【The New England Journal of Medicine】2024年2-3月刊论文导读
期刊介绍： 《新英格兰医学杂志》（The New England Journal of Medicine，简称NEJM），是由美国麻州医学协会所出版的世界一流的综合性医学期刊。发表与各医学专业相关的研究，以及关于医学伦理、公共卫生和医疗政策的文章。文章类型主要是临床研究、综述、病例报告和社论等。这一期刊对生物医学科学与临床实践具有重要意义。该刊创刊于1812年，为周刊，最新影响因子为96.2. 本期文献导读将呈现2024年2-3月这两个月的主要刊物内容。 February 01；Volume 390（5）：389-484 在2024年2月1日，共发表20篇文章，其中包括3篇Perspective，4篇Original articles，1篇Review article，2篇Images in clinical medicine，1篇Clinical problem-solving，3篇Editorials，1篇medicine and society，5篇Correspondence。 1. Live, Attenuated, Tetravalent Butantan–Dengue Vaccine in Children and Adults 用于儿童和成人的减毒四价布坦坦-登革热减毒活疫苗 发表单位：巴西圣保罗布坦坦研究所;巴西圣保罗大学医学院附属临床医院 Abstract BACKGROUND Butantan–Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically confirmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine efficacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) — 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine efficacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regardless of dengue serostatus at baseline, through 2 years of follow-up. 摘要背景 布坦坦-登革热疫苗（Butantan-DV）是一种用于预防登革热的单剂量四价减毒活疫苗，目前正在研究中，但我们还需要有关其总体疗效的数据。 方法 在巴西正在进行的一项3期双盲试验中，我们根据年龄（2~6岁、7~17岁和18~59岁）进行分层后，将参与者随机分配接种布坦坦-登革热疫苗或安慰剂治疗；计划进行5年的随访。该试验的目的是不论基线时的血清状态如何，评估疫苗对接种后28天以上出现的有症状、病毒学确诊的任何血清型登革热的总体疗效（主要疗效终点），并描述截至第21天的安全性（主要安全性终点）。本研究根据每位参与者的2年随访情况评估疫苗效力，并根据截至注射后第21天报告的疫苗相关不良事件评估疫苗安全性。关键次要目标是根据基线时的登革热血清状态和登革热病毒血清型评估疫苗在受试者中的疗效；我们还评估了不同年龄的疗效。 结果 在为期3年的招募期内，有16235名参与者接受了布坦坦-登革热疫苗（10259人）或安慰剂（5976人）治疗。在无登革热暴露史证据的参与者和有登革热暴露史的参与者中，疫苗的总体2年效力分别为79.6%(95%置信区间[CI]， 70.0 ~ 86.3) ~ 73.6% (95% CI, 57.6 ~ 83.7)和89.2% (95% CI, 77.6 ~ 95.6)。疫苗对2~6岁人群的有效率为80.1%（95%CI，66.0~88.4），对7~17岁人群的有效率为77.8%（95%CI，55.6~89.6），对18~59岁人群的有效率为90.0%（95%CI，68.2~97.5）。对DENV-1的有效率为89.5%（95%CI，78.7~95.0），对DENV-2的有效率为69.6%（95%CI，50.8~81.5）。随访期间未检测到DENV-3和DENV-4。与安慰剂相比，布坦坦-登革热疫苗在注射后21天内引起的与疫苗或安慰剂相关的全身性不良反应更为常见（58.3%的参与者 vs 45.6%）。 结论 在2年随访期间，无论基线时的登革热血清状态如何，单剂量布坦坦-登革热疫苗均可预防有症状的DENV-1和DENV-2感染。 February 08；Volume 390（6）：485-580 在2024年2月8日，共发表26篇文章，其中包括6篇Perspective，4篇Original articles，1篇Review article，2篇Images in clinical medicine，1篇Case records of the massachusetts general hospital， 3篇Editorials，2篇medicine and society，5篇Correspondence，2篇Corrections。 2. An Oral Interleukin-23–Receptor Antagonist Peptide for Plaque Psoriasis 一种治疗斑块型银屑病的口服白细胞介素23受体拮抗剂肽 发表单位：加拿大蒙特利尔Innovaderm Research公司;加拿大麦克马斯特大学和Dermatrials研究机构 Abstract BACKGROUND The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23–receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose–response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23–receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. 摘要 背景 单克隆抗体的使用改变了包括银屑病在内的几种免疫介导的炎症性疾病的治疗方法。然而，这些大分子蛋白质必须通过注射给药。JNJ-77242113是一种口服给药的新型白介素23受体拮抗剂肽，它能选择性地阻断白介素23信号传导和下游细胞因子的产生。 方法 在这项2期剂量探索试验中，我们将中到重度斑块状银屑病患者随机分组，分别接受为期16周的JNJ-77242113(剂量为每日1次25 mg、每日2次25 mg、每日1次50 mg、每日1次100 mg或每日2次100 mg)或安慰剂治疗。主要终点是第16周时，银屑病面积和严重程度指数（PASI）评分比基线降低至少75%（PASI 75应答；PASI评分范围为0~72分，评分越高表明银屑病的范围或严重程度越大）。 结果 共有255名患者接受了随机分组。基线时的平均PASI评分为19.1。银屑病的平均病程为18.2年，所有试验组中78%的患者曾接受过系统治疗。第16周时，JNJ-77242113组(25 mg每日1次、25 mg每日2次、50 mg每日1次、100 mg每日1次和100 mg每日2次组分别为37%、51%、58%、65%和79%)中有PASI 75应答的患者百分比高于安慰剂组(9%)，这一发现显示了显著的剂量-反应关系(P<0.001)。最常见的不良事件包括2019年冠状病毒病（安慰剂组12%，JNJ-77242113剂量组11%）和鼻咽炎（分别为5%和7%）。在JNJ-77242113联合剂量组（52%）和安慰剂组（51%）中，发生至少一种不良事件的患者比例相似。没有证据表明JNJ-77242113剂量组的不良事件与剂量增加有关。 结论 经过16周每日一次或两次的口服给药治疗后，白介素23受体拮抗剂肽JNJ-77242113对中重度斑块状银屑病患者的疗效好于安慰剂。 February 15；Volume 390（7）：581-676 在2024年2月15日，共发表20篇文章，其中包括5篇Perspective，4篇Original articles，1篇Clinical practice，1篇Review article，2篇Images in clinical medicine，1篇Case records of the massachusetts general hospital， 2篇Editorials，1篇Clinical decisions，3篇Correspondence。 3. Electronic Nicotine-Delivery Systems for Smoking Cessation 用于戒烟的电子尼古丁传送系统 发表单位：瑞士伯尔尼大学医院初级卫生保健研究所;瑞士洛桑大学医院初级保健与公共卫生研究中心 Abstract BACKGROUND Electronic nicotine-delivery systems — also called e-cigarettes — are used by some tobacco smokers to assist with quitting. Evidence regarding the efficacy and safety of these systems is needed. METHODS In this open-label, controlled trial, we randomly assigned adults who were smoking at least five tobacco cigarettes per day and who wanted to set a quit date to an intervention group, which received free e-cigarettes and e-liquids, standard-of-care smoking-cessation counseling, and optional (not free) nicotine-replacement therapy, or to a control group, which received standard counseling and a voucher, which they could use for any purpose, including nicotine-replacement therapy. The primary outcome was biochemically validated, continuous abstinence from smoking at 6 months. Secondary outcomes included participant-reported abstinence from tobacco and from any nicotine (including smoking, e-cigarettes, and nicotine-replacement therapy) at 6 months, respiratory symptoms, and serious adverse events. RESULTS A total of 1246 participants underwent randomization; 622 participants were assigned to the intervention group, and 624 to the control group. The percentage of participants with validated continuous abstinence from tobacco smoking was 28.9% in the intervention group and 16.3% in the control group (relative risk, 1.77; 95% confidence interval, 1.43 to 2.20). The percentage of participants who abstained from smoking in the 7 days before the 6-month visit was 59.6% in the intervention group and 38.5% in the control group, but the percentage who abstained from any nicotine use was 20.1% in the intervention group and 33.7% in the control group. Serious adverse events occurred in 25 participants (4.0%) in the intervention group and in 31 (5.0%) in the control group; adverse events occurred in 272 participants (43.7%) and 229 participants (36.7%), respectively. CONCLUSIONS The addition of e-cigarettes to standard smoking-cessation counseling resulted in greater abstinence from tobacco use among smokers than smoking-cessation counseling alone. 摘要 背景 一些吸烟者使用电子尼古丁传送系统（也称为电子烟）来帮助戒烟。但是关于这些系统的有效性和安全性还需要验证。 方法 在这项开放标签的对照试验中，我们将每天至少吸五支烟草香烟并希望设定戒烟日期的成年人随机分配到干预组和对照组，干预组接受免费的电子烟和电子烟液、标准戒烟咨询以及可选（但非免费）的尼古丁替代疗法，对照组则接受标准戒烟咨询和一张可用于任何目的的代金券，包括尼古丁替代疗法。主要结局是经过生化验证的6个月持续戒烟。次要结局包括6个月时受试者报告的戒烟情况、戒除任何尼古丁（包括吸烟、电子烟和尼古丁替代疗法）情况、呼吸道症状和严重不良事件。 结果 共有1246名参与者被随机分组，其中622人被分配到干预组，624人被分配到对照组。经验证的持续戒烟的受试者比例为：干预组28.9%，对照组16.3%（相对危险度为 1.77；95%CI为 1.43 - 2.20）。干预组和对照组在6个月访视前7天内戒烟的比例分别为59.6%和38.5%，但不使用任何尼古丁的比例分别为20.1%和33.7%。干预组有25人（4.0%），对照组有31人（5.0%）发生了严重不良事件；分别有272人（43.7%）和229人（36.7%）发生不良事件。 结论 与单独的戒烟咨询相比，在标准戒烟咨询的基础上加用电子烟，可提高吸烟者对烟草的戒断率。 February 22；Volume 390（8）：677-772 在2024年2月22日，共发表21篇文章，其中包括5篇Perspective，4篇Original articles，1篇Review article，2篇Images in clinical medicine，1篇Case records of the massachusetts general hospital， 3篇Editorials，4篇Correspondence，1篇Correction。 4.Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection 替奈普酶在 4.5 至 24 小时内治疗中风并进行灌注成像选择 发表单位：美国斯坦福大学医学院神经病学与神经科学系;美国基因泰克公司 Abstract BACKGROUND Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. METHODS We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P=0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. CONCLUSIONS Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. 摘要 背景 包括替奈普酶在内的溶栓药物通常需要在卒中症状出现后4.5小时内使用。然而有关替奈普酶是否能在卒中4.5小时后带来获益的信息十分有限。 方法 我们对缺血性脑卒中患者进行了一项多中心、双盲、随机、安慰剂对照试验，旨在比较替奈普酶（0.25mg/kg体重，最多25mg）和安慰剂在患者最后一次被确认健康状况良好后的4.5~24小时的治疗效果。患者必须有大脑中动脉或颈内动脉闭塞的证据，并且根据灌注成像确定有可挽救的组织。主要结局是患者在第90天时在改良Rankin量表上的等级得分（范围，0~6分，得分越高表示残疾程度越严重，6分表示死亡）。安全性结局包括死亡和有症状的颅内出血。 结果 本试验共招募了458例患者，其中77.3%的患者随后接受了血栓切除术；228例患者被分配接受替奈普酶治疗，230例患者被分配接受安慰剂治疗。在替奈普酶治疗组和安慰剂治疗组中，患者最后一次被确认健康状况良好与随机分组之间的中位时间分别约为12小时和13小时。两组患者在90天时的改良Rankin量表中位数均为3分。在90天时，替奈普酶组与安慰剂组相比，改良Rankin量表评分分布情况的校正共同比值比为1.13(95%置信区间，0.82 ~ 1.57；P = 0.45)。在安全人群中，替奈普酶组90天的死亡率为19.7%，安慰剂组为18.2%，有症状的颅内出血的发生率分别为3.2%和2.3%。 结论 在大多数已经接受过血管内血栓切除术的、大脑中动脉或颈内动脉闭塞的卒中患者中，与接受安慰剂治疗的患者相比，在卒中发作后4.5~24小时内开始接受替奈普酶治疗的患者并未获得更好的临床结局。两组中有症状的颅内出血的发生率相似。 5. Biomarker Changes during 20 Years Preceding Alzheimer’s Disease 阿尔茨海默病发病前20年的生物标志物变化 发表单位：首都医科大学宣武医院神经疾病高创中心；首都医科大学宣武医院神经变性病与记忆障碍疾病临床诊疗与研究中心北京市老年认知障碍重点实验室 Abstract BACKGROUND Biomarker changes that occur in the period between normal cognition and the diagnosis of sporadic Alzheimer’s disease have not been extensively investigated in longitudinal studies. METHODS We conducted a multicenter, nested case–control study of Alzheimer’s disease biomarkers in cognitively normal participants who were enrolled in the China Cognition and Aging Study from January 2000 through December 2020. A subgroup of these participants underwent testing of cerebrospinal fluid (CSF), cognitive assessments, and brain imaging at 2-year–to–3-year intervals. A total of 648 participants in whom Alzheimer’s disease developed were matched with 648 participants who had normal cognition, and the temporal trajectories of CSF biochemical marker concentrations, cognitive testing, and imaging were analyzed in the two groups. RESULTS The median follow-up was 19.9 years (interquartile range, 19.5 to 20.2). CSF and imaging biomarkers in the Alzheimer’s disease group diverged from those in the cognitively normal group at the following estimated number of years before diagnosis: amyloid-beta (Aβ)42, 18 years; the ratio of Aβ42 to Aβ40, 14 years; phosphorylated tau 181, 11 years; total tau, 10 years; neurofilament light chain, 9 years; hippocampal volume, 8 years; and cognitive decline, 6 years. As cognitive impairment progressed, the changes in CSF biomarker levels in the Alzheimer’s disease group initially accelerated and then slowed. CONCLUSIONS In this study involving Chinese participants during the 20 years preceding clinical diagnosis of sporadic Alzheimer’s disease, we observed the time courses of CSF biomarkers, the times before diagnosis at which they diverged from the biomarkers from a matched group of participants who remained cognitively normal, and the temporal order in which the biomarkers became abnormal. 摘要 背景 在纵向研究中，尚未对从认知正常到诊断出散发性阿尔茨海默病期间发生的生物标志物变化进行广泛研究。 方法 我们在2000年1月至2020年12月期间参加中国认知与老龄化研究的认知正常参与者开展了一项阿尔茨海默病生物标志物的多中心巢式病例对照研究。这些参与者中的一部分人每隔2-3年接受一次脑脊液（CSF）检测、认知评估和脑成像检查。共有648名患阿尔茨海默病的参与者与648名认知正常的参与者进行了配对，我们分析了两组脑脊液中生化标志物的浓度、认知测试和影像学的时间轨迹。 结果 中位随访时间为19.9年（四分位数间距为19.5-20.2）。阿尔茨海默病组与认知正常组的脑脊液和影像学生物标志物在以下诊断前的估算年数上出现差异：β淀粉样蛋白（Aβ）42，18年；Aβ42/Aβ40比值，14年；磷酸化tau181，11年；总tau，10年；神经丝轻链，9年；海马体积，8年；认知功能下降，6年。随着认知障碍的进展，阿尔茨海默病组的脑脊液生物标志物水平的变化最初加快，随后放缓。 结论 在这项涉及中国参与者的研究中，我们观察了临床诊断为散发性阿尔茨海默病前20年的脑脊液生物标志物的时间变化，这些生物标志物在诊断前与认知正常匹配参与者的生物标志物出现差异的时间，以及这些生物标志物出现异常的时间顺序。 February 29；Volume 390（9）：773-868 在2024年2月29日，共发表21篇文章，其中包括5篇Perspective，4篇Original articles，1篇Review article，2篇Images in clinical medicine，1篇Case records of the massachusetts general hospital， 4篇Editorials，4篇Correspondence。 6. Cognition and Memory after Covid-19 in a Large Community Sample 大型社区样本中感染Covid-19后的认知和记忆情况 发表单位：帝国理工学院脑科学系;帝国理工学院MRC环境与健康研究中心 Abstract Background: Cognitive symptoms after coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are well-recognized. Whether objectively measurable cognitive deficits exist and how long they persist are unclear. Methods: We invited 800,000 adults in a study in England to complete an online assessment of cognitive function. We estimated a global cognitive score across eight tasks. We hypothesized that participants with persistent symptoms (lasting ≥12 weeks) after infection onset would have objectively measurable global cognitive deficits and that impairments in executive functioning and memory would be observed in such participants, especially in those who reported recent poor memory or difficulty thinking or concentrating ("brain fog"). Results: Of the 141,583 participants who started the online cognitive assessment, 112,964 completed it. In a multiple regression analysis, participants who had recovered from Covid-19 in whom symptoms had resolved in less than 4 weeks or at least 12 weeks had similar small deficits in global cognition as compared with those in the no-Covid-19 group, who had not been infected with SARS-CoV-2 or had unconfirmed infection (-0.23 SD [95% confidence interval {CI}, -0.33 to -0.13] and -0.24 SD [95% CI, -0.36 to -0.12], respectively); larger deficits as compared with the no-Covid-19 group were seen in participants with unresolved persistent symptoms (-0.42 SD; 95% CI, -0.53 to -0.31). Larger deficits were seen in participants who had SARS-CoV-2 infection during periods in which the original virus or the B.1.1.7 variant was predominant than in those infected with later variants (e.g., -0.17 SD for the B.1.1.7 variant vs. the B.1.1.529 variant; 95% CI, -0.20 to -0.13) and in participants who had been hospitalized than in those who had not been hospitalized (e.g., intensive care unit admission, -0.35 SD; 95% CI, -0.49 to -0.20). Results of the analyses were similar to those of propensity-score-matching analyses. In a comparison of the group that had unresolved persistent symptoms with the no-Covid-19 group, memory, reasoning, and executive function tasks were associated with the largest deficits (-0.33 to -0.20 SD); these tasks correlated weakly with recent symptoms, including poor memory and brain fog. No adverse events were reported. Conclusions Participants with resolved persistent symptoms after Covid-19 had objectively measured cognitive function similar to that in participants with shorter-duration symptoms, although short-duration Covid-19 was still associated with small cognitive deficits after recovery. Longer-term persistence of cognitive deficits and any clinical implications remain uncertain. 摘要 背景 由严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）引起的2019年新型冠状病毒病（Covid-19）后的认知症状已得到广泛认可。目前尚不清楚是否存在可客观测量的认知障碍，也不清楚认知障碍会持续多久。 方法 我们在英国的一项研究中邀请了80万成年人完成在线认知功能评估。我们估算了八项任务的总体认知得分。我们假设，感染发病后症状持续存在（持续时间≥12周）的参与者会出现可客观测量的整体认知功能障碍，而且在这些参与者中会观察到执行功能和记忆力受损，尤其是那些报告近期记忆力差或难以思考或集中注意力（"脑雾"）的参与者。 结果 在141583名参与者中，有112964人完成了在线认知评估。在多元回归分析中，与未感染或未确诊感染新冠病毒的无Covid-19组相比，新冠症状在少于4周或至少12周内缓解的Covid-19康复者的总体认知能力有相似的小幅下降（分别为-0.23 SD [95%CI -0.33 ~ -0.13]和-0.24 SD [95%CI{-0.36 ~ -0.12]）。与无Covid-19组相比，症状持续未缓解的参与者的认知能力下降更明显（-0.42 SD；95%CI，-0.53 ~ -0.31）。在原始病毒或 B.1.1.7 变异株为主要流行株的期间感染 SARS-CoV-2 的受试者，相较于感染后期变异株（例如B.1.1.529变异株）的受试者出现更大的认知缺损（例如，B.1 .1.7变异株与B.1.1.529变异株相比为-0.17 SD；95% CI，-0.20 ~ -0.13）。此外，曾住院的受试者与未住院受试者相比认知缺陷更大（例如，入住重症监护室的受试者与未住院受试者相比，-0.35 SD；95% CI，-0.49 ~ -0.20）。分析结果与倾向性评分匹配分析结果相似。在将持续症状未缓解组与无Covid-19组进行比较时，发现记忆、推理和执行功能任务方面的缺陷最大（-0.33 ~ -0.20 SD）；这些任务与近期症状（包括记忆力差和脑雾）的相关性较弱。试验期间无不良事件报告。 结论 感染Covid-19 后持续性症状得到缓解的受试者，其客观测量的认知功能与症状持续时间较短的受试者相似，但短期 Covid-19 感染在康复后仍与轻微认知缺陷有关。认知障碍的长期持续性和任何临床影响目前仍不确定。 7. Simple versus Radical Hysterectomy in Women with Low-Risk Cervical Cancer 低危宫颈癌女性行单纯子宫切除术与根治性子宫切除术的比较 发表单位：加拿大魁北克大学医院中心;加拿大不列颠哥伦比亚大学 Abstract BACKGROUND Retrospective data suggest that the incidence of parametrial infiltration is low in patients with early-stage low-risk cervical cancer, which raises questions regarding the need for radical hysterectomy in these patients. However, data from large, randomized trials comparing outcomes of radical and simple hysterectomy are lacking. METHODS We conducted a multicenter, randomized, noninferiority trial comparing radical hysterectomy with simple hysterectomy including lymph-node assessment in patients with low-risk cervical cancer (lesions of ≤2 cm with limited stromal invasion). The primary outcome was cancer recurrence in the pelvic area (pelvic recurrence) at 3 years. The prespecified noninferiority margin for the between-group difference in pelvic recurrence at 3 years was 4 percentage points. RESULTS Among 700 patients who underwent randomization (350 in each group), the majority had tumors that were stage IB1 according to the 2009 International Federation of Gynecology and Obstetrics (FIGO) criteria (91.7%), that had squamous-cell histologic features (61.7%), and that were grade 1 or 2 (59.3%). With a median follow-up time of 4.5 years, the incidence of pelvic recurrence at 3 years was 2.17% in the radical hysterectomy group and 2.52% in the simple hysterectomy group (an absolute difference of 0.35 percentage points; 90% confidence interval, −1.62 to 2.32). Results were similar in a per-protocol analysis. The incidence of urinary incontinence was lower in the simple hysterectomy group than in the radical hysterectomy group within 4 weeks after surgery (2.4% vs. 5.5%; P=0.048) and beyond 4 weeks (4.7% vs. 11.0%; P=0.003). The incidence of urinary retention in the simple hysterectomy group was also lower than that in the radical hysterectomy group within 4 weeks after surgery (0.6% vs. 11.0%; P<0.001) and beyond 4 weeks (0.6% vs. 9.9%; P<0.001). CONCLUSIONS In patients with low-risk cervical cancer, simple hysterectomy was not inferior to radical hysterectomy with respect to the 3-year incidence of pelvic recurrence and was associated with a lower risk of urinary incontinence or retention. 摘要 背景 回顾性数据表明，早期低危宫颈癌患者子宫旁浸润的发生率较低，这引出了关于这些患者是否需要进行根治性子宫切除术的问题。然而，目前还缺乏比较根治性和单纯性子宫切除术结局的大型随机试验数据。 方法 我们开展了一项多中心、随机、非劣效性试验，在低危宫颈癌（病变≤2厘米，且间质浸润有限）患者中比较了根治性子宫切除术和包括淋巴结评估在内的单纯子宫切除术的治疗效果。主要结局是3年后盆腔区域的癌症复发（盆腔复发）。3年后盆腔复发率组间差异的预设非劣效性界值为4个百分点。 结果 在接受随机分组的700名患者中（每组350人），根据2009年国际妇产科联合会（FIGO）的标准，大多数患者的肿瘤属于IB1期（91.7%），具有鳞状细胞组织学特征（61.7%），且属于1级或2级（59.3%）。中位随访时间为4.5年，根治性子宫切除术组3年盆腔复发率为2.17%，单纯子宫切除术组为2.52%（绝对差异为0.35个百分点；90%CI，-1.62 ~ 2.32）。每个方案分析的结果类似。单纯子宫切除术组术后4周内（2.4% vs. 5.5%；P=0.048）和4周后（4.7% vs. 11.0%；P=0.003）的尿失禁发生率低于根治性子宫切除术组。单纯子宫切除术组在术后4周内（0.6% vs. 11.0%; P<0.001）和4周后（0.6% vs. 9.9%; P<0.001）的尿潴留发生率也低于根治性子宫切除术组。 结论 在低危宫颈癌患者中，就3年盆腔复发率而言，单纯子宫切除术并不比根治性子宫切除术差，而且发生尿失禁或尿潴留的风险较低。 March 07；Volume 390（10）：869-964 在2024年3月7日，共发表19篇文章，其中包括3篇Perspective，4篇Original articles，1篇Review article，2篇Images in clinical medicine，1篇Clinical problem-solving，3篇Editorials，1篇Medicine and society，4篇Correspondence。 8. Omalizumab for the Treatment of Multiple Food Allergies 奥马珠单抗治疗多种食物过敏 发表单位：美国约翰霍普金斯大学医学院儿科部;美国国立卫生研究院 Abstract BACKGROUND Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. 摘要 背景 食物过敏很常见，而且发病率很高；目前唯一获准的治疗方法是针对花生过敏的口服免疫疗法。 方法 在这项试验中，我们评估了奥马珠单抗（一种单克隆抗IgE抗体）作为多种食物过敏患者的单一疗法是否有效和安全。我们筛选了对花生和至少两种试验指定食物（腰果、牛奶、鸡蛋、核桃、小麦和榛子）过敏的1~55岁患者。纳入标准是必须对100mg或更少的花生蛋白和300mg或更少的其他两种食物激发有反应。我们以2:1的比例将参与者随机分配到奥马珠单抗组或安慰剂组，两组分别每2至4周接受一次奥马珠单抗或安慰剂皮下注射一次（剂量基于体重和IgE水平而定），持续16~20周，之后重复激发。主要终点是单次摄入≥600mg花生蛋白而不出现剂量限制性症状。三个关键的次要终点是单次摄入腰果、牛奶和鸡蛋的剂量均达到或超过1000mg，且未出现剂量限制性症状。完成第一阶段研究的前60名参与者（其中59例为儿童或青少年）被纳入为期24周的开放标签扩展试验。 结果 在接受筛查的462人中，有180人被随机分组。分析人群包括177名儿童和青少年（1~17岁）。在接受奥马珠单抗治疗的118人中，共有79人（67%）达到了主要终点标准，而在接受安慰剂治疗的59人中，只有4人（7%）达到了主要终点标准（P<0.001）。关键次要终点的结果与主要终点的结果一致（腰果，41% vs 3%；牛奶，66% vs 10%；鸡蛋，67% vs 0%；所有比较的 P<0.001）。除了奥马珠单抗组的注射部位出现反应较多外，两组的安全性终点没有差异。 结论 对于年仅 1 岁的多种食物过敏患者，在提高对花生和其他常见食物过敏原的反应阈值方面，奥马珠单抗治疗 16 周后效果优于安慰剂。 9. Microplastics and Nanoplastics in Atheromas and Cardiovascular Events 动脉粥样硬化和心血管事件中的微塑料和纳米塑料 发表单位：意大利坎帕尼亚大学 Abstract BACKGROUND Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends to humans is lacking. METHODS We conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis–gas chromatography–mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs. RESULTS A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 μg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 μg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001). CONCLUSIONS In this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected. 摘要 背景 在临床前研究中，微塑料和纳米塑料（MNPs）正逐渐成为心血管疾病的潜在危险因素。目前还没有直接证据表明这种风险会延伸至人类。 方法 我们在因无症状颈动脉疾病而接受颈动脉内膜切除术的患者中开展了一项前瞻性、多中心、观察性研究。利用热裂解-气相色谱-质谱法、稳定同位素分析法和电子显微镜技术，分析了切除的颈动脉斑块标本中是否存在MNPs。用酶联免疫吸附测定法和免疫组织化学方法评估炎症生物标志物。主要终点是颈动脉斑块中检出MNPs的患者与未检出MNPs的患者相比，发生心肌梗死、中风或全因死亡的复合结局。 结果 共有 304 名患者参与了研究，其中 257 人完成了平均（±SD）为 33.7 ± 6.9 个月的随访。150名患者（58.4%）的颈动脉斑块中检测到聚乙烯，平均含量为21.7 ± 24.5μg/mg斑块；31名患者（12.1%）的斑块中也检测到聚氯乙烯，平均含量为5.2±2.4 μg/mg斑块。电子显微镜显示在斑块巨噬细胞和外部碎片中散布着可见的、边缘锯齿状的外来颗粒。放射学检查显示，其中一些颗粒含有氯。在动脉粥样斑块中检测到 MNPs 的患者发生主要终点事件的风险高于未检测到这些物质的患者（HR，4.53；95%CI，2.00-10.27；P<0.001）。 结论 在这项研究中，与未检测到MNPs的患者相比，颈动脉斑块检测到MNPs的患者在34个月的随访中发生心肌梗死、中风或全因死亡的综合风险更高。 March 14；Volume 390（11）：965-1060 在2024年3月14日，共发表22篇文章，其中包括5篇Perspective，4篇Original articles，1篇Review article，2篇Images in clinical medicine，1篇Case records of the Massachusetts general hospital，3篇Editorials，5篇Correspondence，1篇Correction。 10. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening 基于循环游离DNA的血液检测可用于筛查结直肠癌 发表单位：麻省总医院和哈佛医学院 Abstract BACKGROUND Colorectal cancer is the third most diagnosed cancer in adults in the United States. Early detection could prevent more than 90% of colorectal cancer–related deaths, yet more than one third of the screening-eligible population is not up to date with screening despite multiple available tests. A blood-based test has the potential to improve screening adherence, detect colorectal cancer earlier, and reduce colorectal cancer–related mortality. METHODS We assessed the performance characteristics of a cell-free DNA (cfDNA) blood-based test in a population eligible for colorectal cancer screening. The coprimary outcomes were sensitivity for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions) relative to screening colonoscopy. The secondary outcome was sensitivity to detect advanced precancerous lesions. RESULTS The clinical validation cohort included 10,258 persons, 7861 of whom met eligibility criteria and were evaluable. A total of 83.1% of the participants with colorectal cancer detected by colonoscopy had a positive cfDNA test and 16.9% had a negative test, which indicates a sensitivity of the cfDNA test for detection of colorectal cancer of 83.1% (95% confidence interval [CI], 72.2 to 90.3). Sensitivity for stage I, II, or III colorectal cancer was 87.5% (95% CI, 75.3 to 94.1), and sensitivity for advanced precancerous lesions was 13.2% (95% CI, 11.3 to 15.3). A total of 89.6% of the participants without any advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions) identified on colonoscopy had a negative cfDNA blood-based test, whereas 10.4% had a positive cfDNA blood-based test, which indicates a specificity for any advanced neoplasia of 89.6% (95% CI, 88.8 to 90.3). Specificity for negative colonoscopy (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0 to 90.7). CONCLUSIONS In an average-risk screening population, this cfDNA blood-based test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. 摘要 背景 结直肠癌是美国成年人确诊第三大的癌症。早期检测可预防90%以上与结直肠癌相关的死亡，然而，尽管有多种可用的检测方法，仍有超过三分之一的符合筛查条件的人群没有及时进行筛查。基于血液的检测有可能提高筛查的依从性，更早发现结直肠癌，并降低结直肠癌相关死亡率。 方法 我们在符合结直肠癌筛查条件的人群中评估了基于循环游离DNA（cfDNA）的血液检测的性能特征。联合主要结局是相对于结肠镜筛查，该方法对结肠直肠癌的敏感性和对晚期肿瘤（结肠直肠癌或晚期癌前病变）的特异性。次要结局是检测晚期癌前病变的敏感性。 结果 临床验证队列包括10258人，其中7861人符合纳入标准并可进行评估。通过结肠镜检查发现患有结直肠癌的受试者中，有83.1%的受试者的cfDNA检测结果呈阳性，16.9%的受试者检测结果呈阴性，这表明cfDNA检测对结直肠癌的敏感性为83.1%（95% CI，72.2 ~ 90.3）。对I、II或III期结直肠癌的敏感性为87.5% （95% CI，75.3 ~ 94.1），对晚期癌前病变的敏感性为13.2% （95% CI，11.3 ~15.3）。在结肠镜检查未发现任何晚期结直肠肿瘤（结直肠癌或晚期癌前病变）的受试者中，共有89.6%的人的cfDNA血液检测结果为阴性，而10.4%的人的cfDNA血液检测结果为阳性，这表明对任何晚期肿瘤的特异性为89.6% （95% CI，88.8 ~ 90.3）。结肠镜检查阴性（无结直肠癌、晚期癌前病变或非晚期癌前病变）的特异性为89.9%（95% CI，89.0 ~ 90.7）。 结论 在一般风险筛查人群中，这种基于血液的cfDNA检测对结直肠癌的灵敏度为83%，对晚期肿瘤的特异性为90%，对晚期癌前病变的灵敏度为13%。 March 21/28；Volume 390（12）：1061-1156 在2024年3月21/28日，共发表20篇文章，其中包括5篇Perspective，4篇Original articles，1篇Review article，2篇Images in clinical medicine，1篇Case records of the Massachusetts general hospital，2篇Editorials，5篇Correspondence。 11. Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure 产前托吡酯、丙戊酸钠或拉莫三嗪暴露后的自闭症风险 发表单位：哈佛大学陈曾熙公共卫生学院流行病学系;布列根和妇女医院和哈佛医学院 Abstract BACKGROUND Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use. METHODS We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control. RESULTS The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score–adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine. CONCLUSIONS The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. 摘要 背景 母亲在妊娠期间使用丙戊酸钠与儿童神经发育障碍的风险增加有关。虽然大多数关于其他抗癫痫药物的研究并未显示这些疾病的风险会增加，但关于母亲使用托吡酯与自闭症谱系障碍风险的数据有限且相互矛盾。 方法 我们在美国的两个医疗保健使用数据库中确定了一个基于人群的孕妇及其子女队列，数据时间跨度为2000年至2020年。根据从孕19周到分娩期间的处方开具情况来确定是否暴露于特定的抗癫痫药物。将妊娠后半期暴露于托吡酯的儿童与妊娠期间未暴露于任何抗癫痫药物的儿童进行自闭症谱系障碍风险比较。以丙戊酸钠作为阳性对照，拉莫三嗪作为阴性对照。 结果 在所有未暴露于抗癫痫药物的儿童中（4,199,796名儿童），8岁时自闭症谱系障碍的累积发病率为1.9%。如果将儿童限制在有癫痫的母亲所生的儿童中，则在未暴露于抗癫痫药物的情况下，发病率为4.2%(8,815名儿童)，在暴露于托吡酯的情况下，发病率为6.2%(1,030名儿童)，在暴露于丙戊酸的情况下，发病率为10.5%(800名儿童)，在暴露于拉莫三嗪的情况下，发病率为4.1%(4,205名儿童)。在与无抗癫痫药物暴露的患者进行的比较中，托吡酯暴露、丙戊酸暴露和拉莫三嗪暴露的倾向评分校正风险比分别为0.96(95% CI， 0.56 ~ 1.65)、2.67 (95% CI, 1.69 ~ 4.20)和1.00 (95% CI, 0.69 ~ 1.46)。 结论 在产前暴露于所研究的抗癫痫药物的儿童中，自闭症谱系障碍的发病率高于普通人群。然而，在对适应症和其他混杂因素进行校正后，托吡酯和拉莫三嗪的相关性大大降低，而丙戊酸钠的风险仍然增加。 April 04；Volume 390（13）：1157-1251 在2024年4月4日，共发表23篇文章，其中包括4篇Perspective，4篇Original articles，1篇Review article，2篇Images in clinical medicine，1篇Case records of the Massachusetts general hospital，3篇Editorials，1篇Clinical decisions，7篇Correspondence。 12. Trial of Lixisenatide in Early Parkinson’s Disease 利西拉肽治疗早期帕金森病的试验 发表单位：法国帕金森病与运动障碍临床研究网络;法国图卢兹大学医院 Abstract BACKGROUND Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson’s disease. METHODS In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson’s disease. Participants in whom Parkinson’s disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by −0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P=0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS In participants with early Parkinson’s disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson’s disease. 摘要 背景 利西拉肽是一种用于治疗糖尿病的胰高血糖素样肽-1受体激动剂，它在帕金森病小鼠模型中表现出神经保护特性。 方法 在这项2期、双盲、随机、安慰剂对照试验中，我们评估了利西拉肽对帕金森病患者运动障碍进展的影响。我们按照1:1的比例将帕金森病确诊时间不足3年、正在接受稳定剂量的药物治疗且没有运动并发症的受试者随机分组，分别接受每日皮下注射利西拉肽或安慰剂，为期12个月，然后进行为期2个月的洗脱期。主要终点是运动障碍协会-帕金森病统一评定量表（MDS-UPDRS）第III部分（范围为0~132分，得分越高表示运动障碍越严重）评分相对于基线的变化，该评分在12个月时处于用药状态下的患者中进行评估。次要终点包括6个月、12个月和14个月时的其他MDS-UPDRS各部分评分以及等效左旋多巴剂量。 研究结果 共纳入156人，每组78人。两组患者基线时的MDS-UPDRS第Ⅲ部分评分均约为15分。12个月时，利西拉肽组的MDS-UPDRS第III部分评分变化了-0.04分（表明病情好转），安慰剂组则变化了3.04分（表明加重）（差异为3.08；95%CI，0.86~5.30；P=0.007）。经过2个月的冲洗期后，在第14个月时，停药状态下的平均MDS-UPDRS运动评分分别为，利西拉肽组17.7分（95%CI，15.7~19.7）分，安慰剂组20.6分（95%CI，18.5~22.8）分。与次要终点相关的其他结果在两组之间没有显著差异。接受利西拉肽治疗的患者中有46%出现了恶心，13%出现了呕吐。 结论 在一项二期试验中，对于早期帕金森病患者，利西拉肽治疗与安慰剂相比，在12个月时减少了运动障碍的进展，但与胃肠道副作用相关。我们还需要进行更长时间和更大规模的试验来确定利西拉肽对帕金森病患者的疗效和安全性，。 April 11；Volume 390（14）：1253-1348 在2024年4月11日，共发表22篇文章，其中包括5篇Perspective，3篇Original articles，1篇Review article，2篇Images in clinical medicine，1篇Case records of the Massachusetts general hospital，4篇Editorials，1篇Medicine and society，5篇Correspondence。 13. Alectinib in Resected ALK-Positive Non–Small-Cell Lung Cancer 阿来替尼治疗经手术切除的 ALK 阳性非小细胞肺癌 发表单位：广东省人民医院广东省肺癌研究所;中国科学院基础医学与肿瘤研究所 Abstract BACKGROUND Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non–small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease–free survival, overall survival, and safety. RESULTS In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease–free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. 摘要 背景 铂类化疗是可切除的ALK阳性非小细胞肺癌（NSCLC）患者的推荐辅助治疗方法。目前缺乏比较阿来替尼辅助治疗与化疗在切除后alk阳性NSCLC患者中的疗效和安全性的数据。 方法 我们开展了一项全球性的3期、开放标签、随机试验，将完全切除的ALK阳性非小细胞肺癌IB期（肿瘤≥4cm）、II期或IIIA期（根据美国癌症联合委员会和国际癌症控制联盟的《癌症分期手册》第七版进行分类）患者按1:1的比例随机分组，分别接受口服阿来替尼（600mg/次，每天两次）24个月或静脉注射铂类化疗4个21天周期。主要终点是无病生存期，在II期或IIIA期患者中进行分层检验，然后在意向治疗人群中进行检验。其他终点包括中枢神经系统（CNS）无病生存期、总生存期和安全性。 结果 共有257名患者被随机分配接受阿来替尼（130名）或化疗（127名）。在II期或IIIA期肺癌患者中，阿来替尼组2年存活且无病的患者比例为93.8%，化疗组为63.0%（疾病复发或死亡风险比为0.24；95%CI，0.13~0.45；P<0.001）；在意向治疗人群中，阿来替尼组2年存活且无病的患者比例为93.6%，化疗组为63.7%（风险比为0.24；95%CI，0.13~0.43；P<0.001）。与化疗相比，阿来替尼在中枢神经系统无病生存期方面具有临床意义（中枢神经系统疾病复发或死亡的风险比为0.22；95%CI，0.08~0.58）。总生存期数据尚不成熟。未观察到意外的安全性结果。 结论 在经手术切除的IB、II或IIIA期ALK阳性非小细胞肺癌患者中，与铂类化疗相比，阿来替尼辅助治疗可显著延长无病生存期。 14. Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage 早期微创清除脑出血的试验 发表单位：美国埃默里大学医学院;美国格兰迪纪念医院马库斯中风和神经科学中心 Abstract BACKGROUND Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known. METHODS In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients’ assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment. RESULTS A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and −0.013 (95% Bayesian credible interval, −0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration. CONCLUSIONS Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. 摘要 背景 手术清除幕上脑出血的试验通常显示无功能获益。目前尚不清楚早期微创手术清除是否会比药物治疗取得更好的疗效。 方法 在这项纳入急性脑出血患者的多中心随机试验中，我们对手术清除血肿与药物治疗进行了比较。将脑叶或基底节前部出血且血肿量在30~80 ml的患者，在其最后一次确认健康状况以后的24小时内，按1:1的比例随机分配到微创手术清除血肿联合基于指南的药物治疗组（手术组）或仅接受基于指南的药物治疗组（对照组）。主要疗效终点是180天时的效用加权改良Rankin量表（范围为0~1分，根据患者的评估，得分越高表示疗效越好）的平均得分，预设的优效性后验概率阈值为0.975或更高。该试验还包括根据出血部位调整入选标准的适应性规则。主要安全性终点是入组后30天内死亡情况。 结果 共纳入300名患者，其中基底节区前出血占30.7%，脑叶出血占69.3%。在纳入175名患者后，触发了适应性规则，只有脑叶出血患者才被招募。180天时，手术组的效用加权改良Rankin量表平均得分为0.458，对照组为0.374（差异为0.084；95%贝叶斯可信区间为0.005~0.163；手术优效性后验概率为0.981）。脑叶出血患者的组间平均差异为0.127（95%贝叶斯可信区间为0.035~0.219），基底节前部出血患者的组间平均差异为-0.013（95%贝叶斯可信区间为-0.147~0.116）。手术组患者在30天内死亡的比例为9.3%，对照组为18.0%。手术组中有五名患者（3.3%）出现术后再出血和神经功能恶化。 结论 在急性脑出血后24小时内可以进行手术的患者中，微创血肿清除术在180 天时的功能结局优于基于指南的药物治疗。手术的效果似乎归因于对脑叶出血的干预。 汇报人： 倪恬 导师：赵宇 审核：任建君 毛敏姿
