Young Adults Rehabilitation Needs and Experiences following Stroke (YARNS): A review of digital accounts to inform the development of age-appropriate support and rehabilitation.

AIMS: To explore younger adults' experiences of stroke rehabilitation to inform practice, education and future health policy. DESIGN: Qualitative analysis of digital and other media sources on public platforms. METHODS: Between March and June 2020, the experiences of younger adult stroke survivors aged 18 to 45 at the time of the stroke were collected. Data were gathered from publicly available sources, including social media, and from English-speaking users. In total, 117 accounts from 103 participants were identified from films, autobiographical books, blogs, websites, videos, Twitter and Instagram. Data analysis followed narrative and multimodal analysis with a focus on rehabilitation needs. RESULTS: Younger adult stroke survivors make sense of their experience by reflecting on how stroke has impacted their lives. Accounts reflected an emotional journey between the past self, the present self and evolving self, as well as associated challenges such as the impact on relationships and careers. The majority of accounts presented transitions as problematic, including the receipt of the initial diagnosis, or sometimes misdiagnosis, to returning home and achieving long-term rehabilitation goals. Specialist stroke nurses were considered essential in the rehabilitation process. CONCLUSION: A complex process of recovery follows stroke for younger adult stroke populations. Challenges to the rehabilitation process need to be better understood and the role of nursing highlighted in future service provision. A series of age-related challenges were highlighted that require attention to improve the care and support offered. IMPACT: This article informs clinicians, educators, and policymakers of the age-related needs of young adult stroke survivors. Focusing on the individual and the development of age-appropriate person-centred stroke care is important. The study highlights the role of stroke nursing and challenges the current policy focus on older stroke populations as well as arguing for greater awareness of age-appropriate stroke rehabilitation in younger adults following stroke.

Testosterone stimulates cholesterol clearance from human macrophages by activating LXRα.

AIMS: Low testosterone in men is associated with increased cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors including cholesterol, endothelial dysfunction and inflammation as key mediators of atherosclerosis. Although evidence suggests testosterone is anti-atherogenic, its mechanism of action is unknown. The present study investigates whether testosterone exerts anti-atherogenic effects by stimulating cholesterol clearance from macrophages via activation of liver X receptor (LXRα), a nuclear master regulator of cellular cholesterol homeostasis, lipid regulation, and inflammation. MAIN METHODS: Using human monocyte THP-1 cells differentiated into macrophages, the effect of testosterone (1-10 nM) treatment (24-72 h) on the expression of LXRα and LXR- targets apolipoprotein E (APOE), ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding transcription factor 1 (SREBF1) and fatty acid synthase (FAS), was investigated via qPCR and western blotting, with or without androgen receptor blockade with flutamide or LXR antagonism with CPPSS-50. Cholesterol clearance was measured by monitoring fluorescent dehydroergosterol (DHE) cellular clearance and ABCA1 cellular translocation was observed via immunocytochemistry in testosterone treated macrophages. KEY FINDINGS: Testosterone increased mRNA and protein expression of LXRα, APOE, ABCA1, SREBF1 and FAS. These effects were blocked by flutamide and independently by LXR antagonism with CPPSS-50. Furthermore testosterone stimulated cholesterol clearance from the macrophages and promoted the translocation of ABCA1 toward the cell membrane. SIGNIFICANCE: Testosterone acts via androgen receptor-dependent pathways to stimulate LXRα and downstream targets to induce cholesterol clearance in human macrophages. This may, in part, explain the anti-atherogenic effects of testosterone frequently seen clinically.

"This Is the First Time I've Talked About This": Considerations When Conducting Qualitative Research Interviews with Adolescents and Young Adults with Cancer.

Qualitative research is a useful and important way to describe and analyze the experiences of adolescents and young adults (AYAs) with cancer. However, undertaking qualitative research with AYAs living with, or beyond, a cancer diagnosis requires careful planning and a well-informed approach for participants with a high level of vulnerability and who are at a crucial stage developmentally. This article reflects on the challenges of including AYAs with cancer between the ages of 16 and 25 years in qualitative research. By drawing on each author's own experiences of engaging in qualitative research interviews with AYAs with cancer, the article provides suggestions regarding how best to manage challenges and yield valuable data describing their experiences. Insights that are shared between qualitative researchers in this field may assist in preparing for the challenges posed by conducting qualitative research with this group and may help researchers to manage this activity successfully.

Long-term testosterone therapy improves liver parameters and steatosis in hypogonadal men: a prospective controlled registry study.

Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD) and both are prevalent in men with testosterone deficiency. Long-term effects of testosterone therapy (TTh) on NAFLD are not well studied. This observational, prospective, cumulative registry study assesses long-term effects of testosterone undecanoate (TU) on hepatic physiology and function in 505 hypogonadal men (T levels ≤350 ng/dL). Three hundred and twenty one men received TU 1000 mg/12 weeks for up to 12 years following an initial 6-week interval (T-group), while 184 who opted against TTh served as controls (C-group). T-group patients exhibited decreased fatty liver index (FLI, calculated according to Mayo Clinic guidelines) (83.6 ± 12.08 to 66.91 ± 19.38), γ-GT (39.31 ± 11.62 to 28.95 ± 7.57 U/L), bilirubin (1.64 ± 4.13 to 1.21 ± 1.89 mg/dL) and triglycerides (252.35 ± 90.99 to 213 ± 65.91 mg/dL) over 12 years. Waist circumference and body mass index were also reduced in the T-group (107.17 ± 9.64 to 100.34 ± 9.03 cm and 31.51 ± 4.32 to 29.03 ± 3.77 kg/m2). There were 25 deaths (7.8%) in the T-group of which 11 (44%) were cardiovascular related. In contrast, 28 patients (15.2%) died in C-group, and all deaths (100%) were attributed to CVD. These data suggest that long-term TTh improves hepatic steatosis and liver function in hypogonadal men. Improvements in liver function may have contributed to reduced CVD-related mortality.

Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system.

Testosterone deficiency is common in men with cardiovascular disease (CVD), and randomized placebo-controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise-induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO2max) and muscle strength in chronic heart failure (CHF), shortening of the Q-T interval, and improvement of some cardiovascular risk factors. Testosterone deficiency is associated with an adverse CV risk profile and mortality. Clinical and scientific studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid-onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance. Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L-calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra-rapid potassium channel-operated current. Testosterone improves cardiac output, functional exercise capacity, VO2maxand vagally mediated arterial baroreceptor cardiac reflex sensitivity in CHF, and other mechanisms. Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, both factors that could contribute to the improvement in functional exercise capacity may include improved glucose metabolism and muscle strength. Testosterone improves metabolic CV risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism by a combination of genomic and nongenomic actions of glucose uptake and utilization expression of the insulin receptor, glucose transporters, and expression on regulatory enzymes of key metabolic pathways. The effect on high-density lipoprotein-cholesterol (HDL-C) differs between studies in that it has been found to fall, rise, or have no change in levels. Testosterone replacement can suppress the levels of circulating pro-inflammatory cytokines and stimulate the production of interleukin-10 (IL-10) which has anti-inflammatory and anti-atherogenic actions in men with CVD. No effect on C-reactive protein has been detected. No adverse effects on clotting factors have been detected. RCTs have not clearly demonstrated any significant evidence that testosterone improves or adversely affects the surrogate markers of atherosclerosis such as reduction in carotid intima thickness or coronary calcium deposition. Any effect of testosterone on prevention or amelioration of atherosclerosis is likely to occur over years as shown in statin therapy trials and not months as used in testosterone RCTs. The weight of evidence from long-term epidemiological studies supports a protective effect as evidenced by a reduction in major adverse CV events (MACEs) and mortality in studies which have treated men with testosterone deficiency. No RCT where testosterone has been replaced to the normal healthy range has reported a significant benefit or adverse effect on MACE nor has any recent meta-analysis.

Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse.

Testosterone deficiency is commonly associated with obesity, metabolic syndrome, type 2 diabetes and their clinical consequences-hepatic steatosis and atherosclerosis. The testicular feminised mouse (non-functional androgen receptor and low testosterone) develops fatty liver and aortic lipid streaks on a high-fat diet, whereas androgen-replete XY littermate controls do not. Testosterone treatment ameliorates these effects, although the underlying mechanisms remain unknown. We compared the influence of testosterone on the expression of regulatory targets of glucose, cholesterol and lipid metabolism in muscle, liver, abdominal subcutaneous and visceral adipose tissue. Testicular feminised mice displayed significantly reduced GLUT4 in muscle and glycolytic enzymes in muscle, liver and abdominal subcutaneous but not visceral adipose tissue. Lipoprotein lipase required for fatty acid uptake was only reduced in subcutaneous adipose tissue; enzymes of fatty acid synthesis were increased in liver and subcutaneous tissue. Stearoyl-CoA desaturase-1 that catalyses oleic acid synthesis and is associated with insulin resistance was increased in visceral adipose tissue and cholesterol efflux components (ABCA1, apoE) were decreased in subcutaneous and liver tissue. Master regulator nuclear receptors involved in metabolism-Liver X receptor expression was suppressed in all tissues except visceral adipose tissue, whereas PPARγ was lower in abdominal subcutaneous and visceral adipose tissue and PPARα only in abdominal subcutaneous. Testosterone treatment improved the expression (androgen receptor independent) of some targets but not all. These exploratory data suggest that androgen deficiency may reduce the buffering capability for glucose uptake and utilisation in abdominal subcutaneous and muscle and fatty acids in abdominal subcutaneous. This would lead to an overspill and uptake of excess glucose and triglycerides into visceral adipose tissue, liver and arterial walls.

Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice.

AIMS: Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associated with cardiovascular disease (CVD). Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood. MAIN METHODS: Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very low serum testosterone levels, were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis. KEY FINDINGS: Hepatic lipid deposition was increased in Tfm mice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered. SIGNIFICANCE: An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosterone may act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis.

Exploring the feasibility and acceptability of couple-based psychosexual support following prostate cancer surgery: study protocol for a pilot randomised controlled trial.

BACKGROUND: Men who undergo surgery for prostate cancer frequently experience significant side-effects including urinary and sexual dysfunction. These difficulties can lead to anxiety, depression and reduced quality of life. Many partners also experience psychological distress. An additional impact can be on the couple relationship, with changes to intimacy, and unmet psychosexual supportive needs in relation to sexual recovery and rehabilitation. The aim of this exploratory randomised controlled trial pilot study is to determine the feasibility and acceptability of a novel family-relational-psychosexual intervention to support intimacy and reduce distress among couples following prostate cancer surgery and to estimate the efficacy of this intervention. METHODS/DESIGN: The intervention will comprise six sessions of psychosexual and relationship support delivered by experienced couple-support practitioners. Specialist training in delivering the intervention will be provided to practitioners and they will be guided by a detailed treatment manual based on systemic principles. Sixty-eight couples will be randomised to receive either the intervention or standard care (comprising usual follow-up hospital appointments). A pre-test, post-test design will be used to test the feasibility of the intervention (baseline, end of intervention and six-month follow-up) and its acceptability to couples and healthcare professionals (qualitative interviews). Both individual and relational outcome measures will assess sexual functioning, anxiety and depression, couple relationship, use of health services and erectile dysfunction medication/technologies. An economic analysis will estimate population costs of the intervention, compared to usual care, using simple modelling to evaluate the affordability of the intervention. DISCUSSION: Given the increasing incidence and survival of post-operative men with prostate cancer, it is timely and appropriate to determine the feasibility of a definitive trial through a pilot randomised controlled trial of a family-relational-psychosexual intervention for couples. The study will provide evidence about the components of a couple-based intervention, its acceptability to patients and healthcare professionals, and its influence on sexual and relational functioning. Data from this study will be used to calculate sample sizes required for any definitive trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01842438.Registration date: 24 April 2013; Randomisation of first patient: 13 May 2013.

Testosterone and cardiovascular risk in men.

Testosterone deficiency is highly prevalent in men with cardiovascular disease (CVD) and is associated with an increased mortality. Low testosterone also has an adverse effect on several cardiovascular risk factors, which include insulin resistance, diabetes, dyslipidaemia, central adiposity and endothelial dysfunction. Male gender is a well-recognised risk factor for premature CVD and mortality. The question of whether or not testosterone deficiency is a contributory factor to atherogenesis or merely a biomarker of ill health arises. Animal studies and experiments on isolated cells indicate that many of the mechanisms intimate to the atherosclerotic process are beneficially modulated by testosterone. Epidemiological studies have shown that men with endogenous testosterone levels in the mid-upper normal range have reduced cardiovascular events and mortality compared to those with low or lower range, and with high range testosterone. Testosterone replacement in men diagnosed with hypogonadism where mid-normal range levels are achieved have shown a beneficial effect on several cardiovascular risk factors, cardiac ischaemia, functional exercise capacity and improved mortality. Yet studies where patients were either undertreated or given high-dose testosterone have been associated with an increased risk of cardiovascular-related events. Clinical monitoring and titration of testosterone dose is therefore of paramount importance.

Testosterone and insulin resistance in the metabolic syndrome and T2DM in men.

Obesity, type 2 diabetes mellitus and the metabolic syndrome are major risk factors for cardiovascular disease. Studies have demonstrated an association between low levels of testosterone and the above insulin-resistant states, with a prevalence of hypogonadism of up to 50% in men with type 2 diabetes mellitus. Low levels of testosterone are also associated with an increased risk of all-cause and cardiovascular mortality. Hypogonadism and obesity share a bidirectional relationship as a result of the complex interplay between adipocytokines, proinflammatory cytokines and hypothalamic hormones that control the pituitary-testicular axis. Interventional studies have shown beneficial effects of testosterone on components of the metabolic syndrome, type 2 diabetes mellitus and other cardiovascular risk factors, including insulin resistance and high levels of cholesterol. Biochemical evidence indicates that testosterone is involved in promoting glucose utilization by stimulating glucose uptake, glycolysis and mitochondrial oxidative phosphorylation. Testosterone is also involved in lipid homeostasis in major insulin-responsive target tissues, such as liver, adipose tissue and skeletal muscle.

Testosterone: a vascular hormone in health and disease.

Coronary heart disease is a leading cause of premature death in men. Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease (CVD). Furthermore, a low testosterone level is associated in some but not in all observational studies with an increase in cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation: key mediators of atherosclerosis. A bidirectional relationship between low endogenous testosterone levels and concurrent illness complicates attempts to validate causality in this association and potential mechanistic actions are complex. Testosterone is a vasoactive hormone that predominantly has vasodilatory actions on several vascular beds, although some studies have reported conflicting effects. In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure. Although the mechanism of the action of testosterone on vascular tone in vivo is not understood, laboratory research has found that testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells. Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis. The translational effects of testosterone between in vitro animal and human studies, some of which have conflicting effects, will be discussed in this review. We review the evidence for a role of testosterone in vascular health, its therapeutic potential and safety in hypogonadal men with CVD, and some of the possible underlying mechanisms.

Testosterone: a metabolic hormone in health and disease.

Testosterone is a hormone that plays a key role in carbohydrate, fat and protein metabolism. It has been known for some time that testosterone has a major influence on body fat composition and muscle mass in the male. Testosterone deficiency is associated with an increased fat mass (in particular central adiposity), reduced insulin sensitivity, impaired glucose tolerance, elevated triglycerides and cholesterol and low HDL-cholesterol. All these factors are found in the metabolic syndrome (MetS) and type 2 diabetes, contributing to cardiovascular risk. Clinical trials demonstrate that testosterone replacement therapy improves the insulin resistance found in these conditions as well as glycaemic control and also reduces body fat mass, in particular truncal adiposity, cholesterol and triglycerides. The mechanisms by which testosterone acts on pathways to control metabolism are not fully clear. There is, however, an increasing body of evidence from animal, cell and clinical studies that testosterone at the molecular level controls the expression of important regulatory proteins involved in glycolysis, glycogen synthesis and lipid and cholesterol metabolism. The effects of testosterone differ in the major tissues involved in insulin action, which include liver, muscle and fat, suggesting a complex regulatory influence on metabolism. The cumulative effects of testosterone on these biochemical pathways would account for the overall benefit on insulin sensitivity observed in clinical trials. This review discusses the current knowledge of the metabolic actions of testosterone and how testosterone deficiency contributes to the clinical disease states of obesity, MetS and type 2 diabetes and the role of testosterone replacement.

Effect of Testosterone on Inflammatory Markers in the Development of Early Atherogenesis in the Testicular-Feminized Mouse Model.

BACKGROUND: Low levels of serum testosterone in men are associated with cardiovascular disease. Clinical studies show that testosterone replacement therapy (TRT) can improve symptoms of cardiovascular disease and reduce the inflammatory burden evident in atherosclerosis. AIM: We used an in vivo animal model to determine whether testosterone influences mediators of vascular inflammation as part of its beneficial effects on atherogenesis. METHODS: Testicular-feminized (Tfm) mice, which express low endogenous testosterone and a non-functional androgen receptor (AR), were used to assess the effect of androgen status on atheroma formation, serum lipids, and inflammatory mediators. Tfm mice were fed a high-cholesterol diet, received saline or physiological (TRT), and were compared to saline-treated XY littermates. RESULTS: A total of 28 weeks of high-cholesterol diet caused fatty streak formation in the aortic root of XY littermates and Tfm mice, an effect significantly amplified in Tfm mice. Tfm mice on normal diet showed elevated serum tumor necrosis factor-α (TFN-α) and interleukin-6 compared to XY littermates. High-cholesterol diet induced increased monocyte chemoattractant protein-1 (MCP-1) in Tfm mice, and TFN-α and MCP-1 in XY littermates. TRT reduced fatty streak formation and serum interleukin-6 in Tfm mice but had no significant effects on lipid profiles. Monocyte/macrophage staining indicated local inflammation in aortic root fatty streak areas of all mice, with TRT reducing local inflammation through plaque reduction in Tfm mice. Fractalkine (CX3CL1) and its receptor (CX3CR1) were present in fatty streaks of all mice fed a high-cholesterol diet, independent of androgen status. CONCLUSION: These results are consistent with AR-dependent and AR-independent anti-inflammatory actions of testosterone in atheroprotection, although the local anti-inflammatory mechanisms via which testosterone acts remain unknown.