NEJM evidence最新文献

AbstractPacemakers are critical in the management of bradyarrhythmias. The authors review pacemaker fundamentals, indications, and device types, as well as the role of pacemakers in heart failure, emerging advancements, and current limitations.

AbstractMorning Report is a time-honored tradition in which physicians-in-training present cases to their colleagues and clinical experts to collaboratively explore a patient's 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 this case. This report examines the story of a 29-year-old woman who presented to the emergency department with jaundice and oral mucosal bleeding, 2 days after delivering an infant at home at 36 weeks and 2 days of gestation. Using targeted questions, history-taking, physical examination, and diagnostic testing, an illness script emerges. As the case unfolds, the differential diagnosis is refined until a final diagnosis is reached.

Background: Malaria vaccines that target parasite development in mosquitoes offer a strategy to block disease transmission and support control, elimination, and eradication. In this article, we evaluate Pfs230D1-exoprotein A (EPA) and Pfs25-EPA for safety, immunogenicity, and field efficacy in Malian adults.

Methods: We first conducted a comparator-controlled, dose-escalating pilot safety trial, assessing Pfs25-EPA (16 vs. 47 μg) and Pfs230D1-EPA (13 vs. 40 μg), and their combinations, each formulated in the adjuvant AS01, at a 0-, 1-, and 6-month schedule. We then conducted a randomized, double-blind, comparator-controlled main trial to evaluate two Pfs230D1-EPA/AS01 regimens on a 0-, 1-, 4-, 16-month schedule. Pfs230D1-full, consisting of 40 μg of Pfs230D1-EPA plus 50 μg of AS01 for each dose, versus Pfs230D1-fractional, identical to Pfs230D1-full except for the third dose that used 8 μg of Pfs230D1-EPA and 10 μg of AS01. Primary end points were safety and reactogenicity (as-treated population), and secondary end points (as-randomly-assigned population) were immunogenicity by enzyme-linked immunosorbent assay, serum activity by mosquito standard membrane feeding assay (SMFA), and efficacy by direct skin feeding assay (DSF).

Results: In the pilot safety trial, 65 participants received injections (45 Pfs230D1 and/or Pfs25; 20 comparator). In the main phase, 236 participants received injections (56 Pfs230D1-full; 61 Pfs230D1-fractional; 119 comparator). No serious adverse events (SAEs) occurred in vaccinees in the pilot or main phase. Pfs230D1-full and Pfs230D1-fractional regimens induced antibody responses and transmission-reducing activity (based on SMFA) detectable up to approximately 1 year post-vaccination 3. Primary efficacy analysis showed combined Pfs230D1-full and Pfs230D1-fractional groups were not associated with reductions in mosquito positivity rate in the first 6 weeks of year 1 (efficacy, -1.55; 95% confidence interval [CI], -11.05 to 0.46). In the Pfs230D1-full group, DSF positivity was lower by 72.5% (95% CI, 30.4 to 89.1), and the proportion of infected mosquitoes was lower by 77.3% (95% CI, 19.5 to 93.6) over two transmission seasons.

Conclusions: In this trial, Pfs230D1-EPA/AS01 regimens did not result in SAEs and generated antibody responses and functional activity that persisted for up to 1 year postvaccination. Although the primary efficacy estimate did not demonstrate a reduction in parasite transmission during the first 6 weeks of follow-up, the full dosing regimen was associated with reduced transmission events and infected mosquitoes over 2 years. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov ID, NCT02942277.).

Background: Existing antibiotics for uncomplicated urinary tract infections are becoming less reliably effective owing to increasing antimicrobial resistance. Our objective was to evaluate the safety and efficacy of sulopenem/probenecid for uncomplicated urinary tract infections.

Methods: We conducted a double-blind, randomized, controlled, noninferiority trial of 5 days of sulopenem versus amoxicillin/clavulanate for women with uncomplicated urinary tract infection. The primary end point was overall success, defined as combined clinical cure and microbiologic eradication by day 12, evaluated in the microbiologic-modified intent-to-treat population, which comprised all randomly assigned patients who received any trial medication and had a positive urine culture with 10⁵ colony-forming units (CFU)/ml or more of an Enterobacterales uropathogen (e.g., Escherichia coli, Klebsiella species).

Results: A total of 2222 patients were enrolled, and the median age was 51 years (interquartile range, 35-62 years). Ninety-one (9.2%) patients in the primary population (microbiologic-modified intent-to-treat population), the combined population of patients with a positive baseline urine culture and without regard to amoxicillin/clavulanate susceptibility, had a baseline pathogen resistant to three or more classes of antibiotics. Overall success in the microbiologic-modified intent-to-treat population occurred in 318 of 522 (60.9%) participants treated with sulopenem versus 260 of 468 (55.6%) participants treated with amoxicillin/clavulanate (difference, 5.4 percentage points; 95% confidence interval [CI], -0.8 to 11.5), meeting criteria for noninferiority. In the primary population with a baseline uropathogen susceptible to amoxicillin/clavulanate, success occurred in 296 of 480 (61.7%) participants treated with sulopenem versus 243 of 442 (55.0%) participants treated with amoxicillin/clavulanate (difference, 6.7 percentage points; 95% CI, 0.3 to 13.0). In the primary population with a baseline uropathogen not susceptible to amoxicillin/clavulanate, success occurred in 22 of 42 (52.4%) patients treated with sulopenem versus 17 of 25 (68.0%) patients treated with amoxicillin/clavulanate (difference, -15.6 percentage points; 95% CI, -37.5 to 9.1]. Treatment-emergent adverse events occurred more frequently with sulopenem compared with amoxicillin/clavulanate, including diarrhea (8.1% vs. 4.1%), nausea (4.3% vs. 2.9%), and headache (2.2% vs. 1.5%).

Conclusions: Sulopenem was noninferior to amoxicillin/clavulanate for the treatment of adult women with uncomplicated urinary tract infection, but was associated with more frequent mild adverse events. (Funded by Iterum Therapeutics; REASSURE ClinicalTrials.gov number, NCT05584657.).

Background: We conducted a randomized controlled trial to compare intermediate doses (IDAC) with high doses of cytarabine (HDAC) as postinduction therapy in patients 18 to 60 years of age with newly diagnosed acute myeloid leukemia (AML). The main objectives were to evaluate noninferiority in overall survival (OS) after IDAC and safety.

Methods: Patients 18 to 60 years of age with newly diagnosed AML, except those with core-binding factor, acute promyelocytic, Philadelphia chromosome-positive, or post-myeloproliferative neoplasm AML, were eligible. After the induction course, we randomly assigned patients to either IDAC (1500 mg/m²/12 hours) or HDAC (3000 mg/m²/12 hours). Patients with intermediate- and adverse-risk AML were eligible for allogeneic hematopoietic stem cell transplantation (HSCT) in first remission. The primary end point was OS in a predefined per-protocol analysis population. The primary analyses were performed in 1132 randomly assigned patients, with a noninferiority outcome adjusted on the European Leukemia Net (ELN) 2022 risk group, the use of induction anthracycline, the response to induction, and HSCT as a function of time following treatment.

Results: At 5 years, OS was estimated at 59.3% (95% confidence interval [CI], 55.0 to 63.3) in the IDAC group versus 57.5% (95% CI, 53.3 to 61.5) in the HDAC group (adjusted hazard ratio, 0.96; 95% CI, 0.80 to 1.15; noninferiority test, P=0.0042). A preplanned analysis was unable to detect any interaction between IDAC or HDAC treatment effect and patient subgroups, including those defined by the ELN 2022 risk group or response to induction prior to random assignment. In addition, the severity of chemotherapy-induced myelosuppression and the incidence of related adverse events were lower after IDAC.

Conclusions: Our trial shows noninferior outcomes in patients 18 to 60 years of age with newly diagnosed AML treated with low- versus high-dose cytarabine; this occurred with similar or lower toxicities. (Funded by the Regional Clinical Research Office, Angers and others; EudraCT number, 2014-000699-24; ClinicalTrials.gov number, NCT02416388.).

Background: A substantial number of patients with advanced cancer suffer from refractory pain despite comprehensive medical management. In this article, we evaluate a nonopioid analgesic, resiniferatoxin (RTX), a potent agonist of the transient receptor potential vanilloid 1 (TRPV1) ion channel, which selectively interrupts nociceptive activity transmitted by a subpopulation of dorsal root ganglion neurons.

Methods: In this interim analysis of a first-in-human, open-label, Phase 1 study, 19 patients with refractory cancer pain localized to the abdomen and/or lower extremities received one dose of intrathecal RTX. The primary outcome was safety. Secondary outcomes were efficacy assessed over the course of the study using a numerical rating scale measuring the "worst pain" over a 24-hour period. This is a 0 to 10 scale where 0 is "no pain" and 10 is the "worst pain imaginable." Opioid consumption was measured as morphine equivalents used to control pain.

Results: Over 188 days after RTX injection, a total of 213 treatment-emergent adverse events (AEs) were reported among 19 patients treated, including 37 serious adverse events in 14 patients. Nine deaths occurred an average of 70 days after treatment (range from 11 to 140 days). Many of these events, including death, are consistent with the course of advanced cancer. At least one AE occurred in all 19 patients. Three patients experienced loss of heat sensitivity in the dermatomes exposed to RTX (grades I and II). Seven patients experienced urinary retention lasting more than 24 hours (three were grade III). Five patients had AEs related to a transient increase in the electrocardiographic QT interval that resolved within 24 hours (grades I and II). The only grade IV AE was an unstageable decubitus ulcer. RTX was associated with decreased "worst" pain intensity by 38% (pretreatment 8.4±0.4 vs. posttreatment 5.2±0.6) and reduced opioid consumption by 57% measured at posttreatment day 15.

Conclusions: Intrathecal RTX is a single-administration, opioid-sparing analgesic in patients with intractable cancer pain. There were expected and unexpected AEs of various grades with an encouraging initial impact on pain. (Funded by the Intramural Research Program of the National Institutes of Health Clinical Center and others; ClinicalTrials.gov number, NCT00804154).