Evidence-based interventions for identifying candidate quality indicators to assess quality of care in diabetic foot clinics: a scoping review.

BACKGROUND: Foot ulcers in people with diabetes are a serious complication requiring a complex management and have a high societal impact. Quality monitoring systems to optimize diabetic foot care exist, but a formal and more evidence-based approach to develop quality indicators (QIs) is lacking. We aimed to identify a set of candidate indicators for diabetic foot care by adopting an evidence-based methodology. METHODS: A systematic search was conducted across four academic databases: PubMed, Embase CINAHL and Cochrane Library. Studies that reported evidence-based interventions related to organization or delivery of diabetic foot care were searched. Data from the eligible studies were summarized and used to formulate process and structure indicators. The evidence for each candidate QI was described in a methodical and transparent manner. The review process was reported according to the "Preferred Reported Items for Systematic reviews and Meta-Analysis" (PRISMA) statements and its extension for scoping reviews. RESULTS: In total, 981 full-text articles were screened, and 322 clinical studies were used to formulate 42 candidate QIs. CONCLUSIONS: An evidence-based approach could be used to select candidate indicators for diabetic foot ulcer care, relating to the following domains: wound healing interventions, peripheral artery disease, offloading, secondary prevention, and interventions related to organization of care. In a further step, the feasibility of the identified set of indicators will be assessed by a multidisciplinary panel of diabetic foot care stakeholders.

International comparison of glycaemic control in people with type 1 diabetes: an update and extension.

AIMS: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes. METHODS: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA1c (IQR) and proportions of individuals with HbA1c < 58 mmol/mol (<7.5%), 58-74 mmol/mol (7.5-8.9%) and ≥75 mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15-24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA1c < 58 mmol/mol (<7.5%) relative to ≥58 mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA1c category compared to previous estimates were calculated. RESULTS: Median HbA1c varied from 55 to 79 mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA1c < 58 mmol/mol (<7.5%) were 0.91 (0.90-0.92) for women compared to men, 1.68 (1.65-1.71) for people aged <15 years and 0.81 (0.79-0.82) aged15-24 years compared to those aged ≥25 years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA1c  < 58 mmol/l (<7.5%) increased and proportions of people with HbA1c ≥ 75 mmol/mol (≥9.0%) decreased. CONCLUSIONS: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.

The evolving personal, professional and physical impact on healthcare professionals during three COVID-19 waves: A cross-sectional study.

BACKGROUND: The COVID-19 pandemic has led to huge pressure on not only healthcare systems, but also on healthcare professionals. OBJECTIVE: As the pandemic continues, the aim of this study is to evaluate how 10 reactions of healthcare professionals evolved during the first 18 months of COVID-19. METHODS: A repeated cross-sectional study was performed with eight measurement points between April 2020 and September 2021 in Belgium. Participants were asked how frequently (on a scale of 0-10) they experienced positive and negative reactions during normal circumstances and during past week, referred to as before and during COVID-19, respectively. These reactions were stress, fatigue, difficulty sleeping, muscle strain, hypervigilance, leaving profession, headache, doubting knowledge and skills, flashbacks and fear. RESULTS: In total, 13 308 respondents were included in our study. During both the first (March 2020) and second COVID-19 peak (November 2020), the measured personal, professional and physical reactions were significantly higher compared to before COVID-19. The third wave in April 2021 was shorter and less severe with regard to hospital admissions and deaths, yet an important impact on healthcare professionals could still be observed. 'Fatigue,' 'stress,' 'difficulty sleeping' and 'muscle strain' are the most worrying reactions in September 2021, which are increasing compared to the previous measurements. CONCLUSION: Our results showed that acute stress reactions decreased over time but that chronic stress reactions and professional reactions, such as 'intent to leave,' increased. Healthcare organizations and policy makers should realize that 18 months after the start of COVID-19 almost all of the measured reactions continue to be more prevalent than before COVID-19. Moreover, the continuous increase over the last three measurement periods of the number of healthcare professionals who want to leave their profession is alarming. Continuous follow-up of the personal, professional and physical reactions is more than necessary.

General practice patients starting treatment for substance use problems: observations from two data sources across levels of care.

BACKGROUND: In Belgium, the incidence of treatment episodes for substance use problems is monitored by the Network of Sentinel General Practices (SGP), and at higher, specialist care levels by the Treatment Demand Indicator (TDI) surveillance. Using both data sources, we examine 1) how patients starting specialist treatment for substance use problems on referral by their GP compare to those that were referred by non-GP caregivers; 2) how patients starting GP treatment for substance use problems without receiving concurrent specialist treatment compare to those who did. METHODS: Both surveillances are based on the TDI protocol for reporting data to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) on individuals starting treatment as a result of their substance use. Data from 2016 and 2017 were examined using 95% confidence intervals and multivariate logistic regression. RESULTS: According to TDI-data (n = 16,543), determinants of being referred by a GP (versus by a non-GP caregiver) for specialist treatment were age ≥ median (OR 1.25; 95% CI 1.13-1.38), education ≥ secondary level (OR 1.27; 95% CI 1.15-1.41), recent employment (OR 1.71; 1.56-1.88), recent stable accommodation (3.62; 95% CI 3.08-4.26), first treatment episode (OR 1.72; 95% CI 1.57-1.87), recent daily primary substance use (OR 1.46; 95% CI 1.33-1.59) and mono substance use (OR 1.23; 95% CI 1.04-1.48). Type of substance use was a significant determinant with higher odds of using pharmaceuticals (and alcohol) (OR 1.24; 95% CI 1.04-1.48), and lower odds of using cannabis only/primarily (OR 0.73; 95% CI 0.62-0.86), with reference to street drugs minus cannabis only/primarily. According to SGP data (n = 314), determinants of starting GP treatment without concurrent specialist treatment were recent employment (OR 2.58; 95% CI 1.36-4.91), first treatment episode (OR 2.78; 95% CI 1.39-5.55) and living in the Brussels or Walloon region (OR 1.97; 95% CI 1.06-3.66). CONCLUSIONS: This study provides a useful insight into the general practice population treated for substance use problems. It shows that both surveillances consistently found a relatively favourable profile of general practice patients with substance use problems.

Decreasing rates of major lower-extremity amputation in people with diabetes but not in those without: a nationwide study in Belgium.

AIMS/HYPOTHESIS: The reduction of major lower-extremity amputations (LEAs) is one of the main goals in diabetes care. Our aim was to estimate annual LEA rates in individuals with and without diabetes in Belgium, and corresponding time trends. METHODS: Data for 2009-2013 were provided by the Belgian national health insurance funds, covering more than 99% of the Belgian population (about 11 million people). We estimated the age-sex standardised annual amputation rate (first per year) in the populations with and without diabetes for major and minor LEAs, and the corresponding relative risks. To test for time trends, Poisson regression models were fitted. RESULTS: A total of 5438 individuals (52.1% with diabetes) underwent a major LEA, 2884 people with above- and 3070 with below-the-knee major amputations. A significant decline in the major amputation rate was observed in people with diabetes (2009: 42.3; 2013: 29.9 per 100,000 person-years, 8% annual reduction, p < 0.001), which was particularly evident for major amputations above the knee. The annual major amputation rate remained stable in individuals without diabetes (2009: 6.1 per 100,000 person-years; 2013: 6.0 per 100,000 person-years, p = 0.324) and thus the relative risk reduced from 6.9 to 5.0 (p < 0.001). A significant but weaker decrease was observed for minor amputation in individuals with and without diabetes (5% and 3% annual reduction, respectively, p < 0.001). CONCLUSIONS/INTERPRETATION: In this nationwide study, the risk of undergoing a major LEA in Belgium gradually declined for individuals with diabetes between 2009 and 2013. However, continued efforts should be made to further reduce the number of unnecessary amputations.

The German and Belgian accreditation models for diabetic foot services.

The International Working Group on the Diabetic Foot recommends that auditing should be part of the organization of diabetic foot care, the efforts required for data collection and analysis being balanced by the expected benefits. In Germany legislature demands measures of quality management for in- and out-patient facilities, and, in 2003, the Germany Working Group on the Diabetic Foot defined and developed a certification procedure for diabetic foot centres to be recognized as 'specialized'. This includes a description of management facilities, treatment procedures and outcomes, as well as the organization of mutual auditing visits between the centres. Outcome data is collected at baseline and 6 months on 30 consecutive patients. By 2014 almost 24,000 cases had been collected and analysed. Since 2005 Belgian multidisciplinary diabetic foot clinics could apply for recognition by health authorities. For continued recognition diabetic foot clinics need to treat at least 52 patients with a new foot problem (Wagner 2 or more or active Charcot foot) per annum. Baseline and 6-month outcome data of these patients are included in an audit-feedback initiative. Although originally fully independent of each other, the common goal of these two initiatives is quality improvement of national diabetic foot care, and hence exchanges between systems has commenced. In future, the German and Belgian accreditation models might serve as templates for comparable initiatives in other countries. Just recently the International Working Group on the Diabetic Foot initiated a working group for further discussion of accreditation and auditing models (International Working Group on the Diabetic Foot AB(B)A Working Group).

Clinical action measures improve the reliability of feedback on quality of care in diabetes centres: a retrospective cohort study.

BACKGROUND: Assessment of quality of care using classical threshold measures (TM) is open to debate. Measures that take into account the clinician's actions and the longitudinal nature of chronic care are more reliable, although their major limitation is that they require more sophisticated electronic health records. We created a clinical action measure (CAM) for the control of LDL and non-HDL cholesterol from low-complexity data, and investigated how quality of care in individual diabetes centres based on the CAM is related to that based on the classical TM. METHODS: Data was used from 3421 diabetes patients treated in 95 centres, collected in two consecutive retrospective data collections. Patients met the TM when their index value was below target. Patients met the CAM when their index value was below target or above target but for whom treatment initiation or intensification, or possible contraindication, was indicated. RESULTS: Based on the TM, 60-70 % of the patients received good care. This percentage increased significantly using the CAM (+5 %, p < 0.001). At the centre level, the CAM was associated with a higher median score, and a change in position among centres ('poor', 'good' or 'excellent' performer) for 5-10 % of the centres. CONCLUSIONS: Judging quality of diabetes care of a centre based on a TM may be misleading. Low-complexity data available from a quality improvement initiative can be used to construct a more fair and feasible measure of quality of care.

Implementation of a quality improvement initiative in Belgian diabetic foot clinics: feasibility and initial results.

BACKGROUND: This article aims to describe the implementation and initial results of an audit-feedback quality improvement initiative in Belgian diabetic foot clinics. METHODS: Using self-developed software and questionnaires, diabetic foot clinics collected data in 2005, 2008 and 2011, covering characteristics, history and ulcer severity, management and outcome of the first 52 patients presenting with a Wagner grade ≥ 2 diabetic foot ulcer or acute neuropathic osteoarthropathy that year. Quality improvement was encouraged by meetings and by anonymous benchmarking of diabetic foot clinics. RESULTS: The first audit-feedback cycle was a pilot study. Subsequent audits, with a modified methodology, had increasing rates of participation and data completeness. Over 85% of diabetic foot clinics participated and 3372 unique patients were sampled between 2005 and 2011 (3312 with a diabetic foot ulcer and 111 with acute neuropathic osteoarthropathy). Median age was 70 years, median diabetes duration was 14 years and 64% were men. Of all diabetic foot ulcers, 51% were plantar and 29% were both ischaemic and deeply infected. Ulcer healing rate at 6 months significantly increased from 49% to 54% between 2008 and 2011. Management of diabetic foot ulcers varied between diabetic foot clinics: 88% of plantar mid-foot ulcers were off-loaded (P10-P90: 64-100%), and 42% of ischaemic limbs were revascularized (P10-P90: 22-69%) in 2011. CONCLUSIONS: A unique, nationwide quality improvement initiative was established among diabetic foot clinics, covering ulcer healing, lower limb amputation and many other aspects of diabetic foot care. Data completeness increased, thanks in part to questionnaire revision. Benchmarking remains challenging, given the many possible indicators and limited sample size. The optimized questionnaire allows future quality of care monitoring in diabetic foot clinics.

Monitoring COVID-19 in Belgian general practice: A tool for syndromic surveillance based on electronic health records.

BACKGROUND: COVID-19 may initially manifest as flu-like symptoms. As such, general practitioners (GPs) will likely to play an important role in monitoring the pandemic through syndromic surveillance. OBJECTIVES: To present a COVID-19 syndromic surveillance tool in Belgian general practices. METHODS: We performed a nationwide observational prospective study in Belgian general practices. The surveillance tool extracted the daily entries of diagnostic codes for COVID-19 and associated conditions (suspected or confirmed COVID-19, acute respiratory infection and influenza-like illness) from electronic medical records. We calculated the 7-day rolling average for these diagnoses and compared them with data from two other Belgian population-based sources (laboratory-confirmed new COVID-19 cases and hospital admissions for COVID-19), using time series analysis. We also collected data from users and stakeholders about the syndromic surveillance tool and performed a thematic analysis. RESULTS: 4773 out of 11,935 practising GPs in Belgium participated in the study. The curve of contacts for suspected COVID-19 followed a similar trend compared with the curves of the official data sources: laboratory-confirmed COVID-19 cases and hospital admissions but with a 10-day delay for the latter. Data were quickly available and useful for decision making, but some technical and methodological components can be improved, such as a greater standardisation between EMR software developers. CONCLUSION: The syndromic surveillance tool for COVID-19 in primary care provides rapidly available data useful in all phases of the COVID-19 pandemic to support data-driven decision-making. Potential enhancements were identified for a prospective surveillance tool.

Data extracted daily from electronic medical records can be used to monitor the COVID-19 pandemic in general practice.The Barometer provided rapidly available data to support data-driven decision-making.Improvements such as a greater standardisation were identified for a potential future tool using the same technology.

Accounting for Adverse Events Following Immunization in Economic Evaluation: Systematic Review of Economic Evaluations of Pediatric Vaccines Against Pneumococcus, Rotavirus, Human Papillomavirus, Meningococcus and Measles-Mumps-Rubella-Varicella.

OBJECTIVES: Economic evaluations of vaccines should accurately represent all relevant economic and health consequences of vaccination, including losses due to adverse events following immunization (AEFI). We investigated to what extent economic evaluations of pediatric vaccines account for AEFI, which methods are used to do so and whether inclusion of AEFI is associated with study characteristics and the vaccine's safety profile. METHODS: A systematic literature search (MEDLINE, EMBASE, Cochrane Systematic Reviews and Trials, Database of the Centre for Reviews and Dissemination of the University of York, EconPapers, Paediatric Economic Database Evaluation, Tufts New England Cost-Effectiveness Analysis Registry, Tufts New England Global Health CEA, International Network of Agencies for Health Technology Assessment Database) was performed for economic evaluations published between 2014 and 29 April 2021 (date of search) pertaining to the five groups of pediatric vaccines licensed in Europe and the United States since 1998: the human papillomavirus (HPV) vaccines, the meningococcal vaccines (MCV), the measles-mumps-rubella-varicella (MMRV) combination vaccines, the pneumococcal conjugate vaccines (PCV) and the rotavirus vaccines (RV). Rates of accounting for AEFI were calculated, stratified by study characteristics (e.g., region, publication year, journal impact factor, level of industry involvement) and triangulated with the vaccine's safety profile (Advisory Committee on Immunization Practices [ACIP] recommendations and information on safety-related product label changes). The studies accounting for AEFI were analyzed in terms of the methods used to account for both cost and effect implications of AEFI. RESULTS: We identified 112 economic evaluations, of which 28 (25%) accounted for AEFI. This proportion was significantly higher for MMRV (80%, four out of five evaluations), MCV (61%, 11 out of 18 evaluations) and RV (60%, nine out of 15 evaluations) compared to HPV (6%, three out of 53 evaluations) and PCV (5%, one out of 21 evaluations). No other study characteristics were associated with a study's likelihood of accounting for AEFI. Vaccines for which AEFI were more frequently accounted for also had a higher frequency of label changes and a higher level of attention to AEFI in ACIP recommendations. Nine studies accounted for both the cost and health implications of AEFI, 18 studies considered only costs and one only health outcomes. While the cost impact was usually estimated based on routine billing data, the adverse health impact of AEFI was usually estimated based on assumptions. DISCUSSION: Although (mild) AEFI were demonstrated for all five studied vaccines, only a quarter of reviewed studies accounted for these, mostly in an incomplete and inaccurate manner. We provide guidance on which methods to use to better quantify the impact of AEFI on both costs and health outcomes. Policymakers should be aware that the impact of AEFI on cost-effectiveness is likely to be underestimated in the majority of economic evaluations.

Sex differences in diabetic foot ulcer severity and outcome in Belgium.

BACKGROUND: Sex differences are increasingly recognized to play an important role in the epidemiology, treatment and outcomes of many diseases. This study aims to describe differences between sexes in patient characteristics, ulcer severity and outcome after 6 months in individuals with a diabetic foot ulcer (DFU). METHODS: A total of 1,771 patients with moderate to severe DFU participated in a national prospective, multicenter cohort study. Data were collected on demographics, medical history, current DFU and outcome. For data analysis, a Generalized Estimating Equation model and an adjusted Cox proportional hazards regression were used. RESULTS: The vast majority of patients included were male (72%). Ulcers in men were deeper, more frequently displaying probe to bone, and more frequently deeply infected. Twice as many men presented with systemic infection as women. Men demonstrated a higher prevalence of previous lower limb revascularization, while women presented more frequently with renal insufficiency. Smoking was more common in men than in women. No differences in presentation delay were observed. In the Cox regression analysis, women had a 26% higher chance of healing without major amputation as a first event (hazard ratio 1.258 (95% confidence interval 1.048-1.509)). CONCLUSIONS: Men presented with more severe DFU than women, although no increase in presentation delay was observed. Moreover, female sex was significantly associated with a higher probability of ulcer healing as a first event. Among many possible contributing factors, a worse vascular state associated with a higher rate of (previous) smoking in men stands out.

The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy.

In this review, we address clinical aspects and mechanisms of ventricular dysfunction induced by anticancer drugs targeted to the ErbB2 receptor. ErbB2 antagonists prolong survival in cancer, but also interfere with homeostatic processes in the heart. ErbB2 is a coreceptor for ErbB4, which is activated by neuregulin-1. This epidermal growth factor-like growth factor is released from endothelial cells in the endocardium and in the myocardial microcirculation, hence contributing to intercellular crosstalk in the ventricle. We look at the physiological aspects of neuregulin-1/ErbB signaling in the ventricle, and review its (mal)adaptive responses in chronic heart failure. We also compare structural aspects of ErbB receptor activation in cancer and cardiac cells, and analyze the mode of action of current ErbB2 antagonists. This allows us to predict how these drugs interfere with paracrine processes in the ventricle. Differences in the mode of action of individual ErbB2 antagonists affect their impact on the function of the ventricle, considered to be "on-target" or "off-target." Establishing the relation between the cardiac side effects of ErbB2 antagonists and their impact on paracrine ventricular control mechanisms may direct the design of a next generation of ErbB2 inhibitors. For cardiologists, there are lessons to be learned from the unexpected side effects of ErbB2-targeted cancer therapy. The vulnerability of the heart as a pluricellular paracrine system appears greater than anticipated and intercellular crosstalk an essential component of its functional and structural integrity.

Bottom-up approach to build a 'precision' risk factor classification for diabetic foot ulcer healing. Proof-of-concept.

AIMS: Diabetic foot ulcers (DFU) have a complex multifactorial pathophysiology. It is crucial to identify essential prognostic variables to streamline therapeutic actions and quality-of-care audits. Although SINBAD and University of Texas (UT), the most frequently used prognostic classification systems, were prospectively validated, not all individual parameters were shown to have consistent associations with healing. In this study, we used a bottom-up approach relying on robust methods to identify independent predictors of DFU healing. METHODS: 1,664 DFU patients were included by 34 Belgian diabetic foot clinics (DFCs). Twenty-one patient- and foot-related characteristics were recorded at presentation. Predictors of healing were identified using multivariable Cox proportional hazard regression. Multivariable models were built using backward regression with multiple imputation of missing values and bootstrapping. RESULTS: Five essential independent variables were identified: presentation delay, history of minor amputation, ulcer location, surface area and ischemia. This 5 variable-model showed a better performance compared to models based on existing classification systems. CONCLUSIONS: A bottom-up approach was used to build a prognostic classification for DFU healing based on large databases. It offers new insights and allows to tailor the classification to certain clinical settings. These 5 parameters could be used as a 'precision classification' for specialized DFCs.

Burden of COVID-19 on primary care in Belgium: a prospective nationwide observational study from March to August 2020.

BACKGROUND: The COVID-19 outbreak had an important impact on general practice, for example the lack of personal protective equipment (PPE) and the switch to telephone consultations. We installed a monitoring instrument and reported the burden the COVID-19 pandemic placed on Belgian general practitioners (GPs) during the first wave of the pandemic. METHODS: We conducted an observational longitudinal prospective study from the 19th of March until the 17th of August 2020. Daily data were collected by using a structured electronic form integrated into the GPs' electronic medical records (EMRs). Data were collected on the GPs' need for support and workload, epidemiological indicators and the availability of PPE. Reports with graphical presentations were made for GP circles and primary care zones, and governments of different administrative levels had access to all data to guide their policy. RESULTS: A total of 3.769 different GP centres participated, which included more than 10.000 GPs. Throughout the first three weeks, 20% declared they had insufficient resources (personnel and material) for the following week. Approximately 10% continued to report this during the entire study. The majority reported being able to complete their daily tasks without loss of quality. During the first week, 30% indicated an increased workload. Afterwards, this number decreased and stabilized to an average of 10-20%. More than 70% of the consultations in March 2020 were conducted by telephone. This percentage declined in April and stabilized at approximately 30% in June 2020. Consultations due to respiratory symptoms peaked at 4000/100,000 inhabitants at the beginning of the outbreak, then decreased over time along with the COVID-19 incidence. We noticed a lack of disinfectant hand gel, surgical masks and FFP2 masks, the latter remaining problematic in the long term. CONCLUSION: We introduced an instrument in Belgian EMR systems to monitor the burden on GPs during the first wave of the COVID-19 pandemic. The lack of PPE and increased workload were considered to be the main obstacles. A large number of the GP offices switched to teleconsultations to provide healthcare. Our monitoring instrument provided information for policy makers to intervene on a local level.

Activation of the neuregulin/ErbB system during physiological ventricular remodeling in pregnancy.

The neuregulin-1 (NRG1)/ErbB system has emerged as a paracrine endothelium-controlled system in the heart, which preserves left ventricular (LV) performance in pathophysiological conditions. Here, we analyze the activity and function of this system in pregnancy, which imparts a physiological condition of LV hemodynamic overload. NRG1 expression and ErbB receptor activation were studied by Western blot analyses in rats and mice at different stages of pregnancy. LV performance was evaluated by transthoracic echocardiography, and myocardial performance was assessed from twitches of isolated papillary muscles. NRG1/ErbB signaling was inhibited by oral treatment of animals with the dual ErbB1/ErbB2 tyrosine kinase inhibitor lapatinib. Analyses of LV tissue revealed that protein expression of different NRG1 isoforms and levels of phosphorylated ErbB2 and ErbB4 significantly increased after 1-2 wk of pregnancy. Lapatinib prevented phosphorylation of ErbB2 and ERK1/2, but not of ErbB4 and protein kinase B (Akt), revealing that lapatinib only partially inhibited NRG1/ErbB signaling in the LV. Lapatinib did not prevent pregnancy-induced changes in LV mass and did not cause apoptotic cell death or fibrosis in the LV. Nevertheless, lapatinib led to premature maternal death of ∼25% during pregnancy and it accentuated pregnancy-induced LV dilatation, significantly reduced LV fractional shortening, and induced abnormalities of twitch relaxation (but not twitch amplitude) of isolated papillary muscles. This is the first study showing that the NRG1/ErbB system is activated, and plays a modulatory role, during physiological hemodynamic overload associated with pregnancy. Inhibiting this system during physiological overload may cause LV dysfunction in the absence of myocardial cell death.

Effects of nebivolol on vascular endothelial and myocardial function in diabetes mellitus.

BACKGROUND: Nebivolol is a ß1-adrenergic receptor (ß1-AR) antagonist, inducing endothelial nitric oxide (NO) release, most likely due to ß3-AR agonism. Nebivolol is vasculoprotective and cardioprotective in the setting of hypertension. In this study, we investigated the effects of nebivolol, compared with those of bisoprolol, on vascular and myocardial function in diabetic mice. METHODS: Diabetic (Lepr) and nondiabetic mice (Lepr) were treated with vehicle, nebivolol, or bisoprolol for 16 weeks. Endothelium-dependent and endothelial-independent relaxations were studied in isolated aortic segments. Myocardial twitch performance was studied in isolated right ventricular papillary muscles. RESULTS: In aortic segments of diabetic mice, endothelium-dependent relaxations were significantly shifted to the right. This shift was not prevented by chronic nebivolol or bisoprolol treatment. Papillary muscle twitches of diabetic mice displayed a significant delay in the onset of relaxation, and an increased time from peak active force to 50% relaxation, leading to prolonged twitch activity, without changes in twitch amplitude. These changes were not prevented in nebivolol- and bisoprolol-treated diabetic mice. Surprisingly, in nebivolol-treated mice, regardless of diabetic status, twitch duration was further increased. Applying nebivolol to papillary muscles in the organ bath reproduced the changes induced by chronic treatment in vivo; this was not the case for bisoprolol. Nebivolol-induced changes were blunted by a ß3-AR antagonist and by NO synthase (NOS) inhibition. CONCLUSIONS: Diabetes-induced changes in vascular and myocardial function were not prevented by treatment with nebivolol or bisoprolol. Strikingly, myocardial effects of nebivolol differed from those of bisoprolol, by inducing a ß3-AR and NOS-dependent prolongation of twitch activity.

Effect of an Integrated, Multidisciplinary Nationwide Approach to Type 1 Diabetes Care on Metabolic Outcomes: An Observational Real-World Study.

Objective: Achieving good metabolic control in people with type 1 diabetes (T1D) remains a challenge, despite the evolutions in diabetes technologies over the past decade. Here we investigate the evolution of metabolic control in people with T1D, where care is provided by specialized centers with access to technology, diabetes education, and regular follow-up. Methods: Data were cross-sectionally collected between 2010 and 2018 from more than 100 centers in Belgium. The evolutions over time of hemoglobin A1C (HbA1c), low-density lipoprotein (LDL) cholesterol, and systolic blood pressure (SBP) were investigated, together with the evolutions of use of insulin pump (continuous subcutaneous insulin infusion [CSII]), continuous glucose monitoring (CGM), and lipid-lowering and antihypertensive drugs. Association of HbA1c with gender, age, diabetes duration, and technology use was analyzed on the most recent cohort. Results: The study population contained data from 89,834 people with T1D (age 1-80 years). Mean HbA1c decreased from 65 mmol/mol (8.1%) in 2010-2011 to 61 mmol/mol (7.7%) in 2017-2018 (P < 0.0001, adjusted for gender, age, diabetes duration, and technology use). Respectively, mean LDL cholesterol decreased from 2.45 mmol/L (94.6 mg/dL) to 2.29 mmol/L (88.5 mg/dL) (P < 0.0001, adjusted for gender, age, and diabetes duration), and mean SBP remained stable. CGM usage increased, whereas the use of CSII and lipid-lowering and antihypertensive drugs remained stable. Gender, age, diabetes duration, and technology use were independently associated with HbA1c. Conclusions: Our real-world data show that metabolic and lipid control improved over time in a system where T1D care is organized through specialized multidisciplinary centers with emphasis on linking education to provision of technology, and its quality is monitored.

Making Use of Comparable Health Data to Improve Quality of Care and Outcomes in Diabetes: The EUBIROD Review of Diabetes Registries and Data Sources in Europe.

Background: Registries and data sources contain information that can be used on an ongoing basis to improve quality of care and outcomes of people with diabetes. As a specific task of the EU Bridge Health project, we carried out a survey of diabetes-related data sources in Europe. Objectives: We aimed to report on the organization of different sources of diabetes information, including their governance, information infrastructure and dissemination strategies for quality control, service planning, public health, policy and research. Methods: Survey using a structured questionnaire to collect targeted data from a network of collaborating institutions managing registries and data sources in 17 countries in the year 2017. Results: The 18 data sources participating in the study were most frequently academic centres (44.4%), national (72.2%), targeting all types of diabetes (61.1%) covering no more than 10% of the target population (44.4%). Although population-based in over a quarter of cases (27.8%), sources relied predominantly on provider-based datasets (38.5%), fewer using administrative data (16.6%). Data collection was continuous in the majority of cases (61.1%), but 50% could not perform data linkage. Public reports were more frequent (72.2%) as well as quality reports (77.8%), but one third did not provide feedback to policy and only half published ten or more peer reviewed papers during the last 5 years. Conclusions: The heterogeneous implementation of diabetes registries and data sources hampers the comparability of quality and outcomes across Europe. Best practices exist but need to be shared more effectively to accelerate progress and deliver equitable results for people with diabetes.

Ventricular ErbB2/ErbB4 activation and downstream signaling in pacing-induced heart failure.

The neuregulin-1 (NRG-1)/ErbB system has emerged as a cardioprotective system that becomes activated during myocardial stress, most convincingly shown in response to cardiotoxic chemotherapy. Direct evidence of increased ventricular ErbB receptor activity in heart failure unrelated to cardiotoxic drugs is, however, limited. We investigated changes in NRG-1 expression, ErbB receptor phosphorylation and downstream activation of intracellular ErbB targets during rapid pacing and progressive ventricular dysfunction in the dog. Heart failure was induced in dogs by 7 weeks of rapid pacing. Ventricular function was assessed by echocardiography. Messenger RNA expression was investigated in ventricular biopsies using quantitative PCR. Activation of NRG-1/ErbB signaling and of downstream targets was investigated using immunoprecipitation and/or Western blotting. Over the course of 7 weeks of pacing and ventricular dilatation, ventricular levels of NRG-1, but not of other ErbB4 ligands, and of ADAM19, a protease promoting NRG-1 release, progressively increased. In parallel, levels of activated ErbB2 and ErbB4, phosphorylated at tyrosine residues 877/1248 and 1284 respectively, became progressively higher. Similarly, levels of total and phosphorylated PI-3 kinase increased. Surprisingly, however, and in contrast with activation of downstream targets of ErbB receptors in normal hearts, Akt and ERK1/2, remained inactivated. This study shows that ventricular ErbB2 and ErbB4 receptors become activated during the development of pacing-induced heart failure, but that downstream signaling is, at least partly, abrogated. Abrogation of cardioprotective signaling after ErbB activation is an unanticipated phenomenon in the progression of heart failure with possibly major pathophysiological significance. The underlying mechanisms should be further elucidated.

Health-related quality of life in patients with diabetic foot ulceration: study protocol for adaptation and validation of patient-reported outcome measurements (PROMs) in Dutch-speaking patients.

INTRODUCTION: Diabetic foot ulceration (DFU) is a common late-stage complication of diabetes with a large impact on health status and quality of life. Patient-reported outcome measures (PROMs) provide a standardised method of obtaining patients' views on their well-being. The DFU Scale Short Form (DFS-SF) is a validated disease-specific PROM for measuring health-related quality of life among DFU patients. The Lower Extremity Functional Scale (LEFS) is another PROM that can be used to measure physical functioning in patients with lower extremity disorders. The LEFS is not yet validated for DFU. Both instruments are not validated in the Dutch language. The purpose of this study is to culturally adapt and validate the DFS-SF and LEFS questionnaires for Belgian Dutch-speaking patients with DFU. METHODS AND ANALYSIS: This study will be conducted as a monocentre observational cohort study in DFU patients presenting at a hospital-based multidisciplinary diabetic foot clinic. Data will be collected from the medical electronic files and from DFS-SF, LEFS and five-level EuroQol five-dimension questionnaires that will be presented to the patients at defined time points. Reproducibility, internal consistency, floor and ceiling effects, construct validity and responsiveness will be assessed for the DFS-SF and LEFS. ETHICS AND DISSEMINATION: The study protocol has been approved by the Medical Ethics Committee of Onze-Lieve-Vrouw Hospital (Aalst, Belgium). The results of the study will be disseminated through peer-reviewed publications and conference presentations.