Developing a complex intervention to improve prescribing safety in primary care:mixed methods feasibility and optimisation pilot study

Objectives (A) To measure the extent to which different candidate outcome measures identified high-risk prescribing that is potentially changeable by the data-driven quality improvement in primary care (DQIP) intervention.(B) To explore the value of reviewing identified high-risk prescribing to clinicians.(C) To optimise the components of the DQIP intervention.  Design Mixed method study.  Setting General practices in two Scottish Health boards.  Participants 4 purposively sampled general practices of varying size and socioeconomic deprivation.  Outcome measures Prescribing measures targeting (1) high-risk use of the non-steroidal anti-inflammatory drugs (NSAIDs) and antiplatelets; (2) ‘Asthma control’ and (3) ‘Antithrombotics in atrial fibrillation (AF)’.  Intervention The prescribing measures were used to identify patients for review by general practices. The ability of the measures to identify potentially changeable high-risk prescribing was measured as the proportion of patients reviewed where practices identified a need for action. Field notes were recorded from meetings between researchers and staff and key staff participated in semistructured interviews exploring their experience of the piloted intervention processes.  Results Practices identified a need for action in 68%, 25% and 18% of patients reviewed for prescribing measures (1), (2) and (3), respectively. General practitioners valued being prompted to review patients, and perceived that (1) ‘NSAID and antiplatelet’ and (2) ‘antithrombotics in AF’ were the most important to act on. Barriers to initial and ongoing engagement and to sustaining improvements in prescribing were identified.  Conclusions ‘NSAIDs and antiplatelets’ measures were selected as the most suitable outcome measures for the DQIP trial, based on evidence of this prescribing being more easily changeable. In response to the barriers identified, the intervention was designed to include a financial incentive, additional ongoing feedback on progress and reprompting review of patients, whose high-risk prescribing was restarted after a decision to stop.  Trial registration number Clinicaltrials.govNCT01425502

Pharmacist and Data-driven Quality Improvement in Primary Care (P-DQIP):A qualitative study of anticipated implementation factors informed by the Theoretical Domains Framework

Objectives: The quality and safety of drug therapy in primary care are global concerns. The Pharmacist and Data driven Quality Improvement in Primary care (P-DQIP) intervention aims to improve prescribing safety via an informatics tool which facilitates proactive management of drug therapy risks (DTRs) by health-board employed pharmacists with established roles in general practices. Study objectives were (1) to identify and prioritise factors that could influence P-DQIP implementation from the perspective of practice pharmacists, and (2) to identify potentially effective, acceptable and feasible strategies to support P-DQIP implementation. Design: Semi-structured face-to-face interviews using a Theoretical Domains Framework (TDF) informed topic guide. The framework method was used for data analysis. Identified implementation factors were prioritised for intervention based on research team consensus. Candidate intervention functions, behaviour change techniques (BCTs) and policies targeting these were identified from the Behaviour Change Wheel. The final intervention content and modes of delivery were agreed with local senior pharmacists. Setting: General practices from three Health and Social Care Partnerships (HSCPs) in NHS Tayside. Participants: 14 NHS employed practice pharmacists. Results: Identified implementation factors were linked to thirteen theoretical domains (all except intentions) and six (skill, memory/attention/decision-making, behavioural regulation, reinforcement, environmental context/resources, social influences) were prioritised. Three intervention functions (training, enablement, and environmental restructuring) were relevant and were served by two policy categories (guidelines, communication/marketing) and eight BCTs (Instructions on how to perform a behaviour, problem solving, action planning, prompt/cues, goal setting, self-monitoring, feedback, restructuring the social environment). Intervention components encompass an informatics tool, written educational material, a workshop for pharmacists, promotional activities, and small financial incentives. Conclusions: This study explored pharmacists’ perceptions of implementation factors which could influence management of DTRs in general practices to inform implementation of P-DQIP, which will initially be implemented in one Scottish health board with parallel evaluation of effectiveness and implementation

Systematic review of exercise and the long-term outcomes of the treatment for obesity.

We systematically reviewed randomised controlled trials (RCTs) of obesity treatments in adults and assessed long term effects on weight and risk factors for disease

How Much Rugby is Too Much? A Seven-Season Prospective Cohort Study of Match Exposure and Injury Risk in Professional Rugby Union Players.

INTRODUCTION: Numerous studies have documented the incidence and nature of injuries in professional rugby union, but few have identified specific risk factors for injury in this population using appropriate statistical methods. In particular, little is known about the role of previous short-term or longer-term match exposures in current injury risk in this setting. OBJECTIVES: Our objective was to investigate the influence that match exposure has upon injury risk in rugby union. METHOD: We conducted a seven-season (2006/7-2012/13) prospective cohort study of time-loss injuries in 1253 English premiership professional players. Players' 12-month match exposure (number of matches a player was involved in for ≥20 min in the preceding 12 months) and 1-month match exposure (number of full-game equivalent [FGE] matches in preceding 30 days) were assessed as risk factors for injury using a nested frailty model and magnitude-based inferences. RESULTS: The 12-month match exposure was associated with injury risk in a non-linear fashion; players who had been involved in fewer than ≈15 or more than ≈35 matches over the preceding 12-month period were more susceptible to injury. Monthly match exposure was linearly associated with injury risk (hazard ratio [HR]: 1.14 per 2 standard deviation [3.2 FGE] increase, 90% confidence interval [CI] 1.08-1.20; likely harmful), although this effect was substantially attenuated for players in the upper quartile for 12-month match exposures (>28 matches). CONCLUSION: A player's accumulated (12-month) and recent (1-month) match exposure substantially influences their current injury risk. Careful attention should be paid to planning the workloads and monitoring the responses of players involved in: (1) a high (>≈35) number of matches in the previous year, (2) a low (<≈15) number of matches in the previous year, and (3) a low-moderate number of matches in previous year but who have played intensively in the recent past. These findings make a major contribution to evidence-based policy decisions regarding match workload limits in professional rugby union

Exploration of Victoria Crater by the Mars Rover Opportunity

The Mars rover Opportunity has explored Victoria crater, a ~750-meter eroded impact crater formed in sulfate-rich sedimentary rocks. Impact-related stratigraphy is preserved in the crater walls, and meteoritic debris is present near the crater rim. The size of hematite-rich concretions decreases up-section, documenting variation in the intensity of groundwater processes. Layering in the crater walls preserves evidence of ancient wind-blown dunes. Compositional variations with depth mimic those ~6 kilometers to the north and demonstrate that water-induced alteration at Meridiani Planum was regional in scope.Organismic and Evolutionary Biolog

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field