Hypothalamic Neuroendocrine Functions in Rats with Dihydrotestosterone-Induced Polycystic Ovary Syndrome: Effects of Low-Frequency Electro-Acupuncture

Adult female rats continuously exposed to androgens from prepuberty have reproductive and metabolic features of polycystic ovary syndrome (PCOS). We investigated whether such exposure adversely affects estrous cyclicity and the expression and distribution of gonadotropin-releasing hormone (GnRH), GnRH receptors, and corticotrophin-releasing hormone (CRH) in the hypothalamus and whether the effects are mediated by the androgen receptor (AR). We also assessed the effect of low-frequency electro-acupuncture (EA) on those variables. At 21 days of age, rats were randomly divided into three groups (control, PCOS, and PCOS EA; n = 12/group) and implanted subcutaneously with 90-day continuous-release pellets containing vehicle or 5α-dihydrostestosterone (DHT). From age 70 days, PCOS EA rats received 2-Hz EA (evoking muscle twitches) five times/week for 4–5 weeks. Hypothalamic protein expression was measured by immunohistochemistry and western blot. DHT-treated rats were acyclic, but controls had regular estrous cycles. In PCOS rats, hypothalamic medial preoptic AR protein expression and the number of AR- and GnRH-immunoreactive cells were increased, but CRH was not affected; however, GnRH receptor expression was decreased in both the pituitary and hypothalamus. Low-frequency EA restored estrous cyclicity within 1 week and reduced the elevated hypothalamic GnRH and AR expression levels. EA did not affect GnRH receptor or CRH expression. Interestingly, nuclear AR co-localized with GnRH in the hypothalamus. Thus, rats with DHT-induced PCOS have disrupted estrous cyclicity and an increased number of hypothalamic cells expressing GnRH, most likely mediated by AR activation. Repeated low-frequency EA normalized estrous cyclicity and restored GnRH and AR protein expression. These results may help explain the beneficial neuroendocrine effects of low-frequency EA in women with PCOS

Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid

Background: Asthma is a common respiratory disease among both adults and children and short acting inhaled beta-2 agonists are used widely for \u27reliever\u27 bronchodilator therapy. Long acting beta-2 agonists (LABA) were introduced as prospective \u27symptom controllers\u27 in addition to inhaled corticosteroid \u27preventer\u27 therapy (ICS). In this updated review we have included studies in which patients were either not on ICS as a group, or in which some patients, but not all, were on ICS to complement previous systematic reviews of studies where LABA was given in patients uniformly receiving ICS. We have focused particularly on serious adverse events, given previous concerns about potential risks, especially of death, from regular beta-2 agonist use. Objectives: This review aimed to determine the benefit or detriment on the primary outcome of asthma control with the regular use of LABA compared with placebo, in mixed populations in which only some were taking ICS and in populations not using ICS therapy. Search strategy: We carried out searches using the Cochrane Airways Group trial register, most recently in October 2005. We searched bibliographies of identified RCTs for additional relevant RCTs and contacted authors of identified RCTs for other published and unpublished studies. Selection criteria: All randomised studies of at least four weeks duration, comparing a LABA given twice daily with a placebo, in chronic asthma. Selection criteria to this updated review have been altered to accommodate recently published Cochrane reviews on combination and addition of LABA to ICS therapy. Studies in which all individuals were uniformly taking ICS were excluded from this review. Data collection and analysis: Two review authors performed data extraction and study quality assessment independently. We contacted authors of studies for missing data. Main results: Sixty-seven studies (representing 68 experimental comparisons) randomising 42,333 participants met the inclusion criteria. Salmeterol was used as long-acting agent in 50 studies and formoterol fumarate in 17. The treatment period was four to nine weeks in 29 studies, and 12 to 52 weeks in 38 studies. Twenty-four studies did not permit the use of ICS, and forty permitted either inhaled corticosteroid or cromones (in three studies this was unclear). In these studies between 22% and 92% were taking ICS, with a median of 62%. There were significant advantages to LABA treatment compared to placebo for a variety of measurements of airway calibre including morning peak expiratory flow (PEF), evening PEF and FEV1. They were associated with significantly fewer symptoms, less use of rescue medication and higher quality of life scores. This was true whether patients were taking LABA in combination with ICS or not. Findings from SMART (a recently published surveillance study) indicated significant increases in asthma related deaths, respiratory related deaths and combined asthma related deaths and life threatening experiences. The absolute increase in asthma-related mortality was consistent with an increase of around one per 1250 patients treated with LABA for six months, but the confidence intervals are wide (from 700 to 10,000). Post-hoc exploratory subgroups suggested that African-Americans and those not on inhaled corticosteroids were at particular risk for the primary end-point of death or life-threatening asthma event. There was also a suggestion of an increase in exacerbation rate in children. Pharmacologically predicted side effects such as headache, throat irritation, tremor and nervousness were more frequent with LABA treatment. Authors\u27 conclusions: LABA are effective in the control of chronic asthma in the real-life subject groups included. However there are potential safety issues which call into question the safety of LABA, particularly in those asthmatics who are not taking ICS, and it is not clear why African-Americans were found to have significant differences in comparison to Caucasians for combined respiratory-related death and life threatening experiences, but not for asthma-related death

Erythropoiesis-stimulating agents for anaemia in chronic heart failure patients

Chronic heart failure (CHF) is a leading cause of morbidity and mortality worldwide. Anaemia is a common (12-55%) co-morbid condition and is associated with worsening symptoms and increased mortality. Anaemia is treatable and can be targeted in the treatment of patients with CHF. Erythropoiesis-stimulating agents (ESA), supplemented by iron therapy, are used to treat anaemia in chronic kidney disease and cancer, however safety concerns have been raised in these patients. The clinical benefit and safety of these agents in CHF remains unclear

Anti-IgE and chemotherapy: A critical appraisal of treatment options for severe asthma

In this narrative review the scientific rationale for the development of a therapeutic modality for asthma based on decreasing the circulating and cell-bound levels of immunoglobulin-E (IgE) is outlined. The one drug that has so far entered clinical practice to do this is a humanised monoclonal antibody to the Fc portion of the IgE molecule, omalizumab. It is highly effective in reducing IgE blood levels and its established mode of delivery is by subcutaneous injection. The clinical trial development of omalizumab is reviewed and the published data and claims for its efficacy and role in clinical practice is critically appraised. The target group of omalizumab has become focused on severe asthmatics who are still symptomatic after being administered with high-dose inhaled corticosteroids plus long-acting β-agonists. The strongest evidence for effect is in those with frequent severe exacerbations

Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p\ua0value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%(1), much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factorSP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease