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Abstract Intraspecific variation is important for species’ long-term persistence in changing environments. Conservation strategies targeting intraspecific variation often rely on the identification of management or policy units below the species level based on biological differences among populations. To identify management units, this paper examines intraspecific divergence of Lake Trout (Salvelinus namaycush) in Great Slave Lake (GSL), Canada, using low-coverage whole-genome sequencing data. Specifically, we evaluate genetic differentiation and assess the relationship with morphological, mitochondrial, and putatively adaptive divergence. We show that at least three and up to five genetically distinct Lake Trout populations co-occur in GSL and exhibit differences in spatial distribution and body size, with signatures of selection. However, admixture was widespread (60% of the fish) and population structure was shallow (average F ST = 0.022). These findings highlight that, even in the era of whole genome sequencing, identifying discrete management units to implement conservation efforts and policy can remain challenging in systems where gene flow among genetically and ecologically distinct populations is ubiquitous. To give more recognition to this complexity, management efforts should also focus on the area where adaptive variation is evident, and evolutionary acts are at play, to better protect species’ resilience and adaptive potential in some natural systems.

Abstract Background Culex tritaeniorhynchus has long been considered the primary vector of Japanese encephalitis virus (JEV), but until recently, it was considered exotic to Australia. When the species was detected in the country’s Northern Territory (NT) for the first time, the Western Australia (WA) Department of Health was cognisant of the risk it posed to the State because of the shared border and continuous mosquito habitat adjoining the two jurisdictions. The aim of this study was to undertake intensive mosquito surveillance in the Kimberley region to ascertain whether Cx. tritaeniorhynchus was present in WA, define the extent of its distribution and undertake phylogenetic analysis of select specimens to support hypothesized routes of entry into the state. Methods Carbon dioxide (CO2)-baited encephalitis virus surveillance (EVS) mosquito traps were deployed at various sites throughout the Kimberley region by surveillance officers within the Medical Entomology unit of the Western Australia (WA) Department of Health. Mosquitoes were then morphologically identified, and a subset of four specimens were confirmed as Cx. tritaeniorhynchus by molecular identification using Cytochrome Oxidase I (COI) DNA data and phylogenetic analysis. Results From 31 March 2021 to 30 May 2024, a total of 211 female Cx. tritaeniorhynchus specimens were collected from 21 unique trap sites in the Kimberley’s Shire of Wyndham-East Kimberley (SWEK). Four COI DNA barcode regions were amplified and successfully sequenced for analysis. These sequences fell within a clade recognised as Cx. tritaeniorhynchus and specifically all sequences were in a clade with other specimens from the NT and Timor-Leste. Conclusions This study represents the first detection of Cx. tritaeniorhynchus in WA. Given the widespread nature of trap sites that yielded the species and consecutive seasons over which it was observed, the authors surmise that Cx. tritaeniorhynchus is now established within the northeast Kimberley region. The findings are significant given the detection of the species coincides with the first significant outbreak of JEV activity on mainland Australia involving an estimated 45 human cases of Japanese encephalitis, 80 impacted commercial piggeries and widespread feral pig activity. Although the role that Cx. tritaeniorhynchus may play in JEV transmission into the future is not yet understood, it presents a potential risk to public health in the region. Graphical abstract

Abstract Proteins containing both intrinsically disordered regions (IDRs) and RNA binding domains (RBDs) can phase separate in vitro, forming bodies similar to cellular biomolecular condensates. However, how IDR and RBD domains contribute to in vivo recruitment of proteins to biomolecular condensates remains poorly understood. Here, we analyzed the roles of IDRs and RBDs in L-bodies, biomolecular condensates present in Xenopus oocytes. We show that a cytoplasmic isoform of hnRNPAB, which contains two RBDs and an IDR, is highly enriched in L-bodies. While both of these domains contribute to hnRNPAB self-association and phase separation in vitro and mediate enrichment into L-bodies in oocytes, neither the RBDs nor the IDR replicate the localization of full-length hnRNPAB. Our results suggest a model where the combined effects of the IDR and RBDs regulate hnRNPAB partitioning into L-bodies. This model likely has widespread applications as proteins containing RBD and IDR domains are common biomolecular condensate residents.

Abstract A concern in the field of autism electroencephalography (EEG) biomarker discovery is their lack of reproducibility. In the present study, we considered the problem of learning reproducible associations between multiple features of resting state (RS) neural activity and autism, using EEG data collected during a RS paradigm from 36 to 96 month-old children diagnosed with autism (N = 224) and neurotypical children (N = 69). Specifically, EEG spectral power and functional connectivity features were used as inputs to a regularized generalized linear model trained to predict diagnostic group (autism versus neurotypical). To evaluate our model, we proposed a procedure that quantified both the predictive generalization and reproducibility of learned associations produced by the model. When prioritizing both model predictive performance and reproducibility of associations, a highly reproducible profile of associations emerged. This profile revealed a distinct pattern of increased gamma power and connectivity in occipital and posterior midline regions associated with an autism diagnosis. Conversely, model selection based on predictive performance alone resulted in non-robust associations. Finally, we built a custom machine learning model that further empirically improved robustness of learned associations. Our results highlight the need for model selection criteria that maximize the scientific utility provided by reproducibility instead of predictive performance.

Background and Objectives: Patients increasingly turn to YouTube for trustworthy health-related information, prompting a study to evaluate the quality and reliability of videos about hemifacial spasms (HFS) available on the platform. Materials and Methods: In August 2024, a systematic search was conducted using a formal strategy to identify relevant videos. Two independent neurology resident physicians reviewed each video, scoring it with the validated modified DISCERN (mDISCERN) tool for reliability and the Global Quality Scale (GQS) for content quality. Videos were categorized based on their purpose and assessed for video/audio quality, accuracy, comprehensiveness, and procedure-specific content. Results: The study included 44 videos. According to GQS, 17 (38.6 %) were rated as high quality, 14 (31.8 %) as good, 5 (17 %) as medium, and 8 (18.2 %) as poor quality. On the mDISCERN scale, 24 (54.5 %) were deemed reliable, while 9 (20.5 %) were unreliable. Videos created by physicians, academic institutions, and reputable health information websites scored higher on both mDISCERN and GQS compared to other sources. A strong positive correlation was found between mDISCERN and GQS scores (r = 0.925, p

Abstract Background Available descriptive studies on equine pneumonia are outdated or focus on specific horse or bacterial populations. Objectives To describe the clinical presentation and bacterial isolates of adult horses with bacterial pneumonia and identify factors associated with death. Animals One hundred sixteen horses >2 years old with bacterial pneumonia. Methods Retrospective case series. Data regarding history, physical examination, clinicopathologic features, treatment, bacterial culture and sensitivity, and outcome were collected and analyzed retrospectively. Results Historical risk factors were present for 60% of cases, whereas abnormal vital signs on intake were present for

Abstract The effects of heat exposure on negative affect are thought to be central to the observed relationships between hot summer days and deleterious outcomes, such as violent crime or mental health crises. As these relationships are likely to be magnified by the effects of climate change, a better understanding of how consistent or variable the effects of hot weather on affective states is required. The current work combines data gathered from an ecological momentary assessment (EMA) study on individuals’ thermal perceptions, comfort, and affective states in outdoor environments during their daily lives with high spatiotemporal resolution climate-modeled weather variables. Using these data, associations between objective weather variables (temperature, humidity, etc.), perceived heat (thermal perception and comfort), and affective states are examined. Overall, objective weather data reasonably predicted perception and comfort, but only comfort predicted negative affective states. The variance explained across individuals was generally very low in predicting negative affect or comfort, but within-person variance explained was high. In other words, while there may be a relatively consistent relationship between temperature and psychological experience for any given person, there are significant individual differences across people. Age and gender were examined as moderators of these relationships, and while gender had no impact, participant age showed several significant interactions. Specifically, while older adults tended to experience more thermal discomfort and perceived higher temperatures as hotter, the relationship between discomfort and negative affect was lower in older adults. Taken together, these results emphasize the importance of thermal discomfort specifically in predicting negative affect, as well as the high inter-individual variability in thermal perceptions and comfort for the same ambient temperatures.

Abstract Background Xylazine is increasingly prevalent in the unregulated opioid supply in the United States. Exposure to this adulterant can lead to significant harm, including prolonged sedation and necrotic wounds. In the absence of literature describing healthcare providers’ experiences with treating patients who have been exposed to xylazine, we aimed to explore what gaps must be addressed to improve healthcare education and best practices. Methods From October 2023 to February 2024, we conducted a sequential explanatory mixed-methods study, with (1) a quantitative survey phase utilizing convenience sampling of healthcare providers treating patients in Connecticut and (2) a qualitative semi-structured interview phase utilizing purposive sampling of providers with experience treating patients with xylazine exposure. Summary statistics from the survey were tabulated; interview transcripts were analyzed using thematic analysis. Results Seventy-eight eligible healthcare providers participated in our survey. Most participants had heard of xylazine (n = 69, 95.8%) and had some knowledge about this adulterant; however, fewer reported seeing one or more patients exposed to xylazine (n = 46, 59.8%). After sampling from this subgroup, we conducted fifteen in-depth interviews. This qualitative phase revealed five themes: (1) while xylazine is novel and of concern, this is not necessarily exceptional (i.e., there are other emerging issues for patients who use drugs); (2) participants perceived that xylazine was increasingly prevalent in the drug supply, even if they were not necessarily seeing more patients with xylazine-related outcomes (XROs); (3) patients primarily presented with non-XROs, making it difficult to know when conversations about xylazine were appropriate; (4) patients with XROs may experience issues accessing healthcare; (5) providers and their patients are learning together about how to minimize XROs and reduce the sense of helplessness in the face of a novel adulterant. Conclusions Xylazine-specific education for healthcare providers is currently insufficient. Improving this education, as well as resources (e.g., drug checking technologies) and data (e.g., research on prevention and treatment of XROs), is crucial to improve care for patients who use drugs.

Accurately identifying life-threatening prostate cancer (PCa) at time of diagnosis remains an unsolved problem. We evaluated whether DNA methylation status of selected candidate genes can predict the risk of metastasis beyond clinical risk factors in men with untreated PCa. A nested case-control study was conducted among men diagnosed with localized PCa at Kaiser Permanente California between 01/01/1997–12/31/2006 who did not receive curative treatments. Cases were those who developed metastasis within 10 years from diagnosis. Controls were selected using density sampling. Ninety-eight candidate genes were selected from functional categories of cell cycle control, metastasis/tumour suppressors, cell signalling, cell adhesion/motility/invasion, angiogenesis, and immune function, and 41 from pluripotency genes. Cancer DNA from diagnostic biopsy blocks were extracted and analysed. Associations of methylation status were assessed using CpG site level and principal components-based analysis in conditional logistic regressions. In 215 cases and 404 controls, 27 candidate genes were found to be statistically significant in at least one of the two analytical approaches. The agreement between the methods was 25.9% (7 candidate genes, including 2 pluripotency markers). The DNA methylation status of several candidate genes was significantly associated with risk of metastasis in untreated localized PCa patients. These findings may inform future risk prediction models for PCa metastasis beyond clinical characteristics.

Background and objectives: California is one of a few states with mandatory reporting of mortality after coronary artery bypass graft (CABG) surgery. The Affordable Care Act restructured Medicaid, preferentially penalizing patients experiencing poverty because payments to hospitals for isolated surgical events overshadow payments to primary care clinicians. We propose outcomes are superior when hospital networks organize surgical episodes within the context of primary care inside that same network. Design and methods: We listed factors impacting outcomes after CABG. CABG surgery outcome depends upon the integration of issues beginning years preoperatively and extending for decades. Therefore, we studied one health maintenance organization (HMO) from 2009 to 2020 compared to surrounding individual hospitals. We divided 58 hospitals in Northern California in 2009 according to income and population. To focus on changes introduced because of COVID-19, we compared a public database for the subset in 2009 for any relationship between poverty in a zip code and low volumes of CABG in that area to overall mortality in 2020. First, we defined low-income zip codes as those with a higher rate of poverty than the state average or with a lower per capita average income, per Census Bureau. Second, low volume was defined as a population under 165,000 because a hospital adjacent to a larger community can easily transfer care, sharing surgeons and processes. Third, we defined low volume as fewer than 180 CABG per year. Results: Our qualitative evidence synthesis reveals that informal communication and hospital HMO policies improve CABG outcomes. In our small pilot data, Chi-square analysis showed higher crude mortality rates in 1507 CABG in 17 low-income low-volume hospitals versus 8163 CABG in the other 41 Northern California hospitals (2.72% vs 1.69%, p = 0.0064). Low-income low-volume hospitals had a relative mortality risk of 1.61 (95% CI: 1.14–2.27). These hospitals had a mean mortality rate of 3.79%, readmission 11.12%, and stroke 1.84%. A patient undergoing CABG in a low-income low-volume hospital has a 61% higher chance of dying. The number needed to treat analysis shows that one life can potentially be saved for every 97 patients referred to another institution. Conclusion: We describe features of an HMO that contribute to up to fourfold lower mortality rates.

Abstract Fish spawning locations are a crucial input into fisheries management and conservation plans, and many stocks are especially sensitive to the environmental conditions within these localized zones. Globally collated data on spawning locations across many species has been unavailable, hindering global stock assessments and analyses of sustainable development and global environmental change. To address this, we created a geocoded fish spawning dataset using qualitative spawning information from FishBase and Science and Conservation of Fish Aggregations (SCRFA). We cleaned and geocoded the spawning locations of 1,045 marine fish species into 2,931 regions. Each spawning region is defined by one or more polygons, and most spawning regions are associated with spawning months. The resulting dataset covers oceans globally. This dataset will be useful to scientists studying marine fish population dynamics and their interactions with the physical environment on regional to large scales.

Abstract Intrathecal delivery of autologous culture-expanded adipose tissue-derived mesenchymal stem cells (AD-MSC) could be utilized to treat traumatic spinal cord injury (SCI). This Phase I trial (ClinicalTrials.gov: NCT03308565) included 10 patients with American Spinal Injury Association Impairment Scale (AIS) grade A or B at the time of injury. The study’s primary outcome was the safety profile, as captured by the nature and frequency of adverse events. Secondary outcomes included changes in sensory and motor scores, imaging, cerebrospinal fluid markers, and somatosensory evoked potentials. The manufacturing and delivery of the regimen were successful for all patients. The most commonly reported adverse events were headache and musculoskeletal pain, observed in 8 patients. No serious AEs were observed. At final follow-up, seven patients demonstrated improvement in AIS grade from the time of injection. In conclusion, the study met the primary endpoint, demonstrating that AD-MSC harvesting and administration were well-tolerated in patients with traumatic SCI.

Tail biting is a multifactorial behavior that causes welfare and economic challenges in swine production. As of 2024, research exploring the influence of pig social structure on the development of tail biting is limited. The objective of this study was to explore whether social structures of pigs from different litter origins can impact tail biting and, ultimately, tail damage. Pigs (n = 96) were grouped (eight pigs/pen) based on their litter origin: non-littermates (NLM), half-littermates, and littermates (LM). Tail injury scores were assessed twice weekly from 10 to 24 weeks of age, with a maximal tail injury score (MTS) over the study period being used to evaluate victimization by tail biting. Pig behavior was video-recorded at 15, 19, and 23 weeks of age. Association networks based on lying behavior and tail biting interaction networks were evaluated at pen-and pig-levels using social network analysis. Pigs in LM pens experienced higher median MTS compared to pigs in NLM pens (Median = 1.5; Interquartile range = 1–2; p = 0.009). Within association networks, NLM pens had lower degree centralization measures than other pens at both 15 (Estimated marginal mean [EMM] = 0.07; 95% CI = 0.02–0.12; p = 0.003) and 23 weeks (EMM = 0.09; 95% CI = 0.04–0.14; p = 0.01) and pigs in NLM pens had higher weighted degree centrality than those in other pens (EMM = 1.00; 95% CI = 0.90–1.11; p = 0.002), suggesting pigs in NLM pens had more uniform, stronger, and more connections with their pen-mates. In tail biting networks, increased weighted in-degree centrality was associated with increased odds of pigs receiving a more severe MTS (OR = 1.56; 95% CI = 1.08–2.27; p = 0.02). Pigs with increased weighted out-degree centrality tended to have increased odds of receiving a more severe MTS (OR = 1.19; 95% CI = 0.97–1.48; p = 0.09). These preliminary data suggest a potential relationship between social structures and tail biting in growing-finishing pigs.

Abstract Objectives Women remain underrepresented in the emergency medicine (EM) workforce, academic EM, and institutional leadership. In order to support women physicians in EM, we must explore factors that contribute to attrition and workplace satisfaction. For example, tensions between workplace and familial roles are important to consider as women navigate careers in EM. The logistics and stressors of workplace lactation pose a particular challenge during an already stressful time for a new mother returning to work in a busy emergency department (ED), but limited empirical data exist regarding this experience. We aimed to explore the stressors associated with workplace lactation spaces in order to better inform the creation of lactation spaces for individuals working in EDs. Methods Our team used an exploratory qualitative design to investigate lactation‐specific stressors and understand their relationship to individuals’ needs when lactating in EM workplace environments. A total of 40 individuals were interviewed, highlighting post‐pregnancy return‐to‐work (RTW) experiences of medical students, residents, advanced practice professionals, nurses, fellows, and faculty. Interviews were coded and analyzed using thematic analysis. Results We identified both tangible and intangible characteristics of lactation spaces that contribute to stress for lactating individuals. Additionally, we discovered that participants frequently noted a desire to work simultaneously while pumping in order to feel they were self‐actualizing in their dual roles of parent and clinician. Among tangible items, access to a computer within lactation space was a key driver of ability to fulfill dual roles. Among intangible characteristics, we identified three distinct, yet interrelated, subthemes, including the need for lactation spaces to be respectful of individuals’ time, privacy, and general health and well‐being. Conclusions This study suggests that meeting basic lactation needs with thoughtfully designed lactation spaces can empower individuals in their roles both as a lactating parent and a clinician. EM leadership can evaluate existing lactation spaces to ensure they meet the tangible and intangible needs of lactating physicians, trainees, advanced practice professionals, and nurses.

The Blackfeet Nation in northwestern Montana, United States, is implementing its Agriculture Resource Management Plan (ARMP), an Indigenous-led, sustainable agriculture plan prioritizing economic development for Indigenous producers, intergenerational health and well-being of Amskapi Piikani Blackfeet people, and ecological and cultural sensitivities within this sovereign nation and its traditional territories. Since the passage of the American Indian Agricultural Resource Management Act of 1993, only three Tribes have drafted and finalized Agricultural Resource Management Plans (ARMPs). The Blackfeet ARMP is now being held up as a national model of Tribal sovereignty. “Blackfeet Innovation Pathways to Food Sovereignty,” an Indigenous-led research project, emerged from the Blackfeet Nation’s community-based strategic planning process identifying gaps, systemic barriers and impactful solutions for achieving Blackfeet food sovereignty through the implementation of the Blackfeet Nation ARMP, along with research influenced by the ARMP. This paper provides a community case study of the ongoing process and offers a translational model of sustainable agriculture and food sovereignty within Indigenous lands to improve the economic futures of producers and their families, as well as health outcomes for Native communities.

The purpose of this publication is to look at the other side of the profit equation to explore opportunities for Florida’s small and medium-sized farmers to find ways to improve revenues. We can do this by identifying markets where farmers have some measure of control over how much to charge for their food products. Economists describe markets in which businesses may set their own prices as “imperfectly competitive.” The authors aim to answer these common questions: Why are markets considered imperfect? What does this mean to farmers and buyers? What are the added costs and benefits to farmers who decide to sell into imperfect markets?

As climate change intensifies, Inuvialuit in Canada's Western Arctic are facing a rapidly changing environment and associated impacts on human health, safety, and food security. Learning to cope with these changes requires context-based and current information that can inform subsistence activities and environmental management, and no one is better positioned to acquire this information than Inuvialuit themselves. This paper presents findings from in-depth interviews conducted in 2012 with six knowledge holders and seasonal residents of Kendall Island (Ukiivik in Uummarmiutun), a traditional whaling camp situated along the Beaufort Sea coast bordering the Okeevik Tarium Niryutait Marine Protected Area. A transdisciplinary and Inuvialuit-led effort, this research documents observations of change at this culturally important site and explores how residents are adapting to changing conditions. Interview transcripts were analyzed using iterative rounds of qualitative coding in NVivo software. Findings reveal pervasive social and environmental change on Kendall Island and in adjacent harvesting areas and highlight how changing conditions are affecting residents’ lives. This study identifies benchmarks upon which to compare and evaluate subsequent changes at this site and documents Inuvialuit knowledge and perspectives that can inform local-scale environmental monitoring, management, and climate change adaptation planning.

Abstract Objective In this study, we sought to determine the types and prevalence of antimicrobial resistance determinants (ARDs) in Burkholderia spp. strains using the Antimicrobial Resistance Determinant Microarray (ARDM). Results Whole genome amplicons from 22 B. mallei (BM) and 37 B. pseudomallei (BP) isolates were tested for > 500 ARDs using ARDM v.3.1. ARDM detected the following Burkholderia spp.-derived genes, aac(6), bla BP/MBL-3, blaA BPS, penA-BP, and qacE, in both BM and BP while bla BP/MBL-1, macB, bla OXA-42/43 and penA-BC were observed in BP only. The method of denaturing template for whole genome amplification greatly affected the numbers and types of genes detected by the ARDM. Bla TEM was detected in nearly a third of BM and BP amplicons derived from thermally, but not chemically denatured templates. Bla TEM results were confirmed by PCR, with 81% concordance between methods. Sequences from 414-nt PCR amplicons (13 preparations) were 100% identical to the Klebsiella pneumoniae reference gene. Although bla TEM sequences have been observed in B. glumae, B. cepacia, and other undefined Burkholderia strains, this is the first report of such sequences in BM/BP/B. thailandensis (BT) clade. These results highlight the importance of sample preparation in achieving adequate genome coverage in methods requiring untargeted amplification before analysis.

Over the last two decades, the insects-as-food-and-feed industry has rapidly emerged. Its growth is largely because insects require substantially less resources (water, food, and energy) to produce than traditional sources of animal protein, making it a sustainable alternative food option. As this industry continues to grow, veterinarians will likely be called upon to assist in identifying food safety concerns, assessing animal health, implementing biosecurity measures, and formulating/prescribing treatment protocols comparable to what we have seen with the honeybee industry and the institution of veterinary feed directives (VFDs). Similar to other agricultural markets, high animal densities and management practices put insects at high risk for infectious diseases. Veterinarians interested in working with these species will need to become knowledgeable regarding the diseases afflicting the feeder insect industry and how best to diagnose and treat pathogens of concern. Using the edible cricket industry as an example, this review will highlight health and production issues while drawing similarities to other traditional livestock operations. If the insects-as-feed-and-food industry is going to be viable, veterinary involvement will be essential to ensure that insects can be used as a safe source of food for all.

Anthropogenic activities have negatively affected many birds, including owls. The Wildlife Hospital of Louisiana (WHL) has seen a 3.2-fold increase in barred owl (Strix varia) cases over the past eight years (2023, 134; 2015, 42). Because most of these animals present with traumatic injuries, analgesics should be considered in their treatment plan. To date, no study has measured the pharmacokinetics of an analgesic in barred owls. The goals of this study were to determine the harmonic means, times to maximum concentration, and elimination half-lives for single 1 mg/kg and 2 mg/kg intramuscular doses of meloxicam. Twelve barred owls (1 mg/kg, n = 6; 2 mg/kg, n = 6) admitted to the WHL and determined to be clinically normal based on examination and blood work were recruited for this study. Meloxicam was administered intramuscularly, and blood samples were collected intermittently over 12 h to measure plasma concentrations using high-performance liquid chromatography. Both doses had rapid elimination half-lives (1 mg/kg, 0.99 ± 0.1 h; 2 mg/kg, 1.07 ± 0.43 h) and were below the limits of quantification (0.1 µg/mL) by 6–12 h. Based on these results, 1 and 2 mg/kg doses of meloxicam were found to produce plasma concentrations below therapeutic concentrations for less than four hours, making current twice-daily recommended dosing intervals unlikely to provide desired analgesia.

Age-related macular degeneration (AMD) causes blindness due to loss of retinal pigment epithelium (RPE) and photoreceptors (PRs), which comprise the two outermost layers of the retina. Given the small size of the macula and the importance of direct contact between RPE and PRs, the use of scaffolds for targeted reconstruction of the outer retina in later stage AMD and other macular dystrophies is particularly attractive. We developed microfabricated, honeycomb-patterned, biodegradable poly(glycerol sebacate) (PGS) scaffolds to deliver organized, adjacent layers of RPE and PRs to the subretinal space. Furthermore, an optimized process was developed to photocure PGS, shortening scaffold production time from days to minutes. The resulting scaffolds robustly supported the seeding of human pluripotent stem cell-derived RPE and PRs, either separately or as a dual cell-layered construct. These advanced, economical, and versatile scaffolds can accelerate retinal cell transplantation efforts and benefit patients with AMD and other retinal degenerative diseases.

Abstract Background Low birthweight (LBW) infants are at increased risk of morbidity and mortality. Exclusive breastfeeding up to six months is recommended to help them thrive through infection prevention, growth improvements, and enhancements in neurodevelopment. However, limited data exist on the feeding experiences of LBW infants, their caregivers and key community influencers. The qualitative component of the Low Birthweight Infant Feeding Exploration (LIFE) study aimed to understand practices, facilitators, and barriers to optimal feeding options in the first six months for LBW infants in low-resource settings. Methods This study was conducted in four sites in India, Malawi, and Tanzania from July 2019 to August 2020. We conducted 37 focus group discussions with mothers and family members of LBW infants and community leaders and 142 in-depth interviews with healthcare providers, government officials, and supply chain and donor human milk (DHM) experts. Data were analyzed using a framework approach. Results All participants believed that mother’s own milk was best for LBW infants. Direct breastfeeding was predominant and feeding expressed breast milk and infant formula were rare. DHM was a new concept for most. Adequate maternal nutrition, lactation support, and privacy in the facility aided breastfeeding and expression, but perceived insufficient milk, limited feeding counseling, and infant immaturity were common barriers. Most believed that DHM uptake could be enabled through community awareness by overcoming misconceptions, safety concerns, and perceived family resistance. Conclusion This study fills an evidence gap in LBW infant feeding practices and their facilitators and barriers in resource-limited settings. LBW infants face unique feeding challenges such as poor latching and tiring at the breast. Similarly, their mothers are faced with numerous difficulties, including attainment of adequate milk supply, breast pain and emotional stress. Lactation support and feeding counseling could address obstacles faced by mothers and infants by providing psychosocial, verbal and physical support to empower mothers with skills, knowledge and confidence and facilitate earlier, more and better breast milk feeding. Findings on DHM are critical to the future development of human milk banks and highlight the need to solicit partnership from stakeholders in the community and health system.

Abstract Astrocytic tau aggregates are seen in several primary and secondary tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and chronic traumatic encephalopathy (CTE). In all of these diseases, astrocytic tau consists mostly of the longer (4R) tau isoform, even when adjacent neuronal aggregates consist of a mixture of 3- and 4R tau, as in CTE. Even the rare astrocytic tau aggregates seen in Pick’s disease appear to contain both 3R and 4R tau. The reasons for this, and the mechanisms by which astrocytic tau aggregates form, remain unclear. We used a combination of RNA in situ hybridization and immunofluorescence in post-mortem human brain tissue, as well as tau uptake studies in human stem cell-derived astrocytes, to determine the origins of astrocytic tau in 4R tauopathies. We found no differences in tau mRNA expression between diseases or between tau positive and negative astrocytes within PSP. We then found that stem cell-derived astrocytes preferentially take up long isoform (4R) recombinant tau and that this uptake is impaired by induction of reactivity with inflammatory stimuli or nutritional stress. Astrocytes exposed to either 3R or 4R tau also showed downregulation of genes related to astrocyte differentiation. Our findings suggest that astrocytes preferentially take up neuronal 4R tau from the extracellular space, potentially explaining why 4R tau is the predominant isoform in astrocytic tau aggregates.

Objective: Time spent among the 24-h movement behaviors (physical activity [PA], sleep, sedentary behavior [SB]) in the perinatal period is important for maternal and child health. We described changes to 24-h movement behaviors and behavior guideline attainment during pregnancy and postpartum and identified correlates of behavior changes. Methods: This secondary data analysis included the standard of care group (n = 439) from the U.S.-based Lifestyle Interventions For Expectant Moms (LIFE-Moms) consortium, including persons with overweight and obesity. Wrist-worn accelerometry was used to measure movement behaviors early (9–15 weeks) and late (35–36 weeks) pregnancy, and ∼ 1-year postpartum. Sleep and moderate-to-vigorous PA (MVPA) were compared to adult and pregnancy-specific guidelines, respectively. SB was classified into quartiles. PA and SB context were quantified using questionnaires. Mixed models were used to examine changes in behaviors and guidelines and identify correlates. Results: Participants were 31.3 ± 3.5 years, 53.5 % were Black or Hispanic, and 45.1 % had overweight. Sleep duration decreased across time, but participants consistently met the guideline (range: 85.0–93.6 %). SB increased during pregnancy and decreased postpartum, while light PA and MVPA followed the inverse pattern. Participants met slightly fewer guidelines late pregnancy (1.2 ± 0.7 guidelines) but more postpartum (1.7 ± 0.8 guidelines) than early pregnancy (1.4 ± 0.8 guidelines). Black or Hispanic race/ethnicity, higher pregravid body mass index, and non-day work-shift (e.g., night-shift) were identified correlates of lower guideline adherence and varying PA and SB context. Conclusion: Perinatal interventions should consider strategies to prevent SB increase and sustain MVPA to promote guideline adherence.

Background Obstructive sleep apnea (OSA) contributes to the generation, recurrence, and perpetuation of atrial fibrillation, and it is associated with worse outcomes. Little is known about the economic impact of OSA therapy in atrial fibrillation. This retrospective cohort study assessed the impact of positive airway pressure (PAP) therapy adherence on health care resource use and costs in patients with OSA and atrial fibrillation. Methods and Results Insurance claims data for ≥1 year before sleep testing and 2 years after device setup were linked with objective PAP therapy use data. PAP adherence was defined from an extension of the US Medicare 90‐day definition. Inverse probability of treatment weighting was used to create covariate‐balanced PAP adherence groups to mitigate confounding. Of 5867 patients (32% women; mean age, 62.7 years), 41% were adherent, 38% were intermediate, and 21% were nonadherent. Mean±SD number of all‐cause emergency department visits (0.61±1.21 versus 0.77±1.55 [P=0.023] versus 0.95±1.90 [P

Steroid-associated laminitis remains a major concern with use of corticosteroids in horses. Individual case factors such as joint pathology, pre-existing endocrinopathies, or corticosteroid type, dose, and timing influencing steroid-induced laminitis risk have not been investigated. This study aimed to determine if systemic absorption of triamcinolone acetonide (TA) varies between intrasynovial (antebrachiocarpal) and extrasynovial (sacroiliac) injection sites, and to determine the effects of TA absorption on glucose, insulin, cortisol, and adrenocorticotropic hormone (ACTH). Twenty adult horses were randomized into antebrachiocarpal or sacroiliac joint injection groups, and each horse received bilateral injections with a total dose of 18 mg triamcinolone. Blood was collected prior to injection and at 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 60, and 72 h post-injection. Peak TA absorption occurred at 8 h in both groups, and was significantly higher in the intrasynovial group compared to the extrasynovial group (1.397 ng/mL, 0.672 ng/mL, p 20 μU/mL) from both groups experienced a more marked hyperinsulinemia, reaching a mean peak insulin of 197.5 μU/mL as compared to 90.06 μU/mL in those with normal baseline insulin. Cortisol and ACTH were significantly decreased from baseline at timepoints from 4–72 h post-injection in both groups. This study is the first to evaluate drug absorption from the sacroiliac site and demonstrates that drug absorption varies between intrasynovial and extrasynovial injection sites. TA absorption causes metabolic derangements, most notably a marked hyperinsulinemia that is more severe in horses with elevated baseline insulin values. The influence of baseline endocrinopathies on response to corticosteroid administration as well as the effect of corticosteroid-induced metabolic derangements warrant further investigation as risk factors for corticosteroid-associated laminitis.

Abstract Introduction Generalized myasthenia gravis (gMG) is a rare autoimmune disease. Symptoms of gMG are diverse, and understanding of their impact on patients is limited. This qualitative study aimed to provide an in-depth exploration of patients’ daily experiences of gMG. Methods Published qualitative studies were reviewed to identify the most important signs, symptoms, and functional impacts related to the patient experience in gMG. Semi-structured hybrid concept elicitation interviews (allowing spontaneous generation of disease concepts) and cognitive debriefing interviews (assessing the validity of existing disease assessments) were conducted with clinicians and adult patients with gMG. Signs, symptoms, and impacts were reviewed to understand which were most salient (i.e., reported by at least 50% of patients, with disturbance rating 5 or higher [10-point numeric scale]); concept saturation was also assessed. The disease conceptual model was updated. Existing clinical outcomes assessments (COAs) that capture how patients feel, function, and survive were assessed. Results Interviews with patients (n = 24) identified seven new signs and symptoms and 37 new impacts compared with the literature. Concept saturation was reached. Signs and symptoms identified by patients as most important (salient) were shortness of breath, general fatigue, muscle weakness of arms, legs, and neck, dysphonia, dysarthria, trouble swallowing liquids, choking, and heat sensitivity. Patient-identified salient impacts were work life, depression, difficulty walking, grooming hair, showering, and brushing teeth, eating, personal relationships, family life, and participating in social activities. Clinicians considered ocular, respiratory, swallowing, speech/talking, and extremity function as key clinical manifestations of gMG. Patients and clinicians found clinical outcome assessments (COAs) to be conceptually relevant and comprehensive. Conclusion This research provides a holistic understanding of gMG signs, symptoms, and impacts experienced by patients, as observed by patients and clinicians. The conceptual model of gMG highlights the range of signs, symptoms, and impacts that adult patients with gMG experience in their everyday lives, emphasizing the humanistic impact and unmet needs.

Abstract Background Housing environments shape injection drug-related risks and harms and thus represent a critical implementation setting for syringe services programs (SSPs). As critical harm reduction measures, SSPs provide safe injecting equipment to people who inject drugs (PWID). Vancouver, Canada, has well-established syringe distribution programs through which PWID have low-threshold access to unlimited syringes and related injecting equipment, including through non-profit operated supportive housing and single-room occupancy hotels. This study examines the role of housing-based SSPs in distributing injecting equipment to PWID in Vancouver. Methods Between January and March 2020, semi-structured, in-depth interviews were conducted in Vancouver with 26 PWID. Interviews were audio-recorded, transcribed, and coded. Salient themes were identified using inductive and deductive approaches. Results Many participants accessed SSPs in housing facilities and expressed preference for these programs over those offered at other locations and through other health and social services. Three major themes emerged to explain this preference. First, most participants injected in the buildings where they resided, and housing-based SSPs made injecting equipment available when and where it was most needed. Second, many participants preferred to avoid carrying syringes outside of the places where they inject due to fears that syringe possession may lead to criminal charges or confiscation of syringes and/or illicit drugs by police. Third, for some participants, anti-drug user stigma and concerns over unwillingly disclosing their drug use hindered access to SSPs outside of housing settings. Programs operated within housing facilities often offered greater client anonymity along with more supportive and less stigmatizing environments, particularly in the presence of peer staff. Conclusion The current study advances understanding of access to injecting equipment in a setting with city-wide syringe distribution programs. Our findings underscore the benefits of housing-based SSPs and encourage the expansion of such services to maximize access to harm reduction supports for PWID.

Huanglongbing (HLB) is one of the most destructive diseases in citrus, which imperils the sustainability of citriculture worldwide. The presumed causal agent of HLB, ‘Candidatus Liberibacter asiaticus’ (CLas) is a non-culturable phloem-limited α-proteobacterium transmitted by Asian citrus psyllids (ACP, Diaphorina citri Kuwayama). A widely adopted method for HLB diagnosis is based on quantitative real-time polymerase chain reaction (qPCR). Although HLB diagnostic qPCR provides high sensitivity and good reproducibility, it is limited by time-consuming DNA preparation from plant tissue or ACP and the requirement of proper lab instruments including a thermal cycler to conduct qPCR. In an attempt to develop a quick assay that can be deployed in the field for CLas detection, we developed a real-time loop-mediated isothermal amplification (rt-LAMP) assay by targeting the CLas five copy nrdB gene. The rt-LAMP assay using various plant sample types and psyllids successfully detected the nrdB target as low as ~2.6 Log10 copies. Although the rt-LAMP assay was less sensitive than laboratory-based qPCR (detection limit ~10 copies), the data obtained with citrus leaf and bark and ACP showed that the rt-LAMP assay has >96% CLas detection rate, compared to that of laboratory-based qPCR. However, the CLas detection rate in fibrous roots was significantly decreased compared to qPCR due to low CLas titer in some root DNA sample. We also demonstrated that the rt-LAMP assay can be used with a crude leaf DNA extract which is fully deployable in the field for quick and reliable HLB screening.

Abstract The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identify tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces senescence in a subset of tumors, while in others, p53 induces necrosis. We pinpoint cyclophilins as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines poised to undergo p53-mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity, or genetic ablation of specific cyclophilin genes, suppresses p53-mediated necrosis by limiting p53 transcriptional output without impacting p53 chromatin binding. Our study demonstrates that intertumoral heterogeneity in SCLC influences the biological response to p53 restoration, describes a cyclophilin-dependent mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type.

IntroductionThe Coronavirus Disease 2019 (COVID-19) pandemic posed critical challenges in providing care to ovarian cancer (OC) patients, including delays in OC diagnosis and treatment initiation. To accommodate for delays in OC surgery, the Society of Gynecologic Oncology (SGO) recommended preferential use of neoadjuvant chemotherapy during the pandemic. The purpose of this study was to assess the association of the COVID-19 pandemic with neoadjuvant chemotherapy use in patients diagnosed with OC.MethodsThis retrospective cohort study included patients diagnosed with stage II-IV ovarian cancer of epithelial subtype between 01/01/2017-06/30/2021 at Kaiser Permanente Southern California (KPSC), a large integrated healthcare system in the United States. Ovarian cancer patients diagnosed between 2017-2020 were identified from KPSC’s Surveillance, Epidemiology, and End Results (SEER)-affiliated cancer registry. Patients diagnosed in 2021 were identified from the electronic medical records (EMR) using ICD-10 diagnosis codes, followed by medical chart review to validate diagnosis and extract information on histology and stage at diagnosis. March 4, 2020 was used as the cut-off to define pre-pandemic and pandemic periods. Patients diagnosed with COVID-19 between OC diagnosis and treatment completion were excluded. Data on neoadjuvant chemotherapy use were extracted from the cancer registry and EMR, supplemented by chart review. Modified Poisson regression was used to evaluate the association of the pandemic with neoadjuvant chemotherapy use.ResultsOf 566 OC patients, 160 (28.3%) were diagnosed in the pandemic period. Patients diagnosed in the pandemic period were slightly younger (mean age 62.7 vs 64.9 years, p=0.07) and had a higher burden of Charlson comorbidities (p=0.05) than patients diagnosed in pre-pandemic period. No differences in time to treatment initiation were observed by pandemic periods. Neoadjuvant chemotherapy use was documented in 58.7% patients during the pandemic period compared to 47.3% in pre-pandemic period (p=0.01). After adjusting for covariates, patients diagnosed in the pandemic period were 29% more likely to receive neoadjuvant chemotherapy than patients diagnosed in pre-pandemic period [RR(95%CI): 1.29(1.12-1.49)].DiscussionsOvarian cancer patients diagnosed in the COVID-19 pandemic were more likely to receive neoadjuvant chemotherapy than patients diagnosed before the pandemic. Future research on patient outcomes and trends in the post-pandemic period are warranted.

BackgroundMany emerging adults (EAs) are prone to making unhealthy choices, which increase their risk of premature cancer morbidity and mortality. In the era of social media, rigorous research on interventions to promote health behaviors for cancer risk reduction among EAs delivered over social media is limited. Cancer prevention information and recommendations may reach EAs more effectively over social media than in settings such as health care, schools, and workplaces, particularly for EAs residing in rural areas. ObjectiveThis pragmatic randomized trial aims to evaluate a multirisk factor intervention using a social media campaign designed with community advisers aimed at decreasing cancer risk factors among EAs. The trial will target EAs from diverse backgrounds living in rural counties in the Four Corners states of Arizona, Colorado, New Mexico, and Utah. MethodsWe will recruit a sample of EAs (n=1000) aged 18 to 26 years residing in rural counties (Rural-Urban Continuum Codes 4 to 9) in the Four Corners states from the Qualtrics’ research panel and enroll them in a randomized stepped-wedge, quasi-experimental design. The inclusion criteria include English proficiency and regular social media engagement. A social media intervention will promote guideline-related goals for increased physical activity, healthy eating, and human papillomavirus vaccination and reduced nicotine product use, alcohol intake, and solar UV radiation exposure. Campaign posts will cover digital and media literacy skills, responses to misinformation, communication with family and friends, and referral to community resources. The intervention will be delivered over 12 months in Facebook private groups and will be guided by advisory groups of community stakeholders and EAs and focus groups with EAs. The EAs will complete assessments at baseline and at 12, 26, 39, 52, and 104 weeks after randomization. Assessments will measure 6 cancer risk behaviors, theoretical mediators, and participants’ engagement with the social media campaign. ResultsThe trial is in its start-up phase. It is being led by a steering committee. Team members are working in 3 subcommittees to optimize community engagement, the social media intervention, and the measures to be used. The Stakeholder Organization Advisory Board and Emerging Adult Advisory Board were formed and provided initial input on the priority of cancer risk factors to target, social media use by EAs, and community resources available. A framework for the social media campaign with topics, format, and theoretical mediators has been created, along with protocols for campaign management. ConclusionsSocial media can be used as a platform to counter misinformation and improve reliable health information to promote health behaviors that reduce cancer risks among EAs. Because of the popularity of web-based information sources among EAs, an innovative, multirisk factor intervention using a social media campaign has the potential to reduce their cancer risk behaviors. Trial RegistrationClinicalTrials.gov NCT05618158; https://classic.clinicaltrials.gov/ct2/show/NCT05618158 International Registered Report Identifier (IRRID)PRR1-10.2196/50392

This paper investigates spatiotemporal correlates of empathic concern for nature using the EEG/ERP method. The assessment of empathic concern for nature is of much utility as it could give us greater insights into conservation behaviors. Research studies investigating the development of empathy in young children inform us about the interplay of affective and cognitive aspects while perceiving other people in distress and its relationship with prosocial behaviors. However, it is not clear how the brain responds while perceiving nature in distress. Nor are the developmental dynamics of empathic concern for nature concretely known. In this study, eighty-three healthy children, 5–12 years (Mean age = 7.65 years and SD = 2.50 years, 35 girls) participated. Analysis of the differences in neural processing when perceiving images of nature in distress and no distress showed a significant main effect of stimulus type. There was a significant difference in the mean amplitudes of early and late ERP components for distress vs no distress, with distress eliciting a pronounced neural response. There were also significant interaction effects of laterality and age with stimulus type. Correlation analysis of differences in early and late components with age suggests shifting dynamics of empathy for nature from affective arousal to cognitive appraisal. In its novel attempt, this study provides neurophysiological support for the development of empathy for nature during childhood.

This consensus conference report summarizes discussions on sleep apnea care and management. Our goal is to simplify the journey to optimize success for individuals at risk of obstructive sleep apnea and to facilitate diagnostics, monitoring and communication among the entire healthcare team including patients, primary care physicians, sleep specialists, sleep dentists and other key providers. The statement identifies five key problems or unmet needs and contemplates four potential future directions.

We present a near-infrared (NIR) candidate star cluster catalog for the central kiloparsec of M82 based on new JWST NIRCam images. We identify star cluster candidates using the F250M filter, finding 1357 star cluster candidates with stellar masses >10 ^4 M _⊙ . Compared to previous optical catalogs, nearly all (87%) of the candidates we identify are new. The star cluster candidates have a median intrinsic cluster radius of ≈1 pc and stellar masses up to 10 ^6 M _⊙ . By comparing the color–color diagram to dust-free yggdrasil stellar population models, we estimate that the star cluster candidates have A _V ∼ 3−24 mag, corresponding to A _2.5 _μ _m ∼ 0.3−2.1 mag. There is still appreciable dust extinction toward these clusters into the NIR. We measure the stellar masses of the star cluster candidates, assuming ages of 0 and 8 Myr. The slope of the resulting cluster mass function is β = 1.9 ± 0.2, in excellent agreement with studies of star clusters in other galaxies.

Abstract Background Chronic obstructive pulmonary disease (COPD) is a progressive debilitating condition with frequent exacerbations that have a high burden for patients and society. Digital tools may help to reduce the economic burden for patients and payers by improving outcomes. The Propeller platform is a digital self-management tool that facilitates passive monitoring of inhaler medication utilization, potentially assisting the healthcare team to identify patients at risk of a COPD exacerbation who may require further intervention. This study estimated the budget impact of Propeller from commercial payer and Medicare fee-for-service payer perspectives. Methods An Excel-based model was used to estimate the budget impact of Propeller for COPD patients in commercial and Medicare population sizes of 5 million members. Data on prevalence, baseline healthcare resource utilization (HCRU), and baseline use of rescue and controller inhaler medications with unit costs (adjusted to 2020 US dollars) were obtained from peer-reviewed literature. Data on reductions in HCRU during Propeller usage were based on direct evidence. Estimates for costs of remote monitoring were obtained from publicly available information. All patients were assumed to have insurance claims related to ongoing remote monitoring. Results The estimated number of annual eligible COPD patients for commercial and Medicare was 212,200 and 606,600, respectively. Propeller decreased costs by an estimated $2,475 (commercial) and $915 (Medicare) per enrolled patient. The greatest increase in expenditure was for remote monitoring related expenses. After accounting for estimated reductions in hospitalizations, emergency department visits and short-acting beta-agonist use, total net savings were approximately $1.60 and $1.70 per-member per-month for commercial and Medicare payers, respectively. Conclusion Propeller is projected to be cost saving from both the commercial and Medicare payer perspectives.

Abstract The aim of this exploratory study was the assessment of the metabolic profiles of persons with complete spinal cord injury (SCI) in three region-of-interests (pons, cerebellar vermis, and cerebellar hemisphere), with magnetic resonance spectroscopy, and their correlations to clinical scores. Group differences and association between metabolic and clinical scores were examined. Fifteen people with chronic SCI (cSCI), five people with subacute SCI (sSCI) and fourteen healthy controls were included. Group comparison between cSCI and HC showed lower total N-acetyl-aspartate (tNAA) in the pons (p = 0.04) and higher glutathione (GSH) in the cerebellar vermis (p = 0.02). Choline levels in the cerebellar hemisphere were different between cSCI and HC (p = 0.02) and sSCI and HC (p = 0.02). A correlation was reported for choline containing compounds (tCho) to clinical scores in the pons (rho = − 0.55, p = 0.01). tNAA to total creatine (tNAA/tCr ratio) correlated to clinical scores in the cerebellar vermis (rho = 0.61, p = 0.004) and GSH correlated to the independence score in the cerebellar hemisphere (rho = 0.56, p = 0.01). The correlation of tNAA, tCr, tCho and GSH to clinical scores might be indicators on how well the CNS copes with the post-traumatic remodeling and might be further examined as outcome markers.

Abstract Differences in social attention are well-documented in autistic individuals, representing one of the earliest signs of autism. Spontaneous blink rate has been used to index attentional engagement, with lower blink rates reflecting increased engagement. We evaluated novel methods using computer vision analysis (CVA) for automatically quantifying patterns of attentional engagement in young autistic children, based on facial orientation and blink rate, which were captured via mobile devices. Participants were 474 children (17–36 months old), 43 of whom were diagnosed with autism. Movies containing social or nonsocial content were presented via an iPad app, and simultaneously, the device’s camera recorded the children’s behavior while they watched the movies. CVA was used to extract the duration of time the child oriented towards the screen and their blink rate as indices of attentional engagement. Overall, autistic children spent less time facing the screen and had a higher mean blink rate compared to neurotypical children. Neurotypical children faced the screen more often and blinked at a lower rate during the social movies compared to the nonsocial movies. In contrast, autistic children faced the screen less often during social movies than during nonsocial movies and showed no differential blink rate to social versus nonsocial movies.

On November 7th and 8th, 2022, The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), The Coalition for Epidemic Preparedness Innovation (CEPI), The Bill & Melinda Gates Foundation (BMGF), The Biomedical Advanced Research and Development Authority (BARDA), and the Wellcome Trust hosted a virtual workshop entitled “Mucosal Vaccines for SARS-CoV-2: Scientific Gaps and Opportunities.” During the workshop, researchers and vaccine developers from around the world discussed the potential of mucosal vaccines to block SARS-CoV-2 transmission and reviewed the status of SARS-CoV-2 mucosal vaccine research. Here, we summarize key challenges and opportunities in basic, translational, and clinical research that were highlighted during the meeting. We also provide recommendations to advance the field and accelerate the development of mucosal vaccines for SARS-CoV-2.

Abstract Increasing evidence suggests that early motor impairments are a common feature of autism. Thus, scalable, quantitative methods for measuring motor behavior in young autistic children are needed. This work presents an engaging and scalable assessment of visual-motor abilities based on a bubble-popping game administered on a tablet. Participants are 233 children ranging from 1.5 to 10 years of age (147 neurotypical children and 86 children diagnosed with autism spectrum disorder [autistic], of which 32 are also diagnosed with co-occurring attention-deficit/hyperactivity disorder [autistic+ADHD]). Computer vision analyses are used to extract several game-based touch features, which are compared across autistic, autistic+ADHD, and neurotypical participants. Results show that younger (1.5-3 years) autistic children pop the bubbles at a lower rate, and their ability to touch the bubble’s center is less accurate compared to neurotypical children. When they pop a bubble, their finger lingers for a longer period, and they show more variability in their performance. In older children (3-10-years), consistent with previous research, the presence of co-occurring ADHD is associated with greater motor impairment, reflected in lower accuracy and more variable performance. Several motor features are correlated with standardized assessments of fine motor and cognitive abilities, as evaluated by an independent clinical assessment. These results highlight the potential of touch-based games as an efficient and scalable approach for assessing children’s visual-motor skills, which can be part of a broader screening tool for identifying early signs associated with autism.

Clinical genome editing is emerging for rare disease treatment, but one of the major limitations is the targeting of CRISPR editors’ delivery. We delivered base editors to the retinal pigmented epithelium (RPE) in the mouse eye using silica nanocapsules (SNCs) as a treatment for retinal degeneration. Leber congenital amaurosis type 16 (LCA16) is a rare pediatric blindness caused by point mutations in the KCNJ13 gene, a loss of function inwardly rectifying potassium channel (Kir7.1) in the RPE. SNCs carrying adenine base editor 8e (ABE8e) mRNA and sgRNA precisely and efficiently corrected the KCNJ13W53X/W53X mutation. Editing in both patient fibroblasts (47%) and human induced pluripotent stem cell–derived RPE (LCA16-iPSC-RPE) (17%) showed minimal off-target editing. We detected functional Kir7.1 channels in the edited LCA16-iPSC-RPE. In the LCA16 mouse model (Kcnj13W53X/+ΔR), RPE cells targeted SNC delivery of ABE8e mRNA preserved normal vision, measured by full-field electroretinogram (ERG). Moreover, multifocal ERG confirmed the topographic measure of electrical activity primarily originating from the edited retinal area at the injection site. Preserved retina structure after treatment was established by optical coherence tomography (OCT). This preclinical validation of targeted ion channel functional rescue, a challenge for pharmacological and genomic interventions, reinforced the effectiveness of nonviral genome-editing therapy for rare inherited disorders.

Due to the rising annual incidence of lung cancer (LC), new treatment strategies are needed. While various options exist, many, if not all, remain suboptimal. Several studies have shown cryoablation to be a promising approach. Yet, a lack of basic information pertaining to LC response to freezing and requirement for percutaneous access has limited clinical use. In this study, we investigated the A549 lung carcinoma cell line response to freezing. The data show that a single 5 min freeze to −15 °C did not affect cell viability, whereas −20 °C and −25 °C result in a significant reduction in viability 1 day post freeze to

Diabetes exposure during pregnancy affects health outcomes in offspring; however, little is known about in utero exposure to preexisting parental youth-onset type 2 diabetes. Offspring born to participants during the Treatment Options for Type 2 Diabetes in Adolescent and Youth (TODAY) study were administered a questionnaire at the end of the study. Of 457 participants, 37% of women and 18% of men reported 228 offspring, 80% from female participants. TODAY mothers had lower household income (p = 0.0002). At 4.5 years of age (range 0–18 years), 16.7% of offspring were overweight according to the parental report of their primary care provider, with no sex difference. Offspring of TODAY mothers reported more daily medication use compared to TODAY fathers (50/183, 27.7% vs. 6/46, 12.2%, [p = 0.04]), a marker of overall health. TODAY mothers also reported higher rates of recidivism (13/94) than TODAY fathers (0/23). An Individualized Education Plan was reported in 20/94 (21.3%) offspring of TODAY mothers compared to 2/23 (8.7%) of TODAY fathers. This descriptive study, limited by parental self-reports, indicated offspring of participants in TODAY experience significant socioeconomic disadvantages, which, when combined with in utero diabetes exposure, may increase their risk of health and educational disparities.

Abstract Background Malignancy is known to be a major cause of death in adult congenital heart disease (ACHD). However, data regarding cardiovascular and cancer-related outcomes in ACHD are lacking. Methods We conducted a retrospective single-center cohort study comprising patients with ACHD and malignancy. The primary outcome was all-cause mortality. Key secondary outcomes included major adverse cardiovascular and cerebrovascular events (MACCE), cardiotoxicity events and consequent cancer therapy modifications. Results Sixty-eight patients with ACHD and a history of cancer were included in the study. 82% of patients had moderate or great ACHD anatomic complexity. Over a median follow-up of 5 years after cancer diagnosis, 16 (24%) patients died, with 69% of deaths being due to cancer. Univariate predictors of mortality were baseline arrhythmia (OR 3.82, 95% CI 1.15-12.67, p = 0.028), baseline diuretic therapy (OR 3.54, 95% CI 1.04-12.04, p = 0.044) and advanced cancer stage at diagnosis (OR 2.37, 95% CI 1.32-4.25, p = 0.004). MACCE occurred in 40 (59%) patients and was independently predicted by baseline diuretic requirement (OR 9.91, 95% CI 1.12-87.85, p = 0.039). A 14% incidence of cardiotoxicity was seen; 3 patients needed modification and 1 patient needed temporary interruption of cancer therapy for 2 weeks. Conclusions Considerable mortality occurred in this cohort of patients with ACHD and cancer; most deaths were cancer-related. A high rate of MACCE was observed, yet rates of obligatory modification of cancer therapy due to cardiotoxicity were low.

Fishery observers play a crucial role in the management and conservation of fish stocks, but the treatment they receive aboard fishing vessels can affect their ability to perform their duties. Using law enforcement data from the Northeast and Alaska regions, home to the most important commercial fisheries in the United States, we explore the extent of observer harassment, assault, interference, and obstruction (OHAIO). We find that 16% of 10,346 fishery violations reported in the Northeast and Alaska regions from 2014-2018 are observer-related, and over 80% of those involve OHAIO. We trace how OHAIO incidents are reported and processed and propose steps to mitigate the issue.

BackgroundThree years since the onset of COVID-19, pandemic-related trends in child sexual abuse (CSA) remain poorly understood. Common administrative surveillance metrics may have underestimated abuse during the pandemic, given youths’ limited access to mandatory reporters. Research using anonymous service-use data showed increased violence-related online help-seeking but overlooked youth-specific help-seeking for CSA during COVID-19. Understanding pandemic-related trends in CSA can inform abuse detection practices and mental health service provision for youth victims. ObjectiveThe purpose of this study was to harness anonymous help-seeking data from the National Sexual Assault Online Hotline (NSAOH) to glean insights about CSA occurrence in the United States during the COVID-19 pandemic. MethodsWe used an archival sample of victims who contacted NSAOH from 2016 to 2021 (n=41,561). We examined differences in the proportion of youth and adult victims contacting NSAOH during the first COVID-19 year (March 2020 to February 2021) compared to the prior year (March 2019 to February 2020; n=11,719). Further, we compared key characteristics of hotline interactions among youth victims during the first COVID-19 year to the prior year (n=5913). Using joinpoint regression analysis, we examined linear trends in the number of monthly sampled youth and adult victims (excluding victims of unknown age) from 2016 to 2021 who discussed any victimization event (n=26,904) and who discussed recent events (ie, events occurring during the pandemic; n=9932). ResultsMost youth victims were abused by family members prior to (1013/1677, 60.4%) and after (2658/3661, 72.6%) the onset of COVID-19. The number of youth victims contacting NSAOH spiked in March 2020 and peaked in November 2020 for all youth (slope=28.2, 95% CI 18.7-37.7) and those discussing recent events (slope=17.4, 95% CI 11.1-23.6). We observed a decline in youth victims into spring 2021 for all youth (slope=–56.9, 95% CI –91.4 to –22.3) and those discussing recent events (slope=–33.7, 95% 47.3 to -20.0). The number of adult victims discussing any victimization event increased steadily from January 2018 through May 2021 (slope=3.6; 95% CI 2.9-4.2) and then declined (slope=–13.8, 95% CI –22.8 to –4.7). Trends were stable for adults discussing recent events. ConclusionsThis study extends the use of hotline data to understand the implications of the pandemic on CSA. We observed increased youth help-seeking through the NSAOH coinciding with the onset of COVID-19. Trends persisted when limiting analyses to recent victimization events, suggesting increased help-seeking reflected increased CSA during COVID-19. These findings underscore the utility of anonymous online services for youth currently experiencing abuse. Further, the findings support calls for increased youth mental health services and efforts to incorporate online chat into youth-targeted services.

Summary: Autophagy is an essential cellular process that is deeply integrated with innate immune signaling; however, studies that examine the impact of autophagic modulation in the context of inflammatory conditions are lacking. Here, using mice with a constitutively active variant of the autophagy gene Beclin1, we show that increased autophagy dampens cytokine production during a model of macrophage activation syndrome and in adherent-invasive Escherichia coli (AIEC) infection. Moreover, loss of functional autophagy through conditional deletion of Beclin1 in myeloid cells significantly enhances innate immunity in these contexts. We further analyzed primary macrophages from these animals with a combination of transcriptomics and proteomics to identify mechanistic targets downstream of autophagy. Our study reveals glutamine/glutathione metabolism and the RNF128/TBK1 axis as independent regulators of inflammation. Altogether, our work highlights increased autophagic flux as a potential approach to reduce inflammation and defines independent mechanistic cascades involved in this control.