巴洛沙韋酯對流感指示病例家庭接觸者的流感預防效果
Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts
背景
巴洛沙韋酯（巴洛沙韋）（Baloxavir marboxil [baloxavir]）是一種聚合酶酸性蛋白（PA）內切核酸酶抑制劑，在治療無併發症的流感方面具有臨床療效（包括在併發症風險增加的門診患者中）。巴洛沙韋在家庭環境中的暴露後預防效果尚不明確。
Baloxavir marboxil (baloxavir) is a polymerase acidic protein (PA) endonuclease inhibitor with clinical efficacy in the treatment of uncomplicated influenza, including in outpatients at increased risk for complications. The postexposure prophylactic efficacy of baloxavir in the household setting is unclear.方法
我們開展了一項多中心、雙盲、隨機、安慰劑對照試驗，目的是評價在日本2018-2019流感季，在確診流感的指示病例的家庭接觸者中，巴洛沙韋的暴露後預防效果。我們以1:1的比例將參與者分組，兩組分別接受巴洛沙韋或安慰劑單劑給藥。主要終點是在10天期間患經過逆轉錄聚合酶鏈反應確認的臨床流感。我們還評估了巴洛沙韋選擇出的，與藥敏性降低相關的PA置換的發生情況。
We conducted a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the postexposure prophylactic efficacy of baloxavir in household contacts of index patients with confirmed influenza during the 2018–2019 season in Japan. The participants were assigned in a 1:1 ratio to receive either a single dose of baloxavir or placebo. The primary end point was clinical influenza, as confirmed by reverse-transcriptase–polymerase-chain-reaction testing, over a period of 10 days. The occurrence of baloxavir-selected PA substitutions associated with reduced susceptibility was assessed.結果
我們將545個指示病例的總共752名家庭接觸者隨機分組，兩組分別接受巴洛沙韋或安慰劑給藥。指示病例中有95.6%感染了甲型流感病毒，73.6%小於12歲，52.7%接受了巴洛沙韋治療。在可以評價的參與者（巴洛沙韋組374例和安慰劑組375例）中，巴洛沙韋組患臨床流感的百分比顯著低於安慰劑組（1.9% vs. 13.6%）（校正風險比，0.14；95%置信區間[CI]，0.06~0.30；P<0.001）。巴洛沙韋在高危、兒科和未接種疫苗的參與者亞組中有效。巴洛沙韋組的流感感染（不論是否有症狀）風險低於安慰劑組（校正風險比，0.43；95% CI，0.32~0.58）。兩組的不良事件發生率相似（巴洛沙韋組22.2%和安慰劑組20.5%）。在巴洛沙韋組中，我們分別檢測到10例（2.7%）和5例（1.3%）參與者有病毒PA置換I38T/M或E23K。我們未檢測到這些變異體從接受巴洛沙韋治療的指示病例傳播給安慰劑組參與者；然而，不能排除上述變異體傳播給數例巴洛沙韋組參與者。
Result
A total of 752 household contacts of 545 index patients were randomly assigned to receive baloxavir or placebo. Among the index patients, 95.6% had influenza A virus infection, 73.6% were younger than 12 years of age, and 52.7% received baloxavir. Among the participants who could be evaluated (374 in the baloxavir group and 375 in the placebo group), the percentage in whom clinical influenza developed was significantly lower in the baloxavir group than in the placebo group (1.9% vs. 13.6%) (adjusted risk ratio, 0.14; 95% confidence interval [CI], 0.06 to 0.30; P<0.001). Baloxavir was effective in high-risk, pediatric, and unvaccinated subgroups of participants. The risk of influenza infection, regardless of symptoms, was lower with baloxavir than with placebo (adjusted risk ratio, 0.43; 95% CI, 0.32 to 0.58). The incidence of adverse events was similar in the two groups (22.2% in the baloxavir group and 20.5% in the placebo group). In the baloxavir group, the viral PA substitutions I38T/M or E23K were detected in 10 (2.7%) and 5 (1.3%) participants, respectively. No transmission of these variants from baloxavir-treated index patients to participants in the placebo group was detected; however, several instances of transmission to participants in the baloxavir group could not be ruled out.
結論
單劑巴洛沙韋給藥在預防流感患者的家庭接觸者患流感方面顯示出顯著的暴露後預防效果。（由鹽野義製藥[Shionogi]資助；在Japan Primary Registries Network註冊號為JapicCTI-184180。）
Conclusions
Single-dose baloxavir showed significant postexposure prophylactic efficacy in preventing influenza in household contacts of patients with influenza. (Funded by Shionogi; Japan Primary Registries Network number, JapicCTI-184180.)
本周五 中午十二點 app和官網發布全文中譯
生長遲緩且營養不良的腸病患兒的十二指腸微生物群
Duodenal Microbiota in Stunted Undernourished Children with Enteropathy
背景
環境性腸功能障礙（EED）是一種目前了解甚少的小腸疾病，它被認為是兒童營養不良的重要原因，而且是緊迫的全球性健康問題。由於很難對小腸黏膜和微生物群直接取樣，因此難以確定該疾病的發病率、病理學生理特徵以及它在身高和體重增長緩慢中發揮的作用。
Environmental enteric dysfunction (EED) is an enigmatic disorder of the small intestine that is postulated to play a role in childhood undernutrition, a pressing global health problem. Defining the incidence of this disorder, its pathophysiological features, and its contribution to impaired linear and ponderal growth has been hampered by the difficulty in directly sampling the small intestinal mucosa and microbial community (microbiota).方法
這項研究納入了居住在孟加拉國達卡市區貧民窟，有線性生長遲緩，並且未從營養幹預中獲益的110名幼兒（平均年齡，18個月），我們對活檢證實患EED並且有血漿和十二指腸樣本的80名患兒進行了內鏡檢查。我們對這些患兒的4077種血漿蛋白和十二指腸活檢樣本中的2619種蛋白進行了定量分析。利用免培養技術確定了從每名患兒的十二指腸吸出物獲取的微生物群內的細菌菌株水平。此外，我們從居住在同一地區，且年齡匹配的健康兒童獲取了21份血漿樣本和27份糞便樣本。將從十二指腸吸出物培養出的細菌菌株定植到用孟加拉國飼料餵養的年輕無菌小鼠體內。
In this study, among 110 young children (mean age, 18 months) with linear growth stunting who were living in an urban slum in Dhaka, Bangladesh, and had not benefited from a nutritional intervention, we performed endoscopy in 80 children who had biopsy-confirmed EED and available plasma and duodenal samples. We quantified the levels of 4077 plasma proteins and 2619 proteins in duodenal biopsy samples obtained from these children. The levels of bacterial strains in microbiota recovered from duodenal aspirate from each child were determined with the use of culture-independent methods. In addition, we obtained 21 plasma samples and 27 fecal samples from age-matched healthy children living in the same area. Young germ-free mice that had been fed a Bangladeshi diet were colonized with bacterial strains cultured from the duodenal aspirates.
結果
在從患兒獲取的菌株中，共同的一組14個分類群（通常不歸類為腸道病原體）的絕對水平與線性生長呈負相關（年齡別身長z評分，r=-0.49；P=0.003），而與參與免疫炎症應答的十二指腸蛋白呈正相關。糞便微生物群中的這14個十二指腸分類群的表現與從健康兒童獲取的樣本顯著不同（置換多變量方差分析P<0.001）。將從EED患兒獲取，經培養的十二指腸菌株定植到悉生小鼠之後，小鼠發生了小腸腸病。
Result
Of the bacterial strains that were obtained from the children, the absolute levels of a shared group of 14 taxa (which are not typically classified as enteropathogens) were negatively correlated with linear growth (length-for-age z score, r=−0.49; P=0.003) and positively correlated with duodenal proteins involved in immunoinflammatory responses. The representation of these 14 duodenal taxa in fecal microbiota was significantly different from that in samples obtained from healthy children (P<0.001 by permutational multivariate analysis of variance). Enteropathy of the small intestine developed in gnotobiotic mice that had been colonized with cultured duodenal strains obtained from children with EED.結論
這些結果支持生長遲緩與小腸微生物群成分和腸病之間的因果關係，並為開發針對性療法（針對微生物在EED中發揮的作用）提供了理論基礎。（由比爾及梅林達·蓋茨基金會[Bill and Melinda Gates Foundation]等資助；在ClinicalTrials.gov註冊號為NCT02812615。）
Conclusions
These results provide support for a causal relationship between growth stunting and components of the small intestinal microbiota and enteropathy and offer a rationale for developing therapies that target these microbial contributions to EED. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02812615.)Robert Y. Chen, Vanderlene L. Kung, Subhasish Das, et al. Duodenal Microbiota in Stunted Undernourished Children with Enteropathy. DOI: 10.1056/NEJMoa1916004
美國兒童和青少年中的多系統炎症症候群
Multisystem Inflammatory Syndrome in U.S. Children and Adolescents
背景
鑑於兒童多系統炎性症候群（MIS-C）對醫療系統和公共衛生系統的影響，了解該症候群的流行病學特徵和臨床病程及其與2019冠狀病毒病（COVID-19）的時間關聯非常重要。
Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome.方法
從2020年3月15日至5月20日，我們在美國各地的兒科醫療中心對MIS-C進行了針對性的監測。疾病定義包括六項標準：需要住院的重症疾病，年齡<21歲，發熱持續至少24小時，實驗室結果證實為炎症，多系統器官受累，以及有證據證實患者感染嚴重急性呼吸症候群冠狀病毒2（SARS-CoV-2）；前述證據包括逆轉錄酶聚合酶鏈反應（RT-PCR）、抗體檢測或在過去一個月內與COVID-19患者有密切接觸史。臨床醫師將數據轉化為標準化格式。
We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms.結果
本文報告的186例MIS-C患者分布在26個州。患者的中位年齡為8.3歲，男性115例（62%），既往體健的患者為135例（73%），通過RT-PCR或抗體檢測證實SARS-CoV-2陽性者為131例（70%），2020年4月16日後住院者為164例（88%）。受累的器官系統包括消化系統（171例[92%]），心血管系統（149例[80%]），血液系統（142例[76%]），皮膚黏膜（137例[74%]）和呼吸系統（131例[70%]）。中位住院時間為7天（四分位距，4⁓10）；148例患者（80%）入住重症監護病房，37例（20%）接受機械通氣治療，90例（48%）接受血管活性藥物支持，4例（2%）死亡。15例患者（8%）證實出現冠狀動脈瘤（z評分≥2.5），74例（40%）的病情類似川崎病。大多數患者（171例[92%]）出現至少四項生物標誌物（提示炎症）升高。大部分患者接受免疫調節藥物治療：144例（77%）靜脈輸注免疫球蛋白，91例（49%）接受糖皮質激素治療，38例（20%）接受白介素-6或1Ra抑制劑治療。
Result
We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease–like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%).
結論
與SARS-CoV-2相關的兒童多系統炎症症候群可導致既往體健的兒童和青少年患上嚴重且危及生命的疾病。（由美國疾病預防控制中心資助。）
Conclusions
Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.)本周五 中午十二點 app和官網發布全文中譯
紐約州兒童的多系統炎症症候群
Multisystem Inflammatory Syndrome in Children in New York State背景
兒童多系統炎症症候群（MIS-C）與2019冠狀病毒病相關。紐約州衛生署（NYSDOH）建立了覆蓋全州的主動監測系統，旨在明確患該症候群的住院患者。
A multisystem inflammatory syndrome in children (MIS-C) is associated with coronavirus disease 2019. The New York State Department of Health (NYSDOH) established active, statewide surveillance to describe hospitalized patients with the syndrome.方法
紐約州的醫院報告了21歲以下住院患者中的川崎病、中毒性休克症候群、心肌炎和潛在MIS-C的病例，並將病歷發送給NYSDOH。我們描述性地分析了2020年3月1日至5月10日期間符合NYSDOH MIS-C定義的患者，分析的內容包括臨床表現、併發症和結局。
Hospitals in New York State reported cases of Kawasaki’s disease, toxic shock syndrome, myocarditis, and potential MIS-C in hospitalized patients younger than 21 years of age and sent medical records to the NYSDOH. We carried out descriptive analyses that summarized the clinical presentation, complications, and outcomes of patients who met the NYSDOH case definition for MIS-C between March 1 and May 10, 2020.結果
截至2020年5月10日，NYSDOH共收到191個潛在病例的報告。在95例MIS-C確診患者（實驗室檢查證實急性或近期感染嚴重急性呼吸症候群冠狀病毒2 [SARS-CoV-2]）和4例MIS-C疑似患者（符合臨床和流行病學標準）中，53例（54%）為男性；78例中的31例（40%）為黑種人，85例中的31例（36%）為西班牙語裔。31例患者（31%）為0~5歲，42例（42%）為6~12歲，26例（26%）為13~20歲。所有患者均有主觀發熱或寒戰；97%有心動過速，80%有胃腸道症狀，60%有皮疹，56%有結膜充血，27%有黏膜改變。C-反應蛋白、d-二聚體和肌鈣蛋白水平升高的患者比例分別為100%、91%和71%；62%接受了血管加壓藥支持治療，53%有心肌炎證據，80%入住重症監護病房，2例患者死亡。中位住院天數為6天。
Result
As of May 10, 2020, a total of 191 potential cases were reported to the NYSDOH. Of 95 patients with confirmed MIS-C (laboratory-confirmed acute or recent severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection) and 4 with suspected MIS-C (met clinical and epidemiologic criteria), 53 (54%) were male; 31 of 78 (40%) were black, and 31 of 85 (36%) were Hispanic. A total of 31 patients (31%) were 0 to 5 years of age, 42 (42%) were 6 to 12 years of age, and 26 (26%) were 13 to 20 years of age. All presented with subjective fever or chills; 97% had tachycardia, 80% had gastrointestinal symptoms, 60% had rash, 56% had conjunctival injection, and 27% had mucosal changes. Elevated levels of C-reactive protein, d-dimer, and troponin were found in 100%, 91%, and 71% of the patients, respectively; 62% received vasopressor support, 53% had evidence of myocarditis, 80% were admitted to an intensive care unit, and 2 died. The median length of hospital stay was 6 days.
結論
紐約州兒童多系統炎症症候群的出現時間與SARS-CoV-2的廣泛傳播時間重合；這種具有皮膚、黏膜皮膚和胃腸表現的過度炎症性症候群與心臟功能障礙相關。
Conclusions
The emergence of multisystem inflammatory syndrome in children in New York State coincided with widespread SARS-CoV-2 transmission; this hyperinflammatory syndrome with dermatologic, mucocutaneous, and gastrointestinal manifestations was associated with cardiac dysfunction.應用維生素D補充劑預防結核感染和結核病的效果
Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease背景
維生素D代謝產物支持對結核分枝桿菌的固有免疫應答。目前尚無關於補充維生素D對結核感染的預防效果的的3期、隨機、對照試驗數據。
Vitamin D metabolites support innate immune responses to Mycobacterium tuberculosis. Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis infection are lacking.方法
我們將QuantiFERON-TB Gold In-Tube試驗（QFT）結果表明結核分枝桿菌呈陰性的兒童隨機分組，分別連續3年每周口服14,000 IU維生素D3或安慰劑。主要結局是3年隨訪時的陽性QFT結果（表示為兒童的比例）。次要結局包括試驗結束時的血清25-羥基維生素D（25[OH]D）水平，以及結核病、急性呼吸道感染和不良事件的發生率。
We randomly assigned children who had negative results for M. tuberculosis infection according to the QuantiFERON-TB Gold In-Tube assay (QFT) to receive a weekly oral dose of either 14,000 IU of vitamin D3 or placebo for 3 years. The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children. Secondary outcomes included the serum 25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events.結果
共計8851名兒童被隨機分組：4418名被分配至維生素D組，4433名被分配至安慰劑組；95.6%兒童的基線血清25(OH)D水平低於20 ng/mL。在有試驗結束時的有效QFT結果的兒童中，在維生素D組和安慰劑組中，結果為陽性的百分比分別為3.6%（147/4074名兒童）和3.3%（134/4043）（校正的風險比，1.10；95%置信區間[CI]，0.87~1.38；P=0.42）。在維生素D組和安慰劑組中，試驗結束時的平均25(OH)D水平分別為31.0 ng/mL和10.7 ng/mL（平均組間差異，20.3 ng/mL；95% CI，19.9~20.6）。維生素D組21名兒童和安慰劑組25名兒童被診斷為結核病（校正風險比，0.87；95% CI，0.49~1.55）。維生素D組29名兒童和安慰劑組34名兒童為了治療急性呼吸道感染而住院（校正風險比，0.86；95% CI，0.52~1.40）。兩組的不良事件發生率無顯著差異。
Result
A total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children with a valid QFT result at the end of the trial, the percentage with a positive result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87 to 1.38; P=0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of adverse events did not differ significantly between the two groups.
結論
在蒙古缺乏維生素D的學齡兒童中，與安慰劑相比，補充維生素D未降低結核感染、結核病或急性呼吸道感染的風險。（由美國國立衛生研究院資助；在ClinicalTrials.gov註冊號為NCT02276755。）
Conclusions
Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D–deficient schoolchildren in Mongolia. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.)Davaasambuu Ganmaa, Buyanjargal Uyanga, Xin Zhou, et al. SVitamin D Supplements for Prevention of Tuberculosis Infection and Disease. DOI:10.1056/NEJMoa1915176
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