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.

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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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.

Background. Previous studies showed that probiotics could improve glycemic control and attenuate some of the adverse effects of type 2 diabetes. However, whether the effects are generalizable to gestational diabetes mellitus (GDM) remains uncertain. Objective. We conducted a systematic review and meta-analysis to evaluate the effects of probiotic supplement in GDM. Method. PubMed, EMBASE, the Cochrane Library, and EBSCO were systematically searched for relevant literature published through January 2019. Randomized controlled trials (RCTs) assessing the effects of probiotic supplement on one or more of the following in GDM were included: pregnancy outcome (the primary outcome), glycemic control, blood lipid profile, and inflammation and oxidative stress. Two reviewers independently extracted data and assessed the risk of bias in studies. Meta-analysis was conducted by using the fixed effects model unless substantial heterogeneity was found among studies. Results. Eleven randomized trials involving 719 participants were included for analysis. Eight of the trials were from Iran. Probiotics were given alone in eight trials and synbiotics in three trials. Though the components of probiotics varied, Lactobacillus was included in all trials and Bifidobacterium in all except one. The duration of intervention ranged from 4 to 8 weeks. Almost all trials (10/11) had a low risk of bias. Probiotic supplementation reduced the risk of a newborn’s hyperbilirubinemia by 74% and improved four biomarkers for glycemic control (fasting blood glucose, fasting serum insulin, homeostasis model assessment insulin resistance, and quantitative insulin sensitivity check index), two biomarkers for lipid profile (triglycerides and HDL-cholesterol), and four biomarkers for inflammation and oxidative stress (total glutathione, malondialdehyde, nitric oxide, and total antioxidant capacity). But significant heterogeneity was observed in the meta-analyses on the four biomarkers related to glycemic control and on triglycerides, which could not be explained by prespecified subgroup analyses according to the mean age of participants and intervention type (i.e., probiotics or synbiotics). The effects on the risk of preterm delivery, macrosomia and a newborns’ hypoglycemia, gestational age, total cholesterol, and LDL-cholesterol were not statistically significant. Conclusion. Probiotic supplementation seemed to be able to reduce the risk of a newborn’s hyperbilirubinemia and improve glycemic control, blood lipid profiles and inflammation and oxidative stress in pregnant women with GDM. However, due to the heterogeneity among existing studies, the surrogate nature of outcomes, and/or the fact that most studies were from Iran, the clinical significance and generalizability of the above findings remain uncertain. Further studies are warranted to address the limitations of existing evidence and better inform the management of GDM.

Objective. Gestational diabetes mellitus (GDM) is a common metabolic disorder with onset during pregnancy. However, the etiology and pathogenesis of GDM have not been fully elucidated. In this study, we used a metabolomics approach to investigate the relationship between maternal serum metabolites and GDM in early pregnancy. Methods. A nested case-control study was performed. To establish an early pregnancy cohort, pregnant women in early pregnancy ( 10 ‐ 13 + 6 weeks) were recruited. In total, 51 patients with GDM and 51 healthy controls were included. Serum samples were analyzed using an untargeted high-performance liquid chromatography mass spectrometry metabolomics approach. The relationships between metabolites and GDM were analyzed by an orthogonal partial least-squares discriminant analysis. Differential metabolites were evaluated using a KEGG pathway analysis. Results. A total of 44 differential metabolites were identified between GDM cases and healthy controls during early pregnancy. Of these, 26 significant metabolites were obtained in early pregnancy after false discovery rate ( FDR < 0.1 ) correction. In the GDM group, the levels of L-pyroglutamic acid, L-glutamic acid, phenylacetic acid, pantothenic acid, and xanthine were significantly higher and the levels of 1,5-anhydro-D-glucitol, calcitriol, and 4-oxoproline were significantly lower than those in the control group. These metabolites were involved in multiple metabolic pathways, including those for amino acid, carbohydrate, lipid, energy, nucleotide, cofactor, and vitamin metabolism. Conclusions. We identified significant differentially expressed metabolites associated with the risk of GDM, providing insight into the mechanisms underlying GDM in early pregnancy and candidate predictive markers.

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ELABELA (ELA) is considered to be implicated in the pathophysiology of preeclampsia (PE), since ELA-deficient mice exhibited PE-like symptoms and infusion of exogenous ELA normalized the gestational hypertension (GH) and proteinuria. However, no evidence show that circulating ELA is deficient in early placental development among women who destined to develop GH/PE. This nested case-control study was conducted to investigate the association between serum ELA concentration in early pregnancy and the risk of later GH/PE. Participants were recruited and sampled in 10-14+6 weeks of gestation. Definite GH/PE cases were matched 1 : 3 to controls with respect to age and gestational age. Serum concentration of ELA was measured using enzyme immunoassay. Women with later GH ( N = 28 ) had a slightly lower median concentration of ELA (46.72 ng/mL versus 53.54 ng/mL), while those with later PE ( N = 16 ) had a slightly higher median concentration of ELA (74.8 ng/mL versus 66.30 ng/mL) compared to the controls. Yet, both the increments did not reach statistically significant difference (GH: P = 0.380 , PE: P = 0.799 ). ELA serum concentrations were unchanged in first trimester in women with GH/PE. Further studies are still needed to identify the dynamic changes in serum ELA concentrations during the whole pregnancy, especially in those with pregnancy-induced hypertensive disorders.