Alcohol blunts pregnancy-mediated insulin resistance and reduces fetal brain glucose despite elevated fetal gluconeogenesis, and these changes associate with fetal weight outcomes.

Prenatal alcohol exposure (PAE) impairs fetal growth and neurodevelopment. Although alcohol is well known to alter metabolism, its impact on these processes during pregnancy is largely unexplored. Here, we investigate how alcohol affects maternal-fetal glucose metabolism using our established mouse binge model of PAE. In the dam, alcohol reduces the hepatic abundance of glucose and glycolytic intermediates, and the gluconeogenic enzymes glucose-6-phosphtase and phosphoenolpyruvate carboxykinase. Fasting blood glucose is also reduced. In a healthy pregnancy, elevated maternal gluconeogenesis and insulin resistance ensures glucose availability for the fetus. Glucose and insulin tolerance tests reveal that alcohol impairs the dam's ability to acquire insulin resistance. Alcohol-exposed dams have enhanced glucose clearance (p < .05) in early gestation, after just two days of alcohol, and this persists through late term when fetal glucose needs are maximal. However, maternal plasma insulin levels, hepatic insulin signaling, and the abundance of glucose transporter proteins remain unchanged. In the PAE fetus, the expression of hepatic gluconeogenic genes is elevated, and there is a trend for elevated blood and liver glucose levels. In contrast, fetal brain and placental glucose levels remain low. This reduced maternal fasting glucose, reduced hepatic glucose, and elevated glucose clearance inversely correlated with fetal body and brain weight. Taken together, these data suggest that alcohol blunts the adaptive changes in maternal glucose metabolism that otherwise enhance fetal glucose availability. Compensatory attempts by the fetus to increase glucose pools via gluconeogenesis do not normalize brain glucose. These metabolic changes may contribute to the impaired fetal growth and brain development that typifies PAE.

Associations between birth defects with neural crest cell origins and pediatric embryonal tumors.

BACKGROUND: There are few assessments evaluating associations between birth defects with neural crest cell developmental origins (BDNCOs) and embryonal tumors, which are characterized by undifferentiated cells having a molecular profile similar to neural crest cells. The effect of BDNCOs on embryonal tumors was estimated to explore potential shared etiologic pathways and genetic origins. METHODS: With the use of a multistate, registry-linkage cohort study, BDNCO-embryonal tumor associations were evaluated by generating hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox regression models. BDNCOs consisted of ear, face, and neck defects, Hirschsprung disease, and a selection of congenital heart defects. Embryonal tumors included neuroblastoma, nephroblastoma, and hepatoblastoma. Potential HR modification (HRM) was investigated by infant sex, maternal race/ethnicity, maternal age, and maternal education. RESULTS: The risk of embryonal tumors among those with BDNCOs was 0.09% (co-occurring n = 105) compared to 0.03% (95% CI, 0.03%-0.04%) among those without a birth defect. Children with BDNCOs were 4.2 times (95% CI, 3.5-5.1 times) as likely to be diagnosed with an embryonal tumor compared to children born without a birth defect. BDNCOs were strongly associated with hepatoblastoma (HR, 16.1; 95% CI, 11.3-22.9), and the HRs for neuroblastoma (3.1; 95% CI, 2.3-4.2) and nephroblastoma (2.9; 95% CI, 1.9-4.4) were elevated. There was no notable HRM by the aforementioned factors. CONCLUSIONS: Children with BDNCOs are more likely to develop embryonal tumors compared to children without a birth defect. Disruptions of shared developmental pathways may contribute to both phenotypes, which could inform future genomic assessments and cancer surveillance strategies of these conditions.

Healthcare fragmentation, multimorbidity, potentially inappropriate medication, and mortality: a Danish nationwide cohort study.

BACKGROUND: Patients with multimorbidity are frequent users of healthcare, but fragmented care may lead to suboptimal treatment. Yet, this has never been examined across healthcare sectors on a national scale. We aimed to quantify care fragmentation using various measures and to analyze the associations with patient outcomes. METHODS: We conducted a register-based nationwide cohort study with 4.7 million Danish adult citizens. All healthcare contacts to primary care and hospitals during 2018 were recorded. Clinical fragmentation indicators included number of healthcare contacts, involved providers, provider transitions, and hospital trajectories. Formal fragmentation indices assessed care concentration, dispersion, and contact sequence. The patient outcomes were potentially inappropriate medication and all-cause mortality adjusted for demographics, socioeconomic factors, and morbidity level. RESULTS: The number of involved healthcare providers, provider transitions, and hospital trajectories rose with increasing morbidity levels. Patients with 3 versus 6 conditions had a mean of 4.0 versus 6.9 involved providers and 6.6 versus 13.7 provider transitions. The proportion of contacts to the patient's own general practice remained stable across morbidity levels. High levels of care fragmentation were associated with higher rates of potentially inappropriate medication and increased mortality on all fragmentation measures after adjusting for demographic characteristics, socioeconomic factors, and morbidity. The strongest associations with potentially inappropriate medication and mortality were found for ≥ 20 contacts versus none (incidence rate ratio 2.83, 95% CI 2.77-2.90) and ≥ 20 hospital trajectories versus none (hazard ratio 10.8, 95% CI 9.48-12.4), respectively. Having less than 25% of contacts with your usual provider was associated with an incidence rate ratio of potentially inappropriate medication of 1.49 (95% CI 1.40-1.58) and a mortality hazard ratio of 2.59 (95% CI 2.36-2.84) compared with full continuity. For the associations between fragmentation measures and patient outcomes, there were no clear interactions with number of conditions. CONCLUSIONS: Several clinical indicators of care fragmentation were associated with morbidity level. Care fragmentation was associated with higher rates of potentially inappropriate medication and increased mortality even when adjusting for the most important confounders. Frequent contact to the usual provider, fewer transitions, and better coordination were associated with better patient outcomes regardless of morbidity level.

Streamlining quantitative joint-wide medial femoro-tibial histopathological scoring of mouse post-traumatic knee osteoarthritis models.

OBJECTIVES: Histological scoring remains the gold-standard for quantifying post-traumatic osteoarthritis (ptOA) in animal models, allowing concurrent evaluation of numerous joint tissues. Available systems require scoring multiple sections/joint making analysis laborious and expensive. We investigated if a single section allowed equivalent quantitation of pathology in different joint tissues and disease stages, in three ptOA models. METHOD: Male 10-12-week-old C57BL/6 mice underwent surgical medial-meniscal-destabilization, anterior-cruciate-ligament (ACL) transection, non-invasive-ACL-rupture, or served as sham-surgical, non-invasive-ACL-strain, or naïve/non-operated controls. Mice (n = 12/group) were harvested 1-, 4-, 8-, and 16-week post-intervention. Serial sagittal toluidine-blue/fast-green stained sections of the medial-femoro-tibial joint (n = 7/joint, 84 µm apart) underwent blinded scoring of 40 histology-outcomes. We evaluated agreement between single-slide versus entire slide-set maximum or median scores (weighted-kappa), and sensitivity/specificity of single-slide versus median/maximum to detect OA pathology. RESULTS: A single optimal mid-sagittal section showed excellent agreement with median (weighted-kappa 0.960) and maximum (weighted-kappa 0.926) scores. Agreement for individual histology-outcomes was high with only 19/240 median and 15/240 maximum scores having a weighted-kappa ≤0.4, the majority of these (16/19 and 11/15) in control groups. Statistically-significant histology-outcome differences between ptOA models and their controls detected with the entire slide-set were reliably reproduced using a single slide (sensitivity >93.15%, specificity >93.10%). The majority of false-negatives with single-slide scoring were meniscal and subchondral bone histology-outcomes (89%) and occurred in weeks 1-4 post-injury (84%). CONCLUSION: A single mid-sagittal slide reduced the time needed to score diverse histopathological changes by 87% without compromising the sensitivity or specificity of the analysis, across a variety of ptOA models and time-points.

Wnt5a Promotes AT1 and Represses AT2 Lineage-Specific Gene Expression in a Cell-Context-Dependent Manner.

Lung maturation is not limited to proper structural development but also includes differentiation and functionality of various highly specialized alveolar cell types. Alveolar type 1 (AT1s) cells occupy nearly 95% of the alveolar surface and are critical for establishing efficient gas exchange in the mature lung. AT1 cells arise from progenitors specified during the embryonic stage as well as alveolar epithelial progenitors expressing surfactant protein C (Sftpcpos cells) during postnatal and adult stages. Previously, we found that Wnt5a, a non-canonical Wnt ligand, is required for differentiation of AT1 cells during the saccular phase of lung development. To further investigate the role of Wnt5a in AT1 cell differentiation, we generated and characterized a conditional Wnt5a gain-of-function mouse model. Neonatal Wnt5a gain-of-function disrupted alveologenesis through inhibition of cell proliferation. In this setting Wnt5a downregulated ß-catenin-dependent canonical Wnt signaling, repressed AT2 (anti-AT2) and promoted AT1 (pro-AT1) lineage-specific gene expression. In addition, we identified 2 subpopulations of Sftpchigh and Sftpclow alveolar epithelial cells. In Sftpclow cells, Wnt5a exhibits pro-AT1 and anti-AT2 effects, concurrent with inhibition of canonical Wnt signaling. Interestingly, in the Sftpchigh subpopulation, although increasing AT1 lineage-specific gene expression, Wnt5a gain-of-function did not change AT2 gene expression, nor inhibit canonical Wnt signaling. Using primary epithelial cells isolated from human fetal lungs, we demonstrate that this property of Wnt5a is evolutionarily conserved. Wnt5a therefore serves as a selective regulator that ensures proper AT1/AT2 balance in the developing lung.

Fetal anemia and elevated hepcidin in a mouse model of fetal alcohol spectrum disorder.

INTRODUCTION: Prenatal alcohol exposure (PAE) impairs offspring growth and cognition, and this is worsened by concurrent iron deficiency. Alcohol disrupts fetal iron metabolism and produces functional iron deficiency, even when maternal iron status is adequate. We used a mouse model of moderate PAE to investigate the mechanisms underlying this dysregulated iron status. METHODS: C57BL/6J female mice received 3 g/kg alcohol daily from embryonic day (E) 8.5-17.5 and were assessed at E17.5. RESULTS: Alcohol reduced fetal hemoglobin, hematocrit, and red blood cell counts, despite elevated erythropoietin production. Alcohol suppressed maternal hepcidin expression and the upstream iron-sensing BMP/SMAD pathway, consistent with its effects in the nonpregnant state. In contrast, alcohol elevated fetal hepcidin, although this was not accompanied by an upregulation of the BMP/SMAD or proinflammatory IL-6/STAT3 pathways. Fetal expression of hepatic genes contributing to hemoglobin synthesis and iron metabolism were unaffected by alcohol, whereas those affecting ribosome biogenesis were suppressed, suggesting a novel candidate effector for this fetal anemia. CONCLUSION: These data confirm and extend prior observations that PAE disrupts maternal and fetal iron metabolism and impairs the fetus's ability to regulate iron status. We propose this dysregulation increases gestational iron needs and represents a conserved response to PAE. IMPACT: Prenatal alcohol exposure causes a functional iron deficiency in a model that also impairs cognition in later life. Prenatal alcohol exposure causes fetal anemia. This fetal anemia is accompanied by elevated hepcidin and erythropoietin. Findings are consistent with prior observations that prenatal alcohol exposure increases maternal-fetal iron requirements during pregnancy.

Strong recommendations from low certainty evidence: a cross-sectional analysis of a suite of national guidelines.

BACKGROUND: Clinical guidelines should be based on a thorough evaluation of the evidence and generally include a rating of the quality of evidence and assign a strength to recommendations. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance warns against making strong recommendations when the certainty of the evidence is low or very low, but has identified five paradigmatic situations (e.g. life-threatening situations) where this may be justified. AIMS AND OBJECTIVES: We aimed to characterize the strength of recommendations and certainty of the evidence in Irish National Clinical Guidelines using the GRADE approach. METHODS: All National Clinical Guidelines from the National Clinical Effectiveness Committee (NCEC) website using the GRADE approach (fully or partially) were included. All recommendations and their corresponding certainty of the evidence, strength of recommendations and justifications were extracted. Authors classified instances of strong recommendations with low certainty evidence (referred to as discordant recommendations) into one of the five paradigmatic situations. Descriptive statistics were calculated. RESULTS: From the 29 NCEC Clinical Guidelines available at the time of analysis, we identified 8 guidelines using GRADE with a total of 240 recommendations; 38 recommendations did not use the GRADE approach and were excluded. Half of the included guidelines focused on emergency situations. In the final dataset of 202 recommendations, 151 (74.7%) were classified as strong and 51 (25.3%) as conditional. Of the 151 strong recommendations, 55 (36.4%) were supported by high or moderate certainty evidence and 96 (63.6%) by low or very low certainty evidence and were considered discordant. Of these 96 discordant recommendations, 55 (73.7%) were consistent with one of the five paradigmatic situations. However, none were specifically described as such within the guidelines. CONCLUSIONS: The proportion of discordant recommendations identified in this analysis was higher than some previous international studies (range of all strong recommendations being discordant 30-50%), but similar to other guidelines focused on emergency situations. The majority of discordant recommendations could be mapped to one of the five situations, but no National Clinical Guideline explicitly referenced this. Guideline developers require further guidance to enable greater transparency in the reporting of the reasons for discordant recommendations.

A rapid review of measures to support people in isolation or quarantine during the Covid-19 pandemic and the effectiveness of such measures.

This rapid review aimed to identify measures available to support those in isolation or quarantine during the coronavirus disease 2019 (Covid-19) pandemic, and determine their effectiveness in improving adherence to these recommendations and or reducing transmission. The rapid review consisted of two elements, the first was a review of guidance published by national and international agencies relating to measures to support those in isolation (due to case status) or quarantine (due to close contact status) during the Covid-19 pandemic. Five categories of support measures were identified in the international guidance, they were: Psychological, addiction and safety supports, Essential supplies, Financial aid, Information provision and Enforcement. The second element was a rapid literature review of the effectiveness of measures used to support individuals in isolation or quarantine during any pandemic or epidemic setting, due to respiratory pathogens. A systematic search of published peer-reviewed articles and nonpeer-reviewed pre-prints was undertaken from 1 January 2000 to 26 January 2021. Two Australian publications met the inclusion criteria, both based on data from a survey undertaken during the 2009 H1N1 pandemic. The first reported that 55% of households were fully compliant with quarantine recommendations, and that there was increased compliance reported in households that understood what they were meant to do compared with those who reported that they did not (odds ratio [OR]: 2.27, 95% confidence interval [CI]: 1.35-3.80). The second reported that access to paid sick and or carer's leave did not predict compliance with quarantine recommendations (OR: 2.07, 95% CI: 0.82-5.23). Neither reported on reduction in transmission.

Laboratory-based testing for hepatitis C infection using dried blood spot samples: A systematic review and meta-analysis of diagnostic accuracy.

The use of dried blood spot (DBS) samples can facilitate the implementation of reflex testing by circumventing the need for centrifugation and freezing of venous blood samples. This systematic review assessed the accuracy of using DBS samples to diagnose chronic hepatitis C virus (HCV) infection. A comprehensive search was undertaken to identify articles published up to July 2020 evaluating the diagnostic accuracy of anti-HCV, HCV-RNA and HCV core antigen tests using DBS. Screening, data extraction, quality appraisal and Grading of Recommendations, Assessment, Development and Evaluations certainty of the evidence assessment were performed independently by two reviewers. Meta-analysis, meta-regression and sensitivity analyses were conducted. The evidence demonstrates that laboratory-based anti-HCV and HCV-RNA tests using DBS samples have high diagnostic accuracy. All comparisons were between DBS and venous samples. For the detection of anti-HCV, sensitivity was 95% (95% CI: 92%-97%) and specificity was 99% ([95% CI: 98%-99%]; n = 25; I2  = 81%; moderate certainty). For the detection of HCV-RNA, the sensitivity was 95% (95% CI: 93%-97%) and specificity was 97% ([95% CI: 94%-98%]; n = 20; I2  = 52%; moderate certainty). The sensitivity of HCV core antigen tests was 86% (95% CI: 79%-91%) and specificity was 98% ([95% CI: 94%-99%]; n = 5; I2  = 37%; low certainty) compared with HCV-RNA (the gold standard for detecting chronic HCV). DBS samples could facilitate diagnosis of chronic HCV infection as the necessary sequential tests (anti-HCV and then HCV-RNA or HCV core antigen) can be undertaken using the same blood sample. This could reduce loss of patient follow-up and support international efforts towards HCV elimination in both high and low prevalence settings.

Effectiveness of rapid antigen testing for screening of asymptomatic individuals to limit the transmission of SARS-CoV-2: A rapid review.

Rapid antigen detection tests (RADTs) offer advantages over gold-standard reverse transcription polymerase chain reaction (RT-PCR) tests in that they are cheaper and provide faster results, thus enabling prompt isolation of positive SARS-CoV-2 cases and quarantine of close contacts. The aim of this study was to collate and synthesise empirical evidence on the effectiveness of rapid antigen testing for the screening (including serial testing) and surveillance of asymptomatic individuals to limit the transmission of SARS-CoV-2. A rapid review was undertaken in MEDLINE (EBSCO), EMBASE (OVID), Cochrane Library, Europe PMC and Google Scholar up until 19 July 2021, supplemented by a grey literature search. Of the identified 1222 records, 19 reports referring to 16 studies were included. Eight included studies examined the effectiveness of RADTs for population-level screening, four for pre-event screening and four for serial testing (schools, a prison, a university sports programme and in care homes). Overall, there is uncertainty regarding the effectiveness of rapid antigen testing for the screening of asymptomatic individuals to limit the transmission of SARS-CoV-2. This uncertainty is due to the inconsistent results, the relatively low number of studies identified, the predominantly observational and/or uncontrolled nature of the study designs used, and concerns regarding methodological quality. Given this uncertainty, more real-world research evidence in relevant settings, which is of good quality and timely, as well as economic evaluation, is required to inform public policy on the widespread use of RADTs in asymptomatic individuals.

Pharmacological interventions to prevent Covid-19 disease: A rapid review.

The aim of this rapid review was to determine the effectiveness of pharmacological interventions (excluding vaccines) to prevent coronavirus disease 2019 (Covid-19) or reduce the severity of disease. A systematic search of published peer-reviewed articles and non-peer-reviewed pre-prints was undertaken from 1 January 2020 to 17 August 2021. Four randomised controlled trials (RCTs) and one non-RCT were included; three trials (two RCTs and one non-RCT) tested ivermectin with or without carrageenan. While all reported some potential protective effect of ivermectin, these trials had a high risk of bias and the certainty of evidence was deemed to be 'very low'. One RCT tested bamlanivimab compared to placebo and reported a significantly reduced incidence of Covid-19 in the intervention group; this trial had a low risk of bias however the certainty of evidence was deemed 'very low'. The fifth RCT tested casirivimab plus imdevimab versus placebo and reported that the combination of monoclonal antibodies significantly reduced the incidence of symptomatic and asymptomatic SARS-CoV-2 infection, viral load, duration of symptomatic disease and the duration of a high viral load; this trial was deemed to have a low risk of bias, and the certainty of evidence was 'low'. The designations 'low' and 'very low' regarding the certainty of evidence indicate that the estimate of effect is uncertain and therefore is unsuitable for informing decision-making. At the time of writing, there is insufficient high quality evidence to support the use of pharmacological interventions to prevent Covid-19.

Effectiveness of public health measures to prevent the transmission of SARS-CoV-2 at mass gatherings: A rapid review.

Mass gatherings play an important role in society, but since the onset of the Covid-19 pandemic, they have generally been restricted in order to mitigate transmission of SARS-CoV-2. The aim of this study was to summarise the evidence regarding the effectiveness of public health measures at preventing the transmission of SARS-CoV-2 at mass gatherings, and hence inform guidance on the organisation of these events. A rapid review was undertaken in Cochrane, Embase (OVID), Medline (OVID), Google, Web of Science and Europe PMC from 1 January 2020 to 3 June 2021. Of the identified 1,624 citations, 14 articles referring to 11 unique studies were included. This rapid review found evidence from 11 studies (involving approximately 30,482 participants) that implementing a range of measures may reduce the risk of SARS-CoV-2 transmission at mass gatherings; however, it is unlikely that this risk can be eliminated entirely. All studies adopted a layered mitigation approach involving multiple measures, which may be more effective than relying on any single measure. The number and intensity of measures implemented varied across studies, with most implementing resource intense measures. Importantly, all included studies were only of 'fair' to 'poor' quality. In conclusion, there is currently limited evidence on the effectiveness of measures to prevent SARS-CoV-2 transmission at mass gatherings. As mass gatherings recommence, continued adoption of known mitigation measures is required to limit the risk of transmission, as well as ongoing research and surveillance to monitor the potential impact of these events on the wider population and healthcare system.

Recruiting general practitioners and older patients with multimorbidity to randomized trials.

BACKGROUND: Older patients with multimorbidity are under-represented in experimental research. OBJECTIVE: To explore the barriers and facilitators to general practitioner (GP) and older patient recruitment and retention in a cluster randomized controlled trial (RCT). METHOD: This descriptive study uses qualitative and quantitative data from a cluster RCT, designed to evaluate the effectiveness of a medicines optimization intervention. The SPPiRE cluster RCT enrolled 51 general practices and 404 patients aged ≥65 years and prescribed ≥15 medicines. Quantitative data were collected from all recruited practices and 32 additional practices who were enrolled, but unable to recruit sufficient participants. Qualitative data were collected from purposive samples of intervention GPs (18/26), patients (27/208), and researcher logs and analysed thematically using inductive coding. RESULTS: Enrolment rates for practices and patients were 37% and 25%, respectively. Barriers to GP recruitment were lack of resources and to patient recruitment were difficulty understanding trial material and concern about medicines being taken away. GPs' primary motivation was perceived importance of the research question, whereas patients' primary motivation was trust in their GP. All general practices were retained. Thirty-five patients (8.6%) were lost to follow-up for primary outcomes, mainly because they had died and 45% did not return patient-reported outcome measures (PROMs). CONCLUSION: Patient retention for the primary outcome was high, as it was collected directly from patient records. Patient completion of PROM data was poor, reflecting difficulty in understanding trial material. Recruiting older patients with multimorbidity to clinical trials is possible but requires significant resource and planning. TRIAL REGISTRATION: ISRCTN Registry ISRCTN12752680.

Randomized controlled trials (RCTs) often exclude older people with multiple medical conditions. The aim of this study was to explore how and why participants took part in a primary care based RCT that included 51 general practitioners (GPs) and 404 older patients prescribed ≥15 medicines. The RCT was designed to assess the usefulness of a supported medication review. The study team assessed information that was already collected as part of the RCT, to describe the process of inviting and enrolling GPs and older people. This included information on the numbers invited and enrolled and interviews from a smaller sample of GPs (18) and older people (27). The study successfully enrolled the required number of participants but it took 26 months more than planned. 37% of invited GPs and 25% of invited patients took part. GPs felt the research was important but they identified lack of time and resources as barriers to participation. Older people predominantly took part because they trusted their GP but some were wary of having medicines taken away and were put off by trial documentation. It is important that RCTs including older people with multiple medical conditions carefully plan recruitment and pay careful attention to trial documentation.

A scoping review of evidence-based guidance and guidelines published by general practice professional organizations.

BACKGROUND: General practitioners (GPs) need robust, up-to-date evidence to deliver high-quality patient care. There is limited literature regarding the role of international GP professional organizations in developing and publishing clinical guidelines to support GPs clinical decision making. OBJECTIVE: To identify evidence-based guidance and clinical guidelines produced by GP professional organizations and summarize their content, structure, and methods of development and dissemination. METHODS: Scoping review of GP professional organizations following Joanna Briggs Institute guidance. Four databases were searched and a grey literature search was conducted. Studies were included if they were: (i) evidence-based guidance documents or clinical guidelines produced de novo by a national GP professional organization, (ii) developed to support GPs clinical care, and (iii) published in the last 10 years. GP professional organizations were contacted to provide supplementary information. A narrative synthesis was performed. RESULTS: Six GP professional organizations and 60 guidelines were included. The most common de novo guideline topics were mental health, cardiovascular disease, neurology, pregnancy and women's health and preventive care. All guidelines were developed using a standard evidence-synthesis method. All included documents were disseminated through downloadable pdfs and peer review publications. GP professional organizations indicated that they generally collaborate with or endorse guidelines developed by national or international guideline producing bodies. CONCLUSION: The findings of this scoping review provide an overview of de novo guideline development by GP professional organizations and can support collaboration between GP organizations worldwide thus reducing duplication of effort, facilitating reproducibility, and identifying areas of standardization. PROTOCOL REGISTRATION: Open Science Framework: https://doi.org/10.17605/OSF.IO/JXQ26.

Prenatal alcohol exposure causes persistent microglial activation and age- and sex- specific effects on cognition and metabolic outcomes in an Alzheimer's Disease mouse model.

Background: Prenatal alcohol exposure (PAE) causes behavioral deficits and increases risk of metabolic diseases. Alzheimer's Disease (AD) is a neurodegenerative disease that has a higher risk in adults with metabolic diseases. Both present with persistent neuroinflammation.Objectives: We tested whether PAE exacerbates AD-related cognitive decline in a mouse model (3xTg-AD; presenilin/amyloid precursor protein/tau), and assessed associations among cognition, metabolic impairment, and microglial reactivity.Methods: Alcohol-exposed (ALC) pregnant 3xTg-AD mice received 3 g/kg alcohol from embryonic day 8.5-17.5. We evaluated recognition memory and associative memory (fear conditioning) in 8-10 males and females per group at 3 months of age (3mo), 7mo, and 11mo, then assessed glucose tolerance, body composition, and hippocampal microglial activation at 12mo.Results: ALC females had higher body weights than controls from 5mo (p < .0001). Controls showed improved recognition memory at 11mo compared with 3mo (p = .007); this was not seen in ALC mice. Older animals froze more during fear conditioning than younger, and ALC mice were hyper-responsive to the fear-related cue (p = .017). Fasting blood glucose was lower in ALC males and higher in ALC females than controls. Positive associations occurred between glucose and fear-related context (p = .04) and adiposity and fear-related cue (p = .0002) in ALC animals. Hippocampal microglial activation was higher in ALC than controls (p < .0001); this trended to correlate with recognition memory.Conclusions: ALC animals showed age-related cognitive impairments that did not interact with AD risk but did correlate with metabolic dysfunction and somewhat with microglial activation. Thus, metabolic disorders may be a therapeutic target for people with FASDs.

Facilitators and barriers to the introduction of atrial fibrillation screening in primary care: a qualitative descriptive study of general practitioners in primary care.

INTRODUCTION: Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major risk factor for stroke. AF is often asymptomatic and, if identified, treatment can be offered that can reduce stroke risk by up to two thirds. AF screening meets many of the Wilson Jungner criteria for screening. While AF screening is recommended in clinical practice and internationally, the optimal mode and location for AF screening remains under investigation. Primary care has been identified as a potential setting. This study aimed to identify facilitators and barriers to AF screening from the perspective of GPs. METHODS: The study adopted a qualitative descriptive design conducted in the south of Ireland. 58 GPs were invited from the north Cork region to participate in individual interviews at their practices, rural and urban, with a view to recruiting a purposive sample of up to 12 GPs. The interviews were audio-recorded, transcribed verbatim and analysed using a framework analysis. RESULTS: Eight GPs (four male, four female) from five practices participated. Five GPs were from urban practices and three were from rural practices. Facilitators and barriers were sub-categorised into patient facilitators, practice facilitators, GP facilitators, patient barriers, practice barriers, GP barriers, attitudes to AF screening, willingness to facilitate and priority ranking. All eight participants expressed a willingness to engage in AF screening. Time was the barrier discussed most frequently by all participants along with the need for additional staff. Programme structure was the most discussed facilitator by all participants and patient awareness campaigns. DISCUSSION: Despite barriers to AF screening identified by GPs, there was a significant willingness to engage and identify potential facilitators to support such screening.

Which four medication classes have important pharmacogenetic considerations?

ABSTRACT: Medications often are prescribed without knowledge of a patient's pharmacogenetic profile. Initial therapy may require subsequent modification due to adverse reactions or lack of efficacy. Although many variables, including changes in pharmacokinetics, pharmacodynamics, or patient nonadherence, may account for these outcomes, information about a patient's ability to metabolize or transport drugs across membranes may be used to optimize therapy, resulting in improved medication outcomes.

Which patient factors increase the risk of fluoroquinolone-associated reactions?

ABSTRACT: Fluoroquinolones commonly are used to treat a variety of infections in the urinary, gastrointestinal, and respiratory tracts. Clinicians should evaluate patients to ensure that a fluoroquinolone is a safe and effective therapy to treat the infection. This article discusses patient factors that increase the risk for serious adverse drug reactions that can occur with fluoroquinolone use.

GP-delivered medication review of polypharmacy, deprescribing, and patient priorities in older people with multimorbidity in Irish primary care (SPPiRE Study): A cluster randomised controlled trial.

BACKGROUND: There is a rising prevalence of multimorbidity, particularly in older patients, and a need for evidence-based medicines management interventions for this population. The Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care (SPPiRE) trial aimed to investigate the effect of a general practitioner (GP)-delivered, individualised medication review in reducing polypharmacy and potentially inappropriate prescriptions (PIPs) in community-dwelling older patients with multimorbidity in primary care. METHODS AND FINDINGS: We conducted a cluster randomised controlled trial (RCT) set in 51 GP practices throughout the Republic of Ireland. A total of 404 patients, aged ≥65 years with complex multimorbidity, defined as being prescribed ≥15 regular medicines, were recruited from April 2017 and followed up until October 2020. Furthermore, 26 intervention GP practices received access to the SPPiRE website where they completed an educational module and used a template for an individualised patient medication review that identified PIP, opportunities for deprescribing, and patient priorities for care. A total of 25 control GP practices delivered usual care. An independent blinded pharmacist assessed primary outcome measures that were the number of medicines and the proportion of patients with any PIP (from a predefined list of 34 indicators based predominantly on the STOPP/START version 2 criteria). We performed an intention-to-treat analysis using multilevel modelling. Recruited participants had substantial disease and treatment burden at baseline with a mean of 17.37 (standard deviation [SD] 3.50) medicines. At 6-month follow-up, both intervention and control groups had reductions in the numbers of medicines with a small but significantly greater reduction in the intervention group (incidence rate ratio [IRR] 0.95, 95% confidence interval [CI]: 0.899 to 0.999, p = 0.045). There was no significant effect on the odds of having at least 1 PIP in the intervention versus control group (odds ratio [OR] 0.39, 95% CI: 0.140 to 1.064, p = 0.066). Adverse events recorded included mortality, emergency department (ED) presentations, and adverse drug withdrawal events (ADWEs), and there was no evidence of harm. Less than 2% of drug withdrawals in the intervention group led to a reported ADWE. Due to the inability to electronically extract data, primary outcomes were measured at just 2 time points, and this is the main limitation of this work. CONCLUSIONS: The SPPiRE intervention resulted in a small but significant reduction in the number of medicines but no evidence of a clear effect on PIP. This reduction in significant polypharmacy may have more of an impact at a population rather than individual patient level. TRIAL REGISTRATION: ISRCTN Registry ISRCTN12752680.

Secondary crest myofibroblast PDGFRα controls the elastogenesis pathway via a secondary tier of signaling networks during alveologenesis.

Postnatal alveolar formation is the most important and the least understood phase of lung development. Alveolar pathologies are prominent in neonatal and adult lung diseases. The mechanisms of alveologenesis remain largely unknown. We inactivated Pdgfra postnatally in secondary crest myofibroblasts (SCMF), a subpopulation of lung mesenchymal cells. Lack of Pdgfra arrested alveologenesis akin to bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. The transcriptome of mutant SCMF revealed 1808 altered genes encoding transcription factors, signaling and extracellular matrix molecules. Elastin mRNA was reduced, and its distribution was abnormal. Absence of Pdgfra disrupted expression of elastogenic genes, including members of the Lox, Fbn and Fbln families. Expression of EGF family members increased when Tgfb1 was repressed in mouse. Similar, but not identical, results were found in human BPD lung samples. In vitro, blocking PDGF signaling decreased elastogenic gene expression associated with increased Egf and decreased Tgfb family mRNAs. The effect was reversible by inhibiting EGF or activating TGFß signaling. These observations demonstrate the previously unappreciated postnatal role of PDGFA/PDGFRα in controlling elastogenic gene expression via a secondary tier of signaling networks composed of EGF and TGFß.