Pharmacoepidemiology in pregnancy: analysis protocol for an observational cohort study in the UK Clinical Practice Research Datalink

Large numbers of women take prescription and over-the-counter medications during pregnancy. However, there is very little definitive evidence about the potential effects of these drugs on the mothers and offspring. We will investigate the risks and benefits of continuing prescriptive drug use for chronic pre-existing maternal conditions such as diabetes, hypertension and thyroid related conditions throughout pregnancy. If left untreated, these conditions are established risk factors for adverse neonatal and maternal outcomes. However, some treatments for these conditions are associated with adverse neonatal outcomes. Our primary aims are twofold. Firstly, we aim to estimate the beneficial effect on the mother of continuing treatment during pregnancy. Second, we aim to determine whether there is an associated detrimental impact on the neonate of continuation of maternal treatment during pregnancy. To establish this evidence, we will investigate the relationship between maternal drug prescriptions and adverse and beneficial offspring outcomes to provide evidence to guide clinical decisions. We will conduct a hypothesis testing observational intergenerational cohort study using data from the UK Clinical Practice Research Datalink (CPRD). We will apply four statistical methods: multivariable adjusted regression, propensity score regression, instrumental variables analysis and negative control analysis. These methods should account for potential confounding when estimating the association between the drug exposure and maternal or neonatal outcome. In this protocol we describe the aims, motivation, study design, cohort and statistical analyses of our study to aid reproducibility and transparency within research.

Quantile regression analysis of the association between parental rearing and interpersonal sensitivity in Chinese adolescents

Background Parental rearing is well documented as an important influencing factor of interpersonal sensitivity (IS). However, little research has focused on the extent by which various aspects of parental rearing in fluence IS. This study aimed to analyze the effects of parental rearing on IS, using quantile regression. We analyzed the extent of the influence of parental rearing on IS by quantile regression to provide definitive evidence on the family education of adolescents with IS problems. Methods The multiple cross-sectional studies were conducted among 3345 adolescents from Harbin, China, in 1999, 2006, 2009 and 2016. Furthermore, a multistage sampling method (stratified random cluster) was used to select participants. IS was assessed using a subscale of the Symptom Checklist-90-Revision. Perceived parental rearing was assessed using the Egna Minnen av. Barndoms Uppfostran. The ordinary least squares (OLS) linear regression was used to determine the average effect of parental rearing on IS. The quantile regression was conducted to examine the established associations and to further explain the association. Results Paternal emotional warmth was found to be associated with IS across the quantile, especially after the 0.6 quantiles; however, this association was not found for maternal emotional warmth. Paternal punishment was associated with IS at the 0.22–0.27 and 0.60 quantile; however, maternal punishment had no significant effect on IS. QR method found that paternal overinvolvement was associated with IS at the 0.48–0.65 quantiles, but paternal overprotection was associated with IS across the quantile; however, maternal overinvolvement and overprotection was positively correlated with IS at the 0.07–0.95 quantiles. The correlation between paternal rejection and IS was found at the 0.40–0.75 and > 0.90 quantiles; maternal rejection was associated with IS within the 0.05–0.92 quantiles. Conclusions Parental rearing practices predict different magnitudes of IS at varying levels. This study provides suggestions for parents to assess purposefully and systematically, intervene, and ameliorate adolescent IS problems. We also highlight the role of paternal rearing in children’s IS problems, providing new ideas for family education.

Clear evidence against superconductivity in hydrides under high pressure

The Meissner effect, magnetic field expulsion, is a hallmark of superconductivity. Associated with it, superconductors exclude applied magnetic fields. Recently Minkov et al. presented experimental results reportedly showing “definitive evidence of the Meissner effect” in sulfur hydride and lan-thanum hydride under high pressure1. Instead, we show here that the evidence presented in that paper does not support the case for superconductivity in these materials. Together with experimental evidence discussed in earlier papers, we argue that this clearly indicates that hydrides under pressure are not high temperature superconductors.

Oral Antihypertensives for Nonsevere Pregnancy Hypertension: Systematic Review, Network Meta- and Trial Sequential Analyses

Background: We aimed to address which antihypertensives are superior to placebo/no therapy or another antihypertensive for controlling nonsevere pregnancy hypertension and provide future sample size estimates for definitive evidence. Methods: Randomized trials of antihypertensives for nonsevere pregnancy hypertension were identified from online electronic databases, to February 28, 2021 (registration URL: https://www.crd.york.ac.uk/PROSPERO/ ; unique identifier: CRD42020188725). Our outcomes were severe hypertension, proteinuria/preeclampsia, fetal/newborn death, small-for-gestational age infants, preterm birth, and admission to neonatal care. A Bayesian random-effects model generated estimates of direct and indirect treatment comparisons. Trial sequential analysis informed future trials needed. Results: Of 1246 publications identified, 72 trials were included; 61 (6923 women) were informative. All commonly prescribed antihypertensives (labetalol, other β-blockers, methyldopa, calcium channel blockers, and mixed/multi-drug therapy) versus placebo/no therapy reduced the risk of severe hypertension by 30% to 70%. Labetalol decreased proteinuria/preeclampsia (odds ratio, 0.73 [95% credible interval, 0.54–0.99]) and fetal/newborn death (odds ratio, 0.54 [0.30–0.98]) compared with placebo/no therapy, and proteinuria/preeclampsia compared with methyldopa (odds ratio, 0.66 [0.44–0.99]) and calcium channel blockers (odds ratio, 0.63 [0.41–0.96]). No other differences were identified, but credible intervals were wide. Trial sequential analysis indicated that 2500 to 10 000 women/arm (severe hypertension or safety outcomes) to >15 000/arm (fetal/newborn death) would be required to provide definitive evidence. Conclusions: In summary, all commonly prescribed antihypertensives in pregnancy reduce the risk of severe hypertension, but labetalol may also decrease proteinuria/preeclampsia and fetal/newborn death. Evidence is lacking for many other safety outcomes. Prohibitive sample sizes are required for definitive evidence. Real-world data are needed to individualize care.

Association between Tobacco and Tuberculosis: A short narrative review

Tobacco use increases the risk of contracting tuberculosis (TB), and blights the response to treatment of the disease. Although Links between Tobacco and TB have long been suspected, still many Indian patients continue to use tobacco. Our goal is to couple reviews of older and new research to provide definitive evidence of this dangerous connection so as to put an end to the TB epidemic.: Search of studies with English language abstract published between 2000 to June 2020 was undertaken in Google Scholar and PubMed. Search included the use of keywords “tobacco” with “tuberculosis,” “cessation,” or ‘’Tuberculosis Control Programme’’. Reference lists of the articles were examined for other relevant titles that included effective estimates of tobacco exposure in relation to tuberculosis outcomes.: Available evidence shows a strong association between tobacco and tuberculosis. People who use tobacco unknowingly put themselves at high risk of getting this disease. Reduction in the prevalence of tobacco use is urgent to bring about collateral benefits in the control of the TB problem.It is high time that TB control programs must begin to address tobacco control. Within the healthcare system opportunities must be created to provide encouragement for the TB patients so that it is easier for them to overcome this addiction.There urgent need for research in the field of tobacco and tuberculosis so as to reduce the burden of tuberculosis in India.

Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation

Mast cells (MCs) are key mediators of allergic inflammation through the activation of cross-linked immunoglobulin E (IgE) bound to the high-affinity IgE receptor (FcϵRI) on the cell surface, leading to the release of biologically potent mediators, either from preformed granules or newly synthesized. Pharmacological inhibitors have been developed to target a key signaling protein phosphatase in this pathway, calcineurin, yet there is a lack of genetic and definitive evidence for the various isoforms of calcineurin subunits in FcϵRI-mediated responses. In this study, we hypothesized that deficiency in the calcineurin Aα isoform will result in a decreased allergic immune response by the MCs. In a model of passive cutaneous anaphylaxis, there was a reduction in vascular permeability in MC-deficient mouse tissues reconstituted with calcineurin subunit A (CnAα) gene-knockout (<i>CnAα</i>^−/−) MCs, and in vitro experiments identified a significant reduction in release of preformed mediators from granules. Furthermore, released levels of de novo synthesized cytokines were reduced upon FcϵRI activation of <i>CnAα</i>^−/− MCs in vitro. Characterizing the mechanisms associated with this deficit response, we found a significant impairment of nuclear factor of kappa light polypeptide gene enhancer in B cell phosphorylation and impaired nuclear factor kappa-light-chain-enhancer of activated B-cell inhibitor alpha (NF-κB) activation. Thus, we concluded that <i>CnAα</i> contributes to the release of preformed mediators and newly synthesized mediators from FcϵRI-mediated activation of MCs, and this regulation includes NF-κB signaling.

Frailty in Indigenous Populations: A Scoping Review

Background: Indigenous populations experience high rates of age-related illness when compared to their non-Indigenous counterparts. Frailty is a challenging expression of aging and an important public health priority. The purpose of this review was to map what the existing literature reports around frailty in Indigenous populations and to highlight the current gaps in frailty research within the Indigenous landscape.Method: Scoping review of English language original research articles focusing on frailty within Indigenous adult populations in settler colonial countries (Australia, Canada, New Zealand and USA). Ten electronic databases and eight relevant institutional websites were searched from inception to October 2020.Results: Nine articles met our inclusion criteria, finding this population having a higher prevalence of frailty and frailty occurring at younger ages when compared to their non-Indigenous counterparts, but two did not use a formal frailty tool. Females presented with higher levels of frailty. No culturally specific frailty tool was identified, and the included articles did not assess strategies or interventions to manage or prevent frailty in Indigenous peoples.Conclusions: There was little definitive evidence of the true frailty prevalence, approaches to frailty screening and of potential points of intervention to manage or prevent the onset of frailty. Improvements in the quality of evidence are urgently needed, along with further research to determine the factors contributing to higher rates of frailty within Indigenous populations. Incorporation of Indigenous views of frailty, and instruments and programs that are led and designed by Indigenous communities, are crucial to address this public health priority.

Abstract 11156: Thoracic Bioimpedance Ventilation Waveforms: Increased Amplitude with Larger Tidal Volume and Female Sex

Introduction: Effective ventilation during 30:2 CPR has been linked to improved outcomes, but definitive evidence is lacking. We developed a method to identify thoracic bioimpedance ventilation waveforms from defibrillator recordings. Hypothesis: Bioimpedance ventilation waveform amplitude is proportional to tidal volume. It is possible to identify a minimum amplitude for a valid ventilation waveform. Methods: To determine the relationship between tidal volume and bioimpedance waveform amplitude, we studied 26 healthy volunteers (12 males and 14 females). Volunteers breathed fixed positive pressure tidal volumes (250mL, 300 mL, 400 mL, 600 mL, and 800 mL) given by a Maquet SERVO-I ventilator (Getinge US Sales, Wayne, NJ, USA) through a mouthpiece while a Lifepak12 (Physio-Control, Redmond, WA) defibrillator recorded thoracic bioimpedance through electrode pads placed on the chest. We measured the impedance amplitudes of six breaths at each tidal volume and the weight and height of each volunteer. We set the minimum effective tidal volume at 250 mL. Results: For males and females, respectively, mean (±SD) was 180.1±8 cm vs. 164±3.5 cm, and mean weight was 85.6±9.6 kg vs. 58.3±8.6 kg. Median (IQR) bioimpedance amplitude for each tidal volume split by sex is shown in the Figure (Y-axis, 1 mm = 0.25 Ohm). Conclusion: Bioimpedance amplitude is proportional to tidal volume and also varies by height, weight, and sex. Sex may be a possible surrogate for height and weight. The minimum amplitude is 0.375 Ohm for a valid bioimpedance ventilation waveform.

Wolbachia endosymbionts in two Anopheles species indicates independent acquisitions and lack of prophage elements

Wolbachia is a genus of obligate bacterial endosymbionts that infect a diverse range of arthropod species as well as filarial nematodes, with its single described species, Wolbachia pipientis, divided into several 'supergroups' based on multilocus sequence typing. Wolbachia strains in mosquitoes have been shown to inhibit the transmission of human pathogens including Plasmodium malaria parasites and arboviruses. Despite their large host range, Wolbachia strains within the major malaria vectors of the Anopheles (A.) gambiae and A. funestus complexes appear at low density based solely on PCR-based methods. Questions have been raised as to whether this represents a true endosymbiotic relationship. However, recent definitive evidence for two distinct, high-density strains of supergroup B Wolbachia within A. demeilloni and A. moucheti has opened exciting possibilities to explore naturally occurring Wolbachia endosymbionts in Anopheles for biocontrol strategies to block Plasmodium transmission. Here we utilise genomic analyses to demonstrate that both Wolbachia strains have retained all key metabolic and transport pathways despite their smaller genome size. We further confirm the presence of cytoplasmic incompatibility factor genes, despite noticeably few prophage regions. Additionally, phylogenetic analysis indicates that these Wolbachia strains may have been introduced into these two Anopheles species via horizontal transmission events, and unlikely to be by ancestral acquisition and subsequent loss events in the Anopheles gambiae species complex. These are the first Wolbachia genomes that enable us to study the relationship between natural strains Plasmodium malaria parasites and their Anopheline hosts.

Do Oncologic Outcomes From Head and Neck Versus Truncal and Extremity Melanoma Differ? A Single-Institution Single-Subspecialty Experience

Background Outcomes are thought to be worse in head and neck (H&N) melanoma patients. However, definitive evidence of inferior outcomes in H&N melanoma in the modern era is lacking. We sought to ascertain whether H&N melanomas carry a worse prognosis than melanomas of other sites. Methods All patients who underwent excision for primary melanoma by fellowship-trained surgical oncologists at a single institution from 2014 to 2020 were queried from the electronic medical record. Patients who had AJCC eighth edition stage I-III disease were included. Results Of 1127 patients, 28.7% had primary H&N melanoma. H&N patients were more likely to be male, older, and present with more advanced AJCC stage. Median follow-up was 20.0 months (IQR 26.4). On multivariable analyses controlling for other variables, H&N melanoma was associated with worse RFS. Notably, H&N melanoma was not associated with worse MSS, DMFS, or OS on univariate or multivariable analyses. Among patients who recurred, H&N patients were significantly more likely to recur locally compared to non-H&N patients. On subgroup analysis, scalp melanoma was also associated with worse RFS compared to patients with melanoma in locations other than the scalp. When patients with scalp melanoma were excluded from analysis, non-scalp H&N RFS was not significantly different from the non-H&N group on univariate or multivariable analyses. Discussion In this series from a high-volume tertiary referral center, the differences in rates and sites of recurrence between H&N and non-H&N melanoma do not impact melanoma-specific or overall survival, suggesting that H&N melanoma patients should be treated similarly with respect to regional and systemic therapies.