CHOICE: Choosing Health Options In Chronic Care Emergencies

Background Over 70% of the health-care budget in England is spent on the care of people with long-term conditions (LTCs), and a major cost component is unscheduled health care. Psychological morbidity is high in people with LTCs and is associated with a range of adverse outcomes, including increased mortality, poorer physical health outcomes, increased health costs and service utilisation. Objectives The aim of this programme of research was to examine the relationship between psychological morbidity and use of unscheduled care in people with LTCs, and to develop a psychosocial intervention that would have the potential to reduce unscheduled care use. We focused largely on emergency hospital admissions (EHAs) and attendances at emergency departments (EDs). Design A three-phase mixed-methods study. Research methods included systematic reviews; a longitudinal prospective cohort study in primary care to identify people with LTCs at risk of EHA or ED admission; a replication study in primary care using routinely collected data; an exploratory and feasibility cluster randomised controlled trial in primary care; and qualitative studies to identify personal reasons for the use of unscheduled care and factors in routine consultations in primary care that may influence health-care use. People with lived experience of LTCs worked closely with the research team. Setting Primary care. Manchester and London. Participants People aged ≥ 18 years with at least one of four common LTCs: asthma, coronary heart disease, chronic obstructive pulmonary disease (COPD) and diabetes. Participants also included health-care staff. Results Evidence synthesis suggested that depression, but not anxiety, is a predictor of use of unscheduled care in patients with LTCs, and low-intensity complex interventions reduce unscheduled care use in people with asthma and COPD. The results of the prospective study were that depression, not having a partner and life stressors, in addition to prior use of unscheduled care, severity of illness and multimorbidity, were independent predictors of EHA and ED admission. Approximately half of the cost of health care for people with LTCs was accounted for by use of unscheduled care. The results of the replication study, carried out in London, broadly supported our findings for risk of ED attendances, but not EHAs. This was most likely due to low rates of detection of depression in general practitioner (GP) data sets. Qualitative work showed that patients were reluctant to use unscheduled care, deciding to do so when they perceived a serious and urgent need for care, and following previous experience that unscheduled care had successfully and unquestioningly met similar needs in the past. In general, emergency and primary care doctors did not regard unscheduled care as problematic. We found there are missed opportunities to identify and discuss psychosocial issues during routine consultations in primary care due to the ‘overmechanisation’ of routine health-care reviews. The feasibility trial examined two levels of an intervention for people with COPD: we tried to improve the way in which practices manage patients with COPD and developed a targeted psychosocial treatment for patients at risk of using unscheduled care. The former had low acceptability, whereas the latter had high acceptability. Exploratory health economic analyses suggested that the practice-level intervention would be unlikely to be cost-effective, limiting the value of detailed health economic modelling. Limitations The findings of this programme may not apply to all people with LTCs. It was conducted in an area of high social deprivation, which may limit the generalisability to more affluent areas. The response rate to the prospective longitudinal study was low. The feasibility trial focused solely on people with COPD. Conclusions Prior use of unscheduled care is the most powerful predictor of unscheduled care use in people with LTCs. However, psychosocial factors, particularly depression, are important additional predictors of use of unscheduled care in patients with LTCs, independent of severity and multimorbidity. Patients and health-care practitioners are unaware that psychosocial factors influence health-care use, and such factors are rarely acknowledged or addressed in consultations or discussions about use of unscheduled care. A targeted patient intervention for people with LTCs and comorbid depression has shown high levels of acceptability when delivered in a primary care context. An intervention at the level of the GP practice showed little evidence of acceptability or cost-effectiveness. Future work The potential benefits of case-finding for depression in patients with LTCs in primary care need to be evaluated, in addition to further evaluation of the targeted patient intervention

Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial: study protocol for a multicentre international trial of cardiac output-guided fluid therapy with low-dose inotrope infusion compared with usual care in patients undergoing major elective gastrointestinal surgery.

INTRODUCTION: Postoperative morbidity and mortality in older patients with comorbidities undergoing gastrointestinal surgery are a major burden on healthcare systems. Infections after surgery are common in such patients, prolonging hospitalisation and reducing postoperative short-term and long-term survival. Optimal management of perioperative intravenous fluids and inotropic drugs may reduce infection rates and improve outcomes from surgery. Previous small trials of cardiac-output-guided haemodynamic therapy algorithms suggested a modest reduction in postoperative morbidity. A large definitive trial is needed to confirm or refute this and inform widespread clinical practice. METHODS: The Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial is a multicentre, international, parallel group, open, randomised controlled trial. 2502 high-risk patients undergoing major elective gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intravenous fluid combined with low-dose inotrope infusion, or usual care. The trial intervention will be carried out during and for 4 hours after surgery. The primary outcome is postoperative infection of Clavien-Dindo grade II or higher within 30 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation; however, outcome assessors will be blinded when feasible. Participant recruitment started in January 2017 and is scheduled to last 3 years, within 50 hospitals worldwide. ETHICS/DISSEMINATION: The OPTIMISE II trial has been approved by the UK National Research Ethics Service and has been approved by responsible ethics committees in all participating countries. The findings will be disseminated through publication in a widely accessible peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: ISRCTN39653756.The OPTIMISE II trial is supported by Edwards Lifesciences (Irvine, CA) and the UK National Institute for Health Research through RMP’s NIHR Professorship

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Integrated disease management interventions for patients with chronic obstructive pulmonary disease

Contains fulltext : 125984.pdf (publisher's version ) (Open Access)BACKGROUND: In people with chronic obstructive pulmonary disease (COPD) there is considerable variation in symptoms, limitations and well-being, which often complicates medical care. To improve quality of life (QoL) and exercise tolerance, while reducing the number of exacerbations, a multidisciplinary program including different elements of care is needed. OBJECTIVES: To evaluate the effects of integrated disease management (IDM) programs or interventions in people with COPD on health-related QoL, exercise tolerance and number of exacerbations. SEARCH METHODS: We searched the Cochrane Airways Group Register of trials, CENTRAL, MEDLINE, EMBASE and CINAHL for potentially eligible studies (last searched 12 April 2012). SELECTION CRITERIA: Randomized controlled trials evaluating IDM programs for COPD compared with controls were included. Included interventions consisted of multidisciplinary (two or more health care providers) and multi-treatment (two or more components) IDM programs with a duration of at least three months. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data; if required, we contacted authors for additional data. We performed meta-analyses using random-effects modeling. We carried out sensitivity analysis for allocation concealment, blinding of outcome assessment, study design and intention-to-treat analysis. MAIN RESULTS: A total of 26 trials involving 2997 people were included, with a follow-up ranging from 3 to 24 months. Studies were conducted in 11 different countries. The mean age of the included participants was 68 years, 68% were male and the mean forced expiratory volume in one second (FEV1)% predicted value was 44.3% (range 28% to 66%). Participants were treated in all types of healthcare settings: primary (n = 8), secondary (n = 12), tertiary care (n = 1), and in both primary and secondary care (n = 5). Overall, the studies were of high to moderate methodological quality.Compared with controls, IDM showed a statistically and clinically significant improvement in disease-specific QoL on all domains of the Chronic Respiratory Questionnaire after 12 months: dyspnea (mean difference (MD) 1.02; 95% confidence interval (CI) 0.67 to 1.36); fatigue (MD 0.82; 95% CI 0.46 to 1.17); emotional (MD 0.61; 95% CI 0.26 to 0.95) and mastery (MD 0.75; 95% CI 0.38 to 1.12). The St. George's Respiratory Questionnaire (SGRQ) for QoL reached the clinically relevant difference of four units only for the impact domain (MD -4.04; 95% CI -5.96 to -2.11, P < 0.0001). IDM showed a significantly improved disease-specific QoL on the activity domain of the SGRQ: MD -2.70 (95% CI -4.84 to -0.55, P = 0.01). There was no significant difference on the symptom domain of the SGRQ: MD -2.39 (95% CI -5.31 to 0.53, P = 0.11). According to the GRADE approach, quality of evidence on the SGRQ was scored as high quality, and on the CRQ as moderate quality evidence. Participants treated with an IDM program had a clinically relevant improvement in six-minute walking distance of 43.86 meters compared with controls after 12 months (95% CI 21.83 to 65.89; P < 0.001, moderate quality). There was a reduction in the number of participants with one or more hospital admissions over three to 12 months from 27 per 100 participants in the control group to 20 (95% CI 15 to 27) per 100 participants in the IDM group (OR 0.68; 95% CI 0.47 to 0.99, P = 0.04; number needed to treat = 15). Hospitalization days were significantly lower in the IDM group compared with controls after 12 months (MD -3.78 days; 95% CI -5.90 to -1.67, P < 0.001). Admissions and hospital days were graded as high quality evidence. No adverse effects were reported in the intervention group. No difference between groups was found on mortality (OR 0.96; 95%CI 0.52 to 1.74). There was insufficient evidence to refute or confirm the long term effectiveness of IDM. AUTHORS' CONCLUSIONS: In these COPD participants, IDM not only improved disease-specific QoL and exercise capacity, but also reduced hospital admissions and hospital days per person

Improving the accuracy of recombinant protein production through integration of bioinformatics, statistical and mass spectrometry methodologies

Heterologous protein production is a key technology for biotechnological, health sciences and many other research fields. Various approaches have been developed for its optimization, but the research emphasis has been on optimization of protein yield rather than protein quality. In this study, we have established a workflow for synthetic gene optimization for heterologous protein expression that combines bioinformatics, laboratory experiments, mass spectrometry and statistical analysis. Two gene primary structure analysis platforms, Anaconda and EuGene, and multivariate optimization methods were employed to re-design the Plasmodium falciparum lysyl-tRNA synthetase gene for optimal expression in Escherichia coli. Synthetic genes were expressed from common vectors, and amino acid mis-incorporations in the expressed proteins were detected and quantified using mass spectrometry. The association between the identified amino acid mis-incorporations and 23 gene variables was then analysed. The synthetic genes yielded significantly higher levels of protein relative to the wild-type gene, but 71 amino acid mis-incorporation sites were observed along the whole protein and across the synthetic genes that were statistically associated with specific codons and protein secondary structures. The optimization method that led to production of the most accurate protein was based on a multivariate approach that combined variables that are known to influence mRNA translation.publishe