OBJECTIVE: Abdominal obesity and type 2 diabetes are associated with insulin resistance and low bone turnover along with an increased fracture risk. The mode of action is poorly understood. The bone resorption marker, C-terminal telopeptide type 1 collagen (CTX), and to a lesser extent, the bone formation marker, Procollagen type 1 N-terminal propeptide (P1NP) appear to be inhibited by food consumption. The link between food consumption, insulin resistance and bone turnover remains to be clarified. Primarily we aimed to compare the postprandial CTX, P1NP and PTH responses by two frequently applied methods in assessing metabolic health; oral glucose tolerance test (OGTT) and mixed meal tolerance test. Secondly, we explored the effect of insulin resistance on bone marker responses.

METHODS: We enrolled 64 subjects with abdominal obesity. Following 10 h of fasting, subjects initially underwent a standard OGTT (300 kcal) and approximately one week later a mixed meal tolerance test (1130 kcal). Circulating CTX, P1NP and PTH were assessed on both days at time = 0, after 30 min and after 90 min for comparison of the two interventions. We analyzed glucose and insulin levels for the assessment of insulin resistance. Additionally, we measured plasma calcium levels along with the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide 2 (GLP-2) in an attempt to identify possible mediators of the postprandial bone response.

RESULTS: CTX, P1NP and PTH were suppressed by OGTT and the mixed meal; the latter induced a more pronounced suppression after 90 min. Calcium levels were similar between OGTT and meal. GIP and GLP-2 levels increased after both interventions, although only the meal induced a sustained increase after 90 min. Fasting P1NP was inversely associated with insulin resistance. The meal-induced suppression of P1NP (but not CTX or PTH) was inversely associated with level of insulin resistance.

CONCLUSION: The acute postprandial suppression of bone turnover markers is extended after ingestion of a mixed meal compared to an OGTT. The response appears to be independent of gender and prompted by a reduction in PTH. The study additionally indicates a possible link between the development of insulin resistance and low bone turnover - which may be of key essence in the development of the fragile bone structure and increased fracture risk demonstrated in subjects with abdominal obesity and T2D.

BACKGROUND: Body weight variability (BWV) is common in the general population and may act as a risk factor for obesity or diseases. The correct identification of these patterns may have prognostic or predictive value in clinical and research settings. With advancements in technology allowing for the frequent collection of body weight data from electronic smart scales, new opportunities to analyze and identify patterns in body weight data are available.

OBJECTIVE: This study aims to compare multiple methods of data imputation and BWV calculation using linear and nonlinear approaches.

METHODS: In total, 50 participants from an ongoing weight loss maintenance study (the NoHoW study) were selected to develop the procedure. We addressed the following aspects of data analysis: cleaning, imputation, detrending, and calculation of total and local BWV. To test imputation, missing data were simulated at random and using real patterns of missingness. A total of 10 imputation strategies were tested. Next, BWV was calculated using linear and nonlinear approaches, and the effects of missing data and data imputation on these estimates were investigated.

RESULTS: Body weight imputation using structural modeling with Kalman smoothing or an exponentially weighted moving average provided the best agreement with observed values (root mean square error range 0.62%-0.64%). Imputation performance decreased with missingness and was similar between random and nonrandom simulations. Errors in BWV estimations from missing simulated data sets were low (2%-7% with 80% missing data or a mean of 67, SD 40.1 available body weights) compared with that of imputation strategies where errors were significantly greater, varying by imputation method.

CONCLUSIONS: The decision to impute body weight data depends on the purpose of the analysis. Directions for the best performing imputation methods are provided. For the purpose of estimating BWV, data imputation should not be conducted. Linear and nonlinear methods of estimating BWV provide reasonably accurate estimates under high proportions (80%) of missing data.

Objective: To investigate whether a dose-response relationship exists between volume of exercise and discontinuation of glucose-lowering medication treatment in patients with type 2 diabetes. Patients and Methods: Secondary analyses of a randomized controlled exercise-based lifestyle intervention trial (April 29, 2015 to August 17, 2016). Patients with non–insulin-dependent type 2 diabetes were randomly assigned to an intensive lifestyle intervention (U-TURN) or standard-care group. Both groups received lifestyle advice and objective target-driven medical regulation. Additionally, the U-TURN group received supervised exercise and individualized dietary counseling. Of the 98 randomly assigned participants, 92 were included in the analysis (U-TURN, n=61, standard care, n=31). Participants in the U-TURN group were stratified into tertiles based on accumulated volumes of exercise completed during the 1-year intervention. Results: Median exercise levels of 178 (interquartile range [IQR], 121-213; lower tertile), 296 (IQR, 261-310; intermediate tertile), and 380 minutes per week (IQR, 355-446; upper tertile) were associated with higher odds of discontinuing treatment with glucose-lowering medication, with corresponding odds ratios of 12.1 (95% CI, 1.2-119; number needed to treat: 4), 30.2 (95% CI, 2.9-318.5; 3), and 34.4 (95% CI, 4.1-290.1; 2), respectively, when comparing with standard care. Cardiovascular risk factors such as glycated hemoglobin A_1c levels, fitness, 2-hour glucose levels, and triglyceride levels were improved significantly in the intermediate and upper tertiles, but not the lower tertile, compared with the standard-care group. Conclusion: Exercise volume is associated with discontinuation of glucose-lowering medication treatment in a dose-dependent manner, as are important cardiovascular risk factors in well-treated participants with type 2 diabetes and disease duration less than 10 years. Further studies are needed to support these findings. Study Registration: ClinicalTrials.gov registration (NCT02417012).

Overloading of tendon tissue with resulting chronic pain (tendinopathy) is a common disorder in occupational-, leisure- and sports-activity, but its pathogenesis remains poorly understood. To investigate the very early phase of tendinopathy, Achilles and patellar tendons were investigated in 200 physically active patients and 50 healthy control persons. Patients were divided into three groups: symptoms for 0-1 months (T1), 1-2 months (T2) or 2-3 months (T3). Tendinopathic Achilles tendon cross-sectional area determined by ultrasonography (US) was ~25% larger than in healthy control persons. Both Achilles and patellar anterior-posterior diameter were elevated in tendinopathy, and only later in Achilles was the width increased. Increased tendon size was accompanied by an increase in hypervascularization (US Doppler flow) without any change in mRNA for angiogenic factors. From patellar biopsies taken bilaterally, mRNA for most growth factors and tendon components remained unchanged (except for TGF-beta1 and substance-P) in early tendinopathy. Tendon stiffness remained unaltered over the first three months of tendinopathy and was similar to the asymptomatic contra-lateral tendon. In conclusion, this suggests that tendinopathy pathogenesis represents a disturbed tissue homeostasis with fluid accumulation. The disturbance is likely induced by repeated mechanical overloading rather than a partial rupture of the tendon.

BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.

OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.

DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.

SETTING: Online Delphi survey and consensus conference.

PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).

RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.

CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.

PATIENT SUMMARY: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.

Importance: Behavioral therapy and cognitive-behavioral therapy (CBT) programs targeting a single class of problems have not been widely implemented. The population of youths with common mental health problems is markedly undertreated. Objective: To determine the effectiveness of a new transdiagnostic CBT program (Mind My Mind [MMM]) compared with management as usual (MAU) in youths with emotional and behavioral problems below the threshold for referral to mental health care. Design, Setting, and Participants: This pragmatic, multisite, randomized clinical trial of MMM vs MAU was conducted from September 7, 2017, to August 28, 2019, including 8 weeks of postintervention follow-up, in 4 municipalities in Denmark. Consecutive help-seeking youths were randomized (1:1) to the MMM or the MAU group. Main inclusion criteria were age 6 to 16 years and anxiety, depressive symptoms, and/or behavioral disturbances as a primary problem. Data were analyzed from August 12 to October 25, 2019. Interventions: The MMM intervention consisted of 9 to 13 weekly, individually adapted sessions of manualized CBT delivered by local psychologists. The MAU group received 2 care coordination visits to enhance usual care. Main Outcomes and Measures: The primary outcome was change in mental health problems reported by parents at week 18, using the Strengths and Difficulties Questionnaire (SDQ) Impact scale (range, 0-10 points, with higher scores indicating greater severity of distress and impairment). Primary and secondary outcomes were assessed in the intention-To-Treat population at week 18. Maintenance effects were assessed at week 26. Results: A total of 396 youths (mean [SD] age, 10.3 [2.4] years; 206 [52.0%] boys) were randomized to MMM (n = 197) or MAU (n = 199), with primary outcome data available in 177 (89.8%) and 167 (83.9%), respectively, at 18 weeks. The SDQ Impact score decreased by 2.34 points with MMM and 1.23 with MAU, from initial scores of 4.12 and 4.21, respectively (between-group difference, 1.10 [95% CI, 0.75-1.45]; P <.001; Cohen d = 0.60). Number of responders (≥1-point reduction in SDQ Impact score) was greater with MMM than with MAU (144 of 197 [73.1%] vs 93 of 199 [46.7%]; number needed to treat, 4 [95% CI, 3-6]). Secondary outcomes indicated statistically significant benefits in parent-reported changes of anxiety, depressive symptoms, daily functioning, school attendance, and the principal problem. All benefits were maintained at week 26 except for school attendance. Conclusions and Relevance: In this randomized clinical trial, the scalable transdiagnostic cognitive-behavioral intervention MMM outperformed MAU in a community setting on multiple, clinically relevant domains in youth with emotional and behavioral problems. Trial Registration: ClinicalTrials.gov Identifier: NCT03535805.