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BackgroundThe rapid evolution of conversational and generative artificial intelligence (AI) has led to the increased deployment of AI tools in healthcare settings. While these conversational AI tools promise efficiency and expanded access to healthcare services, there are growing concerns ethically, practically and in terms of inclusivity. This study aimed to identify activities which reduce bias in conversational AI and make their designs and implementation more equitable.MethodsA qualitative research approach was employed to develop an analytical framework based on the content analysis of 17 guidelines about AI use in clinical settings. A stakeholder consultation was subsequently conducted with a total of 33 ethnically diverse community members, AI designers, industry experts and relevant health professionals to further develop a roadmap for equitable design and implementation of conversational AI in healthcare. Framework analysis was conducted on the interview data.ResultsA 10-stage roadmap was developed to outline activities relevant to equitable conversational AI design and implementation phases: 1) Conception and planning, 2) Diversity and collaboration, 3) Preliminary research, 4) Co-production, 5) Safety measures, 6) Preliminary testing, 7) Healthcare integration, 8) Service evaluation and auditing, 9) Maintenance, and 10) Termination.DiscussionWe have made specific recommendations to increase conversational AI's equity as part of healthcare services. These emphasise the importance of a collaborative approach and the involvement of patient groups in navigating the rapid evolution of conversational AI technologies. Further research must assess the impact of recommended activities on chatbots' fairness and their ability to reduce health inequalities.

BackgroundIn 2020 the World Health Organization (WHO) declared that Malawi had successfully eliminated lymphatic filariasis (LF) as a public health problem. Understanding clinical case distributions at a national and sub-national level is important, so essential care packages can be provided to individuals living with LF symptoms. This study aimed to develop a national database and map of LF clinical cases across Malawi using geostatistical modelling approaches, programme-identified clinical cases, antigenaemia prevalence and climate information.MethodologyLF clinical cases identified through programme house-to-house surveys across 90 sub-district administrative boundaries (Traditional Authority (TA)) and antigenaemia prevalence from 57 sampled villages in Malawi were used in a two-step geostatistical modelling process to predict LF clinical cases across all TAs of the country. First, we modelled antigenaemia prevalence in relation to climate covariates to predict nationwide antigenaemia prevalence. Second, we modelled clinical cases for unmapped TAs based on our antigenaemia prevalence spatial estimates.Principle findingsThe models estimated 20,938 (95% CrI 18,091 to 24,071) clinical cases in unmapped TAs (70.3%) in addition to the 8,856 (29.7%), programme-identified cases in mapped TAs. In total, the overall national number of LF clinical cases was estimated to be 29,794 (95% CrI 26,957 to 32,927). The antigenaemia prevalence and clinical case mapping and modelling found the highest burden of disease in Chikwawa and Nsanje districts in the Southern Region and Karonga district in the Northern Region of the country.ConclusionsThe models presented in this study have facilitated the development of the first national LF clinical case database and map in Malawi, the first endemic country in sub-Saharan Africa. It highlights the value of using existing LF antigenaemia prevalence and clinical case data together with modelling approaches to produce estimates that may be used for the WHO dossier requirements, to help target limited resources and implement long-term health strategies.

BackgroundLymphatic filariasis (LF) is a parasitic disease transmitted by mosquitoes, causing severe pain, disfiguring, and disabling clinical conditions such as lymphoedema and hydrocoele. LF is a global public health problem affecting 72 countries, primarily in Africa and Asia. Since 2000, the World Health Organization (WHO) has led the Global Programme to Eliminate Lymphatic Filariasis (GPELF) to support all endemic regions. This paper focuses on the achievements of the Malawi LF Elimination Programme between 2000 and 2020 to eliminate LF as a public health problem, making it the second sub-Saharan country to receive validation from the WHO.Methodology/principal findingsThe Malawi LF Programme addressed the widespread prevalence of LF infection and disease across the country, using the recommended WHO GPELF strategies and operational research initiatives in collaboration with key national and international partners. First, to stop the spread of infection (i.e., interrupt transmission) and reduce the circulating filarial antigen prevalence from as high as 74.4% to below the critical threshold of 1-2% prevalence, mass drug administration (MDA) using a two-drug regime was implemented at high coverage rates (>65%) of the total population, with supplementary interventions from other programmes (e.g., malaria vector control). The decline in prevalence was monitored and confirmed over time using several impact assessment and post-treatment surveillance tools including the standard sentinel site, spot check, and transmission assessment surveys and alternative integrated, hotspot, and easy-access group surveys. Second, to alleviate suffering of the affected populations (i.e., control morbidity) the morbidity management and disability prevention (MMDP) package of care was implemented. Specifically, clinical case estimates were obtained via house-to-house patient searching activities; health personnel and patients were trained in self-care protocols for lymphoedema and/or referrals to hospitals for hydrocoele surgery; and the readiness and quality of treatment and services were assessed with new survey tools.ConclusionsMalawi's elimination of LF will ensure that future generations are not infected and suffer from the disfiguring and disabling disease. However, it will be critical that the Malawi LF Elimination programme remains vigilant, focussing on post-elimination surveillance and MMDP implementation and integration into routine health systems to support long-term sustainability and ongoing success.SummaryLymphatic filariasis, also known as elephantiasis, is a disabling, disfiguring, and painful disease caused by a parasite that infected mosquitoes transmit to millions of people worldwide. Since 2000, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) has supported endemic countries such as Malawi in south-eastern Africa, to eliminate the disease as a public health problem. The Malawi National LF Elimination Programme has worked tirelessly over the past two decades to implement the GPELF recommended strategies to interrupt the transmission with a two-drug regime, and to alleviate suffering in patients with lymphoedema and/or hydrocoele through morbidity management and disability prevention. Additionally, the LF Programme has collaborated with national and international stakeholders to implement a range of supplementary operational research projects to address outstanding knowledge gaps and programmatic barriers. In 2020, the World Health Organisation validated that Malawi had successfully eliminated LF as a public health problem, making it the second country in sub-Saharan Africa to achieve this, which is remarkable given that Malawi previously had very high infection rates. The LF Programme now remains vigilant, putting its efforts towards post-elimination surveillance and the continued implementation of care for patients with chronic conditions. Malawi's elimination of LF will ensure that future generations are not affected by this devastating disease.

Near infrared spectroscopy coupled with predictive modeling is a growing field of study for addressing questions in wildlife science aimed at improving management strategies and conservation outcomes for managed and threatened fauna. To date, the majority of spectroscopic studies in wildlife and fisheries applied chemometrics and predictive modeling with a single-algorithm approach. By contrast, multi-model approaches are used routinely for analyzing spectroscopic datasets across many major industries (e.g., medicine, agriculture) to maximize predictive outcomes for real-world applications. In this study, we conducted a benchmark modeling exercise to compare the performance of several machine learning algorithms in a multi-class problem utilizing a multivariate spectroscopic dataset obtained from live animals. Spectra obtained from live individuals representing eleven amphibian species were classified according to taxonomic designation. Seven modeling techniques were applied to generate prediction models, which varied significantly (p < 0.05) with regard to mean classification accuracy (e.g., support vector machine: 95.8 ± 0.8% vs. K-nearest neighbors: 89.3 ± 1.0%). Through the use of a multi-algorithm approach, candidate algorithms can be identified and applied to more effectively model complex spectroscopic data collected for wildlife sciences. Other key considerations in the predictive modeling workflow that serve to optimize spectroscopic model performance (e.g., variable selection and cross-validation procedures) are also discussed.

Objectives1) To compare the effect of the self-report distress tool (DT) and rapid mental health referral process (MH) on vocational training program attendance. 2) To compare the effect of the DT and MH on vocational training program completion. 3) To compare the effect of the DT an MH on post-vocational training program employment.DesignPragmatic, multi-centre, 2x2 factorial, cluster randomized, superiority study with 4 parallel groups and primary endpoints of vocational program attendance and completion at 12 weeks and post-program employment at 24 months. Cluster randomization of each training cohort will be performed with a 1:1:1:1 allocation ratio using a site stratified, permuted-block group schema. Final sample size is expected to be 400 participants (100 per group).ParticipantsStudents enrolled in Community Builder's Trades & Diversity Training Program in either the city of Barrie or Sudbury (in Ontario, Canada) will be eligible for enrollment if they have an active Ontario Health Insurance Plan number and Canadian Social Insurance Number and provide written informed consent prior to Training program commencement.OutcomesThe primary outcome includes: 1) Difference in proportion of absence-free program days from date of randomization, where absence-free days are defined as being present in class or work setting for ≥ 8 hours from Monday to Thursday during the 12-week program duration.Trial registrationClinicalTrials.gov NCT05626374 (November 23, 2022).

[This corrects the article DOI: 10.1371/journal.pone.0264826.].

More than 50% of caudates are threatened with extinction and are in need of ex-situ breeding programs to support conservation efforts and species recovery. Unfortunately, many salamander populations under human care can experience reproductive failure, primarily due to missing environmental cues necessary for breeding. Assisted reproductive technologies (ARTs) are a useful suite of techniques for overcoming or bypassing these missing environmental cues to promote breeding. Exogenous hormones are used to stimulate natural breeding behaviors or gamete expression for in-vitro fertilization or biobanking and are typically administered intramuscularly in caudates. While effective, intramuscular injection is risky to perform in smaller-bodied animals, resulting in health and welfare risks. This research investigated the spermiation response to hormone administration through a non-invasive oral bioencapsulation route using the tiger salamander (Ambystoma tigrinum) as a model species. Male salamanders were randomly rotated six weeks apart through four treatments (n = 11 males/treatment) in which animals received a resolving dose of gonadotropin-releasing hormone (GnRH) as follows: (1) Prime-Only (0.0 μg/g); (2) Low (0.25 μg/g); (3) Medium (1.0 μg/g); and (4) High (2.0 μg/g). All males were given a GnRH priming dose (0.25 μg/g) 24 hours prior to the resolving dose. Exogenous hormone was delivered inside of a cricket (Gryllodes sigillatus) that was presented as a food item by tweezers. Sperm samples were collected at 1, 3, 6, 9, 12, and 24 hours after the resolving dose and analyzed for quantity and quality. For all treatments, sperm concentration was produced in an episodic pattern over time. The Prime-Only treatment had a lower (p < 0.05) percent of sperm exhibiting normal morphology compared to treatments utilizing a resolving dose of GnRH. Overall, oral administration of GnRH is a feasible route of inducing spermiation in salamanders, yielding sperm of sufficient quantity and quality for in-vitro fertilization and biobanking efforts.

Among the consequences of systemic racism in health care are significant health disparities among Black/African American individuals with comorbid physical and mental health conditions. Despite decades of studies acknowledging health disparities based on race, significant change has not occurred. There are shockingly few evidence-based antiracism interventions. New paradigms are needed to intervene on, and not just document, racism in health care systems. We are developing a transformative paradigm for new antiracism interventions for primary care settings that integrate mental and physical health care. The paradigm is the first of its kind to integrate community-based participatory research and systems science, within an established model of early phase translation to rigorously define new antiracism interventions. This protocol will use a novel application of systems sciences by combining the qualitative systems sciences methods (group model building; GMB) with quantitative methods (simulation modeling) to develop a comprehensive and community-engaged view of both the drivers of racism and the potential impact of antiracism interventions. Community participants from two integrated primary health care systems will engage in group GMB workshops with researchers to 1) Describe and map the complex dynamic systems driving racism in health care practices, 2) Identify leverage points for disruptive antiracism interventions, policies and practices, and 3) Review and prioritize a list of possible intervention strategies. Advisory committees will provide feedback on the design of GMB procedures, screen potential intervention components for impact, feasibility, and acceptability, and identify gaps for further exploration. Simulation models will be generated based on contextual factors and provider/patient characteristics. Using Item Response Theory, we will initiate the process of developing core measures for assessing the effectiveness of interventions at the organizational-systems and provider levels to be tested under a variety of conditions. While we focus on Black/African Americans, we hope that the resulting transformative paradigm can be applied to improve health equity among other marginalized groups.

PurposeTo identify experiences of boredom and associations with psychosocial well-being during and following homelessness.MethodsUsing a convergent, mixed-methods explanatory design, we conducted quantitative interviews with 164 participants) (n = 102 unhoused; n = 62 housed following homelessness) using a 92-item protocol involving demographic components and seven standardized measures of psychosocial well-being. A sub-sample (n = 32) was approached to participate in qualitative interviews. Data were analyzed by group (unhoused; housed). Quantitative data were analyzed using descriptive statistics designed to generate insights into boredom, meaningful activity engagement, and their associations with psychosocial well-being during and following homelessness. Qualitative data were analyzed using thematic analysis. Quantitative and qualitative findings were integrated at the stage of discussion.ResultsQuantitative analyses revealed small to moderate correlations between boredom and increased hopelessness (rs = .376, p < .01), increased drug use (rs = .194, p < .05), and lowered mental well-being (rs = -.366, p < .01). There were no statistically significant differences between unhoused and housed participants on any standardized measures. Hierarchical regression analyses revealed that housing status was not a significant predictor of boredom or meaningful activity engagement (p>.05). Qualitative interviews revealed profound boredom during and following homelessness imposing negative influences on mental well-being and driving substance use.ConclusionsBoredom and meaningful activity are important outcomes that require focused attention in services designed to support individuals during and following homelessness. Attention to this construct in future research, practice, and policy has the potential to support the well-being of individuals who experience homelessness, and to contribute to efforts aimed at homelessness prevention.

Kale is a nutrient-dense leafy vegetable associated with wide-ranging health benefits. It is tolerant of drought and temperature fluctuations, and could thus serve an increasingly important role in providing a safe and nutritious food supply during the climate crisis, while kale's ease of cultivation and ability to be grown in a wide range of soils make it a good fit for urban agriculture. In this pilot study we explored potential differences between kale grown at urban versus rural farms. We planted kale seedlings (Darkibor variety) at three urban and four rural farms in and around Baltimore City, Maryland, instructed farmers to cultivate them using their usual growing practices, harvested the kale from fields and points of distribution, and analyzed it for concentrations of carotenoids, vitamins C and K1, ten nutritional elements, and eight non-essential metals. Although sample sizes for some analyses were in some cases too small to produce statistically significant results, we identified potentially meaningful differences in concentrations of several components between urban and rural kale samples. Compared to urban samples, mean concentrations of carotenoids and vitamins were 22-38% higher in rural field samples. By contrast, mean concentrations for eight nutritional elements were higher in urban field samples by as much as 413% for iron. Compared to rural field samples, mean concentrations of nine non-essential metals were higher in urban samples, although lead and cadmium concentrations for all samples were below public health guidelines. Some urban-rural differences were more pronounced than those identified in prior research. For six elements, variance within urban and rural farms was greater than variance between urban and rural farms, suggesting urbanicity may not be the primary driver of some observed differences. For some nutrients, mean concentrations were higher than upper ranges reported in prior estimates, suggesting kale may have the potential to be more nutrient-dense than previously estimated. The nutritive and metals composition of this important crop, and the factors that influence it, merit continued investigation given its growing popularity.

With the decline of bee populations worldwide, studies determining current wild bee distributions and diversity are increasingly important. Wild bee identification is often completed by experienced taxonomists or by genetic analysis. The current study was designed to compare two methods of identification including: (1) morphological identification by experienced taxonomists using images of field-collected wild bees and (2) genetic analysis of composite bee legs (multiple taxa) using metabarcoding. Bees were collected from conservation grasslands in eastern Iowa in summer 2019 and identified to the lowest taxonomic unit using both methods. Sanger sequencing of individual wild bee legs was used as a positive control for metabarcoding. Morphological identification of bees using images resulted in 36 unique taxa among 22 genera, and >80% of Bombus specimens were identified to species. Metabarcoding was limited to genus-level assignments among 18 genera but resolved some morphologically similar genera. Metabarcoding did not consistently detect all genera in the composite samples, including kleptoparasitic bees. Sanger sequencing showed similar presence or absence detection results as metabarcoding but provided species-level identifications for cryptic species (i.e., Lasioglossum). Genus-specific detections were more frequent with morphological identification than metabarcoding, but certain genera such as Ceratina and Halictus were identified equally well with metabarcoding and morphology. Genera with proportionately less tissue in a composite sample were less likely to be detected using metabarcoding. Image-based methods were limited by image quality and visible morphological features, while genetic methods were limited by databases, primers, and amplification at target loci. This study shows how an image-based identification method compares with genetic techniques, and how in combination, the methods provide valuable genus- and species-level information for wild bees while preserving tissue for other analyses. These methods could be improved and transferred to a field setting to advance our understanding of wild bee distributions and to expedite conservation research.

African swine fever (ASF) is a devastating disease of domestic pigs that has spread across the globe since its introduction into Georgia in 2007. The etiological agent is a large double-stranded DNA virus with a genome of 170 to 180 kb in length depending on the isolate. Much of the differences in genome length between isolates are due to variations in the copy number of five different multigene families that are encoded in repetitive regions that are towards the termini of the covalently closed ends of the genome. Molecular epidemiology of African swine fever virus (ASFV) is primarily based on Sanger sequencing of a few conserved and variable regions, but due to the stability of the dsDNA genome changes in the variable regions occur relatively slowly. Observations in Europe and Asia have shown that changes in other genetic loci can occur and that this could be useful in molecular tracking. ASFV has been circulating in Western Africa for at least forty years. It is therefore reasonable to assume that changes may have accumulated in regions of the genome other than the standard targets over the years. At present only one full genome sequence is available for an isolate from Western Africa, that of a highly virulent isolate collected from Benin during an outbreak in 1997. In Cameroon, ASFV was first reported in 1981 and outbreaks have been reported to the present day and is considered endemic. Here we report three full genome sequences from Cameroon isolates of 1982, 1994 and 2018 outbreaks and identify novel single nucleotide polymorphisms and insertion-deletions that may prove useful for molecular epidemiology studies in Western Africa and beyond.

Delays in illness recognition, healthcare seeking, and in the provision of appropriate clinical care are common in resource-limited settings. Our objective was to determine the frequency of delays in the "Three Delays-in-Healthcare", and factors associated with delays, among deceased infants and children in seven countries with high childhood mortality. We conducted a retrospective, descriptive study using data from verbal autopsies and medical records for infants and children aged 1-59 months who died between December 2016 and February 2022 in six sites in sub-Saharan Africa and one in South Asia (Bangladesh) and were enrolled in Child Health and Mortality Prevention Surveillance (CHAMPS). Delays in 1) illness recognition in the home/decision to seek care, 2) transportation to healthcare facilities, and 3) the receipt of clinical care in healthcare facilities were categorized according to the "Three Delays-in-Healthcare". Comparisons in factors associated with delays were made using Chi-square testing. Information was available for 1,326 deaths among infants and under 5 children. The majority had at least one identified delay (n = 854, 64%). Waiting >72 hours after illness recognition to seek health care (n = 422, 32%) was the most common delay. Challenges in obtaining transportation occurred infrequently when seeking care (n = 51, 4%). In healthcare facilities, prescribed medications were sometimes unavailable (n = 102, 8%). Deceased children aged 12-59 months experienced more delay than infants aged 1-11 months (68% vs. 61%, P = 0.018). Delays in seeking clinical care were common among deceased infants and children. Additional study to assess the frequency of delays in seeking clinical care and its provision among children who survive is warranted.

Hearing loss is an important global public health issue which can be alleviated through treatment with hearing aids. However, most people who would benefit from hearing aids do not receive them, in part due to challenges in accessing hearing aids and related services, which are most salient in low- and middle-income countries (LMIC) and other resource-limited settings. Innovative approaches for hearing aid service delivery can overcome many of the challenges related to access, including that of limited human resources trained to provide ear and hearing care. The purpose of this systematic scoping review is to synthesize evidence on service delivery approaches for hearing aid provision in LMIC and resource-limited settings. We searched 3 databases (PubMed, Scopus, Ovid MEDLINE) for peer-reviewed articles from 2000 to 2022 that focused on service delivery approaches related to hearing aids in LMIC or resource-limited settings. Fifteen peer-reviewed articles were included, which described hospital-based (3 studies), large-scale donation program (1 studies), community-based (7 studies), and remote (telehealth; 4 studies) service delivery approaches. Key findings are that hearing aid services can be successfully delivered in hospital- and community-based settings, and remotely, and that both qualified hearing care providers and trained non-specialists can provide quality hearing aid services. Service delivery approaches focused on community-based and remote care, and task sharing among qualified hearing care providers and trained non-specialists can likely improve access to hearing aids worldwide, thereby reducing the burden of untreated hearing loss.

BackgroundKinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown.MethodsTo understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy.ResultsC. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells.ConclusionWe report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.

While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs and cause dramatic tumor regression in aggressive human and mouse CRPC models. Notably, EZH2 and HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation and histone deacetylation, respectively. Accordingly, we show that suppression of both EZH2 and HDAC are required to derepress/induce a subset of EZH2 targets, by promoting the sequential demethylation and acetylation of histone H3. Moreover, we find that the induction of one of these targets, ATF3, which is a broad stress response gene, is critical for the therapeutic response. Importantly, in human tumors, low ATF3 levels are associated with decreased survival. Moreover, EZH2- and ATF3-mediated transcriptional programs inversely correlate and are most highly/lowly expressed in advanced disease. Together, these studies identify a promising therapeutic strategy for CRPC and suggest that these two major epigenetic regulators buffer prostate cancers from a lethal response to cellular stresses, thereby conferring a tractable therapeutic vulnerability.

While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs and cause dramatic tumor regression in aggressive human and mouse CRPC models. Notably, EZH2 and HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation and histone deacetylation, respectively. Accordingly, we show that suppression of both EZH2 and HDAC are required to derepress/induce a subset of EZH2 targets, by promoting the sequential demethylation and acetylation of histone H3. Moreover, we find that the induction of one of these targets, ATF3, which is a broad stress response gene, is critical for the therapeutic response. Importantly, in human tumors, low ATF3 levels are associated with decreased survival. Moreover, EZH2- and ATF3-mediated transcriptional programs inversely correlate and are most highly/lowly expressed in advanced disease. Together, these studies identify a promising therapeutic strategy for CRPC and suggest that these two major epigenetic regulators buffer prostate cancers from a lethal response to cellular stresses, thereby conferring a tractable therapeutic vulnerability. Epigenetic, transcriptional, and functional studies show that two major epigenetic regulators (EZH2 and HDAC) buffer advanced prostate cancer from lethal stress responses, revealing a promising combination therapy for castration-resistant disease.

The genomic sequence of the horse has been available since 2009, providing critical resources for discovering important genomic variants regarding both animal health and population structures. However, to fully understand the functional implications of these variants, detailed annotation of the horse genome is required. Due to the limited availability of functional data for the equine genome, as well as the technical limitations of short-read RNA-seq, existing annotation of the equine genome contains limited information about important aspects of gene regulation, such as alternate isoforms and regulatory elements, which are either not transcribed or transcribed at a very low level. To solve above problems, the Functional Annotation of the Animal Genomes (FAANG) project proposed a systemic approach to tissue collection, phenotyping, and data generation, adopting the blueprint laid out by the Encyclopedia of DNA Elements (ENCODE) project. Here we detail the first comprehensive overview of gene expression and regulation in the horse, presenting 39,625 novel transcripts, 84,613 candidate cis-regulatory elements (CRE) and their target genes, 332,115 open chromatin regions genome wide across a diverse set of tissues. We showed substantial concordance between chromatin accessibility, chromatin states in different genic features and gene expression. This comprehensive and expanded set of genomics resources will provide the equine research community ample opportunities for studies of complex traits in the horse.

Since industrialization began, atmospheric CO2 ([CO2]) has increased from 270 to 415 ppm and is projected to reach 800-1000 ppm this century. Some Arabidopsis thaliana (Arabidopsis) genotypes delayed flowering in elevated [CO2] relative to current [CO2], while others showed no change or accelerations. To predict genotype-specific flowering behaviors, we must understand the mechanisms driving flowering response to rising [CO2]. [CO2] changes alter photosynthesis and carbohydrates in plants. Plants sense carbohydrate levels, and exogenous carbohydrate application influences flowering time and flowering transcript levels. We asked how organismal changes in carbohydrates and transcription correlate with changes in flowering time under elevated [CO2]. We used a genotype (SG) of Arabidopsis that was selected for high fitness at elevated [CO2] (700 ppm). SG delays flowering under elevated [CO2] (700 ppm) relative to current [CO2] (400 ppm). We compared SG to a closely related control genotype (CG) that shows no [CO2]-induced flowering change. We compared metabolomic and transcriptomic profiles in these genotypes at current and elevated [CO2] to assess correlations with flowering in these conditions. While both genotypes altered carbohydrates in response to elevated [CO2], SG had higher levels of sucrose than CG and showed a stronger increase in glucose and fructose in elevated [CO2]. Both genotypes demonstrated transcriptional changes, with CG increasing genes related to fructose 1,6-bisphosphate breakdown, amino acid synthesis, and secondary metabolites; and SG decreasing genes related to starch and sugar metabolism, but increasing genes involved in oligosaccharide production and sugar modifications. Genes associated with flowering regulation within the photoperiod, vernalization, and meristem identity pathways were altered in these genotypes. Elevated [CO2] may alter carbohydrates to influence transcription in both genotypes and delayed flowering in SG. Changes in the oligosaccharide pool may contribute to delayed flowering in SG. This work extends the literature exploring genotypic-specific flowering responses to elevated [CO2].

This Cleavage Under Targets and Release Using Nuclease (CUT&RUN) protocol produces genomic occupancy data for a protein of interest in the protozoan parasite Trypanosoma brucei. The data produced is analyzed in a similar way as that produced by ChIP-seq. While we describe the protocol for parasites carrying an epitope tag for the protein of interest, antibodies against the native protein could be used for the same purpose.

Clinical tumor tissues that are preserved as formalin-fixed paraffin-embedded (FFPE) samples result in extensive cross-linking, fragmentation, and chemical modification of RNA, posing significant challenges for RNA-seq-based gene expression profiling. This study sought to define an optimal RNA-seq protocol for FFPE samples. We employed a common RNA extraction method and then compared RNA-seq library preparation protocols including RNAaccess, RiboZero and PolyA in terms of sequencing quality and concordance of gene expression using FFPE and case-matched fresh-frozen (FF) triple-negative breast cancer (TNBC) tissues. We found that RNAaccess, a method based on exome capture, produced the most concordant results. Applying RNAaccess to FFPE gastric cancer tissues, we established a minimum RNA DV200 requirement of 10% and a RNA input amount of 10ng that generated highly reproducible gene expression data. Lastly, we demonstrated that RNAaccess and NanoString platforms produced highly concordant expression profiles from FFPE samples for shared genes; however, RNA-seq may be preferred for clinical biomarker discovery work because of the broader coverage of the transcriptome. Taken together, these results support the selection of RNA-seq RNAaccess method for gene expression profiling of FFPE samples. The minimum requirements for RNA quality and input established here may allow for inclusion of clinical FFPE samples of sub-optimal quality in gene expression analyses and ultimately increasing the statistical power of such analyses.

BackgroundWhiplash associated disorders (WAD) are the most common non-hospitalised injuries resulting from a motor vehicle crash. Half of individuals with WAD experience ongoing pain and disability. Furthermore, individuals with persistent WAD have lower levels of aerobic capacity and isometric strength compared with age-matched controls. It is not known whether these differences are associated with increased levels of pain and disability, or with reduced physical activity (PA) participation.ObjectiveOur primary aim was to compare PA levels in individuals with persistent WAD with healthy controls. Secondary aims were to: compare objective and subjective measurements of PA; explore factors that may influence PA; and describe proportions of these populations meeting World Health Organisation PA guidelines.MethodsObjective (ActiGraph accelerometer; seven days) and subjective (International Physical Activity Questionnaire (IPAQ)) PA data were collected for n = 53 age-matched participants (WAD n = 28; controls n = 25).ResultsIndependent sample t-tests showed no significant difference in objectively measured PA (p>0.05) between WAD and controls. For the subjective measure (IPAQ), controls reported more overall weekly PA (t = 0.219, pConclusionsIndividuals with WAD had levels of physical and mental health quality-of-life significantly lower than controls and below population norms yet participated in similar levels of PA. Given that increased perceptions of mental health quality-of-life were positively associated with objectively measured MVPA and subjectively reported overall PA, strategies to help people with WAD achieve adequate doses of MVPA may be beneficial. ActiGraph-measured and IPAQ-reported PA were discordant. Hence, IPAQ may not be a reliable measure of habitual PA in WAD.

During the COVID-19 pandemic, many public schools across the United States shifted from fully in-person learning to alternative learning modalities such as hybrid and fully remote learning. In this study, data from 14,688 unique school districts from August 2020 to June 2021 were collected to track changes in the proportion of schools offering fully in-person, hybrid and fully remote learning over time. These data were provided by Burbio, MCH Strategic Data, the American Enterprise Institute's Return to Learn Tracker and individual state dashboards. Because the modalities reported by these sources were incomplete and occasionally misaligned, a model was needed to combine and deconflict these data to provide a more comprehensive description of modalities nationwide. A hidden Markov model (HMM) was used to infer the most likely learning modality for each district on a weekly basis. This method yielded higher spatiotemporal coverage than any individual data source and higher agreement with three of the four data sources than any other single source. The model output revealed that the percentage of districts offering fully in-person learning rose from 40.3% in September 2020 to 54.7% in June of 2021 with increases across 45 states and in both urban and rural districts. This type of probabilistic model can serve as a tool for fusion of incomplete and contradictory data sources in order to obtain more reliable data in support of public health surveillance and research efforts.

Recent evidence suggests that spatial language in preschool positively affects the development of verbal number skills, as indexed by aggregated performances on counting and number naming tasks. We firstly aimed to specify whether spatial language (the knowledge of locative prepositions) significantly relates to both of these measures. In addition, we assessed whether the predictive value of spatial language extends beyond verbal number skills to numerical subdomains without explicit verbal component, such as number writing, symbolic magnitude classifications, ordinal judgments and numerosity comparisons. To determine the unique contributions of spatial language to these numerical skills, we controlled in our regression analyses for intrinsic and extrinsic spatial abilities, phonological awareness as well as age, socioeconomic status and home language. With respect to verbal number skills, it appeared that spatial language uniquely predicted forward and backward counting but not number naming, which was significantly affected only by phonological awareness. Regarding numerical tasks that do not contain explicit verbal components, spatial language did not relate to number writing or numerosity comparisons. Conversely, it explained unique variance in symbolic magnitude classifications and was the only predictor of ordinal judgments. These findings thus highlight the importance of spatial language for early numerical development beyond verbal number skills and suggest that the knowledge of spatial terms is especially relevant for processing cardinal and ordinal relations between symbolic numbers. Promoting spatial language in preschool might thus be an interesting avenue for fostering the acquisition of these symbolic numerical skills prior to formal schooling.

Background Non-medical health-related social needs (social needs) are major contributors to worse health outcomes and may have an adverse impact on cardiovascular risk factors and cardiovascular disease. The present study evaluated the effect of a closed-loop community-based pathway in reducing social needs among Black men in a lifestyle change program. Methods Black men (n = 70) from a large Midwestern city participated in Black Impact, a 24-week community-based team lifestyle change single-arm pilot trial adapted from the Diabetes Prevention Program and American Heart Association’s (AHA) Check, Change, Control Blood Pressure Self-Management Program, which incorporates AHA’s Life’s Simple 7 (LS7) framework. Participants were screened using the Centers for Medicare and Medicaid Services (CMS) Accountable Health Communities Health-Related Social Needs Screening Tool. Participants with affirmative responses were referred to a community hub pathway to address social needs. The primary outcome for this analysis is change in social needs based on the CMS social needs survey at 12 and 24 weeks using mixed effect logistic regressions with random intercepts for each participant. Change in a LS7 score (range 0–14) from baseline to 12 and 24 weeks was evaluated using a linear mixed-effects model stratified by baseline social needs. Results Among 70 participants, the mean age of participants was 52 ±10.5 years. The men were sociodemographically diverse, with annual income ranging from Conclusions The Black Impact lifestyle change single-arm pilot program showed that a referral to a closed-loop community-based hub reduced social needs in Black men. We found no association of social needs with baseline or change in LS7 scores. Further evaluation of community-based strategies to advance the attainment of LS7 and address social needs among Black men in larger trials is warranted.

Malaria vectors have demonstrated resistance to pyrethroid-based insecticides used in insecticide-treated nets, diminishing their effectiveness. This systematic review and meta-analysis investigated two forms of dual active-ingredient (DAI) insecticide-treated nets (ITN(s)) for malaria prevention. A comprehensive search was conducted on July 6th 2022. The databases searched included PubMed, Embase, CINAHL, amongst others. Trials were eligible if they were conducted in a region with ongoing malaria transmission. The first DAI ITN investigated were those that combined a pyrethroid with a non-pyrethroid insecticides. The second DAI ITN investigated were that combined a pyrethroid with an insect growth regulator. These interventions were compared against either a pyrethroid-only ITN, or ITNs treated with pyrethroid and piperonyl-butoxide. Assessment of risk of bias was conducted in duplicate using the Cochrane risk of bias 2 tool for cluster-randomised trials. Summary data was extracted using a custom data-extraction instrument. This was conducted by authors THB, JCS and SH. Malaria case incidence was the primary outcome and has been meta-analysed, adverse events were narratively synthesised. The review protocol is registered on PROSPERO (CRD42022333044). From 9494 records, 48 reports were screened and 13 reports for three studies were included. These studies contained data from 186 clusters and all reported a low risk of bias. Compared to pyrethroid-only ITNs, clusters that received pyrethroid-non-pyrethroid DAI ITNs were associated with 305 fewer cases per 1000-person years (from 380 fewer cases to 216 fewer cases) (IRR = 0.55, 95%CI: 0.44–0.68). However, this trend was not observed in clusters that received pyrethroid-insect growth regulator ITNs compared to pyrethroid-only ITNs (from 280 fewer cases to 135 more) (IRR = 0.90, 95%CI: 0.73–1.13). Pyrethroid-non-pyrethroid DAI ITNs demonstrated consistent reductions in malaria case incidence and other outcomes across multiple comparisons. Pyrethroid-non-pyrethroid DAI ITNs may present a novel intervention for the control of malaria.

The motivations behind China's allocation of health aid to Africa remain complex due to limited information on the details of health aid project activities. Insufficient knowledge about the purpose of China's health aid hinders our understanding of China's comprehensive role in supporting Africa's healthcare system. To address this gap, our study aimed to gain better insights into China's health aid priorities and the factors driving these priorities across Africa. To achieve this, we utilized AidData's Chinese Official Finance Dataset and adhered to the Organisation for Economic Co-operation and Development (OECD) guidelines. We reclassified all 1,026 health projects in Africa, originally categorized under broad 3-digit OECD-DAC sector codes, into more specific 5-digit CRS codes. By analyzing the project count and financial value, we assessed the shifting priorities over time. Our analysis revealed that China's priorities in health aid have evolved between 2000 and 2017. In the early 2000s, China primarily allocated aid to basic health personnel and lacked diversity in sub-sectors. However, after 2004, China shifted its focus more toward basic infrastructure and reduced emphasis on clinical-level staff. Furthermore, China's interest in addressing malaria expanded both in scale and depth between 2006 and 2009. This trend continued in 2012 and 2014 when China responded to the Ebola outbreak by shifting its focus from basic infrastructure to infectious diseases. In summary, our findings demonstrate the changes in China's health aid strategy, starting with addressing diseases already eliminated in China and gradually transitioning towards global health security, health system strengthening, and shaping the governance mechanisms.

BackgroundAntiretroviral therapy (ART) decreases perinatal HIV transmission, but concerns exist regarding maternal and infant safety. We compared the incidence of congenital malformations and other adverse outcomes in pregnancies exposed to integrase inhibitor (INSTI) versus non-INSTI ART.SettingSingle-site review of all pregnancies among women living with HIV between 2008 and 2018.MethodsWe used binomial family generalized estimating equations to model the relationship of congenital anomalies and pregnancy outcomes with exposure to INSTI or dolutegravir (DTG) versus non-INSTI ART.ResultsAmong 257 pregnancies, 77 women received ≥1 INSTI (54 DTG, 14 elvitegravir, 15 raltegravir), 167 received non-INSTI, and 3 had missing data. Fifty congenital anomalies were identified in 36 infants. Infants with first-trimester DTG or any first-trimester INSTI exposure had higher odds of congenital anomalies than infants with first-trimester non-INSTI exposure (OR = 2.55; 95%CI = 1.07-6.10; OR = 2.61; 95%CI = 1.15-5.94, respectively). Infants with INSTI exposure after the second trimester had no increased odds of anomalies. Women with INSTI exposure had higher odds of preeclampsia (OR = 4.73; 95%CI = 1.70-13.19). Among women who received INSTI, grade ≥3 laboratory abnormalities were noted in 2.6% while receiving the INSTI and 3.9% while not receiving the INSTI, versus 16.2% in women who received non-INSTI. There was no association between INSTI exposure and other pregnancy outcomes.ConclusionIn our cohort, first-trimester INSTI exposure was associated with increased rates of congenital anomalies and use of INSTI during pregnancy was associated with preeclampsia. These findings underscore the need for continued monitoring of the safety of INSTI in pregnancy.

IntroductionPrevious studies have found mixed associations between body mass index (BMI) and adolescent idiopathic scoliosis (AIS) incidence and progression. The aim of this study was to examine the association between BMI and the incidence of posterior spine fusion (PSF) among pediatric patients with AIS.MethodsThis was a retrospective cohort study of patients diagnosed with AIS at a single large tertiary care center between January 1, 2014 and December 31, 2020. BMI-for-age percentiles were used to categorize BMI into four categories: underweight (ResultsA total of 2,258 patients met the inclusion criteria with 2,113 patients (93.6%) who did not undergo PSF during the study period and 145 patients (6.4%) who did undergo PSF. At baseline, 7.3% of patients were categorized as underweight, 73.2% were healthy weight, 10.2% were overweight, and 9.3% were obese. Compared to those in the healthy weight group, there was no significant association between PSF and being underweight (adjusted odds ratio [AOR] 1.64, 95% CI 0.90-2.99, p = 0.107), being overweight (AOR 1.25, 95% CI 0.71-2.20, p = 0.436), or being obese (AOR 1.19, 95% CI 0.63-2.27, p = 0.594).ConclusionsThis study did not find a statistically significant association between underweight, overweight, or obese BMI category and incident PSF among patients with AIS. These findings add to the current mixed evidence on the relationship between BMI and surgical risk and may support the recommendation of conservative treatment to patients regardless of BMI.

IntroductionMany people with mental health problems utilise a range of complementary medicine (CM) practitioners, products, and practices. Psychologists are likely to consult with clients who are seeking and using CM, in some form, as part of their wider mental health treatment. The aim of this research is to determine how much, and in what ways, Australian psychologists recommend CM products and/or practices, and/or initiate referrals to CM practitioners as part of their clinical practice and to explore if these behaviours have any association with the characteristics of the psychologist or their wider practice.MethodsSurvey data was collected from psychologists in clinical practice who self-selected to participate between February and April 2021. Participation in the study was via an online 79-item questionnaire exploring core aspects of CM engagement in psychology clinical practice.ResultsAmongst the 202 psychologists who completed the survey, mind/body approaches (90.5%) were the most recommended CM and cultural/spiritual approaches the least recommended CM (7.5%). Participants also reported referring to CM practitioners with naturopaths the most common focus of their referrals (57.9%) and cultural and spiritual practitioners the least common focus of their referrals (6.69%). Our analysis shows the demographic and practice characteristics of a psychologist are generally not predictors of a psychologist's engagement with CM in their clinical practice.ConclusionsSubstantial numbers of psychologists recommend CM products and practices and/or refer clients to CM practitioners. Alongside subjecting CM interventions for mental health to an evidence-base assessment, the broader discipline of psychology needs to also consider psychologist engagement with CM in clinical practice in order to help ensure cultural-sensitivity, client safety and client choice.

Since 2008, spotted-wing drosophila, Drosophila suzukii, has become a major pest of soft, thin-skinned fruits in the USA, causing significant annual yield losses. Historically, the native blueberry maggot fly, Rhagoletis mendax, has been a key blueberry pest in eastern North America and a driver of insecticide usage. After its invasion in 2011 into New Jersey (USA), D. suzukii has supplanted R. mendax as the main target of insecticide applications in the state. However, the impact of D. suzukii on the native R. mendax has not been documented, particularly in relation to local climate. Historical monitoring data from New Jersey blueberry farms were used to assess the role of climate on R. mendax and D. suzukii populations. Seasonal trap captures of R. mendax adults have decreased after D. suzukii invasion, while D. suzukii trap captures have increased. Similarly, D. suzukii first captures have occurred earlier each year, while R. mendax has been captured later in the growing season. Winter freezing and summer growing degree days were found to significantly correlate with D. suzukii activity. Using downscaled climate simulations, we projected that D. suzukii will arrive in New Jersey blueberry fields up to 5 days earlier on average by 2030 and 2 weeks earlier by 2050 with warming temperatures, exacerbating yield losses and insecticide usage. As regional temperatures are projected to warm and the invasive range continues to expand, we predict the rate of phenological development of the invasive D. suzukii and its impact on native insects to change noticeably, bringing new challenges for pest management strategies.

ObjectivesCohort studies must implement effective retention strategies to produce internally valid and generalizable results. Ensuring all study participants are retained, particularly those involved in the criminal legal system, ensures study findings and future interventions will be relevant to this group, who are often lost to follow-up: critical to achieving health equity. Our objective was to characterize retention strategies and describe overall retention among an 18-month longitudinal cohort study of persons on community supervision prior to and during the COVID-19 pandemic.MethodsWe implemented various retention strategy best-practices (e.g., multiple forms of locator information, training study staff on rapport building, study-branded items). During the COVID-19 pandemic, we developed and describe new retention strategies. We calculated overall retention and analyzed differences between those retained and lost to follow-up by demographic characteristics.ResultsPrior to the start of the COVID-19 pandemic, 227 participants enrolled across three sites (N = 46 North Carolina; N = 99 Kentucky; N = 82 Florida). Of these, 180 completed the final 18-month visit, 15 were lost to follow-up, and 32 were ineligible. This resulted in an overall retention of 92.3% (180/195). While most participant characteristics did not differ by retention status, a greater proportion of those experiencing unstable housing were lost to follow-up.ConclusionOur findings highlight that when retention strategies are flexible, particularly during a pandemic, high retention is still achievable. In addition to retention best-practices (e.g., frequent requests for updated locator information) we suggest other studies consider retention strategies beyond the study participant (e.g., paying participant contacts) and incentivize on-time study visit completion (e.g., providing a bonus when completed the study visit on time).

Access to palliative care, and more specifically the alleviation of avoidable physical and psychosocial suffering is increasingly recognized as a necessary component of humanitarian response. Palliative approaches to care can meet the needs of patients for whom curative treatment may not be the aim, not just at the very end of life but alleviation of suffering more broadly. In the past several years many organizations and sectoral initiatives have taken steps to develop guidance and policies to support integration of palliative care. However, it is still regarded by many as unfeasible or aspirational in crisis contexts; particularly where care for persons with life threatening conditions or injuries is logistically, legally, and ethically challenging. This article presents a synthesis of findings from five qualitative sub-studies within a research program on palliative care provision in humanitarian crises that sought to better understand the ethical and practical dimensions of humanitarian organizations integrating palliative care into emergency responses. Our multi-disciplinary, multi-national team held 98 in-depth semi-structured interviews with people with experiences in natural disasters, refugee camps in Rwanda and Jordan, and in Ebola Treatment Centers in Guinea. Participants included patients, family members, health care workers, and other staff of humanitarian agencies. We identified four themes from descriptions of the struggles and successes of applying palliative care in humanitarian settings: justification and integration of palliative care into humanitarian response, contextualizing palliative care approaches to crisis settings, the importance of being attentive to the 'situatedness of dying', and the need for retaining a holistic approach to care. We discuss these findings in relation to the ideals embraced in palliative care and corresponding humanitarian values, concluding that palliative care in humanitarian response is essential for responding to avoidable pain and suffering in humanitarian settings.

Access to palliative care, and more specifically the alleviation of avoidable physical and psychosocial suffering is increasingly recognized as a necessary component of humanitarian response. Palliative approaches to care can meet the needs of patients for whom curative treatment may not be the aim, not just at the very end of life but alleviation of suffering more broadly. In the past several years many organizations and sectoral initiatives have taken steps to develop guidance and policies to support integration of palliative care. However, it is still regarded by many as unfeasible or aspirational in crisis contexts; particularly where care for persons with life threatening conditions or injuries is logistically, legally, and ethically challenging. This article presents a synthesis of findings from five qualitative sub-studies within a research program on palliative care provision in humanitarian crises that sought to better understand the ethical and practical dimensions of humanitarian organizations integrating palliative care into emergency responses. Our multi-disciplinary, multi-national team held 98 in-depth semi-structured interviews with people with experiences in natural disasters, refugee camps in Rwanda and Jordan, and in Ebola Treatment Centers in Guinea. Participants included patients, family members, health care workers, and other staff of humanitarian agencies. We identified four themes from descriptions of the struggles and successes of applying palliative care in humanitarian settings: justification and integration of palliative care into humanitarian response, contextualizing palliative care approaches to crisis settings, the importance of being attentive to the ‘situatedness of dying’, and the need for retaining a holistic approach to care. We discuss these findings in relation to the ideals embraced in palliative care and corresponding humanitarian values, concluding that palliative care in humanitarian response is essential for responding to avoidable pain and suffering in humanitarian settings.

BackgroundNon-medical health-related social needs (social needs) are major contributors to worse health outcomes and may have an adverse impact on cardiovascular risk factors and cardiovascular disease. The present study evaluated the effect of a closed-loop community-based pathway in reducing social needs among Black men in a lifestyle change program.MethodsBlack men (n = 70) from a large Midwestern city participated in Black Impact, a 24-week community-based team lifestyle change single-arm pilot trial adapted from the Diabetes Prevention Program and American Heart Association's (AHA) Check, Change, Control Blood Pressure Self-Management Program, which incorporates AHA's Life's Simple 7 (LS7) framework. Participants were screened using the Centers for Medicare and Medicaid Services (CMS) Accountable Health Communities Health-Related Social Needs Screening Tool. Participants with affirmative responses were referred to a community hub pathway to address social needs. The primary outcome for this analysis is change in social needs based on the CMS social needs survey at 12 and 24 weeks using mixed effect logistic regressions with random intercepts for each participant. Change in a LS7 score (range 0-14) from baseline to 12 and 24 weeks was evaluated using a linear mixed-effects model stratified by baseline social needs.ResultsAmong 70 participants, the mean age of participants was 52 ±10.5 years. The men were sociodemographically diverse, with annual income ranging from ConclusionsThe Black Impact lifestyle change single-arm pilot program showed that a referral to a closed-loop community-based hub reduced social needs in Black men. We found no association of social needs with baseline or change in LS7 scores. Further evaluation of community-based strategies to advance the attainment of LS7 and address social needs among Black men in larger trials is warranted.

PurposeBevacizumab-related imaging abnormality (BRIA), appearing as areas of restricted diffusion on magnetic resonance imaging (MRI) and representing atypical coagulative necrosis pathologically, has been observed in patients with brain tumors receiving radiotherapy and bevacizumab. We investigated the role of cumulative radiation dose in BRIA development in a voxel-wise analysis.MethodsPatients (n = 18) with BRIA were identified. All had high-grade gliomas or brain metastases treated with radiotherapy and bevacizumab. Areas of BRIA were segmented semi-automatically on diffusion-weighted MRI with apparent diffusion coefficient (ADC) images. To avoid confounding by possible tumor, hypoperfusion was confirmed with perfusion imaging. ADC images and radiation dose maps were co-registered to a high-resolution T1-weighted MRI and registration accuracy was verified. Voxel-wise normal tissue complication probability analyses were performed using a logistic model analyzing the relationship between cumulative voxel equivalent total dose in 2 Gy fractions (EQD2) and BRIA development at each voxel. Confidence intervals for regression model predictions were estimated with bootstrapping.ResultsAmong 18 patients, 39 brain tumors were treated. Patients received a median of 4.5 cycles of bevacizumab and 1-4 radiation courses prior to BRIA appearance. Most (64%) treated tumors overlapped with areas of BRIA. The median proportion of each BRIA region of interest volume overlapping with tumor was 98%. We found a dose-dependent association between cumulative voxel EQD2 and the relative probability of BRIA (β0 = -5.1, β1 = 0.03 Gy-1, γ = 1.3).ConclusionsBRIA is likely a radiation dose-dependent phenomenon in patients with brain tumors receiving bevacizumab and radiotherapy. The combination of radiation effects and tumor microenvironmental factors in potentiating BRIA in this population should be further investigated.

BackgroundAs diagnostic tests for COVID-19 were broadly deployed under Emergency Use Authorization, there emerged a need to understand the real-world utilization and performance of serological testing across the United States.MethodsSix health systems contributed electronic health records and/or claims data, jointly developed a master protocol, and used it to execute the analysis in parallel. We used descriptive statistics to examine demographic, clinical, and geographic characteristics of serology testing among patients with RNA positive for SARS-CoV-2.ResultsAcross datasets, we observed 930,669 individuals with positive RNA for SARS-CoV-2. Of these, 35,806 (4%) were serotested within 90 days; 15% of which occurred 30%) in some datasets-limiting our ability to examine differences in serological testing by race. In datasets where race/ethnicity information was available, we observed a greater distribution of White individuals among those serotested; however, the time between RNA and serology tests appeared shorter in Black compared to White individuals. Test manufacturer data was available in half of the datasets contributing to the analysis.ConclusionOur results inform the underlying context of serotesting during the first year of the COVID-19 pandemic and differences observed between claims and EHR data sources-a critical first step to understanding the real-world accuracy of serological tests. Incomplete reporting of race/ethnicity data and a limited ability to link test manufacturer data, lab results, and clinical data challenge the ability to assess the real-world performance of SARS-CoV-2 tests in different contexts and the overall U.S. response to current and future disease pandemics.