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Purpose: To report the case of an adult female who presented on different occasions with recurrent uveitis provoked by initiating therapy of two recently approved agents, dabrafenib and pembrolizumab, for treatment of metastatic melanoma. Observations: A 61 year old female presented with bilateral anterior uveitis after initiating therapy with dabrafenib for advanced metastatic melanoma. Her symptoms resolved and exam improved with oral and topical steroid therapy. Months later, she was started on pembrolizumab and transitioned off dabrafenib. Within days of starting pembrolizumab, she developed recurrent bilateral uveitis. This responded to escalating doses of topical and oral corticosteroid therapy and resolved following discontinuation of pembrolizumab. Nine months later, our patient received her third dose of pembrolizumab due to further progression of melanoma and within three days developed blurry vision, photophobia and subsequent ophthalmologic exam demonstrated bilateral panuveitis. Conclusions and importance: Dabrafenib and pembrolizumab therapy have both previously been associated with uveitis. Here, we document a case of a woman who developed acute uveitis in response to beginning therapy with dabrafenib and then later developed acute uveitis soon after initiating pembrolizumab. To our knowledge, this is the first time this uncommon side-effect has been reported in the same patient after receiving sequential targeted agents and checkpoint inhibitors.

Introduction: This study examines the dose-response relationship between moderate-to-vigorous physical activity and cardiometabolic measures in adolescents., Methods: Cross-sectional spline analyses were performed using 2003-2016 National Health and Nutrition Examination Survey data among adolescents (aged 12-19 years, N=9,195) on objectively measured (2003-2006) and self-reported (2007-2016) weekly mean minutes of moderate-to-vigorous physical activity and cardiometabolic measures (systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein, BMI, and cardiorespiratory fitness). Inflection points were determined for nonlinear relationships., Results: For objective moderate-to-vigorous physical activity, female adolescents had significant nonlinear associations with inflection points at 90 minutes/week for BMI percentile and systolic blood pressure. Male adolescents had inflection points at 150 weekly minutes of objective activity for BMI percentile and cardiorespiratory fitness. BMI percentile was about 7% lower for female and male adolescents at 150 weekly minutes of objectively measured moderate-to-vigorous physical activity than at 0 minutes. For self-reported moderate-to-vigorous physical activity, inflection points were at 375 minutes/week (diastolic blood pressure for female adolescents) and 500 minutes/week (systolic blood pressure for male adolescents)., Conclusions: Among several significant dose-response relationships between physical activity and cardiometabolic health in adolescents, consistent and often nonlinear relationships were identified for BMI, with inflection points at 90-150 minutes of objective moderate-to-vigorous physical activity. Notable differences in associations and linearity were identified by sex and physical activity measure (objective or self-reported). These results support calls for any increase in physical activity among adolescents and suggest that recommendations closer to the adult guidelines of 150 weekly minutes of physical activity may be health promoting and more attainable for youth than the current recommendation of 420 weekly minutes., (Copyright © 2020 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Pediatric accountable health communities (AHCs) are emerging collaborative models that integrate care across health and social service sectors. We aimed to identify needed capabilities and potential solutions for implementing pediatric AHCs., Methods: We conducted a directed content analysis of responses to a Request for Information (RFI) from the Center for Medicare & Medicaid Innovation on the Integrated Care for Kids Model (n = 1550 pages from 202 respondents). We then interviewed pediatric health policy stakeholders (n = 18) to further investigate responses from the RFI. All responses were coded using a consensual qualitative research approach in 2019., Results: To facilitate service integration, respondents emphasized the need for cross-sector organizational alignment and data sharing. Recommended solutions included designating "Bridge Organizations" to operationalize service integration across sectors and developing integrated data sharing systems. Respondents called for improved validation and collection methods for data relating to school performance, social drivers of health, family well-being, and patient experience. Recommended solutions included aligning health and education data privacy regulations and utilizing metrics with cross-sector relevance. Respondents identified that mechanisms are needed to blend health and social service funding in alternative payment models (APMs). Recommended solutions included guidance on cross-sector care coordination payments, shared savings arrangements, and capitation to maximize spending flexibility., Conclusions: Pediatric AHCs could provide more integrated, high-value care for children. Respondents highlighted the need for shared infrastructure and cross-sector alignment of measures and financing., Implications: Insights and solutions from this study can inform policymakers planning or implementing innovative, child-centered AHC models., Level of Evidence: Level V., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Disruptive mood dysregulation disorder (DMDD) codifies severe, chronic irritability. Youths with bipolar disorder (BD) also present with irritability, but with an episodic course. To date, it is not clear whether aberrant white matter microstructure-a well-replicated finding in BD-can be observed in DMDD and relates to symptoms of irritability., Method: We acquired diffusion tensor imaging data from 118 participants (BD = 36, DMDD = 44, healthy volunteers (HV = 38). Images of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were processed with tract-based spatial statistics controlling for age and sex. The data were also used to train Gaussian process classifiers to predict diagnostic group., Results: In BD vs DMDD, FA in the corticospinal tract was reduced. In DMDD vs HV, reductions in FA and AD were confined to the anterior corpus callosum. In BD vs HV, widespread reductions in FA and increased RD were observed. FA in the anterior corpus callosum and corticospinal tract was negatively associated with irritability. The Gaussian process classifier could not discriminate between BD and DMDD, but achieved 68% accuracy in predicting DMDD vs HV and 75% accuracy in predicting BD vs HV., Conclusion: Aberrant white matter microstructure was associated with both categorical diagnosis and the dimension of irritability. Alterations in DMDD were regionally discrete and related to reduced AD. In BD, we observed widespread increases in RD, supporting the hypothesis of altered myelination in BD. These findings will contribute to the pathophysiological understanding of DMDD and its differentiation from BD., Clinical Trial Registration Information: Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder; https://clinicaltrials.gov/; NCT00025935; Child & Adolescent Bipolar Disorder Brain Imaging and Treatment Study; https://clinicaltrials.gov/; NCT00006177., (Published by Elsevier Inc.)

Purpose: Guidelines recommend 150 minutes of weekly moderate-to-vigorous physical activity (MVPA) for all adults, although physical activity level correlation with cardiometabolic health is not well characterized for young adults. We determined the dose-response relationship of MVPA on measures of cardiometabolic health in young adults., Methods: We examined young adults (aged 20-29 years; N = 5,395, 47.9% female) in the 2003-2016 National Health and Nutrition Examination Survey. Exposures were objective (accelerometer based) and self-reported weekly mean minutes of MVPA. Cardiometabolic outcome measures were body mass index (BMI), high-density lipoprotein (HDL), total cholesterol, systolic blood pressure, and diastolic blood pressure. The dose-response relationships were assessed with unadjusted spline analyses. Sex-stratified outcomes were modeled using multivariable linear regression with mean estimated change presented for 150-minute dose increases of MVPA., Results: Among females, associations between objective activity and cardiometabolic measures were all linear. Compared with no activity, 150 minutes of objective activity was associated with a lower BMI (-1.37 kg/m 2 ) and total cholesterol (-4.89 mg/dL), whereas 150 minutes of self-reported activity was associated with a higher HDL (1 mg/dL) and lower diastolic blood pressure (-.42 mm Hg). Among males, an inflection point was identified in the dose-response curves for objective activity with BMI around 100 minutes. Compared with no activity, 150 self-reported minutes was associated with lower BMI (-.26 kg/m 2 ), higher HDL (.52 mg/dL), and lower total cholesterol (-1.35 mg/dL)., Conclusions: The dose-response relationships between physical activity and cardiometabolic markers in young adults were predominantly linear, supporting public health calls for any increase in physical activity in this population., (Copyright © 2020 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Importance: Comorbidity is ubiquitous in psychiatry, but it is unclear how to differentiate neural mechanisms of co-occurring symptoms. Pediatric irritability and anxiety symptoms are prevalent and frequently co-occur. Threat orienting is pertinent to both phenotypes and is an ideal context in which to examine their unique and common neural mechanisms., Objectives: To decompose the unique and shared variances of pediatric irritability and anxiety symptoms and to determine neural correlates of these differentiated phenotypes during threat orienting., Design, Setting, and Participants: This investigation was a cross-sectional functional magnetic resonance imaging study. The setting was a research clinic at the National Institute of Mental Health. Participants were youth aged 8 to 18 years spanning multiple diagnostic categories (141 youth with disruptive mood dysregulation disorder, anxiety disorder, and/or attention-deficit/hyperactivity disorder and 56 healthy youth). This combination provided wide variation in levels of irritability and anxiety symptoms. Data were acquired between June 30, 2012, and June 28, 2016., Main Outcomes and Measures: Participants and parents rated youth's irritability on the Affective Reactivity Index and anxiety on the Screen for Child Anxiety Related Emotional Disorders. Bifactor analysis decomposed the unique and shared variances. A functional magnetic resonance imaging dot-probe task assessed attention orienting to angry (ie, threat) vs neutral faces. Whole-brain analyses examined associations between the bifactor-derived phenotypes and both neural activity and amygdala functional connectivity., Results: Among 197 participants included in the final analysis, the mean (SD) age was 13.1 (2.7) years, and 91 (46.2%) were female. The best-fit bifactor model (Comparative Fit Index, 0.959; Root Mean Square Error of Approximation, 0.066) included unique factors of parent-reported irritability, youth-reported irritability, and anxiety, as well as a common factor of negative affectivity. When the task required attention away from threat, higher parent-reported irritability was associated with increased activity in the insula, caudate, dorsolateral and ventrolateral prefrontal cortex, and inferior parietal lobule (t189≥4.15 for all, P < .001 for all). In contrast, higher anxiety was associated with decreased amygdala connectivity to the cingulate, thalamus, and precentral gyrus (t189≤-4.19 for all, P < .001 for all). These distinctive neural correlates did not emerge using a diagnostic approach., Conclusions and Relevance: A latent variable approach to parsing co-occurring symptom dimensions revealed a novel double dissociation. During orientation away from threat, only irritability was associated with neural activity, whereas only anxiety was associated with amygdala connectivity. Despite the challenges of symptom co-occurrence for clinical neuroscience, data-driven phenotyping may facilitate a path forward.

Objective: Irritability in disruptive mood dysregulation disorder (DMDD) may be associated with a biased tendency to judge ambiguous facial expressions as angry. We conducted three experiments to explore this bias as a treatment target. We tested: 1) whether youth with DMDD express this bias; 2) whether judgment of ambiguous faces can be altered in healthy youth by training; and 3) whether such training in youth with DMDD is associated with reduced irritability and associated changes in brain function., Methods: Participants in all experiments made happy versus angry judgments of faces that varied along a happy to angry continuum. These judgments were used to quantify a "balance point," the facial expression at which a participant's judgment switches from predominantly happy to predominantly angry. We first compared balance points in youth with DMDD (n = 63) versus healthy youth (n = 26). We then conducted a double-blind, randomized controlled trial of active versus sham balance-point training in 19 healthy youth. Finally, we piloted open, active balance-point training in 14 youth with DMDD, with 10 completing an implicit functional MRI (fMRI) face-emotion processing task., Results: Relative to healthy youth, DMDD youth manifested a shifted balance point, expressed as a tendency to classify ambiguous faces as angry rather than happy. In both healthy and DMDD youth, active training is associated with a shift in balance point toward more happy judgments. In DMDD, evidence suggests that active training may be associated with decreased irritability and changes in activation in the lateral orbitofrontal cortex., Conclusions: These results set the stage for further research on computer-based treatment targeting interpretation bias of angry faces in DMDD. Such treatment may decrease irritability and alter neural responses to subtle expressions of happiness and anger.

After suture of the anterior cruciate ligament without anatomical augmentation, used as a routine method, 88 patients were followed up after a minimum of 2 years using the Lysholm score and the activity scale. Residual laxity was checked clinically and with the KT-1000. For comparison, 20 patients with chronic symptomatic anterolateral instability were followed up who had been operated on using the Eriksson technique during the same time period. Postoperative treatment was a limited functional approach. The peripheral ligament structures were treated following the Hughston and Müller principles. In two-thirds of the knees lateral tenodesis was added. The results of the suture method were disappointing and inferior to the results obtained by the Eriksson technique (trend). The Lysholm score was 77 and 82, respectively. The activity scale was 4.4 (recreational sports) for both groups. The Lachmann sign (KT-1000) in side-to-side comparison (89 N) showed a residual laxity of 1.9 mm and 0.8 mm (average), respectively. In no series was tractopexy of demonstrable advantage. The final conclusion must be that the suture method (with iliotibial tract tenodesis) is not superior to guided conservative treatment. Despite an unfavorable situation preoperatively, the (abandoned) technique of ligament substitution is superior to the suture method (trend). In isokinetic testing dominant knees fare better. In good results, a high hamstrings-quadriceps ratio is typical. The reasons for this are not well-trained hamstrings, but the relative insufficiency of the quadriceps mechanism.