A randomised controlled trial investigating the effect of an intensive lifestyle intervention v. standard care in adults with type 2 diabetes immediately after initiating insulin therapy

Obesity and type 2 diabetes are inextricably linked. It is therefore unfortunate that insulin, the ultimate treatment to improve glycaemic control in type 2 diabetes, is associated with significant weight gain. The aim of the present investigation was to ascertain whether a dietitian-led intensive lifestyle intervention could attenuate weight gain associated with commencing insulin therapy. Subjects (n 50) with type 2 diabetes, within 4 weeks of starting insulin therapy, were randomly allocated to a control or intervention group. The control group continued with standard care whilst the intervention group followed a dietitian-led intensive lifestyle intervention. Over 6 months the control group gained 4.9 (sd 3.6) kg (P < 0.001), whilst the intervention group maintained their weight (-0.6 (sd 5.1) kg (NS). The difference in weight change between the groups was 5.5 kg (P < 0.001). The control group had significant increases whilst the intervention group had slight decreases in: BMI (+1.7 (sd 1.3) kg/m (P < 0.001) v. -0.3 (sd 2.0) kg/m (NS)), waist circumference (+5.3 (sd 5.0) cm (P < 0.001) v. -0.4 (sd 5.2) cm (NS)) and percentage body fat (+1.5 (sd 2.0) % (P < 0.001) v. -0.4 (sd 2.8) % (NS)). Differences between the groups for these parameters were significant (P < 0.01). Throughout the study, both groups experienced significant reductions in HbA1c, but only minor changes in blood lipids. The present study demonstrates that weight gain is not an inevitable consequence of starting insulin therapy, but attenuation of the weight gain requires a high level of intervention. The first 6 months to 1 year after initiating insulin therapy provides the ideal 'window of opportunity'

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy

Background: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy.Patients and methods: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately.Results: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors.Conclusions: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.</p

Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma

Results The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P = 0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P = 0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P = 0.02). However, a specified efficacy-stopping boundary (two-sided P = 0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib- trametinib group. Conclusions A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.Background Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations.Methods In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted

Impact of coronavirus disease 2019 (COVID-19) outbreak on acute admissions at the emergency and cardiology departments across Europe

PURPOSE: We evaluated whether the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) pandemic was associated with changes in the pattern of acute cardiovascular admissions across European centers.METHODS: We set-up a multicenter, multinational, pan-European observational registry in 15 centers from 12 countries. All consecutive acute admissions to emergency departments and cardiology departments throughout a 1-month period during the COVID-19 outbreak were compared with an equivalent 1-month period in 2019. The acute admissions to cardiology departments were classified into 5 major categories: acute coronary syndrome, acute heart failure, arrhythmia, pulmonary embolism, and other.RESULTS: Data from 54,331 patients were collected and analyzed. Nine centers provided data on acute admissions to emergency departments comprising 50,384 patients: 20,226 in 2020 compared with 30,158 in 2019 (incidence rate ratio [IRR] with 95% confidence interval [95%CI]: 0.66 [0.58-0.76]). The risk of death at the emergency departments was higher in 2020 compared to 2019 (odds ratio [OR] with 95% CI: 4.1 [3.0-5.8], P < 0.0001). All 15 centers provided data on acute cardiology departments admissions: 3007 patients in 2020 and 4452 in 2019; IRR (95% CI): 0.68 (0.64-0.71). In 2020, there were fewer admissions with IRR (95% CI): acute coronary syndrome: 0.68 (0.63-0.73); acute heart failure: 0.65 (0.58-0.74); arrhythmia: 0.66 (0.60-0.72); and other: 0.68(0.62-0.76). We found a relatively higher percentage of pulmonary embolism admissions in 2020: odds ratio (95% CI): 1.5 (1.1-2.1), P = 0.02. Among patients with acute coronary syndrome, there were fewer admissions with unstable angina: 0.79 (0.66-0.94); non-ST segment elevation myocardial infarction: 0.56 (0.50-0.64); and ST-segment elevation myocardial infarction: 0.78 (0.68-0.89).CONCLUSION: In the European centers during the COVID-19 outbreak, there were fewer acute cardiovascular admissions. Also, fewer patients were admitted to the emergency departments with 4 times higher death risk at the emergency departments. (C) 2020 Published by Elsevier Inc.Cardiolog

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 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

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Protein/energy ratios of current diets in developed and developing countries compared with a safe protein/energy ratio: implications for recommended protein and amino acid intakes

Revised estimates of protein and amino acid requirements are under discussion by the Food and Agriculture Organization (FAO)/World Health Organization (WHO), and have been proposed in a recent report on Dietary Reference Intakes (DRIs) from the USA. The nature and magnitude of these requirements are not entirely resolved, and no consideration has been given to the potential influence of metabolic adaptation on dietary requirements. We have examined the implications of these new values, and of the conceptual metabolic framework in which they are used, for defining the nutritional adequacy of protein intakes in developed and developing countries. We have expressed proposed values for protein requirements in relation to energy requirements, predicted for physical activity levels of 1.5, 1.75 and 2.0 times basal metabolic rate, in order to generate reference ratios for protein energy/total energy (reference P/E ratio) as a function of age, body weight, gender and physical activity level. Proposed values for amino acid requirements have been used to adjust the available digestible P/E ratio of foods and diets for protein quality. Focusing on the diets of UK omnivores and vegetarians and on diets in India, the risk of protein deficiency is evaluated from a comparison of P/E ratios of metabolic requirements with protein-quality-adjusted P/E ratios of intakes. A qualitative and conservative estimate of risk of deficiency is made by comparing the adjusted P/E ratio of the intake with a reference P/E ratio calculated for age, body weight, gender and physical activity according to FAO/WHO/United Nations University. A semi-quantitative estimate of risk of deficiency has also been made by the cut point approach, calculated as the proportion of the intake distribution below the mean P/E ratio of the requirement. Values for the quality-adjusted P/E ratio of the diet range from 0.126 for the UK omnivore diet to 0.054 for a rice-based diet of adults in West Bengal, which is lysine-limited, falling to 0.050 for 1-year-old children. The reference P/E ratio for men and women increases with age, is higher for females than males, is higher for small compared with large adults at any age and decreases with physical activity. Thus if a particular diet is potentially limiting in protein, protein deficiency is most likely in large, elderly sedentary women followed by the adolescent female and least likely in moderately active young children, the opposite of what has usually been assumed. Within the currently accepted framework, the diets do not meet the protein needs of the entire population of the UK, have a significant risk of deficiency throughout India for all except extremely active small adults, and are grossly inadequate for all population groups, apart from physically active young children in West Bengal, regardless of body weight or level of food intake. The lysine limitation of the cereal-based Indian diets is dependent on the choice of lysine requirement values from the published range. We consider that the value selected is too high, because of uncertainties and inconsistencies in the approaches used. A more appropriate choice from the lower end of the range would remove the lysine limitation of cereal-based diets, and reduce some of the perceived risk of deficiency. However, diets remain limited by the amount of digestible protein for many population groups, especially in West Bengal. In the context of risk management, one option would be to accept the current values and the conceptual metabolic framework within which they have been derived. This would have major implications for the supplies of high-quality protein to the developing countries. An alternative option would be to re-evaluate the currently proposed values for the requirements for protein and amino acids. We conclude that the choice of values for the adult lysine requirement should be re-evaluated and that serious consideration should be given to the extent to which adaptive mechanisms might enable the metabolic requirement for protein to be met from current intakes. This will entail a better understanding of the relationships between dietary protein and health