The Rory Morrison WMUK Registry for Waldenström macroglobulinaemia: The growth of a national registry for a rare disorder.

National registries are used globally to characterise patient demographics, treatment choices and mortality to inform and improve clinical management. Waldenström macroglobulinaemia (WM) is a rare, treatment-responsive B-cell lymphoproliferative disorder with diverse clinical features and variable outcomes. To prospectively chart changes in the management of WM in the UK, the Rory Morrison Registry (RMR) was developed to systematically collect real-world data. Here we describe the development of the RMR, demonstrate its feasibility and describe preliminary observations. The RMR was devised as a collaborative project between patients and clinicians, under the auspices of the UK Charity for WM in 2016. Patients may be registered after the point of diagnosis and those with historic diagnosis were also eligible. Data collection fields were compiled by focus groups of clinicians, patients, industry and commissioning partners. The RMR launched in November 2017 and as of March 2022, there were 22 participating centres and 1305 patients registered. Median follow-up was 6.4 years, five-year overall survival 90.7% (95% confidence interval [CI] 88.4%-92.5%) and 10-year overall survival 79.3% (95% CI 75.7%-82.4%). There has been a clear evolution in treatments including a rapid growth in the use of Bruton's tyrosine kinase inhibitors in relapsed disease since their availability in the UK.

Predicting reactivity to drug metabolism: beyond P450s-modelling FMOs and UGTs.

We present a study based on density functional theory calculations to explore the rate limiting steps of product formation for oxidation by Flavin-containing Monooxygenase (FMO) and glucuronidation by the UDP-glucuronosyltransferase (UGT) family of enzymes. FMOs are responsible for the modification phase of metabolism of a wide diversity of drugs, working in conjunction with Cytochrome P450 (CYP) family of enzymes, and UGTs are the most important class of drug conjugation enzymes. Reactivity calculations are important for prediction of metabolism by CYPs and reactivity alone explains around 70-85% of the experimentally observed sites of metabolism within CYP substrates. In the current work we extend this approach to propose model systems which can be used to calculate the activation energies, i.e. reactivity, for the rate-limiting steps for both FMO oxidation and glucuronidation of potential sites of metabolism. These results are validated by comparison with the experimentally observed reaction rates and sites of metabolism, indicating that the presented models are suitable to provide the basis of a reactivity component within generalizable models to predict either FMO or UGT metabolism.

Bariatric surgery for patients with type 2 diabetes mellitus requiring insulin: Clinical outcome and cost-effectiveness analyses.

BACKGROUND: Although bariatric surgery is well established as an effective treatment for patients with obesity and type 2 diabetes mellitus (T2DM), there exists reluctance to increase its availability for patients with severe T2DM. The aims of this study were to examine the impact of bariatric surgery on T2DM resolution in patients with obesity and T2DM requiring insulin (T2DM-Ins) using data from a national database and to develop a health economic model to evaluate the cost-effectiveness of surgery in this cohort when compared to best medical treatment (BMT). METHODS AND FINDINGS: Clinical data from the National Bariatric Surgical Registry (NBSR), a comprehensive database of bariatric surgery in the United Kingdom, were extracted to analyse outcomes of patients with obesity and T2DM-Ins who underwent primary bariatric surgery between 2009 and 2017. Outcomes for this group were combined with data sourced from a comprehensive literature review in order to develop a state-transition microsimulation model to evaluate cost-effectiveness of bariatric surgery versus BMT for patients over a 5-year time horizon. The main outcome measure for the clinical study was insulin cessation at 1-year post-surgery: relative risks (RR) summarising predictive factors were determined, unadjusted, and after adjusting for variables including age, initial body mass index (BMI), duration of T2DM, and weight loss. Main outcome measures for the economic evaluation were total costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) at willingness-to-pay threshold of GBP£20,000. A total of 2,484 patients were eligible for inclusion, of which 1,847 had 1-year follow-up data (mean age of 51 years, mean initial BMI 47.2 kg/m2, and 64% female). 67% of patients no longer required insulin at 1-year postoperatively: these rates persisted for 4 years. Roux-en-Y gastric bypass (RYGB) was associated with a higher rate of insulin cessation (71.7%) than sleeve gastrectomy (SG; 64.5%; RR 0.92, confidence interval (CI) 0.86-0.99) and adjustable gastric band (AGB; 33.6%; RR 0.45, CI 0.34-0.60; p < 0.001). When adjusted for percentage total weight loss and demographic variables, insulin cessation following surgery was comparable for RYGB and SG (RR 0.97, CI 0.90-1.04), with AGB having the lowest cessation rates (RR 0.55, CI 0.40-0.74; p < 0.001). Over 5 years, bariatric surgery was cost saving compared to BMT (total cost GBP£22,057 versus GBP£26,286 respectively, incremental difference GBP£4,229). This was due to lower treatment costs as well as reduced diabetes-related complications costs and increased health benefits. Limitations of this study include loss to follow-up of patients within the NBSR dataset and that the time horizon for the economic analysis is limited to 5 years. In addition, the study reflects current medical and surgical treatment regimens for this cohort of patients, which may change. CONCLUSIONS: In this study, we observed that in patients with obesity and T2DM-Ins, bariatric surgery was associated with high rates of postoperative cessation of insulin therapy, which is, in turn, a major driver of overall reductions in direct healthcare cost. Our findings suggest that a strategy utilising bariatric surgery for patients with obesity and T2DM-Ins is cost saving to the national healthcare provider (National Health Service (NHS)) over a 5-year time horizon.

Islam and Motivation to Quit Smoking: Public Health Policy Implications.

In the WHO Eastern Mediterranean Regional Office some 14 years ago, a 'religiously inspired approach' was proposed to combat tobacco use. This promoted a useful debate in the region. The purpose of this paper is to argue the need to identify the role which Islamic beliefs and teachings play (1) in influencing individual motivation to quit smoking and (2) in gaining support for public policies to reduce smoking. Ramadan and Hajj are taken as key points. These, it is argued, are times when Muslim religious motivation to abstain from smoking is strongest. This paper concludes that there is an insufficient evidence base on which to adopt a religiously inspired approach. All of civil society, including religious Muslim authorities, should rather supplement the efforts of health professionals to encourage smoking cessation.

Predicting Regioselectivity of AO, CYP, FMO, and UGT Metabolism Using Quantum Mechanical Simulations and Machine Learning.

Unexpected metabolism in modification and conjugation phases can lead to the failure of many late-stage drug candidates or even withdrawal of approved drugs. Thus, it is critical to predict the sites of metabolism (SoM) for enzymes, which interact with drug-like molecules, in the early stages of the research. This study presents methods for predicting the isoform-specific metabolism for human AOs, FMOs, and UGTs and general CYP metabolism for preclinical species. The models use semi-empirical quantum mechanical simulations, validated using experimentally obtained data and DFT calculations, to estimate the reactivity of each SoM in the context of the whole molecule. Ligand-based models, trained and tested using high-quality regioselectivity data, combine the reactivity of the potential SoM with the orientation and steric effects of the binding pockets of the different enzyme isoforms. The resulting models achieve κ values of up to 0.94 and AUC of up to 0.92.

Bariatric-Metabolic Surgery Utilisation in Patients With and Without Diabetes: Data from the IFSO Global Registry 2015-2018.

BACKGROUND: Comparative international practice of patients undergoing bariatric-metabolic surgery for type 2 diabetes mellitus (T2DM) is unknown. We aimed to ascertain baseline age, sex, body mass index (BMI) and types of operations performed for patients with T2DM submitted to the IFSO Global Registry. MATERIALS AND METHODS: Cross-sectional analysis of patients having primary surgery in 2015-2018 for countries with ≥90% T2DM data completion and ≥ 1000 submitted records. RESULTS: Fifteen countries including 11 national registries met the inclusion criteria. The rate of T2DM was 24.2% (99,537 of 411,581 patients, country range 12.0-55.1%) and 77.1% of all patients were women. In every country, patients with T2DM were older than those without T2DM (overall mean age 49.2 [SD 11.4] years vs 41.8 [11.9] years, all p < 0.001). Men were more likely to have T2DM than women, odds ratio (OR) 1.68 (95% CI 1.65-1.71), p < 0.001. Men showed higher rates of T2DM for BMI <35 kg/m2 compared to BMI ≥35.0 kg/m2, OR 2.76 (2.52-3.03), p < 0.001. This was not seen in women, OR 0.78 (0.73-0.83), p < 0.001. Sleeve gastrectomy was the commonest operation overall, but less frequent for patients with T2DM, patients with T2DM 54.9% vs without T2DM 65.8%, OR 0.63 (0.63-0.64), p < 0.001. Twelve out of 15 countries had higher proportions of gastric bypass compared to non-bypass operations for T2DM, OR 1.70 (1.67-1.72), p < 0.001. CONCLUSION: Patients with T2DM had different characteristics to those without T2DM. Older men were more likely to have T2DM, with higher rates of BMI <35 kg/m2 and increased likelihood of food rerouting operations.

Bariatric Surgery Worldwide: Baseline Demographic Description and One-Year Outcomes from the Fourth IFSO Global Registry Report 2018.

BACKGROUND: Since 2014, the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) has produced an annual report of all bariatric surgery submitted to the Global Registry. We describe baseline demographics of international practice from the 4th report. METHODS: The IFSO Global Registry amalgamated data from 51 different countries, 14 of which provided data from their national registries. Data were available from 394,431 individual records, of which 190,177 were primary operations performed since 2014. RESULTS: Data were submitted on 72,645 Roux en Y gastric bypass operations (38.2%), 87,467 sleeve gastrectomy operations (46.0%), 14,516 one anastomosis gastric bypass procedures (7.6%) and 9534 gastric banding operations (5.0%) as the primary operation since 2014. The median patient body mass index (BMI) pre-surgery was 41.7 kg m2 (inter-quartile range: 38.3-46.1 kg m2). Following gastric bypass, 84.1% of patients were discharged within 2 days of surgery; and 84.5% of sleeve gastrectomy patients were discharged within 3 days. Assessing operations performed between 2012 and 2016, at one year after surgery, the mean recorded percentage weight loss was 28.9% and 66.1% of those taking medication for type 2 diabetes were recorded as not using them. The proportion of patients no longer receiving treatment for diabetes was highly dependent on weight loss achieved. There was marked variation in access and practice. CONCLUSIONS: A global description of patients undergoing bariatric surgery is emerging. Future iterations of the registry have the potential to describe the operated patients comprehensively.

Bariatric Surgery Worldwide: Baseline Demographic Description and One-Year Outcomes from the Second IFSO Global Registry Report 2013-2015.

BACKGROUND: Five International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) surveys since 1998 have estimated the volume and type of bariatric surgery being done in constituent member countries. These reports did not include baseline demographic descriptions. METHODS: An IFSO Global Registry pilot project in 2014 demonstrated that it was possible to amalgamate large numbers of individual patient data from different local and national database systems. Here we describe demographic data from the second report for 54,490 patients from 31 countries operated in the 3 calendar years 2013-2015 and follow up data from 66,560 of 112,544 patients in 2009-2015. RESULTS: Most procedures (97.8%) were performed laparoscopically and 73.3% (95% CI: 73.0-73.7%, range 54.2 to 80.3%) were female. The average age was 42.0 years (95% CI 41.9-42.1, inter-quartile range 33.0-51.0 years) and the median body mass index was 43.3 kg/m2 (inter-quartile range 39.4-48.8 kg/m2). Before surgery, 22.0% patients had type 2 diabetes (inter-country variation 7.4-63.2%); 31.9% were hypertensive (15.8-92.7%); 17.6% had depression (0.0-46.3%); 27.8% took medication for musculoskeletal pain (0.0-58.9%); 18.9% had sleep apnea (0.0-63.2%); and 29.6% of patients had gastro-esophageal reflux disease (9.1-90.9%). Gastric bypass was the most prevalent operation (49.4%), followed by sleeve gastrectomy (40.7%) and gastric banding (5.5%). The 1-year total weight loss for patients with available data was 30.53% (95% CI: 30.22-30.84%) and in the cohort 2009-15 was 30.4% with a follow-up rate of 59.14%. In the 2009-2015 cohort, 64.7% of patients on treatment for diabetes preoperatively were not on treatment postoperatively. CONCLUSIONS: There is widespread variation in access to surgery and in baseline patient characteristics in the countries submitting data to the IFSO Global Registry.

Single-stage conversions from failed gastric band to sleeve gastrectomy versus Roux-en-Y gastric bypass: results from the United Kingdom National Bariatric Surgical Registry.

BACKGROUND: For patients in whom laparoscopic adjustable gastric band has failed, conversion to Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy are both options for further surgical treatment. There are limited data comparing these 2 procedures. The National Bariatric Surgery Registry is a comprehensive United Kingdom-wide database of bariatric procedures, in which preoperative demographic characteristics and clinical outcomes are prospectively recorded. OBJECTIVES: To compare perioperative complication rate and short-term outcomes of patients undergoing single-stage conversion of gastric band to Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy. SETTING: United Kingdom national bariatric surgery database. METHODS: From the National Bariatric Surgical Registry data set, we identified 141 patients undergoing single-stage conversion from gastric band to either gastric bypass (113) or sleeve gastrectomy (28) between 2009 and 2014, and analyzed their clinical outcomes. RESULTS: With respect to perioperative outcomes gastric bypass was associated with a higher incidence of readmission or reintervention postoperatively (16 versus 0; P = .04). There was no difference in percentage excess weight loss between sleeve gastrectomy and gastric bypass at final follow-up at 1 year (52.1% versus 57.1% respectively; P = .4). CONCLUSIONS: Conversion from band to sleeve or bypass give comparable good early excess weight loss; however, conversion to sleeve is associated with a better perioperative safety profile.

Obesity surgery makes patients healthier and more functional: real world results from the United Kingdom National Bariatric Surgery Registry.

BACKGROUND: The National Bariatric Surgery Registry (NBSR) is the largest bespoke database in the field in the United Kingdom. OBJECTIVES: Our aim was to analyze the NBSR to determine whether the effects of obesity surgery on associated co-morbidities observed in small randomized controlled clinical trials could be replicated in a "real life" setting within U.K. healthcare. SETTING: United Kingdom. METHODS: All NBSR entries for operations between 2000 and 2015 with associated demographic and co-morbidity data were analyzed retrospectively. RESULTS: A total of 50,782 entries were analyzed. The patients were predominantly female (78%) and white European with a mean age of 45 ± 11 years and a mean body mass index of 48 ± 8 kg/m2. Over 5 years of follow-up, statistically significant reductions in the prevalence of type 2 diabetes, hypertension, dyslipidemia, sleep apnea, asthma, functional impairment, arthritis, and gastroesophageal reflux disease were observed. The "remission" of these co-morbidities was evident 1 year postoperatively and reached a plateau 2 to 5 years after surgery. Obesity surgery was particularly effective on functional impairment and diabetes, almost doubling the proportion of patients able to climb 3 flights of stairs and halving the proportion of patients with diabetes related hyperglycemia compared with preoperatively. Surgery was safe with a morbidity of 3.1% and in-hospital mortality of .07% and a reduced median inpatient stay of 2 days, despite an increasingly sick patient population. CONCLUSIONS: Obesity surgery in the U.K. results not only in weight loss, but also in substantial improvements in obesity-related co-morbidities. Appropriate support and funding will help improve the quality of the NBSR data set even further, thus enabling its use to inform healthcare policy.

What do people think about running barefoot/with minimalist footwear? A thematic analysis.

OBJECTIVES: Barefoot running describes when individuals run without footwear. Minimalist running utilizes shoes aimed to mimic being barefoot. Although these forms of running have become increasingly popular, we still know little about how recreational runners perceive them. DESIGN: In-depth interviews with eight recreational runners were used to gather information about their running experiences with a focus on barefoot and minimalist running. METHODS: Interviews were analysed using a latent level thematic analysis to identify and interpret themes within the data. RESULTS: Although participants considered barefoot running to be 'natural', they also considered it to be extreme. Minimalist running did not produce such aversive reactions. 'Support' reassured against concerns and was seen as central in protecting vulnerable body parts and reducing impact forces, but lacked a common or clear definition. A preference for practical over academic knowledge was found. Anecdotal information was generally trusted, as were running stores with gait assessment, but not health professionals. CONCLUSION: People often have inconsistent ideas about barefoot and minimalist running, which are often formed by potentially biased sources, which may lead people to make poor decisions about barefoot and minimalist running. It is important to provide high-quality information to enable better decisions to be made about barefoot and minimalist running. STATEMENT OF CONTRIBUTION: What is already known on this subject? There is no known work on the psychology behind barefoot and minimalist running. We believe our study is the first qualitative study to have investigated views of this increasingly popular form of running. What does this study add? The results suggest that although barefoot running is considered 'natural', it is also considered 'extreme'. Minimalist running, however, did not receive such aversive reactions. 'Support' was a common concern among runners. Although 'support' reassured against concerns and was seen as central in protecting vulnerable body parts and reducing impact forces, it lacked a common or clear definition. A preference for practical over academic knowledge was found. Anecdotal information was generally trusted, as were running stores with gait assessment, but not health professionals.

Attribution of extreme weather and climate-related events.

Extreme weather and climate-related events occur in a particular place, by definition, infrequently. It is therefore challenging to detect systematic changes in their occurrence given the relative shortness of observational records. However, there is a clear interest from outside the climate science community in the extent to which recent damaging extreme events can be linked to human-induced climate change or natural climate variability. Event attribution studies seek to determine to what extent anthropogenic climate change has altered the probability or magnitude of particular events. They have shown clear evidence for human influence having increased the probability of many extremely warm seasonal temperatures and reduced the probability of extremely cold seasonal temperatures in many parts of the world. The evidence for human influence on the probability of extreme precipitation events, droughts, and storms is more mixed. Although the science of event attribution has developed rapidly in recent years, geographical coverage of events remains patchy and based on the interests and capabilities of individual research groups. The development of operational event attribution would allow a more timely and methodical production of attribution assessments than currently obtained on an ad hoc basis. For event attribution assessments to be most useful, remaining scientific uncertainties need to be robustly assessed and the results clearly communicated. This requires the continuing development of methodologies to assess the reliability of event attribution results and further work to understand the potential utility of event attribution for stakeholder groups and decision makers. WIREs Clim Change 2016, 7:23-41. doi: 10.1002/wcc.380 For further resources related to this article, please visit the WIREs website.

The UK National Flap Registry (UKNFR): A National Database for all pedicled and free flaps in the UK.

The UK National Flap Registry (UKNFR) is a cross-speciality National Clinical Audit with participation by the British Association of Plastic Reconstructive and Aesthetic Surgeons (BAPRAS), British Association of Head and Neck Oncologists (BAHNO), British Association of Oral and Maxillofacial Surgeons (BAOMS) and Association of Breast Surgery (ABS). The aim of UKNFR is to collect information about all major pedicled and free flap operations carried out in the UK and through that, assess the quality of care we provide for patients. This audit will allow appropriate comparison of clinical performance with national standards and provide useful data on changing trends. Participation in audit is integral to appraisal and revalidation in the UK.

The European Association for Cardio-Thoracic Surgery (EACTS) database: an introduction.

OBJECTIVES: Continuous monitoring of surgical outcomes through benchmarking and the identification of best practices has become increasingly important. A structured approach to data collection, coupled with validation, analysis and reporting, is a powerful tool in these endeavours. However, inconsistencies in standards and practices have made comparisons within and between European countries cumbersome. The European Association for Cardio-Thoracic Surgery (EACTS) has established a large international database with the goals of (i) working with other organizations towards universal data collection and creating a European-wide repository of information on the practice of cardio-thoracic surgery, and (ii) disseminating that information in scientific, peer-reviewed articles. We report on the process of data collection, as well as on an overview of the data in the database. METHODS: The EACTS Database Committee met for the first time in Monaco, September 2002, to establish the ground rules for the process of setting up the database. Subsequently, data have been collected and merged by Dendrite Clinical Systems Ltd. RESULTS: As of December 2008, the database included 1,074,168 patient records from 366 hospitals located in 29 countries. The latest submission from the years 2006-08 included 404,721 records. The largest contributors were the UK (32.0%), Germany (20.9%) and Belgium (7.3%). Isolated coronary bypass surgery was the most frequently performed operation; the proportion of surgical workload that comprised isolated coronary artery bypass grafting varied from country to country: 30% in Spain and almost 70% in Denmark. Isolated valve procedures constituted 12% of all procedures in Norway and 32% in Spain. Baseline demographics showed an increase in the mean age and the percentage of patients that were female over time. Remarkably, the mortality rates for all procedures declined over the period analysed, to 2.2% (95% confidence interval [CI] 2.2-2.3%) for isolated coronary bypass, 3.4% (95% CI 3.3-3.5%) for isolated valve and 6.2% (95% CI 6.0-6.5%) for bypass + valve procedures. CONCLUSION: The EACTS database has proven to be an important step forward in providing opportunities for monitoring cardiac surgical care across Europe. As the database continues to expand, it will facilitate research projects, establish benchmarking standards and identify potential areas for quality improvements.