军人脑内的慢性创伤性脑病
Chronic Traumatic Encephalopathy in the Brains of Military Personnel
背景
暴露于战斗中的军人可能有持续性神经精神后遗症；此类后遗症在某些情况下被归因于慢性创伤性脑病（CTE）。关于军人脑内CTE的数据有限。
Persistent neuropsychiatric sequelae may develop in military personnel who are exposed to combat; such sequelae have been attributed in some cases to chronic traumatic encephalopathy (CTE). Only limited data regarding CTE in the brains of military service members are available.
方法
我们对连续的225个脑进行了神经病理学检查，以确定是否有CTE；这些脑来自专门研究已故军人脑部的脑库。此外，我们还检查了回顾性收集的死者既往信息，包括爆炸暴露、参与身体接触运动、其他类型的颅脑损伤（TBI）和神经精神障碍。
We performed neuropathological examinations for the presence of CTE in 225 consecutive brains from a brain bank dedicated to the study of deceased service members. In addition, we reviewed information obtained retrospectively regarding the decedents’ histories of blast exposure, contact sports, other types of traumatic brain injury (TBI), and neuropsychiatric disorders.
结果
在我们检查的225个脑中，经过神经病理学检查，10个（4.4%）有CTE；一半CTE病例只有单一诊断病灶。在有爆炸暴露史的死者的45个脑中，3个有CTE，相比之下，在无爆炸暴露史的死者的180个脑中，7个有CTE（相对危险度，1.71；95%置信区间[CI]，0.46~6.37）；在有TBI（原因是服役期间，头部撞击物体后受伤，但无相关爆炸暴露史，称为军事TBI）的死者的21个脑中，3个有CTE，相比之下，在无上述TBI的死者的204个脑中，7个有CTE（相对危险度，4.16；95% CI，1.16~14.91）。有CTE的脑全部来自参与过身体接触运动的死者；在参与过身体接触运动的60名参与者中，10名有CTE，相比之下，在未参与过身体接触运动的165名参与者中，有CTE的人数为0（相对危险度的点估计值无法计算；95% CI，6.16~无限）。在平民生活中发生过非运动相关TBI的死者的44个脑中，8个有CTE，相比之下，在平民生活中未发生过上述情况的死者的181个脑中，2个有CTE（相对危险度，16.45；95% CI，3.62~74.79）。
Result
Neuropathological findings of CTE were present in 10 of the 225 brains (4.4%) we examined; half the CTE cases had only a single pathognomonic lesion. Of the 45 brains from decedents who had a history of blast exposure, 3 had CTE, as compared with 7 of 180 brains from those without a history of blast exposure (relative risk, 1.71; 95% confidence interval [CI], 0.46 to 6.37); 3 of 21 brains from decedents with TBI from an injury during military service caused by the head striking a physical object without associated blast exposure (military impact TBI) had CTE, as compared with 7 of 204 without this exposure (relative risk, 4.16; 95% CI, 1.16 to 14.91). All brains with CTE were from decedents who had participated in contact sports; 10 of 60 contact-sports participants had CTE, as compared with 0 of 165 who had not participated in contact sports (point estimate of relative risk not computable; 95% CI, 6.16 to infinity). CTE was present in 8 of 44 brains from decedents with non–sports-related TBI in civilian life, as compared with 2 of 181 brains from those without such exposure in civilian life (relative risk, 16.45; 95% CI, 3.62 to 74.79).
结论
CTE证据在来自军人的一系列脑中很少见，而且常表现为微小的神经病理学变化。在参与过身体接触运动的死者以及在平民生活中曾因其他原因发生TBI的死者中，CTE的风险比高于曾暴露于爆炸或曾发生其他军事TBI的死者，但由于CTE病例数量少，且置信区间宽，因此我们无法就因果关系得出结论。（由美国国防部—国防大学脑组织库和神经病理学项目[Department of Defense–Uniformed Services University Brain Tissue Repository and Neuropathology Program]以及Henry M. Jackson军事医学发展基金会[Henry M. Jackson Foundation for the Advancement of Military Medicine]资助。）
Conclusions
Evidence of CTE was infrequently found in a series of brains from military personnel and was usually reflected by minimal neuropathologic changes. Risk ratios for CTE were numerically higher among decedents who had contact-sports exposure and other exposures to TBI in civilian life than among those who had blast exposure or other military TBI, but the small number of CTE cases and wide confidence intervals preclude causal conclusions. (Funded by the Department of Defense–Uniformed Services University Brain Tissue Repository and Neuropathology Program and the Henry M. Jackson Foundation for the Advancement of Military Medicine.)
David S. Priemer, Diego Iacono, C. Harker Rhodes, Chronic Traumatic Encephalopathy in the Brains of Military Personnel. DOI: 10.1056/NEJMoa2203199
磷酸二酯酶4B优先抑制剂治疗特发性肺纤维化的试验
Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis
背景
磷酸二酯酶4（PDE4）抑制与抗炎和抗纤维化作用相关，这些作用可能对特发性肺纤维化患者有益。
Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis.
在这项2期、双盲、安慰剂对照试验中，我们在特发性肺纤维化患者中研究了BI 1015550（一种口服PDE4B亚型优先抑制剂）的疗效和安全性。我们以2:1的比例将患者随机分组，分别接受BI 1015550每日2次、每次18 mg，或者接受安慰剂。主要终点是12周时用力肺活量（FVC）相对于基线的变化，我们根据背景治疗是否使用抗纤维化药物，使用贝叶斯方法分别进行了主要终点分析。
In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent.
共计147例患者被随机分组，两组患者分别接受BI 1015550或安慰剂。在未使用背景抗纤维化药物的患者中，BI 1015550组和安慰剂组FVC的中位变化分别为5.7 ml（95%可信区间，-39.1~50.5）和-81.7 ml（95%可信区间，-133.5~-44.8）（中位差异，88.4 ml；95%可信区间，29.5~154.2；BI 1015550优于安慰剂的概率，0.998）。在使用背景抗纤维化药物的患者中，BI 1015550组和安慰剂组FVC的中位变化分别为2.7 ml（95%可信区间，-32.8~38.2）和-59.2 ml（95%可信区间，-111.8~-17.9）（中位差异，62.4 ml；95%可信区间，6.3~125.5；BI 1015550优于安慰剂的概率，0.986）。重复测量的混合模型分析提供的结果与贝叶斯分析结果一致。最频繁的不良事件是腹泻。共计13例患者因不良事件终止BI 1015550治疗。两个试验组发生严重不良事件或重度不良事件的患者百分比相似。
Result
A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, –39.1 to 50.5) in the BI 1015550 group and –81.7 ml (95% credible interval, –133.5 to –44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, –32.8 to 38.2) in the BI 1015550 group and –59.2 ml (95% credible interval, –111.8 to –17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups.
结论
在这项安慰剂对照试验中，BI 1015550单独治疗或者与背景抗纤维化药物联合治疗均可防止特发性肺纤维化患者肺功能减退。（由勃林格殷格翰资助；13050-013在ClinicalTrials.gov注册号为NCT04419506。）
Conclusions
In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.)
Luca Richeldi, Arata Azuma, Vincent Cottin, Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis. DOI: 10.1056/NEJMoa2201737
肌内注射AZD7442（tixagevimab–cilgavimab）预防COVID-19
Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19
背景
单克隆抗体复方药物AZD7442包含tixagevimab和cilgavimab，它们是两种抗SARS-CoV-2的单克隆抗体，半衰期长，而且已在动物模型中显示出预防和治疗效应。人体药代动力学数据表明，AZD7442的半衰期长，可达到约90天。
The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days.
在正在进行的3期试验中，我们纳入了符合以下标准的成人（≥18岁）：接种COVID-19疫苗后应答不足的风险高，暴露于SARS-CoV-2的风险高，或以上两项风险均高。我们以2:1的比例将参与者随机分组，两组分别接受单剂（连续两次肌内注射，一次含tixagevimab，另一次含cilgavimab）300 mg AZD7442或生理盐水安慰剂，并在主要分析中接受了长达183天随访。主要安全性终点是接受单剂AZD7442后的不良事件发生率。主要效力终点是接受AZD7442或安慰剂之后至第183日（包含当日）发生的有症状COVID-19（通过逆转录酶聚合酶链反应确诊SARS-CoV-2感染）。
In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase–polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183.
结果
共计5197名参与者接受了随机分组，并接受了单剂AZD7442或安慰剂（AZD7442组3460人，安慰剂组1737人）。主要分析是在30%参与者知晓随机分组结果之后进行。总体而言，AZD7442组3461名参与者中的1221名（35.3%）和安慰剂组1736名参与者中的593名（34.2%）报告了至少一起不良事件，其中大多数为轻度或中度。AZD7442组3441名参与者中的8名（0.2%）和安慰剂组1731名参与者中的17名（1.0%）发生了有症状COVID-19（相对危险度降幅，76.7%；95%置信区间[CI]，46.0~90.0；p<0.001）；中位6个月的延长随访期显示，相对危险度降幅为82.8%（95% CI，65.8~91.4）。该试验出现5例重症或危重症COVID-19和2例COVID-19相关死亡，全部发生于安慰剂组。
Result
A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19–related deaths occurred, all in the placebo group.
结论
单剂AZD7442可有效预防COVID-19，且无明显的安全性问题。（由阿斯利康和美国政府资助；PROVENT在ClinicalTrials.gov注册号为NCT04625725。）
Conclusions
A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.)
Myron J. Levin, Andrew Ustianowski, Stéphane De Wit, Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19. DOI: 10.1056/NEJMoa2116620
天然和混合免疫力对SARS-CoV-2的防护力及免疫力减弱情况
Protection and Waning of Natural and Hybrid Immunity to SARS-CoV-2
背景
SARS-CoV-2感染可产生有助于预防再感染的天然免疫力。最近有研究表明，接种BNT162b2疫苗产生的免疫力会逐渐减弱。天然和混合免疫力的时间进程尚不明确。
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provides natural immunity against reinfection. Recent studies have shown waning of the immunity provided by the BNT162b2 vaccine. The time course of natural and hybrid immunity is unknown.
应用以色列卫生部（Ministry of Health）数据库，我们提取了既往发生过SARS-CoV-2感染或已接种COVID-19疫苗的所有人在2021年8—9月（当时B.1.617.2[delta]变异株是主要流行株）的数据。我们应用针对混杂因素校正的泊松回归方法比较了自产生免疫力的上一次事件以来，作为时间函数的感染率。
Using the Israeli Ministry of Health database, we extracted data for August and September 2021, when the B.1.617.2 (delta) variant was predominant, on all persons who had been previously infected with SARS-CoV-2 or who had received coronavirus 2019 vaccine. We used Poisson regression with adjustment for confounding factors to compare the rates of infection as a function of time since the last immunity-conferring event.
结果
自接种BNT162b2疫苗或上次感染以来，每100,000人-风险日（person-days at risk）的SARS-CoV-2感染病例数（校正后的感染率）随时间推移而增加。在感染后已康复的未接种疫苗者中，上述感染率在之前4~<6个月发生感染的人群中为10.5，在之前≥1年发生感染的人群中升高至30.2。在既往感染后接种过一剂疫苗的人群中，校正后的上述感染率在之前2个月内接种疫苗的人群中低（3.7），但在之前≥6个月接种疫苗的人群中升高至11.6。在既往未发生过感染，并已接种两剂疫苗的人群中，校正后的上述感染率在之前2个月内接种疫苗的人群中为21.1，在之前≥6个月接种疫苗的人群中升高至88.9。
Result
The number of cases of SARS-CoV-2 infection per 100,000 person-days at risk (adjusted rate) increased with the time that had elapsed since vaccination with BNT162b2 or since previous infection. Among unvaccinated persons who had recovered from infection, this rate increased from 10.5 among those who had been infected 4 to less than 6 months previously to 30.2 among those who had been infected 1 year or more previously. Among persons who had received a single dose of vaccine after previous infection, the adjusted rate was low (3.7) among those who had been vaccinated less than 2 months previously but increased to 11.6 among those who had been vaccinated at least 6 months previously. Among previously uninfected persons who had received two doses of vaccine, the adjusted rate increased from 21.1 among those who had been vaccinated less than 2 months previously to 88.9 among those who had been vaccinated at least 6 months previously.
结论
在既往发生过SARS-CoV-2感染的人群中（无论是否接种过疫苗，也无论在感染前还是感染后接种过一剂疫苗），自产生免疫力的上一次事件以来，免疫力对再感染的防护力都随时间推移而减弱；然而，这一防护力高于既往未发生感染的人群在接种第二剂疫苗后相同时间的防护力。感染后接种一剂疫苗可增强对再感染的防护力。
Conclusions
Among persons who had been previously infected with SARS-CoV-2 (regardless of whether they had received any dose of vaccine or whether they had received one dose before or after infection), protection against reinfection decreased as the time increased since the last immunity-conferring event; however, this protection was higher than that conferred after the same time had elapsed since receipt of a second dose of vaccine among previously uninfected persons. A single dose of vaccine after infection reinforced protection against reinfection.
Yair Goldberg, Micha Mandel, Yinon M. Bar-On, Protection and Waning of Natural and Hybrid Immunity to SARS-CoV-2. DOI: 10.1056/NEJMoa2118946
