Good Hope Hospital

Abstract 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-19 1,2 , 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 diseases 3–7 . 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.

INTRODUCTION: Compliance with the ventilator care bundle affects the rate of ventilator-associated pneumonia. It was not known, however, whether compliance with sepsis care bundles has an impact on outcome. The aims of the present study were to determine the rate of compliance with 6-hour and 24-hour sepsis bundles and to determine the impact of the compliance on hospital mortality in patients with severe sepsis or septic shock. METHODS: We conducted a prospective observational study on 101 consecutive adult patients with severe sepsis or septic shock on medical or surgical wards, or in accident and emergency areas at two acute National Health Service Trust Teaching hospitals in England. The main outcome measures were: the rate of compliance with 6-hour and 24-hour sepsis care bundles adapted from the Surviving Sepsis Campaign guidelines on patients' clinical care; and the difference in hospital mortality between the compliant and the non-compliant groups. RESULTS: The median age of the patients was 69 years (interquartile range 51 to 78), and 53% were male. The sources of infection were sought and confirmed in 87 of 101 patients. The chest was the most common source (50%), followed by the abdomen (22%). The rate of compliance with the 6-hour sepsis bundle was 52%. Compared with the compliant group, the non-compliant group had a more than twofold increase in hospital mortality (49% versus 23%, relative risk (RR) 2.12 (95% confidence interval (CI) 1.20 to 3.76), P = 0.01) despite similar age and severity of sepsis. Compliance with the 24-hour sepsis bundle was achieved in only 30% of eligible candidates (21/69). Hospital mortality was increased in the non-compliant group from 29% to 50%, with a 76% increase in risk for death, although the difference did not reach statistical significance (RR 1.76 (95% CI 0.84 to 3.64), P = 0.16). CONCLUSION: Non-compliance with the 6-hour sepsis bundle was associated with a more than twofold increase in hospital mortality. Non-compliance with the 24-hour sepsis bundle resulted in a 76% increase in risk for hospital death. All medical staff should practise these relatively simple, easy and cheap bundles within a strict timeframe to improve survival rates in patients with severe sepsis and septic shock.

BACKGROUND: Postoperative cognitive dysfunction (POCD) after noncardiac surgery is strongly associated with increasing age in elderly patients; middle-aged patients (aged 40-60 yr) may be expected to have a lower incidence, although subjective complaints are frequent. METHODS: The authors compared the changes in neuropsychological test results at 1 week and 3 months in patients aged 40-60 yr, using a battery of neuropsychological tests, with those of age-matched control subjects using Z-score analysis. They assessed risk factors and associations of POCD with measures of subjective cognitive function, depression, and activities of daily living. RESULTS: At 7 days, cognitive dysfunction as defined was present in 19.2% (confidence interval [CI], 15.7-23.1) of the patients and in 4.0% (CI, 1.6-8.0) of control subjects (P < 0.001). After 3 months, the incidence was 6.2% (CI, 4.1-8.9) in patients and 4.1% (CI, 1.7-8.4) in control subjects (not significant). POCD at 7 days was associated with supplementary epidural analgesia and reported avoidance of alcohol consumption. At 3 months, 29% of patients had subjective symptoms of POCD, and this finding was associated with depression. Early POCD was associated with reports of lower activity scores at 3 months. CONCLUSIONS: Postoperative cognitive dysfunction occurs frequently but resolves by 3 months after surgery. It may be associated with decreased activity during this period. Subjective report overestimates the incidence of POCD. Patients may be helped by recognition that the problem is genuine and reassured that it is likely to be transient.

BACKGROUND: Physical activity may be associated with reduced risk of colorectal cancer. The main aim of this paper is to review the available evidence for a link between exercise and large bowel cancer. METHODS: A Cochrane-type methodology was performed. Data extracted included, type of study, type of physical activity measured and the numerical results. The risk ratios (RR) of the studies have been pooled according to the type of study, type of exercise, type of cancer and sex. Pooling was undertaken using fixed effect meta-analysis. A random effect meta-analysis was used where substantial heterogeneity existed. RESULT: Data from 19 cohort studies showed a statistically significant reduction in the risk of colon cancer in physically active males, RR being 0.79 (95% CI 0.72-0.87) and 0.78 (95% CI 0.68-0.91) for occupational and recreational activities, respectively. In women only recreational activities are protective against colon cancer (RR = 0.71, 95%CI 0.57-0.88). Case-control studies showed significantly reduced risks of colon cancer in both sexes irrespective of the type of activity. No protection against rectal cancer is seen in either sex. CONCLUSION: There is considerable evidence that physical activity is associated with reduced risk of colon cancer in both males and females.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

BACKGROUND: Severe sepsis is likely to account for around 37,000 deaths annually in the UK. Five years after the international Surviving Sepsis Campaign (SSC) care bundles were published, care standards in the management of patients with severe sepsis are achieved in fewer than one in seven patients. METHODS: This was a prospective observational cohort study across a 500-bed acute general hospital, to assess the delivery and impact of two interventions: the SSC resuscitation bundle and a new intervention designed to facilitate delivery, the sepsis six. Process measures included compliance with the bundle and the sepsis six; the outcome measure was mortality at hospital discharge. RESULTS: Data from 567 patients were suitable for analysis. Compliance with the bundle increased from baseline. 84.6% of those receiving the sepsis six (n = 220) achieved the resuscitation bundle compared with only 5.8% of others. Delivery of the interventions had an association with reduced mortality: for the sepsis six (n = 220), 20.0% compared with 44.1% (p < 0.001); for the resuscitation bundle (n = 204), 5.9% compared with 51% (p < 0.001). Those receiving the sepsis six were much more likely to receive the full bundle. Those seen by the sepsis team had improved compliance with bundles and reduced mortality. CONCLUSIONS: This study supports the SSC resuscitation bundle, and is suggestive of an association with reduced mortality although does not demonstrate causation. It demonstrates that simplified pathways, such as the sepsis six, and education programmes such as survive sepsis can contribute to improving the rate of delivery of these life-saving interventions.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

BACKGROUND: Reports on the incidence and causes of sudden cardiac death among young athletes have relied largely on estimated rates of participation and varied methods of reporting. We sought to investigate the incidence and causes of sudden cardiac death among adolescent soccer players in the United Kingdom. METHODS: From 1996 through 2016, we screened 11,168 adolescent athletes with a mean (±SD) age of 16.4±1.2 years (95% of whom were male) in the English Football Association (FA) cardiac screening program, which consisted of a health questionnaire, physical examination, electrocardiography, and echocardiography. The FA registry was interrogated to identify sudden cardiac deaths, which were confirmed with autopsy reports. RESULTS: During screening, 42 athletes (0.38%) were found to have cardiac disorders that are associated with sudden cardiac death. A further 225 athletes (2%) with congenital or valvular abnormalities were identified. After screening, there were 23 deaths from any cause, of which 8 (35%) were sudden deaths attributed to cardiac disease. Cardiomyopathy accounted for 7 of 8 sudden cardiac deaths (88%). Six athletes (75%) with sudden cardiac death had had normal cardiac screening results. The mean time between screening and sudden cardiac death was 6.8 years. On the basis of a total of 118,351 person-years, the incidence of sudden cardiac death among previously screened adolescent soccer players was 1 per 14,794 person-years (6.8 per 100,000 athletes). CONCLUSIONS: Diseases that are associated with sudden cardiac death were identified in 0.38% of adolescent soccer players in a cohort that underwent cardiovascular screening. The incidence of sudden cardiac death was 1 per 14,794 person-years, or 6.8 per 100,000 athletes; most of these deaths were due to cardiomyopathies that had not been detected on screening. (Funded by the English Football Association and others.).

INTRODUCTION: The role of testosterone supplementation (TS) as a treatment for male sexual dysfunction remains questionable. AIM: The aim of this study was to attempt a meta-analysis on the effect of TS on male sexual function and its synergism with the use of phosphodiesterase type 5 inhibitor (PDE5i). METHODS: An extensive Medline, Embase, and Cochrane search was performed. MAIN OUTCOME MEASURES: All randomized controlled trials (RCTs) comparing the effect of TS vs. placebo or the effect of TS as add on to PDE5is on sexual function were included. Data extraction was performed independently by two of the authors (A. M. Isidori and G. Corona), and conflicts resolved by the third investigator (M. Maggi). RESULTS: Out of 1,702 retrieved articles, 41 were included in the study. In particular, 29 compared TS vs. placebo, whereas 12 trials evaluated the effect of TS as add on to PDE5is. TS is able to significantly ameliorate erectile function and to improve other aspects of male sexual response in hypogonadal patients. However, the presence of possible publication bias was detected. After applying "trim and fill" method, the positive effect of TS on erectile function and libido components retained significance only in RCTs partially or completely supported by pharmaceutical companies (confidence interval [0.04-0.53] and [0.12; 0.52], respectively). In addition, we also report that TS could be associated with an improvement in PDE5i outcome. These results were not confirmed in placebo-controlled studies. The majority of studies, however, included mixed eugonadal/hypogonadal subjects, thus imparting uncertainty to the statistical analyses. CONCLUSIONS: TS plays positive effects on male sexual function in hypogonadal subjects. The role of TS is uncertain in men who are not clearly hypogonadal. The apparent difference between industry-supported and independent studies could depend on trial design more than on publication bias. New RCTs exploring the effect of TS in selected cases of PDE5i failure that persistently retain low testosterone levels are advisable.

* A significant proportion of men with erectile dysfunction (ED) exhibit early signs of coronary artery disease (CAD), and this group may develop more severe CAD than men without ED (Level 1, Grade A). * The time interval among the onset of ED symptoms and the occurrence of CAD symptoms and cardiovascular events is estimated at 2-3 years and 3-5 years respectively; this interval allows for risk factor reduction (Level 2, Grade B). * ED is associated with increased all-cause mortality primarily due to increased cardiovascular mortality (Level 1, Grade A). * All men with ED should undergo a thorough medical assessment, including testosterone, fasting lipids, fasting glucose and blood pressure measurement. Following assessment, patients should be stratified according to the risk of future cardiovascular events. Those at high risk of cardiovascular disease should be evaluated by stress testing with selective use of computed tomography (CT) or coronary angiography (Level 1, Grade A). * Improvement in cardiovascular risk factors such as weight loss and increased physical activity has been reported to improve erectile function (Level 1, Grade A). * In men with ED, hypertension, diabetes and hyperlipidaemia should be treated aggressively, bearing in mind the potential side effects (Level 1, Grade A). * Management of ED is secondary to stabilising cardiovascular function, and controlling cardiovascular symptoms and exercise tolerance should be established prior to initiation of ED therapy (Level 1, Grade A). * Clinical evidence supports the use of phosphodiesterase 5 (PDE5) inhibitors as first-line therapy in men with CAD and comorbid ED and those with diabetes and ED (Level 1, Grade A). * Total testosterone and selectively free testosterone levels should be measured in all men with ED in accordance with contemporary guidelines and particularly in those who fail to respond to PDE5 inhibitors or have a chronic illness associated with low testosterone (Level 1, Grade A). * Testosterone replacement therapy may lead to symptomatic improvement (improved wellbeing) and enhance the effectiveness of PDE5 inhibitors (Level 1, Grade A). * Review of cardiovascular status and response to ED therapy should be performed at regular intervals (Level 1, Grade A).

BACKGROUND: Myocardial scarring at the LV pacing site leads to incomplete resynchronization and a suboptimal symptomatic response to CRT. We sought to determine whether the use of late gadolinium cardiovascular magnetic resonance (LGE-CMR) to guide left ventricular (LV) lead deployment influences the long-term outcome of cardiac resynchronization therapy (CRT). METHODS: 559 patients with heart failure (age 70.4 ± 10.7 yrs [mean ± SD]) due to ischemic or non-ischemic cardiomyopathy underwent CRT. Implantations were either guided (+CMR) or not guided (-CMR) by LGE-CMR prior to implantation. Fluoroscopy and LGE-CMR were used to localize the LV lead tip and and myocardial scarring retrospectively. Clinical events were assessed in three groups: +CMR and pacing scar (+CMR+S); CMR and not pacing scar (+CMR-S), and; LV pacing not guided by CMR (-CMR). RESULTS: Over a maximum follow-up of 9.1 yrs, +CMR+S had the highest risk of cardiovascular death (HR: 6.34), cardiovascular death or hospitalizations for heart failure (HR: 5.57) and death from any cause or hospitalizations for major adverse cardiovascular events (HR: 4.74) (all P < 0.0001), compared with +CMR-S. An intermediate risk of meeting these endpoints was observed for -CMR, with HRs of 1.51 (P = 0.0726), 1.61 (P = 0.0169) and 1.87 (p = 0.0005), respectively. The +CMR+S group had the highest risk of death from pump failure (HR: 5.40, p < 0.0001) and sudden cardiac death (HR: 4.40, p = 0.0218), in relation to the +CMR-S group. CONCLUSIONS: Compared with a conventional implantation approach, the use of LGE-CMR to guide LV lead deployment away from scarred myocardium results in a better clinical outcome after CRT. Pacing scarred myocardium was associated with the worst outcome, in terms of both pump failure and sudden cardiac death.

BACKGROUND: To validate a new practical Sepsis Severity Score for patients with complicated intra-abdominal infections (cIAIs) including the clinical conditions at the admission (severe sepsis/septic shock), the origin of the cIAIs, the delay in source control, the setting of acquisition and any risk factors such as age and immunosuppression. METHODS: The WISS study (WSES cIAIs Score Study) is a multicenter observational study underwent in 132 medical institutions worldwide during a four-month study period (October 2014-February 2015). Four thousand five hundred thirty-three patients with a mean age of 51.2 years (range 18-99) were enrolled in the WISS study. RESULTS: Univariate analysis has shown that all factors that were previously included in the WSES Sepsis Severity Score were highly statistically significant between those who died and those who survived (p < 0.0001). The multivariate logistic regression model was highly significant (p < 0.0001, R2 = 0.54) and showed that all these factors were independent in predicting mortality of sepsis. Receiver Operator Curve has shown that the WSES Severity Sepsis Score had an excellent prediction for mortality. A score above 5.5 was the best predictor of mortality having a sensitivity of 89.2 %, a specificity of 83.5 % and a positive likelihood ratio of 5.4. CONCLUSIONS: WSES Sepsis Severity Score for patients with complicated Intra-abdominal infections can be used on global level. It has shown high sensitivity, specificity, and likelihood ratio that may help us in making clinical decisions.

Severe sepsis is a major cause of morbidity and mortality, claiming between 36 000 and 64 000 lives annually in the UK, with a mortality rate of 35%. International guidelines for the management of severe sepsis were published in 2004 by the Surviving Sepsis Campaign and condensed into two Care Bundles. In 2010, the Campaign published results from its improvement programme showing that, although an absolute mortality reduction of 5.4% was seen over a 2 year period in line with increasing compliance with the Bundles, reliability was not achieved and Bundle compliance reached only 31%. This article explores current challenges in sepsis care and opportunities for further improvements. Basic care tasks [microbiological sampling and antibiotic delivery within 1 h, fluid resuscitation, and risk stratification using serum lactate (or alternative)] are likely to benefit patients most, yet are unreliably performed. Barriers include lack of awareness and robust process, the lack of supporting controlled trials, and complex diagnostic criteria leading to recognition delays. Reliable, timely delivery of more complex life-saving tasks (such as early goal-directed therapy) demands greater awareness, faster recognition and initiation of basic care, and more effective collaboration between clinicians and nurses on the front line, in critical care and in specialist support services, such as microbiology and infectious diseases. Organizations such as Survive Sepsis, the Surviving Sepsis Campaign and the Global Sepsis Alliance are working to raise awareness and promote further improvement initiatives. Future developments will focus on sepsis biomarkers and microarray techniques to rapidly screen for pathogens, risk stratification using genetic profiling, and the development of novel therapeutic agents targeting immunomodulation.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

BACKGROUND: The variability of peak expiratory flow (PEF) is now commonly used in the diagnosis and management of asthma. It is essential for PEF meters to have a linear response in order to obtain an unbiased measurement of PEF variability. As the accuracy and linearity of portable PEF meters have not been rigorously tested in recent years this aspect of their performance has been investigated. METHODS: The response of several portable PEF meters was tested with absolute standards of flow generated by a computer driven, servo controlled pump and their response was compared with that of a pneumotachograph. RESULTS: For each device tested the readings were highly repeatable to within the limits of accuracy with which the pointer position can be assessed by eye. The between instrument variation in reading for six identical devices expressed as a 95% confidence limit was, on average across the range of flows, +/- 8.5 l/min for the Mini-Wright, +/- 7.9 l/min for the Vitalograph, and +/- 6.4 l/min for the Ferraris. PEF meters based on the Wright meter all had similar error profiles with overreading of up to 80 l/min in the mid flow range from 300 to 500 l/min. This overreading was greatest for the Mini-Wright and Ferraris devices, and less so for the original Wright and Vitalograph meters. A Micro-Medical Turbine meter was accurate up to 400 l/min and then began to underread by up to 60 l/min at 720 l/min. For the low range devices the Vitalograph device was accurate to within 10 l/min up to 200 l/min, with the Mini-Wright overreading by up to 30 l/min above 150 l/min. CONCLUSION: Although the Mini-Wright, Ferraris, and Vitalograph meters gave remarkably repeatable results their error profiles for the full range meters will lead to important errors in recording PEF variability. This may lead to incorrect diagnosis and bias in implementing strategies of asthma treatment based on PEF measurement.

AIM: To determine whether myocardial scarring, quantified using late gadolinium enhancement-cardiovascular magnetic resonance (LGE-CMR), predicts response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: A total of 45 patients with ischaemic cardiomyopathy [age 67.1 +/- 10.4 years (mean +/- SD)] underwent assessment of 6 min walking distance (6MWD) and quality of life (QoL) before and after CRT. Scar size (percentage of left ventricular mass), location, and transmurality were assessed prior to CRT using LGE-CMR. Responders (survived for 1 year with no heart failure hospitalizations, and improvement by >or=1 NYHA classes or >or=25% 6MWD) had a higher left ventricular ejection fraction (P = 0.048), smaller scars (<33%) (P = 0.009), and fewer scars with >or=51% transmurality (P = 0.002). Scar size correlated negatively with change in 6MWD (r = -0.54, P < 0.001) and positively with changes in QoL scores (r = 0.35, P = 0.028). Responder rates in patients with <33% scar were higher than in those with >or=33% scar (82 vs. 35%, P < 0.01). Responder rates in patients with scar transmurality <51% were higher than in those with >or=51% (89 vs. 46%, P < 0.01). Among the patients with posterolateral scars, a transmurality value of >or=51% was associated with a particularly poor response rate (23%), compared with scars with <51% transmurality (88%, P < 0.001). In multivariate analyses, both scar size (P = 0.022) and transmurality (P = 0.004) emerged as predictors of response. In patients with posterolateral scars, pacing outside the scar was associated with a better responder rate than pacing over the scar (86 vs. 33%, P = 0.004). CONCLUSIONS: In patients with ischaemic cardiomyopathy, a scar size >or=33%, a transmurality >or=51%, and pacing over a posterolateral scar are associated with a suboptimal response to CRT.

INTRODUCTION: Sexual dysfunction, particularly erectile dysfunction (ED), is common in men with type 2 diabetes, occurring in up to 75% of cases. The prevalence of hypogonadism is also high in men with diabetes and low testosterone is associated with both sexual dysfunction and a reduced response to oral therapy for ED. AIM: This study aimed to determine the effect of testosterone replacement with long-acting Testosterone Undecanoate (TU) on sexual function, mood and quality of life vs. placebo over a treatment period of 30 weeks followed by 52 weeks of open-label medication. The study was conducted in a primary care population of men with type 2 diabetes attending their primary care physician for routine visits. METHODS: The male diabetic populations of seven general practices were screened at routine diabetes visits to detect symptomatic men with total testosterone levels of 12 nmol/L or less or with free testosterones of 250 pmol/L or less. Two hundred eleven men were screened. A double-blind placebo-controlled study was conducted in 199 men with type 2 diabetes and hypogonadism treated for 30 weeks with either 1,000 mg of TU or matching placebo followed by 52-week open-label follow on. MAIN OUTCOME MEASURES: The primary outcome measure, International Index of Erectile Function (IIEF), was used to evaluate sexual dysfunction, and the Ageing Male Symptom (AMS), Hospital Anxiety and Depression Scale, and Global Efficacy Question were used as secondary outcome measures to assess mood and self-reported quality of life. RESULTS: Testosterone replacement therapy with long-acting TU improved all domains of sexual function at 30 weeks (erectile function [EF], P = 0.005; intercourse satisfaction, P = 0.015; sexual desire, P = 0.001; overall satisfaction, P = 0.05; and orgasm, P = 0.04), with benefit as early as 6 weeks. Improvements in AMS score were significant in men without depression (P = 0.02) and the presence of depression at baseline was associated with marked reduction in response to both sexual function and psychological scores. All responses in sexual function continued to improve significantly up to 18 months with an improvement in EF score of 4.31 from baseline. In a small cohort of 35 men taking phosphodiesterase type 5 inhibitors, there was no change during the double-blind phase but a nine-point improvement in EF domain during 52-week open-label treatment. After 30 weeks, 46% vs. 17% of patients on active therapy vs. placebo felt that the treatment had improved their health, reaching 70% after open-label therapy. Less obese and older patients responded better to testosterone therapy. There were no significant adverse events. CONCLUSION: TU significantly improved all domains of the IIEF and patient reported quality of life at 30 weeks and more significantly after 52-week open-label extension. Improvement was most marked in less obese patient and those without coexisting depression. In men with type 2 diabetes, trials of therapy may need to be given for much longer than 3-6 months suggested in current guidelines.

Prognosis and appropriate treatment goals for older adults with diabetes vary greatly according to frailty. It is now recognised that changes may be needed to diabetes management in some older people. Whilst there is clear guidance on the evaluation of frailty and subsequent target setting for people living with frailty, there remains a lack of formal guidance for healthcare professionals in how to achieve these targets. The management of older adults with type 2 diabetes is complicated by comorbidities, shortened life expectancy and exaggerated consequences of adverse effects from treatment. In particular, older adults are more prone to hypoglycaemia and are more vulnerable to its consequences, including falls, fractures, hospitalisation, cardiovascular events and all-cause mortality. Thus, assessment of frailty should be a routine component of a diabetes review for all older adults, and glycaemic targets and therapeutic choices should be modified accordingly. Evidence suggests that over-treatment of older adults with type 2 diabetes is common, with many having had their regimens intensified over preceding years when they were in better health, or during more recent acute hospital admissions when their blood glucose levels might have been atypically high, and nutritional intake may vary. In addition, assistance in taking medications, as often occurs in later life following implementation of community care strategies or admittance to a care home, may dramatically improve treatment adherence, leading to a fall in glycated haemoglobin (HbA1c) levels. As a person with diabetes gets older, simplification, switching or de-escalation of the therapeutic regimen may be necessary, depending on their level of frailty and HbA1c levels. Consideration should be given, in particular, to de-escalation of therapies that may induce hypoglycaemia, such as sulphonylureas and shorter-acting insulins. We discuss the use of available glucose-lowering therapies in older adults and recommend simple glycaemic management algorithms according to their level of frailty.

INTRODUCTION: The association between testosterone deficiency and insulin resistance in men with type 2 diabetes is well established and current endocrine society guidelines recommend the measurement of testosterone levels in all men with type 2 diabetes or erectile dysfunction. AIM: We report the first double-blind, placebo-controlled study conducted exclusively in a male type 2 diabetes population to assess metabolic changes with long-acting testosterone undecanoate (TU). METHODS: The type 2 diabetes registers of seven general practices identified 211 patients for a 30-week double-blind, placebo-controlled study of long-acting TU 1,000 mg followed by 52 weeks of open-label use. Because of the established impact of age, obesity, and depression on sexual function, these variables were also assessed for influence on metabolic parameters. MAIN OUTCOME MEASURE: Changes in glycated hemoglobin (HbA1c) and the level of testosterone at which response are achieved. RESULTS: Treatment with TU produced a statistically significant reduction in HbA1c at 6 and 18 weeks and after a further 52 weeks of open-label medication most marked in poorly controlled patients with baseline HbA1c greater than 7.5 where the reduction was 0.41% within 6 weeks, and a further 0.46% after 52 weeks of open-label use. There was significant reduction in waist circumference, weight, and body mass index in men without depression, and improvements were related to achieving adequate serum levels of testosterone. There were no significant safety issues. CONCLUSIONS: Testosterone replacement therapy significantly improved HbA1c, total cholesterol, and waist circumference in men with type 2 diabetes. Improvements were less marked in men with depression at baseline, and therapeutic responses were related to achieving adequate serum testosterone levels. Current advice on 3- to 6-month trials of therapy may be insufficient to achieve maximal response. Patients reported significant improvements in general health.

OBJECTIVE: To evaluate, in a phase II study, the efficacy and safety of a topical eutectic mixture for premature ejaculation (TEMPE), a metered-dose aerosol spray containing a eutectic mixture of lidocaine and prilocaine, as a treatment for PE. PATIENTS AND METHODS: Men with PE (Diagnostic and Statistical Manual-IV definition) aged 18-75 years were randomized into a double-blind, placebo-controlled study in the UK and the Netherlands. Efficacy variables included the mean change in intravaginal ejaculatory latency time (IELT) from baseline and the proportion of patients who achieved an IELT of > or = 4, > or = 3 or > or = 2 min on two occasions, and the effect of TEMPE on the index of ejaculatory control (IEC) and sexual quality-of-life (SQoL) scores of patients and their partners. Safety and adverse event data were also collected. Fifty-four patients were randomized and received study treatment. RESULTS: The observed mean change in IELT from baseline to the end of the treatment period was 3.8 min in the TEMPE group and 0.7 min in the placebo group, and when adjusted for baseline and centre was 2.4 times higher in the TEMPE than the placebo group (P < 0.01). The efficacy of TEMPE in increasing IELT was further supported by positive trends in the other efficacy endpoints. The proportion of men who had an IELT time > or = 2, > or = 3 or > or = 4 min on two occasions after treatment was 11/20 (55%), 8/20 (40%) and 5/25 (20%) in the TEMPE group, and 8/23 (35%), 3/23 (13%) and 3/23 (13%) in the placebo group, respectively, although these differences were not statistically significant. Improvements in IEC and SQoL (male and female) scores also showed trends towards greater efficacy for TEMPE than placebo. In all, 35 of 42 (83%) patients considered the spray easy to use. Mild to moderate local numbness occurred in three (12%) of the TEMPE-treated patients but did not lead to discontinuation. CONCLUSION: Topical treatment with TEMPE produced a statistically and clinically significant increase in IELT compared with placebo, and resulted in positive trends in ejaculatory control and SQoL. TEMPE was considered easy to use and was well tolerated. The data support the conduct of further large-scale studies to establish the utility of TEMPE as a first-line treatment for PE.