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Metformin is widely used in pregnancy, despite lack of long-term safety for children. We hypothesised that metformin exposure in utero is associated with increased cardiovascular risk. We tested this hypothesis in a follow-up study of children born to obese mothers who had participated in a randomised controlled trial of metformin versus placebo in pregnancy (EMPOWaR). We measured body composition, peripheral blood pressure (BP), arterial pulse wave velocity and central haemodynamics (central BP and augmentation index) using an oscillometric device in 40 children of mean (SD) age 5.78 (0.93) years, exposed to metformin (n = 19) or placebo (n = 21) in utero. There were no differences in any of the anthropometric or vascular measures between metformin and placebo-exposed groups in univariate analyses, or after adjustment for potential confounders including the child’s behaviour, diet and activity levels. Post-hoc sample size calculation indicated we would have detected large clinically significant differences between the groups but would need an unfeasible large number to detect possible subtle differences in key cardiovascular risk parameters in children at this age of follow-up. Our findings suggest no evidence of increased cardiovascular risk in children born to obese mothers who took metformin in pregnancy and increase available knowledge of the long-term safety of metformin on childhood outcomes.
Stratospheric airships are lighter-than-air vehicles that work at an altitude of 20km in the lower calm portion of the stratosphere. They can be used as real-time surveillance platforms for environment monitoring and civil communication. Solar energy is the ideal power choice for long-endurance stratospheric airships. Attitude control is important for airships so that they can point at a target for observation or adjust the attitude to improve the output performance of solar panels. Stratospheric airships have a large volume and semi-flexible structure. The typical actuators used are aerodynamic surfaces, vectored thrust and ballonets. However, not all these actuators can work well under special working conditions, such as low density and low speed. In this study, moving-mass control is introduced to stratospheric airships because its control efficiency is independent of airspeed and atmospheric density. A nonlinear feedback controller based on generalised inverse with a nonlinear mapping module is designed to implement moving-mass control. Such a new station keeping scheme with moving masses is proposed for airships with different working situations.
Inflammatory diets are increasingly recognized as a modifiable determinant of mental illness. However, there is a dearth of studies in early life and across the full mental wellbeing spectrum (mental illness to positive wellbeing) at the population level. This is a critical gap given that inflammatory diet patterns and mental wellbeing trajectories typically establish by adolescence. We examined associations of inflammatory diet scores with mental wellbeing in 11-12 year-olds and mid-life adults. Throughout Australia, 1759 11-12 year-olds (49% girls) and 1812 parents (88% mothers) contributed cross-sectional population-based data. Alternate inflammatory diet scores were calculated from a 26-item food frequency questionnaire, based on prior literature and prediction of inflammatory markers respectively. Participants reported negatively- and positively-framed mental wellbeing via psychosocial health, quality of life and life satisfaction surveys. We used causal inference modelling techniques via generalized linear regression models (mean differences and risk ratios (RR)) to examine how inflammatory diets might influence mental wellbeing. In children and adults respectively, a one standard deviation (SD) higher literature-derived inflammatory diet score conferred between a 44% (RR 95%CI:1.2-1.8) to 57% (RR 95%CI:1.3-2.0) and 54% (95%CI: 1.2-2.0) to 86% (RR 95%CI:1.4-2.4) higher risk of being in the worst mental wellbeing category (i.e. <16th percentile) across outcome measures. Results for inflammation-derived scores were similar. Body mass index (BMI) mediated effects (21-39%) in adults. Inflammatory diet patterns were cross-sectionally associated with mental wellbeing at age 11-12 years, with similar effects observed in mid-adulthood. Reducing inflammatory dietary components in childhood could improve population-level mental wellbeing across the lifecourse.
The two-dimensional laminar flow of a viscous fluid induced by peristalsis due to a moving wall wave has been studied previously for a rectangular channel, a circular tube and a concentric circular annulus. Here, we study peristaltic flow in a non-axisymmetric annular tube: in this case, the flow is three-dimensional, with motions in the azimuthal direction. This type of geometry is motivated by experimental observations of the pulsatile flow of cerebrospinal fluid along perivascular spaces surrounding arteries in the brain, which is at least partially driven by peristaltic pumping due to pulsations of the artery. These annular perivascular spaces are often eccentric and the outer boundary is seldom circular: their cross-sections can be well matched by a simple, adjustable model consisting of an inner circle (the outer wall of the artery) and an outer ellipse (the outer edge of the perivascular space), not necessarily concentric. We use this geometric model as a basis for numerical simulations of peristaltic flow: the adjustability of the model makes it suitable for other applications. We concentrate on the general effects of the non-axisymmetric configuration on the flow and do not attempt to specifically model perivascular pumping. We use a finite-element scheme to compute the flow in the annulus driven by a propagating sinusoidal radial displacement of the inner wall. Unlike the peristaltic flow in a concentric circular annulus, the flow is fully three-dimensional: azimuthal pressure variations drive an oscillatory flow in and out of the narrower gaps, inducing an azimuthal wiggle in the streamlines. We examine the dependence of the flow on the elongation of the outer elliptical wall and the eccentricity of the configuration. We find that the time-averaged volumetric flow is always in the same direction as the peristaltic wave and decreases with increasing ellipticity or eccentricity. The additional shearing motion in the azimuthal direction will increase mixing and enhance Taylor dispersion in these flows, effects that might have practical applications.
Glutamine synthetase (GS) and glutamate synthase (GOGAT) play a central role in plant nitrogen (N) metabolism. In order to study the effect of powdery mildew (Blumeria graminis f. sp. tritici, Bgt) on N metabolism, field experiments were carried out to evaluate GS and GOGAT activity, GS expression and grain protein content (GPC) in susceptible (Xi'nong 979) and resistant (Zhengmai 103) wheat cultivars under three treatments. The three treatments were no inoculation (CK), inoculated once with Bgt (MP) and inoculated nine times with Bgt (HP). For Xi'nong 979, the activities of GS and GOGAT in grains as well as GS activity in flag leaves increased at 10–15 days after anthesis (DAA), and decreased significantly at 15 or 20–30 DAA in HP and MP. However, GS activity in grains decreased from 20 DAA, which was later than that of flag leaves (15 DAA). At the same time, GS expression in grains was up-regulated at early stage, with GS1 at 10 DAA and GS2 at 15 DAA, followed by a continuous down-regulation. This result indicated that GS and GOGAT activity as well as GS expression were inhibited by powdery mildew, indicating that N metabolism in grains was inhibited at 20–30 DAA. The current study also found out that the yield of the susceptible cultivar decreased significantly, while its GPC increased obviously in HP. It was shown that the increase of GPC was not due to the enhancement of N metabolism, but due to the passive increase caused by yield reduction.
The justice literature has coalesced around the notion that actors (e.g., supervisors) tend to utilize the norm of equity for resource allocation decisions because it is generally considered most fair when employees who contribute more to the organization receive more resources. Yet, actors might sometimes utilize a need norm to allocate resources to those most in need. Studies that have addressed need-based resource allocations have assumed a relatively straightforward conceptualization of need. However, research from related areas suggests that multiple characteristics of the need itself could trigger actors’ use of a need norm to allocate resources. We advance a theoretical framework that outlines various need characteristics that drive actors’ use of a need norm. The framework draws on the processes outlined in attribution theory and integrates those with the content domains addressed in fairness theory. A discussion of the implications for justice, attribution, and fairness theory research follows.
This study aimed to examine the association between caloric asymmetry and response to treatment in patients with vestibular migraine.
Dizziness Handicap Inventory scores were compared between patients with less than and more than 25 per cent asymmetry (using Cohen effect size) in a cohort of definite vestibular migraine patients who underwent caloric testing between August 2016 and March 2019.
A total of 31 patients (mean age: 48.7 ± 20.0 years; mean follow up: 9.1 ± 8.1 months) were included. Mean caloric asymmetry was 15.1 ± 15.6 per cent, with 6 (19.4 per cent) patients having asymmetry more than 25 per cent. Overall, patients experienced significant improvement in Dizziness Handicap Inventory total (d = 0.623 (95 per cent confidence interval, 0.007, 1.216)), emotional domain (d = 0.635 (95 per cent confidence interval, 0.019, 1.229)) and functional domain (d = 0.769 (95 per cent confidence interval, 0.143, 1.367)) but not physical domain (d = 0.227 (95 per cent confidence interval, −0.370, 0.815)) scores. Patients with more than 25 per cent asymmetry had no significant improvement in Dizziness Handicap Inventory scores, whereas those with less than 25 per cent asymmetry had significant improvement in Dizziness Handicap Inventory functional domain scores only (d = 0.636 (95 per cent confidence interval, 0.004, 1.244)).
Vestibular migraine patients with peripheral vestibular weakness on caloric testing may be less likely to improve after treatment compared with those without.
Community characteristics, such as collective efficacy, a measure of community strength, can affect behavioral responses following disasters. We measured collective efficacy 1 month before multiple hurricanes in 2005, and assessed its association to preparedness 9 months following the hurricane season.
Participants were 631 Florida Department of Health workers who responded to multiple hurricanes in 2004 and 2005. They completed questionnaires that were distributed electronically approximately 1 month before (6.2005-T1) and 9 months after (6.2006-T2) several storms over the 2005 hurricane season. Collective efficacy, preparedness behaviors, and socio-demographics were assessed at T1, and preparedness behaviors and hurricane-related characteristics (injury, community-related damage) were assessed at T2. Participant ages ranged from 21-72 (M(SD) = 48.50 (10.15)), and the majority were female (78%).
In linear regression models, univariate analyses indicated that being older (B = 0.01, SE = 0.003, P < 0.001), White (B = 0.22, SE = 0.08, P < 0.01), and married (B = 0.05, SE = 0.02, p < 0.001) was associated with preparedness following the 2005 hurricanes. Multivariate analyses, adjusting for socio-demographics, preparedness (T1), and hurricane-related characteristics (T2), found that higher collective efficacy (T1) was associated with preparedness after the hurricanes (B = 0.10, SE = 0.03, P < 0.01; and B = 0.47, SE = 0.04, P < 0.001 respectively).
Programs enhancing collective efficacy may be a significant part of prevention practices and promote preparedness efforts before disasters.
ABSTRACT IMPACT: Screening the effect of thousands of non-coding genetic variants will help identify variants important in the etiology of diseases OBJECTIVES/GOALS: Massively parallel reporter assays (MPRAs) can experimentally evaluate the impact of genetic variants on gene expression. In this study, our objective was to systematically evaluate the functional activity of 3’-UTR SNPs associated with neurological disorders and use those results to help understand their contributions to disease etiology. METHODS/STUDY POPULATION: To choose variants to evaluate with the MPRA, we first gathered SNPs from the GWAS Catalog that were associated with any neurological disorder trait with p-value < 10-5. For each SNP, we identified the region that was in linkage disequilibrium (r2 > 0.8) and retrieved all the common 3’-UTR SNPs (allele-frequency > 0.05) within that region. We used an MPRA to measure the impact of these 3’-UTR variants in SH-SY5Y neuroblastoma cells and a microglial cell line. These results were then used to train a deep-learning model to predict the impact of variants and identify features that contribute to the predictions. RESULTS/ANTICIPATED RESULTS: Of the 13,515 3’-UTR SNPs tested, 400 and 657 significantly impacted gene expression in SH-SY5Y and microglia, respectively. Of the 84 SNPs significantly impacted in both cells, the direction of impact was the same in 81. The direction of eQTL in GTEx tissues agreed with the assay SNP effect in SH-SY5Y cells but not microglial cells. The deep-learning model predicted sequence activity level correlated with the experimental activity level (Spearman’s corr = 0.45). The deep-learning model identified several predictive motifs similar to motifs of RNA-binding proteins. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study demonstrates that MPRAs can be used to evaluate the effect of non-coding variants, and the results can be used to train a machine learning model and interpret its predictions. Together, these can help identify causal variants and further understand the etiology of diseases.
Diverse and abundant fossil taxa have been described in the lower Cambrian Shipai Formation in the Three Gorges area of Hubei Province, South China, but the taxonomy and diversity of the co-occurring brachiopod fauna are still far from clear. Here we describe the brachiopod fauna recovered from the Shipai Formation in the Three Gorges area of South China, including representatives of the subphylum Linguliformea: linguloids (Lingulellotreta ergalievi, Eoobolus malongensis, and Neobolidae gen. indet. sp. indet.), and an acrotretoid (Linnarssonia sapushanensis); and representatives from the subphylum Rhynchonelliformea: the calcareous-shelled Kutorginates (Kutorgina sinensis, Kutorgina sp., and Nisusia liantuoensis). This brachiopod assemblage and the first occurrence of Linnarssonia sapushanensis shell beds permit correlation of the Shipai Formation in the Three Gorges area of Hubei Province with the Stage 4 Wulongqing Formation in the Wuding area of eastern Yunnan. This correlation is further strengthened by the first appearance datum (FAD) of the rhynchonelliform brachiopod Nisusia in the upper silty mudstone of both the Shipai and Wulongqing formations. The new well-preserved material, derived from siliciclastic rocks, also gives critical new insights into the fine shell structure of L. sapushanensis. Microstructural studies on micromorphic acrotretoids (like Linnarssonia) have previously been restricted to fossils that were acid-etched from limestones. This is the first study to carry out detailed comparative ultrastructural studies on acrotretoid shells preserved in siliciclastic rocks. This work reveals a hollow tube and solid column microstructure in the acrotretoid shells from the Shipai Formation, which is likely to be equivalent of traditional column and central canal observed in shells dissolved from limestones.
To investigate the influences of dietary riboflavin (RF) addition on nutrient digestion and rumen fermentation, eight rumen cannulated Holstein bulls were randomly allocated into four treatments in a repeated 4 × 4 Latin square design. Daily addition level of RF for each bull in control, low RF, medium RF and high RF was 0, 300, 600 and 900 mg, respectively. Increasing the addition level of RF, DM intake was not affected, average daily gain tended to be increased linearly and feed conversion ratio decreased linearly. Total tract digestibilities of DM, organic matter, crude protein (CP) and neutral-detergent fibre (NDF) increased linearly. Rumen pH decreased quadratically, and total volatile fatty acids (VFA) increased quadratically. Acetate molar percentage and acetate:propionate ratio increased linearly, but propionate molar percentage and ammonia-N content decreased linearly. Rumen effective degradability of DM increased linearly, NDF increased quadratically but CP was unaltered. Activity of cellulase and populations of total bacteria, protozoa, fungi, dominant cellulolytic bacteria, Prevotella ruminicola and Ruminobacter amylophilus increased linearly. Linear increase was observed for urinary total purine derivatives excretion. The data suggested that dietary RF addition was essential for rumen microbial growth, and no further increase in performance and rumen total VFA concentration was observed when increasing RF level from 600 to 900 mg/d in dairy bulls.
The aim of this study was to explore the frequency and distribution of gene mutations that are related to isoniazid (INH) and rifampin (RIF)-resistance in the strains of the multidrug-resistant tuberculosis (MDR-TB) Mycobacterium tuberculosis (M.tb) in Beijing, China. In this retrospective study, the genotypes of 173 MDR-TB strains were analysed by spoligotyping. The katG, inhA genes and the promoter region of inhA, in which genetic mutations confer INH resistance; and the rpoB gene, in which genetic mutations confer RIF resistance, were sequenced. The percentage of resistance-associated nucleotide alterations among the strains of different genotypes was also analysed. In total, 90.8% (157/173) of the MDR strains belonged to the Beijing genotype. Population characteristics were not significantly different among the strains of different genotypes. In total, 50.3% (87/173) strains had mutations at codon S315T of katG; 16.8% (29/173) of strains had mutations in the inhA promoter region; of them, 5.5% (15/173) had point mutations at −15 base (C→T) of the inhA promoter region. In total, 86.7% (150/173) strains had mutations at rpoB gene; of them, 40% (69/173) strains had mutations at codon S531L of rpoB. The frequency of mutations was not significantly higher in Beijing genotypic MDR strains than in non-Beijing genotypes. Beijing genotypic MDR-TB strains were spreading in Beijing and present a major challenge to TB control in this region. A high prevalence of katG Ser315Thr, inhA promoter region (−15C→T) and rpoB (S531L) mutations was observed. Molecular diagnostics based on gene mutations was a useful method for rapid detection of MDR-TB in Beijing, China.
Lifestyle interventions are an important and viable approach for preventing cognitive deficits. However, the results of studies on alcohol, coffee and tea consumption in relation to cognitive decline have been divergent, likely due to confounds from dose–response effects. This meta-analysis aimed to find the dose–response relationship between alcohol, coffee or tea consumption and cognitive deficits.
Prospective cohort studies or nested case-control studies in a cohort investigating the risk factors of cognitive deficits were searched in PubMed, Embase, the Cochrane and Web of Science up to 4th June 2020. Two authors searched the databases and extracted the data independently. We also assessed the quality of the studies with the Newcastle-Ottawa scale. Stata 15.0 software was used to perform model estimation and plot the linear or nonlinear dose–response relationship graphs.
The search identified 29 prospective studies from America, Japan, China and some European countries. The dose–response relationships showed that compared to non-drinkers, low consumption (<11 g/day) of alcohol could reduce the risk of cognitive deficits or only dementias, but there was no significant effect of heavier drinking (>11 g/day). Low consumption of coffee reduced the risk of any cognitive deficit (<2.8 cups/day) or dementia (<2.3 cups/day). Green tea consumption was a significant protective factor for cognitive health (relative risk, 0.94; 95% confidence intervals, 0.92–0.97), with one cup of tea per day brings a 6% reduction in risk of cognitive deficits.
Light consumption of alcohol (<11 g/day) and coffee (<2.8 cups/day) was associated with reduced risk of cognitive deficits. Cognitive benefits of green tea consumption increased with the daily consumption.
The NIH Clinical and Translational Science Awards (CTSA) Program supports the creation of program infrastructure promoting scientific collaboration and improvement in translational research. While most evaluations of these and similar programs focus on scientific outcomes such as grants and publications, few studies investigate the underlying mechanisms through which large infrastructure grants produce scientific or translational benefits. This study investigated how engagement – researchers’ interactions with CTSA-funded resources – can help to increase scientific productivity.
Authors 1) developed process indicators to define engagement in the CTSA infrastructure at Washington University in St. Louis in four general categories (core service use, internal funding, mentor-mentee opportunities, and leadership roles); 2) explored the relationship between CTSA engagement and scholarly productivity; and 3) compared the relationships between engagement and productivity across gender and race/ethnicity. Mixed effects Poisson regressions modeled productivity outcomes on engagement, controlling for demographic and academic characteristics.
CTSA members who were engaged were more likely to publish papers and submit grants when compared to others. They were more likely to receive external grant awards – 10% to 20% percent more – than those who were not engaged. Productivity disparities between men and women and to a lesser extent across categories of race and ethnicity persisted even in samples matched on previous productivity levels.
CTSAs could see larger growth in scientific productivity by increasing researcher engagement and addressing demographic disparities – possibly through focused communications to raise awareness of opportunities – and dissemination of case studies and success stories of engagement to membership.
To address appropriateness of antibiotic use, we implemented an electronic framework to evaluate antibiotic “never events” (NEs) at 2 medical centers. Patient-level vancomycin administration records were classified as NEs or non-NEs. The objective framework allowed capture of true-positive vancomycin NEs in one-third of patients identified by the electronic strategy.
Previous studies have revealed associations of meteorological factors with tuberculosis (TB) cases. However, few studies have examined their lag effects on TB cases. This study was aimed to analyse nonlinear lag effects of meteorological factors on the number of TB notifications in Hong Kong. Using a 22-year consecutive surveillance data in Hong Kong, we examined the association of monthly average temperature and relative humidity with temporal dynamics of the monthly number of TB notifications using a distributed lag nonlinear models combined with a Poisson regression. The relative risks (RRs) of TB notifications were >1.15 as monthly average temperatures were between 16.3 and 17.3 °C at lagged 13–15 months, reaching the peak risk of 1.18 (95% confidence interval (CI) 1.02–1.35) when it was 16.8 °C at lagged 14 months. The RRs of TB notifications were >1.05 as relative humidities of 60.0–63.6% at lagged 9–11 months expanded to 68.0–71.0% at lagged 12–17 months, reaching the highest risk of 1.06 (95% CI 1.01–1.11) when it was 69.0% at lagged 13 months. The nonlinear and delayed effects of average temperature and relative humidity on TB epidemic were identified, which may provide a practical reference for improving the TB warning system.
The Chinese culture of filial piety has historically emphasised children's responsibility for their ageing parents. Little is understood regarding the inverse: parents’ responsibility and care for their adult children. This paper uses interviews with 50 families living in rural China's Anhui Province to understand intergenerational support in rural China. Findings indicate that parents in rural China take on large financial burdens in order to sustain patrilineal traditions by providing housing and child care for their adult sons. These expectations lead some rural elders to become migrant workers in order to support their adult sons while others provide live-in grandchild-care, moving into their children's urban homes or bringing grandchildren into their own homes. As the oldest rural generations begin to require ageing care of their own, migrant children are unable to provide the sustained care and support expected within the cultural tradition of xiao. This paper adds to the small body of literature that examines the downward transfer of support from parents to their adult children in rural China. The authors argue that there is an emerging cultural rupture in the practice of filial piety – while the older generation is fulfilling their obligations of upbringing and paying for adult children's housing and child care; these adult children are not necessarily available or committed to the return of care for their ageing parents. The authors reveal cultural and structural lags that leave millions of rural ageing adults vulnerable in the process of urbanisation in rural China.