Search

BACKGROUND: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously. METHODS: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII. RESULTS: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P

Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain.In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion.Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

Hard to Swallow A previously healthy 20-year-old college student presented before the Covid-19 pandemic with a 3-day history of throat pain, malaise, cough, and chills. She had no congestion or rhi...

Missing the Target A 58-year-old man presented to the emergency department with a 2-week history of pelvic pain on the left side, with subsequent development of severe pain in the abdomen, lower ba...

E-Cigarettes and the Harm-Reduction Continuum In recent years, there has been a trend of acknowledging the importance of a harm-reduction approach in policy discussions about e-cigarettes. But some...

A 32-year-old woman presented to her physician with a 3-week history of spontaneous bruising on her arms, legs, and back. The bruising began shortly after she had had sore throat, coryza, and malaise for several days, symptoms that had resolved without intervention.

A 47-year-old man presented to an urgent care ambulatory clinic with a 3-day history of swelling around his left eye and a sensation of tightness in his throat. It had become difficult for him to swallow solids, and he felt as though food was sticking in his throat.

A 52-year-old man presented to the emergency department with general weakness and swelling in his legs. Symmetric swelling had begun 4 weeks earlier and had progressed to the point that it was difficult for him to wear shoes.

A Shocking Turn of Events This interactive case features a 38-year-old woman with symptoms of an upper respiratory infection, shortness of breath, and palpitations. An ECG showed abnormal findings. Test your diagnostic and therapeutic skills at NEJM.org.

A 67-year-old man presented with a 3-day history of chest tightness, wheezing, coughing, and dyspnea. He had a history of asthma but had not had major exacerbations for 20 years. He did not have fever, sputum production, hemoptysis, orthopnea, or edema.

A 27-year-old primigravid woman at 25 weeks 5 days of gestation presented to the emergency department in respiratory distress. One day earlier, a cough producing blood-tinged, frothy sputum had developed and worsened. She also noted shortness of breath and chest pain.

This interactive feature presents the case of a 41-year-old man who presented to the emergency department with excruciating abdominal pain of sudden onset. Test your diagnostic and therapeutic skills at NEJM.org.

A Disturbing Decline A 29-year-old woman with a history of systemic lupus erythematosus presented with diarrhea that had been ongoing for several days and had initially been accompanied by nausea a...

A 35-year-old man presented to the emergency department after having an episode of syncope while playing soccer. Loss of consciousness, which lasted only seconds, was preceded by a brief period of lightheadedness. The patient reported no nausea, diaphoresis, chest pain, or dyspnea.

A 65-year-old man presented with a 4-month history of fevers, sweats, fatigue, and weakness. He also reported that pain in his feet and calves was sufficiently distracting that he could not enjoy reading.

A 52-year-old man presented to the emergency department with an acute onset of palpitations and chest pressure. He had felt well until 2 days earlier, when epigastric burning, fatigue, weakness, and emesis had developed.

Raw produce is an increasingly recognized vehicle for salmonellosis. We investigated a nationwide outbreak that occurred in the United States in 2008.We defined a case as diarrhea in a person with laboratory-confirmed infection with the outbreak strain of Salmonella enterica serotype Saintpaul. Epidemiologic, traceback, and environmental studies were conducted.Among the 1500 case subjects, 21% were hospitalized, and 2 died. In three case-control studies of cases not linked to restaurant clusters, illness was significantly associated with eating raw tomatoes (matched odds ratio, 5.6; 95% confidence interval [CI], 1.6 to 30.3); eating at a Mexican-style restaurant (matched odds ratio, 4.6; 95% CI, 2.1 to ∞) and eating pico de gallo salsa (matched odds ratio, 4.0; 95% CI, 1.5 to 17.8), corn tortillas (matched odds ratio, 2.3; 95% CI, 1.2 to 5.0), or salsa (matched odds ratio, 2.1; 95% CI, 1.1 to 3.9); and having a raw jalapeño pepper in the household (matched odds ratio, 2.9; 95% CI, 1.2 to 7.6). In nine analyses of clusters associated with restaurants or events, jalapeño peppers were implicated in all three clusters with implicated ingredients, and jalapeño or serrano peppers were an ingredient in an implicated item in the other three clusters. Raw tomatoes were an ingredient in an implicated item in three clusters. The outbreak strain was identified in jalapeño peppers collected in Texas and in agricultural water and serrano peppers on a Mexican farm. Tomato tracebacks did not converge on a source.Although an epidemiologic association with raw tomatoes was identified early in this investigation, subsequent epidemiologic and microbiologic evidence implicated jalapeño and serrano peppers. This outbreak highlights the importance of preventing raw-produce contamination.

An 18-year-old black woman presented with fever, ear pain, and dull discomfort on the right side of the chest that was unchanged with movement or inspiration. She had no other symptoms and had previously been well, aside from mild exercise-induced asthma. Chest radiography was performed, and the images showed air-space opacities in the base of the right lung and the perihilar region of the left lung.

A 73-year-old man presented with a history of progressive, symmetric edema that began in the lower extremities and extended to involve his thighs, scrotum, and arms. He had dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea, as well as chest pressure on mild exertion.

BACKGROUND Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot–Marie–Tooth disease. METHODS We identified a family with a recessive form of Charcot–Marie–Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members. RESULTS We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot–Marie–Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome. CONCLUSIONS As shown in this study of a family with Charcot–Marie–Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.

Functional decline in physically frail, elderly persons is associated with substantial morbidity. It is uncertain whether such functional decline can be prevented.We randomly assigned 188 persons 75 years of age or older who were physically frail and living at home to undergo a six-month, home-based intervention program that included physical therapy and that focused primarily on improving underlying impairments in physical abilities, including balance, muscle strength, ability to transfer from one position to another, and mobility, or to undergo an educational program (as a control). The primary outcome was the change between base line and 3, 7, and 12 months in the score on a disability scale based on eight activities of daily living: walking, bathing, upper- and lower-body dressing, transferring from a chair, using the toilet, eating, and grooming. Scores on the scale ranged from 0 to 16, with higher scores indicating more severe disability.Participants in the intervention group had less functional decline over time, according to their disability scores, than participants in the control group. The disability scores in the intervention and control groups were 2.3 and 2.8, respectively, at base line; 2.0 and 3.6 at 7 months (P=0.008 for the comparison between the groups in the change from base line); and 2.7 and 4.2 at 12 months (P=0.02). The benefit of the intervention was observed among participants with moderate frailty but not those with severe frailty. The frequency of admission to a nursing home did not differ significantly between the intervention group and the control group (14 percent and 19 percent, respectively; P=0.37).A home-based program targeting underlying impairments in physical abilities can reduce the progression of functional decline among physically frail, elderly persons who live at home.

This interactive feature presents a 43-year-old man who presented to the emergency department with abrupt onset of abdominal pain. Test your diagnostic and therapeutic skills at NEJM.org.