medRxiv preprint generally longer incubation and serial interval of less severe cases suggests a high risk of longterm epidemic in the absence of appropriate control measures.

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Ischemic postconditioning (PostC) and perconditioning (PerC) provide practical methods for protecting the heart against ischemia-reperfusion (I/R) injury, but their combined effects have not been studied in detail. Using an in vivo rat I/R model, we tested 1) whether additive effects were produced when local PostC was preceded by varying doses of remote PerC, and whether the optimal PostC+PerC regime is additive to local ischemic preconditioning (IPC), and 2) how combined PostC+PerC alters the activity of the reperfusion injury salvage kinase pathway. The optimal combination of PerC and PostC therapy was produced by PerC delivered with four cycles of 5 min of limb ischemia followed by 5-min reperfusion. This resulted in lower infarct size (22.56 +/- 4.45%) compared with rats with PostC alone (29.39 +/- 3.66%) and PerC alone (33.49 +/- 5.81%) and complementary differences in the generation of reactive oxygen species and apoptotic signaling. However, this optimal combination of PostC+PerC resulted in protection similar to local IPC alone (18.8 +/- 2.54%, P = 0.13), and when added to IPC there was no additional protection (19.62 +/- 2.89%, P = 0.675). Akt and ERK1/2 phosphorylation was induced by PostC and PerC and maximally by combined PostC+PerC treatment, and protection was abolished by phosphatidylinositol 3-kinase or ERK1/2 inhibitors. This study shows that neither PostC nor a maximized "dose" of PerC leads to optimal kinase signaling or cardioprotection compared with IPC alone. However, combined PostC+PerC may result in complementary effects on kinase signaling to recapitulate the effects of local IPC. Finally, combined PostC+PerC is not additive to IPC, suggesting that each works via a common pathway.

Background: Dysbiosis of human gut microbiota is associated with a wide range of metabolic disorders, including gestational diabetes mellitus (GDM). Yet whether gut microbiota dysbiosis participates in the etiology of GDM remains largely unknown.Objectives: Our study was initiated to determine whether the alternations in gut microbial composition during early pregnancy linked to the later development of GDM, and explore the feasibility of microbial biomarkers for the early prediction of GDM. Study design:This nested case-control study was based upon an early pregnancy follow-up cohort (ChiCTR1900020652). Gut microbiota profiles of 98 subjects with GDM and 98 matched healthy controls during the early pregnancy (10-15 weeks) were assessed via 16S rRNA gene amplicon sequencing of V4 region. The data set was randomly split into a discovery set and a validation set, the former was used to analyze the differences between GDM cases and controls in gut microbial composition and functional annotation, and to establish an early identification model of GDM, then the performance of the model was verified by the external validation set.Results: Bioinformatic analyses revealed changes to gut microbial composition with significant differences in relative abundance between the groups. Specifically, Eisenbergiella, Tyzzerella 4, and Lachnospiraceae NK4A136 were enriched in the GDM group, whereas Parabacteroides, Megasphaera, Eubacterium eligens group, etc. remained dominant in the controls. Correlation analysis revealed that GDM-enriched genera Eisenbergiella and Tyzzerella 4 were positively correlated with fasting blood glucose levels, while three control-enriched genera (Parabacteroides, Parasutterella, and Ruminococcaceae UCG 002) were the opposite. Further, GDM functional annotation modules revealed enrichment of modules for sphingolipid metabolism, starch and sucrose metabolism, etc., while lysine biosynthesis and nitrogen metabolism were reduced. Finally, five genera and two clinical indices were included in the linear discriminant analysis model for the prediction of GDM; the areas under receiver operating characteristic curves of the training and validation sets were 0.736 (95% confidence interval: 0.663-0.808) and 0.696 (0.575-0.818), respectively. Ma et al. Gut Bacterial Dysbiosis Before GDMConclusions: Gut bacterial dysbiosis in early pregnancy was found to be associated with the later development of GDM, and gut microbiota-targeted biomarkers might be utilized as potential predictors of GDM.

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Metformin has garnered more interest as a chemo-preventive agent given the increased liver cancer risk in diabetic patients. This work was undertaken to better understand the effect of metformin use on liver cancer risk in diabetic patients.A comprehensive literature search was performed in PubMed, Embase, BIOSIS Previews, Web of Science, and Cochrane Library through July 30, 2016. Meta-analyses were performed using Stata version 12.0, with odds ratio (ORs) and 95% confidence intervals (CIs) as effect measures.Twenty-three studies were included. Meta-analysis of 19 studies involving 550,882 diabetic subjects suggested that metformin use reduced the ratio of liver cancer by 48% (OR = 0.52; 95% CI, 0.40–0.68) compared with nonusers. The protective effect was validated in all the exploratory subgroup analyses, except that pooled result of post hoc analyses of 2 randomized controlled trials found no significant difference between subjects with metformin and those without, with OR being 0.84 (95% CI, 0.10–6.83). After adjusting for hepatitis B/C virus infection, cirrhosis, obesity, behavioral factors, and time-related bias, the association was stable, pooled OR ranged from 0.42 to 0.75.A protective effect for liver cancer was found in diabetic metformin users. However, more randomized clinical evidence is still needed to verify the results.

A combined measles-mumps-rubella-varicella (MMRV) vaccine is expected to facilitate universal immunization against these 4 diseases. This study was undertaken to synthesize current research findings of the immunogenicity and safety of MMRV in healthy children.We searched PubMed, Embase, BIOSIS Previews, Web of Science, Cochrane Library, and other databases through September 9, 2014. Eligible randomized controlled trials (RCTs) were selected and collected independently by 2 reviewers. Meta-analysis was conducted using Stata 12.0 and RevMan 5.3.Twenty-four RCTs were included in qualitative synthesis. Nineteen RCTs compared single MMRV dose with measles-mumps-rubella vaccine with or without varicella vaccine (MMR + V/MMR). Similar seroconversion rates of these 4 viruses were found between comparison groups. There were comparable geometric mean titers (GMTs) against mumps and varicella viruses between MMRV group and MMR + V/MMR group. MMRV group achieved enhanced immune response to measles component, with GMT ratio of 1.66 (95% confidence interval [CI] 1.48, 1.86; P < 0.001) for MMRV versus MMR and 1.62 (95% CI 1.51, 1.70; P < 0.001) for MMRV versus MMR + V. Meanwhile, immune response to rubella component in MMRV group was slightly reduced, GMT ratios were 0.81 (95% CI 0.78, 0.85; P < 0.001) and 0.79 (95% CI 0.76, 0.83; P < 0.001), respectively. Well tolerated safety profiles were demonstrated except higher incidence of fever (relative risks 1.12–1.60) and measles/rubella-like rash (relative risks 1.44–1.45) in MMRV groups.MMRV had comparable immunogenicity and overall safety profiles to MMR + V/MMR in healthy children based on current evidence.

Background The estimates of several key epidemiological parameters of the COVID-19 pandemic are often based on small sample sizes or are inaccurate for various reasons. Objective The aim of this study is to obtain more robust estimates of the incubation period, serial interval, frequency of presymptomatic transmission, and basic reproduction number (R0) of COVID-19 based on a large case series. Methods We systematically retrieved and screened 20,658 reports of laboratory-confirmed COVID-19 cases released by the health authorities of China, Japan, and Singapore. In addition, 9942 publications were retrieved from PubMed and China National Knowledge Infrastructure (CNKI) through April 8, 2020. To be eligible, a report had to contain individual data that allowed for accurate estimation of at least one parameter. Widely used models such as gamma distributions were fitted to the data sets and the results with the best-fitting values were presented. Results In total, 1591 cases were included for the final analysis. The mean incubation period (n=687) and mean serial interval (n=1015 pairs) were estimated to be 7.04 (SD 4.27) days and 6.49 (SD 4.90) days, respectively. In 40 cases (5.82%), the incubation period was longer than 14 days. In 32 infector-infectee pairs (3.15%), infectees’ symptom onsets occurred before those of infectors. Presymptomatic transmission occurred in 129 of 296 infector-infectee pairs (43.58%). R0 was estimated to be 1.85 (95% CI 1.37-2.60). Conclusions This study provides robust estimates of several epidemiological parameters of COVID-19. The findings support the current practice of 14-day quarantine of persons with potential exposure, but also suggest the need for additional measures. Presymptomatic transmission together with the asymptomatic transmission reported by previous studies highlight the importance of adequate testing, strict quarantine, and social distancing.