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Though gut microbiome disturbance may be involved in the etiology of gestational diabetes mellitus (GDM), data on the gut microbiome's dynamic change during pregnancy and associations with gestational glucose metabolism are still inadequate. In this prospective study comprising 120 pairs of GDM patients and matched pregnant controls, a decrease in the diversity of gut microbial species and changes in the microbial community composition with advancing gestation are found in controls, while no such trends are observed in GDM patients. Multivariable analysis identifies 10 GDM‐related species (e.g., Alistipes putredinis), and the integrated associations of these species with glycemic traits are modified by habitual intake of fiber‐rich plant foods. In addition, the microbial metabolic potentials related to fiber fermentation (e.g., mannan degradation pathways) and their key enzymes consistently emerge as associated with both GDM status and glycemic traits. Microbial features especially those involved in fiber fermentation, provide an incremental predictive value in a prediction model with established risk factors of GDM. These data suggest that the gut microbiome remodeling with advancing gestation is different in GDM patients compared with controls, and dietary fiber fermentation contributes to the influence of gut microbiome on gestational glycemic regulation. The temporal remodeling in gut microbiota during pregnancy is related to the development of gestational diabetes mellitus (GDM). Habitual intake of fiber‐rich foods modifies the associations of microbial species with glycemic traits during pregnancy. Microbial features measured at early pregnancy provides an incremental predictive value when added to traditional predictive model for GDM risk.

Mineral micronutrients are critical for basic physiological function, and variable availability of minerals over the landscape can influence foraging decisions. Sodium is essential for nerve function and osmotic balance; however, it can be limiting in some environments, such as those at high elevations. Koalas (Phascolarctos cinereus) living in subalpine regions have been observed eating Eucalyptus mannifera bark, an unusual food choice for a folivore. We hypothesized that sodium may be deficient in leaves at high-elevation sites, and that the bark from trees could be a potential sodium source. We compared the mineral content of eucalypt bark and leaves in 3 areas where koalas chew bark and in leaves of a preferred food tree of koalas, E. viminalis, across a range of elevations. Individual chewed trees were rare compared to non-chewed conspecifics and patchily distributed. Bark from chewed E. mannifera trees had significantly higher concentrations of sodium than plant parts from non-chewed neighboring conspecifics and other Eucalyptus species trees. We also found that E. viminalis foliage had significantly less sodium at higher elevations than lowland populations. We propose that koalas have developed the unusual bark-eating behavior to meet sodium requirements in an otherwise sodium-poor landscape. Given the physiological importance of sodium, behavioral adaptations such as these may be critical to the ability of mammalian herbivores to survive in nutrient-deficient landscapes.

Background In Ethiopia, malaria has declined in the last decade; only a small number of cases have been reported, primarily from hotspots. The contribution of house proximity to water bodies and the role of migration in malaria transmission has not yet been examined in detail in northwest Ethiopia. Individual and household-level environmental and socio-demographic drivers of malaria heterogeneity were explored contextually in meso-endemic villages around Lake Tana, northwest Ethiopia. Methods A health facility-based paired age-sex matched case–control study involving 303 matched pairs was undertaken from 10 October 2016, to 30 June 2017. Geo-referencing of case households, control households, proximate water bodies, and health centres was carried out. A pretested and structured questionnaire was used to collect data on socio-demography, household assets, housing, travel history, and malaria intervention measures. Medians (interquartile range) were computed for continuous variables. Pearson’s Chi square/Fisher’s exact test was used to detect significant differences in proportions. Principal component analysis was performed to estimate household wealth. Stratified analysis was used to confirm confounding and interaction. A multivariable conditional logistic regression model was used to detect risk factors for malaria. Results Of 303 malaria cases, 59 (19.5% [15.4–24.3]) were imported malaria cases whereas 244 (80.5% [75.7–84.6]) were locally acquired malaria cases. In bivariate analysis, marital status, educational status, and bed net ownership were significantly associated with malaria cases. In multivariable adjustment, travel to malarious lowlands in the preceding month (adjusted mOR = 7.32; 95% CI 2.40–22.34), household member’s travel to malarious lowlands (adjusted mOR = 2.75; 95% CI 1.02–7.44), and inadequate health information on malaria (adjusted mOR = 1.57; 95% CI 1.03–2.41) were predictors of malaria. Stratified analysis confirmed that elevation of households and travel to malarious lowlands were not effect modifiers. Travel to malarious lowlands had a confounding effect on malaria but elevation of households did not. Conclusions In this study, travel to farms in the lowlands and inadequate health information on malaria were risk factors for malaria in villages around Lake Tana. This evidence is critical for the design of improved strategic interventions that consider imported malaria cases and approaches for accessing health information on malaria control in northwest Ethiopia.

Objective In this study, we performed a meta‐analysis and a propensity score‐matched case–control study to evaluate the efficacy and safety of belimumab in patients with lupus nephritis (LN). Methods We analyzed the data from three randomized controlled trials (RCTs) to assess the effects of belimumab treatment on renal improvement and adverse effects. Our study included a total of six LN patients who received belimumab treatment and an additional six LN patients who received standard therapy. All participants were followed up for a duration exceeding 96 weeks to evaluate the outcomes of the treatments. Results Our meta‐analysis incorporated data from three articles involving a total of 666 patients. The results of the analysis revealed that a higher proportion of patients who received belimumab treatment experienced renal improvement compared to those in the control group. The patients in belimumab group had a higher renal complete response rate and proteinuria improvement rate compared to the control group. However, belimumab treatment did not increase the renal partial response rate compared to the control group. The belimumab group also exhibited a higher proportion of patients who achieved normalization of antidouble‐stranded DNA, as well as normalization of low C3 and C4 levels. In our case–control study, significant improvement in proteinuria was demonstrated with belimumab at Week 48 (p = 0.037) and at all subsequent time points (all p < 0.05). Over the course of 96 weeks, belimumab treatment was associated with renal function stabilization and an increase in C3 and C4 levels. Moreover, the use of belimumab resulted in a reduction in glucocorticoid dosage at Week 24 (p = 0.02). Additionally, patients receiving belimumab treatment had a lower risk of severe treatment‐emergent adverse events, and no other significant adverse effects were observed between the two groups. Conclusions In patients with LN, the utilization of belimumab therapy has demonstrated notable improvements in renal response rates. Additionally, it has shown a decreased likelihood of serious treatment‐related adverse events and a diminished need for glucocorticoid dosage when compared to the active control group. Belimumab increased the rates of renal response in patients with lupus nephritis. Belimumab decreased the risk of severe treatment‐emergent adverse events and the dose of glucocorticoid compared to active control in patients with lupus nephritis.

Similar to global trends, neonatal mortality has fallen only slightly in Indonesia over the period 1990-2010, with a high proportion of deaths in the first week of life. This study aimed to identify risk factors associated with neonatal deaths of low and normal birthweight infants that were amenable to health service intervention at a community level in a relatively poor province of Indonesia. A matched case-control study of neonatal deaths reported from selected community health centres (puskesmas) was conducted over 10 months in 2013. Cases were singleton births, born by vaginal delivery, at home or in a health facility, matched with two controls satisfying the same criteria. Potential variables related to maternal and neonatal risk factors were collected from puskesmas medical records and through home visit interviews. A conditional logistic regression was performed to calculate odds ratios using the clogit procedure in Stata 11. Combining all significant variables related to maternal, neonatal, and delivery factors into a single multivariate model, six factors were found to be significantly associated with a higher risk of neonatal death. The factors identified were as follows: neonatal complications during birth; mother noting a health problem during the first 28 days; maternal lack of knowledge of danger signs for neonates; low Apgar score; delivery at home; and history of complications during pregnancy. Three risk factors (neonatal complication at delivery; neonatal health problem noted by mother; and low Apgar score) were significantly associated with early neonatal death at age 0-7 days. For normal birthweight neonates, three factors (complications during delivery; lack of early initiation of breastfeeding; and lack of maternal knowledge of neonatal danger signs) were found to be associated with a higher risk of neonatal death. The study identified a number of factors amenable to health service intervention associated with neonatal deaths in normal and low birthweight infants. These factors include maternal knowledge of danger signs, response to health problems noted by parents in the first month, early initiation of breastfeeding, and delivery at home. Addressing these factors could reduce neonatal deaths in low resource settings.

Genetic variants in FOXO3 are associated with longevity. Here, we assessed whether blood DNA methylation at FOXO3 was associated with cancer risk, survival, and mortality. We used data from eight prospective case–control studies of breast (n = 409 cases), colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869), and urothelial (n = 428) cancer and B-cell lymphoma (n = 438). Case–control pairs were matched on age, sex, country of birth, and smoking (lung cancer study). Conditional logistic regression was used to assess associations between cancer risk and methylation at 45 CpGs of FOXO3 included on the HumanMethylation450 assay. Mixed-effects Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with cancer survival (total n = 2286 deaths). Additionally, using data from 1088 older participants, we assessed associations of FOXO3 methylation with overall and cause-specific mortality (n = 354 deaths). Methylation at a CpG in the first exon region of FOXO3 (6:108882981) was associated with gastric cancer survival (HR = 2.39, 95% CI: 1.60–3.56, p = 1.9 × 10−5). Methylation at three CpGs in TSS1500 and gene body was associated with lung cancer survival (p < 6.1 × 10−5). We found no evidence of associations of FOXO3 methylation with cancer risk and mortality. Our findings may contribute to understanding the implication of FOXO3 in longevity.

Background 39% of neonatal deaths in India occur on the first day of life, and 57% during the first three days of births. However, the association between postnatal care (PNC) for newborns and neonatal mortality has not hitherto been examined. The paper aims to examine the association of PNC for newborns with neonatal mortality in India. Methods Data from District Level Household Survey, waive three (DLHS-3) conducted in 2007–08 is utilized in the study. We used conditional logit regression models to examine the association of PNC with neonatal mortality. The matching variables included birth order and the age of the mother at the birth of the newborn. Results The findings suggest no association between check-up of newborns within 24 hours of birth and neonatal mortality. However, the place where the newborns were examined was significantly associated with neonatal mortality. Moreover, findings do reveal that children of mothers who were advised on ‘keeping baby warm (kangaroo care) after birth’ during their antenatal sessions were significantly less likely to die during the neonatal period compared to those children whose mothers were not advised about the same. Conclusions The findings are relevant because ‘keeping baby warm’ is one of the most cost-effective and easiest interventions to save babies from dying during the neonatal period. Though randomized controlled trials have already demonstrated the effectiveness of ‘keeping baby warm’, for the first time this has been found effective in a large-scale population-based study. The findings are of immense value for a country like India where the neonatal mortality rates are unacceptably high.

We propose a method for assessing variable importance in matched case–control investigations and other highly stratified studies characterized by high dimensional data (p ≫ n). In simulated and real data sets, we show that the algorithm proposed performs better than a conventional univariate method (conditional logistic regression) and a popular multivariable algorithm (random forests) that does not take the matching into account. The methods are applicable to wide ranging, high impact clinical studies including metabolomic, proteomic studies and neuroimaging analyses, such as those assessing stroke and Alzheimer's disease. The methods proposed have been implemented in a freely available R library (http://cran.r-project.org/web/packages/RPCLR/index.html).

Background: In China, and in Shandong province, the proportionate contribution of birth defects to infant mortality has increased, and congenital heart disease (CHD) is now the most common cause of birth defects. The cause of approximately 90% of cases of congenital heart disease is multifactorial. Little is known about modifiable environmental risk factors or regional differences. We investigated putative environmental risk factors for congenital heart disease in the Shandong province of China in order to improve prevention of CHD. Methods: We conducted a hospital-based 1:2 matched case-control study of 164 patients with congenital heart diseases and 328 controls, all of whom were retrospectively interviewed. Univariate and multivariate analyses were conducted to identify environmental risk factors for CHD. Results: The environmental risk factors associated with CHD were mother's education level (odds ratio [OR], 0.31; 95% confidence interval [CI], 0.15-0.67), neonatal asphyxia or hypoxia (OR, 3.74; 95% CI, 1.25-11.18), number of previous pregnancies (OR, 2.68; 95% CI, 1.44-4.97), maternal upper respiratory tract infection (OR, 4.12; 95% CI, 1.56-10.85), maternal infection (OR, 7.98; 95% CI, 2.14-29.72), maternal B-mode ultrasound examination (OR, 4.05; 95% CI, 1.48-11.08), and maternal mental stress (OR, 3.93; 95% CI, 1.94-7.94) during early pregnancy. No significant interactions were observed among these factors. Conclusions: Augmenting maternal mental healthcare, obtaining regular health counseling and testing during pregnancy, preventing upper respiratory tract infections, limiting medication during early pregnancy, offering health promotion and health education to women of childbearing age (especially those with less formal education), and improving obstetric procedures and techniques may lower the occurrence of congenital heart disease.

Case‐crossover designs are widely used to study short‐term exposure effects on the risk of acute adverse health events. While the frequentist literature on this topic is vast, there is no Bayesian work in this general area. The contribution of this paper is twofold. First, the paper establishes Bayesian equivalence results that require characterization of the set of priors under which the posterior distributions of the risk ratio parameters based on a case‐crossover and time‐series analysis are identical. Second, the paper studies inferential issues under case‐crossover designs in a Bayesian framework. Traditionally, a conditional logistic regression is used for inference on risk‐ratio parameters in case‐crossover studies. We consider instead a more general full likelihood‐based approach which makes less restrictive assumptions on the risk functions. Formulation of a full likelihood leads to growth in the number of parameters proportional to the sample size. We propose a semi‐parametric Bayesian approach using a Dirichlet process prior to handle the random nuisance parameters that appear in a full likelihood formulation. We carry out a simulation study to compare the Bayesian methods based on full and conditional likelihood with the standard frequentist approaches for case‐crossover and time‐series analysis. The proposed methods are illustrated through the Detroit Asthma Morbidity, Air Quality and Traffic study, which examines the association between acute asthma risk and ambient air pollutant concentrations.