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Background: ADHD is highly comorbid with Delayed Sleep Phase Syndrome (DSPS). Both are associated with obesity and diabetes, which can be caused by long-term dysregulations of appetite and glucose metabolism. This study explores hormones involved in these processes and the effects of chronotherapeutic interventions in a small sample of adults with ADHD and DSPS. Methods: Exploratory, secondary analysis of data from the PhASE study, a three-armed randomized clinical trial, are presented, including 37 adults (18-53 years) with ADHD and DSPS receiving three weeks of 0.5 mg/day (1) placebo, (2) melatonin, or (3) melatonin plus 30 minutes of bright light therapy (BLT). Leptin (appetite-suppressing), ghrelin (appetite-stimulating), insulin, insulin-like growth factor-1 (IGF-1), and glucose were measured from blood collected at 08:00 hours. Salivary cortisol was collected during the first 30 minutes after awakening and self-reported appetite was assessed. Results: Baseline leptin and IGF-1 levels were higher than reference ranges, and ghrelin and cortisol levels were lower, while insulin and glucose were normal. Melatonin treatment decreased leptin and insulin. Other outcomes remained unchanged and melatonin + BLT had no effects. Conclusion: Due to the small sample size and exploratory nature of the study, results should be interpreted with caution. Overall, these results show no strong indications for dysregulation of appetite and glucose metabolism to suggest high risk of obesity and diabetes in this small sample of adults with ADHD and DSPS. However, baseline appetite was suppressed, likely because measurements took place in the early morning which could be considered the biological night for this study population. Melatonin treatment seemed to cause subtle changes in appetite-regulating hormones suggesting increased appetite. Chronotherapeutic treatment may affect appetite-regulating hormones by advancing the biological rhythm and/or altering eating behaviors, but this remains to be investigated in larger samples using detailed food diaries.

Long COVID is a chronic and often disabling illness with long-term consequences. Although progress has been made in the clinical characterization of long COVID, no approved treatments exist and disconnects between patients and researchers threaten to hinder future progress. Incorporating patients as active collaborators in long COVID research can bridge the gap and accelerate progress toward treatments and cures.

Climate change is dramatically altering the environmental context in which marine resources are harvested and managed. A growing field of academic literature has begun to explore the adaptive capacity of fishers and managers to respond to this change, but much of this field is abstract and theory-driven. Therefore, it is unclear whether this literature accurately reflects the adaptation priorities of fishery management practitioners, or whether there are gaps in the literature that these practitioners could fill with on-the-ground knowledge. Second, even if these principles of adaptive capacity are perfectly aligned with management practitioners’ priorities, it is unclear to what extent these principles are actively considered in the decision making process, and if not, why. This study seeks to address these questions by confronting fisheries professionals with academic ideas around adaptive capacity through a series of semi-structured interviews with federal fishery managers and scientists whose work informs decision making in the United States regional fishery management system. The study then uses these interviews to identify three low-cost, high-impact action items that could make concepts from the academic literature more accessible and useful to these practitioners and expand the literature by incorporating practitioners’ expertise. These action items are: 1) distinguish adaptive capacity from adaptive management, 2) use practitioner insights to contextualize the elements of adaptive capacity within the constraints and opportunities of governance systems, and 3) expand academic research to explicitly consider the capacity to adapt on appropriate timelines given the scale and pace of systemic change.

Third-harmonic generation microscopy is a powerful label-free nonlinear imaging technique, providing essential information about structural characteristics of cells and tissues without requiring external labelling agents. In this work, we integrated a recently developed compact adaptive optics module into a third-harmonic generation microscope, to measure and correct for optical aberrations in complex tissues. Taking advantage of the high sensitivity of the third-harmonic generation process to material interfaces and thin membranes, along with the 1,300-nm excitation wavelength used here, our adaptive optical third-harmonic generation microscope enabled high-resolution in vivo imaging within highly scattering biological model systems. Examples include imaging of myelinated axons and vascular structures within the mouse spinal cord and deep cortical layers of the mouse brain, along with imaging of key anatomical features in the roots of the model plant Brachypodium distachyon. In all instances, aberration correction led to enhancements in image quality.

OBJECTIVES: Precision medicine is data-driven health care tailored to individual patients based on their unique attributes, including biologic profiles, disease expressions, local environments, and socioeconomic conditions. Emergency medicine (EM) has been peripheral to the precision medicine discourse, lacking both a unified definition of precision medicine and a clear research agenda. We convened a national consensus conference to build a shared mental model and develop a research agenda for precision EM. METHODS: We held a conference to (1) define precision EM, (2) develop an evidence-based research agenda, and (3) identify educational gaps for current and future EM clinicians. Nine preconference workgroups (biomedical ethics, data science, health professions education, health care delivery and access, informatics, omics, population health, sex and gender, and technology and digital tools), comprising 84 individuals, garnered expert opinion, reviewed relevant literature, engaged with patients, and developed key research questions. During the conference, each workgroup shared how they defined precision EM within their domain, presented relevant conceptual frameworks, and engaged a broad set of stakeholders to refine precision EM research questions using a multistage consensus-building process. RESULTS: A total of 217 individuals participated in this initiative, of whom 115 were conference-day attendees. Consensus-building activities yielded a definition of precision EM and key research questions that comprised a new 10-year precision EM research agenda. The consensus process revealed three themes: (1) preeminence of data, (2) interconnectedness of research questions across domains, and (3) promises and pitfalls of advances in health technology and data science/artificial intelligence. The Health Professions Education Workgroup identified educational gaps in precision EM and discussed a training roadmap for the specialty. CONCLUSIONS: A research agenda for precision EM, developed with extensive stakeholder input, recognizes the potential and challenges of precision EM. Comprehensive clinician training in this field is essential to advance EM in this domain.

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

Adherens junction-associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1-/- and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.

Smartphone sensors are used increasingly in the assessment of ataxias. To date, there is no specific consensus guidance regarding a priority set of smartphone sensor measurements, or standard assessment criteria that are appropriate for clinical trials. As part of the Ataxia Global Initiative Digital-Motor Biomarkers Working Group (AGI WG4), aimed at evaluating key ataxia clinical domains (gait/posture, upper limb, speech and oculomotor assessments), we provide consensus guidance for use of internal smartphone sensors to assess key domains. Guidance was developed by means of a literature review and a two stage Delphi study conducted by an Expert panel, which surveyed members of AGI WG4, representing clinical, research, industry and patient-led experts, and consensus meetings by the Expert panel to agree on standard criteria and map current literature to these criteria. Seven publications were identified that investigated ataxias using internal smartphone sensors. The Delphi 1 survey ascertained current practice, and systems in use or under development. Wide variations in smartphones sensor use for assessing ataxia were identified. The Delphi 2 survey identified seven measures that were strongly endorsed as priorities in assessing 3/4 domains, namely gait/posture, upper limb, and speech performance. The Expert panel recommended 15 standard criteria to be fulfilled in studies. Evaluation of current literature revealed that none of the studies met all criteria, with most being early-phase validation studies. Our guidance highlights the importance of consensus, identifies priority measures and standard criteria, and will encourage further research into the use of internal smartphone sensors to measure ataxia digital-motor biomarkers.

Purpose: Sexual and gender minority (SGM) individuals may receive social support through active use of social media (i.e., posting and interacting). This study examined associations between active social media use, social support, and health indicators in a large sample of SGM adults in the United States. Methods: Data were derived from the 2017 wave of The PRIDE Study, a national cohort study of SGM health. SGM-identified adults reporting social media use (N = 5995) completed measures of active social media use, social support, depressive symptoms, cigarette smoking, hazardous drinking, sleep, and physical activity. Regression models examined main and interactive effects of active social media use and social support on health indicators. Results: The sample reported a moderate level of active social media use (mean [M] = 3.2 [1.0], scale = 1-5) and relatively high social support (M = 16.7 [3.3], scale = 4-20); 31.8% reported moderate-to-severe depressive symptoms. Participants with greater active social media use were more likely to experience depressive symptoms (adjusted odds ratio [AOR] = 1.18, 95% confidence interval [CI] = 1.10-1.26), cigarette smoking (AOR = 1.11, 95% CI = 1.01-1.22), insufficient sleep (AOR = 1.13, 95% CI = 1.06-1.21), and physical inactivity (AOR = 1.09, 95% CI = 1.02-1.15) than those with less active social media use. Active social media use did not significantly interact with social support to predict any health indicators (p values >0.159). Conclusions: Among SGM adults, active social media use was associated with several negative health indicators. Active social media use may increase health risks, or SGM adults with poor health may actively use social media to maintain social connections. Moderate active social media use may be compatible with health.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis.

Students' well-being, learning activities, and learning success are key student outcomes that can be affected by challenging times such as the COVID-19 pandemic. Thus, it is vital to investigate the role of important personal (resilience, self-efficacy) and social resources (support from family, friends, teachers, important other) for central student outcomes (life satisfaction as a vital aspect of well-being, learning activities, and learning success) alongside perception of the COVID-19 situation. While the pandemic affected all of society, adolescents as a group who face core developmental challenges were especially vulnerable towards being negatively affected by the pandemic. Thus, analyses are based on 220 adolescent students (60.9% female, 37.7% male, 1.4% diverse) in Germany who were 16.21 years old on average (SD = 0.88) at time of data collection in May 2021. Students filled out an online questionnaire on sociodemographics and variables of interest. Path models revealed that perceiving the COVID-19 pandemic as stressful was negatively related to life satisfaction ([beta] = -0.27). Furthermore, perceiving the COVID-19 pandemic as stressful was negatively related to students' self-efficacy ([beta] = -0.22) and positively to support from an important other ([beta] = 0.32). Moreover, several resources were mainly positively related to our central student outcomes ([beta] = 0.13-0.41), and perception of the COVID-19 situation mediated two of those relations. Results underscore the importance of students' self-efficacy, which was related to all student outcomes. Furthermore, the results and methodological issues can impact further research and practice.

Background: The meanings of neurodevelopmental conditions are socially and culturally defined. We explored how parents of a child with Down syndrome experienced public and professional understandings of Down syndrome. Method: Qualitative interviews with 25 parents of a child with Down syndrome living in Denmark. From a reflexive thematic analysis, we developed themes describing understandings (i.e., attitudes or perceptions) of Down syndrome. Results: The parents experienced that the Down syndrome diagnosis acted as a 'label'; this had perceived positive and negative consequences for the child. The parents felt others understood Down syndrome as severe and undesirable. This attitude was tied to the existence of prenatal screening. Finally, to the parents, professional support for their child expressed an understanding of children with Down syndrome as valued individuals. Conclusions: Parents encountered ambiguous understandings of Down syndrome. This should be recognised by professionals who may shape such understandings.