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Inhibition of the PARP superfamily tankyrase enzymes suppresses Wnt/β-catenin signalling in tumour cells. Here, we describe here a novel, drug-like small molecule inhibitor of tankyrase MSC2504877 that inhibits the growth of APC mutant colorectal tumour cells. Parallel siRNA and drug sensitivity screens showed that the clinical CDK4/6 inhibitor palbociclib, causes enhanced sensitivity to MSC2504877. This tankyrase inhibitor-CDK4/6 inhibitor combinatorial effect is not limited to palbociclib and MSC2504877 and is elicited with other CDK4/6 inhibitors and toolbox tankyrase inhibitors. The addition of MSC2504877 to palbociclib enhances G 1 cell cycle arrest and cellular senescence in tumour cells. MSC2504877 exposure suppresses the upregulation of Cyclin D2 and Cyclin E2 caused by palbociclib and enhances the suppression of phospho-Rb, providing a mechanistic explanation for these effects. The combination of MSC2504877 and palbociclib was also effective in suppressing the cellular hyperproliferative phenotype seen in Apc defective intestinal stem cells in vivo . However, the presence of an oncogenic Kras p.G12D mutation in mice reversed the effects of the MSC2504877/palbociclib combination, suggesting one molecular route that could lead to drug resistance.

The application of ozone to drinking water was examined using bench-scale and pilot-scale systems over a range of operating conditions. The effects of pH, temperature, and reactor configuration on disinfection by-product formation and Bacillus subtilis spore inactivation were investigated and assessed as to their statistical significance. Temperature and pH were shown to significantly effect bromate formation, while reactor configuration did not have a significant impact. The parameters examined (pH, temperature, reactor configuration) had varying effects on aldehyde and carboxylic acid formation. Bacillus subtilis inactivation was shown to be significantly impacted by temperature and reactor configuration, while pH effects were not significant. In addition, observed Bacillus subtilis inactivation results were compared to published Cryptosporidium inactivation data. Results suggest that Bacillus subtilis may have the potential to serve as an indicator organism and thereby aid in assessment of adequate Cryptosporidium inactivation.

BackgroundVeterans Health Administration (VHA) is committed to providing high-quality care and addressing health disparities for vulnerable Veterans. To meet these goals, VA policymakers need guidance on how to address social determinants in operations planning and day-to-day clinical care for Veterans.MethodMEDLINE (OVID), CINAHL, PsycINFO, and Sociological Abstracts were searched from inception to January 2017. Additional articles were suggested by peer reviewers and/or found through search of work associated with US and VA cohorts. Eligible articles compared Veterans vs non-Veterans, and/or Veterans engaged with those not engaged in VA healthcare. Our evidence maps summarized study characteristics, social determinant(s) addressed, and whether health behaviors, health services utilization, and/or health outcomes were examined. Qualitative syntheses and quality assessment were performed for articles on rurality, trauma exposure, and sexual orientation.ResultsWe screened 7242 citations and found 131 eligible articles—99 compared Veterans vs non-Veterans, and 40 included engaged vs non-engaged Veterans. Most articles were cross-sectional and addressed socioeconomic factors (e.g., education and income). Fewer articles addressed rurality (N = 20), trauma exposure (N = 17), or sexual orientation (N = 2); none examined gender identity. We found no differences in rural residence between Veterans and non-Veterans, nor between engaged and non-engaged Veterans (moderate strength evidence). There was insufficient evidence for role of rurality in health behaviors, health services utilization, or health outcomes. Trauma exposures, including from events preceding military service, were more prevalent for Veterans vs non-Veterans and for engaged vs non-engaged Veterans (low-strength evidence); exposures were associated with smoking (low-strength evidence).DiscussionLittle published literature exists on some emerging social determinants. We found no differences in rural residence between our groups of interest, but trauma exposure was higher in Veterans (vs non-Veterans) and engaged (vs non-engaged). We recommend consistent measures for social determinants, clear conceptual frameworks, and analytic strategies that account for the complex relationships between social determinants and health.

Major organ complications have been reported in patients hospitalised for COVID-19; most studies lacked controls.BACKGROUNDMajor organ complications have been reported in patients hospitalised for COVID-19; most studies lacked controls.Examine major organ damage postdischarge among adults hospitalised for COVID-19 versus non-COVID-19 controls.OBJECTIVEExamine major organ damage postdischarge among adults hospitalised for COVID-19 versus non-COVID-19 controls.MEDLINE, Embase and Cochrane Library from 1 January 2020 to 19 May 2021.DATA SOURCESMEDLINE, Embase and Cochrane Library from 1 January 2020 to 19 May 2021.English language studies of adults discharged from hospital for COVID-19; reporting major organ damage. Single review of abstracts; independent dual review of full text.STUDY ELIGIBILITY CRITERIAEnglish language studies of adults discharged from hospital for COVID-19; reporting major organ damage. Single review of abstracts; independent dual review of full text.Study quality was assessed using the Joanna Briggs Institute Appraisal Checklist for Cohort Studies. Outcome data were not pooled due to heterogeneity in populations, study designs and outcome assessment methods; findings are narratively synthesised.STUDY APPRAISAL AND SYNTHESIS METHODSStudy quality was assessed using the Joanna Briggs Institute Appraisal Checklist for Cohort Studies. Outcome data were not pooled due to heterogeneity in populations, study designs and outcome assessment methods; findings are narratively synthesised.Of 124 studies in a full evidence report, 9 included non-COVID controls and are described here. Four of the nine (three USA, one UK) used large administrative databases. Four of the remaining five studies enrolled <600 COVID-19 patients. Mean or median age ranged from 49 to 70 years with 46%-94% male and 48%-78% White race; 10%-40% had been in intensive care units. Follow-up ranged from 4 weeks to 22 weeks postdischarge. Four used hospitalised controls, three non-hospitalised controls and two were unclear. Studies used various definitions of, and methods to assess, major organ damage outcomes. While the magnitude of effect differed across studies, incident cardiac, pulmonary, liver, acute and chronic kidney, stroke, diabetes, and coagulation disorders were consistently greater in adults hospitalised for COVID-19 compared with non-COVID-19 controls.RESULTSOf 124 studies in a full evidence report, 9 included non-COVID controls and are described here. Four of the nine (three USA, one UK) used large administrative databases. Four of the remaining five studies enrolled <600 COVID-19 patients. Mean or median age ranged from 49 to 70 years with 46%-94% male and 48%-78% White race; 10%-40% had been in intensive care units. Follow-up ranged from 4 weeks to 22 weeks postdischarge. Four used hospitalised controls, three non-hospitalised controls and two were unclear. Studies used various definitions of, and methods to assess, major organ damage outcomes. While the magnitude of effect differed across studies, incident cardiac, pulmonary, liver, acute and chronic kidney, stroke, diabetes, and coagulation disorders were consistently greater in adults hospitalised for COVID-19 compared with non-COVID-19 controls.Applicability to subgroups (age, gender, COVID-19 severity, treatment, vaccination status) and non-hospitalised patients is unknown.LIMITATIONSApplicability to subgroups (age, gender, COVID-19 severity, treatment, vaccination status) and non-hospitalised patients is unknown.Postacute COVID-19 major organ damage is common and likely higher than controls. However, there is substantial uncertainty. More consistent reporting of clinical outcomes and pre-COVID health status along with careful selection of control groups are needed to address evidence gaps.CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGSPostacute COVID-19 major organ damage is common and likely higher than controls. However, there is substantial uncertainty. More consistent reporting of clinical outcomes and pre-COVID health status along with careful selection of control groups are needed to address evidence gaps.CRD42020204788.PROSPERO REGISTRATION NUMBERCRD42020204788.

Since 2020, the SHOT-SWITCH research project has monitored the proportion of wild-shot common pheasants Phasianus colchicus in Great Britain that were killed using lead and non-lead shot. This was set up in response to UK shooting and rural organisations’ announcement that game shooters should make a full voluntary transition from lead to non-lead shotgun ammunition by 2025 and initiatives by retailers and wholesalers of game meat products. In the study’s fifth and final season (2024/2025), 99% of pheasants obtained from businesses other than Waitrose & Partners had been killed using lead ammunition. There has only been a slight, non-significant downward trend in the proportion of pheasants killed using lead shot over the five-year transition period. Although some food retailers have stated their intention to cease selling game meat products from animals killed using lead ammunition, our study indicates that these initiatives have made limited progress so far. It appears that voluntary efforts to encourage shooters to switch from lead to non-lead shotgun ammunition for game shooting have been unsuccessful and have been diminishing as the deadline for complete transition approached.

Background The prevalence of severe and complex obesity is increasing worldwide and surgery may offer an effective and lasting treatment. Laparoscopic adjustable gastric band and Roux-en-Y gastric bypass surgery are the two main surgical procedures performed. Design This open parallel-group randomised controlled trial will compare the effectiveness, cost-effectiveness and acceptability of gastric band (Band) versus gastric bypass (Bypass) in adults with severe and complex obesity. It has an internal pilot phase (in two centres) with integrated qualitative research to establish effective and optimal methods for recruitment. Adults with a body mass index (BMI) of 40 kg/m 2 or more, or a BMI of 35 kg/m 2 or more and other co-morbidities will be recruited. At the end of the internal pilot the study will expand into more centres if the pre-set progression criteria of numbers and rates of eligible patients screened and randomised are met and if the expected rates of retention and adherence to treatment allocation are achieved. The trial will test the joint hypotheses that Bypass is non-inferior to Band with respect to more than 50% excess weight loss and that Bypass is superior to Band with respect to health related quality of life (HRQOL, EQ-5D) at three years. Secondary outcomes include other weight loss measures, waist circumference and remission/resolution of co-morbidities; generic and symptom-specific HRQOL; nutritional blood test results; resource use; eating behaviours and adverse events. A core outcome set for reporting the results of obesity surgery will be developed and a systematic review of the evidence for sleeve gastrectomy undertaken to inform the main study design. Discussion By-Band is the first pragmatic study to compare the two most commonly performed bariatric surgical procedures for severe and complex obesity. The design will enable and empower surgeons to learn to recruit and participate in a randomised study. Early evidence shows that timely recruitment is possible. Trial registration Current Controlled Trials ISRCTN00786323 .

In 2020, UK shooting and rural organisations pledged to achieve a voluntary transition from the use of lead shotgun ammunition to non-lead alternatives for hunting by 2025. The SHOT-SWITCH research project was set up in 2020 to monitor progress towards this aim by examining the proportions of wild-shot common pheasants Phasianus colchicus available to consumers in Great Britain that were killed using lead and non-lead shot. In the study’s third season, 2022/2023, 94% of pheasants sampled had been killed using lead ammunition. Statistically, this is a significantly smaller proportion than in the preceding two seasons (both > 99% lead), but it remains large. We found no direct evidence of any effect of recent voluntary initiatives to promote the replacement of lead with non-lead ammunition by suppliers and retailers of wild-shot game.

The 2023/2024 shooting season was the fourth since UK shooting and rural organisations announced their intention that hunters should make a full voluntary transition from the use of lead to non-lead shotgun ammunition by 2025. The SHOT-SWITCH research project has monitored the proportions of wild-shot common pheasants Phasianus colchicus available to consumers in Great Britain that were killed using lead and non-lead shot in each of the shooting seasons since the beginning of the transition. In the study’s fourth season, 2023/2024, 93% of pheasants obtained during the usual sampling period had been killed using lead ammunition. Whilst this indicates a marginal decline in the proportion of pheasants shot using lead since the beginning of the transition, when it was over 99%, much remains to be done if the intended full voluntary transition to non-lead shotgun ammunition is to be achieved in its final season (2024/2025). Some food retailers intend to cease selling game meat products from animals killed using lead ammunition. Our study indicates that whilst all of a small sample of pheasant carcasses obtained from one of these retailers (Marks & Spencer) were from birds killed using non-lead shot, a larger sample obtained from another of the retailers (Waitrose) had mostly been killed using lead shot.