Dietary nitrate supplementation reduces circulating platelet-derived extracellular vesicles in coronary artery disease patients on clopidogrel therapy: a randomised, double-blind, placebo-controlled study

Extracellular vesicles (EVs) are implicated in the pathogenesis of cardiovascular disease (CVD). Specifically, platelet-derived EVs are highly pro-coagulant, promoting thrombin generation and fibrin clot formation. Nitrate supplementation exerts beneficial effects in CVD, via an increase in nitric oxide (NO) bioavailability. Clopidogrel is capable of producing NO-donating compounds, such as S-nitrosothiols (RSNO) in the presence of nitrite and low pH. The aim of this study was to assess the effect of nitrate supplementation with versus without clopidogrel therapy on circulating EVs in coronary artery disease (CAD) patients. In this randomized, double-blind, placebo-controlled study, CAD patients with (n = 10) or without (n = 10) clopidogrel therapy received a dietary nitrate supplement (SiS nitrate gel) or identical placebo. NO metabolites and platelet activation were measured using ozone-based chemiluminescence and multiple electrode aggregometry. EV concentration and origin were determined using nanoparticle tracking analysis and time-resolved fluorescence. Following nitrate supplementation, plasma RSNO was elevated (4.7 ± 0.8 vs 0.2 ± 0.5 nM) and thrombin-receptor mediated platelet aggregation was reduced (−19.9 ± 6.0 vs 4.0 ± 6.4 U) only in the clopidogrel group compared with placebo. Circulating EVs were significantly reduced in this group (−1.183e11 ± 3.15e10 vs −9.93e9 ± 1.84e10 EVs/mL), specifically the proportion of CD41+ EVs (−2,120 ± 728 vs 235 ± 436 RFU [relative fluorescence unit]) compared with placebo. In vitro experiments demonstrated clopidogrel–SNO can reduce platelet-EV directly (6.209e10 ± 4.074e9 vs 3.94e11 ±  1.91e10 EVs/mL). In conclusion, nitrate supplementation reduces platelet-derived EVs in CAD patients on clopidogrel therapy, increasing patient responsiveness to clopidogrel. Nitrate supplementation may represent a novel approach to moderating the risk of thrombus formation in CAD patients

British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice

BACKGROUND: Testosterone deficiency (TD) is an increasingly common problem with significant health implications, but its diagnosis and management can be challenging. AIM: To review the available literature on TD and provide evidence-based statements for UK clinical practice. METHODS: Evidence was derived from Medline, EMBASE, and Cochrane searches on hypogonadism, testosterone (T) therapy, and cardiovascular safety from May 2005 to May 2015. Further searches continued until May 2017. OUTCOMES: To provide a guideline on diagnosing and managing TD, with levels of evidence and grades of recommendation, based on a critical review of the literature and consensus of the British Society of Sexual Medicine panel. RESULTS: 25 statements are provided, relating to 5 key areas: screening, diagnosis, initiating T therapy, benefits and risks of T therapy, and follow-up. 7 statements are supported by level 1, 8 by level 2, 5 by level 3, and 5 by level 4 evidence. CLINICAL IMPLICATIONS: To help guide UK practitioners on effectively diagnosing and managing primary and age-related TD. STRENGTHS AND LIMITATIONS: A large amount of literature was carefully sourced and reviewed, presenting the best evidence available at the time. However, some statements provided are based on poor-quality evidence. This is a rapidly evolving area of research and recommendations are subject to change. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions and take personal values and preferences and individual circumstances into account. Many issues remain controversial, but in the meantime, clinicians need to manage patient needs and clinical expectations armed with the best clinical evidence and the multidisciplinary expert opinion available. CONCLUSION: Improving the diagnosis and management of TD in adult men should provide somatic, sexual, and psychological benefits and subsequent improvements in quality of life. Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. J Sex Med 2017;14:1504-1523

British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men-2017.

BACKGROUND This is an update of the 2008 British Society for Sexual Medicine (BSSM) guidelines. AIM To provide up-to-date guidance for U.K. (and international) health care professionals managing male sexual dysfunction. METHODS Source information was obtained from peer-reviewed articles, meetings, and presentations. A search of Embase, MEDLINE, and Cochrane Reviews was performed, covering the search terms "hypogonadism," "eugonadal or hypogonadism or hypogonadal or gonadal," and "low or lower testosterone," starting from 2009 with a cut-off date of September 2017. OUTCOMES We offer evidence-based statements and recommendations for clinicians. RESULTS Expert guidance for health care professionals managing male sexual dysfunction is included. CLINICAL TRANSLATION Current U.K. management has been largely influenced by non-evidence guidance from National Health Service departments, largely based on providing access to care limited by resources. The 2008 BSSM guidelines to date have been widely quoted in U.K. policy decision making. CONCLUSIONS There is now overwhelming evidence that erectile dysfunction is strongly associated with cardiovascular disease, such that newly presenting patients should be thoroughly evaluated for cardiovascular and endocrine risk factors, which should be managed accordingly. Measurement of fasting serum glucose, lipid profile, and morning total testosterone should be considered mandatory in all newly presenting patients. Patients attending their primary care physician with chronic cardiovascular disease should be asked about erectile problems. There can no longer be an excuse for avoiding discussions about sexual activity due to embarrassment. Hackett G, Kirby M, Wylie K, et al. British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men-2017. J Sex Med 2018;15:430-457

The British Society for Sexual Medicine Guidelines on Male Adult Testosterone Deficiency, with Statements for Practice

Testosterone deficiency (TD) is an increasingly common problem with significant health implications, but its diagnosis and management can be challenging. A multi-disciplinary panel from BSSM reviewed the available literature on TD and provide evidence-based statements for clinical practice. Evidence was derived from Medline, EMBASE and Cochrane searches on hypogonadism, testosterone therapy (T Therapy) and cardiovascular safety from May 2017 to September 2022. This revealed 1,714 articles, including 52 clinical trials and 32 placebo-controlled randomised controlled trials. A total of twenty-five statements are provided, relating to five key areas: screening, diagnosis, initiating T Therapy, benefits and risks of T Therapy, and follow-up. Seven statements are supported by level 1 evidence, eight by level 2, five by level 3, and five by level 4. Recent studies have demonstrated that low levels of testosterone in men are associated with increased risk of incident type 2 diabetes mellitus, worse outcomes in chronic kidney disease and COVID 19 infection with increased all-cause mortality, along with significant quality of life implications. These guidelines should help practitioners to effectively diagnose and manage primary and age-related TD