Antibiotic-associated diarrhoea (AAD) occurs most frequently in older (≥65 years) inpatients exposed to broad-spectrum antibiotics. When caused by Clostridium difficile, AAD can result in life-threatening illness. Although underlying disease mechanisms are not well understood, microbial preparations have been assessed in the prevention of AAD. However, studies have been mostly small single-centre trials with varying quality, providing insufficient data to reliably assess effectiveness. We aimed to do a pragmatic efficacy trial in older inpatients who would be representative of those admitted to National Health Service (NHS) and similar secondary care institutions and to recruit a sufficient number of patients to generate a definitive result. We did a multicentre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial of inpatients aged 65 years and older and exposed to one or more oral or parenteral antibiotics. A computer-generated randomisation scheme was used to allocate participants (in a 1:1 ratio) to receive either a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 × 10(10) organisms, one per day for 21 days, or an identical placebo. Patients, study staff, and specimen and data analysts were masked to assignment. The primary outcomes were occurrence of AAD within 8 weeks and C difficile diarrhoea (CDD) within 12 weeks of recruitment. Analysis was by modified intention-to-treat. This trial is registered, number ISRCTN70017204. Of 17,420 patients screened, 1493 were randomly assigned to the microbial preparation group and 1488 to the placebo group. 1470 and 1471, respectively, were included in the analyses of the primary endpoints. AAD (including CDD) occurred in 159 (10·8%) participants in the microbial preparation group and 153 (10·4%) participants in the placebo group (relative risk [RR] 1·04; 95% CI 0·84-1·28; p=0·71). CDD was an uncommon cause of AAD and occurred in 12 (0·8%) participants in the microbial preparation group and 17 (1·2%) participants in the placebo group (RR 0·71; 95% CI 0·34-1·47; p=0·35). 578 (19·7%) participants had one or more serious adverse event; the frequency of serious adverse events was much the same in the two study groups and none was attributed to participation in the trial. We identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in prevention of AAD or CDD. An improved understanding of the pathophysiology of AAD is needed to guide future studies. Health Technology Assessment programme; National Institute for Health Research, UK.

Probiotics may offer a safe intervention in acute infectious diarrhoea to reduce the duration and severity of the illness. To assess the effects of probiotics in proven or presumed acute infectious diarrhoea. We searched the Cochrane Infectious Diseases Group's trials register (July 2010), the Cochrane Controlled Trials Register (The Cochrane Library Issue 2, 2010), MEDLINE (1966 to July 2010), EMBASE (1988 to July 2010), and reference lists from studies and reviews. We also contacted organizations and individuals working in the field, and pharmaceutical companies manufacturing probiotic agents. Randomized and quasi‐randomized controlled trials comparing a specified probiotic agent with a placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent. Two reviewers independently assessed the methodological quality of the trial and extracted data. Primary outcomes were the mean duration of diarrhoea, stool frequency on day 2 after intervention and ongoing diarrhoea on day 4. A random‐effects model was used. Sixty‐three studies met the inclusion criteria with a total of 8014 participants. Of these, 56 trials recruited infants and young children. The trials varied in the definition used for acute diarrhoea and the end of the diarrhoeal illness, as well as in the risk of bias. The trials were undertaken in a wide range of different settings and also varied greatly in organisms tested, dosage, and participants' characteristics. No adverse events were attributed to the probiotic intervention. Probiotics reduced the duration of diarrhoea, although the size of the effect varied considerably between studies. The average of the effect was significant for mean duration of diarrhoea (mean difference 24.76 hours; 95% confidence interval 15.9 to 33.6 hours; n=4555, trials=35) diarrhoea lasting ≥4 days (risk ratio 0.41; 0.32 to 0.53; n=2853, trials=29) and stool frequency on day 2 (mean difference 0.80; 0.45 to 1.14; n=2751, trials=20). The differences in effect size between studies was not explained by study quality, probiotic strain, the number of different strains, the viability of the organisms, dosage of organisms, the causes of diarrhoea, or the severity of the diarrhoea, or whether the studies were done in developed or developing countries. Used alongside rehydration therapy, probiotics appear to be safe and have clear beneficial effects in shortening the duration and reducing stool frequency in acute infectious diarrhoea. However, more research is needed to guide the use of particular probiotic regimens in specific patient groups. Probiotiques pour le traitement de la diarrhée aiguë d'origine infectieuse Les probiotiques pourraient constituer une intervention sûre pour réduire la durée et la gravité de la diarrhée aiguë d'origine infectieuse. Évaluer les effets des probiotiques dans la diarrhée aiguë d'origine infectieuse avérée ou présumée. Nous avons consulté le registre d'essais cliniques du groupe Cochrane sur les maladies infectieuses (juillet 2010), le registre Cochrane des essais contrôlés (Bibliothèque Cochrane numéro 2, 2010), MEDLINE (de 1966 à juillet 2010), EMBASE (de 1988 à juillet 2010) ainsi que les références bibliographiques des études et revues. Nous avons également contacté des organisations et des individus travaillant dans ce domaine, ainsi que des sociétés pharmaceutiques fabriquant des agents probiotiques. Les essais contrôlés randomisés et quasi‐randomisés comparant un agent probiotique spécifique à un placebo ou à une absence de probiotique chez des patients atteints de diarrhée aiguë d'origine infectieuse avérée ou présumée. Deux évaluateurs ont évalué la qualité méthodologique des essais et extrait les données de manière indépendante. Les critères de jugement principaux étaient la durée moyenne de la diarrhée, la fréquence des selles deux jours après l'intervention et la persistance de la diarrhée à quatre jours. Un modèle à effets aléatoires a été utilisé. Soixante‐trois études portant sur un total de 8 014 participants remplissaient les critères d’inclusion. Sur ces 63 études, 56 recrutaient des nourrissons et de jeunes enfants. Les essais définissaient la diarrhée aiguë et la résolution de la maladie diarrhéique de différentes manières et présentaient différents risques de biais. Les essais avaient été réalisés dans de nombreux environnements différents et présentaient une importante variabilité en termes d'organismes testés, de posologie et de caractéristiques des participants. Aucun événement indésirable n'était attribué au traitement probiotique. Les probiotiques réduisaient la durée de la diarrhée, mais la taille de l'effet variait considérablement d'une étude à l'autre. L'effet moyen était significatif en termes de durée moyenne de la diarrhée (différence moyenne de 24,76 heures ; intervalle de confiance à 95 %, entre 15,9 et 33,6 heures ; n = 4 555, 35 essais) de diarrhée durant ≥ 4 jours (risque relatif de 0,41 ; 0,32 à 0,53 ; n = 2 853, 29 essais) et de fréquence des selles au bout de deux jours (différence moyenne de 0,80 ; 0,45 à 1,14 ; n = 2 751, 20 essais). Les différences entre les études en termes de taille d’effet ne s'expliquaient pas par la qualité des études, la souche de probiotique, le nombre de souches différentes, la viabilité des organismes, la dose d'organisme utilisée, les causes de la diarrhée ou la gravité de la diarrhée, non plus que par la réalisation des études dans des pays développés ou en voie de développement. Utilisés parallèlement à la réhydratation, les probiotiques semblent sûrs et présentent des effets clairement bénéfiques en termes de réduction de la durée et de la fréquence des selles dans la diarrhée aiguë d'origine infectieuse. Néanmoins, des recherches supplémentaires sont nécessaires afin d'orienter l'utilisation des différents schémas probiotiques chez des groupes de patients spécifiques. Probióticos para o tratamento de diarreia aguda infecciosa Os probióticos podem ser uma intervenção segura na diarreia aguda infecciosa para reduzir a duração e a gravidade da doença. Avaliar os efeitos dos probióticos em casos comprovados ou suspeitos de diarreia aguda infecciosa. Pesquisamos as seguintes bases de dados: Cochrane Infectious Diseases Group's Trials Register (julho de 2010), The Cochrane Controlled Trials Register (The Cochrane Library edição 2, 2010), MEDLINE (1966 a julho de 2010), EMBASE (1988 a julho de 2010) e listas de referências de estudos e revisões. Também contactamos organizações e pessoas que trabalham nessa área e as empresas farmacêuticas que fabricam agentes probióticos. Incluímos ensaios clínicos randomizados e quasi‐randomizados que compararam um agente probiótico específico com um placebo ou nenhum probiótico em casos comprovados ou suspeitos de diarreia aguda infecciosa. Dois revisores avaliaram independentemente a qualidade metodológica dos estudos e extraíram os dados. Os desfechos primários foram a duração média da diarreia, a frequência das evacuações no segundo dia após a intervenção e a persistência da diarreia no quarto dia. Utilizamos um modelo de efeitos aleatórios. Sessenta e três estudos preencheram os critérios de inclusão, com um total de 8.014 participantes. Destes, 56 estudos recrutaram lactentes e crianças jovens. Os estudos variaram quanto à definição utilizada para diarreia aguda e o fim da doença diarreica e também variaram quanto ao risco de viés. Os estudos foram realizados em uma ampla gama de cenários diferentes e também variaram muito quanto aos organismos testados, dosagem e características dos participantes. Nenhum evento adverso foi atribuído ao uso de probióticos. Os probióticos reduziram a duração da diarreia, embora o tamanho do efeito tenha variado consideravelmente entre os estudos. O efeito médio foi significativo para a duração média da diarréia (diferença de médias 24,76 horas; intervalo de confiança de 95%, 95% CI, 15,9‐33,6 horas; n = 4555, 35 estudos), diarreia com duração maior ou igual a quatro dias (risco relativo, RR, 0,41; 95% CI 0,32 a 0,53; n = 2,853, 29 estudos) e frequência de evacuações no segundo dia (diferença de médias de 0,80; 0,45 a 1,14; n = 2.751, 20 estudos). As diferenças no tamanho do efeito entre os estudos não foram explicadas pela qualidade do estudo, cepa probiótica, viabilidade e dosagem dos organismos, causas ou gravidade da diarreia, ou se os estudos foram feitos em países desenvolvidos ou em desenvolvimento. Usados concomitantemente com a terapia de reidratação, os probióticos parecem ser seguros e ter efeitos benéficos claros na redução da duração e da frequência das evacuações em casos de diarreia aguda infecciosa. No entanto, mais pesquisas são necessárias para orientar o uso de determinados regimes de probióticos em grupos específicos de pacientes. Tradução do Centro Cochrane do Brasil (Michele Palmeira da Silva). 用益生菌(Probiotics)治療急性感染性腹瀉 益生菌可能是作為急性感染性腹瀉的一種安全治療方法，用以減少疾病的嚴重性與發生時間。 評估益生菌對於被證實或假設是急性感染性腹瀉的效果。 我們搜尋了Cochrane Infectious Diseases Group's trials register (2010年七月), the Cochrane Controlled Trials Register (The Cochrane Library Issue 2, 2010年), MEDLINE (1966年 到 2010年七月), EMBASE (1988年到 2010年七月) 及各項研究與回顧文獻所組成的參考名單。我們同時也向在此領域做研究的組織、工作者與製造益生菌產品的藥劑公司。 利用隨機和半隨機對照試驗(Randomized and quasi‐randomized controlled trials)比較被證實已感染或推論被某種感染源引起急性腹瀉的病人其使用特定益生菌製劑、安慰劑或非益生菌製劑的情形。 兩位回顧作者獨立評估試驗的品質並回收其數據。主要目標是腹瀉的平均時間，經治療後第2天的排便頻率與第4天持續腹瀉的情形。並搭配使用隨機效應模型。 總共有63項研究8014名符合納入試驗的標準的受試者。這些試驗中，56項試驗招募的對象是嬰兒與孩童。這些試驗對於急性腹瀉與腹瀉結束的定義都不一樣，所以也存在試驗偏差的風險。這些試驗在廣泛又不同的設定與不同有機體、劑量和參與者特色等條件下進行，並且益生菌療法無產生任何副作用。 儘管在各個研究中，影響的效果大小不一，總歸來說益生菌可以減短腹瀉的持續時間。 一般來說，對於影響腹瀉平均持續時間的效果明顯(平均差 24.76小時；95%信賴區間 15.9到33.6小時；N=4555，35個試驗) 腹瀉持續時間大於4天(風險比0.41；0.32到0.53；N=2853，29個試驗)以及第2天的大便頻率(平均差 0.80；0.45到1.14；N=2751，20個試驗)。 從研究品質、益生菌菌株、數量不同的菌株、有機體存活力、有機體劑量或是腹瀉的嚴重程度亦或是研究是否在已開發或開發中國家進行等等面向，並沒有辦法解釋為什麼對疾病影響的效果大小不一。 與輸液療法並用，益生菌是安全的且對於縮短急性感染性腹瀉持續時間與大便頻率的效果相當明顯。然而，對於特定患者群體如何使用特定益生菌療法還需要用更多研究以指導如何進行。 翻譯者：臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan) 本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行 聯絡E‐mail：cochranetaiwan@tmu.edu.tw

The Malaria Genomic Epidemiology Network reports a large multicenter association study for severe malaria due to Plasmodium falciparum in 11,890 cases and 17,441 controls from 12 locations in Africa, Asia and Oceania. They examine 27 loci previously associated with severe malaria and replicate associations at the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but they fail to replicate other previously reported associations. Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10−4 with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

Background Probiotics may be effective in reducing the duration of acute infectious diarrhoea. Objectives To assess the effects of probiotics in proven or presumed acute infectious diarrhoea. Search methods We searched the trials register of the Cochrane Infectious Diseases Group, MEDLINE, and Embase from inception to 17 December 2019, as well as the Cochrane Controlled Trials Register (Issue 12, 2019), in the Cochrane Library, and reference lists from studies and reviews. We included additional studies identified during external review. Selection criteria Randomized controlled trials comparing a specified probiotic agent with a placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent. Data collection and analysis Two review authors independently applied inclusion criteria, assessed risk of bias, and extracted data. Primary outcomes were measures of diarrhoea duration (diarrhoea lasting ≥ 48 hours; duration of diarrhoea). Secondary outcomes were number of people hospitalized in community studies, duration of hospitalization in inpatient studies, diarrhoea lasting ≥ 14 days, and adverse events. Main results We included 82 studies with a total of 12,127 participants. These studies included 11,526 children (age < 18 years) and 412 adults (three studies recruited 189 adults and children but did not specify numbers in each age group). No cluster‐randomized trials were included. Studies varied in the definitions used for "acute diarrhoea" and "end of the diarrhoeal illness" and in the probiotic(s) tested. A total of 53 trials were undertaken in countries where both child and adult mortality was low or very low, and 26 where either child or adult mortality was high. Risk of bias was high or unclear in many studies, and there was marked statistical heterogeneity when findings for the primary outcomes were pooled in meta‐analysis. Effect size was similar in the sensitivity analysis and marked heterogeneity persisted. Publication bias was demonstrated from funnel plots for the main outcomes. In our main analysis of the primary outcomes in studies at low risk for all indices of risk of bias, no difference was detected between probiotic and control groups for the risk of diarrhoea lasting ≥ 48 hours (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.91 to 1.09; 2 trials, 1770 participants; moderate‐certainty evidence); or for duration of diarrhoea (mean difference (MD) 8.64 hours shorter, 95% CI 29.4 hours shorter to 12.1 hours longer; 6 trials, 3058 participants; very low‐certainty evidence). Effect size was similar and marked heterogeneity persisted in pre‐specified subgroup analyses of the primary outcomes that included all studies. These included analyses limited to the probiotics Lactobacillus rhamnosus GG and Saccharomyces boulardii. In six trials (433 participants) of Lactobacillus reuteri, there was consistency amongst findings (I² = 0%), but risk of bias was present in all included studies. Heterogeneity also was not explained by types of participants (age, nutritional/socioeconomic status captured by mortality stratum, region of the world where studies were undertaken), diarrhoea in children caused by rotavirus, exposure to antibiotics, and the few studies of children who were also treated with zinc. In addition, there were no clear differences in effect size for the primary outcomes in post hoc analyses according to decade of publication of studies and whether or not trials had been registered. For other outcomes, the duration of hospitalization in inpatient studies on average was shorter in probiotic groups than in control groups but there was marked heterogeneity between studies (I² = 96%; MD ‐18.03 hours, 95% CI ‐27.28 to ‐8.78, random‐effects model: 24 trials, 4056 participants). No differences were detected between probiotic and control groups in the number of people with diarrhoea lasting ≥ 14 days (RR 0.49, 95% CI 0.16 to 1.53; 9 studies, 2928 participants) or in risk of hospitalization in community studies (RR 1.26, 95% CI 0.84 to 1.89; 6 studies, 2283 participants). No serious adverse events were attributed to probiotics. Authors' conclusions Probiotics probably make little or no difference to the number of people who have diarrhoea lasting 48 hours or longer, and we are uncertain whether probiotics reduce the duration of diarrhoea. This analysis is based on large trials with low risk of bias.