NEJM evidence最新文献

AbstractSodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) improve quality of life, functional capacity, and survival, and reduce hospitalization in adults with heart failure (HF). However, most controlled trials to date have enrolled few adults with advanced HF and multiple chronic illnesses. Despite favorable evidence in adults with HF, the safety and effectiveness of SGLT2 inhibitors on patient-centered outcomes in adults with advanced HF and multiple chronic illnesses remain unknown. This Tomorrow's Trial reviews the existing evidence and proposes a trial to address the question, "Do SGLT2 inhibitors improve end-of-life care in adults with advanced heart failure?"

Morning 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 examines the story of a 62-year-old woman who presented with diarrhea and fatigue 8 weeks after haploidentical hematopoietic stem-cell transplantation. Using targeted questions, physical examination, and diagnostic testing, an illness script for the presentation emerges. As the clinical course progresses, the differential is refined until a final diagnosis is made.

Background: Diagnosis of endometriosis is a challenge. The recent development of a saliva-based micro-ribonucleic acid (miRNA) signature for the diagnosis of endometriosis may enable a timelier and less invasive approach, but this requires external validation.

Methods: The prospective, multicenter validation of the salivary miRNA signature of endometriosis (ENDOmiRNA) study aimed to assess the diagnostic accuracy, validate the biological reproducibility, and evaluate the clinical utility of a saliva miRNA signature of endometriosis. The study population comprised patients 18 to 43 years of age with signs and symptoms suggestive of endometriosis, who were recruited from diverse medical settings. Patients received a diagnosis of endometriosis by imaging, laparoscopic procedure, or both. All patients who were determined to not have endometriosis were classified as controls (and all underwent laparoscopy). Assessment of endometriosis status based on the saliva miRNA signature was established blinded to patients' endometriosis status, as determined by imaging and/or laparoscopy and/or histology.

Results: The external validation population was composed of 971 patients, including patients from a prior interim analysis, with an overall endometriosis prevalence of 77%. The saliva miRNA signature had an accuracy (defined as the probability of correct classification for both positive and negative results) of 96.6% (95% confidence interval [CI], 95.2 to 97.6%), a sensitivity of 97.3% (95% CI, 96.4 to 98.0%), a specificity of 94.1% (95% CI, 91.0 to 96.4%), a positive predictive value of 98.2% (95% CI, 97.3 to 98.9%), a negative predictive value of 91.3% (95% CI, 88.3 to 93.4%), a positive likelihood ratio of 16.6 (95% CI, 10.8 to 26.9), and a negative likelihood ratio of 0.03 (95% CI, 0.02 to 0.04). Among patients with surgical confirmation of the diagnosis, misclassification, underestimation, and overestimation rates were 4.6%, 2.4%, and 2.2%, respectively, for the saliva miRNA signature and 27.2%, 15.1%, and 12.2%, respectively, for imaging (either transvaginal ultrasound, magnetic resonance imaging, or both).

Conclusions: This prospective, multicenter external validation study demonstrated the accurate performance of a saliva-based miRNA signature for the diagnosis of endometriosis in this cohort. (Funded by Ziwig; ClinicalTrials.gov number, NCT05244668.).

Background: Older men with metastatic hormone-sensitive prostate cancer (mHSPC) are more likely to have comorbid medical conditions and die from causes other than prostate cancer. We aimed to determine if age impacts the overall survival (OS) benefit from systemic treatment intensification (TI) with androgen receptor pathway inhibitors (ARPIs) and/or chemotherapy in mHSPC.

Methods: A systematic literature search in MEDLINE, Embase, and conference proceedings was conducted to identify randomized phase 3 trials in mHSPC evaluating the role of TI between January 1, 2010, and January 1, 2024. Age was dichotomized as 70 years or older in all trials, except as 75 years or older in one trial. Meta-analyses were performed with random-effects modeling. Meta-regression was performed using Hartung-Knapp methods. Individual patient data (IPD) from three trials (TITAN, ARASENS, and LATITUDE) were used to validate the aggregate meta-analysis.

Results: Eleven randomized comparisons (n=13,648 patients; 8324 younger men and 5162 older men) were included in the aggregate meta-analysis. Overall, TI was associated with improved OS (hazard ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.78). There was an interaction between age and TI on OS (P-interaction <0.001; younger men: hazard ratio, 0.63; 95% CI, 0.56 to 0.70; older men: hazard ratio, 0.82; 95% CI, 0.74 to 0.90). TI was not associated with improvement in OS in older men treated in trials utilizing predominantly triplet therapy (hazard ratio, 0.94; 95% CI, 0.77 to 1.14). These results were similar in the IPD analysis. In the IPD analysis, ARPI addition was associated with improved OS in men 70 years or older with high-volume synchronous disease (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but not in low-volume synchronous disease (hazard ratio, 0.89; 95% CI, 0.61 to 1.30).

Conclusions: We observed an interaction between age and systemic TI on OS for men with mHSPC. Our data provide information on potential treatment strategies for men 70 years or older, especially in low-volume synchronous disease, where radiotherapy to the primary site is the standard of care. (Funded by the National Institutes of Health and others.).

Background: Clinical trials of low-density lipoprotein cholesterol (LDL-C)-lowering medicines have shown improvement in cardiovascular disease risk. However, representation across diverse communities in such trials is limited. We set out to study whether or not more diverse human genetic studies could provide an opportunity to test whether these trial results can be generalized to poorly populations poorly represented in drug clinical trials.

Methods: We included six cohorts across 967,325 individuals (54.5% female), including 65,258 African, 45,393 admixed American, 179,521 East Asian, 616,045 European, 4686 Middle Eastern, and 56,422 South Asian individuals. Genetic ancestry was determined using genetic principal components and k-nearest neighbors. We constructed ancestry-specific LDL-C polygenic risk scores (PGS) using genome-wide association study (GWAS) summary statistics trained and externally validated on each ancestry. We associated each PGS with population LDL-C, scaled for a 40 mg/dl increase, and tested these scores against coronary artery disease (CAD) risk using hierarchical Bayesian meta-analyses.

Results: The associations between genetically predicted LDL-C levels and observed LDL-C were consistent across ancestries, supporting the validity of our genetic proxy. When scaled to mimic a 40 mg/dl increase in LDL-C, the PGS showed positive but heterogeneous associations with CAD. Posterior odds ratios for CAD ranged from 1.35 (95% credible interval, 1.05 to 1.68) in African populations to 1.82 (95% credible interval, 1.33 to 2.97) in Middle Eastern populations. Bayesian analysis revealed that 97.9% of posterior samples showed all population means greater than 0 on a log scale with a between-ancestry posterior variance (τ²) of 0.062 (95% credible interval, 0.001 to 0.352).

Conclusions: Our findings demonstrated a consistent association between LDL-C and CAD risk across diverse ancestry groups that are often poorly represented in clinical trials, although effect magnitudes varied. (Funded by the National Institutes of Health and others.).

AbstractDirect-to-consumer genetic testing has become increasingly popular, offering individuals easy access to genetic data without the involvement of health care professionals. However, as availability grows, clinicians face challenges in interpreting and integrating this information into clinical care. This review provides insights for health professionals about the evolving landscape of direct-to-consumer genetic testing, with a focus on test offerings, limitations, challenges, and ethical concerns. It also highlights issues that can arise with direct-to-consumer genetic testing in the pediatric setting. Clinicians can play a pivotal role in guiding patients and families through the complexities of direct-to-consumer genetic testing, ensuring that decisions are informed and risks are minimized.

AbstractIn 2016, many clinicians and investigators in the field of sleep apnea were surprised when a large multinational clinical trial of continuous positive airway pressure (CPAP) therapy failed to demonstrate a reduction in cardiovascular events in patients with sleep apnea and established cardiovascular disease. When a review of the trial data suggested that CPAP nonadherence among trial participants might explain the negative results, it became clear that new approaches were needed. In this Clinical Trials Case Study, we share our experience designing a trial to evaluate a peer-support strategy to improve CPAP adherence. We address how patients were the drivers of research ideas and discuss how the return on investment in such patient-engaged approaches to research can be high for patients, trialists, and, ultimately, public health. Our experience could serve as a road map for investigators who have the same trepidation as we once did to create, engage, and empower a patient-stakeholder committee. Such knowledge could help clinical trials accomplish the stated goals for various chronic medical conditions.