156 research outputs found

    Chronic paternal alcohol exposures induce dose-dependent changes in offspring craniofacial shape and symmetry

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    Although dose-response analyses are a fundamental tool in developmental toxicology, few studies have examined the impacts of toxicant dose on the non-genetic paternal inheritance of offspring disease and dysgenesis. In this study, we used geometric morphometric analyses to examine the impacts of different levels of preconception paternal alcohol exposure on offspring craniofacial shape and symmetry in a mouse model. Procrustes ANOVA followed by canonical variant analysis of geometric facial relationships revealed that Low-, Medium-, and High-dose treatments each induced distinct changes in craniofacial shape and symmetry. Our analyses identified a dose threshold between 1.543 and 2.321 g/kg/day. Below this threshold, preconception paternal alcohol exposure induced changes in facial shape, including a right shift in facial features. In contrast, above this threshold, paternal exposures caused shifts in both shape and center, disrupting facial symmetry. Consistent with previous clinical studies, changes in craniofacial shape predominantly mapped to regions in the lower portion of the face, including the mandible (lower jaw) and maxilla (upper jaw). Notably, high-dose exposures also impacted the positioning of the right eye. Our studies reveal that paternal alcohol use may be an unrecognized factor contributing to the incidence and severity of alcohol-related craniofacial defects, complicating diagnostics of fetal alcohol spectrum disorders

    A knowledge management tool for public health: health-evidence.ca

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    <p>Abstract</p> <p>Background</p> <p>The ultimate goal of knowledge translation and exchange (KTE) activities is to facilitate incorporation of research knowledge into program and policy development decision making. Evidence-informed decision making involves translation of the best available evidence from a systematically collected, appraised, and analyzed body of knowledge. Knowledge management (KM) is emerging as a key factor contributing to the realization of evidence-informed public health decision making. The goal of health-evidence.ca is to promote evidence-informed public health decision making through facilitation of decision maker access to, retrieval, and use of the best available synthesized research evidence evaluating the effectiveness of public health interventions.</p> <p>Methods</p> <p>The systematic reviews that populate health evidence.ca are identified through an extensive search (1985-present) of 7 electronic databases: MEDLINE, EMBASE, CINAHL, PsycINFO, Sociological Abstracts, BIOSIS, and SportDiscus; handsearching of over 20 journals; and reference list searches of all relevant reviews. Reviews are assessed for relevance and quality by two independent reviewers. Commonly-used public health terms are used to assign key words to each review, and project staff members compose short summaries highlighting results and implications for policy and practice.</p> <p>Results</p> <p>As of June 2010, there are 1913 reviews in the health-evidence.ca registry in 21 public health and health promotion topic areas. Of these, 78% have been assessed as being of strong or moderate methodological quality. Health-evidence.ca receives approximately 35,000 visits per year, 20,596 of which are unique visitors, representing approximately 100 visits per day. Just under half of all visitors return to the site, with the average user spending six minutes and visiting seven pages per visit. Public health nurses, program managers, health promotion workers, researchers, and program coordinators are among the largest groups of registered users, followed by librarians, dieticians, medical officers of health, and nutritionists. The majority of users (67%) access the website from direct traffic (e.g., have the health-evidence.ca webpage bookmarked, or type it directly into their browser).</p> <p>Conclusions</p> <p>Consistent use of health-evidence.ca and particularly the searching for reviews that correspond with current public health priorities illustrates that health-evidence.ca may be playing an important role in achieving evidence-informed public health decision making.</p

    Update of the tolerable upper intake level for vitamin D for infants

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    Following a request from the European Commission, the Panel&nbsp;on Dietetic Products, Nutrition and Allergies (NDA) was asked to revise the tolerable upper intake level (UL) for vitamin D for infants ( 64&nbsp;1&nbsp;year) set in 2012. From its literature review, the Panel&nbsp;concluded that the available evidence on daily vitamin D intake and the risk of adverse health outcomes (hypercalciuria, hypercalcaemia, nephrocalcinosis and abnormal growth patterns) cannot be used alone for deriving the UL for infants. The Panel&nbsp;conducted a meta-regression analysis of collected data, to derive a dose\u2013response relationship between daily supplemental intake of vitamin D and mean achieved serum 25(OH)D concentrations. Considering that a serum 25(OH)D concentration of 200&nbsp;nmol/L or below is unlikely to pose a risk of adverse health outcomes in infants, the Panel&nbsp;estimated the percentage of infants reaching a concentration above this value at different intakes of vitamin D. Based on the overall evidence, the Panel&nbsp;kept the UL of 25&nbsp;\u3bcg/day for infants aged up to 6 months and set a UL of 35&nbsp;\u3bcg/day for infants 6\u201312&nbsp;months. The Panel&nbsp;was also asked to advise on the safety of the consumption of infant formulae with an increased maximum vitamin D content of 3&nbsp;\u3bcg/100&nbsp;kcal (Commission Delegated Regulation (EU) 2016/127 repealing Directive 2006/141/EC in 2020). For infants aged up to 4&nbsp;months, the intake assessment showed that the use of infant formulae containing vitamin D at 3&nbsp;\u3bcg/100&nbsp;kcal may lead some infants to receive an intake above the UL of 25&nbsp;\u3bcg/day from formulae alone without considering vitamin D supplemental intake. For infants aged 4\u201312&nbsp;months, the 95th percentile of vitamin D intake (high consumers) estimated from formulae and foods fortified or not with vitamin&nbsp;D does not exceed the ULs, without considering vitamin D supplemental intake

    Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

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    textabstractThe classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research

    Interventions to treat premature ejaculation: a systematic review short report

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    Background: Premature ejaculation (PE) is commonly defined as ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it. PE can be either lifelong and present since first sexual experiences (primary), or acquired (secondary), beginning later (Godpodinoff ML. Premature ejaculation: clinical subgroups and etiology. J Sex Marital Ther 1989;15:130–4). Treatments include behavioural and pharmacological interventions. Objective: To systematically review evidence for clinical effectiveness of behavioural, topical and systemic treatments for PE. Data sources: The following databases were searched from inception to 6 August 2013 for published and unpublished research evidence: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects and the Health Technology Assessment database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science. The US Food and Drug Administration website and the European Medicines Agency (EMA) website were also searched. Methods: Randomised controlled trials (RCTs) in adult men with PE were eligible (or non-RCTs in the absence of RCTs). RCT data were extrapolated from review articles when available. The primary outcome was intravaginal ejaculatory latency time (IELT). Data were meta-analysed when possible. Other outcomes included sexual satisfaction, control over ejaculation, relationship satisfaction, self-esteem, quality of life, treatment acceptability and adverse events (AEs). Results: A total of 103 studies (102 RCTs, 65 from reviews) were included. RCTs were available for all interventions except yoga. The following interventions demonstrated significant improvements (p < 0.05) in arithmetic mean difference in IELT compared with placebo: topical anaesthetics – eutectic mixture of local anaesthetics (EMLA®, AstraZeneca), topical eutectic mixture for PE (Plethora Solutions Ltd) spray; selective serotonin reuptake inhibitors (SSRIs) – citalopram (Cipramil®, Lundbeck), escitalopram (Cipralex®, Lundbeck), fluoxetine, paroxetine, sertraline, dapoxetine (Priligy®, Menarini), 30 mg or 60 mg; serotonin–noradrenaline reuptake inhibitors – duloxetine (Cymbalta®, Eli Lilly & Co Ltd); tricyclic antidepressants – inhaled clomipramine 4 mg; phosphodiesterase-5 (PDE5) inhibitors – vardenafil (Levitra®, Bayer), tadalafil (Cialis®, Eli Lilly & Co Ltd); opioid analgesics – tramadol (Zydol SR®, Grünenthal). Improvements in sexual satisfaction and other outcomes compared with placebo were evident for SSRIs, PDE5 inhibitors and tramadol. Outcomes for interventions not compared with placebo were as follows: behavioural therapies – improvements over wait list control in IELT and other outcomes, behavioural therapy plus pharmacotherapy better than either therapy alone; alpha blockers – terazosin (Hytrin®, AMCO) not significantly different to antidepressants in ejaculation control; acupuncture – improvements over sham acupuncture in IELT, conflicting results for comparisons with SSRIs; Chinese medicine – improvements over treatment as usual; delay device – improvements in IELT when added to stop–start technique; yoga – improved IELT over baseline, fluoxetine better than yoga. Treatment-related AEs were evident with most pharmacological interventions. Limitations: Although data extraction from reviews was optimised when more than one review reported data for the same RCT, the reliability of the data extraction within these reviews cannot be guaranteed by this assessment report. Conclusions: Several interventions significantly improved IELT. Many interventions also improved sexual satisfaction and other outcomes. However, assessment of longer-term safety and effectiveness is required to evaluate whether or not initial treatment effects are maintained long term, whether or not dose escalation is required, how soon treatment effects end following treatment cessation and whether or not treatments can be stopped and resumed at a later time. In addition, assessment of the AEs associated with long-term treatment and whether or not different doses have differing AE profiles is required

    Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

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    IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
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