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Cliffs harbor unique and specialized biodiversity that warrants attention and conservation. At the same time, cliffs are under increased threat from anthropogenic disturbance and climate change. Since cliffs are highly heterogeneous, spatially isolated, and often inaccessible compared to nearby habitats, land managers require up-to-date and site-specific information to protect them. Cliffs are often overlooked due to the technical and logistical challenges posed by surveying these environments, but field inventorying and monitoring can fill this gap. We present three case studies of cliff monitoring in action: mapping populations of an endemic rare plant in the Southern Appalachian Mountains (US), photo-sampling of cliff specialist plants in Spain, and surveying peregrine falcons in Western North Carolina (US). These case studies highlight the application of various monitoring techniques, the possibilities for collaboration among stakeholders, and some ways that data from monitoring can inform cliff conservation and stewardship. To facilitate the development of easy-to-implement monitoring, we outline three approaches and associated best practices for monitoring cliff plants. Methods range from simple photo point monitoring to more in-depth species inventories and could be implemented by community scientists alongside a broader audience interested in providing up-to-date data on cliff environments. We call for action, urging the expansion and advancement of cliff biodiversity monitoring.

Abstract Controlling crystal growth alignment in low-dimensional perovskites (LDPs) for solar cells has been a persistent challenge, especially for low-n LDPs (n 1.7 eV) impeding charge flow. Here we overcome such transport limits by inducing vertical crystal growth through the addition of chlorine to the precursor solution. In contrast to 3D halide perovskites (APbX3), we find that Cl substitutes I in the equatorial position of the unit cell, inducing a vertical strain in the perovskite octahedra, and is critical for initiating vertical growth. Atomistic modelling demonstrates the thermodynamic stability and miscibility of Cl/I structures indicating the preferential arrangement for Cl-incorporation at I-sites. Vertical alignment persists at the solar cell level, giving rise to a record 9.4% power conversion efficiency with a 1.4 V open circuit voltage, the highest reported for a 2 eV wide band gap device. This study demonstrates an atomic-level understanding of crystal tunability in low-n LDPs and unlocks new device possibilities for smart solar facades and indoor energy generation.

Abstract Colorectal cancer (CRC) ranks among the most prevalent malignancies worldwide, driving a quest for comprehensive characterization methods. We report a characterization of the ex vivo autofluorescence lifetime fingerprint of colorectal tissues obtained from 73 patients that underwent surgical resection. We specifically target the autofluorescence characteristics of collagens, reduced nicotine adenine (phosphate) dinucleotide (NAD(P)H), and flavins employing a fiber-based dual excitation (375 nm and 445 nm) optical imaging system. Autofluorescence-derived parameters obtained from normal tissues, adenomatous lesions, and adenocarcinomas were analyzed considering the underlying clinicopathological features. Our results indicate that differences between tissues are primarily driven by collagen and flavins autofluorescence parameters. We also report changes in the autofluorescence parameters associated with NAD(P)H that we tentatively attribute to intratumoral heterogeneity, potentially associated to the presence of distinct metabolic subpopulations. Changes in autofluorescence signatures of malignant tumors were also observed with lymphatic and venous invasion, differentiation grade, and microsatellite instability. Finally, we characterized the impact of radiative treatment in the autofluorescence fingerprints of rectal tissues and observed a generalized increase in the mean lifetime of radiated adenocarcinomas, which is suggestive of altered metabolism and structural remodeling. Overall, our preliminary findings indicate that multiparametric autofluorescence lifetime measurements have the potential to significantly enhance clinical decision-making in CRC, spanning from initial diagnosis to ongoing management. We believe that our results will provide a foundational framework for future investigations to further understand and combat CRC exploiting autofluorescence measurements.

Purpose – The purpose of this research study was to examine school leaders’ critical perspectives about the nature of their partnerships with K-12 schools and two Educator Preparation Programs (EPP). Design/methodology/approach – Data were collected through interviews with K-12 school leaders to obtain partners’ critical perspectives about school–EPP partnerships. The interviews were coded thematically and oriented around the central concept of working to represent the interplay of the participants and their collaborators’ perceptions of the nature and dimensions of school–EPP partnerships. Findings – The analysis resulted in the construction of a mosaic of school leaders’ collective lived experiences using a statewide conceptual framework as a guide. Four themes emerged from our interviews with school partners: (a) the need for dynamic, responsive and synergistic partnerships; (b) the need to monitor and maintain the underlying structure and integrity of the partnership; (c) the culture of interns as colleagues or as visitors; and (d) the need to innovate. Originality/value – Four themes emerged from our interviews with school partners: (1) the need for dynamic, responsive and synergistic partnerships; (2) the need to monitor and maintain the underlying structure and integrity of partnerships; (3) the culture of interns as colleagues or interns as visitors; and (4) the need to innovate.

Abstract Background Dry eye disease (DED) is a prevalent condition affecting over 16 million patients in the USA. DED and the symptoms of ocular discomfort are debilitating and a significant burden on patients. If left untreated, DED can progress to cause severe pathology. Treatment is often initiated by patients without consulting a healthcare professional. This study investigated the safety and efficacy of a novel lipid-containing eye drop (BTC), which might better mimic the components of natural tears. Methods This was a multicenter, randomized, double-masked, active control, two arm, parallel group study of eye drops in adult subjects with self-reported DED. Subjects were randomly assigned to BTC or control (commercially available non-lipid eye drops; NLED) arm and were followed for 30 days. Assessments using visual analog scale and patient-reported outcomes (PRO) questionnaires, non-invasive tear break up time, slit-lamp examination, and subject-reported ocular symptoms were conducted at baseline and at days 7 and 30. The primary endpoint was change in overall ocular comfort score from baseline to day 30. Results 158 subjects were randomized, of whom 130 completed the study per protocol (PP). Mean (SD) age was 47.8 (14.14) years. The mean (95% CI) change in overall comfort scores at the 30-day follow-up in the PP population was 21.4 (15.1, 27.7) for the test drop and 10.0 (3.9, 16.1) for the comparator. The mean (95% CI) treatment difference was 11.3 (2.6, 20.1); this met the pre-defined requirements for non-inferiority. There was no significant difference in the proportion of eyes with reported ocular symptoms between the groups. At day 7, the OR (95% CI) was 0.967 (0.528, 1.770) and at day 30 was 1.160 (0.610, 2.203). There were no Grade 3 or higher corneal edema, corneal neovascularization, corneal staining, conjunctival injection, tarsal abnormalities or any other biomicroscopy findings, and no corneal infiltrates observed during the study. Conclusions The investigational lipid eye drop BTC was noninferior to the commercially available non-lipid comparator in all parameters measured and has the potential to provide an effective therapy for subjects with symptoms of dry eye who would benefit from a lipid-based artificial tear. Trial Registration NCT03995355 ( http://www.clinicaltrials.gov ), registered June 24, 2019.

Abstract Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Varicocele has a prevalence of 15% in the population and represents a primary cause of infertility in 40% of cases and a secondary cause in approximately 80% of cases. It is considered the major correctable cause of male infertility. Despite its high prevalence in the infertile population, a large number of patients with varicocele do not experience reproductive difficulties. For this reason, it is still highly debated which parameters could be used to predict which patients with varicocele will be most likely to benefit from its repair. The main international and European guidelines state that treatment should only be considered in infertile patients with abnormal sperm quality. However, these guidelines do not help physicians to identify which of these patients may benefit from the treatment. Therefore, this narrative review collects the evidence in the literature on the usefulness of some factors as predictors of improvement, highlighting how some of them may be effective in an initial selection of patients to be treated, while others are promising but further studies are needed. Finally, a brief consideration on the possible role of artificial intelligence is proposed.

ABSTRACT Purpose: The gubernaculum seems to be the most important anatomical structure in the testicular migration process. The objective of this paper is to review current literature regarding the role of gubernaculum testis nerves in testicular migration. We conducted a comprehensive literature review about the gubernaculum testis innervation. A PubMed database search was performed in April 2024, focusing on gubernaculum testis and cryptorchidism and genitofemoral nerve (GFN) and calcitonin gene-related peptide (CGRP) gene. The gubernaculum has its own nerve supply, the GFN, descending on the anteromedial surface of the psoas muscle from L1-L2 segments. The second phase of testicular descent is regulated by androgens and CGRP, released from the sensory nucleus of the GFN. The GFN doesn't directly play a role in testicular migration but there is a theory that shows a regulatory function of this nerve in hormonal action during this process. The gubernaculum testis has important structural alterations during the testicular migration and the genitofemoral nerve and CGRP gene are of great importance in this process. The genitofemoral nerve provides motor innervation to the cremaster muscle and gubernaculum, which helps regulate the position of the testes within the scrotum.

Abstract Background Mobile Integrated Health-Community Paramedicine (MIH-CP) is a novel approach that may reduce the rural-urban disparity in vaccination uptake in the United States. MIH-CP providers, as physician extenders, offer clinical follow-up and wrap-around services in homes and communities, uniquely positioning them as trusted messengers and vaccine providers. This study explores stakeholder perspectives on feasibility and acceptability of community paramedicine vaccination programs. Methods We conducted semi-structured qualitative interviews with leaders of paramedicine agencies with MIH-CP, without MIH-CP, and state/regional leaders in Indiana. Interviews were audio recorded, transcribed verbatim, and analyzed using content analysis. Results We interviewed 24 individuals who represented EMS organizations with MIH-CP programs (MIH-CP; n = 10), EMS organizations without MIH-CP programs (non-MIH-CP; n = 9), and state/regional administrators (SRA; n = 5). Overall, the sample included professionals with an average of 19.6 years in the field (range: 1–42 years). Approximately 75% (n = 14) were male, and all identified as non-Hispanic white. MIH-CPs reported they initiated a vaccine program to reach underserved areas, operating as a health department extension. Some MIH-CPs integrated existing services, such as food banks, with vaccine clinics, while other MIH-CPs focused on providing vaccinations as standalone initiatives. Key barriers to vaccination program initiation included funding and vaccinations being a low priority for MIH-CP programs. However, participants reported support for vaccine programs, particularly as they provided an opportunity to alleviate health disparities and improve community health. MIH-CPs reported low vaccine hesitancy in the community when community paramedics administered vaccines. Non-CP agencies expressed interest in launching vaccine programs if there is clear guidance, sustainable funding, and adequate personnel. Conclusions Our study provides important context on the feasibility and acceptability of implementing an MIH-CP program. Findings offer valuable insights into reducing health disparities seen in vaccine uptake through community paramedics, a novel and innovative approach to reduce health disparities in rural communities.

Abstract Recent advances in imaging suggested that spatial organization of hematopoietic cells in their bone marrow microenvironment (niche) regulates cell expansion, governing progression, and leukemic transformation of hematological clonal disorders. However, our ability to interrogate the niche in pre-malignant conditions has been limited, as standard murine models of these diseases rely largely on transplantation of the mutant clones into conditioned mice where the marrow microenvironment is compromised. Here, we leveraged live-animal microscopy and ultralow dose whole body or focal irradiation to capture single cells and early expansion of benign/pre-malignant clones in the functionally preserved microenvironment. 0.5 Gy whole body irradiation (WBI) allowed steady engraftment of cells beyond 30 weeks compared to non-conditioned controls. In-vivo tracking and functional analyses of the microenvironment showed no change in vessel integrity, cell viability, and HSC-supportive functions of the stromal cells, suggesting minimal inflammation after the radiation insult. The approach enabled in vivo imaging of Tet2 +/− and its healthy counterpart, showing preferential localization within a shared microenvironment while forming discrete micro-niches. Notably, stationary association with the niche only occurred in a subset of cells and would not be identified without live imaging. This strategy may be broadly applied to study clonal disorders in a spatial context.

Abstract While multiple factors impact disease, artificial intelligence (AI) studies in medicine often use small, non-diverse patient cohorts due to data sharing and privacy issues. Federated learning (FL) has emerged as a solution, enabling training across hospitals without direct data sharing. Here, we present FL-PedBrain, an FL platform for pediatric posterior fossa brain tumors, and evaluate its performance on a diverse, realistic, multi-center cohort. Pediatric brain tumors were targeted due to the scarcity of such datasets, even in tertiary care hospitals. Our platform orchestrates federated training for joint tumor classification and segmentation across 19 international sites. FL-PedBrain exhibits less than a 1.5% decrease in classification and a 3% reduction in segmentation performance compared to centralized data training. FL boosts segmentation performance by 20 to 30% on three external, out-of-network sites. Finally, we explore the sources of data heterogeneity and examine FL robustness in real-world scenarios with data imbalances.

Abstract Background Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. Methods To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Results Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Conclusion Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.

Allochthonous inputs often link nutrient cycles between different ecosystems as nitrogen (N) that originates in one ecosystem is transferred to another. Mobile animals such as birds and fish can translocate nutrients between locations. Consequently, animal-mediated nutrient subsidies can shape plant communities, especially in nutrient-poor ecosystems. Terrestrial cliffs are typically nutrient-poor, receiving N from atmospheric deposition and cliff-top runoff. Cliff nesting birds deposit N-rich excrement onto the cliff during nesting, yet this potential nutrient input has rarely been demonstrated. Here we document an allochthonous input of N from cliff-nesting birds to terrestrial cliff vegetation. We sampled mineral N and vegetation on eight cliff systems in western North Carolina (USA) with nests from peregrine falcon (F. peregrinus; two sites) and common raven (Corvus corax; five sites). Two sites had nests but species identity was not confirmed. Cliff faces below bird nests had higher levels of ammonium (NH4+) than did faces without nests. Both ammonium and nitrate (NO3−) explained variability in cliff vegetation community composition, but site-level characteristics explained more of the variation than did N inputs alone. Lichens, the dominant taxonomic group, contributed the most to this variation and had higher species richness and diversity below nests. Indicator species analysis identified two nitrophilic lichen species below nests: Flavoplaca citrina and Physcia caesia. A third nitrophilic lichen, Polycauliona candelaria (syn. Xanthoria candelaria) was also found under nests. Bird excrement is likely a significant subsidy to nutrient-poor terrestrial cliff ecosystems, thus linking cliffs to more productive ecosystems and highlighting the need to include birds in conservation and management of cliffs.

Abstract We evaluate deconvolution methods, which infer levels of immune infiltration from bulk expression of tumor samples, through a community-wide DREAM Challenge. We assess six published and 22 community-contributed methods using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells. Several published methods predict most cell types well, though they either were not trained to evaluate all functional CD8+ T cell states or do so with low accuracy. Several community-contributed methods address this gap, including a deep learning-based approach, whose strong performance establishes the applicability of this paradigm to deconvolution. Despite being developed largely using immune cells from healthy tissues, deconvolution methods predict levels of tumor-derived immune cells well. Our admixed and purified transcriptional profiles will be a valuable resource for developing deconvolution methods, including in response to common challenges we observe across methods, such as sensitive identification of functional CD4+ T cell states.

Abstract Background Spanish-speakers with non-English language preference and complex medical needs suffer disparities in quality of care, safety, and health outcomes. Communication challenges during prolonged hospitalizations for complex illnesses negatively influence how this group engages in their care and decision-making while hospitalized. Limited literature capturing the perspectives of Spanish-speaking patients in this context exists. Given the impact of language barriers on care and medical decision-making, this study documents the experiences of Spanish-speaking patients with NELP and hospitalized with complex care needs as well as caregivers and community leaders. Methods Using community-engaged recruitment strategies and semi-structured interviews and a focus group, we gathered insights from Spanish-speaking patients hospitalized for prolonged periods, caregivers, and community leaders from three geographic regions. Data were deidentified, transcribed, translated, coded in duplicate, and analyzed guided by grounded theory using NVivo. Results We interviewed 40 participants: 27 patients, 10 caregivers and 3 community leaders. We identified four major themes: (1) Disconnected experiences impeding interactions, communication, and decision-making (2) Inadequate interpreter services (3) Benefits and consequences of family at the bedside (4) Community -informed recommendations. Conclusion The study showed that in-person interpreters were preferred to virtual interpreters; yet interpreter access was suboptimal. This resulted in ad hoc family interpretation. Participants noted language negatively impacted patient’s hospital experience, including decreasing confidence in medical decision-making. Recommendations from patients, caregivers, and community leaders included expanding interpreter access, bolstering interpreter quality and accuracy, and increasing resources for patient education.

Abstract The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20–89 years; 33% female) and 885 controls (age: 19–84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen’s d effect sizes reached d = −1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Abstract Terrestrial groundwater travels through subterranean estuaries before reaching the sea. Groundwater‐derived nutrients drive coastal water quality, primary production, and eutrophication. We determined how dissolved inorganic nitrogen (DIN), dissolved inorganic phosphorus (DIP), and dissolved organic nitrogen (DON) are transformed within subterranean estuaries and estimated submarine groundwater discharge (SGD) nutrient loads compiling > 10,000 groundwater samples from 216 sites worldwide. Nutrients exhibited complex, nonconservative behavior in subterranean estuaries. Fresh groundwater DIN and DIP are usually produced, and DON is consumed during transport. Median total SGD (saline and fresh) fluxes globally were 5.4, 2.6, and 0.18 Tmol yr−1 for DIN, DON, and DIP, respectively. Despite large natural variability, total SGD fluxes likely exceed global riverine nutrient export. Fresh SGD is a small source of new nutrients, but saline SGD is an important source of mostly recycled nutrients. Nutrients exported via SGD via subterranean estuaries are critical to coastal biogeochemistry and a significant nutrient source to the oceans.

Abstract Images collected during NASA’s Double Asteroid Redirection Test (DART) mission provide the first resolved views of the Didymos binary asteroid system. These images reveal that the primary asteroid, Didymos, is flattened and has plausible undulations along its equatorial perimeter. At high elevations, its surface is rough and contains large boulders and craters; at low elevations its surface is smooth and possesses fewer large boulders and craters. Didymos’ moon, Dimorphos, possesses an intimate mixture of boulders, several asteroid-wide lineaments, and a handful of craters. The surfaces of both asteroids include boulders that are large relative to their host body, suggesting that both asteroids are rubble piles. Based on these observations, our models indicate that Didymos has a surface cohesion ≤ 1 Pa and an interior cohesion of ∼10 Pa, while Dimorphos has a surface cohesion of

Abstract Planetary defense efforts rely on estimates of the mechanical properties of asteroids, which are difficult to constrain accurately from Earth. The mechanical properties of asteroid material are also important in the interpretation of the Double Asteroid Redirection Test (DART) impact. Here we perform a detailed morphological analysis of the surface boulders on Dimorphos using images, the primary data set available from the DART mission. We estimate the bulk angle of internal friction of the boulders to be 32.7 ± 2. 5° from our measurements of the roundness of the 34 best-resolved boulders ranging in size from 1.67–6.64 m. The elongated nature of the boulders around the DART impact site implies that they were likely formed through impact processing. Finally, we find striking similarities in the morphology of the boulders on Dimorphos with those on other rubble pile asteroids (Itokawa, Ryugu and Bennu). This leads to very similar internal friction angles across the four bodies and suggests that a common formation mechanism has shaped the boulders. Our results provide key inputs for understanding the DART impact and for improving our knowledge about the physical properties, the formation and the evolution of both near-Earth rubble-pile and binary asteroids.

Abstract Background Health and social sector organizations are increasingly working together to mitigate socioeconomic adversity within their communities. We sought to learn about the motivations, experiences, and perspectives of organizations engaged in these collaborations. Methods We conducted semi-structured, 60-minute interviews with 34 leaders from 25 health and social sector organizations between January-April 2021. Interviews explored motivations, benefits and challenges, and ways in which health sector organizations can most effectively address community-level socioeconomic adversity. Interviews were audio recorded and transcribed; themes were coded using Dedoose software. Results Partnerships were primarily motivated by mission-driven organizations and key health sector leaders who were interested in addressing root causes of poor health; policies such as certificate of need laws and value-based care incentives that aligned community-level investments with health sector organizations’ financial interests facilitated these efforts. While partnerships were mostly regarded as mutually beneficial ways to increase impact (for the health sector) and resource access (for the social sector), social sector organizations voiced frustrations regarding the outsized expectations, unsustained interest, and lack of partnership from their health sector collaborators. Despite these frustrations, both health and social sector interviewees supported the health sector’s continued involvement in community-level socioeconomic initiatives and expansion of policy and systems efforts. Conclusions Cross-sector, community-level socioeconomic initiatives were mutually beneficial, but social sector organizations experienced more frustrations. Policy and organizational changes within the health sector can further mobilize and sustain support for these efforts.

Abstract Background Behavioral or mental health disorders are common in children, adolescents, and young adults. Medication use is increasingly common, with few data describing drug-drug combinations in ambulatory settings. The objectives of this study were to describe the pharmaco-epidemiology of behavioral and mental health (BMH) medications among children, adolescents, and young adults in New York Medicaid and assess the prevalence of contraindicated drug pairs within this population. Methods This observational cross-sectional study evaluated New York State Medicaid managed care and fee-for-service enrollees under 21 years of age dispensed BMH medications in 2014. Main outcomes included number of members with prescriptions filled; number filling > 1 medication prescription concurrently for ≥ 30 days (polypharmacy), and number and nature of potentially contraindicated drug pairs. Results Of 2,430,434 children, adolescents, and young adults, 422,486 (17.4%) had a visit associated with a BMH diagnosis and 141,363 (5.8%) received one or more BMH medications. With 84 distinct medications evaluated, polypharmacy was common, experienced by 53,388 individuals (37.8% of those with a prescription filled), generating 11,115 distinct drug combinations. 392 individuals filled prescriptions for a contraindicated pair of ≥ 2 BMH medications for 30 days or longer. With ≥ 1 day overlap, 651 were exposed to contraindicated medications. The most common contraindicated pairs increased potential risk for prolonged QT interval and serotonin syndrome (n = 378 and n = 250 patients, respectively). Most combinations involved ziprasidone (3247.1 per 10,000 ziprasidone prescriptions filled). Conclusions With nearly 6% of members dispensed a BMH medication, contraindicated drug pairs were uncommon. However, any of those combinations represent a potential risk. Clinicians should attend to the balance of potential risks and benefits before contraindicated pairs are dispensed. The methodology described could serve as a basis for monitoring such rare instances and might reduce harm.

Abstract Background Previous studies have identified a diverse group of microbial taxa that differ between patients with multiple sclerosis (MS) and the healthy population. However, interpreting findings on MS-associated microbiota is challenging, as there is no true consensus. It is unclear whether there is gut microbiota commonly altered in MS across studies. Methods To answer this, we performed a meta-analysis based on the 16S rRNA gene sequencing data from seven geographically and technically diverse studies comprising a total of 524 adult subjects (257 MS and 267 healthy controls). Analysis was conducted for each individual study after reprocessing the data and also by combining all data together. The blocked Wilcoxon rank-sum test and linear mixed-effects regression were used to identify differences in microbial composition and diversity between MS and healthy controls. Network analysis was conducted to identify bacterial correlations. A leave-one-out sensitivity analysis was performed to ensure the robustness of the findings. Results The microbiome community structure was significantly different between studies. Re-analysis of data from individual studies revealed a lower relative abundance of Prevotella in MS across studies, compared to controls. Meta-analysis found that although alpha and beta diversity did not differ between MS and controls, a higher abundance of Actinomyces and a lower abundance of Faecalibacterium were reproducibly associated with MS. Additionally, network analysis revealed that the recognized negative Bacteroides-Prevotella correlation in controls was disrupted in patients with MS. Conclusions Our meta-analysis identified common gut microbiota associated with MS across geographically and technically diverse studies.

Abstract Background Despite success in HIV treatment, diagnosis and management of hypertension (HTN) and cardiovascular disease (CVD) remains suboptimal among people living with HIV (PLWH) in Botswana, with an overall HTN control of only 19% compared to 98% HIV viral suppressed. These gaps persist despite CVD primary care national guidelines and availability of free healthcare including antihypertensive medications. Our study aims to develop and test strategies to close the HTN care gap in PLWH, through integration into HIV care, leveraging the successful national HIV care and treatment program and strategies. Methods The InterCARE trial is a cluster randomized controlled hybrid type 2 effectiveness-implementation trial at 14 sites designed to enroll 4652 adults living with HIV and HTN plus up to 2326 treatment partners. Primary outcomes included effectiveness (HTN control) and implementation outcomes using the Reach Effectiveness Adoption Implementation and Maintenance framework, with explanatory mixed methods used to understand variability in outcomes. InterCARE trial’s main strategies include healthcare worker HTN and CVD care training plus long-term practice facilitation, electronic health record (EHR) documentation of key indicators and use of reminders, and use of treatment partners to provide social support to people living with HIV and HTN. InterCARE started with formative research to identify contextual factors influencing care gaps using the Consolidated Framework for Implementation Research. Results were used to adapt initial and develop additional implementation strategies to address barriers and leverage facilitators. The package was pilot tested in two clinics, with findings used to further adapt or add strategies for the clinical trial. Discussion If successful, the InterCARE model can be scaled up to HIV clinics nationwide to improve diagnosis, management, and support in Botswana. The trial will provide insights for scale-up of HTN integration into HIV care in the region. Trial registration ClinicalTrials.gov reference NCT05414526. Registered 18 May 2022, https://clinicaltrials.gov/study/NCT05414526?term=NCT05414526.&rank=1 .

Abstract Background Successful HIV treatment programs have turned HIV into a chronic condition, but noncommunicable diseases such as hypertension jeopardize this progress. Hypertension control rates among people with HIV (PWH) are low owing to gaps in patient awareness, diagnosis, effective treatment, and management of both conditions at separate clinic visits. Integrated management, such as in our study, InterCARE, can enhance HIV-hypertension integration and blood pressure (BP) control. Methods Our pilot study was conducted in two Botswana HIV clinics between October 2021 and November 2022. Based on our formative work, we adopted three main strategies; Health worker training on HTN/cardiovascular disease (CVD) management, adaptation of HIV Electronic Health Record (EHR) for HTN/CVD care, and use of treatment partners to support PWH with hypertension for implementation. We employed the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework to assess implementation effectiveness and outcomes for BP control at baseline, 6 and 12 months. HIV viral load (VL) suppression was also measured to assess impact of integration on HIV care. Results We enrolled 290 participants; 35 (12.1%) were lost to follow-up, leaving 255 (87.9%) at 12-months. Median age was 54 years (IQR 46–62), and 77.2% were females. Our interventions significantly improved BP control to

Abstract Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver’s balance of redox buffering and triglyceride production.

Abstract Background Sex trafficking victims often have touchpoints with salons for waxing, styling, and other body modification services required by traffickers. Recently, some states have administered laws requiring salon professionals to receive intimate partner violence (IPV)-related training, with even fewer states mandating training on identifying sex trafficking. This study aimed to understand how salon professionals have witnessed evidence of violence, including IPV and sex trafficking, in the workplace and to explore the differences in their approach to each type of victim. Methods In-depth interviews were conducted with salon professionals (N = 10) and law enforcement professionals/policymakers (N = 5). Content and thematic analysis techniques were used. Results Salon professionals typically identified potential violence through signs such as bruises, odd behavior, and client disclosures, prompting them to engage in cautious conversations. Yet, few were trained to identify and intervene. Often, they responded to suspected violence by talking with the client, sharing concerns with salon leadership, directly intervening on the client’s behalf, or contacting the police. Law enforcement and salon professionals had suggestions about improving salon professionals’ recognition of and response to violence, including training on victim-focused resources, creating a safe environment, and building relationships with law enforcement. They also suggested strengthening community partnerships to increase resource advocacy and reporting. Conclusions One-on-one salon services may provide a unique opportunity to intervene and identify victims of violence, especially when empowered through additional training and collaborative partnerships with community-oriented policing initiates. Implementing training and community-based initiatives could aid salon professionals in gaining greater confidence in knowing what to do when serving a client who is a victim of IPV or sex trafficking.

Abstract Background As cancer centers have increased focus on patient-centered, evidenced-based care, implementing efficient programs that facilitate effective patient-clinician communication remains critical. We implemented an electronic health record-integrated patient-reported symptom and needs monitoring program (‘cPRO’ for cancer patient-reported outcomes). To aid evaluation of cPRO implementation, we asked patients receiving care in one of three geographical regions of an academic healthcare system about their experiences. Methods Using a sequential mixed-methods approach, we collected feedback in two waves. Wave 1 included virtual focus groups and interviews with patients who had completed cPRO. In Wave 2, we administered a structured survey to systematically examine Wave 1 themes. All participants had a diagnosed malignancy and received at least 2 invitations to complete cPRO. We used rapid and traditional qualitative methods to analyze Wave 1 data and focused on identifying facilitators and barriers to cPRO implementation. Wave 2 data were analyzed descriptively. Results Participants (n = 180) were on average 62.9 years old; were majority female, White, non-Hispanic, and married; and represented various cancer types and phases of treatment. Wave 1 participants (n = 37) identified facilitators, including cPRO’s perceived value and favorable usability, and barriers, including confusion about cPRO’s purpose and various considerations for responding. High levels of clinician engagement with, and patient education on, cPRO were described as facilitators while low levels were described as barriers. Wave 2 (n = 143) data demonstrated high endorsement rates of cPRO’s usability on domains such as navigability (91.6%), comprehensibility (98.7%), and relevance (82.4%). Wave 2 data also indicated low rates of understanding cPRO’s purpose (56.7%), education from care teams about cPRO (22.5%), and discussing results of cPRO with care teams (16.3%). Conclusions While patients reported high value and ease of use when completing cPRO, they also reported areas of confusion, emphasizing the importance of patient education on the purpose and use of cPRO and clinician engagement to sustain participation. These results guided successful implementation changes and will inform future improvements.

Managing residential care facilities (RCFs) includes the ability to manage adverse events while maintaining a human rights-based approach to care and support. Literature investigating rights-based approaches in RCFs is scarce; therefore, an investigation of the current approach in RCFs will inform improvements. This study sought to identify whether RCFs in Ireland upheld a rights-based approach during the course of adverse events by analyzing notifications of adverse events from 2021 taken from the Database of Statutory Notifications from Social Care in Ireland. Data analysis was conducted independently by two researchers. Notifications of adverse events were coded according to whether the human rights principles of fairness, respect, equality, dignity, and autonomy were upheld or violated during the adverse event and its subsequent management. There was some evidence of violations, including staff violations during adverse events and their management, as well as residents violating fellow residents’ autonomy, respect, and dignity in notifications of “serious injury” and “allegations of abuse.” However, overall, good practice was identified, with residents’ human rights upheld by staff. Our findings indicate that a rights-based approach to care and support is being upheld during adverse events and their management, which may indicate that such an approach to care and support has been adopted

Abstract Background Botswana serves as a model of success for HIV with 95% of people living with HIV (PLWH) virally suppressed. Yet, only 19% of PLWH and hypertension have controlled blood pressure. To address this gap, InterCARE, a care model that integrates HIV and hypertension care through a) provider training; b) adapted electronic health record; and c) treatment partners (peer support), was designed. This study presents results from our baseline assessment of the determinants and factors used to guide adaptations to InterCARE implementation strategies prior to a hybrid type 2 effectiveness-implementation study. Methods This study employed a convergent mixed methods design across two clinics (one rural, one urban) to collect quantitative and qualitative data through facility assessments, 100 stakeholder surveys (20 each PLWH and hypertension, existing HIV treatment partners, clinical healthcare providers (HCPs), and 40 community leaders) and ten stakeholder key informative interviews (KIIs). Data were analyzed using descriptive statistics and deductive qualitative analysis organized by the Consolidated Framework for Implementation Research (CFIR) and compared to identify areas of convergence and divergence. Results Although 90.3% of 290 PLWH and hypertension at the clinics were taking antihypertensive medications, 52.8% had uncontrolled blood pressure. Results from facility assessments, surveys, and KIIs identified key determinants in the CFIR innovation and inner setting domains. Most stakeholders (> 85%) agreed that InterCARE was adaptable, compatible and would be successful at improving blood pressure control in PLWH and hypertension. HCPs agreed that there were insufficient resources (40%), consistent with facility assessments and KIIs which identified limited staffing, inconsistent electricity, and a lack of supplies as key barriers. Adaptations to InterCARE included a task-sharing strategy and expanded treatment partner training and support. Conclusions Integrating hypertension services into HIV clinics was perceived as more advantageous for PLWH than the current model of hypertension care delivered outside of HIV clinics. Identified barriers were used to adapt InterCARE implementation strategies for more effective intervention delivery. Trial registration ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT05414526 . Registered 18 May 2022 – Retrospectively registered.

Abstract Cancer patients often undergo rounds of trial-and-error to find the most effective treatment because there is no test in the clinical practice for predicting therapy response. Here, we conduct a clinical study to validate the zebrafish patient-derived xenograft model (zAvatar) as a fast predictive platform for personalized treatment in colorectal cancer. zAvatars are generated with patient tumor cells, treated exactly with the same therapy as their corresponding patient and analyzed at single-cell resolution. By individually comparing the clinical responses of 55 patients with their zAvatar-test, we develop a decision tree model integrating tumor stage, zAvatar-apoptosis, and zAvatar-metastatic potential. This model accurately forecasts patient progression with 91% accuracy. Importantly, patients with a sensitive zAvatar-test exhibit longer progression-free survival compared to those with a resistant test. We propose the zAvatar-test as a rapid approach to guide clinical decisions, optimizing treatment options and improving the survival of cancer patients.

Abstract The explosion and abundance of digital data could facilitate large-scale research for psychiatry and mental health. Research using so-called “real world data”—such as electronic medical/health records—can be resource-efficient, facilitate rapid hypothesis generation and testing, complement existing evidence (e.g. from trials and evidence-synthesis) and may enable a route to translate evidence into clinically effective, outcomes-driven care for patient populations that may be under-represented. However, the interpretation and processing of real-world data sources is complex because the clinically important ‘signal’ is often contained in both structured and unstructured (narrative or “free-text”) data. Techniques for extracting meaningful information (signal) from unstructured text exist and have advanced the re-use of routinely collected clinical data, but these techniques require cautious evaluation. In this paper, we survey the opportunities, risks and progress made in the use of electronic medical record (real-world) data for psychiatric research.

Anatoxin-a is a globally occurring, yet understudied, chiral cyanobacterial toxin that threatens public health and the environment. It has led to numerous dog. livestock and bird poisonings and although it has been studied in rodent models, comparatively little research has occurred in aquatic species. To advance a comparative toxicology understanding of this toxin in alternative vertebrate models, developing zebrafish and fathead minnow were exposed to environmentally relevant and elevated levels (13–4400 μg/L) of (+) anatoxin-a to examine potential mortality and sublethal effects, including photolocomotor behavior and gene expression responses. We observed significantly higher mortality (p 0.05) transcriptional changes were observed in the fathead minnow model. These differential responses between commonly employed species employed as alternative vertebrate models in toxicology research and chemicals risk assessments highlight the need for more comparative studies to understand sensitivities and variations in organismal response. Furthermore, we identified higher mortality, refractory behavioral effects, and gene expression in (+) anatoxin-a exposed fish when compared to previously reported (±) anatoxin-a (racemic 50:50 enantiomer mixture) studies, which is frequently used as a surrogate chemical for experimental work. Our findings identify the importance of understanding species and enantiomer specific effects of natural toxins.

ABSTRACT Snow crab (Chionoecetes opilio) in the eastern Bering Sea (EBS) supports a valuable crab fishery that harvests large males. To better understand the potential impact of the presence of snow‐Tanner hybrids (C. opilio × C. bairdi) on snow crab mating dynamics, the maternal lineage of hybrids was evaluated using single nucleotide polymorphisms (SNPs). Contrary to results from a previous study that indicated hybrids result only from crosses between Tanner crab (C. bairdi) males and snow crab females, results from this study showed hybrids result from bidirectional parental crosses. SNP and microsatellite markers were used to evaluate the species and number of males detected as mates in female sperm reserves acquired during mating and as sires among embryos in brooded clutches. The incidence of interspecies mating between female snow crab and Tanner crab or hybrid males was low (2%), suggesting interspecies mating is not currently a pressing fishery management concern. Most females had stored sperm from either a single mate (59%) or two mates (32%), which reflects fewer mates than observed for other snow crab populations. Few females were observed with either no stored sperm (5%) or sperm from three to four mates (4%). Single (82%) or dual (18%) paternity was found among embryos in brooded clutches. Sperm from some mates appeared to be fully utilized for fertilization of the brooded clutch for 35% of females. In contrast to findings for other snow crab populations, no significant differences were detected in the numbers of mates or sires between primiparous and multiparous females. The low extent of polyandry observed may suggest that female snow crab in the EBS have limited mating opportunities, potentially leading to insufficient sperm reserves to fertilize subsequent clutches without remating.

Variation in the mutual responsiveness of social partners to each other can be reflected in behavioral suites that covary with neural activity in ways that track the salience or valence of interactions. Juvenile social isolation alters social behavior and neural activity during social interaction, but whether and how it alters the covariation between behavior and neural activity has not been as well explored. To address this issue, four classes of experimental subjects: isolated males, socially housed males, isolated females, and socially housed females, were paired with an opposite-sex social partner that had been socially housed. Social behaviors and c-Fos expression in the serotonergic dorsal raphe nucleus (DRN) were then measured in subjects following the social interactions. Relative to social housing, postweaning isolation led to a decrease in the density of neurons double-labeled for tryptophan hydroxylase and c-Fos in the dorsomedial subdivision of the DRN, regardless of sex. Vocal and non-vocal behaviors were also affected by isolation. In interactions with isolated males, both ultrasonic vocalization (USVs) and broadband vocalizations (squeaks) increased in conjunction with greater male investigation of females. Neural and behavioral measures also correlated with each other. In the isolated male group, the density of double-labeled neurons in the dorsomedial DRN was negatively correlated with USV production and positively correlated with a principal component of non-vocal behavior corresponding to greater defensive kicking by females and less investigation and mounting behavior. This correlation was reversed in direction for socially housed males, and for isolated males versus isolated females. These findings confirm that the dynamics of social interactions are reflected in c-Fos activation in the dorsomedial DRN, and suggest an altered responsiveness of serotonergic neurons to social interaction following social isolation in males, in parallel with an altered male response to female cues.

BackgroundOlder adults with multiple chronic conditions (MCC) and polypharmacy often face challenges with medication adherence. Nonadherence can lead to suboptimal treatment outcomes, adverse drug events, and poor quality of life. ObjectiveTo facilitate medication adherence among older adults with MCC and polypharmacy in primary care, we are adapting a technology-enabled intervention previously implemented in a specialty clinic. The objective of this study was to obtain multilevel feedback to inform the adaptation of the proposed intervention (Phenotyping Adherence Through Technology-Enabled Reports and Navigation [PATTERN]). MethodsWe conducted a formative qualitative study among patients, clinicians, and clinic administrators affiliated with a large academic health center in Chicago, Illinois. Patient eligibility included being aged 65 years or older, living with MCC, and contending with polypharmacy. Eligibility criteria for clinicians and administrators included being employed by any primary care clinic affiliated with the participating health center. Individual semistructured interviews were conducted remotely by a trained member of the study team using interview guides informed by the Exploration, Preparation, Implementation, and Sustainment Framework. Thematic analysis of interview audio recordings drew from the Rapid Identification of Themes from Audio Recordings procedures. ResultsIn total, we conducted 25 interviews, including 12 with clinicians and administrators, and 13 with patients. Thematic analysis revealed participants largely found the idea of technology-based medication adherence monitoring to be acceptable and appropriate for the target population in primary care, although several concerns were raised; we discuss these in detail. ConclusionsOur medication adherence monitoring intervention, adapted from specialty care, will be implemented in primary care. Formative interviews, informed by the Exploration, Preparation, Implementation, and Sustainment Framework and conducted among patients, clinicians, and administrators, have identified intervention adaptation needs. Results from this study could inform other interventions using the patient portal with older adults.

BackgroundMicro- and nanoplastics (MNPs) are emerging pollutants of concern with ubiquitous presence in global ecosystems. MNPs pose potential implications for human health; however, the health impacts of MNP exposures are not yet understood. Recent evidence suggests that MNPs can cross the placental barrier, underlying the urgent need to understand their impact on reproductive health and development. ObjectiveThe Actionable eUropean ROadmap for early-life health Risk Assessment of micro- and nanoplastics (AURORA) project will investigate MNP exposures and their biological and health effects during pregnancy and early life, which are critical periods due to heightened vulnerability to environmental stressors. The AURORA project will enhance exposure assessment capabilities for measuring MNPs, MNP-associated chemicals, and plastic additives in human tissues, including placenta and blood. MethodsIn this interdisciplinary project, we will advance methods for in-depth characterization and scalable chemical analytical strategies, enabling high-resolution and large-scale toxicological, exposure assessment, and epidemiological studies. The AURORA project performs observational studies to investigate determinants and health impacts of MNPs by including 800 mother-child pairs from 2 existing birth cohorts and 110 women of reproductive age from a newly established cohort. This will be complemented by toxicological studies using a tiered-testing approach and epidemiological investigations to evaluate associations between maternal and prenatal MNP exposures and health perturbations, such as placental function, immune-inflammatory responses, oxidative stress, accelerated aging, endocrine disruption, and child growth and development. The ultimate goal of the AURORA project is to create an MNP risk assessment framework and identify the remaining knowledge gaps and priorities needed to comprehensively assess the impact of MNPs on early-life health. ResultsIn the first 3 years of this 5-year project (2021-2026), progress was made toward all objectives. This includes completion of recruitment and data collection for new and existing cohorts, development of analytical methodological protocols, and initiation of the toxicological tiered assessments. As of September 2024, data analysis is ongoing and results are expected to be published starting in 2025. ConclusionsAs plastic pollution increases globally, it is imperative to understand the impact of MNPs on human health, particularly during vulnerable developmental stages such as early life. The contributions of the AURORA project will inform future risk assessment. International Registered Report Identifier (IRRID)DERR1-10.2196/63176

Purpose: 2-Fluorodeoxyglucose-PET (FDG-PET) is a powerful tool to study glucose metabolism in mammalian brains, but cellular sources of glucose uptake and metabolic connectivity during aging are not yet understood. Methods: Healthy wild-type mice of both sexes (2–21 months of age) received FDG-PET and cell sorting after in vivo tracer injection (scRadiotracing). FDG uptake per cell was quantified in isolated microglia, astrocytes and neurons. Cerebral FDG uptake and metabolic connectivity were determined by PET. A subset of mice received measurement of blood glucose levels to study associations with cellular FDG uptake during aging. Results: Cerebral FDG-PET signals in healthy mice increased linearly with age. Cellular FDG uptake of neurons increased between 2 and 12 months of age, followed by a strong decrease towards late ages. Contrarily, FDG uptake in microglia and astrocytes exhibited a U-shaped function with respect to age, comprising the predominant cellular source of higher cerebral FDG uptake in the later stages. Metabolic connectivity was closely associated with the ratio of glucose uptake in astroglial cells relative to neurons. Cellular FDG uptake was not associated with blood glucose levels and increasing FDG brain uptake as a function of age was still observed after adjusting for blood glucose levels. Conclusion: Trajectories of astroglial glucose uptake drive brain FDG-PET alterations and metabolic connectivity during aging.

Addressing the tremendous burden of early-life adversity requires constructive dialogues between scientists and policy makers to improve population health. Whereas dialogues focused on several aspects of early-life adversity have been initiated, discussion of an underrecognized form of adversity that has been observed across multiple contexts and cultures is only now emerging. Here we provide evidence for “why unpredictability?”, including: 1. Evidence that exposures to unpredictability affect child neurodevelopment, with influences that persist into adulthood. 2. The existence of a translational non-human animal model of exposure to early life unpredictability that can be capitalized upon to causally probe neurobiological mechanisms. 3. Evidence that patterns of signals in the early environment promote brain maturation across species. 4. The uneven distribution of unpredictability across demographic populations that illuminates a possible focal point for enhancing health equity. We then outline the potential of unpredictability in terms of the “what”; that is, how might the concept of unpredictability be leveraged to inform policy? We emphasize the importance of interdisciplinary and community partnerships to the success of this work and describe our community-engaged research project. Finally, we highlight opportunities for the science of unpredictability to inform policies in areas such as screening, immigration, criminal justice, education, childcare, child welfare, employment, healthcare and housing.

Climate change is a complex, global issue that is impacting human health in various ways, with healthcare being a significant contributor to carbon emissions in the United States. This review discusses the environmental impact of important aspects of gynecologic oncology care, including surgery, anesthesia care, radiology, chemotherapy, and radiation oncology. Operating room energy and material use is highlighted, with a focus on the environmental impact of robotic surgery. The contribution of certain anesthetic gases in increasing greenhouse gas emissions is addressed. Additionally, the environmental impacts of radiologic imaging, chemotherapy, and radiation oncology are also discussed. Despite the complexity of climate change, there are multiple strategies on the individual and institutional level that can help mitigate the environmental impact of gynecologic oncology care. Individual efforts include practicing red bag stewardship, limiting single use-supplies, decreasing the use of potentially deleterious anesthetics, and supporting research into alternative dosing for chemotherapy and radiation which requires less patient travel. Institutional strategies include investing in efficient HVAC systems, utilizing reusable and reprocessed materials and devices, and purchasing renewable energy sources. Both individuals and institutions can advocate with industry and government at all levels for practices and policies that support lower carbon emissions. By recognizing our role in reducing carbon emissions, we can work towards improving the well-being of our patients and the larger community.

Abstract Neural Crest cells (NC) are a multipotent cell population that give rise to a multitude of cell types including Schwann cells (SC) in the peripheral nervous system (PNS). Immature SC interact with neuronal axons via the neuregulin 1 (NRG1) ligand present on the neuronal surface and ultimately form the myelin sheath. Multiple attempts to derive functional SC from pluripotent stem cells have met challenges with respect to expression of mature markers and axonal sorting. Here, they hypothesized that sustained signaling from immobilized NRG1 (iNRG1) might enhance the differentiation of NC derived from glabrous neonatal epidermis towards a SC phenotype. Using this strategy, NC derived SC expressed mature markers to similar levels as compared to explanted rat sciatic SC. Signaling studies revealed that sustained NRG1 signaling led to yes‐associated protein 1 (YAP) activation and nuclear translocation. Furthermore, NC derived SC on iNRG1 exhibited mature SC function as they aligned with rat dorsal root ganglia (DRG) neurons in an in vitro coculture model; and most notably, aligned on neuronal axons upon implantation in a chick embryo model in vivo. Taken together their work demonstrated the importance of signaling dynamics in SC differentiation, aiming towards development of drug testing platforms for de‐myelinating disorders.

Abstract Introduction In 2021, Jamaica's maternal mortality ratio doubled as a result of COVID‐19‐related deaths. Yet, COVID‐19 vaccination among pregnant Jamaican women remained low. In the United States, COVID‐19 vaccination is lower among pregnant women who have had multiple pregnancies (multigravidas) versus women who were pregnant for the first time (primigravidas). We examined whether this pattern exists in Jamaica. Methods A cross‐sectional survey of a convenience sample of 79 pregnant Jamaican women recruited from a teaching hospital (May–July 2022) was used to assess self‐reported COVID‐19 vaccination and medical mistrust beliefs—operationalized as low vaccine confidence, government mistrust, and race‐based mistrust—by gravidity. We used modified Poisson regression to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for vaccination by gravidity, adjusting for age, education, and comorbidities. Results Thirty‐nine (49%) of the participants were multigravidas. Socioeconomic status was similar between multigravidas and primigravidas. COVID‐19 vaccination was lower in multigravidas (46%) than primigravidas (75%) after adjusting for age, education, and comorbidities (aPR = 0.67, 95% CI = 0.46–0.99; p = 0.044). Vaccine confidence was lower in multigravidas (p = 0.044). Government mistrust and race‐based mistrust did not differ between the two groups. Conclusion In Jamaica, multigravidas may have lower COVID‐19 vaccine uptake and lower vaccine confidence compared with primigravidas. Understanding the distinct needs of pregnant subpopulations is essential for crafting effective maternal vaccination campaigns.

Substance use, including cigarettes and cannabis, is associated with poorer sustained attention in late adolescence and early adulthood. Previous studies were predominantly cross-sectional or under-powered and could not indicate if impairment in sustained attention was a predictor of substance use or a marker of the inclination to engage in such behavior. This study explored the relationship between sustained attention and substance use across a longitudinal span from ages 14 to 23 in over 1000 participants. Behaviors and brain connectivity associated with diminished sustained attention at age 14 predicted subsequent increases in cannabis and cigarette smoking, establishing sustained attention as a robust biomarker for vulnerability to substance use. Individual differences in network strength relevant to sustained attention were preserved across developmental stages and sustained attention networks generalized to participants in an external dataset. In summary, brain networks of sustained attention are robust, consistent, and able to predict aspects of later substance use.

The ubiquitous Torque teno virus (TTV) establishes a chronically persistent infection in the human host. TTV has not been associated with any apparent disease, but, as part of the human virome, it may confer a regulatory imprint on the human immune system with as yet unclear consequences. However, so far, only few studies have characterized the TTV-specific immune responses or the overall immunological imprints by TTV. Here, we reveal that TTV infection leads to a highly exhausted TTV-specific CD8+ T-cell response, hallmarked by decreased IFN-γ production and the expression of the inhibitory NKG2A-receptor. On a functional level, we identified a panel of highly polymorphic TTV-encoded peptides that lead to an expansion of regulatory NKG2A+ natural killer, NKG2A+CD4+, and NKG2A+CD8+ T cells via the stabilization of the non-classical HLA-E molecule. Our results thus demonstrate that TTV leads to a distinct imprint on the human immune system that may further regulate overall human immune responses in infectious, autoimmune, and malignant diseases.

Background: Sleep problems occur in many university students which affects their mental health and daily functioning. Cognitive behavioural therapy for insomnia (CBT-I) has been proven effective in adults but research in university students, who struggle to maintain a 24-hour rhythm, is still limited. We hypothesize that a guided digital CBT-I intervention, enriched with components on the biological clock (‘i-Sleep & BioClock’) will be effective in reducing insomnia severity and improving mental health outcomes for students with sleep problems. Objectives: We aim to evaluate the effectiveness of a guided online sleep and biological clock self-help intervention in improving sleep, depression symptoms, anxiety symptoms, functioning, academic performance, and quality of life in university students at 6 weeks and 18 weeks. Methods: This is a two-arm parallel-group superiority randomized controlled trial, comparing a 5-week guided online ‘i-Sleep & BioClock’ intervention to online psychoeducation (PE). We aim to include 192 university students (Bachelor, Master, and PhD) with at least subthreshold insomnia (Insomnia Severity Index ≥10), aged ≥16, who can speak Dutch or English. We are excluding students with current risk for suicide or night shifts. The primary outcome is insomnia severity. Secondary outcomes include sleep estimates (sleep and light exposure diary), depression, anxiety, functioning, quality of life, and academic performance. The effectiveness of the intervention compared to online PE will be evaluated using linear mixed models. Discussion: The current study tests the effectiveness of an online self-help intervention for university students who suffer from sleep problems. This trial builds upon an open feasibility study and will provide evidence of an online guided self-help program for students. The findings of this study will determine the potential wider dissemination of the intervention to address the high need for available and accessible help for students experiencing insomnia. Trial registration: ClinicalTrials.Gov (NCT06023693), registered on August 3rd, 2023.

Background: Proteomics offers potential for detecting and monitoring anorexia nervosa (AN) and its variant, atypical AN (atyp-AN). However, research has been limited by small protein panels, a focus on adult AN, and lack of replication. Methods: In this study, we performed Olink multiplex profiling of 92 inflammation-related proteins in females with AN/atyp-AN (n = 64), all of whom were ≤90% of expected body weight, and age-matched healthy control individuals (n = 44). Results: Five proteins differed significantly between the primary AN/atyp-AN group and the healthy control group (lower levels: HGF, IL-18R1, TRANCE; higher levels: CCL23, LIF-R). The expression levels of 3 proteins (lower IL-18R1, TRANCE; higher LIF-R) were uniquely disrupted in participants with AN in our primary model. No unique expression levels emerged for atyp-AN. In the total sample, 12 proteins (ADA, CD5, CD6, CXCL1, FGF-21, HGF, IL-12B, IL18, IL-18R1, SIRT2, TNFSF14, TRANCE) were positively correlated with body mass index and 5 proteins (CCL11, FGF-19, IL8, LIF-R, OPG) were negatively correlated with body mass index in our primary models. Conclusions: Our results replicate the results of a previous study that demonstrated a dysregulated inflammatory status in AN and extend those results to atyp-AN. Of the 17 proteins correlated with body mass index, 11 were replicated from a previous study that used similar methods, highlighting the promise of inflammatory protein expression levels as biomarkers of AN disease monitoring. Our findings underscore the complexity of AN and atyp-AN by highlighting the inability of the identified proteins to differentiate between these 2 subtypes, thereby emphasizing the heterogeneous nature of these disorders.

Objectives: Total hip arthroplasty is a successful procedure for treating advanced osteoarthritis (OA). Metal bearing surfaces remain one of the most widely implanted prosthesis, however approximately 10% of patients develop adverse local tissue reactions (ALTRs), namely lymphocytic predominant soft tissue reaction with or without necrosis and osteolysis resulting in high revision rates. The mechanism(s) for these reactions remains unclear although T lymphocyte mediated type IV hypersensitivity to cobalt (Co) and chromium (Cr) ions have been described. The purpose of this study was to determine the prolonged effects of Co and Cr metal ions on synovial fibroblasts to better understand the impact of the synovial membrane in the development of ALTRs. Methods: Human synovial fibroblast-like cells were isolated from donors undergoing arthroplasty. DNA content and Alamar blue assay were used to determine cellular viability against exposure to Co and Cr. A beta-galactosidase assay was used to determine the development of cellular senescence. Western blotting and RT-qPCR were employed to determine changes in senescent associated secretory factors, signaling and anti-oxidant enzyme expression. A fluorescent assay was used to measure accumulation of hydrogen peroxide. Results: We demonstrate that prolonged cobalt exposure results in a downregulation of the enzyme catalase resulting in cytosolic accumulation of hydrogen peroxide, decreased Akt activity and cellular senescence. Senescent fibroblasts demonstrated upregulation of proinflammatory cytokines IL-1β and TNFα in addition to the neurotrophic factor NGF. Conclusion: Our results provide evidence that metal ions induce a senescent associated secretory phenotype in synovial fibroblasts that could contribute to the development of adverse local tissue reactions.

Abstract Liquid biopsy has emerged as a promising non-invasive strategy for cancer diagnosis, enabling the detection of various circulating biomarkers, including circulating tumor cells (CTCs), circulating tumor nucleic acids (ctNAs), circulating tumor-derived small extracellular vesicles (sEVs), and circulating proteins. Surface-enhanced Raman scattering (SERS) biosensors have revolutionized liquid biopsy by offering sensitive and specific detection methodologies for these biomarkers. This review comprehensively examines the application of SERS-based biosensors for identification and analysis of various circulating biomarkers including CTCs, ctNAs, sEVs and proteins in liquid biopsy for cancer diagnosis. The discussion encompasses a diverse range of SERS biosensor platforms, including label-free SERS assay, magnetic bead-based SERS assay, microfluidic device-based SERS system, and paper-based SERS assay, each demonstrating unique capabilities in enhancing the sensitivity and specificity for detection of liquid biopsy cancer biomarkers. This review critically assesses the strengths, limitations, and future directions of SERS biosensors in liquid biopsy for cancer diagnosis.

Abstract The gut microbiota influences human health and the development of chronic diseases. However, our understanding of potentially protective or harmful microbe-host interactions at the molecular level is still in its infancy. To gain further insights into the hidden gut metabolome and its impact, we identified a cryptic non-ribosomal peptide BGC in the genome of Bacillus cereus DSM 28590 from the mouse intestine ( www.dsmz.de/miBC ), which was predicted to encode a thiazol(in)e substructure. Cloning and heterologous expression of this BGC revealed that it produces bacillamide D. In-depth functional evaluation showed potent cytotoxicity and inhibition of cell migration using the human cell lines HCT116 and HEK293, which was validated using primary mouse organoids. This work establishes the bacillamides as selective cytotoxins from a bacterial gut isolate that affect mammalian cells. Our targeted structure-function-predictive approach is demonstrated to be a streamlined method to discover deleterious gut microbial metabolites with potential effects on human health.

Abstract As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs are shed and remade daily. Defects in this process, due to mutations, cause retinitis pigmentosa (RP). Whilst fundamental for vision, the mechanism of photoreceptor disc generation is poorly understood. Here, we show membrane deformation required for disc genesis is driven by dynamic actin changes in a process akin to ectocytosis. We show RPGR, a leading RP gene, regulates actin-binding protein activity central to this process. Actin dynamics, required for disc formation, are perturbed in Rpgr mouse models, leading to aborted membrane shedding as ectosome-like vesicles, photoreceptor death and visual loss. Actin manipulation partially rescues this, suggesting the pathway could be targeted therapeutically. These findings help define how actin-mediated dynamics control outer segment turnover.