NEJM evidence最新文献

{"title":"Clinical Safety and Preliminary Efficacy of Regulatory T Cells for ALS.","authors":"Neil A Shneider, Alex V Nesta, Olivia M Rifai, Julia Yasek, Wassim Elyaman, Sonya Aziz-Zaman, Mi-Ae Lyu, Samuel H S Levy, Benjamin N Hoover, George Vlad, Meixian Huang, Ke Zeng, Tara Sadeghi, Anupama Reddy, Christopher R Flowers, Simrit Parmar","doi":"10.1056/EVIDoa2400249","DOIUrl":"https://doi.org/10.1056/EVIDoa2400249","url":null,"abstract":"<p><strong>Background: </strong>Peripheral and neuroinflammation have been previously associated with progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving progressive loss of motor neurons. We hypothesize that regulatory T cell (Treg) therapy can resolve inflammation and preserve function in those patients with ALS.</p><p><strong>Methods: </strong>Participants with ALS received infusions of a fixed dose (100×10⁶ cells) of umbilical cord blood-derived, allogeneic, nonhuman leukocyte antigen-matched, cryopreserved Treg product (TREG), administered as four weekly infusions followed by six monthly infusions. No lymphodepletion, immunosuppression, or interleukin 2 was administered. The primary outcome was dose-limiting toxicity, including infusion reaction within 24 hours (as graded by National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 4.0) and/or regimen-related death, or grade 3 or 4 cytokine release syndrome within 14 days postinfusion. We measured clinical response using the Revised ALS Functional Rating Scale (ALSFRS-R; range 0 to 48, with lower numbers indicating lower functional ability). Exploratory analyses measured serum and plasma neurofilament light (NfL) and inflammatory biomarkers.</p><p><strong>Results: </strong>Six participants with a median age of 48.5 years (range 27 to 66 years) and baseline ALSFRS-R score of 31.5 (range 23 to 43) were treated with a median of 11 (range 6 to 22) TREG infusions in an ambulatory setting. No dose-limiting toxicity was observed. In participants with sufficient data points (n=4), the mean ALSFRS-R slope of decline was -1.66±1.03 points/month before treatment, -0.41±0.45/month during treatment, and -0.60±0.59/month posttreatment. Biomarkers including NfL and inflammatory markers MIP-1δ (macrophage inflammatory protein-1 delta), CTACK (cutaneous T cell-attracting chemokine), and GROα (growth-regulated oncogene alpha) exhibited different relationships with ALSFRS-R score between participants.</p><p><strong>Conclusions: </strong>This study demonstrates the preliminary safety of \"off-the-shelf\", allogeneic Treg-cell therapy.</p>","PeriodicalId":74256,"journal":{"name":"NEJM evidence","volume":"4 5","pages":"EVIDoa2400249"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Larsucosterol for the Treatment of Alcohol-Associated Hepatitis.","authors":"","doi":"10.1056/EVIDx2500084","DOIUrl":"https://doi.org/10.1056/EVIDx2500084","url":null,"abstract":"","PeriodicalId":74256,"journal":{"name":"NEJM evidence","volume":"4 5","pages":"EVIDx2500084"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Randomized Trial of Shared Decision-Making in Code Status Discussions.","authors":"Christoph Becker, Sebastian Gross, Katharina Beck, Simon A Amacher, Alessia Vincent, Jonas Mueller, Nina Loretz, Rene Blatter, Chantal Bohren, Tabita Urben, Armon Arpagaus, Rainer Schaefert, Philipp Schuetz, Nina Kaegi-Braun, Lena Stalder, Jörg D Leuppi, Drahomir Aujesky, Christine Baumgartner, Balthasar Hug, Hannah Schmieg, Valentina Delfine, Thomas Peters, Arnoud J Templeton, Stefano Bassetti, Sabina Hunziker","doi":"10.1056/EVIDoa2400422","DOIUrl":"https://doi.org/10.1056/EVIDoa2400422","url":null,"abstract":"<p><strong>Background: </strong>The effect of a shared decision-making approach on patients' code status decisions remains unknown. We compared an approach for shared decision-making with usual care to evaluate the effect on patients' code status preferences and quality of decision-making.</p><p><strong>Methods: </strong>In a pragmatic cluster-randomized controlled trial conducted in six teaching hospitals in Switzerland, we randomly assigned residents to conduct code status discussions based on either an approach incorporating didactic teaching, observation, and feedback and a shared decision-making checklist with a decision aid, or usual care. The primary end point was patients choosing a do-not-resuscitate (DNR) code status in the event of a cardiac arrest. The key secondary end point was patients' decisional uncertainty, measured by the Decisional Conflict Scale (range 0 to 100, with lower scores indicating lower decisional uncertainty).</p><p><strong>Results: </strong>A total of 206 residents caring for 2663 medical patients were included in the trial. Compared with patients in the usual care group, patients in the intervention group had a significantly higher frequency of choosing DNR as their code status (685/1370 (50.0%) vs. 481/1293 (37.2%); adjusted risk ratio, 1.37 (95% confidence interval, 1.25 to 1.50); P<0.001). The intervention was associated with lower decisional uncertainty (Decisional Conflict Scale score, 14.4±15.3 vs. 21.8±20.2 points; adjusted difference, -7.06 (95% confidence interval, -9.43 to -4.68).</p><p><strong>Conclusions: </strong>An approach for shared decision-making that included the discussion of expected outcomes had a significant influence on the code status of medical patients, with a higher preference for DNR code status, and was associated with less uncertainty around the decision. (Funded by the Swiss National Science Foundation and the Swiss Society of General Internal Medicine; ClinicalTrials.gov number, NCT03872154.).</p>","PeriodicalId":74256,"journal":{"name":"NEJM evidence","volume":"4 5","pages":"EVIDoa2400422"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory T Cell-Based Therapies - A New Piece of the ALS Therapeutic Puzzle?","authors":"Elena Abati","doi":"10.1056/EVIDe2500078","DOIUrl":"https://doi.org/10.1056/EVIDe2500078","url":null,"abstract":"","PeriodicalId":74256,"journal":{"name":"NEJM evidence","volume":"4 5","pages":"EVIDe2500078"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Instrumental Variables in Randomized Trials.","authors":"","doi":"10.1056/EVIDx2500085","DOIUrl":"10.1056/EVIDx2500085","url":null,"abstract":"","PeriodicalId":74256,"journal":{"name":"NEJM evidence","volume":" ","pages":"EVIDcx2500085"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Goals-of-Care Conversations - What Is the Goal?","authors":"Chad R Beck, Bruno L Ferreyro","doi":"10.1056/EVIDe2500063","DOIUrl":"https://doi.org/10.1056/EVIDe2500063","url":null,"abstract":"","PeriodicalId":74256,"journal":{"name":"NEJM evidence","volume":"4 5","pages":"EVIDe2500063"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Efficacy of Senolytic UBX1325 in Diabetic Macular Edema.","authors":"Sharon Klier, Jamie Dananberg, Lauren Masaki, Robert B Bhisitkul, Arshad M Khanani, Raj Maturi, Hani Salehi-Had, Craig H Mallinckrodt, Joshua M Rathmell, Anirvan Ghosh, Przemyslaw Sapieha","doi":"10.1056/EVIDoa2400009","DOIUrl":"https://doi.org/10.1056/EVIDoa2400009","url":null,"abstract":"<p><strong>Background: </strong>We tested the ability of a single intravitreal injection of foselutoclax (hereafter UBX1325), a novel senolytic small molecule inhibitor of antiapoptotic protein B-cell lymphoma-extra large, to mitigate the impact of diabetic macular edema.</p><p><strong>Methods: </strong>Patients with diabetic macular edema with prior suboptimal response to anti-vascular endothelial growth factor treatment were randomly assigned (1:1) to either a single intravitreal injection of 10 μg of UBX1325 or sham and were followed for up to 48 weeks. The primary trial objective was to evaluate the safety and side-effect profile of UBX1325 as assessed by ocular and systemic treatment-emergent adverse events (TEAEs). Our secondary objective was to probe efficacy, defined as mean changes from baseline for UBX1325 versus sham in best corrected visual acuity measured in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters (range, 0-100 letters, higher scores indicate better vision) and retinal structure.</p><p><strong>Results: </strong>Between June 2021 and April 2022, 65 participants (32.3% women) were randomly assigned to either UBX1325 (n=32) or sham (n=33). There were four TEAEs of Grade 3 or greater in the sham group, of which three were considered serious, while there were five in the UBX1325 group of Grade 3 or greater and considered serious. There were no apparent between-group differences with respect to vital signs, electrocardiograms, or routine blood chemistries. For the secondary outcome of efficacy, the difference between UBX1325 and sham in mean change to week 48 in best corrected visual acuity was 5.6 more ETDRS letters (95% confidence interval, -1.5 to 12.7).</p><p><strong>Conclusions: </strong>In this sham-controlled trial there were no TEAEs that led to discontinuation of treatment with UBX1325 compared with sham. There were trends suggestive of potential efficacy; larger trials are needed to further evaluate these findings. (Funded by UNITY Biotechnology; ClinicalTrials.gov number, NCT04857996.).</p>","PeriodicalId":74256,"journal":{"name":"NEJM evidence","volume":"4 5","pages":"EVIDoa2400009"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction versus Concurrent Chemotherapy for Advanced Nasopharyngeal Carcinoma.","authors":"Pei-Yu Huang, Xu-Yin Chen, Xi Ding, Ling Guo, Hao-Yuan Mo, Xiong Zou, Chong-Yang Duan, Li Ling, Rui You, Xin Yang, You-Ping Liu, Yu-Long Xie, Yi-Nuan Zhang, Jing-Yu Cao, Si-Han Liu, Zi-Meng Wang, Qi Yang, Chao Lin, Si-Yuan Chen, Yan-Feng Ouyang, Yong-Long Liu, Kai Wen, Xiao-Tong Duan, Rou Jiang, Rong-Zeng Liu, Tao Yu, Fang Qiu, Yi-Jun Hua, Ka-Jia Cao, Dong-Hua Luo, Ming-Yuan Chen","doi":"10.1056/EVIDoa2400214","DOIUrl":"https://doi.org/10.1056/EVIDoa2400214","url":null,"abstract":"<p><strong>Background: </strong>Cisplatin-based concurrent chemoradiotherapy (CCRT) is the mainstay treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC), which usually leads to intolerable toxicities. We investigated whether or not induction chemotherapy (IC) plus intensity-modulated radiation therapy (IMRT) could replace CCRT.</p><p><strong>Methods: </strong>This is an open-label, phase 3, noninferiority trial. Patients with stage T1-4N2-3 or T3-4N0-1 LA-NPC were randomly assigned (1:1) to receive gemcitabine (1000 mg/m²) and cisplatin (80 mg/m²) for two cycles followed by IMRT, or IMRT plus concomitant weekly cisplatin (40 mg/m²) for up to seven cycles. Two-year failure-free survival (FFS) was the primary end point, and noninferiority was confirmed by an upper limit of the 95% confidence interval (CI) for a hazard ratio of less than 2.12 (absolute margin of -10 percentage points). Secondary end points include overall survival, locoregional recurrence-free survival, distant metastasis-free survival, toxicity profile, and quality of life (QoL).</p><p><strong>Results: </strong>We enrolled 124 patients in the IC group and 125 patients in the CCRT group. The median follow-up was 60 months. Two-year FFS was 90.2% for IC versus 86.3% for CCRT, with a hazard ratio of 0.636 (95% CI, 0.267 to 1.514) and an absolute difference of 3.9 percentage points (95% CI, -5.2 to 13.0). Compared with the CCRT group, fewer grade ≥3 adverse events occurred in the IC group (47.5% vs. 61.5%; P=0.029), including leukopenia, anemia, mucositis, nausea, and dysphagia. IC was associated with better QoL, including global health status, social and cognitive functioning, fatigue, nausea and vomiting, pain, appetite loss, and constipation.</p><p><strong>Conclusions: </strong>For 2-year FFS for LA-NPC, gemcitabine and cisplatin IC plus IMRT alone was noninferior to CCRT. (Funded by Key-Area Research and Development of Guangdong Province and others.).</p>","PeriodicalId":74256,"journal":{"name":"NEJM evidence","volume":"4 5","pages":"EVIDoa2400214"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tension-Free Vaginal Tape versus Polyacrylamide Hydrogel Injection for Stress Urinary Incontinence - 5-Year Follow-Up.","authors":"Anna-Maija Itkonen Freitas, Camilla Isaksson, Päivi Rahkola-Soisalo, Maarit Mentula, Tomi S Mikkola","doi":"10.1056/EVIDoa2400216","DOIUrl":"https://doi.org/10.1056/EVIDoa2400216","url":null,"abstract":"<p><strong>Background: </strong>Tension-free vaginal tape has been the gold standard of treatment for female stress urinary incontinence, but concerns have risen about the safety of mesh. Transurethral injection of polyacrylamide hydrogel (PAHG) is a minimally invasive alternative. However, the long-term safety, efficacy, and patient satisfaction of PAHG is undefined.</p><p><strong>Methods: </strong>We conducted a randomized, controlled, noninferiority (margin 20%) trial at Helsinki University Hospital, Finland, comparing tension-free vaginal tape with PAHG treatment. The primary outcome was patient satisfaction. Secondary outcomes were effectiveness and complications. The results at 1 and 3 years have been previously reported. Herein, we report the 5-year follow-up.</p><p><strong>Results: </strong>Of the 223 women originally randomly assigned to a treatment group, 212 women underwent treatment as randomly assigned and, at 5 years, 195 (92.0%) women attended the follow-up. The median satisfaction score (visual analog scale: range, 0 to 100; higher scores indicated higher satisfaction) was 98 (interquartile range, 86 to 100) in the tension-free vaginal tape group, and 90 (interquartile range, 75 to 99) in the PAHG group, whereas a score of 80 or more was reached in 89 (92.7%) and 74 (74.7%) participants (difference, 18.0 percentage points; 95% confidence interval [CI], 7.7 to 28.0), respectively. Thus, PAHG did not meet the noninferiority criteria set in our trial. Within the 5-year follow-up, a peri- or postoperative complication before crossover between the groups was detected in 42 (43.8%) women in the tension-free vaginal tape group and 22 (22.2%) women in the PAHG group (difference, 21.5 percentage points; 95% CI, 8.4 to 33.8).</p><p><strong>Conclusions: </strong>In long-term follow-up, treatment of stress urinary incontinence with PAHG was not noninferior to treatment with tension-free vaginal tape with respect to patient satisfaction scores. Complications were twice as common in the tension-free vaginal tape group. (Funded by Helsinki University Hospital and Contura; ClinicalTrials.gov number, NCT02538991.).</p>","PeriodicalId":74256,"journal":{"name":"NEJM evidence","volume":"4 5","pages":"EVIDoa2400216"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural Experiments to Inform Clinical Practice.","authors":"Atheendar S Venkataramani, Elizabeth F Bair","doi":"10.1056/EVIDra2400268","DOIUrl":"https://doi.org/10.1056/EVIDra2400268","url":null,"abstract":"<p><p>AbstractNatural experiments refer to events or practices that result in similar individuals receiving different services or interventions for arbitrary reasons. In the clinical context, researchers may wish to leverage natural experiments to estimate the causal impact of a particular treatment on a health outcome in situations where randomized clinical trial data are unavailable and other observational research designs are likely to yield biased results. This review provides an overview of natural experiments, discusses the potential for natural experiments to establish cause and effect, illustrates applications to specific clinical questions, and outlines situations and practices where natural experiments are most likely to answer the question at hand. Overall, while natural experiments have become popular in health policy, the widespread application of these approaches to specific clinical questions faces several challenges.</p>","PeriodicalId":74256,"journal":{"name":"NEJM evidence","volume":"4 5","pages":"EVIDra2400268"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}