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Abstract Aims We aimed to determine the association between serum interleukin‐6 (IL‐6) concentrations and new‐onset heart failure (HF) in persons with type 2 diabetes (T2D). Methods and results We performed a case–control study nested in the Diabetes Care System Cohort, a prospective cohort of persons with T2D in primary care. We included 724 participants, of whom 141 developed HF during 5 years of follow‐up and 583 were age‐ and sex‐matched controls. IL‐6 was measured at baseline and categorized into four groups: Group 1 was composed of participants with IL‐6 below the detection limit of 1.5 pg/mL, and the remainder were divided into tertiles. We performed logistic regression analyses with categorized IL‐6 or continuous IL‐6 as the determinant and new‐onset HF as the outcome adjusted for follow‐up time, age, sex, glycated haemoglobin, estimated glomerular filtration rate, albumin/creatinine ratio, and cardiovascular disease at baseline. Effect modification by sex was tested. Participants were 70.7 ± 9.0 years, and 38% were women. In comparison with Group 1, all tertiles were associated with an increased risk of HF with odds ratios of 2.1 [95% confidence interval (CI): 1.2–2.9], 2.8 (95% CI: 2.0–3.7), and 2.1 (95% CI: 1.3–3.0), respectively, for Tertiles 1–3. Continuous IL‐6 was associated with the development of HF with an odds ratio of 1.2 (95% CI: 1.0–1.5). No effect modification by sex was observed. Conclusions Higher IL‐6 levels are associated with the development of HF in persons with T2D. Further research should determine whether IL‐6‐lowering interventions could prevent the development of HF.

Abstract Background Older patients with type 2 diabetes mellitus (T2D) have an increased risk of hypoglycaemic episodes when using sulphonylureas or insulin. In the Netherlands, guidelines exist for reducing glucose-lowering medication in older patients. However, evidence is lacking that a medication reduction in older patients can be safely pursued. Here, we will examine if promoting the deprescribing of insulin/sulphonylureas with a deprescribing programme (DPP) in general practice affects T2D-complications in older overtreated patients. Methods We will perform a 1:1 cluster randomised controlled trial in 86 general practices in the Netherlands. The DPP will consist of education sessions with general practitioners and practice nurses about reducing glucose-lowering medication in older patients (≥ 70 years). Topics of the sessions include the necessity of deprescribing, tools to initiate deprescribing and strategies to discuss deprescribing with patients (shared decision making). The DPP further includes a support programme with practice visits. The study will employ a selection tool to identify possibly overtreated older patients from the electronic medical records of the general practitioner. Eligibility for enrolment in the study will be based on HbA1c targets indicated by the Dutch guidelines, which depend on age, diabetes duration, presence of frailty, and life expectancy. The control group will provide usual care. We aim to include 406 patients. The follow-up period will be 2 years. For the primary outcome, the effect of the DPP on T2D-complications will be assessed by counting the cumulative incidence of events related to under- and overtreatment in T2D as registered in the electronic medical records. We shall perform an intention-to-treat analysis and an analysis including only patients for whom deprescribing was initiated. The implementation of the DPP in general practice will be evaluated quantitatively and qualitatively using the Extended Normalisation Process Theory (ENPT) and the Reach, Efficacy – Adoption, Implementation and Maintenance (RE-AIM) model. Other secondary outcomes include quality of life, cognitive functioning, events related to overtreatment or undertreatment, biomarkers of health, amount of blood glucose-lowering medication prescriptions, and cost-effectiveness. Discussion This study will provide insight into the safety and feasibility of a programme aimed at deprescribing sulphonylureas/insulin in older people with T2D who are treated in general practice. Trial registration ISRCTN Registry, ISRCTN50008265 , registered 09 March, 2023.

Abstract Background Social jetlag is a chronic disruption of sleep timing that is characterized by different sleep timing during workdays and free days. Social jetlag has been associated with disturbed glucose metabolism, insulin resistance, and increased risk of metabolic syndrome and type 2 diabetes. In this study, we aim to investigate whether a combination of bright light therapy in the morning, bright light reduction in the evening and sleep advance instructions for 3 weeks reduces social jetlag and if this results in improvement of glycemic and metabolic control, sleep, mood and quality of life after 3 and 12 weeks in people with prediabetes and type 2 diabetes and to assess possible mediators, compared to regular sleep habits. Methods In this randomized controlled trial, 60 people with prediabetes or type 2 diabetes with > 1 h social jetlag will be recruited. The intervention consists of bright light therapy (5000 lx) emitted by Vitamine-L (Lumie, UK) for 30 min each morning, combined with the advice to follow sleep advance instructions and to wear bright light-dimming goggles every evening for a period of 3 weeks. The control group adheres to their regular sleep habits and conditions. The primary outcome is glycated hemoglobin (HbA1c) after 12 weeks comparing the intervention and control in an intention-to-treat analysis. Secondary outcomes at 3 and 12 weeks are (1) social jetlag; (2) insulin sensitivity, fasting blood glucose, glucose-lowering medication use, and frequency of perceived hypoglycemia; (3) metabolic outcomes, including body mass index (BMI), waist circumference, body fat percentage, and blood pressure; (4) mood, including depression, fatigue and anxiety (measured with questionnaires); and (5) quality of life measured using EQ5D questionnaire. To assess other factors that might play a role as possible mediators, we will measure (para)sympathetic nervous system activity assessed with ECGs and electrochemical skin conductance tests, sleep quality and sleep phase distribution assessed with a sleep measuring headband (ZMax), the Dim Light Melatonin Onset in saliva samples (in a subgroup) at 3 and 12 weeks, the feeling of satiety and satiation with a 10-cm visual analog scale (VAS), diet using a food frequency questionnaire, and physical activity using an accelerometer (ActiGraph). Discussion Social jetlag can contribute to poorer glycemic control and metabolic control in those with type 2 diabetes. With this intervention, we aim to reduce social jetlag and thereby improve glycemic and metabolic control. This could offer a way to improve overall population health and to reduce the disease burden of type 2 diabetes. Trial registration ISRCTN registry ISRCTN11967109 . Registered on 9 May 2024.

Background: Subclinical thyroid diseases are often the subject of debate concerning their clinical significance, the appropriateness of diagnostic testing, and possible treatment. This systematic review addresses the variation in international guidelines for subclinical hyperthyroidism, focusing on diagnostic workup, treatment, and follow-up recommendations. Methods: Following the PRISMA guidelines, we searched PubMed, Embase, and guideline-specific databases and included clinical practice guidelines with recommendations on subclinical hyperthyroidism. Guideline recommendations were extracted, and quality assessment was performed using selected questions of the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Results: Of the 2624 records screened, 22 guidelines were included, which were published between 2007 and 2021. Guideline quality was generally intermediate to low. Diagnostic approaches differed substantially, particularly in the extent of recommended testing. Treatment initiation depended on TSH levels, age, and comorbidities, but the level of detail regarding defining precise comorbidities varied. Recommendations for monitoring intervals for follow-up ranged from 3 to 12 months. Conclusion: This review underscores the existing variability in (inter)national guidelines concerning subclinical hyperthyroidism. There is a need for clear recommendations in guidelines considering diagnostic workup, treatment, and follow-up of subclinical hyperthyroidism. In order to establish this, future research should focus on determining clear and evidence-based intervention thresholds.

Summary: Background: 1H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals. Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by 1H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors. Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates. Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal. Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.

Jetty A Overbeek,1,2 Giel Nijpels,2 Karin MA Swart,1,2 Marieke T Blom,2,3 Petra JM Elders,2,3 Ron MC Herings1,4 1PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands; 2Amsterdam UMC, Location Vrije Universiteit Amsterdam, Department of General Practice, Amsterdam, Netherlands; 3Amsterdam Public Health, Health Behaviors & Chronic Diseases, Amsterdam, Netherlands; 4Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Epidemiology and Data Science, Amsterdam, NetherlandsCorrespondence: Jetty A Overbeek, Email jetty.overbeek@pharmo.nlAims/Hypothesis: Only a few studies reported the incidence of type 2 diabetes (T2D). Understanding recent trends in diabetes is vital for planning future diabetes care. This study updated national trends in the prevalence and incidence of type 2 diabetes (T2D) in the Netherlands from 2004– 2020.Methods: The DIAbetes, MANagement and Treatment (DIAMANT) cohort was used. A cross-sectional design with yearly measurements for the study period was used. The prevalence was calculated by dividing the total number of people with T2D by the total number of all residents. The incidence was calculated by dividing new cases of T2D by the resident population at risk during the calendar year of interest.Results: Among men, the prevalence of T2D in the Netherlands increased from 2.3% in 2004 to 6.3% in 2020. Women’s prevalence increased from 2.3% in 2004 to 5.3% in 2020. During 2005– 2009, the incidence rate for both men and women was relatively stable Between 2010 and 2020, the incidence rate fell about 1.5 per 1000 in both men and women.Conclusion: From 2004– 2020, the prevalence of T2D in the Netherlands more than doubled, with a decreasing incidence from 2010 onwards.Plain Language Summary: Research in contextWhat is already known about this subject?Many studies have reported the increasing prevalence of type 2 diabetes (T2D). However, only a few studies reported the incidence.In a recent systematic review of all these studies, the incidence fell in over a third of the most high-income populations and increased in a minority of populations. Data from the Netherlands were included, but they date back to 1996.Understanding recent trends in diabetes, the prevalence and incidence are vital for planning future diabetes care.What is the key question?To update national trends in the prevalence and incidence of T2D in the Netherlands for 2004-2020.What are the new findings?During 2004-2020, the prevalence of T2D in the Netherlands more than doubled, with a decreasing incidence from 2010 onwards.How might this impact on clinical practice in the foreseeable future?It demonstrates the effectiveness of preventive strategies, public health education and awareness campaigns contributing to this trend.Keywords: type 2 diabetes, prevalence, incidence, epidemiology

Background: : Qualitative research shows barriers in access to healthcare for persons with a migration background, possibly leading to healthcare inequalities. We aimed to compare healthcare use between older community-dwelling persons with a migration background and native Dutch persons with dementia. Methods: : Observational cohort study using electronic health records of NIVEL Primary Care Database (2013–2014) linked to nationwide administrative registries managed by Statistics Netherlands. We included all community-dwelling persons with dementia in the Netherlands aged 65 years and older. Negative binomial and logistic regression analyses were conducted to assess differences in healthcare use outcomes. The largest migrant groups (persons born in Surinam, Turkey and Morocco) were studied separately. Results: : 138,864 persons with dementia were included in the study, whereof 3,991 persons with a migration background and 132,477 native Dutch persons. Moroccan-born persons showed 1.46 higher odds of having an unplanned hospital admission compared to native Dutch persons (95 % Confidence Interval [CI] 1.22–1.74). Persons with a migration background used less professional home care (Odds Ratio [OR] 0.55, 95 %CI 0.51–0.59), and received less home visits from their general practitioner (OR 0.50, 95 %CI 0.43–0.57) than native Dutch persons. Moroccan-born persons had more often an out-of-hours general practitioner consultation compared to native Dutch persons (Incidence Rate Ratio 1.36, 95 %CI 1.18–1.57). Conclusions: : We found significant quantitative differences in healthcare use between persons with a migration background and native Dutch persons with dementia. Further research is needed to gain insight into the reasons of these differences, with consideration of specific migration background.

Background Pelvic organ prolapse is common, causes unpleasant symptoms and negatively affects women’s quality of life. In the UK, most women with pelvic organ prolapse attend clinics for pessary care. Objectives To determine the clinical effectiveness and cost-effectiveness of vaginal pessary self-management on prolapse-specific quality of life for women with prolapse compared with clinic-based care; and to assess intervention acceptability and contextual influences on effectiveness, adherence and fidelity. Design A multicentre, parallel-group, superiority randomised controlled trial with a mixed-methods process evaluation. Participants Women attending UK NHS outpatient pessary services, aged ≥ 18 years, using a pessary of any type/material (except shelf, Gellhorn or Cube) for at least 2 weeks. Exclusions: women with limited manual dexterity, with cognitive deficit (prohibiting consent or self-management), pregnant or non-English-speaking. Intervention The self-management intervention involved a 30-minute teaching appointment, an information leaflet, a 2-week follow-up telephone call and a local clinic telephone helpline number. Clinic-based care involved routine appointments determined by centres’ usual practice. Allocation Remote web-based application; minimisation was by age, pessary user type and centre. Blinding Participants, those delivering the intervention and researchers were not blinded to group allocation. Outcomes The patient-reported primary outcome (measured using the Pelvic Floor Impact Questionnaire-7) was prolapse-specific quality of life, and the cost-effectiveness outcome was incremental cost per quality-adjusted life-year (a specifically developed health Resource Use Questionnaire was used) at 18 months post randomisation. Secondary outcome measures included self-efficacy and complications. Process evaluation data were collected by interview, audio-recording and checklist. Analysis was by intention to treat. Results Three hundred and forty women were randomised (self-management, n = 169; clinic-based care, n = 171). At 18 months post randomisation, 291 questionnaires with valid primary outcome data were available (self-management, n = 139; clinic-based care, n = 152). Baseline economic analysis was based on 264 participants (self-management, n = 125; clinic-based care, n = 139) with valid quality of life and resource use data. Self-management was an acceptable intervention. There was no group difference in prolapse-specific quality of life at 18 months (adjusted mean difference −0.03, 95% confidence interval −9.32 to 9.25). There was fidelity to intervention delivery. Self-management was cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained, with an estimated incremental net benefit of £564.32 and an 80.81% probability of cost-effectiveness. At 18 months, more pessary complications were reported in the clinic-based care group (adjusted mean difference 3.83, 95% confidence interval 0.81 to 6.86). There was no group difference in general self-efficacy, but self-managing women were more confident in pessary self-management activities. In both groups, contextual factors impacted on adherence and effectiveness. There were no reported serious unexpected serious adverse reactions. There were 32 serious adverse events (self-management, n = 17; clinic-based care, n = 14), all unrelated to the intervention. Skew in the baseline data for the Pelvic Floor Impact Questionnaire-7, the influence of the global COVID-19 pandemic, the potential effects of crossover and the lack of ethnic diversity in the recruited sample were possible limitations. Conclusions Self-management was acceptable and cost-effective, led to fewer complications and did not improve or worsen quality of life for women with prolapse compared with clinic-based care. Future research is needed to develop a quality-of-life measure that is sensitive to the changes women desire from treatment. Study registration This study is registered as ISRCTN62510577. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/82/01) and is published in full in Health Technology Assessment; Vol. 28, No. 23. See the NIHR Funding and Awards website for further award information. Plain language summary Pelvic organ prolapse is a common and distressing condition experienced by large numbers of women. Prolapse is when the organs that are usually in the pelvis drop down into the vagina. Women experience a feeling of something coming down into the vagina, along with bowel, bladder and sexual problems. One possible treatment is a vaginal pessary. The pessary is a device that is inserted into the vagina and holds the pelvic organs back in their usual place. Women who use a vaginal pessary usually come back to clinic every 6 months to have their pessary removed and replaced; this is called clinic-based care. However, it is possible for a woman to look after the pessary herself; this is called self-management. This study compared self-management with clinic-based care. Three hundred and forty women with prolapse took part; 171 received clinic-based care and 169 undertook self-management. Each woman had an equal chance of being in either group. Women in the self-management group received a 30-minute teaching appointment, an information leaflet, a 2-week follow-up telephone call and a telephone number for their local centre. Women in the clinic-based care group returned to clinic as advised by the treating healthcare professional. Self-management was found to be acceptable. Women self-managed their pessary in ways that suited their lifestyle. After 18 months, there was no difference between the groups in women’s quality of life. Women in the self-management group experienced fewer pessary complications than women who received clinic-based care. Self-management costs less to deliver than clinic-based care. In summary, self-management did not improve women’s quality of life more than clinic-based care, but it did lead to women experiencing fewer complications and cost less to deliver in the NHS. The findings support self-management as a treatment pathway for women using a pessary for prolapse. Scientific summary Background Pelvic organ prolapse (hereafter prolapse) is the descent of some, or all, of the female pelvic organs from their usual position in the pelvis into the vagina. Prolapse is a common problem, with studies suggesting that up to 65% of women may be affected. Prolapse incidence increases with age. As the population ages, prolapse presents a growing health problem. Women who experience prolapse report bothersome symptoms that negatively affect their quality of life and body image. Symptoms include a feeling of ‘something coming down’ into the vagina; urinary, bowel and sexual symptoms; and pain. Prolapse can be treated conservatively or surgically. Between 10% and 30% of women who have prolapse surgery may need repeat surgery, and the controversy around the use of surgical mesh has brought the focus onto conservative treatment options. One conservative treatment option is vaginal pessary. The pessary is an inexpensive mechanical device that is inserted into the vagina to support the pelvic organs. Pessaries are widely used in the NHS, with two-thirds of women initially choosing a vaginal pessary to treat their prolapse symptoms. The current UK care pathway for women who use a pessary as treatment for prolapse is that the pessary is usually fitted at a gynaecological clinic, or occasionally at a general practitioner surgery, and the woman returns approximately every 6 months to have it removed and replaced with a new one. However, having to return to clinic every 6 months may be inconvenient for women, having a pessary permanently in situ may interfere with sexual intercourse, and the patient may require a review in clinic before 6 months because the pessary has fallen out or because of pessary complications (e.g. vaginal discomfort). An alternative to clinic-based pessary care is pessary self-management, whereby a woman removes and reinserts the pessary herself at home, thus offering her more control over her ability to maintain and improve her own health. Research in other clinical domains suggests that self-management is beneficial because people improve their self-efficacy (confidence) in looking after their own health. To the best of our knowledge, there is no current evidence on the effectiveness of pessary self-management for women with prolapse. The treatment of prolapse with self-care pessary (TOPSY) study aims to fill that evidence gap. Objective The TOPSY trial aimed to evaluate the clinical effectiveness and cost-effectiveness of self-management of a vaginal pessary on the prolapse-specific quality of life of women with pelvic organ prolapse when compared with clinic-based care. Clinic-based care is the standard operating model for many pessary services across the UK. The process evaluation undertaken concurrently with the trial aimed to assess, using a mixed-methods design, intervention acceptability, pathways to effectiveness, adherence to treatment and fidelity. Methods We undertook a parallel-group, multicentre, randomised controlled trial, with individual randomisation, which assessed the superiority of self-management compared with clinic-based pessary care for women who used a pessary for prolapse. Allocation was carried out remotely via a web-based computer system, with minimisation by age (< 65/≥ 65 years), pessary user type (new user/existing user) and centre. A sample size of 330 women (165 per group) was required to provide 90% power to detect a difference of 20 points in the Pelvic Floor Impact Questionnaire-7 score (which measures prolapse-specific quality of life) at 18 months after randomisation, assuming a standard deviation of 50, two-sided alpha of 0.05 and 20% loss to follow-up. Participants were recruited from 21 UK centres where pessary care was routinely provided. Women who were new pessary users (had used a pessary for ≤ 3 months) and existing users (had used a pessary for > 3 months) were identified by centre staff and via patient notes, clinic lists, caseloads and referral letters. Potentially eligible women were sent an invitation letter or approached in clinic by centre staff. Women were eligible for inclusion if they were aged ≥ 18 years, were using a pessary of any material or type (except shelf, Gellhorn or cube pessaries) and had retained the pessary for at least 2 weeks. Women were excluded if they had limited manual dexterity that would affect their ability to remove and replace their pessary; were judged by their healthcare team to have a cognitive deficit such that it was not possible for them to provide informed consent or to self-manage; were pregnant; or had insufficient understanding of the English language (the self-management intervention was only available in English). The primary outcome of effectiveness was prolapse-specific quality of life, measured using the Pelvic Floor Impact Questionnaire-7, and of cost-effectiveness was incremental cost per quality-adjusted life-year at 18 months post randomisation. Interim follow-ups were undertaken at 6 and 12 months. Secondary outcome measures included generic quality of life [measured using the EuroQol-5 Dimensions, five-level (EQ-5D-5L)]; pelvic floor symptoms (measured using the Pelvic Floor Distress Inventory-20); sexual function (measured using the prolapse/incontinence sexual questionnaire-IUGA-Revised); self-efficacy (measured using the General Self-efficacy Scale); pessary complications; pessary use; and pessary confidence. Resource use data were collected using a specifically developed health Resource Use Questionnaire. Study centres received a training visit during which the principles of self-management were explained and the intervention delivery staff were trained in the components of the intervention. Each centre also received a training manual that provided written guidance on the intervention. Women randomised to self-management received: a 30-minute self-management teaching appointment where they were taught to, and given the opportunity to try to, remove, clean and reinsert their own pessary a self-management information leaflet that provided written and diagrammatic information on pessary self-management a 2-week follow-up telephone call to assess if they had been able to remove, clean and reinsert their pessary since the teaching appointment and to assess any difficulties they experienced a telephone helpline number for their local clinical centre. Women in the clinic-based care group received routine appointments at which their pessary was removed and cleaned, or changed for a new one, and replaced by a healthcare professional. The interval between the appointments was determined by the usual practice of the centre. A concurrent mixed-methods process evaluation was undertaken to assess intervention acceptability, pathways to effectiveness, adherence to treatment and fidelity. Recruiting staff at centres were asked to audio-record a sample of their recruitment discussions. Staff delivering the intervention were asked to record a sample of self-management teaching appointments and 2-week follow-up telephone calls and to complete a checklist for every self-management teaching session undertaken to allow assessment of fidelity to the intervention. A subsample of women who were randomised in the trial and consented to take part in an additional interview study were interviewed at baseline and 18 months. Eligible women who declined to be randomised but were willing to take part in an interview study were also interviewed at baseline and 18 months. The Pessary Use Questionnaire included an open question about women’s experiences of their trial group. The interviews and open questions aimed to assess acceptability, adherence and pathways to effectiveness. Finally, recruiting centre staff and healthcare professionals who delivered the intervention were invited to take part in an interview to increase understanding of pathways to effectiveness and fidelity. A within-trial economic evaluation was conducted to compare the costs and benefits, measured in quality-adjusted life-years, of self-management with clinic-based care over the 18 months post randomisation. In addition, a decision-analytic model was developed using the trial data to extend the analysis over a 5-year period. Healthcare resource use data were collected from the clinic visit and telephone support case report forms and from the participant-completed Resource Use Questionnaire. Costs were attached to resource use from published sources. Health state utility values were elicited from responses to the EQ-5D-5L to estimate the difference in quality-adjusted life-years between the trial groups. The trial analysis followed the intention to treat principle, and the analyses of all study elements were documented in prespecified analysis plans. The qualitative analysis for the process evaluation followed framework analysis methods and, where appropriate, case study analytic methods. Results Key results: trial Three hundred and forty women were randomised: 169 to the self-management group and 171 to the clinic-based care group. At 18 months post randomisation, 291 questionnaires with valid primary outcome data were available: 139 (82.2%) in the self-management group and 152 (88.9%) in the clinic-based care group. There was no evidence of a difference between the groups in prolapse-specific quality of life (measured using the Pelvic Floor Impact Questionnaire-7) at 18 months (adjusted mean difference −0.03, 95% confidence interval −9.32 to 9.25). Sensitivity analysis of the primary outcome showed no significant difference between the groups under a range of different assumptions and prespecified sensitivity analyses. A subgroup analysis of the primary outcome showed no significant effect of trial group by subgroup interactions (subgroups were age < 65 vs. ≥ 65 years, new vs. existing pessary user and hysterectomy vs. no hysterectomy at baseline). At the 18-month follow-up, a greater proportion of pessary complications were reported in the clinic-based care group than in the self-management group (adjusted mean difference 3.83, 95% confidence interval 0.81 to 6.86). There was no difference between the groups in general self-efficacy, but women in the self-management group were more confident in their ability to manage pessary-related problems and to insert and remove their pessary. An analysis adjusting for clinic-based care appointments cancelled due to the COVID-19 pandemic did not alter the findings. Key results: process evaluation Self-management was reported to be an acceptable intervention to women and to healthcare professionals. Women (whether they received self-management or not) and healthcare professionals reported benefits from pessary self-management to women and the NHS and valued the possibilities provided to women who could self-manage their pessary, such as flexibility and independence in using the pessary as needed. There was fidelity to self-management intervention delivery and there was minimal variance in the delivery of clinic-based care across the study centres. Self-management delivery can be integrated within existing service structures. Interview data demonstrated that women’s adherence to their allocated group ranged from not adherent at all to completely adherent in all aspects, and this was the case in both groups. The COVID-19 pandemic did have an impact on adherence, especially among those in the clinic-based care group when clinic appointments were suspended, which led some women to remove their own pessary. Although the pandemic might have had some effect on adherence, multiple other contextual factors influenced adherence, such as good general health, which influenced it in both groups. Multiple contextual factors impacted on pathways to effectiveness for both trial groups. There was variance in women’s quality of life in both groups across the 18 months’ follow-up. The pessary itself influenced women’s quality of life, regardless of trial group. There was at least the potential for self-management to further enhance that quality of life over and above the influence of the pessary itself. Women in the self-management group had different self-efficacy from those in the clinic-based group. Women in the self-management group felt more confident in addressing common problems with their pessary, such as discharge or slippage, on their own without the need for additional clinic appointments. Key results: economic evaluation The within-trial economic analysis indicated that clinic-based care was dominated by self-management. There was no significant difference in the mean number of quality-adjusted life-years gained between self-management and clinic-based care (0.021), but the mean cost was lower for self-management than for clinic-based care (£578 vs. £728). The incremental net benefit estimated at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained was £564, with an 80.8% probability of cost-effectiveness. The modelling results are consistent with the trial analysis. The incremental net benefit at 5 years was estimated as £4221 and the probability that self-management is a cost-effective intervention was estimated as 69.7%. Key results: synthesis There was no evidence that self-management improved prolapse-specific or general quality of life more than clinic-based care. Although qualitative findings suggested that quality of life had the potential to be improved more in the self-management group, this did not translate beyond participant-level data. The proposed mechanism of action for the intervention was self-efficacy. General self-efficacy did not differ between the groups at 18 months. Women who self-managed were more confident in their abilities to insert and remove their pessary and to manage problems experienced with their pessary than women in the clinic-based care group. There was fidelity to the self-management and clinic-based care intervention delivery, with the groups receiving different interventions, confirming that the trial was a true test. There was variance in adherence to trial group by the women; approximately 40% of the clinic-based care group removed the pessary themselves at least once at some point during follow-up, and 34 women in the self-management group crossed over to clinic-based care. Women in the self-management group reported fewer complications than women in the clinic-based care group. Experience of complications led to a greater likelihood of women discontinuing pessary use. Conclusions Implications for health care Healthcare professionals and policy-makers can be confident that in offering self-management as an option to women who use a vaginal pessary to manage pelvic organ prolapse they are offering an acceptable intervention that will not make women’s quality of life better or worse than clinic-based care. Self-management will, however, reduce the pessary-related complications that women experience and will cost the NHS less to deliver than standard clinic-based care models. Self-management of vaginal pessaries should be offered as part of NHS services from the outset of pessary care and as part of routine, ongoing care. In offering self-management to women, healthcare professionals should explain the lower complication rates experienced by women who self-manage and the possible mechanisms that may lead to that reduction (such as women’s confidence in removing the pessary when experiencing discomfort). Healthcare professionals who deliver self-management training may wish to add further information about options for pessary removal into that training, as women found pessary removal more difficult than pessary insertion. Recommendations for research (in priority order) Future research is needed to identify constructs that are important to women in measuring their prolapse-specific quality of life. This may necessitate the generation of a new measure that has greater sensitivity to quality-of-life constructs beyond the symptomatic changes linked to the pessary itself. Future trials of self-management should test the effectiveness of self-management with a wide range of ethnic groups and with women of different abilities to assess its effectiveness in these populations. This may include the testing of devices that support pessary removal or insertion. Future research is needed that focuses on self-management follow-up. For example, can follow-up be women-initiated, or does it need to be planned at specific intervals? Future research on pessary self-management is needed to look at possible links between pessary continuation and complications, including which specific complications are more likely to lead to discontinuation. Study registration This study is registered as ISRCTN62510577. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/82/01) and is published in full in Health Technology Assessment; Vol. 28, No. 23. See the NIHR Funding and Awards website for further award information.

AbstractObjective To assess the cultural competence (CC) of GP trainees and GP trainers.Design and setting: A cross-sectional survey study was conducted at the GP Training Institute of Amsterdam UMC.Subjects We included 92 GP trainees and 186 GP trainers.Main outcome measures We measured the three domains of cultural competency: 1) knowledge, 2) culturally competent attitudes and 3) culturally competent skills. Regression models were used to identify factors associated with levels of CC. Participants rated their self-perceived CC at the beginning and end of the survey, and the correlation between self-perceived and measured CC was assessed.Results Approximately 94% of the GP trainees and 81% of the GP trainers scored low on knowledge; 45% and 42%, respectively, scored low on culturally competent attitudes. The level of culturally competent skills was moderate (54.3%) or low (48.4%) for most GP trainees and GP trainers. The year of residency and the GP training institute were significantly associated with one or more (sub-)domains of CC in GP trainees. Having >10% migrant patients and experience as a GP trainer were positively associated with one or more (sub-) domains of cultural competence in GP trainers. The correlation between measured and self-perceived CC was positive overall but very weak (Spearman correlation coefficient ranging from −0.1–0.3).Conclusion The level of cultural competence was low in both groups, especially in the knowledge scores. Cultural competence increased with experience and exposure to an ethnically diverse patient population. Our study highlights the need for cultural competence training in the GP training curricula.

Abstract An 11‐year‐old, female‐neutered beagle was presented with a growing soft tissue mass arising within the deep tissues of the left cranial cervical region. At presentation, facial asymmetry was evident along with palpable lymphadenomegaly. Magnetic resonance imaging demonstrated a locally invasive cervical mass with intracranial invasion through focal osteolysis of the occipital bone. After antihistamine administration, cytology confirmed mast cell tumour (MCT) with metastasis to local lymph nodes and liver. The owner chose to pursue lomustine and prednisolone, which were dispensed, but, before home administration, prolonged seizures/status epilepticus occurred prompting euthanasia. Postmortem examination confirmed a high‐grade MCT associated with, and infiltrating through, muscle, calvarium, dura mata, leptomeninges and the underlying brain. We present the clinical, imaging, and pathological findings of an unprecedented case of extracranial MCT tumour causing osteolysis of an imperforate flat bone (occipital bone) and intracranial invasion.

IntroductionType 2 diabetes (T2D) onset, progression and outcomes differ substantially between individuals. Multi-omics analyses may allow a deeper understanding of these differences and ultimately facilitate personalised treatments. Here, in an unsupervised “bottom-up” approach, we attempt to group T2D patients based solely on -omics data generated from plasma.MethodsCirculating plasma lipidomic and proteomic data from two independent clinical cohorts, Hoorn Diabetes Care System (DCS) and Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS), were analysed using Similarity Network Fusion. The resulting patient network was analysed with Logistic and Cox regression modelling to explore relationships between plasma -omic profiles and clinical characteristics.ResultsFrom a total of 1,134 subjects in the two cohorts, levels of 180 circulating plasma lipids and 1195 proteins were used to separate patients into two subgroups. These differed in terms of glycaemic deterioration (Hazard Ratio=0.56;0.73), insulin sensitivity and secretion (C-peptide, p=3.7e-11;2.5e-06, DCS and GoDARTS, respectively; Homeostatic model assessment 2 (HOMA2)-B; -IR; -S, p=0.0008;4.2e-11;1.1e-09, only in DCS). The main molecular signatures separating the two groups included triacylglycerols, sphingomyelin, testican-1 and interleukin 18 receptor.ConclusionsUsing an unsupervised network-based fusion method on plasma lipidomics and proteomics data from two independent cohorts, we were able to identify two subgroups of T2D patients differing in terms of disease severity. The molecular signatures identified within these subgroups provide insights into disease mechanisms and possibly new prognostic markers for T2D.

Introduction There is conflicting evidence whether lower extremity arterial calcification coincides with coronary arterial calcification (CAC). The aims of this study were to investigate the associations between (1) femoral and crural calcification with CAC, and (2) femoral and crural calcification pattern with CAC.Research design and methods This cross-sectional study included 405 individuals (74% men, 62.6±10.9 years) from the ARTEMIS cohort study at high risk of cardiovascular disease (CVD) who underwent a CT scan of the femoral, crural and coronary arteries. High CVD risk was defined as history/presence of cerebrovascular disease, coronary artery disease, abdominal aortic aneurysm, renal artery stenosis, peripheral artery disease or CVD risk factors: diabetes mellitus type 2, hypertension, hyperlipidemia. Calcification score within each arterial bed was expressed in Agatston units. Dominant calcification patterns (intimal, medial, absent/indistinguishable) were determined via a CT-guided histologically validated scoring algorithm. Multivariable-adjusted multinomial logistic regression analyses were used. Replication was performed in an independent population of individuals with diabetes mellitus type 2 (Early-HFpEF cohort study).Results Every 100-point increase in femoral and crural calcification score was associated with 1.23 (95% CI=1.09 to 1.37, p

Apolipoprotein-CIII (apo-CIII) inhibits the clearance of triglycerides from circulation and is associated with an increased risk of diabetes complications. It exists in four main proteoforms: O-glycosylated variants containing either zero, one, or two sialic acids and a non-glycosylated variant. O-glycosylation may affect the metabolic functions of apo-CIII. We investigated the associations of apo-CIII glycosylation in blood plasma, measured by mass spectrometry of the intact protein, and genetic variants with micro- and macrovascular complications (retinopathy, nephropathy, neuropathy, cardiovascular disease) of type 2 diabetes in a DiaGene study (n = 1571) and the Hoorn DCS cohort (n = 5409). Mono-sialylated apolipoprotein-CIII (apo-CIII1) was associated with a reduced risk of retinopathy (β = −7.215, 95% CI −11.137 to −3.294) whereas disialylated apolipoprotein-CIII (apo-CIII2) was associated with an increased risk (β = 5.309, 95% CI 2.279 to 8.339). A variant of the GALNT2-gene (rs4846913), previously linked to lower apo-CIII0a, was associated with a decreased prevalence of retinopathy (OR = 0.739, 95% CI 0.575 to 0.951). Higher apo-CIII1 levels were associated with neuropathy (β = 7.706, 95% CI 2.317 to 13.095) and lower apo-CIII0a with macrovascular complications (β = −9.195, 95% CI −15.847 to −2.543). In conclusion, apo-CIII glycosylation was associated with the prevalence of micro- and macrovascular complications of diabetes. Moreover, a variant in the GALNT2-gene was associated with apo-CIII glycosylation and retinopathy, suggesting a causal effect. The findings facilitate a molecular understanding of the pathophysiology of diabetes complications and warrant consideration of apo-CIII glycosylation as a potential target in the prevention of diabetes complications.

Background Up to 30% of children have constipation at some stage in their life. Although often short-lived, in one-third of children it progresses to chronic functional constipation, potentially with overflow incontinence. Optimal management strategies remain unclear. Objective To determine the most effective interventions, and combinations and sequences of interventions, for childhood chronic functional constipation, and understand how they can best be implemented. Methods Key stakeholders, comprising two parents of children with chronic functional constipation, two adults who experienced childhood chronic functional constipation and four health professional/continence experts, contributed throughout the research. We conducted pragmatic mixed-method reviews. For all reviews, included studies focused on any interventions/strategies, delivered in any setting, to improve any outcomes in children (0–18 years) with a clinical diagnosis of chronic functional constipation (excluding studies of diagnosis/assessment) included. Dual reviewers applied inclusion criteria and assessed risk of bias. One reviewer extracted data, checked by a second reviewer. Scoping review: We systematically searched electronic databases (including Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature) (January 2011 to March 2020) and grey literature, including studies (any design) reporting any intervention/strategy. Data were coded, tabulated and mapped. Research quality was not evaluated. Systematic reviews of the evidence of effectiveness: For each different intervention, we included existing systematic reviews judged to be low risk of bias (using the Risk of Bias Assessment Tool for Systematic Reviews), updating any meta-analyses with new randomised controlled trials. Where there was no existing low risk of bias systematic reviews, we included randomised controlled trials and other primary studies. The risk of bias was judged using design-specific tools. Evidence was synthesised narratively, and a process of considered judgement was used to judge certainty in the evidence as high, moderate, low, very low or insufficient evidence. Economic synthesis: Included studies (any design, English-language) detailed intervention-related costs. Studies were categorised as cost-consequence, cost-effectiveness, cost-utility or cost-benefit, and reporting quality evaluated using the consensus health economic criteria checklist. Systematic review of implementation factors: Included studies reported data relating to implementation barriers or facilitators. Using a best-fit framework synthesis approach, factors were synthesised around the consolidated framework for implementation research domains. Results Stakeholders prioritised outcomes, developed a model which informed evidence synthesis and identified evidence gaps. Scoping review 651 studies, including 190 randomised controlled trials and 236 primary studies, conservatively reported 48 interventions/intervention combinations. Effectiveness systematic reviews studies explored service delivery models (n = 15); interventions delivered by families/carers (n = 32), wider children’s workforce (n = 21), continence teams (n = 31) and specialist consultant-led teams (n = 42); complementary therapies (n = 15); and psychosocial interventions (n = 4). One intervention (probiotics) had moderate-quality evidence; all others had low to very-low-quality evidence. Thirty-one studies reported evidence relating to cost or resource use; data were insufficient to support generalisable conclusions. One hundred and six studies described implementation barriers and facilitators. Conclusions Management of childhood chronic functional constipation is complex. The available evidence remains limited, with small, poorly conducted and reported studies. Many evidence gaps were identified. Treatment recommendations within current clinical guidelines remain largely unchanged, but there is a need for research to move away from considering effectiveness of single interventions. Clinical care and future studies must consider the individual characteristics of children. Study registration This study is registered as PROSPERO CRD42019159008. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 128470) and is published in full in Health Technology Assessment; Vol. 28, No. 5. See the NIHR Funding and Awards website for further award information. Plain language summary Between 5% and 30% of children experience constipation at some stage. In one-third of these children, this progresses to chronic functional constipation. Chronic functional constipation affects more children with additional needs. We aimed to find and bring together published information about treatments for chronic functional constipation, to help establish best treatments and treatment combinations. We did not cover assessment or diagnosis of chronic functional constipation. This project was guided by a ‘stakeholder group’, including parents of children with constipation, people who experienced constipation as children, and healthcare professionals/continence experts. We carried out a ‘scoping review’ and a series of ‘systematic reviews’. Our ‘scoping review’ provides an overall picture of research about treatments, with 651 studies describing 48 treatments. This helps identify important evidence gaps. ‘Systematic reviews’ are robust methods of bringing together and interpreting research evidence. Our stakeholder group decided to structure our systematic reviews to reflect who delivered the interventions. We brought together evidence about how well treatments worked when delivered by families/carers (32 studies), the wider children’s workforce (e.g. general practitioner, health visitor) (21 studies), continence teams (31 studies) or specialist consultant-led teams (42 studies). We also considered complementary therapies (15 studies) and behavioural strategies (4 studies). Care is affected by what is done and how it is done. We brought together evidence about different models of delivering care (15 studies), barriers and facilitators to implementation of treatments (106 studies) and costs (31 studies). Quality of evidence was mainly low to very low. Despite numerous studies, there was often insufficient information to support generalisable conclusions. Our findings generally agreed with current clinical guidelines. Management of childhood chronic functional constipation should be child-centred, multifaceted and adapted according to the individual child, their needs, the situation in which they live and the health-care setting in which they are looked after. Research is needed to address our identified evidence gaps. Scientific summary Background Chronic functional constipation (CFC) in childhood is common; it is estimated to affect 5–30% of school-aged children, becoming chronic in around one-third of cases. CFC has negative effects on quality of life (QoL) of children, families and carers, with increasing impact as the child gets older. Although rarely life-threatening, CFC is an unpleasant and distressing condition, associated with a wide range of complications, including physical discomfort, missed school, poor school performance, social isolation and reduced involvement in group activities. More than a third of children with CFC will present clinically with behavioural problems as a result of the constipation. The healthcare costs of childhood CFC are significant. Treatments are usually directed at symptom control since limited diagnostics mean no underlying cause is identified in more than 95% of cases, thus limiting ability to stratify treatments. There are a number of different interventions available for the management of CFC; however, the optimal strategy for combining and implementing interventions for individual circumstances remain unclear. National Institute for Health and Care Research (NIHR) commissioned this work to address the question: ‘What are the most effective interventions, and combinations and sequences of interventions, for childhood chronic functional constipation (CFC), and how can they best be implemented?’ Objectives Specific research questions (RQs) answered by this project were: RQ1: What is the current evidence relating to management strategies for childhood CFC? (Scoping review). RQ2: What are the most effective childhood CFC strategies and combinations of strategies in relation to outcomes of importance to stakeholders and/or cost to the patient/NHS? [Systematic review (SR) of evidence of effectiveness and cost effectiveness]. RQ3: What factors are associated with implementation success or failure of childhood CFC strategies and combinations of strategies for different subgroups? (SR of factors affecting implementation). RQ4: What are the evidence gaps in childhood CFC management strategies? Design We conducted a three-stage pragmatic mixed-method study. In stage 1, we completed a broad, comprehensive scoping review. In stage 2, we conducted focused SRs evaluating effectiveness, cost effectiveness and factors affecting implementation. In stage 3, we integrated findings, generating interactive evidence maps, exploring complementarity between our findings and published clinical guidelines, and identifying evidence gaps. Methods Patient and public involvement Stakeholder involvement was central to our project. We formed a stakeholder group (SG) from across the UK, comprising people with lived experience of childhood CFC, parents of children with CFC, healthcare professionals and representatives of relevant charities. We adhered to key principles for research co-production. The SG provided continuous project oversight and completed specific activities. These activities included development of an intervention taxonomy and logic model, agreement on outcomes for the review, identifying evidence gaps and reaching consensus on clinical implications. Scoping review Our scoping review was based on a systematic search of several electronic databases including medical literature analysis and retrieval system online (MEDLINE), excerpta medica database (EMBASE) and Cumulative Index to Nursing and Allied Health Literature (CINAHL; January 2011 to March 2020), as well as searches of grey literature, contacting experts and forward citation tracking. We included papers, regardless of study design, which investigated, reported or discussed any strategy, delivered in any setting, aimed at improving any outcomes in children (aged 0–18 years) with a clinical diagnosis of CFC. We did not include studies of assessment/diagnosis. We included studies involving children with or without additional needs but excluded those with a recognisable cause of constipation such as anorectal malformation, Hirschsprung’s disease, intestinal nerve abnormalities, metabolic or endocrine causes. Eligible abstracts and full texts were independently reviewed by two reviewers. Data were extracted by one reviewer and cross-checked by a second. Two reviewers independently applied descriptive codes to categorise the type of study, aim/focus of the study, outcomes, types of interventions/intervention combinations, and availability of data relating to effectiveness, economics or implementation factors. In keeping with scoping review methodology, we did not formally assess research quality. Data were summarised within an evidence gap map. Systematic reviews of evidence of effectiveness For our SRs of evidence of effectiveness, we considered all studies identified in the scoping review and ‘tagged’ them as studies of effectiveness. We included any studies investigating effectiveness of any intervention, or combination of interventions, aimed at improving outcomes in children with CFC. Informed by our stakeholders, we grouped studies according to whether the intervention was one that would be delivered by families/carers (‘Level 0’), the wider children’s workforce (e.g. general practitioner, health visitor) (‘Level 1’), continence teams (‘Level 2’) or specialist consultant-led teams (‘Level 3’). We also considered different models of service delivery, and complementary and psychosocial therapies. For each different intervention, we adopted a hierarchical, step-wise approach to inclusion of different study designs. If there was a comprehensive SR, judged to be low risk of bias (ROB) [using risk of bias assessment tool for systematic reviews (ROBIS) criteria, assessed by two independent reviewers], this was also included. Where we included a SR, we also included any randomised controlled trials (RCTs) published after the date of the search in the review. Where there was no SR, we included RCTs and other primary studies of intervention effectiveness. Data were extracted on study methods, participant characteristics, intervention characteristics [using template for intervention description and replication (TIDieR) framework], outcomes and key findings. ROB was judged using tools appropriate to the study design [e.g. Cochrane ROB tool for RCTs, critical appraisals skills programme (CASP) tools for cohort studies, Joanna Briggs Institute (JBI) tools for qualitative evidence, Ways of Evaluating Important and Relevant Data (WEIRD) tool for other study designs]. Relevant meta-analyses within included SRs were updated with any new RCTs following the methods reported in the SR. A narrative synthesis of evidence of effectiveness for each intervention, delivered within ‘level’ 0 to 3 was presented, with a process of considered judgement used to judge certainty in the evidence as high, moderate, low, very low or insufficient evidence. Economic evaluation For our SR of economic studies, we considered any economic evidence identified in our scoping review and conducted additional searching of electronic databases and citation tracking following best practice guidance. We included all types of study detailing costs related to interventions aimed at children with CFC that were published in English, regardless of study design. One reviewer extracted data, including details of economic evaluations, and these were checked by a second reviewer. Studies were categorised as cost-consequence, cost-effectiveness, cost-utility or cost-benefit and their quality evaluated using the consensus health economic criteria (CHEC) checklist, and data were brought together into a narrative synthesis. Systematic review of factors affecting implementation For our SR of factors affecting implementation, we included studies which were identified in the scoping review as explicitly reporting data relating to key participant variables, barriers, facilitators, equity factors and adherence. One reviewer systematically identified, extracted and coded [using the consolidated framework for implementation research (CFIR)] barriers and facilitators, and a second reviewer checked this. We used a best fit framework synthesis approach combining deductive and inductive thematic approaches to identify barriers and facilitators. Data were brought together in a narrative synthesis organised around the CFIR domains. Integration of findings Our integration of findings from the SRs was informed by decisions taken by our stakeholders, including development of a logic model. We explored agreements between our findings and recommendations within previously published guidelines. We brought our findings together within interactive evidence maps, and systematically identified evidence gaps. Results The scoping review included 651 studies, including 190 RCTs and 236 primary studies. Forty-eight interventions (or combinations of interventions) were reported. Studies were mainly conducted in high-income countries; no studies from low-income countries were identified. The most frequently reported interventions were delivered by carers, prior to healthcare professional involvement (22%); these were primarily lifestyle interventions focused on diet. The least frequently reported were psychosocial interventions (3%). Children were recruited from a variety of settings including hospitals, clinical outpatients, and other community settings. Interventions were generally delivered face to face either at home or within a variety of hospital settings such as the emergency department. Interventions were rarely delivered in education settings (e.g. school-based settings) (n = 5) or residential care/looked after population (n = 1) settings. The most frequently reported outcome measurement was defaecation frequency, which was reported in one-third of studies within the scoping review. School attendance or absenteeism was the least frequently reported outcome (n = 8 studies). Our SRs of effectiveness included 32 studies (including 2 SRs) which explored effectiveness of interventions delivered by families/carers (‘Level 0’); 21 studies (including 2 SRs) which explored effectiveness of interventions delivered by wider children’s workforce (‘Level 1’); 31 studies (including 1 SR) which explored effectiveness of interventions delivered by continence teams (‘Level 2’); 42 studies (no SRs) which explored effectiveness of interventions delivered by specialist consultant-led teams (‘Level 3’); 15 studies (no SRs) which explored effectiveness of different models of service delivery; 15 studies (2 SRs) which explored effectiveness of complementary therapies; and 4 studies (1 SR) which explored effectiveness of psychosocial interventions. Interventions for which there was some evidence of potential benefit included, within Level 0: a trial of cows’ milk-free diet, educational interventions for parents, selenium supplements. Within Level 1: laxatives, physical exercise focused on pelvic floor muscle, combined pharmacological, diet and behaviour programme. Within Level 2: combined oral and enema therapy, transanal irrigation, biofeedback (for children with abnormal defaecation dynamics), combined treatment programmes. Within Level 3: botulinum toxin, antegrade continence enema (ACE)/Malone antegrade continence enema (MACE), sacral modulation. Models of care delivery which may be beneficial included nurse-led clinics, an algorithm, or care pathway, used in primary care settings, specialist (Level 2) services and web-based information, following an appointment with a specialist. Complementary therapies for which there was some evidence of effectiveness included: connective tissue manipulation (CTM) for children with cerebral palsy (CP), and some herbal/traditional medicines. There was some evidence in favour of behavioural therapy. Interventions which evidence suggests may not be beneficial include, probiotics, additional dietary fibre, increased fluid intake and biofeedback (for children with normal defaecation dynamics). Evidence relating to probiotics was judged to be moderate quality, but for all other interventions was considered low to very low quality. There was insufficient evidence to support conclusions relating to several other interventions. We identified 31 studies which reported some evidence relating to cost or resource use, of which 20 were cost-of-illness studies. Fewer than 30% of the studies employed a formal economic evaluation study design. Most studies were poorly reported with limited details. Data included in this review were insufficient to support any generalisable conclusions relating to cost or resource use. One hundred and six studies described multiple barriers and facilitators across the five domains of the CFIR framework. The most commonly reported factors related to ‘successfulness’ of an intervention included; whether the intervention was adaptable, flexible and offered an advantage over an alternative solution; understanding the tension for change (i.e. why clinicians and families felt that the changes were needed now); the taboo nature of constipation and the reluctance of children, families, healthcare professionals and wider society to openly engage in discussion about constipation; a lack of understanding of what children and their families need; self-efficacy, coupled with individual knowledge and beliefs; and engagement of champions to support children. Research gaps were identified through evidence maps and stakeholder discussions. Key topics considered priorities for future research relate to recognition of CFC; information provision; diet; laxatives and combinations of laxatives; behavioural therapy and psychological support. Future research studies should address what works for which individual child, and when, including children with and without additional needs. Research to explore the optimal delivery of services, including identification of key components and features of effective teams and criteria for referring children from one ‘level’ to the next, is needed. Conclusions We conducted a comprehensive review of all evidence relating to interventions, and combinations of interventions, for children with CFC. The finding from our review are generally in agreement with the current guideline recommendations, where recommendations exist. A significant proportion of interventions for which we found evidence had not been addressed within current guidelines. This project has highlighted that research in this field often does not adhere to recognised standards for conduct and reporting or consider the complexities of interventions for CFC. We found no evidence which gave us high certainty in the findings; and we only had moderate certainty relating to one intervention (probiotics, with evidence demonstrating that probiotics may not have any beneficial – or harmful – effect). Our certainty about all other findings was low to very low or, in many cases, we judged that the evidence was insufficient to support any generalised conclusions. The current evidence base rarely measured outcomes deemed of highest priority to children and families, and many studies failed to describe the complex nature of the treatments that a child may be receiving. This limits the conclusions that can be made from the current evidence. Further, the limitations within the evidence base reduce confidence in recommendations and create a barrier to implementation of best practice, impairing progress in efforts to improve outcomes for this group of children. Our findings do not indicate that changes are necessarily needed to the treatment recommendations within current clinical guidelines. However, management of childhood CFC is complex, and there is no simple ‘one size fits all’ approach. Clinical care and future studies must consider the individual characteristics of each child with constipation, and the context – or environment – within which they live. Key goals of successful management of CFC should be early recognition of symptoms and delivery of interventions by families/carers, achieved by providing children and families/carers with effective education and support from members of the wider children’s workforce (primary care services). Development, evaluation and implementation of strategies to enhance the delivery of services focused on individualised care, combining lifestyle and behavioural strategies with laxatives are a priority. To avoid further research waste, it is essential that future research addresses the questions which are of the highest priority to key stakeholders and has the highest possible standards of conduct and reporting. Future research studies should address what works for which individual child, and when, including children with and without additional needs. Future research into any interventions for childhood CFC should take into account relevant evidence relating to the development and evaluation of complex interventions. Study registration This study is registered as PROSPERO CRD42019159008. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 128470) and is published in full in Health Technology Assessment; Vol. 28, No. 5. See the NIHR Funding and Awards website for further award information.

Aim: To uncover differences in small non‐coding RNAs (sncRNAs) in individuals with type 2 diabetes (T2D) categorized into five clusters based on individual characteristics, which may aid in the identification of those prone to rapid progression. Materials and Methods: In the Hoorn Diabetes Care System (DCS) cohort, participants were clustered by age, body mass index (BMI), and glycated haemoglobin, C‐peptide and high‐density lipoprotein (HDL) cholesterol levels, yielding severe insulin‐deficient diabetes, severe insulin‐resistant diabetes (SIRD), mild obesity‐related diabetes (MOD), mild diabetes, and mild diabetes with high HDL cholesterol clusters (n = 412). Utilizing plasma sncRNA‐sequencing, we identified distinct cluster‐specific sncRNAs. Validation was performed in a smaller DCS Hoorn dataset (n = 138). To elucidate their potential functions, we examined tissue expression, identified potential targets or (co‐)regulated proteins, conducted gene set enrichment analyses on the targets through Reactome, and examined tissue expression of the (co‐)regulated proteins. Results: The insulin‐resistant cluster exhibited aberrant expression of 10 sncRNAs, while the high BMI cluster featured eight differentially expressed sncRNAs. Multiple (co‐)regulated proteins were identified for sncRNAs associated with both clusters. Proteins associated with both clusters showed enrichment for metabolism. Proteins that specifically and only associated with the SIRD cluster showed enrichment for immune‐related signalling. Furthermore, MOD cluster‐specific associated proteins showed enrichment for the complement system. Conclusions: Our research showed differential sncRNA levels among type 2 diabetes clusters. This may reflect and could deepen our understanding of molecular mechanisms, in development, progression, and risk factors for each cluster. [ABSTRACT FROM AUTHOR]

In the quest for sustainable paints and coatings, bio-based resources for the polymeric binder constituents are key. Recently, we introduced poly-butenolides as bio-based acrylate replacement for solventborne and 100% solids (UV-curing) coatings. Here, we report the first step towards aqueous poly-butenolide dispersions, enabling the use of this novel binder technology platform in waterborne coatings. [ABSTRACT FROM AUTHOR]

Aims: We aimed to determine the association between serum interleukin‐6 (IL‐6) concentrations and new‐onset heart failure (HF) in persons with type 2 diabetes (T2D). Methods and results: We performed a case–control study nested in the Diabetes Care System Cohort, a prospective cohort of persons with T2D in primary care. We included 724 participants, of whom 141 developed HF during 5 years of follow‐up and 583 were age‐ and sex‐matched controls. IL‐6 was measured at baseline and categorized into four groups: Group 1 was composed of participants with IL‐6 below the detection limit of 1.5 pg/mL, and the remainder were divided into tertiles. We performed logistic regression analyses with categorized IL‐6 or continuous IL‐6 as the determinant and new‐onset HF as the outcome adjusted for follow‐up time, age, sex, glycated haemoglobin, estimated glomerular filtration rate, albumin/creatinine ratio, and cardiovascular disease at baseline. Effect modification by sex was tested. Participants were 70.7 ± 9.0 years, and 38% were women. In comparison with Group 1, all tertiles were associated with an increased risk of HF with odds ratios of 2.1 [95% confidence interval (CI): 1.2–2.9], 2.8 (95% CI: 2.0–3.7), and 2.1 (95% CI: 1.3–3.0), respectively, for Tertiles 1–3. Continuous IL‐6 was associated with the development of HF with an odds ratio of 1.2 (95% CI: 1.0–1.5). No effect modification by sex was observed. Conclusions: Higher IL‐6 levels are associated with the development of HF in persons with T2D. Further research should determine whether IL‐6‐lowering interventions could prevent the development of HF. [ABSTRACT FROM AUTHOR]