Royal Derby Hospital

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

BACKGROUND: Sentinel lymph node biopsy in women with operable breast cancer is routinely used in some countries for staging the axilla despite limited data from randomized trials on morbidity and mortality outcomes. We conducted a multicenter randomized trial to compare quality-of-life outcomes between patients with clinically node-negative invasive breast cancer who received sentinel lymph node biopsy and patients who received standard axillary treatment. METHODS: The primary outcome measures were arm and shoulder morbidity and quality of life. From November 1999 to October 2003, 1031 patients were randomly assigned to undergo sentinel lymph node biopsy (n = 515) or standard axillary surgery (n = 516). Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy (depending on the protocol at the treating institution). Intention-to-treat analyses of data at 1, 3, 6, and 12 months after surgery are presented. All statistical tests were two-sided. RESULTS: The relative risks of any lymphedema and sensory loss for the sentinel lymph node biopsy group compared with the standard axillary treatment group at 12 months were 0.37 (95% confidence interval [CI] = 0.23 to 0.60; absolute rates: 5% versus 13%) and 0.37 (95% CI = 0.27 to 0.50; absolute rates: 11% versus 31%), respectively. Drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly lower in the sentinel lymph node biopsy group (all P < .001), and axillary operative time was reduced (P = .055). Overall patient-recorded quality of life and arm functioning scores were statistically significantly better in the sentinel lymph node biopsy group throughout (all P < or = .003). These benefits were seen with no increase in anxiety levels in the sentinel lymph node biopsy group (P > .05). CONCLUSION: Sentinel lymph node biopsy is associated with reduced arm morbidity and better quality of life than standard axillary treatment and should be the treatment of choice for patients who have early-stage breast cancer with clinically negative nodes.

The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. The publication of 'Quality Care: service standards for the healthcare of people with IBD' in 2009. The introduction of the Montreal classification for Crohn's disease and ulcerative colitis. The revision of recommendations for the use of immunosuppressive therapy. The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohn's disease and ulcerative colitis. The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. The availablity of new data on the role of reconstructive surgery in ulcerative colitis. The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohn's and Colitis Organisation (ECCO) https://www.ecco-ibd.eu/index.php (accessed Oct 2010).

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.

BACKGROUND: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. METHODS: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. FINDINGS: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS. INTERPRETATION: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. FUNDING: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

BACKGROUND: Iron deficiency anaemia (IDA) occurs in 2-5% of adult men and postmenopausal women in the developed world and is a common cause of referral to gastroenterologists. Gastrointestinal (GI) blood loss from colonic cancer or gastric cancer, and malabsorption in coeliac disease are the most important causes that need to be sought. DEFINING IRON DEFICIENCY ANAEMIA: The lower limit of the normal range for the laboratory performing the test should be used to define anaemia (B). Any level of anaemia should be investigated in the presence of iron deficiency (B). The lower the haemoglobin the more likely there is to be serious underlying pathology and the more urgent is the need for investigation (B). Red cell indices provide a sensitive indication of iron deficiency in the absence of chronic disease or haemoglobinopathy (A). Haemoglobin electrophoresis is recommended when microcytosis and hypochromia are present in patients of appropriate ethnic background to prevent unnecessary GI investigation (C). Serum ferritin is the most powerful test for iron deficiency (A). INVESTIGATIONS: Upper and lower GI investigations should be considered in all postmenopausal female and all male patients where IDA has been confirmed unless there is a history of significant overt non-GI blood loss (A). All patients should be screened for coeliac disease (B). If oesophagogastroduodenoscopy (OGD) is performed as the initial GI investigation, only the presence of advanced gastric cancer or coeliac disease should deter lower GI investigation (B). In patients aged >50 or with marked anaemia or a significant family history of colorectal carcinoma, lower GI investigation should still be considered even if coeliac disease is found (B). Colonoscopy has advantages over CT colography for investigation of the lower GI tract in IDA, but either is acceptable (B). Either is preferable to barium enema, which is useful if they are not available. Further direct visualisation of the small bowel is not necessary unless there are symptoms suggestive of small bowel disease, or if the haemoglobin cannot be restored or maintained with iron therapy (B). In patients with recurrent IDA and normal OGD and colonoscopy results, Helicobacter pylori should be eradicated if present. (C). Faecal occult blood testing is of no benefit in the investigation of IDA (B). All premenopausal women with IDA should be screened for coeliac disease, but other upper and lower GI investigation should be reserved for those aged 50 years or older, those with symptoms suggesting gastrointestinal disease, and those with a strong family history of colorectal cancer (B). Upper and lower GI investigation of IDA in post-gastrectomy patients is recommended in those over 50 years of age (B). In patients with iron deficiency without anaemia, endoscopic investigation rarely detects malignancy. Such investigation should be considered in patients aged >50 after discussing the risk and potential benefit with them (C). Only postmenopausal women and men aged >50 years should have GI investigation of iron deficiency without anaemia (C). Rectal examination is seldom contributory, and, in the absence of symptoms such as rectal bleeding and tenesmus, may be postponed until colonoscopy. Urine testing for blood is important in the examination of patients with IDA (B). MANAGEMENT: All patients should have iron supplementation both to correct anaemia and replenish body stores (B). Parenteral iron can be used when oral preparations are not tolerated (C). Blood transfusions should be reserved for patients with or at risk of cardiovascular instability due to the degree of their anaemia (C).

BACKGROUND: The social rank theory of psychopathology suggests that with the evolution of social hierarchies various psychobiological mechanisms became attuned to the success or failure in conflict situations. Specifically, subordinates and those who have lost status are at greater risk of pathology than winners and those of higher status. In this theory concepts of defeat and entrapment are seen to be of special relevance to the study of depression. We outline the role of defeat and entrapment within the social rank theory of depression. METHODS: New self-report measures of entrapment and defeat were developed and used to test predictions of the social rank theory of depression. Both a sample of students and depressed patients were assessed with these new scales and other social rank measures (e.g. social comparison and submissive behaviour). RESULTS: The entrapment and defeat measures were found to have good psychometric properties and significantly correlated with depression. They were also strongly associated with other rank variables. Defeat maintained a strong association with depression even after controlling for hopelessness (r = 0.62), whereas the relationship between hopelessness and depression was substantially reduced when controlling for defeat. Entrapment and defeat added substantially to the explained variance of depression after controlling for the other social rank variables. CONCLUSIONS: Defeat and entrapment appear to be promising variables for the study of depression. These variables may also help to develop linkages between human and animal models of psychopathology.

OBJECTIVES: There is increasing evidence that helping people develop compassion for themselves and others has powerful impacts on negative affect and promotes positive affect. However, clinical observations suggest that some individuals, particularly those high in self-criticism, can find self-compassion and receiving compassion difficult and can be fearful of it. This study therefore developed measures of fear of: compassion for others, compassion from others, and compassion for self. We also explored the relationship of these fears with established compassion for self and compassion for others measures, self-criticism, attachment styles, and depression, anxiety, and stress. METHOD: Students (N= 222) and therapists (N= 53) completed measures of fears of compassion, self-compassion, compassion for others, self-criticism, adult attachment, and psychopathology. RESULTS: Fear of compassion for self was linked to fear of compassion from others, and both were associated with self-coldness, self-criticism, insecure attachment, and depression, anxiety, and stress. In a multiple regression, self-criticism was the only significant predictor of depression. CONCLUSION: This study suggests the importance of exploring how and why some people may actively resist engaging in compassionate experiences or behaviours and be fearful of affiliative emotions in general. This has important implications for therapeutic interventions and the therapeutic relationship because affiliative emotions are major regulators of threat-based emotions.

OBJECTIVES: Self-critical people, compared with those who self-reassure, are at increased risk of psychopathology. However, there has been little work on the different forms and functions of these self-experiences. This study developed two self-report scales to measure forms and functions of self-criticism and self-reassurance and explore their relationship to depression. METHODS: A self-report scale measuring forms of self-criticism and self-reassuring, and a scale measuring possible functions of self-criticism, together with a measure of depression and another self-criticism scale (LOSC), were given to 246 female students. RESULTS: Self-criticizing vs. self-reassuring separated into two components. Forms of self-criticizing separated into two components related to: being self-critical, dwelling on mistakes and sense of inadequacy; and a second component of wanting to hurt the self and feeling self-disgust/hate. The reasons/functions for self-criticism separated into two components. One was related to desires to try to self-improve (called self-improving/correction), and the other to take revenge on, harm or hurt the self for failures (called self-harming/persecuting). Mediation analysis suggested that wanting to harm the self may be particularly pathogenic and is positively mediated by the effects of hating the self and negatively mediated by being able to self-reassure and focus on one's positives. CONCLUSIONS: Self-criticism is not a single process but has different forms, functions, and underpinning emotions. This indicates a need for more detailed research into the variations of self-criticism and the mechanisms for developing self-reassurance.

BACKGROUND: Ovarian cancer has a high case-fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. METHODS: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50-74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032. FINDINGS: In the prevalence screen, 50 078 (98.9%) women underwent MMS, and 48 230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1894 (3.9%) women in the USS group required clinical evaluation. 97 of 50 078 (0.2%) women from the MMS group and 845 of 48 230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0-61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers. INTERPRETATION: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.

BACKGROUND: The optimal management of patients found to have multivessel disease while undergoing primary percutaneous coronary intervention (P-PCI) for ST-segment elevation myocardial infarction is uncertain. OBJECTIVES: CvLPRIT (Complete versus Lesion-only Primary PCI trial) is a U.K. open-label randomized study comparing complete revascularization at index admission with treatment of the infarct-related artery (IRA) only. METHODS: After they provided verbal assent and underwent coronary angiography, 296 patients in 7 U.K. centers were randomized through an interactive voice-response program to either in-hospital complete revascularization (n = 150) or IRA-only revascularization (n = 146). Complete revascularization was performed either at the time of P-PCI or before hospital discharge. Randomization was stratified by infarct location (anterior/nonanterior) and symptom onset (≤ 3 h or >3 h). The primary endpoint was a composite of all-cause death, recurrent myocardial infarction (MI), heart failure, and ischemia-driven revascularization within 12 months. RESULTS: Patient groups were well matched for baseline clinical characteristics. The primary endpoint occurred in 10.0% of the complete revascularization group versus 21.2% in the IRA-only revascularization group (hazard ratio: 0.45; 95% confidence interval: 0.24 to 0.84; p = 0.009). A trend toward benefit was seen early after complete revascularization (p = 0.055 at 30 days). Although there was no significant reduction in death or MI, a nonsignificant reduction in all primary endpoint components was seen. There was no reduction in ischemic burden on myocardial perfusion scintigraphy or in the safety endpoints of major bleeding, contrast-induced nephropathy, or stroke between the groups. CONCLUSIONS: In patients presenting for P-PCI with multivessel disease, index admission complete revascularization significantly lowered the rate of the composite primary endpoint at 12 months compared with treating only the IRA. In such patients, inpatient total revascularization may be considered, but larger clinical trials are required to confirm this result and specifically address whether this strategy is associated with improved survival.

Biopsy material taken from the brain of a patient with CreutzfeldtJakob disease with status spongiosus induced a similar fatal encephalopathy in a chimpanzee 13 months after inoculation.

BACKGROUND: Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS: We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS: A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS: Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

Insulin resistance (IR) in skeletal muscle is a key defect mediating the link between obesity and type 2 diabetes, a disease that typically affects people in later life. Sarcopenia (age-related loss of muscle mass and quality) is a risk factor for a number of frailty-related conditions that occur in the elderly. In addition, a syndrome of 'sarcopenic obesity' (SO) is now increasingly recognised, which is common in older people and is applied to individuals that simultaneously show obesity, IR and sarcopenia. Such individuals are at an increased risk of adverse health events compared with those who are obese or sarcopenic alone. However, there are no licenced treatments for sarcopenia or SO, the syndrome is poorly defined clinically and the mechanisms that might explain a common aetiology are not yet well characterised. In this review, we detail the nature and extent of the clinical syndrome, highlight some of the key physiological processes that are dysregulated and discuss some candidate molecular pathways that could be implicated in both metabolic and anabolic defects in skeletal muscle, with an eye towards future therapeutic options. In particular, the potential roles of Akt/mammalian target of rapamycin signalling, AMP-activated protein kinase, myostatin, urocortins and vitamin D are discussed.

We investigated how myofibrillar protein synthesis (MPS) and muscle anabolic signalling were affected by resistance exercise at 20-90% of 1 repetition maximum (1 RM) in two groups (25 each) of post-absorptive, healthy, young (24 +/- 6 years) and old (70 +/- 5 years) men with identical body mass indices (24 +/- 2 kg m(-2)). We hypothesized that, in response to exercise, anabolic signalling molecule phosphorylation and MPS would be modified in a dose-dependant fashion, but to a lesser extent in older men. Vastus lateralis muscle was sampled before, immediately after, and 1, 2 and 4 h post-exercise. MPS was measured by incorporation of [1,2-(13)C] leucine (gas chromatography-combustion-mass spectrometry using plasma [1,2-(13)C]alpha-ketoisocaparoate as surrogate precursor); the phosphorylation of p70 ribosomal S6 kinase (p70s6K) and eukaryotic initiation factor 4E binding protein 1 (4EBP1) was measured using Western analysis with anti-phosphoantibodies. In each group, there was a sigmoidal dose-response relationship between MPS at 1-2 h post-exercise and exercise intensity, which was blunted (P < 0.05) in the older men. At all intensities, MPS fell in both groups to near-basal values by 2-4 h post-exercise. The phosphorylation of p70s6K and 4EBP1 at 60-90% 1 RM was blunted in older men. At 1 h post-exercise at 60-90% 1 RM, p70s6K phosphorylation predicted the rate of MPS at 1-2 h post-exercise in the young but not in the old. The results suggest that in the post-absorptive state: (i) MPS is dose dependant on intensity rising to a plateau at 60-90% 1 RM; (ii) older men show anabolic resistance of signalling and MPS to resistance exercise.

Diabetic nephropathy (DN) is a major healthcare challenge. It occurs in up to 50% of those living with diabetes, is a major cause of end-stage kidney disease (ESKD) that requires treatment with dialysis or renal transplantation, and is associated with significantly increased cardiovascular morbidity and mortality. DN is a clinical syndrome characterized by persistent albuminuria and a progressive decline in renal function, but it is increasingly recognized that the presentation and clinical course of kidney disease in diabetes is heterogeneous. The term diabetic kidney disease (DKD) is now commonly used to encompass the spectrum of people with diabetes who have either albuminuria or reductions in renal function. In this article, the clinical presentation and approach to diagnosis of DKD will be discussed, as will its prognosis. The general principles of management of DKD will also be reviewed with reference to current international guidelines.

Diabetes was first recognized 3500 years ago by the Ancient Egyptians. One of the first clinical descriptions was by Aretaeus, who practised in Cappadocia around 120 AD. He wrote that the condition was ‘fortunately rare’, but ‘short will be the life of the man in whom the disease is fully developed’ [ 1]. In modern society, the first statement is far from true. The incidence of diabetes has doubled every 20 years since 1945 [ 2]. In 1994 the world wide prevalence of type 2 (non-insulin dependent) diabetes was 99 million (1.8% of the population); by 2010 it is estimated that this figure will rise to 215 million (3.8%) [ 3]. The second statement is as true today as it was almost 2000 years ago. In the West, 44% of patients with type 2 diabetes die within 10 years of diagnosis [ 4], mostly from macrovascular disease; the incidence of and mortality from cardiovascular disease are 2–3 times greater than in the general population [ 5]. As the majority of patients develop complications, which are present in up to 50% even at the time of diagnosis [ 6], type 2 diabetes imposes a significant burden on health services, as well as on the individuals who suffer from this progressive and incurable disease. Currently the 2% of the UK population with diabetes consume 5% of the health service budget; by comparison the 12% with arthritis consume just 1.9% [ 7]. With the increasing prevalence of the condition, these figures will escalate. Prevention would be the ideal solution, but is currently a remote prospect. In the meantime any way of significantly reducing the burden of diabetes-related complications will have a major impact on patient well-being and on cost effectiveness of management. Until the early 1990s, there was no evidence that our management of diabetes had any beneficial impact on the incidence of vascular complications. On the contrary, the pioneering study of the 1960s, the University Group Diabetes Program (UGDP) [ 8], suggested that treatment with tolbutamide might be harmful. The study was designed to assess the impact of blood glucose lowering therapies on complications, with patients being randomly allocated to placebo, tolbutamide, phenformin, or insulin. The study was stopped after 8 years because of an increase in cardiovascular deaths in those receiving tolbutamide. However, for many years the design and conduct of the UGDP were subject to fierce debate which was never satisfactorily resolved; uncertainty continued about treatment and glycaemic targets for type 2 diabetes. The Diabetes Control and Complications Trial (DCCT), published in 1993 [ 9], showed that intensive glycaemic control (i.e. keeping blood glucose as near to normal as possible) reduces the incidence and progression of microvascular complications (retinopathy, nephropathy and neuropathy) in type 1 diabetes. Whether the same holds true in type 2 diabetes remained uncertain. Intensive treatment often results in hyperinsulinaemia, with weight gain and an increase in hypoglycaemia [ 9], both of which have theoretical adverse effects on macrovascular disease, the major life threatening complication of type 2 diabetes. Patients with type 2 diabetes frequently have other risk factors for macrovascular disease, such as hypertension and hyperlipidaemia, the former having a prevalence of 40%-60% [ 10, 11]. Antihypertensive therapy reduces the risk of both cardiovascular and cerebrovascular disease in the general population [ 12], but to what extent these findings apply to type 2 diabetes was again not clear. The United Kingdom Prospective Diabetes Study (UKPDS) was conceived to explore these uncertainties and provide clearer guidelines for the management of type 2 diabetes. UKPDS–the principal questions. UKPDS–embedded studies. Design of UKPDS. The UKPDS was set up in the late 1970s, by Dr Robert Turner and colleagues in Oxford. Over 7600 subjects at 23 centres across the UK were considered for inclusion; 5102 took part. It was the largest and longest study ever undertaken in diabetes; median follow-up was 10 years. As well as attempting to resolve unanswered clinical issues, the study generated a huge epidemiological database, comprising over 20 million data items. The primary aim was to determine the effect of intensive glycaemic control on the incidence of complications; the secondary aim was to assess whether there were differences between treatments (Figure 1). Protocol amendments were made to add topics not originally included. These strengthened the study by broadening its scope, but at the cost of complicating the treatment allocation, conduct and analysis of the study. Numerous substudies were embedded (Figure 2), the most notable being the Hypertension in Diabetes Study. Over 30 papers have been published from the UKPDS database, and many more are in preparation or planned. Key points. Subjects were randomized to receive ‘conventional’ or ‘intensive’ therapy. In the former, the intention was to keep patients aymptomatic, with a fasting plasma glucose less than 15 mmol l−1; in the latter, the target fasting glucose was 6 mmol l−1. When diet failed to achieve these targets, subjects were randomized to sulphonylureas, insulin or metformin, the latter in obese patients only. When single treatments failed, combinations were used. The results were primarily expressed in terms of aggregate end points: ‘any diabetes related end point’, which included both microvascular and macrovascular events, and ‘diabetes related death’. Twenty-one single end points were also defined. The emphasis on aggregate end-points allowed the study outcomes to be presented in a clinically meaningful way, i.e. overall risk. Their use also reduced the number of treatment comparisons, thus minimizing the chances of false-positive results, but had the disadvantage of concealing the magnitude of effects on individual end points. Intensive glucose control significantly reduced any diabetes-related end point, but had no effect on mortality. The predominant effect of tighter control was a reduction of microvascular disease by a quarter, largely due to a reduction in laser photocoagulation. There was also a trend, just short of statistical significance, towards a reduction in macrovascular disease. No threshold was seen, i.e. any improvement in glycaemic control is beneficial. These findings are similar to those of the DCCT and a more recent study in Japanese patients with type 2 diabetes, in whom 6 years’ intensive therapy with insulin reduced the incidence of microvascular complications [ 15]. That the reduced occurrence of myocardial infarction was not significant may be due to type 2 statistical error. The study was set up to detect a 15% difference in events over the 10 years’ study period, and a larger number of macrovascular than microvascular events occurred, but the separation of HbA1c between intensive and conventionally treated groups was disappointingly low: 0.9% (half that in the DCCT). Had the separation of HbA1c between groups been greater, a significant effect of intensive control on macrovascular disease might have been demonstrated. The secondary aim of the study was to compare the effects of different treatments for diabetes, since some have theoretical advantages and disadvantages. For example, sulphonylureas close myocardial ATP-sensitive potassium channels, which could impair ischaemia induced vasodilatation [ 16], perhaps explaining the results of the UGDP. In addition, some studies have suggested that hyperinsulinaemic states are atherogenic [ 17], and the increased incidence of hypoglycaemia with intensive control with insulin could theoretically precipitate a cerebrovascular or cardiovascular event. The UKPDS showed no difference in outcome between treatments, which is at first sight reassuring, but the study was powered to assess the effects of intensive therapy in general and it is unclear whether there is adequate power in this subgroup analysis. In addition, actual therapy often differed from allocated treatment, especially as patients required additional treatment over time. The results of this aspect of the study should therefore be interpreted with caution. The results of metformin treatment are the most controversial [ 14]. Metformin use was associated with fewer aggregate end-points (including overall mortality) in obese patients. However the number of patients allocated to metformin was less than 10% of all those randomised. The findings could also be interpreted as indicating that insulin and sulphonylureas are equally harmful in the obese, possibly as a consequence of hyperinsulinaemia. An unexpected finding was that the addition of metformin to sulphonylureas (in both obese and nonobese patients) was associated with increased mortality. The numbers involved in this subgroup analysis were very small, with few deaths (26 vs 14 in the group treated with sulphonylureas alone) and no difference in the incidence of heart attacks or strokes between the groups, only in the proportion who died. Furthermore, the mortality in the group treated by sulphonylureas alone was unexpectedly low. The authors therefore concluded that this anomalous result was likely to be have been due to chance. One thousand one hundred and forty-eight patients took part. Half the participants were allocated to ‘tight control’ (target blood pressure less than 150/85 mm Hg) and were randomised to either atenolol or captopril, with other agents added as necessary. The remainder were allocated to ‘less tight control’ (target blood pressure less than 180/105 mm Hg); in these patients, drugs other than β-adrenoceptor blockers and ACE inhibitors were used. Mean blood pressure was 144/82 mm Hg in the tight control group, compared with 154/87 mm Hg in the less tight control group. One-third of patients allocated to tight control required three more drugs in the attempt to achieve the target blood pressure. Tight control of blood pressure reduced both diabetes-related morbidity and mortality. Unlike glycaemic control, there was a significant effect on macrovascular as well as microvascular complications, with strokes and heart failure reduced by a half. Myocardial infarction was reduced by a fifth, but this was not statistically significant. As in the glucose control study, no threshold for risk was seen in the hypertension study. These are very impressive results, establishing that blood pressure control is at least as important as glycaemic control, if not more so, in the prevention of complications in type 2 diabetes. In the last 2 years, the results of several other studies of hypertension which have included patients with diabetes have been published. These also demonstrated a reduction in macrovascular risk, including myocardial infarction [ 20, 21]. A variety of agents was used, but blood pressure differences between treatment and control groups were comparable with the UKPDS, and protective effects were observed despite shorter periods of follow up (2–5 years). Thus there is no doubt of the significance of blood pressure control in type 2 diabetes, but there remains the question whether particular drugs have advantages or disadvantages. The UKPDS compared captopril and atenolol, both drugs having theoretical benefits. In the general population with hypertension, β-adrenoceptor blockers reduce macrovascular events and are specifically cardioprotective, reducing sudden death and further myocardial events in those with prior myocardial infarction[ 22]. ACE inhibitors improve survival in patients with heart failure [ 23, 24]; in type 1 diabetes, they reduce the progression of nephropathy [ 25, 26] and possibly retinopathy [ 27], but whether ACE inhibitors have specific advantages over other antihypertensive agents in type 2 diabetes is not yet agreed. Recently the ABCD trial showed a reduction in myocardial infarction in diabetic hypertensive subjects treated with an ACE inhibitor compared with a calcium channel blocker [ 28], but it was not clear whether the ACE inhibitor was especially beneficial or the calcium channel blocker relatively harmful, particularly as the groups were inadequately matched for concomitant medication. The UKPDS found that captopril and atenolol were equally effective as antihypertensive agents, in preventing macrovascular complications and in reducing the progression of retinopathy and albuminuria. The ACE inhibitor was however, better tolerated. These results are again reassuring at first sight, but, as with the glucose control study, type 2 errors cannot be excluded; there was a trend in favour of the atenolol treated group. Limitations of the study. Outstanding questions. Therapeutic implications. The UKPDS demonstrated that any improvement in glycaemic control and blood pressure reduces diabetes-related complications. In trials such as this, patients are selected both by investigators and by themselves. The observation that UKPDS patients had a lower mortality than the general population with type 2 diabetes may be a reflection of this. What was achievable and acceptable to a trial population cannot be necessarily translated to everyone with type 2 diabetes. This must be remembered when applying the results of the study to clinical practice. There is no doubt that aggressive management of blood pressure is important, particularly in reducing macrovascular disease, the main cause of morbidity and mortality in these patients. A target blood pressure of less than 140/80 is suggested by the authors. The fact that benefits are achieved within 2 or 3 years means that all patients should be treated irrespective of age. Clearly, achieving this goal will require aggressive follow up (patients in the UKPDS were seen 3 monthly), and this may not be acceptable to all patients. With one third requiring 3 or more agents to maintain target blood pressures, compliance will certainly be a problem in some. Whether intensive glycaemic control should be routinely introduced in type 2 diabetes is more controversial. Despite achieving statistical significance, the absolute risk reduction from intensive glycaemic control is small, with a reduction of 5 events over 10 years compared with 16 for blood pressure (Table 1). Furthermore, the benefits of glucose reduction did not accrue for several years, unlike intensive blood pressure control. Intensive glycaemic control, particularly with insulin, also leads to morbidity from hypoglycaemia and weight gain. Thus, unlike blood pressure control, intensive glycaemic control is not suitable for all patients, particularly the elderly, or those with existing severe complications. The small absolute risk reduction also needs to be compared with the possible effects of other risk factor interventions, e.g. treatment with aspirin, lipid lowering drugs or antioxidants. Despite these limitations, the UKPDS provides evidence and quantitative guidelines for those in whom intensive control is achievable. The study also assessed effects of intensive treatment on quality of life; no adverse effect was apparent. One scale demonstrated that poor quality of life is related to complications rather than the treatments given [unpublished]. This is reassuring in implementing the results of the study, though the results may not apply equally to an unselected population. One aspect of management inadequately addressed by the study is the optimal combination of drugs to be used either for glucose or blood pressure control. Different agents seemed equally effective, but the possibility of type 2 errors in these subgroup analyses cannot be excluded, as already discussed. To date, the effectiveness of insulin and oral hypoglycaemic agent combinations is not known, although there are unpublished data from the study on the combination of insulin and sulphonylureas. Data on possible dose-dependent effects of insulin, and the combination of insulin and metformin are lacking. For now, until further information is available, clinical practice should be based on achieving glucose and blood pressure reduction by whatever means best suits an individual patient. In the study, patients were reviewed 3 monthly, rather than 6–12 monthly as in routine clinical practice, which has considerable resource implications. The reduction in blood pressure [ 29] and glucose [unpublished] achieved were relatively cheap, £48 and £22 per patient per year, respectively, when the benefits were discounted. These figures are valuable ammunition in the battle to improve services for patients. With 50% of patients presenting with complications, the issue of screening should also be addressed. The UKPDS provides management guidelines for selected patients, but leaves many questions unanswered. The advantages of good care have been more clearly defined than ever before, but the huge gulf between the benefits achieved in the study and the many frustrations of everyday practice remains. In most centres, there are large numbers of patients with poor control of both blood glucose and blood pressure. Type 2 diabetes must at least be taken more seriously.

BACKGROUND AND OBJECTIVES: Hemodialysis (HD)-induced myocardial stunning driven by ischemia is a recognized complication of HD, which can be ameliorated by HD techniques that improve hemodynamics. In nondialysis patients, repeated ischemia leads to chronic reduction in left ventricular (LV) function. HD may initiate and drive the same process. In this study, we examined the prevalence and associations of HD-induced repetitive myocardial injury and long-term effects on LV function and patient outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Seventy prevalent HD patients were assessed for evidence of subclinical myocardial injury at baseline using serial echocardiography and followed up after 12 mo. Intradialytic blood pressure, hematologic and biochemical samples, and patient demographics were also collected at both time points. RESULTS: Sixty-four percent of patients had significant myocardial stunning during HD. Age, ultrafiltration volumes, intradialytic hypotension, and cardiac troponin-T (cTnT) levels were independent determinants associated with its presence. Myocardial stunning was associated with increased relative mortality at 12 mo (P = 0.019). Cox regression analysis showed increased hazard of death in patients with myocardial stunning and elevated cTnT than in patients with elevated cTnT alone (P < 0.02). Patients with myocardial stunning who survived 12 mo had significantly lower LV ejection fractions at rest and on HD (P < 0.001). CONCLUSIONS: HD-induced myocardial stunning is common, and may contribute to the development of heart failure and increased mortality in HD patients. Enhanced understanding of dialysis-induced cardiac injury may provide novel therapeutic targets to reduce currently excessive rates of cardiovascular morbidity and mortality.

The coronavirus pandemic (COVID-19) will undoubtedly have psychological impacts for healthcare workers, which could be sustained; frontline workers will be particularly at risk. Actions are needed to mitigate the impacts of COVID-19 on mental health by protecting and promoting the psychological wellbeing of healthcare workers during and after the outbreak. We developed and evaluated a digital learning package using Agile methodology within the first three weeks of UK outbreak. This e-package includes evidence-based guidance, support and signposting relating to psychological wellbeing for all UK healthcare employees. A three-step rapid development process included public involvement activities (PPIs) (STEP 1), content and technical development with iterative peer review (STEP 2), and delivery and evaluation (STEP 3). The package outlines the actions that team leaders can take to provide psychologically safe spaces for staff, together with guidance on communication and reducing social stigma, peer and family support, signposting others through psychological first aid (PFA), self-care strategies (e.g., rest, work breaks, sleep, shift work, fatigue, healthy lifestyle behaviours), and managing emotions (e.g., moral injury, coping, guilt, grief, fear, anxiety, depression, preventing burnout and psychological trauma). The e-package includes advice from experts in mental wellbeing as well as those with direct pandemic experiences from the frontline, as well as signposting to public mental health guidance. Rapid delivery in STEP 3 was achieved via direct emails through professional networks and social media. Evaluation included assessment of fidelity and implementation qualities. Essential content was identified through PPIs (n = 97) and peer review (n = 10) in STEPS 1 and 2. The most important messages to convey were deemed to be normalisation of psychological responses during a crisis, and encouragement of self-care and help-seeking behaviour. Within 7 days of completion, the package had been accessed 17,633 times, and healthcare providers had confirmed immediate adoption within their health and wellbeing provisions. Evaluation (STEP 3, n = 55) indicated high user satisfaction with content, usability and utility. Assessment of implementation qualities indicated that the package was perceived to be usable, practical, low cost and low burden. Our digital support package on ‘psychological wellbeing for healthcare workers’ is free to use, has been positively evaluated and was highly accessed within one week of release. It is available here: Supplementary Materials. This package was deemed to be appropriate, meaningful and useful for the needs of UK healthcare workers. We recommend provision of this e-package to healthcare workers alongside wider strategies to support their psychological wellbeing during and after the COVID-19 pandemic.