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OBJECTIVE Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction. RESEARCH DESIGN AND METHODS As an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions. RESULTS After establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (P < 5 × 10−8). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10−8), lower reduction in HbA1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10−58). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (P = 4.80 × 10−8). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10−7), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor. CONCLUSIONS We have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.

Aims/hypothesis Approximately 25% of people with type 2 diabetes experience a foot ulcer and their risk of amputation is 10–20 times higher than that of people without type 2 diabetes. Prognostic models can aid in targeted monitoring but an overview of their performance is lacking. This study aimed to systematically review prognostic models for the risk of foot ulcer or amputation and quantify their predictive performance in an independent cohort. Methods A systematic review identified studies developing prognostic models for foot ulcer or amputation over minimal 1 year follow-up applicable to people with type 2 diabetes. After data extraction and risk of bias assessment (both in duplicate), selected models were externally validated in a prospective cohort with a 5 year follow-up in terms of discrimination (C statistics) and calibration (calibration plots). Results We identified 21 studies with 34 models predicting polyneuropathy, foot ulcer or amputation. Eleven models were validated in 7624 participants, of whom 485 developed an ulcer and 70 underwent amputation. The models for foot ulcer showed C statistics (95% CI) ranging from 0.54 (0.54, 0.54) to 0.81 (0.75, 0.86) and models for amputation showed C statistics (95% CI) ranging from 0.63 (0.55, 0.71) to 0.86 (0.78, 0.94). Most models underestimated the ulcer or amputation risk in the highest risk quintiles. Three models performed well to predict a combined endpoint of amputation and foot ulcer (C statistics >0.75). Conclusions/interpretation Thirty-four prognostic models for the risk of foot ulcer or amputation were identified. Although the performance of the models varied considerably, three models performed well to predict foot ulcer or amputation and may be applicable to clinical practice. Graphical abstract

Objective A history of an eating disorder (ED) might constitute a risk for symptom deterioration and relapse during COVID‐19 pandemic. This longitudinal study investigates ED symptom trajectories until the first COVID‐19 lockdown in Spring 2020 in patients with a history of binge eating disorder (BED). Method Participants of the randomised‐controlled BED treatment trial IMPULS participated in a re‐assessment directly after the first COVID‐19 lockdown in Germany. We used expert‐rated clinical interviews and self‐report to investigate binge eating (BE) frequency, ED and general psychopathology, distress, emotion regulation and sense of coherence. Symptom trajectories were analysed for baseline when entering the trial, end of trial participation and the time point directly after lockdown. BE frequency was assessed on a recall basis for 4 weeks directly before lockdown and 4 weeks during lockdown. Results BE frequency, general ED pathology and depressive symptoms markedly increased after as compared to before the COVID‐19 outbreak. Individuals scoring high on reappraisal as emotion regulation strategy and sense of coherence scored lower on general ED pathology. Conclusion Individuals with a history of an ED are at risk for symptom deterioration and relapse during the pandemic. Intervention and service dissemination strategies are needed to support vulnerable groups throughout the pandemic., Highlights A well‐described sample of previously treatment‐seeking patients with binge eating disorder was reassessed directly after the first COVID‐19 lockdown in spring 2020.Binge eating frequency was markedly increased after as compared to before the COVID‐19 outbreak.General eating disorder pathology and depressive symptoms were markedly increased after the COVID‐19 outbreak as compared to trial termination.Individuals with a history of an eating disorder are at risk for symptom deterioration and relapse during the pandemic.

Purpose Partial meniscectomy is a common orthopedic procedure intended to improve knee pain and function in patients with irreparable meniscal tears. However, 6–25% of partial meniscectomy patients experience persistent knee pain after surgery. In this randomized controlled trial (RCT) involving subjects with knee pain following partial meniscectomy, it was hypothesized that treatment with a synthetic medial meniscus replacement (MMR) implant provides significantly greater improvements in knee pain and function compared to non-surgical care alone. Methods In this prospective, multicenter RCT, subjects with persistent knee pain following one or more previous partial meniscectomies were randomized to receive either MMR or non-surgical care. This analysis evaluated the 1-year outcomes of this 2-year clinical trial. Patient-reported knee pain, function, and quality of life were measured using nine separate patient-reported outcomes. The primary outcomes were the pain subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS) and the average of all five KOOS subscales (KOOS Overall). Treatment cessation was defined as permanent device removal in the MMR group and any surgical procedure to the index knee in the non-surgical care group. Results Treated subjects had a median age of 52 years old (range 30–69 years) and one or more previous partial meniscectomies at a median of 34 months (range 5–430 months) before trial entry. Among 127 subjects treated with either MMR (n = 61) or non-surgical care (n = 66), 11 withdrew from the trial or were lost to follow-up (MMR, n = 0; non-surgical care, n = 11). The magnitude of improvement from baseline to 1 year was significantly greater in subjects who received MMR in both primary outcomes of KOOS Pain (P = 0.013) and KOOS Overall (P = 0.027). Treatment cessation was reported in 14.5% of non-surgical care subjects and only 4.9% of MMR subjects (n.s.). Conclusion Treatment with the synthetic MMR implant resulted in significantly greater improvements in knee pain, function, and quality of life at 1 year of follow-up compared to treatment with non-surgical care alone. Level of evidence I.

Breastfeeding is an effective way to protect and promote the health of the infant and mother. Cultural, social, economic, medical, or psychological factors might interfere with successful breastfeeding. Therefore, maternal eating disorders (EDs) may have detrimental effects on the decision of breastfeeding initiation and on its continuation. There is limited knowledge about the breastfeeding practices of mothers with EDs. We performed a systematic review to generate more evidence in this area. A search was conducted in PubMed and PsycINFO, and several journals were hand searched for relevant publications. Of N = 3904 hits, 13 full texts were included in the qualitative analysis. The findings on total duration of BF between mothers with and without EDs were mixed, but women with EDs showed more negative experiences and emotional problems during BF. There was not enough evidence to conclude on breastfeeding initiation, or on the duration of exclusive breastfeeding. Maternal EDs might have a negative impact on BF practices with possible negative effects on the maternal-child feeding environment. Further studies with comparable data and information on the women’s partners’ attitudes about breastfeeding are needed.

Toxoplasmosis is caused by Toxoplasma gondii, an apicomplexan parasite that is able to infect any nucleated cell in any warm-blooded animal. Toxoplasma gondii infects around 2 billion people and, whilst only a small percentage of infected people will suffer serious disease, the prevalence of the parasite makes it one of the most damaging zoonotic diseases in the world. Toxoplasmosis is a disease with multiple manifestations: it can cause a fatal encephalitis in immunosuppressed people; if first contracted during pregnancy, it can cause miscarriage or congenital defects in the neonate; and it can cause serious ocular disease, even in immunocompetent people. The disease has a complex epidemiology, being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops, or by consumption of intracellular cysts in undercooked meat from intermediate hosts. In this review we examine current and future approaches to control toxoplasmosis, which encompass a variety of measures that target different components of the life cycle of T. gondii. These include: education programs about the parasite and avoidance of contact with infectious stages; biosecurity and sanitation to ensure food and water safety; chemo- and immunotherapeutics to control active infections and disease; prophylactic options to prevent acquisition of infection by livestock and cyst formation in meat; and vaccines to prevent shedding of oocysts by definitive feline hosts.

Deamidation of asparaginyl (Asn) peptides is a spontaneous post-translational modification that plays a significant role in degenerative diseases and other biological processes under physiological conditions. In the gas phase, deamidation of protonated peptides is a major fragmentation channel upon activation by collision-induced dissociation. Here, we present a full description of the deamidation process from protonated asparagine-serine, [AsnSer+H]+, -via infrared (IR) action spectroscopy and threshold collision-induced dissociation (TCID) experiments in combination with theoretical calculations. The IR results demonstrate that deamidation proceeds via bifurcating reaction pathways leading to furanone- and succinimide-type product ion structures, with a population analysis indicating the latter product dominates. Theory demonstrates that nucleophilic attack of the peptidyl amide oxygen onto the Asn side chain leads to furanone formation, whereas nudeophilic attack by the peptidyl amide nitrogen onto the Asn side-chain carbonyl carbon leads to the formation of the succinimide product structure. TCID experiments find that furanone formation has a threshold energy of 145 +/- 12 kJ/mol and succinimide formation occurs with a threshold energy of 131 +/- 12 kJ/mol, consistent with theoretical energies and with the spectroscopic results indicating that succinimide dominates. The results provide information regarding the inductive and steric effects of the Ser side chain on the deamidation process. The other major channel observed in the TCID experiments of [AsnSer+H]+ is dehydration, where a threshold energy of 104 +/- 10 kJ/mol is determined. A complete IR and theoretical analysis of this pathway is also provided. As for deamidation, a bifurcating pathway is found with both dominant oxazoline and minor diketopiperazine products identified. Here, the Ser side chain is directly involved in both pathways.

Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics strategies are being increasingly applied in metabolite screening for a wide variety of medical conditions. The long-standing "grand challenge" in the utilization of this approach is metabolite identification-confidently determining the chemical structures of m/z-detected unknowns. Here, we use a novel workflow based on the detection of molecular features of interest by high-throughput untargeted LC-MS analysis of patient body fluids combined with targeted molecular identification of those features using infrared ion spectroscopy (IRIS), effectively providing diagnostic IR fingerprints for mass-isolated targets. A significant advantage of this approach is that in silico-predicted IR spectra of candidate chemical structures can be used to suggest the molecular structure of unknown features, thus mitigating the need for the synthesis of a broad range of physical reference standards. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine metabolism, resulting from a mutation in the ALDH7A1 gene that leads to an accumulation of toxic levels of alpha-aminoadipic semialdehyde (alpha-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While alpha-AASA and P6C are known biomarkers for PDE in urine, their instability makes them poor candidates for diagnostic analysis from blood, which would be required for application in newborn screening protocols. Here, we use combined untargeted metabolomics-IRIS to identify several new biomarkers for PDE-ALDH7A1 that can be used for diagnostic analysis in urine, plasma, and cerebrospinal fluids and that are compatible with analysis in dried blood spots for newborn screening. The identification of these novel metabolites has directly provided novel insights into the pathophysiology of PDE-ALDH7A1.

Screening for kidney diseases is of vital importance due to their current prevalence worldwide. The diagnosis and monitoring of kidney diseases rely on kidney disease biomarkers (KDBs), which include traditional KDBs such as serum creatinine and proteinuria as well as novel biomarkers such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-ß-d-glucosaminidase (NAG), cystatin C, etc. The latter has been highly recognised for early and accurate diagnosis of kidney disease in the past decades. Fluorescence techniques have recently drawn considerable attention in the area of biomedicine due to the merits of high sensitivity, rapidity and cost efficiency. The combination of fluorescence technologies and KDBs has been proven by many studies to be a promising strategy for the prediction of kidney disease. Thus, in this review, we summarize recent advances of fluorescence technologies applied in the detection of traditional and novel KDBs. Due to the space limit, we focus on four traditional KDBs and eight novel KDBs as representatives. The design of fluorescent molecules, establishment of detection assays, and sensing mechanism of fluorescent probes are discussed in detail. Finally, future challenges and opportunities in this field are also analyzed. Through this review, we hope to inspire the discovery of novel fluorescence techniques with excellent performance in the early diagnosis of kidney diseases.

Aims/hypothesis In this study we examined the cost-effectiveness of three different screening strategies for diabetic retinopathy: using a personalised adaptive model, annual screening (fixed intervals), and the current Dutch guideline (stratified based on previous retinopathy grade). Methods For each individual, optimal diabetic retinopathy screening intervals were determined, using a validated risk prediction model. Observational data (1998–2017) from the Hoorn Diabetes Care System cohort of people with type 2 diabetes were used (n = 5514). The missing values of retinopathy grades were imputed using two scenarios of slow and fast sight-threatening retinopathy (STR) progression. By comparing the model-based screening intervals to observed time to develop STR, the number of delayed STR diagnoses was determined. Costs were calculated using the healthcare perspective and the societal perspective. Finally, outcomes and costs were compared for the different screening strategies. Results For the fast STR progression scenario, personalised screening resulted in 11.6% more delayed STR diagnoses and €11.4 less costs per patient compared to annual screening from a healthcare perspective. The personalised screening model performed better in terms of timely diagnosis of STR (8.8% less delayed STR diagnosis) but it was slightly more expensive (€1.8 per patient from a healthcare perspective) than the Dutch guideline strategy. Conclusions/interpretation The personalised diabetic retinopathy screening model is more cost-effective than the Dutch guideline screening strategy. Although the personalised screening strategy was less effective, in terms of timely diagnosis of STR patients, than annual screening, the number of delayed STR diagnoses is low and the cost saving is considerable. With around one million people with type 2 diabetes in the Netherlands, implementing this personalised model could save €11.4 million per year compared with annual screening, at the cost of 658 delayed STR diagnoses with a maximum delayed time to diagnosis of 48 months. Graphical abstract

Current meta-analyses demonstrate convincing evidence regarding the efficacy of exercise on depression, insomnia, anxiety disorders, schizophrenia and ADHD. However, exercise and sports therapy approaches for patients with psychological disorders are mostly integrated in psychiatric inpatient or rehabilitation settings, but not applied in the outpatient sector. Thus, the German Health sector does not take the advantage of the compelling therapeutic effects of exercise. This review covers the theoretical and empirical fundamentals of the effects of exercise and illustrates practical implications by means of the presentation of the group-therapeutic exercise program ImPuls, that was specifically designed for patients with psychological disorders in outpatient settings. ImPuls integrates current evidence of the effects of exercise (type of sport, duration, frequency, intensity) and the facilitation of motivational and volitional strategies to support patients to integrate exercise in their daily life routines.

Anorexia nervosa (AN) is a life‐threatening eating disorder, characterised by persistent pathological weight loss behaviours and an intense fear of weight gain and food consumption. Although there is an abundance of scientific theories on the neurobiological, psychological and sociocultural factors thought to be involved in the maintenance of AN, there is little experimental research testing these ideas. The need for theory firmly grounded in empirical evidence becomes strikingly clear when we consider that current treatments for patients with AN are limited in their effectiveness, and relapse after treatment is common.

Objective The selection of adequate portion sizes plays a key role in the nutritional treatment of eating disorders (EDs). There is limited knowledge concerning the estimation of portion sizes in individuals with EDs. Method We performed a systematic review according to the PRISMA statement to synthesise current evidence in this field. Of N = 584 hits, four full-texts were included in the qualitative synthesis. Results While patients with anorexia nervosa (AN) tend to overestimate the size of energy-dense food items and small to medium sized meal portions, they do not show a different estimation compared to healthy controls when judging the amount of food pieces. Large portion sizes were associated with increased anxiety in patients with AN. Discussion The overestimation of food portion sizes seems to be driven by attitudinal and/or higher cognitive factors associated with AN. Differences between the studies are discussed and suggestions for future studies are given.

Objective.Cardiovascular (CV) disease (CVD) risk is increased in rheumatoid arthritis (RA). However, longterm followup studies investigating this risk are scarce.Methods.The CARRÉ (CARdiovascular research and RhEumatoid arthritis) study is a prospective cohort study investigating CVD and its risk factors in 353 patients with longstanding RA. CV endpoints were assessed at baseline and 3, 10, and 15 years after the start of the study and are compared to a reference cohort (n = 2540), including a large number of patients with type 2 diabetes (DM).Results.Ninety-five patients with RA developed a CV event over 2973 person-years, resulting in an incidence rate of 3.20 per 100 person-years. Two hundred fifty-seven CV events were reported in the reference cohort during 18,874 person-years, resulting in an incidence rate of 1.36 per 100 person-years. Age- and sex-adjusted HR for CV events were increased for RA (HR 2.07, 95% CI 1.57–2.72, p < 0.01) and DM (HR 1.51, 95% CI 1.02–2.22, p = 0.04) compared to the nondiabetic participants. HR was still increased in RA (HR 1.82, 95% CI 1.32–2.50, p < 0.01) after additional adjustment for CV risk factors. Patients with both RA and DM or insulin resistance had the highest HR for developing CVD (2.21, 95% CI 1.01–4.80, p = 0.046 and 2.67, 95% CI 1.30–5.46, p < 0.01, respectively).Conclusion.The incidence rate of CV events in established RA was more than double that of the general population. Patients with RA have an even higher risk of CVD than patients with DM. This risk remained after adjustment for traditional CV risk factors, suggesting that systemic inflammation is an independent contributor to CV risk.

Objective Previous studies have shown that feedback-informed treatment can improve outcomes of psychological treatments. This randomized controlled effectiveness trial evaluated the effect of progress feedback on treatment duration, symptom reduction, and dropout in individual cognitive behavioral therapies (CBTs). A control condition where CBT was combined with low-intensive monitoring of progress was compared to an experimental condition where CBT was combined with a high-intensive form of feedback. Method Data of 368 outpatients (57.9% female, mean age 41.4 years, SD = 12.2) in secondary care were analyzed using multilevel analyses. Treatment duration was assessed with the number of sessions clients received. Symptom reduction was measured with the Symptom Checklist Revised. Possible moderators of the effect of intensive progress feedback on outcome were explored. Results Clients achieved the same amount of symptom reduction in significantly fewer sessions in the high-intensive feedback condition. Additionally, dropout was significantly lower in the high-intensive feedback condition. Post hoc analyses assessing clients' diagnoses as a possible moderator showed that clients with personality disorders (mainly Cluster C) achieved more symptom reduction in fewer sessions when high-intensity feedback was provided. Also, a high degree of implementation within the experimental condition was associated with fewer treatment sessions. Conclusion In sum, the use of high-intensive client feedback reduced treatment duration and reduced dropout of CBT. Thus, feedback-informed CBTs seem to be a promising adaptation of conventional CBT. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

This study aimed to evaluate the diagnostic performance of echocardiographic markers of heart failure with preserved ejection fraction (HFpEF) and left ventricular diastolic dysfunction (LVDD) in comparison with the gold standard of cardiac catheterization. Diagnosing HFpEF is challenging, as symptoms are non-specific and often absent at rest. A clear need exists for sensitive echocardiographic markers to diagnose HFpEF. We systematically searched for studies testing the diagnostic value of novel echocardiographic markers for HFpEF and LVDD. Two investigators independently reviewed the studies and assessed the risk of bias. Results were meta-analysed when four or more studies reported a similar diagnostic measure. Of 353 studies, 20 fulfilled the eligibility criteria. The risk of bias was high especially in the patients’ selection domain. The highest diagnostic performance was demonstrated by a multivariable model combining echocardiographic, clinical and arterial function markers with an area under the curve of 0.95 (95% CI, 0.89–0.98). A meta-analysis of four studies indicated a reasonable diagnostic performance for left atrial strain with an AUC of 0.83 (0.70–0.95), a specificity of 93% (95% CI, 90–97%) and a sensitivity of 77% (95% CI, 59–96%). Moreover, the addition of exercise E/e′ improved the sensitivity of HFpEF diagnostic algorithms up to 90%, compared with 60 and 34% of guidelines alone. Despite the heterogeneity of the included studies, this review supported the current multivariable-based approach for the diagnosis of HFpEF and LVDD and showed a potential diagnostic role for exercise echocardiography and left atrial strain. Larger well-designed studies are needed to evaluate the incremental value of novel diagnostic tools to current diagnostic algorithms. Electronic supplementary material The online version of this article (10.1007/s10741-020-09985-1) contains supplementary material, which is available to authorized users.

OBJECTIVE Biased attention for disorder-relevant information plays a crucial role in the maintenance of different mental disorders including eating disorders and might be of use to define recovery beyond symptom-related criteria. METHOD We assessed attention deployment using eye tracking in a cued choice viewing paradigm to two different categories of disorder-relevant stimuli in 24 individuals with acute anorexia nervosa (AN), 20 weight-recovered individuals with a history of AN (WRAN) and 23 healthy control participants (CG). Picture pairs consisted of a food stimulus or a picture depicting physical activity and a matched control stimulus (household item/physical inactivity). Participants rated the valence of stimuli afterwards. RESULTS The groups did not differ in initial attention deployment. In later processing stages, AN patients showed a generalized attentional avoidance of food and control pictures as compared to CG, while WRAN individuals were in between. AN patients showed an attentional bias toward physical activity pictures as compared to WRAN individuals, but not the CG. AN individuals rated the food pictures and the pictures showing physical inactivity as less pleasant than the CG, while WRAN individuals were in between. DISCUSSION Attention deployment is partly changed in WRAN as compared to the acute AN group, especially with regard to a shift away from illness-compatible stimuli (physical activity), and this might be a useful recovery criterion. Valence rating of food stimuli might be an additional useful tool to distinguish between acutely ill and weight-recovered individuals. Attentional biases for illness-compatible stimuli might qualify as a valuable approach to defining recovery in AN.

IntroductionAlthough associations of total plasma N-glycome (TPNG) with type 2 diabetes have been reported, little is known on the role of TPNG in type 2 diabetes complications, a major cause of type 2 diabetes-related morbidity and mortality. Here, we assessed TPNG in relation to type 2 diabetes complications in subsamples of two Dutch cohorts using mass spectrometry (n=1815 in DiaGene and n=1518 in Hoorn Diabetes Care System).Research design and methodsBlood plasma samples and technical replicates were pipetted into 96-well plates in a randomized manner. Peptide:N-glycosidase F (PNGase F) was used to release N-glycans, whereafter sialic acids were derivatized for stabilization and linkage differentiation. After total area normalization, 68 individual glycan compositions were quantified in total and were used to calculate 45 derived traits which reflect structural features of glycosylation. Associations of glycan features with prevalent and incident microvascular or macrovascular complications were tested in logistic and Cox regression in both independent cohorts and the results were meta-analyzed.ResultsOur results demonstrated similarities between incident and prevalent complications. The strongest association for prevalent cardiovascular disease was a high level of bisection on a group of diantennary glycans (A2FS0B; OR=1.38, p=1.34×10−11), while for prevalent nephropathy the increase in 2,6-sialylation on triantennary glycans was most pronounced (A3E; OR=1.28, p=9.70×10−6). Several other TPNG features, including fucosylation, galactosylation, and sialylation, firmly demonstrated associations with prevalent and incident complications of type 2 diabetes.ConclusionsThese findings may provide a glance on how TPNG patterns change before complications emerge, paving the way for future studies on prediction biomarkers and potentially disease mechanisms.

Objectives To identify and assess the quality and accuracy of prognostic models for nephropathy and to validate these models in external cohorts of people with type 2 diabetes. Design Systematic review and external validation. Data sources PubMed and Embase. Eligibility criteria Studies describing the development of a model to predict the risk of nephropathy, applicable to people with type 2 diabetes. Methods Screening, data extraction, and risk of bias assessment were done in duplicate. Eligible models were externally validated in the Hoorn Diabetes Care System (DCS) cohort (n=11 450) for the same outcomes for which they were developed. Risks of nephropathy were calculated and compared with observed risk over 2, 5, and 10 years of follow-up. Model performance was assessed based on intercept adjusted calibration and discrimination (Harrell’s C statistic). Results 41 studies included in the systematic review reported 64 models, 46 of which were developed in a population with diabetes and 18 in the general population including diabetes as a predictor. The predicted outcomes included albuminuria, diabetic kidney disease, chronic kidney disease (general population), and end stage renal disease. The reported apparent discrimination of the 46 models varied considerably across the different predicted outcomes, from 0.60 (95% confidence interval 0.56 to 0.64) to 0.99 (not available) for the models developed in a diabetes population and from 0.59 (not available) to 0.96 (0.95 to 0.97) for the models developed in the general population. Calibration was reported in 31 of the 41 studies, and the models were generally well calibrated. 21 of the 64 retrieved models were externally validated in the Hoorn DCS cohort for predicting risk of albuminuria, diabetic kidney disease, and chronic kidney disease, with considerable variation in performance across prediction horizons and models. For all three outcomes, however, at least two models had C statistics >0.8, indicating excellent discrimination. In a secondary external validation in GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland), models developed for diabetic kidney disease outperformed those for chronic kidney disease. Models were generally well calibrated across all three prediction horizons. Conclusions This study identified multiple prediction models to predict albuminuria, diabetic kidney disease, chronic kidney disease, and end stage renal disease. In the external validation, discrimination and calibration for albuminuria, diabetic kidney disease, and chronic kidney disease varied considerably across prediction horizons and models. For each outcome, however, specific models showed good discrimination and calibration across the three prediction horizons, with clinically accessible predictors, making them applicable in a clinical setting. Systematic review registration PROSPERO CRD42020192831.

Contains fulltext : 237516.pdf (Publisher’s version ) (Open Access) BackgroundPyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important cofactor pyridoxal-5'-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop. Early diagnosis and treatment, preferably based on newborn screening, could optimize long-term clinical outcome. However, no suitable PDE-ALDH7A1 newborn screening biomarkers are currently available.MethodsWe combined the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy to discover and identify biomarkers in plasma that would allow for PDE-ALDH7A1 diagnosis in newborn screening.ResultsWe identified 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) as a PDE-ALDH7A1 biomarker, and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP) as a biomarker. The suitability of 2-OPP as a potential PDE-ALDH7A1 newborn screening biomarker in dried bloodspots was shown. Additionally, we found that 2-OPP accumulates in brain tissue of patients and Aldh7a1-knockout mice, and induced epilepsy-like behavior in a zebrafish model system.ConclusionThis study has opened the way to newborn screening for PDE-ALDH7A1. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.FundingSociety for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), United for Metabolic Diseases (UMD), Stofwisselkracht, Radboud University, Canadian Institutes of Health Research, Dutch Research Council (NWO), and the European Research Council (ERC).

Objectives To assess the interobserver agreement in categories of electrocardiogram (ECG) abnormalities using the Minnesota Code criteria. Methods We used a random sample of 180 ECGs from people with type 2 diabetes. ECG abnormalities were classified and coded using the Minnesota ECG Classification. Each ECG was independently rated on several abnormalities by an experienced rater (rater 1) and by two cardiologists (raters 2 and 3) trained to apply the Minnesota codes on four Minnesota codes; 1-codes as an indication for myocardial infarction, 4 en 5-codes as an indication for ischemic abnormalities, 3-codes as an indication for left ventricle hypertrophy, 7-1-codes as an indication for ventricular conduction abnormalities, and 8-3-codes as an indication for atrial fibrillation / atrial flutter. After all pairwise tables were summed, the overall agreement, the specific positive and negative agreement were calculated with a 95% confidence interval (CI) for each abnormality. Also, Kappa’s with a 95% CI were calculated. Results The overall agreement (with 95% CI) were for myocardial infarction, ischemic abnormalities, left ventricle hypertrophy, conduction abnormalities and atrial fibrillation/atrial flutter respectively: 0.87 (0.84–0.91), 0.79 (0.74–0.84), 0.81 (0.76–0.85), 0.93 (0.90–0.95), 0.96 (0.93–0.97). Conclusion This study shows that the overall agreement of the Minnesota code is good to excellent.

Introduction Autosomal dominant polycystic kidney disease (ADPKD) causes kidney failure typically in adulthood, but the disease starts in utero. Copeptin, epidermal growth factor (EGF), and monocyte chemoattractant protein-1 (MCP-1) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models. Methods In a cross-sectional study, plasma copeptin, urinary EGF, and urinary MCP-1 were evaluated in a pediatric ADPKD cohort and compared with age-, sex-, and body mass index (BMI)-matched healthy controls. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells, and fetal kidney tissue. Results Fifty-three genotyped ADPKD patients and 53 controls were included. The mean (SD) age was 10.4 (5.9) versus 10.5 (6.1) years (P = 0.543), and the estimated glomerular filtration rate (eGFR) was 122.7 (39.8) versus 114.5 (23.1) ml/min per 1.73 m2 (P = 0.177) in patients versus controls, respectively. Plasma copeptin and EGF secretion were comparable between groups. The median (interquartile range) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 [213.8]) compared with controls (154.7 [98.0], P = 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration. Conclusion An increase in tubular MCP-1 secretion is an early event in ADPKD. MCP-1 is an early disease severity marker and a potential treatment target., Graphical abstract

Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inheritable kidney disease characterized by the development of fluid-filled cysts in all nephron segments, leading to loss of renal function. Mutations in PKD1 or PKD2, which encode polycystin-1 and polycystin-2, are the most common cause of ADPKD. The molecular mechanisms underlying cystogenesis are poorly characterized but it is postulated that disturbed calcium homeostasis is a primary event in cystogenesis. The precise molecular players that cause this disturbance are still a poorly explored area, especially in relevant human cell types. We therefore aim to characterize the profile of calcium-coupled receptors and channels in a human renal epithelial cell model, to identify which receptors and channels are present and whether their function is affected in ADPKD. Method Human urine-derived conditionally immortalized proximal tubule epithelial cells (ciPTECs) of ADPKD patients and healthy controls were screened for calcium-coupled GPCRs, using a GPCR agonist library on Fura-2 loaded cell populations seeded in 96-well format using the Flexstation3 (Molecular Devices). Validation of specific hits was done using single-cell measurements with a fluorescence microscope and built-in perfusion system. The expression of TRP channels and STIM/Orai proteins was determined via qPCR. Results From a library of 418 GPCR agonists a selective amount of calcium-coupled GPCRs was found functionally active in ciPTECs. ciPTECs from both healthy controls and ADPKD patients were found to functionally express purinergic -, histamine -, serotonin and dopamine receptors. Through qPCR we found expression of various TRP channels, including TRPML1, TRPC1/3, TRPM3/4/7, TRPV4 and TRPA1, as well as high expression of STIM1/2 and Orai1/2/3. Conclusion We describe the first thorough characterization of molecular players involved in calcium signalling mechanisms in human renal epithelial cells, including the profile of calcium-coupled GPCRs and the expression of TRP channels and STIM/Orai proteins, of further interest to investigate disturbed calcium dynamics in ADPKD.

Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either the PKD1 or PKD2 gene. While kidney failure typically occurs in adulthood, the disease starts in utero. The best change of preserving renal function long term might be the use of agents with few side effects as early as possible. For this approach, both better early prognostic stratification and novel treatment options are needed. The pediatric phase of ADPKD, while kidney function is still normal and before significant tissue destruction has occurred could be the best stage both to identify and study prognostic biomarkers as well as to identify novel targets for early treatment. Copeptin (a surrogate for vasopressin), epidermal growth factor (EGF) ( a measure for functional tubular mass) and monocyte chemoattractant protein-1 (MCP-1) ( a chemoattractant for macrophages) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models. Method A monocentric cross-sectional study in a tertiary referral center was performed. All consenting genotyped ADPKD patients attending the outpatient pediatric ADPKD clinic of the university hospital of Leuven and age, sex and BMI matched healthy controls were included between June and October 2017. Plasma copeptin, urinary EGF and urinary MCP-1 were evaluated. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells and fetal kidney tissue. Results 53 genotyped ADPKD patients and 53 controls were included. Mean (SD) age was 10.4 (5.9) vs 10.5 (6.1) years (P=0.543), and eGFR 122.7 (39.8) vs 114.5 (23.1) ml/min/1.73 m2 (P= 0.177) in patients vs controls respectively. Outcome parameters in table. Plasma copeptin and EGF secretion were comparable between both groups. Median (IQR) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 (213.8)) compared to controls (154.7 (98.0)) (P= 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion triggered by fetal bovine serum. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration. Conclusion An increase in tubular MCP-1 secretion is an early event in ADPKD, long before kidney function decline and in children with few kidney cysts. MCP-1 is a promising early disease severity marker and a potential treatment target.

ObjectiveTo develop an algorithm (sCOVID) to predict the risk of severe complications of COVID- 19 in a community-dwelling population to optimise vaccination scenarios.DesignPopulation based cohort studySetting264 Dutch general practices contributing to the NL-COVID databaseParticipants6074 people aged 0-99 diagnosed with COVID-19Main outcome measuresSevere complications (hospitalisation, institutionalisation, death). The algorithm was developed from a training dataset comprising 70% of the patients and validated in the remaining 30%. Potential predictor variables included age, sex, a chronic co-morbidity score (CCS) based on risk factors for COVID-19 complications as defined by the National Institute of Public Health and the Environment (RIVM), obesity, neighborhood deprivation score (NDS), first or second COVID wave, and confirmation test. Six different population vaccination scenarios were explored: 1) random (naive), 2) random for persons above 60 years (60plus), 3) oldest patients first in age bands of five years (oldest first), 4) target population of the annual influenza vaccination program (influenza) and 5) those 25-65 years of age first (worker), and 6) risk-based using the prediction algorithm (sCOVID). For each vaccination strategy the amount of vaccinations needed to reach a 50% reduction of severe complications was calculated.ResultsSevere complications were reported in 243 (4.8%) people with 59 (20.3%) nursing home admissions, 181 (62.2%) hospitalisations and 51 (17.5%) deaths. The algorithm included age, sex, CCS, NDS, wave, and confirmation test with a c statistic of 0.91 (95% CI 0.88-0.94) in the validation set. Applied to different vaccination scenarios, the proportion of people needed to be vaccinated to reach a 50% reduction of severe complications was 67.5%, 50.0%, 26.1%, 16.0%, 10.0%, and 8.4% for the worker, naive, infuenza, 60plus, oldest first, and sCOVID scenarios respectively.ConclusionCOVID-19 related severe complications will be reduced most efficiently when vaccinations are risk-based, prioritizing the highest risk group using the sCOVID algorithm. The vaccination scenario, prioritising oldest people in age bands of 5 years down to 60 years of age, performed second best. The sCOVID algorithm can readily be applied to identify persons with highest risks from data in the electronic health records of GPs.What is already known on this topic?Severe COVID-19 complications may be reduced when persons at the highest risk will be vaccinated first.To identify persons at a high risk for hospitalization or death in the general population, a limited number of prediction algorithms have been developed.Most of these algorithms were based on data from the first wave of infections (spring 2020) when widespread testing was not always possible, limiting the usefulness of these algorithms.What this study addsIncluding data up to January 2021, we developed and validated a prediction algorithm (sCOVID) with a c-statistic of 0.91 (95% CI 0.88-0.94) based on age, sex, chronic comorbidity score, economic status, wave, and a confirmation test to identify patients in the general population that are at risk of severe COVID-19 complication.Using the algorithm, a 50% reduction of patients with severe complications could be obtained with a vaccination coverage of only 8%. This vaccination scenario based on this algorithm was superior to other calculated vaccination scenarios.The sCOVID algorithm can readily be implemented in the electronic health records of general practitioners.

IntroductionEarly recognition of individuals with increased risk of sudden cardiac arrest (SCA) remains challenging. SCA research so far has used data from cardiologist care, but missed most SCA victims, since they were only in general practitioner (GP) care prior to SCA. Studying individuals with type 2 diabetes (T2D) in GP care may help solve this problem, as they have increased risk for SCA, and rich clinical datasets, since they regularly visit their GP for check-up measurements. This information can be further enriched with extensive genetic and metabolic information.AimTo describe the study protocol of the REcognition of Sudden Cardiac arrest vUlnErability in Diabetes (RESCUED) project, which aims at identifying clinical, genetic and metabolic factors contributing to SCA risk in individuals with T2D, and to develop a prognostic model for the risk of SCA.MethodsThe RESCUED project combines data from dedicated SCA and T2D cohorts, and GP data, from the same region in the Netherlands. Clinical data, genetic data (common and rare variant analysis) and metabolic data (metabolomics) will be analysed (using classical analysis techniques and machine learning methods) and combined into a prognostic model for risk of SCA.ConclusionThe RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses.

© 2020 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UKAim: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. Methods: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. Results: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1–4. Participants in Subgroups 2–4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (β = 0.36, 95% CI 0.13–0.58), Subgroup 3 (β = 0.30; 95% CI 0.10–0.50) and Subgroup 2 (β = 0.18; 95% CI 0.04–0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. Conclusions: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1), also known as antiquitin deficiency, is an inborn error of lysine metabolism that presents with refractory epilepsy in newborns. Bi-allelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important co-factor pyridoxal-5’-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but despite this treatment, intellectual disability may occur. Early diagnosis and treatment, preferably based on newborn screening, potentially optimize long-term clinical outcome. However, the currently known diagnostic PDE-ALDH7A1 biomarkers are incompatible with newborn screening procedures. Using a combination of the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy, we have been able to discover novel biomarkers for PDE-ALDH7A1: 2S,6S-and 2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) and 6-oxopiperidine-2-carboxylic acid (6-oxoPIP). We demonstrate the applicability of 2-OPP as a PDE-ALDH7A1 biomarker in newborn screening. Additionally, we show that 2-OPP accumulates in brain tissue of patients and Aldh7a1 knock-out mice, and induces epilepsy-like behavior in a zebrafish model system. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.

Purpose Body image has a significant impact on the outcome of obesity surgery. This study aims to perform a semantic evaluation of body shapes in obesity surgery patients and a group of controls. Materials and Methods Thirty-four obesity surgery (OS) subjects, stable after weight loss (average 48.03 ± 18.60 kg), and 35 overweight/obese controls (MC), were enrolled in this study. Body dissatisfaction, self-esteem, and body perception were evaluated with self-reported tests, and semantic evaluation of body shapes was performed with three specific tasks constructed with realistic human body stimuli. Results The OS showed a more positive body image compared to HC (p p p p = 0.011). Both groups showed a mental underestimation of their body shapes. Conclusion OS patients are more psychologically burdened and have more difficulties in judging their bodies than overweight/obese peers. Their mental body representations seem not to be linked to their own BMI. Our findings provide helpful insight for the design of specific interventions in body image in obese and overweight people, as well as in OS.

Objective: Maternal eating disorders (EDs) are associated with adverse pregnancy and child outcomes. There is limited research investigating the influence of maternal EDs on foetal brain development. Method: Using foetal magnetoencephalography (fMEG), an auditory sequence was presented for 10min to assess brain response latencies in foetuses of mothers with (n=12) and without (n=11) a history of anorexia nervosa (AN) in the third trimester of pregnancy. ED history and severity were assessed using the structured clinical expert interview eating disorder examination (EDE) and the self-report questionnaire EDE-Q. Results: Foetuses of mothers with AN showed delayed foetal brain responses to auditory stimulation compared to foetuses of control women. Self-reported ED symptom severity explained 34% of variance in foetal brain response latencies in the AN group. Conclusions: ED pathology was strongly associated with foetal brain response latencies in the third trimester with longer latencies in foetuses of women with a history of AN reporting more ED symptoms. Follow-up on the children is pivotal to investigate if fMEG outcomes are associated with later child development.

Aims: TheAmerican Diabetes Association, and the joint European Society of Cardiology and European Association for the Study of Diabetes guidelines recommend a resting ECG in people with type 2 diabetes with hypertension or suspected cardiovascular disease (CVD). However, knowledge on the prevalence of ECG abnormalities is incomplete. We aimed to analyse the prevalence of ECG abnormalities and their cross-sectional associations with cardiovascular risk factors in people with type 2 diabetes. Methods: We used data of the Diabetes Care System cohort obtained in 2018. ECG abnormalities were defined using the Minnesota Classification and categorised into types of abnormalities. The prevalence was calculated for the total population (n = 8068) and the subgroup of people without a history of CVD (n = 6494). Logistic regression models were used to asses cross-sectional associations. Results: Approximately one-third of the total population had minor (16.0%) or major (13.1%) ECG abnormalities. Of the participants without a CVD history, approximately one-quarter had minor (14.9%) ormajor (9.1%) ECG abnormalities, and for those with hypertension or very high CVD risk, the prevalencewas 27.5% and 39.6%, respectively. ECG abnormalities were significantly and consistently associated with established CVD risk factors. Conclusions: Resting ECG abnormalities are common in all people with type 2 diabetes (29.1%), including those without a history of CVD (24.0%), and their prevalence is related to traditional cardiovascular risk factors such as older age, male sex, hypertension, lower HDL cholesterol, higher BMI, and smoking behaviour.

Context There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. Objective To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). Design 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. Main outcome measures Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. Results In total, 125 metabolites were significantly associated (PFDR = 1.5×10–32 − 0.046; β = −11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after. Conclusions This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.

Aim Subclasses of different glycaemic disturbances could explain the variation in characteristics of individuals with type 2 diabetes (T2D). We aimed to examine the association between subgroups based on their glucose curves during a five-point mixed-meal tolerance test (MMT) and metabolic traits at baseline and glycaemic deterioration in individuals with T2D. Methods The study included 787 individuals with newly diagnosed T2D from the Diabetes Research on Patient Stratification (IMI-DIRECT) Study. Latent class trajectory analysis (LCTA) was used to identify distinct glucose curve subgroups during a five-point MMT. Using general linear models, these subgroups were associated with metabolic traits at baseline and after 18 months of follow up, adjusted for potential confounders. Results At baseline, we identified three glucose curve subgroups, labelled in order of increasing glucose peak levels as subgroup 1–3. Individuals in subgroup 2 and 3 were more likely to have higher levels of HbA1c, triglycerides and BMI at baseline, compared to those in subgroup 1. At 18 months (n = 651), the beta coefficients (95% CI) for change in HbA1c (mmol/mol) increased across subgroups with 0.37 (-0.18–1.92) for subgroup 2 and 1.88 (-0.08–3.85) for subgroup 3, relative to subgroup 1. The same trend was observed for change in levels of triglycerides and fasting glucose. Conclusions Different glycaemic profiles with different metabolic traits and different degrees of subsequent glycaemic deterioration can be identified using data from a frequently sampled mixed-meal tolerance test in individuals with T2D. Subgroups with the highest peaks had greater metabolic risk.

Background It has been suggested that psychosocial functioning improves after bariatric surgery, but the mechanism of this effect remains unclear. We propose that body image mediates the association between %EWL and improvement in depressive symptoms. Materials and Methods To investigate this hypothesis, we conducted a mediation analysis in longitudinal data from 52 patients after LSG. Results %EWL had no direct effect on depressive symptoms as assessed through the patient health questionnaire (PHQ-9), but a small indirect effect that was mediated through negative evaluation of the body (BIQ-20). Conclusions We interpret this observation in the context of complex individual etiologies of obesity and argue for a stronger focus on psychological interventions in aftercare regimes. This may be specifically relevant for patients with eating disorders or a desire for body contouring surgery.

Background. While polypharmacy is common in long-term residential psychiatric patients, prescription combinations may, from an evidence-based perspective, be irrational. Potentially, many psychiatric patients are treated on the basis of a poor diagnosis. We therefore evaluated the DITSMI model (i.e., Diagnose, Indicate, and Treat Severe Mental Illness), an intervention that involves diagnosis (or re-diagnosis) and appropriate treatment for severely mentally ill long-term residential psychiatric patients. Our main objective was to determine whether DITSMI affected changes over time regarding diagnoses, pharmacological treatment, psychosocial functioning, and bed utilization. Methods. DITSMI was implemented in a consecutive patient sample of 94 long-term residential psychiatric patients during a longitudinal cohort study without a control group. The cohort was followed for three calendar years. Data were extracted from electronic medical charts. As well as diagnoses, medication use and current mental status, we assessed psychosocial functioning using the Health of the Nations Outcome Scale (HoNOS). Bed utilization was assessed according to length of stay (LOS). Change was analyzed by comparing proportions of these data and testing them with chi-square calculations. We compared the numbers of diagnoses and medication changes, the proportions of HoNOS scores below cut-off, and the proportions of LOS before and after provision of the protocol. Results. Implementation of the DITSMI model was followed by different diagnoses in 49% of patients, different medication in 67%, some improvement in psychosocial functioning, and a 40% decrease in bed utilization. Conclusions. Our results suggest that DITSMI can be recommended as an appropriate care for all long-term residential psychiatric patients.

Background: \ud Microalbuminuria is an early sign of kidney disease in people with diabetes and indicates increased risk of cardiovascular disease. We tested whether a urinary proteomic risk classifier (CKD273) score was associated with development of microalbuminuria and whether progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone.\ud \ud Methods: \ud In this multicentre, prospective, observational study with embedded randomised controlled trial (PRIORITY), we recruited people with type 2 diabetes, normal urinary albumin excretion, and preserved renal function from 15 specialist centres in ten European countries. All participants (observational cohort) were tested with the CKD273 classifier and classified as high risk (CKD273 classifier score >0·154) or low risk (≤0·154). Participants who were classified as high risk were entered into a randomised controlled trial and randomly assigned (1:1), by use of an interactive web-response system, to receive spironolactone 25 mg once daily or matched placebo (trial cohort). The primary endpoint was development of confirmed microalbuminuria in all individuals with available data (observational cohort). Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone (trial cohort, intention-to-treat population) and association between CKD273 risk score and measures of impaired renal function based on estimated glomerular filtration rate (eGFR; observational cohort). Adverse events (particularly gynaecomastia and hyperkalaemia) and serious adverse events were recorded for the intention-to-treat population (trial cohort). This study is registered with the EU Clinical Trials Register (EudraCT 20120-004523-4) and ClinicalTrials.gov (NCT02040441) and is completed.\ud \ud Findings: \ud Between March 25, 2014, and Sept 30, 2018, we enrolled and followed-up 1775 participants (observational cohort), 1559 (88%) of 1775 participants had a low-risk urinary proteomic pattern and 216 (12%) had a high-risk pattern, of whom 209 were included in the trial cohort and assigned to spironolactone (n=102) or placebo (n=107). The overall median follow-up time was 2·51 years (IQR 2·0–3·0). Progression to microalbuminuria was seen in 61 (28%) of 216 high-risk participants and 139 (9%) of 1559 low-risk participants (hazard ratio [HR] 2·48, 95% CI 1·80–3·42; p

Binge eating disorder (BED) is associated with deficient response inhibition. Malfunctioning response inhibition is linked to hypoactivation of the dorsolateral prefrontal cortex (dlPFC), where excitability could be increased by anodal transcranial direct current stimulation (tDCS). Response inhibition can be assessed using an antisaccade task which requires supressing a dominant response (i.e. saccade) towards a newly appearing picture in the visual field. We performed a double-blind, randomised, placebo-controlled proof-of-concept-study in which we combined a food-modified antisaccade task with tDCS in people with BED. We expected task learning and modulatory tDCS effects. Sixteen people were allocated to a 1 mA condition, 15 people to a 2 mA condition. Each participant underwent the food-modified antisaccade task at three measurement points: baseline without stimulation, anodal verum and sham stimulation at the right dlPFC in a crossover design. The error rate and the latencies of correct antisaccades decreased over time. No tDCS effect on the error rate could be observed. Compared to sham stimulation, 2 mA tDCS decreased the latencies of correct antisaccades, whereas 1 mA tDCS increased it. Self-reported binge eating episodes were reduced in the 2 mA condition, while there was no change in the 1 mA condition. Participants demonstrated increased response inhibition capacities by a task learning effect concerning the error rate and latencies of correct antisaccades over time as well as a nonlinear tDCS effect represented by ameliorated latencies in the 2 mA and impaired latencies in the 1 mA condition. The reduction of binge eating episodes might indicate a transfer effect to everyday life. Given that the reduction in binge eating was observed before tDCS administration, this effect could not be the result of neuromodulation. Randomized clinical trials are needed to fully understand this reduction, and to explore the efficacy of a combined antisaccade and tDCS training for BED.

Contains fulltext : 220142.pdf (Publisher’s version ) (Closed access) An instrument is needed for quantitatively evaluating changes in social support in people with mental illness, but no gold standard is available. The Social Network Map is a structured interview for assessing social support that is used in individual care settings, yet provides overwhelming output (16-128 data points per assessment). A method comprising two factors (quality and quantity of the social network) was developed. The psychometric properties were judged to be sufficient. This study shows that data from the Social Network Map can be analysed at the group level, yet further research on the psychometric properties is needed. 9 p.

Haemophilus influenzae is a Gram-negative bacterium that can be classified into typeable (types a through f) and nontypeable (NTHi) groups. This opportunistic pathogen asymptomatically colonizes the mucosal epithelium of the upper respiratory tract, from where it spreads to other neighboring regions, potentially leading to disease. Infection with NTHi can cause otitis media, sinusitis, conjunctivitis, exacerbations of chronic obstructive pulmonary disease, and pneumonia, but it is increasingly causing invasive disease, including bacteremia and meningitis. Invasive NTHi strains are more resistant to complement-mediated killing. However, the mechanisms of complement resistance have never been studied in large numbers of invasive NTHi strains. In this study, we determined the relationship between binding of IgG or IgM and the bacterial survival in normal human serum for 267 invasive H. influenzae strains from Spain, Portugal, and the Netherlands, of which the majority (200 [75%]) were NTHi. NTHi bacteria opsonized with high levels of IgM had the lowest survival in human serum. IgM binding to the bacterial surface, but not IgG binding, was shown to be associated with complement-mediated killing of NTHi strains. We conclude that evasion of IgM binding by NTHi strains increases survival in blood, thereby potentially contributing to their ability to cause severe invasive diseases. info:eu-repo/semantics/publishedVersion

Tripartite interactions among insect vectors, midgut bacteria, and viruses may determine the ability of insects to transmit pathogenic arboviruses. Here, we investigated the impact of gut bacteria on the susceptibility of Culicoides nubeculosus and Culicoides sonorensis biting midges for Schmallenberg virus, and of Aedes aegypti mosquitoes for Zika and chikungunya viruses. Gut bacteria were manipulated by treating the adult insects with antibiotics. The gut bacterial communities were investigated using Illumina MiSeq sequencing of 16S rRNA, and susceptibility to arbovirus infection was tested by feeding insects with an infectious blood meal. Antibiotic treatment led to changes in gut bacteria for all insects. Interestingly, the gut bacterial composition of untreated Ae. aegypti and C. nubeculosus showed Asaia as the dominant genus, which was drastically reduced after antibiotic treatment. Furthermore, antibiotic treatment resulted in relatively more Delftia bacteria in both biting midge species, but not in mosquitoes. Antibiotic treatment and subsequent changes in gut bacterial communities were associated with a significant, 1.8-fold increased infection rate of C. nubeculosus with Schmallenberg virus, but not for C. sonorensis. We did not find any changes in infection rates for Ae. aegypti mosquitoes with Zika or chikungunya virus. We conclude that resident gut bacteria may dampen arbovirus transmission in biting midges, but not so in mosquitoes. Use of antimicrobial compounds at livestock farms might therefore have an unexpected contradictory effect on the health of animals, by increasing the transmission of viral pathogens by biting midges.

Background Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and length of follow-up. Here, we characterize glycemic variability over time and whether its relation to diabetes-related complications and mortality is independent from diabetes- and follow-up duration. Materials and methods Individuals with type 2 diabetes (n = 6770) from the Hoorn Diabetes Care System cohort were included in this study. The coefficient of variation (CV) was calculated over 5-year sliding intervals. People divided in quintiles based on their CV. Cox proportional hazard models were used to investigate the role of glycemic CV as risk factor in diabetes-related complications and mortality. Results The coefficient of variation of glucose (FG-CV) increased with time, in contrast to HbA1c (HbA1c-CV). People with a high FG-CV were those with an early age of diabetes onset (ΔQ5–Q1 = − 2.39 years), a higher BMI (ΔQ5–Q1 = + 0.92 kg/m2), an unfavorable lipid profile, i.e. lower levels of HDL-C (ΔQ5–Q1 = − 0.06 mmol/mol) and higher triglycerides (ΔQ5–Q1 =+ 1.20 mmol/mol). People with the highest FG-CV in the first 5-year interval showed an increased risk of insulin initiation, retinopathy, macrovascular complications and mortality independent of mean glycemia, classical risk factors and medication use. For HbA1c, the associations were weaker and less consistent. Conclusions Individuals with a higher FG-CV have an unfavorable metabolic profile and have an increased risk of developing micro- and macrovascular complications and mortality. The association of HbA1c-CV with metabolic outcomes and complications was less consistent in comparison to FG-CV.

Background: The hypothalamic neuropeptide oxytocin regulates reproductive behavior and mother-infant interaction, and conclusive studies in humans indicate that oxytocin is also a potent modulator of psychosocial function. Pilot experiments have yielded first evidence that this neuropeptide moreover influences eating behavior. Methods: We briefly summarize currently available studies on the involvement of the oxytocin system in the pathophysiology of eating disorders, as well as on the effects of oxytocin administration in patients with these disorders. Results: Brain administration of oxytocin in animals with normal weight, but also with diet-induced or genetically induced obesity, attenuates food intake and reduces body weight. In normal-weight and obese individuals, acute intranasal oxytocin delivery curbs calorie intake from main dishes and snacks. Such effects might converge with the poignant social and cognitive impact of oxytocin to also improve dysfunctional eating behavior in the therapeutic context. This assumption has received support in first studies showing that oxytocin might play a role in the disease process of anorexia nervosa. In contrast, respective experiments in patients with bulimia nervosa and binge eating disorder are still scarce. Conclusions: We propose a framework of oxytocin’s role and its therapeutic potential in eating disorders that aims at integrating social and metabolic aspects of its pharmacological profile, and ponder perspectives and limitations of oxytocin use in the clinical setting.

Type 2 diabetes is associated with an increased risk of developing macro and microvascular complications. Nevertheless, there is substantial heterogeneity between people with type 2 diabetes in their risk of developing such complications. Personalised medicine for people with type 2 diabetes may aid in efficient and tailored diabetes care for those at increased risk of developing such complications. Recently, progress has been made in the development of personalised diabetes care in several areas. Particularly for the risk prediction of cardiovascular disease, retinopathy and nephropathy, innovative methods have been developed for prediction and tailored monitoring or treatment to prevent such complications. For other complications or subpopulations of people with type 2 diabetes, such as the frail elderly, efforts are currently ongoing to develop such methods. In this review, we discuss the recent developments in innovations of personalised diabetes care for different complications and subpopulations of people with type 2 diabetes, their performance and modes of application in clinical practice.

This study investigates the role of body image self-appraisal in predicting the outcomes of outpatient psychotherapy in patients with anorexia nervosa (AN). Multiple linear regression analyses and a path-analysis model were applied to test the study hypotheses that body image at baseline predicts treatment outcomes of outpatient psychotherapy in patients with AN at follow-up measurement. The analyses were conducted as secondary analyses in a subgroup (n = 148) of the anorexia nervosa treatment of outpatient-cohort (ANTOP-study) (N = 242) of patients with AN. The results show that Negative Evaluation of the Body at baseline predicts perceived stress during psychotherapy, which in turn predicts depressive symptoms at the end of therapy which in turn predicts the outcomes body mass index and EDI-2 sum score at 12 months follow-up. The results underline the importance of body image disturbance in the course of AN and call for body image as a central target of psychotherapeutic interventions in patients with AN.

Aim: \ud To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273.\ud \ud Methods: \ud We conducted a prospective, randomized, double‐blind, placebo‐controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high‐ or low‐risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis.\ud \ud Results: \ud A total of 1777 participants from 15 centres were included, with 12.3% of these having a high‐risk proteomic pattern. Participants in the high‐risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low‐risk group (n=1559, P

Aims. To date, studies on the role of eating traits in weight loss success have only included obese people without type 2 diabetes mellitus (T2DM), thereby disregarding negative effects of T2DM-related metabolic changes. Our aim was to assess the association between eating traits and weight change after a lifestyle intervention in people with T2DM. Methods. For the current study, we reexamined data from a six-month intervention in 120 participants. We determined eating traits at baseline, using the DEBQ, which were used to produce three groups: unsuccessful dietary restrained (high restraint, high emotional/external eating scores), successful dietary restrained (high restraint, low emotional/external eating scores), and reference (low restraint, high or low emotional/external eating scores). Linear regression was used to study the association between the eating trait groups and weight changes after six months, while correcting for possible confounders. Results. On average, the weight loss success was limited, with a third of the participants being weight stable, a third losing weight > −1 kg (average loss −2.6 ± 1.9 kg), and a third gaining weight > +1 kg (average gain +3.3 ± 1.9 kg). When compared to the reference group, the unsuccessful dietary restrained gained weight during the intervention (beta = 1.2 kg, confidence interval (CI)% = 0.1; 2). No significant change was observed in the succesful dietary restrained group. Conclusions. The eating trait of being unsuccessfully dietary restrained is associated with weight-loss failure after a six-month lifestyle intervention in people with T2DM.

Children with atopic dermatitis show an increased risk to develop asthma later in life, a phenomenon referred to as "atopic march," which emphasizes the need for secondary prevention therapies. This study aimed to investigate whether relief of skin inflammation by glucocorticoids and peroxisome proliferator-activated receptor agonists might influence the subsequent development of asthma in a murine model for the atopic march in which mice were repeatedly exposed to house dust mite via the skin, followed by exposure to house dust mite in lungs. To abrogate atopic dermatitis, mice received topical treatment with glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma agonists. Nuclear receptor ligand effects were assessed on primary keratinocytes and dendritic cells, as central players in skin inflammation. Prior house dust mite-induced skin inflammation aggravates allergic airway inflammation and induces a mixed T helper type 2/T helper type 17 response in the lungs. Cutaneous combined activation of glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma reduced skin inflammation to a higher extent compared to single activation. Additive anti-inflammatory effects were more prominent in dendritic cells, as compared to keratinocytes. Alleviation of allergic skin inflammation by activation of glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma appeared insufficient to avoid the allergic immune response in the lungs, but efficiently reduced asthma severity by counteracting the Th17 response. Glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma co-activation represents a potent remedy against allergic skin inflammation and worsening of atopic march.

Contains fulltext : 183787.pdf (Publisher’s version ) (Closed access) The distinction between mental health and mental illness has long been the subject of debate, especially in the last decade where there has been a shift in focus in mental health care from symptom reduction to the improvement of positive mental health. Art therapists have been influenced by this shift and in this study, we investigate: (1) whether art therapy improves mental health and/or reduces mental illness; and (2) what the relationship is between mental health and mental illness. We used secondary data (n = 74) from patients diagnosed with personality disorders from a pretest-posttest art therapy intervention, with 10 weeks in between the repeated measures. The indicators in the domains of mental health and mental illness we used were: symptom distress, flexibility, well-being, mindfulness, and schema modes. We used repeated measures ANOVA and effect sizes to examine the effects of art therapy and the Pearson correlation to examine the relationship between illness and health outcomes. Results indicated significant effects of art therapy in both domains. Furthermore, after creation of a single mental health and a mental illness score we found that the correlation between them was high. We conclude that art therapy both promotes mental health and reduces mental illness. The large correlation between these domains in patients with personality disorders suggests that we might be dealing with two sides of the same coin. 6 p.

Contingency management in stipulating weight gain is routinely used in the treatment of anorexia nervosa, however, empirical investigations concerning its effectiveness have been scarce. This systematic review was conducted according to the PRISMA statement. Of N = 973 hits, 42 full-texts were included in the qualitative synthesis (11 theoretical texts, 19 case reports, 12 descriptive, cohort, and controlled trials). A central topic in the included publications concerns the enhancement of patients' autonomy through participation in the contingency management process. This heightened autonomy is achieved by using contingency contracts. Positive short-term effects on weight gain were shown, whereas follow-up results were heterogeneous. Although contingency contracts are widely used in clinical practice, our systematic review shows that empirical evidence on underlying mechanisms and efficacy is still scarce. Using an explicit treatment contract can enhance patients' motivation, compliance, and autonomy. Clinical practice should see further development including innovative motivation enhancing and conflict dissolving techniques in addressing the pronounced ambivalence often shown by patients with anorexia nervosa.

Contains fulltext : 192520.pdf (Publisher’s version ) (Closed access) Objective: Children of parents with an anxiety disorder have a higher risk of developing an anxiety disorder than children of parents without an anxiety disorder. Parental anxiety is not regarded as a causal risk factor itself, but is likely to be mediated via other mechanisms, for example via cognitive factors. We investigated whether children of parents with an anxiety disorder would show an interpretation bias corresponding to the diagnosis of their parent. We also explored whether children's interpretation biases were explained by parental anxiety and/or children’s levels of anxiety. Method: In total, 44 children of parents with a panic disorder (PD), 27 children of parents with a social anxiety disorder (SAD), 7 children of parents with SAD/PD, and 84 children of parents without an anxiety disorder (controls) participated in this study. Parents and children filled out the Screen for Child Anxiety Related Disorders (SCARED) questionnaire, and children performed two ambiguous scenario tasks: one with and one without video priming. Results: Children of parents with PD displayed significantly more negative interpretations of panic scenarios and social scenarios than controls. Negative interpretations of panic scenarios were explained by parental PD diagnosis and children’s anxiety levels. These effects were not found for children of parents with SAD. Priming did not affect interpretation. Conclusion: Our results showed that children of parents with PD have a higher chance of interpreting ambiguous situations more negatively than children of parents without anxiety disorders. More research is needed to study whether this negative bias predicts later development of anxiety disorders in children. 9 p.