Glyceryl trinitrate-induced vasodilation is inhibited by ultraviolet irradiation despite enhanced nitric oxide generation: evidence for formation of a nitric oxide conjugate

ABSTRACT Our objective was to determine whether a stabilized form of nitric oxide (NO) such as an S-nitrosothiol, rather than NO itself, is the vasoactive metabolite produced when glyceryl trinitrate (GTN) interacts with vascular smooth muscle. In a control study, NO formation was measured by a chemiluminescenceheadspace gas method during the incubation of a prototype S-nitrosothiol, namely, S-nitroso-N-acetylpenicillamine (SNAP), in Krebs' solution. NO formation from SNAP was increased when the incubation was carried out in the presence of UV light, indicating that homolytic photolysis of the S-nitrosothiol had occurred. When GTN was incubated with bovine pulmonary artery (BPA) in the absence of UV light, NO was not measurable until 5 min of incubation. By contrast, in the presence of UV light, NO was measurable as early as 0.5 min, and by 5 min, it was higher than that observed in the absence of UV light. BPA rings were relaxed with SNAP and GTN in the absence of UV light, and EC 50 values of 0.24 Ϯ 0.28 M and 10 Ϯ 6 nM, respectively, were observed. In the presence of UV light, the vasodilator response of BPA to SNAP and GTN was attenuated, and EC 50 values of 2.7 Ϯ 3.0 M and 49 Ϯ 23 nM, respectively, were observed. Our results are consistent with the idea that GTN biotransformation by vascular smooth muscle results in the production of a stabilized form of NO, possibly an S-nitrosothiol, and that degradation of this metabolite by UV light results in NO formation accompanied by decreased vasodilation

Patients’ Perceptions and Experiences of Familial Hypercholesterolemia, Cascade Genetic Screening and Treatment

Background: Familial hypercholesterolemia (FH) is a serious genetic disorder affecting approximately 1 in every 300 to 500 individuals and is characterised by excessively high low-density lipoprotein (LDL) cholesterol levels, substantially increased risk of early-onset coronary heart disease (CHD) and premature mortality. If FH is untreated, it leads to a greater than 50 % risk of CHD in men by the age of 50 and at least 30 % in women by the age of 60. FH can be diagnosed through genetic screening and effectively managed through pharmacological treatment and lifestyle changes. Purpose: Familial hypercholesterolemia (FH) is a genetic health condition that increases the risk of cardiovascular disease. Although FH can be effectively managed with appropriate pharmacological and dietary interventions, FH detection rate through genetic screening remains low. The present study explored perceptions and experiences of FH patients (N = 18) involved in a genetic cascade screening programme. Methods: Face-to-face interviews were conducted to assess patients’ knowledge and understanding of FH, explore factors linked to adherence to health-protective behaviours and examine perceptions of genetic screening. Results: Thematic analysis of interviews revealed four themes: disease knowledge, severity of FH, lifestyle behavioural change and barriers to cascade screening and treatment. Participants recognised FH as a permanent, genetic condition that increased their risk of CHD and premature mortality. Many participants dismissed the seriousness of FH and the importance of lifestyle changes because they perceived it to be effectively managed through medication. Despite positive attitudes toward screening, many participants reported that relatives were reluctant to attend screening due to their relatives’ ‘fatalistic’ outlook or low motivation. Participants believed that they had insufficient authority or control to persuade family members to attend screening and welcomed greater hospital assistance for contact with relatives. Conclusions: Findings support the adoption of direct methods of recruitment to cascade screening led by medical professionals, who were perceived as having greater authority. Other implications included the need for clinicians to provide clear information, particularly to those who are asymptomatic, related to the seriousness of FH and the necessity for adherence to medication and lifestyle changes

Symptomatic benefits of testosterone treatment in patient subgroups : a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis

Acknowledgments This work was supported by the UK National Institute for Health and Care Research (NIHR)'s Health Technology Assessment Programme (project number 17/68/01). The views expressed herein are those of the authors and not necessarily those of the National Health Service, the NIHR Health Technology Assessment Programme, or the UK Department of Health and Social Care. The Health Services Research Unit at the University of Aberdeen is funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. The Section of Endocrinology and Investigative Medicine at Imperial College London is funded by grants from the Medical Research Council, the Biotechnology and Biological Sciences Research Council, NIHR, an Integrative Mammalian Biology Capacity Building Award, and an FP7-HEALTH-2009-241592 EuroCHIP grant, and is supported by the NIHR Biomedical Research Centre Funding Scheme. WSD is funded by an NIHR Research Professorship. CNJ is funded by an NIHR Post-Doctoral Fellowship. ShB receives NIH research grant funding. The authors are grateful to the clinical and methodological experts and patient partners who contributed to the advisory group for this study.Peer reviewedPublisher PD

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis

Background Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. Methods We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. Findings 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60–72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95–7·10]; τ²=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40–2·89]; τ²=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males’ Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). Interpretation In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-mediumterm testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity

Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ 2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ 2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017

Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2\ub75th percentile and 100 as the 97\ub75th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59\ub74 (IQR 35\ub74–67\ub73), ranging from a low of 11\ub76 (95% uncertainty interval 9\ub76–14\ub70) to a high of 84\ub79 (83\ub71–86\ub77). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030