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Significant evidence suggests that the failure of clinically tested epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (e.g. erlotinib, lapatinib, gefitinib) in glioblastoma (GBM) patients is primarily attributed to insufficient brain penetration, resulting in inadequate exposure to the targeted cells. Molecular imaging tools can facilitate GBM drug development by visualizing drug biodistribution and confirming target expression and localization. To assess brain exposure via PET molecular imaging, we synthesized fluorine-18 isotopologues of two brain-penetrant EGFR tyrosine kinase inhibitors developed specifically for GBM. Adapting our recently reported radiofluorination of N-arylsydnones, we constructed an ortho-disubstituted [18F]fluoroarene as the key intermediate. The radiotracers were produced on an automated synthesis module in 7-8% activity yield with high molar activity. In vivo PET imaging revealed rapid brain uptake in rodents and tumor accumulation in an EGFR-driven orthotopic GBM xenograft model.

Background: Schools have become a primary access point for mental health services to cover the gap between need and service utilization that has long existed, particularly among vulnerable populations. This study aims to identify the profiles of comprehensive school mental and behavioral health system (CSMBHS) needs and examine related characteristics. Methods: We used the 2019 National Survey of Drug Use and Health (NSDUH) collected from a nationally representative sample in the United States. The sample included 6th through 12th-grade adolescents who had received CSMBHS services in the last 12 months (N = 1346). The study conducted latent class analysis and multinomial logistic regression using Vermunt's 3-step approach. Results: The analysis identified 3 profiles of student CSMBHS service need: depression needs (42%), multiple endorsements in most needs (depressed, friend, and school problems; 6.5%), and low endorsement (51.4%). Findings suggest that the profiles differed by age, a lifetime major depressive episode, family income, and use of other mental health services. Implications for School Health, Policy, Practice, and Equity: Emphasis should be placed on proactively identifying student needs and advocating for appropriate interventions based on student needs. Conclusions: The study reveals important information regarding how schools best support students in need and in seeking services.

Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or "primed" by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.

IntroductionRates of overweight and obesity have increased in the military, particularly in the U.S. Navy. While the Navy has implemented weight-management programs like ShipShape, findings on the effectiveness of these programs are mixed. Further knowledge on the characteristics of service members (SMs) who participate in these programs may help inform course curricula and improve outcomes. This study aimed to (1) examine characteristics of SMs referred to the Navy's ShipShape program at a large military treatment facility, (2) compare these characteristics among SMs who did and did not enroll in a randomized clinical trial of ShipShape (ShipShape study participants), and (3) compare demographic and health characteristics of ShipShape study participants to that of a random and similarly sized sample of Navy SMs who responded to the 2015 DoD Health-Related Behaviors Survey (HRBS).Materials and methodsData from active duty Navy SMs referred to the ShipShape program at a large military treatment facility were evaluated (n = 225). A subset of these SMs enrolled in the ShipShape study (n = 187). Among enrolled SMs, data from 147 who completed all measures were compared to that of HRBS respondents. Univariate ANOVA and chi-square analyses were used to examine (1) demographic and motivational differences between SMs who did and did not enroll in the ShipShape study and (2) differences in demographics and medical and mental health conditions between ShipShape study participants and Navy HRBS respondents.ResultsThe majority of SMs referred to ShipShape were female with an average age of 28.3 years. Compared to SMs who did not enroll in the ShipShape study (n = 38), ShipShape study participants were more likely to be female, less likely to be Hispanic, and had higher motivation and emotional eating scores. Compared to Navy HRBS respondents (n = 164), ShipShape study participants (n = 147) were younger, more likely to be female, non-Hispanic, enlisted, and obese. Further, ShipShape study participants reported significantly fewer medical health conditions but higher rates of probable depression, anxiety, and PTSD and were more likely to report receiving current mental health treatment than HRBS respondents.ConclusionOverweight or obese SMs seeking weight loss in the ShipShape study were relatively young, female, non-Hispanic, motivated, but with greater emotional eating. ShipShape study participants endorsed few medical health conditions but had higher rates of probable mental health conditions compared to the HRBS sample. These findings suggest that SMs referred to Navy weight-management programs are likely experiencing comorbid mental health conditions which may interfere with the effectiveness of their weight loss efforts. The descriptive nature of this study and the focus on Navy SMs in only one ShipShape program may decrease the generalizability of our findings to participants at other locations. Nonetheless, these findings demonstrate the potential need for Navy weight-management programs that incorporate mental health treatment and address the specific needs of female and diverse SMs. A more comprehensive curriculum could improve the results of weight-management efforts, increase SM quality of life and fitness and thereby operational readiness.

The 18F labeling of unprotected peptides and sugars with a Au(III)-[18F]fluoroaryl complex is reported. The chemoselective method generates 18F-labeled S-aryl bioconjugates in an aqueous environment in 15 min with high radiochemical yields and displays excellent functional group tolerance. This approach utilizes an air and moisture stable, robust organometallic Au(III) complex and highlights the versatility of designer organometallic reagents as efficient agents for rapid radiolabeling.

PurposeA Cognitive Task Force (CTF) was established for the MissionAD program with the aim of reducing the screen failure (SF) rate to ∼30% and thereby reduce unnecessary subject burden, site burden, and excess trial costs.Methods/subjectsThe MissionAD program consisted of 2 global phase 3 studies evaluating the BACE inhibitor elenbecestat in subjects with early Alzheimer disease. The CTF monitored and engaged with MissionAD clinical sites to provide support through collegial discussions to maximize the efficiency of the preconsent recruitment phase.ResultsThe CTF significantly improved cognitive screening efficiency in the MissionAD program, with a 24% decline in cognitive SF rate for the sites that the CTF contacted. The study-wide 11.5% reduction in cognitive SF rates were likely further driven by wider country-level initiatives in which CTF members held CTF-specific Investigator meetings with the recruitment staff, speaking to all sites on a country level regardless of their recruitment performance.ConclusionsThe establishment of a CTF to support efficient cognitive screening is highly recommended for future Alzheimer disease studies. Additional benefits included improved site relationships, increased engagement in MissionAD and access to a group of cognitive experts for consulting, with a focus on achieving more efficient trial recruitment.

Despite the heterogeneity in autism, socioemotional difficulties are often framed as universal. Increasing evidence, however, suggests that socioemotional difficulties may be explained by alexithymia, a distinct yet frequently co-occurring condition. If, as some propose, autistic traits are responsible for socioemotional impairments, then alexithymia may itself be a symptom of autism. We aimed to determine whether alexithymia should be considered a product of autism or regarded as a separate condition. Using factor-analytic and network approaches, we provide evidence that alexithymic and autistic traits are distinct. We argue that: (1) models of socioemotional processing in autism should conceptualise difficulties as intrinsic to alexithymia; and (2) assessment of alexithymia is crucial for diagnosis and personalised interventions.

Wintertime episodes of high aerosol concentrations occur frequently in urban and agricultural basins and valleys worldwide. These episodes often arise following development of persistent cold-air pools (PCAPs) that limit mixing and modify chemistry. While field campaigns targeting either basin meteorology or wintertime pollution chemistry have been conducted, coupling between interconnected chemical and meteorological processes remains an insufficiently studied research area. Gaps in understanding the coupled chemical-meteorological interactions that drive high pollution events make identification of the most effective air-basin specific emission control strategies challenging. To address this, a September 2019 workshop occurred with the goal of planning a future research campaign to investigate air quality in Western U.S. basins. Approximately 120 people participated, representing 50 institutions and 5 countries. Workshop participants outlined the rationale and design for a comprehensive wintertime study that would couple atmospheric chemistry and boundary-layer and complex-terrain meteorology within western U.S. basins. Participants concluded the study should focus on two regions with contrasting aerosol chemistry: three populated valleys within Utah (Salt Lake, Utah, and Cache Valleys) and the San Joaquin Valley in California. This paper describes the scientific rationale for a campaign that will acquire chemical and meteorological datasets using airborne platforms with extensive range, coupled to surface-based measurements focusing on sampling within the near-surface boundary layer, and transport and mixing processes within this layer, with high vertical resolution at a number of representative sites. No prior wintertime basin-focused campaign has provided the breadth of observations necessary to characterize the meteorological-chemical linkages outlined here, nor to validate complex processes within coupled atmosphere-chemistry models.

This study examines the role of human-animal interaction (HAI) in relations between sexual and gender minority (SGM) stress, personal hardiness, and psychological stress during emerging adulthood. Data for the current sample reflect 136 SGM emerging adults between the ages of 18 to 21 years who reported living with a companion animal in the past year (37.5% racial/ethnic minority, 49.2% transgender or gender -expansive, 98.5% sexual minority). Mediation was tested using structural equation modeling with a bootstrapping approach. We found evidence of an indirect effect of microaggressions on personal hardiness. Specifically, increases in microaggressions were associated with increases in HAI; in turn, increases in HAI were associated with higher levels of personal hardiness. No other statistically significant indirect effects were identified in our model. We discuss the implications of these findings for enhancing community capacity to empower and facilitate successful coping among SGM emerging adults.

This article narrates the experiences of four former PhD students who completed the transition from graduate student to graduates with PhDs during unprecedented external events: The COVID-19 pandemic and a period of civil unrest in response to the 2020 police killings of George Floyd and Breonna Taylor. The authors reflect on some commonalities in how they were able to adjust and persevere to completion.

ObjectiveDespite empirical support for interdisciplinary pain rehabilitation programs improving functioning and quality of life, access to this treatment approach has decreased dramatically over the last 20 years within the United States but has grown significantly in the Department of Veterans Affairs (VA). Between 2009 and 2019, VA pain rehabilitation programs accredited by the Commission on Accreditation of Rehabilitation Facilities increased 10-fold in the VA, expanding from two to 20. The aim of this collaborative observational evaluation was to examine patient outcomes across a subset of six programs at five sites.MethodsOutcomes were assessed using agreed-upon measures of patient-reported pain intensity, pain interference across various domains, pain catastrophizing, and sleep.ResultsA total of 931 patients enrolled in the selected VA interdisciplinary pain programs, with 84.1% of participants completing the full course of treatment. Overall, all programs showed significant improvements from pretreatment to posttreatment in nearly all patient-reported outcomes. The effect sizes ranged from medium to large. Notably, the results demonstrate that positive outcomes were typical despite differences in structure and resources across programs.ConclusionsThe adverse impacts of opioid use have highlighted the importance of chronic pain treatment approaches that emphasize team-based care focused on functional improvements. This study represents the first and largest analysis of outcomes across chronic pain rehabilitation programs and demonstrates the need for increased access to similar comprehensive approaches to pain management across the health care system. Further, it suggests that a variety of structures may be effective, encouraging flexibility in adopting this interdisciplinary approach.