latency reflects less sleepiness). Secondary outcomes included subjective sleepiness measured by the Karolinska Sleepiness Scale (range 1-9, with higher values indicating greater sleepiness) as well as clinician- and patient-assessed change in clinical condition, using the Clinical Global Impression of Change and Patient Global Impression of Change questionnaires (scores range from 1-7 for both scales, but higher scores indicate worse condition for the clinical scale and improved condition for the patient scale).

Results: After 4 weeks, patients treated with solriamfetol were significantly less sleepy than those treated with placebo (9.4-minute longer sleep latency; 95% confidence interval [CI], 5.7 to 13.0; P<0.001). Solriamfetol treatment was associated with changed subjective sleepiness (Karolinska Sleepiness Scale difference, -1.2; 95% CI, -1.7 to -0.7), and changed clinician (odds ratio 3.7; 95% CI, 1.3 to 10.4) and patient (odds ratio, 4.2; 95% CI, 1.5 to 11.6) ratings. Overall, 55% of patients who received any treatment with solriamfetol and 63% of patients receiving placebo reported any adverse event; the most common adverse events were headache and nausea.

Conclusions: In this randomized trial of a treatment for excessive sleepiness in early-morning shift workers with SWD, solriamfetol significantly improved sleepiness compared with placebo. (Funded by Axsome Therapeutics and others; ClinicalTrials.gov number, NCT04788953.).

Background: Antenatal treatment with nipocalimab, a neonatal Fc receptor (FcRn) blocker, delayed or prevented fetal anemia, as compared with a historical benchmark, in a phase 2 study of early-onset severe hemolytic disease of the fetus and newborn (HDFN). We report on the fetal and neonatal pharmacokinetics of nipocalimab and infant immunity through 96 weeks after birth.

Methods: The UNITY study was a single-group, open-label study assessing pregnant individuals at high risk of early-onset severe HDFN treated with weekly intravenous nipocalimab (30 or 45 mg/kg) from 14 to 35 weeks' gestation, unless discontinued for safety-related stopping criteria or intrauterine transfusion initiation. Pharmacokinetics were assessed in maternal, fetal, and infant blood and colostrum or breast milk; FcRn receptor occupancy and immunoglobulin G (IgG) were measured in neonatal and maternal blood; and infant IgG and safety were monitored through 96 weeks after birth.

Results: Safety analysis included 12 live-born infants from 13 pregnancies (one fetal loss occurred following intrauterine transfusion complications). Nipocalimab concentrations were maintained in maternal participants at pharmacologically active concentrations (greater than 10 μg/ml) during the weekly dosing intervals, but were observed at low concentrations (10 μg/ml or less) in one of four fetal cordocenteses (0.04 μg/ml), one of 11 cord blood samples (0.7 μg/ml), three of seven colostrum samples (less than 4 μg/ml), and two of nine breast milk samples (less than 2 μg/ml). Low infant IgG at birth (cord blood median, 175 mg/dl; range, 92-941) reached levels consistent with a physiologic nadir by 24 weeks after birth (median, 273 mg/dl; range, 153-429) and recovered to normal range (with one exception) between 16 and 96 weeks (median, 762 mg/dl; range, 407-925). Infectious adverse events were primarily mild to moderate and typical for early childhood. Protective titers to age-appropriate vaccinations (diphtheria and tetanus) were observed in six of seven infants at or before 96 weeks.

Conclusions: In this cohort of 12 live-born infants, antenatal treatment with nipocalimab resulted in low levels of detectable drug in fetal, neonatal, and infant samples. Treatment was associated with low IgG levels at birth; however, unusual or unexpected childhood illnesses or impaired vaccine responses were not observed. (Funded by Johnson & Johnson; ClinicalTrials.gov number, NCT03842189.).

AbstractMorning Report is a time-honored tradition where physicians-in-training present cases to their colleagues and clinical experts to collaboratively examine an interesting patient presentation. The Morning Report section seeks to carry on this tradition by presenting a patient's chief concern and story, inviting the reader to develop a differential diagnosis and discover the diagnosis alongside the authors of the case. This report discusses the story of a 44-year-old man who sought evaluation for back pain and weakness. Using questions, physical examination, and testing, an illness script for the presentation emerges. As the clinical course progresses, the differential is refined until a final diagnosis is made.

AbstractAlthough evidence-based therapies for patients with heart failure (HF) have decreased all-cause mortality, the residual risk of other clinically relevant outcomes - such as worsening HF - remains high. In this context, contemporary HF trials have increasingly employed composite primary outcomes that include worsening HF, commonly defined as episodes resulting in hospitalization for HF or urgent ambulatory visits with use of intravenous HF pharmacotherapies. In this Clinical Trials Workshop, we propose that the definition of worsening HF in clinical trials be expanded to include HF episodes treated with ambulatory oral diuretic intensification (ODI). Using previously reported post hoc analyses of pharmacotherapy trials in chronic HF, we highlight the prognostic significance of ODI and examine the implications of including ODI on anticipated event rates and estimated treatment effect. We propose a standardized definition of ODI and discuss challenges and regulatory considerations of incorporating ODI into HF trial end points.

Background: We previously demonstrated that sputum total mucin concentration is an objective marker for chronic bronchitis (CB). This current study introduces a novel Mucin Quantitative Score (MUCQ) that combines total mucin concentration and mucin composition to improve the assessment of risk, onset of clinically diagnosed disease, and progression of muco-obstructive lung diseases.

Methods: Patients from the SPIROMICS (SubPopulations and InteRmediate Outcome Measures in COPD Study) cohort were classified as having CB, or not, based on clinical questionnaires. Using the measured total mucin, MUC5AC, and MUC5B concentrations in sputum samples, we calculated MUCQ as [Total mucin]×([MUC5AC]÷[MUC5B])÷100 μg/ml, which is a unitless, weighted concentration score. Our primary outcome was the net reclassification of patients with a diagnosis of CB, or not, based on total mucin concentrations in their sputum compared with using the MUCQ score. Participants were first classified as CB- positive or -negative using a total mucin concentration threshold of 2306 μg/ml, then reclassified using the MUCQ threshold of 4.30. Associated z statistics and a P value for the primary outcome are reported.

Results: Among 164 patients in the SPIROMICS cohort with clinically defined CB, using the MUCQ score up-classified 18 patients who were currently smoking to a diagnosis of CB and down-classified 5 patients who were currently smoking and 3 control participants who had never smoked, compared with the classification of CB was based on total mucin concentrations alone (P=0.001). In addition, MUCQ correlated with other clinical and pathological indices of chronic airway disease and airway obstruction.

Conclusions: The MUCQ metric was superior in distinguishing patients with CB compared to a total mucin concentration. Trials are needed to ascertain the prospective use of MUCQ metrics in research and clinical settings for assessment, management, and tracking therapeutic responses in CB and potentially other muco-obstructive conditions. (Funded by the National Institutes of Health and others.).

AbstractA clade Ib mpox virus (MPXV) outbreak in Central and Eastern Africa has led to multiple travel-associated infections. In October 2025, clade Ib MPXV infection was confirmed in three unvaccinated, hospitalized men in California reporting no international travel. Phylogenetic analysis revealed clustering of these three MPXV infections with one recent travel-associated MPXV infection. This report provides evidence for local transmission of clade Ib MPXV in the Americas, occurring among gay, bisexual, and other men who have sex with men and their social networks.