West China Second University Hospital of Sichuan University

BACKGROUND: Despite remarkable progress in the improvement of child survival between 1990 and 2015, the Millennium Development Goal (MDG) 4 target of a two-thirds reduction of under-5 mortality rate (U5MR) was not achieved globally. In this paper, we updated our annual estimates of child mortality by cause to 2000-15 to reflect on progress toward the MDG 4 and consider implications for the Sustainable Development Goals (SDG) target for child survival. METHODS: We increased the estimation input data for causes of deaths by 43% among neonates and 23% among 1-59-month-olds, respectively. We used adequate vital registration (VR) data where available, and modelled cause-specific mortality fractions applying multinomial logistic regressions using adequate VR for low U5MR countries and verbal autopsy data for high U5MR countries. We updated the estimation to use Plasmodium falciparum parasite rate in place of malaria index in the modelling of malaria deaths; to use adjusted empirical estimates instead of modelled estimates for China; and to consider the effects of pneumococcal conjugate vaccine and rotavirus vaccine in the estimation. FINDINGS: In 2015, among the 5·9 million under-5 deaths, 2·7 million occurred in the neonatal period. The leading under-5 causes were preterm birth complications (1·055 million [95% uncertainty range (UR) 0·935-1·179]), pneumonia (0·921 million [0·812 -1·117]), and intrapartum-related events (0·691 million [0·598 -0·778]). In the two MDG regions with the most under-5 deaths, the leading cause was pneumonia in sub-Saharan Africa and preterm birth complications in southern Asia. Reductions in mortality rates for pneumonia, diarrhoea, neonatal intrapartum-related events, malaria, and measles were responsible for 61% of the total reduction of 35 per 1000 livebirths in U5MR in 2000-15. Stratified by U5MR, pneumonia was the leading cause in countries with very high U5MR. Preterm birth complications and pneumonia were both important in high, medium high, and medium child mortality countries; whereas congenital abnormalities was the most important cause in countries with low and very low U5MR. INTERPRETATION: In the SDG era, countries are advised to prioritise child survival policy and programmes based on their child cause-of-death composition. Continued and enhanced efforts to scale up proven life-saving interventions are needed to achieve the SDG child survival target. FUNDING: Bill & Melinda Gates Foundation, WHO.

BACKGROUND At the end of 2019, the COVID-19 outbreak began in Wuhan, Hubei, China, and spread rapidly to the whole country within 1 month. This new epidemic caused a great mental reaction among the public. This study aimed to assess and compare the prevalence and associated factors of anxiety and depression among the public affected by quarantine and those unaffected during the COVID-19 outbreak in southwestern China in early Feb. 2020. MATERIAL AND METHODS Data were collected using the self-rating anxiety scale (SAS) and the self-rating depression scale (SDS) administered to 1593 respondents aged 18 years and above. The respondents were grouped as 'affected group' and 'unaffected group' on the basis of whether they or their families/colleagues/classmates/neighbors had been quarantined. RESULTS Among 1593 participants, the prevalence of anxiety and depression was approximately 8.3% and 14.6%, respectively, and the prevalence in the affected group (12.9%, 22.4%) was significantly higher than that in the unaffected group (6.7%, 11.9%). Lower average household income, lower education level, having a higher self-evaluated level of knowledge, being more worried about being infected, having no psychological support, greater property damage, and lower self-perceived health condition were significant associated with higher scores on the SAS and SDS. People living in Chongqing had higher SAS and SDS scores than those living in Yunnan Province. CONCLUSIONS The prevalence of anxiety and depression of the affected group are higher than in the unaffected group during the COVID-19 outbreak in southwestern China in early Feb. 2020. The government should focus more on providing economic and medical support to improve the general population's mental state.

Oral bacteria directly affect the disease status of dental caries and periodontal diseases. The dynamic oral microbiota cooperates with the host to reflect the information and status of immunity and metabolism through two-way communication along the oral cavity and the systemic organs. The oral cavity is one of the most important interaction windows between the human body and the environment. The microenvironment at different sites in the oral cavity has different microbial compositions and is regulated by complex signaling, hosts, and external environmental factors. These processes may affect or reflect human health because certain health states seem to be related to the composition of oral bacteria, and the destruction of the microbial community is related to systemic diseases. In this review, we discussed emerging and exciting evidence of complex and important connections between the oral microbes and multiple human systemic diseases, and the possible contribution of the oral microorganisms to systemic diseases. This review aims to enhance the interest to oral microbes on the whole human body, and also improve clinician's understanding of the role of oral microbes in systemic diseases. Microbial research in dentistry potentially enhances our knowledge of the pathogenic mechanisms of oral diseases, and at the same time, continuous advances in this frontier field may lead to a tangible impact on human health.

BACKGROUND: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. METHODS: We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. FINDINGS: =59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 μmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 μmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 μmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001). INTERPRETATION: The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 μmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. FUNDING: Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust.

Cancer remains a significant risk to human health. Nanomedicine is a new multidisciplinary field that is garnering a lot of interest and investigation. Nanomedicine shows great potential for cancer diagnosis and treatment. Specifically engineered nanoparticles can be employed as contrast agents in cancer diagnostics to enable high sensitivity and high-resolution tumor detection by imaging examinations. Novel approaches for tumor labeling and detection are also made possible by the use of nanoprobes and nanobiosensors. The achievement of targeted medication delivery in cancer therapy can be accomplished through the rational design and manufacture of nanodrug carriers. Nanoparticles have the capability to effectively transport medications or gene fragments to tumor tissues via passive or active targeting processes, thus enhancing treatment outcomes while minimizing harm to healthy tissues. Simultaneously, nanoparticles can be employed in the context of radiation sensitization and photothermal therapy to enhance the therapeutic efficacy of malignant tumors. This review presents a literature overview and summary of how nanotechnology is used in the diagnosis and treatment of malignant tumors. According to oncological diseases originating from different systems of the body and combining the pathophysiological features of cancers at different sites, we review the most recent developments in nanotechnology applications. Finally, we briefly discuss the prospects and challenges of nanotechnology in cancer.

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in immune regulation. It can activate janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. As one of the important signal transduction pathways in cells, JAK2/STAT3 signaling pathway plays a critical role in cell proliferation and differentiation by affecting the activation state of downstream effector molecules. The activation of JAK2/STAT3 signaling pathway is involved in tumorigenesis and development. It contributes to the formation of tumor inflammatory microenvironment and is closely related to the occurrence and development of many human tumors. This article focuses on the relationship between IL-6/JAK2/STAT3 signaling pathway and liver cancer, breast cancer, colorectal cancer, gastric cancer, lung cancer, pancreatic cancer and ovarian cancer, hoping to provide references for the research of cancer treatment targeting key molecules in IL-6/JAK2/STAT3 signaling pathway.

STUDY QUESTION: What is the prevalence of polycystic ovary syndrome (PCOS) in Han Chinese women from different communities? SUMMARY ANSWER: The prevalence of PCOS in Chinese women aged 19-45 years is 5.6%. WHAT IS KNOWN ALREADY: The prevalence of PCOS is reported to range from 5 to 10% but to the best of our knowledge the Han Chinese population has not been studied. STUDY DESIGN, SIZE, DURATION: A large-scale epidemiological study was carried out between October 2007 and September 2011 in 15 924 Han Chinese women of reproductive age (19-45 years) from the 10 provinces and municipalities in China. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 16 886 women from 152 cities and 112 villages were involved in the study. All study participants received a questionnaire and underwent a physical and transvaginal ultrasound examination. Blood samples were collected from a subsample of women (n = 3565) for analysis of metabolic markers and hormones. Based on the Rotterdam PCOS criteria, we assessed hyperandrogenism (H), chronic anovulation (O) and polycystic ovaries (P). Following diagnosis, women with PCOS were assigned to one of four different phenotypes. Finally, the prevalence and related risks of PCOS among Chinese women were estimated based on all the data sources. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 16 886 women were initially involved in the study and 15 924 eligible participants then completed the study; the overall response rate was 94.3% (15 924/16 886). The prevalence of PCOS in the Chinese community population was 5.6% (894/15 924). Blood samples were analyzed from 833 of these women who were assigned to the four PCOS phenotypes as follows: 19% H + O, 37% H + P, 15% O + P and 29% H + O + P. Comparing the 833 women with PCOS to 2732 women without PCOS indicated that PCOS occurs in younger women (P < 0.05) and these women were prone not only to menstrual problems, hyperandrogenism, PCO and infertility but also metabolic syndrome (MS) and insulin resistance (IR). However, there was no significant difference in the rate of hypertension or hyperlipemia between the two groups. Obese patients with PCOS had a higher rate of MS (16 versus 48%), IR (7 versus 28%), hypertension (8 versus 30%) and hyperlipemia (48 versus 73%) compared with non-obese patients (all P < 0.05), respectively. The rates of metabolic complications in patients with PCOS increased with age. LIMITATIONS, REASONS FOR CAUTION: Age and ethnic origin contribute to the differing manifestations of PCOS; therefore, sampling is one of the most important issues in epidemiological research into PCOS. Owing to the mobility of the Chinese population, the survey among resident populations caused a certain deviation in the age distribution. WIDER IMPLICATIONS OF THE FINDINGS: The prevention and treatment of PCOS, particularly in those who are obese, are essential in Chinese women of reproductive age.

Abstract The therapeutic outcome of photothermal therapy (PTT) remains impeded by the transparent depth of light. Combining PTT with immunotherapy provides strategies to solve this problem. Regulating metabolism‐related enzymes is a promising strategy to stimulate immune response. Here, a nanosystem (NLG919/IR780 micelles) with the properties of photothermal conversion and regulation of the tryptophan metabolic pathway is used to suppress the growth of the tumor margin beyond effective PTT and promote tumor PTT and immunotherapy. It is revealed that mild heat treatment promotes the growth of the tumor margin beyond effective PTT for the upregulation of heat shock protein (HSP), indoleamine 2,3‐dioxygenase (IDO), and programmed death‐ligand 1 (PD‐L1). The NLG919/IR780 micelles can effectively inhibit the activity of IDO but do not affect the level of IDO expression. NLG919/IR780 micelles can effectively accumulate in the tumor and can migrate to lymph nodes and the lymphatic system. In vivo antitumor studies reveal that NLG919/IR780 micelles effectively suppress the growth of tumor margin following PTT in primary tumors. NLG919/IR780 micelle‐mediated PTT and IDO inhibition further stimulate the activation of T lymphocytes, inhibiting the growth of distal tumors (abscopal effect). The results demonstrate that the NLG919/IR780 micelles combine PTT and immunotherapy and suppress the tumor margin as well as distal tumor growth post photothermal therapy.

OBJECTIVE: To develop a reference of population-based gestational age-specific birth weight percentiles for contemporary Chinese. METHODS: Birth weight data was collected by the China National Population-based Birth Defects Surveillance System. A total of 1,105,214 live singleton births aged ≥28 weeks of gestation without birth defects during 2006-2010 were included. The lambda-mu-sigma method was utilized to generate percentiles and curves. RESULTS: Gestational age-specific birth weight percentiles for male and female infants were constructed separately. Significant differences were observed between the current reference and other references developed for Chinese or non-Chinese infants. CONCLUSION: There have been moderate increases in birth weight percentiles for Chinese infants of both sexes and most gestational ages since 1980s, suggesting the importance of utilizing an updated national reference for both clinical and research purposes.

Since December 2019, there has been an outbreak of novel coronavirus (2019-nCoV) infection in China. Two cases of neonates with positive 2019-nCoV tests have been reported. Due to the immature immune system and the possibility of vertical transmission from mother to infant, neonates have become a high-risk group susceptible to 2019-nCoV, which emphasize a close cooperation from both perinatal and neonatal pediatrics. In neonatal intensive care unit (NICU), to prevent and control infection, there should be practical measures to ensure the optimal management of children potentially to be infected. According to the latest 2019-nCoV national management plan and the actual situation, the Chinese Neonatal 2019-nCoV expert working Group has put forward measures on the prevention and control of neonatal 2019-nCoV infection.

OBJECTIVE: To evaluate the value of fasting plasma glucose (FPG) value in the first prenatal visit to diagnose gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: Medical records of 17,186 pregnant women attending prenatal clinics in 13 hospitals in China, including the Peking University First Hospital (PUFH), were examined. Patients with pre-GDM were excluded; data for FPG at the first prenatal visit and one-step GDM screening with 75-g oral glucose tolerance test (OGTT) performed between 24 and 28 weeks of gestation were collected and analyzed. RESULTS: The median ± SD FPG value was 4.58 ± 0.437. FPG decreased with increasing gestational age. FPG level at the first prenatal visit was strongly correlated with GDM diagnosed at 24-28 gestational weeks (χ(2) = 959.3, P < 0.001). The incidences of GDM were 37.0, 52.7, and 66.2%, respectively, for women with FPG at the first prenatal visit between 5.10 and 5.59, 5.60 and 6.09, and 6.10-6.99 mmol/L. The data of PUFH were not statistically different from other hospitals. CONCLUSIONS: Pregnant women (6.10 ≤ FPG < 7.00 mmol/L) should be considered and treated as GDM to improve outcomes; for women with FPG between 5.10 and 6.09 mmol/L, nutrition and exercise advice should be provided. An OGTT should be performed at 24-28 weeks to confirm or rule out GDM. Based on our data, we cannot support an FPG value ≥5.10 mmol/L at the first prenatal visit as the criterion for diagnosis of GDM.

Oxidative stress (OS) has received extensive attention in the last two decades, because of the discovery that abnormal oxidation status was related to patients with chronic diseases, such as diabetes, cardiovascular, polycystic ovary syndrome (PCOS), cancer, and neurological diseases. OS is considered as a potential inducing factor in the pathogenesis of PCOS, which is one of the most common complex endocrine disorders and a leading cause of female infertility, affecting 4%-12% of women in the world, as OS has close interactions with PCOS characteristics, just as insulin resistance (IR), hyperandrogenemia, and chronic inflammation. It has also been shown that DNA mutations and alterations induced by OS are involved in cancer pathogenesis, tumor cell survival, proliferation, invasion, angiogenesis, and so on. Furthermore, recent studies show that the females with PCOS are reported to have an increasing risk of cancers. As a result, the more serious OS in PCOS is regarded as an important potential incentive for the increasing risk of cancers, and this study aims to analyze the possibility and potential pathogenic mechanism of the above process, providing insightful thoughts and evidences for preventing cancer potentially caused by PCOS in clinic.

Physical exercise is able to improve skeletal health. However, the mechanisms are poorly known. Irisin, a novel exercise-induced myokine, secreted by skeletal muscle in response to exercise, have been shown to mediate beneficial effects of exercise in many disorders. In the current study, we demonstrated that irisin promotes osteoblast proliferation, and increases the expression of osteoblastic transcription regulators, such as Runt-related transcription factor-2, osterix/sp7; and osteoblast differentiation markers, including alkaline phosphatase, collagen type 1 alpha-1, osteocalcin, and osteopontin in vitro. Irisin also increase ALP activity and calcium deposition in cultured osteoblast. These osteogenic effects were mediated by activating the p38 mitogen-activated protein kinase (p-p38 MAPK) and extracellular signal-regulated kinase (ERK). Inhibition of p38 MAPK by SB023580 or pERK by U0126 abolished the proliferation and up-regulatory effects of irisin on Runx2 expression and ALP activity. Together our observation suggest that irisin directly targets osteoblast, promoting osteoblast proliferation and differentiation via activating P38/ERK MAP kinase signaling cascades in vitro. Whether irisin can be utilized as the therapeutic agents for osteopenia and osteoporosis is worth to be further pursued.

The gut microbiota represents a large community of microorganisms that play an important role in immune regulation and maintenance of homeostasis. Living bacteria receive increasing interest as potential therapeutics for gut disorders, because they inhibit the colonization of pathogens and positively regulate the composition of bacteria in gut. However, these treatments are often accompanied by antibiotic administration targeting pathogens. In these cases, the efficacy of therapeutic bacteria is compromised by their susceptibility to antibiotics. Here, we demonstrate that a single-cell coating composed of tannic acids and ferric ions, referred to as 'nanoarmor', can protect bacteria from the action of antibiotics. The nanoarmor protects both Gram-positive and Gram-negative bacteria against six clinically relevant antibiotics. The multiple interactions between the nanoarmor and antibiotic molecules allow the antibiotics to be effectively absorbed onto the nanoarmor. Armored probiotics have shown the ability to colonize inside the gastrointestinal tracts of levofloxacin-treated rats, which significantly reduced antibiotic-associated diarrhea (AAD) resulting from the levofloxacin-treatment and improved some of the pre-inflammatory symptoms caused by AAD. This nanoarmor strategy represents a robust platform to enhance the potency of therapeutic bacteria in the gastrointestinal tracts of patients receiving antibiotics and to avoid the negative effects of antibiotics in the gastrointestinal tract.

Gel due to the enhanced antibacterial and antioxidant properties. Through the multi-crosslinking strategy, the hydrogels show enhanced mechanical properties, fabulous bio-adhesion, superior hemostatic performance and promoting healing ability, thereby have an appealing application value for the first-aid hemostasis and infected wound healing.

OBJECTIVE: To provide clinical management guidelines for novel coronavirus (COVID-19) in pregnancy. METHODS: On February 5, 2020, a multidisciplinary teleconference comprising Chinese physicians and researchers was held and medical management strategies of COVID-19 infection in pregnancy were discussed. RESULTS: Ten key recommendations were provided for the management of COVID-19 infections in pregnancy. CONCLUSION: Currently, there is no clear evidence regarding optimal delivery timing, the safety of vaginal delivery, or whether cesarean delivery prevents vertical transmission at the time of delivery; therefore, route of delivery and delivery timing should be individualized based on obstetrical indications and maternal-fetal status.

Hypoxia-ischemia (H/I) brain injury results in various degrees of damage to the body, and the immature brain is particularly fragile to oxygen deprivation. Hypothermia and erythropoietin (EPO) have long been known to be neuroprotective in ischemic brain injury. Brain-derived neurotrophic factor (BDNF) has recently been recognized as a potent modulator capable of regulating a wide repertoire of neuronal functions. This review was based on studies concerning the involvement of BDNF in the protection of H/I brain injury following a search in PubMed between 1995 and December, 2011. We initially examined the background of BDNF, and then focused on its neuroprotective mechanisms against ischemic brain injury, including its involvement in promoting neural regeneration/cognition/memory rehabilitation, angiogenesis within ischemic penumbra and the inhibition of the inflammatory process, neurotoxicity, epilepsy and apoptosis. We also provided a literature overview of experimental studies, discussing the safety and the potential clinical application of BDNF as a neuroprotective agent in the ischemic brain injury.

Background Antibiotics alter the microbial balance commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent AAD via providing gut barrier, restoration of the gut microflora, and other potential mechanisms of action. Objectives The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose) used for the prevention of AAD in children. Search methods MEDLINE, Embase, CENTRAL, CINAHL, and the Web of Science (inception to 28 May 2018) were searched along with registers including the ISRCTN and Clinicaltrials.gov. We also searched the NICE Evidence Services database as well as reference lists from relevant articles. Selection criteria Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of diarrhea secondary to antibiotic use were considered for inclusion. Data collection and analysis Study selection, data extraction, and risk of bias assessment were conducted independently by two authors. Dichotomous data (incidence of AAD, adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and continuous data (mean duration of diarrhea) as mean difference (MD), along with corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. For studies reporting on microbiome characteristics using heterogeneous outcomes, we describe the results narratively. The certainty of the evidence was evaluated using GRADE. Main results Thirty-three studies (6352 participants) were included. Probiotics assessed included Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., orStreptococcus spp., alone or in combination. The risk of bias was determined to be high in 20 studies and low in 13 studies. Complete case (patients who did not complete the studies were not included in the analysis) results from 33 trials reporting on the incidence of diarrhea show a precise benefit from probiotics compared to active, placebo or no treatment control. After 5 days to 12 weeks of follow-up, the incidence of AAD in the probiotic group was 8% (259/3232) compared to 19% (598/3120) in the control group (RR 0.45, 95% CI 0.36 to 0.56; I² = 57%, 6352 participants; NNTB 9, 95% CI 7 to 13; moderate certainty evidence). Nineteen studies had loss to follow-up ranging from 1% to 46%. After making assumptions for those lost, the observed benefit was still statistically significant using an extreme plausible intention-to-treat (ITT) analysis, wherein the incidence of AAD in the probiotic group was 12% (436/3551) compared to 19% (664/3468) in the control group (7019 participants; RR 0.61; 95% CI 0.49 to 0.77; P &lt;0.00001; I² = 70%). An a priori available case subgroup analysis exploring heterogeneity indicated that high dose (≥ 5 billion CFUs per day) is more effective than low probiotic dose (&lt; 5 billion CFUs per day), interaction P value = 0.01. For the high dose studies the incidence of AAD in the probiotic group was 8% (162/2029) compared to 23% (462/2009) in the control group (4038 participants; RR 0.37; 95% CI 0.30 to 0.46; P = 0.06; moderate certainty evidence). For the low dose studies the incidence of AAD in the probiotic group was 8% (97/1155) compared to 13% (133/1059) in the control group (2214 participants; RR 0.68; 95% CI 0.46 to 1.01; P = 0.02). Again, assumptions for loss to follow-up using an extreme plausible ITT analysis was statistically significant. For high dose studies the incidence of AAD in the probiotic group was 13% (278/2218) compared to 23% (503/2207) in control group (4425 participants; RR 0.54; 95% CI 0.42 to 0.70; P &lt;0.00001; I² = 68%; moderate certainty evidence). None of the 24 trials (4415 participants) that reported on adverse events reported any serious adverse events attributable to probiotics. Adverse event rates were low. After 5 days to 4 weeks follow-up, 4% (86/2229) of probiotics participants had an adverse event compared to 6% (121/2186) of control participants (RD 0.00; 95% CI-0.01 to 0.01; P &lt; 0.00001; I² = 75%; low certainty evidence). Common adverse events included rash, nausea, gas, flatulence, abdominal bloating, and constipation. After 10 days to 12 weeks of follow-up, eight studies recorded data on our secondary outcome, the mean duration of diarrhea; with probiotics reducing diarrhea duration by almost one day (MD-0.91; 95% CI-1.38 to-0.44; P &lt;0.00001; low certainty evidence). One study reported on microbiome characteristics, reporting no difference in changes with concurrent antibiotic and probiotic use. Authors’ conclusions The overall evidence suggests a moderate protective effect of probiotics for preventing AAD (NNTB 9, 95% CI 7 to 13). Using five criteria to evaluate the credibility of the subgroup analysis on probiotic dose, the results indicate the subgroup effect based on high dose probiotics (≥ 5 billion CFUs per day) was credible. Based on high-dose probiotics, the NNTB to prevent one case of diarrhea is 6 (95% CI 5 to 9). The overall certainty of the evidence for the primary endpoint, incidence of AAD based on high dose probiotics was moderate due to the minor issues with risk of bias and inconsistency related to a diversity of probiotic agents used. Evidence also suggests that probiotics may moderately reduce the duration of diarrhea, a reduction by almost one day. The benefit of high dose probiotics (e.g. Lactobacillus rhamnosus orSaccharomyces boulardii) needs to be confirmed by a large well-designed multi-centered randomized trial. It is premature to draw firm conclusions about the efficacy and safety of ’other’ probiotic agents as an adjunct to antibiotics in children. Adverse event rates were low and no serious adverse events were attributable to probiotics. Although no serious adverse events were observed among inpatient and outpatient children, including small studies conducted in the intensive care unit and in the neonatal unit, observational studies not included in this review have reported serious adverse events in severely debilitated or immuno-compromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation.

BACKGROUND: Transcription factor 7-like 2 (TCF7L2) has been shown to be associated with type 2 diabetes mellitus (T2MD) in multiple ethnic groups in the past two years, but, contradictory results were reported for Chinese and Pima Indian populations. The authors then performed a large meta-analysis of 36 studies examining the association of type 2 diabetes mellitus (T2DM) with polymorphisms in the TCF7L2 gene in various ethnicities, containing rs7903146 C-to-T (IVS3C>T), rs7901695 T-to-C (IVS3T>C), a rs12255372 G-to-T (IVS4G>T), and rs11196205 G-to-C (IVS4G>C) polymorphisms and to evaluate the size of gene effect and the possible genetic mode of action. METHODS: Literature-based searching was conducted to collect data and three methods, that is, fixed-effects, random-effects and Bayesian multivariate mete-analysis, were performed to pool the odds ratio (OR). Publication bias and study-between heterogeneity were also examined. RESULTS: The studies included 35,843 cases of T2DM and 39,123 controls, using mainly primary data. For T2DM and IVS3C>T polymorphism, the Bayesian OR for TT homozygotes and TC heterozygotes versus CC homozygote was 1.968 (95% credible interval (CrI): 1.790, 2.157), 1.406 (95% CrI: 1.341, 1.476), respectively, and the population attributable risk (PAR) for the TT/TC genotypes of this variant is 16.9% for overall. For T2DM and IVS4G>T polymorphism, TT homozygotes and TG heterozygotes versus GG homozygote was 1.885 (95%CrI: 1.698, 2.088), 1.360 (95% CrI: 1.291, 1.433), respectively. Four ORs among these two polymorphisms all yielded significant between-study heterogeneity (P < 0.05) and the main source of heterogeneity was ethnic differences. Data also showed significant associations between T2DM and the other two polymorphisms, but with low heterogeneity (P > 0.10). Pooled ORs fit a codominant, multiplicative genetic model for all the four polymorphisms of TCF7L2 gene, and this model was also confirmed in different ethnic populations when stratification of IVS3C>T and IVS4G>T polymorphisms except for Africans, where a dominant, additive genetic mode is suggested for IVS3C>T polymorphism. CONCLUSION: This meta-analysis demonstrates that four variants of TCF7L2 gene are all associated with T2DM, and indicates a multiplicative genetic model for all the four polymorphisms, as well as suggests the TCF7L2 gene involved in near 1/5 of all T2MD. Potential gene-gene and gene-environmental interactions by which common variants in the TCF7L2 gene influence the risk of T2MD need further exploration.

OBJECTIVE: To examine how the relaxation of the one child policy and policies to reduce caesarean section rates might have affected trends over time in caesarean section rates and perinatal and pregnancy related mortality in China. DESIGN: Observational study. SETTING: China's National Maternal Near Miss Surveillance System (NMNMSS). PARTICIPANTS: 6 838 582 births at 28 completed weeks or more of gestation or birth weight ≥1000 g in 438 hospitals in the NMNMSS between 2012 and 2016. MAIN OUTCOME MEASURES: Obstetric risk was defined using a modified Robson classification. The main outcome measures were changes in parity and age distributions and relative frequency of each Robson group, crude and adjusted trends over time in caesarean section rates within each risk category (using Poisson regression with a robust variance estimator), and trends in perinatal and pregnancy related mortality over time. RESULTS: Caesarean section rates declined steadily between 2012 and 2016 (crude relative risk 0.91, 95% confidence interval 0.89 to 0.93), reaching an overall hospital based rate of 41.1% in 2016. The relaxation of the one child policy was associated with an increase in the proportion of multiparous births (from 34.1% in 2012 to 46.7% in 2016), and births in women with a uterine scar nearly doubled (from 9.8% to 17.7% of all births). Taking account of these changes, the decline in caesarean sections was amplified over time (adjusted relative risk 0.82, 95% confidence interval 0.81 to 0.84). Caesarean sections declined noticeably in nulliparous women (0.75, 0.73 to 0.77) but also declined in multiparous women without a uterine scar (0.65, 0.62 to 0.77). The decrease in caesarean section rates was most pronounced in hospitals with the highest rates in 2012, consistent with the government's policy of targeting hospitals with the highest rates. Perinatal mortality declined from 10.1 to 7.2 per 1000 births over the same period (0.87, 0.83 to 0.91), and there was no change in pregnancy related mortality over time. CONCLUSIONS: China is the only country that has succeeded in reverting the rising trends in caesarean sections. China's success is remarkable given that the changes in obstetric risk associated with the relaxation of the one child policy would have led to an increase in the need for caesarean sections. China's experience suggests that change is possible when strategies are comprehensive and deal with the system level factors that underpin overuse as well as the various incentives at work during a clinical encounter.