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Donkeys (Equus asinus) and mules represent approximately 50% of the entire domestic equine population in the world and play an essential role in the lives of thousands of people, primarily in developing countries [...].

INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) for HIV-1 infection is over 99% effective in protecting against HIV acquisition when used consistently and appropriately. However, PrEP uptake and persistent use remains suboptimal, with a substantial gap in utilization among key populations who could most benefit from PrEP. In Latin America specifically, there is poor understanding of barriers to PrEP uptake and persistence among transgender (trans) women. METHODS: In April-May 2018, we conducted qualitative interviews lasting 25-45 min as part of an end-of-project evaluation of TransPrEP, a pilot RCT that examined the impact of a social network-based peer support intervention on PrEP adherence among trans women in Lima, Peru. Participants in the qualitative evaluation, all adult trans women, included individuals who either (1) screened eligible to participate in the TransPrEP pilot, but opted not to enroll (n = 8), (2) enrolled, but later withdrew (n = 6), (3) were still actively enrolled at the time of interview and/or successfully completed the study (n = 16), or (4) were study staff (n = 4). Interviews were audio recorded and transcribed verbatim. Codebook development followed an immersion/crystallization approach, and coding was completed using Dedoose. RESULTS: Evaluation participants had a mean age of 28.2 years (range 19-47). When describing experiences taking PrEP, participant narratives highlighted side effects that spanned three domains: physical side effects, such as prolonged symptoms of gastrointestinal distress or somnolence; economic challenges, including lost income due to inability to work; and social concerns, including interpersonal conflicts due to HIV-related stigma. Participants described PrEP use within a broader context of social and economic marginalization, with a focus on daily survival, and how PrEP side effects negatively contributed to these stressors. Persistence was, in some cases, supported through the interventions educational workshops. CONCLUSION: This research highlights the ways that physical, economic, and social side effects of PrEP can impact acceptability and persistence among trans women in Peru, amplifying and layering onto existing stressors including economic precarity. Understanding the unique experiences of trans women taking PrEP is crucial to informing tailored interventions to improve uptake and persistence.

ImportanceUrinary tract infection (UTI) is the second most common infection leading to hospitalization and is often associated with gram-negative multidrug-resistant organisms (MDROs). Clinicians overuse extended-spectrum antibiotics although most patients are at low risk for MDRO infection. Safe strategies to limit overuse of empiric antibiotics are needed.ObjectiveTo evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO risk estimates could reduce use of empiric extended-spectrum antibiotics for treatment of UTI.Design, setting, and participantsCluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time and risk-based CPOE prompts; 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in noncritically ill adults (≥18 years) hospitalized with UTI with an 18-month baseline (April 1, 2017-September 30, 2018) and 15-month intervention period (April 1, 2019-June 30, 2020).InterventionsCPOE prompts recommending empiric standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics who have low estimated absolute risk (

ImportancePneumonia is the most common infection requiring hospitalization and is a major reason for overuse of extended-spectrum antibiotics. Despite low risk of multidrug-resistant organism (MDRO) infection, clinical uncertainty often drives initial antibiotic selection. Strategies to limit empiric antibiotic overuse for patients with pneumonia are needed.ObjectiveTo evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO infection risk estimates could reduce empiric extended-spectrum antibiotics for non-critically ill patients admitted with pneumonia.Design, setting, and participantsCluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time MDRO risk-based CPOE prompts; n = 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in non-critically ill adults (≥18 years) hospitalized with pneumonia. There was an 18-month baseline period from April 1, 2017, to September 30, 2018, and a 15-month intervention period from April 1, 2019, to June 30, 2020.InterventionCPOE prompts recommending standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics during the empiric period who have low estimated absolute risk (

Meningiomas are the most common primary intracranial tumors and can be associated with significant morbidity and mortality. Radiologists, neurosurgeons, neuro-oncologists, and radiation oncologists rely on brain MRI for diagnosis, treatment planning, and longitudinal treatment monitoring. However, automated, objective, and quantitative tools for non-invasive assessment of meningiomas on multi-sequence MR images are not available. Here we present the BraTS Pre-operative Meningioma Dataset, as the largest multi-institutional expert annotated multilabel meningioma multi-sequence MR image dataset to date. This dataset includes 1,141 multi-sequence MR images from six sites, each with four structural MRI sequences (T2-, T2/FLAIR-, pre-contrast T1-, and post-contrast T1-weighted) accompanied by expert manually refined segmentations of three distinct meningioma sub-compartments: enhancing tumor, non-enhancing tumor, and surrounding non-enhancing T2/FLAIR hyperintensity. Basic demographic data are provided including age at time of initial imaging, sex, and CNS WHO grade. The goal of releasing this dataset is to facilitate the development of automated computational methods for meningioma segmentation and expedite their incorporation into clinical practice, ultimately targeting improvement in the care of meningioma patients.

BACKGROUND: Artemisinin resistance in Plasmodium falciparum threatens global malaria elimination efforts. To contain and then eliminate artemisinin resistance in Eastern Myanmar a network of community-based malaria posts was instituted and targeted mass drug administration (MDA) with dihydroartemisinin-piperaquine (three rounds at monthly intervals) was conducted. The prevalence of artemisinin resistance during the elimination campaign (2013-2019) was characterized. METHODS: Throughout the six-year campaign Plasmodium falciparum positive blood samples from symptomatic patients and from cross-sectional surveys were genotyped for mutations in kelch-13-a molecular marker of artemisinin resistance. RESULT: The program resulted in near elimination of falciparum malaria. Of 5162 P. falciparum positive blood samples genotyped, 3281 (63.6%) had K13 mutations. The prevalence of K13 mutations was 73.9% in 2013 and 64.4% in 2019. Overall, there was a small but significant decline in the proportion of K13 mutants (p

Despite extensive research on sex/gender differences in posttraumatic stress disorder (PTSD), underlying mechanisms are still not fully understood. Here we present a systematic overview of three sex/gender-related risk pathways. We assessed 16 risk factors as well as 3-month PTSD severity in a prospective cohort study (n=2924) of acutely traumatized individuals and investigated potential mediators in the pathway between sex assigned at birth and PTSD severity using multiple mediation analysis with regularization. Six risk factors were more prevalent/severe in women, and none were more pronounced in men. Analyses showed that acute stress disorder, neuroticism, lifetime sexual assault exposure, anxiety sensitivity, and pre-trauma anxiety symptoms fully mediated and uniquely contributed to the relationship between sex assigned at birth and PTSD severity. Our results demonstrate different risk mechanisms for women and men. Such knowledge can inform targeted interventions. Our systematic approach to differential risk pathways can be transferred to other mental disorders to guide sex- and gender-sensitive mental health research.

BackgroundDetection and containment of hospital outbreaks currently depend on variable and personnel-intensive surveillance methods. Whether automated statistical surveillance for outbreaks of health care-associated pathogens allows earlier containment efforts that would reduce the size of outbreaks is unknown.MethodsWe conducted a cluster-randomized trial in 82 community hospitals within a larger health care system. All hospitals followed an outbreak response protocol when outbreaks were detected by their infection prevention programs. Half of the hospitals additionally used statistical surveillance of microbiology data, which alerted infection prevention programs to outbreaks. Statistical surveillance was also applied to microbiology data from control hospitals without alerting their infection prevention programs. The primary outcome was the number of additional cases occurring after outbreak detection. Analyses assessed differences between the intervention period (July 2019 to January 2022) versus baseline period (February 2017 to January 2019) between randomized groups. A post hoc analysis separately assessed pre-coronavirus disease 2019 (Covid-19) and Covid-19 pandemic intervention periods.ResultsReal-time alerts did not significantly reduce the number of additional outbreak cases (intervention period versus baseline: statistical surveillance relative rate [RR]=1.41, control RR=1.81; difference-in-differences, 0.78; 95% confidence interval [CI], 0.40 to 1.52; P=0.46). Comparing only the prepandemic intervention with baseline periods, the statistical outbreak surveillance group was associated with a 64.1% reduction in additional cases (statistical surveillance RR=0.78, control RR=2.19; difference-in-differences, 0.36; 95% CI, 0.13 to 0.99). There was no similarly observed association between the pandemic versus baseline periods (statistical surveillance RR=1.56, control RR=1.66; difference-in-differences, 0.94; 95% CI, 0.46 to 1.92).ConclusionsAutomated detection of hospital outbreaks using statistical surveillance did not reduce overall outbreak size in the context of an ongoing pandemic. (Funded by the Centers for Disease Control and Prevention; ClinicalTrials.gov number, NCT04053075. Support for HCA Healthcare's participation in the study was provided in kind by HCA.).

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

The historical increase in the occurrence of extreme weather events in Spain during the last thirty years makes it a perfect location for the evaluation of climate change. Modeling the effects of climate change on domestic animals genetic diversity may help to anticipate challenging situations. However, animal populations short life cycle and patent lack of historical information during extended periods of time drastically compromise the evaluation of climate change effects. Locally adapted breeds gene pool is the base for their improved resilience and plasticity in response to climate changes extreme climatic conditions. The preservation of these domestic resources offers selection alternatives to breeders who seek such improved adaptability. The Spanish endangered autochthonous Hispano-Arabian horse breed is perfectly adapted to the conditions of the territory where it was created, developed, and widespread worldwide. The possibility to trace genetic diversity in the Hispano-Arabian breed back around seven decades and its global ubiquity make this breed an idoneous reference subject to act as a model for other international populations. Climate changes shaping effects on the genetic diversity of the Hispano-Arabian horse breeds historical population were monitored from 1950 to 2019 and evaluated. Wind speed, gust speed, or barometric pressure have greater repercussions than extreme temperatures on genetic diversity. Extreme climate conditions, rather than average modifications of climate, may push breeders/owners to implement effective strategies in the short to medium term, but the effect will be plausible in the long term due to breed sustainability and enhanced capacity of response to extreme climate events. When extreme climatic conditions occur, breeders opt for mating highly diverse unrelated individuals, avoiding the production of a large number of offspring. People in charge of domestic population conservation act as catalyzers of the regulatory changes occurring during breeds climate change adaptive process and may identify genes conferring their animals with greater adaptability but still maintaining enhanced performance. This model assists in determining how owners of endangered domestic populations should plan their breeding strategies, seeking the obtention of animals more resilient and adapted to climate-extreme conditions. This efficient alternative is focused on the obtention of increased profitability from this population and in turn ensuring their sustainability.

UNLABELLED: PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.

Amyloid-β (Aβ) oligomers are implicated in the onset of Alzheimers disease (AD). Herein, quinoline-derived half-curcumin-dioxaborine (Q-OB) fluorescent probe was designed for detecting Aβ oligomers by finely tailoring the hydrophobicity of the biannulate donor motifs in donor-π-acceptor structure. Q-OB shows a great sensing potency in dynamically monitoring oligomerization of Aβ during amyloid fibrillogenesis in vitro. In addition, we applied this strategy to fluorometrically analyze Aβ self-assembly kinetics in the cerebrospinal fluids (CSF) of AD patients. The fluorescence intensity of Q-OB in AD patients CSF revealed a marked change of log (I/I0) value of 0.34 ± 0.13 (cognitive normal), 0.15 ± 0.12 (mild cognitive impairment), and 0.14 ± 0.10 (AD dementia), guiding to distinguish a state of AD continuum for early diagnosis of AD. These studies demonstrate the potential of our approach can expand the currently available preclinical diagnostic platform for the early stages of AD, aiding in the disruption of pathological progression and the development of appropriate treatment strategies.

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

BACKGROUND: Post-traumatic stress disorder (PTSD) and substance use (tobacco, alcohol, and cannabis) are highly comorbid. Many factors affect this relationship, including sociodemographic and psychosocial characteristics, other prior traumas, and physical health. However, few prior studies have investigated this prospectively, examining new substance use and the extent to which a wide range of factors may modify the relationship to PTSD. METHODS: The Advancing Understanding of RecOvery afteR traumA (AURORA) study is a prospective cohort of adults presenting at emergency departments (N = 2,943). Participants self-reported PTSD symptoms and the frequency and quantity of tobacco, alcohol, and cannabis use at six total timepoints. We assessed the associations of PTSD and future substance use, lagged by one timepoint, using the Poisson generalized estimating equations. We also stratified by incident and prevalent substance use and generated causal forests to identify the most important effect modifiers of this relationship out of 128 potential variables. RESULTS: At baseline, 37.3% (N = 1,099) of participants reported likely PTSD. PTSD was associated with tobacco frequency (incidence rate ratio (IRR): 1.003, 95% CI: 1.00, 1.01, p = 0.02) and quantity (IRR: 1.01, 95% CI: 1.001, 1.01, p = 0.01), and alcohol frequency (IRR: 1.002, 95% CI: 1.00, 1.004, p = 0.03) and quantity (IRR: 1.003, 95% CI: 1.001, 1.01, p = 0.001), but not with cannabis use. There were slight differences in incident compared to prevalent tobacco frequency and quantity of use; prevalent tobacco frequency and quantity were associated with PTSD symptoms, while incident tobacco frequency and quantity were not. Using causal forests, lifetime worst use of cigarettes, overall self-rated physical health, and prior childhood trauma were major moderators of the relationship between PTSD symptoms and the three substances investigated. CONCLUSION: PTSD symptoms were highly associated with tobacco and alcohol use, while the association with prospective cannabis use is not clear. Findings suggest that understanding the different risk stratification that occurs can aid in tailoring interventions to populations at greatest risk to best mitigate the comorbidity between PTSD symptoms and future substance use outcomes. We demonstrate that this is particularly salient for tobacco use and, to some extent, alcohol use, while cannabis is less likely to be impacted by PTSD symptoms across the strata.

After parturition, a rapid transition occurs from the intrauterine to the extrauterine milieu, exposing neonates to physiological circumstances characterized by oxidative conditions that instigate the generation of reactive oxygen species. These free radicals play pivotal roles in physiological processes; however, an imbalance between their production and the removal of antioxidants can result in severe cellular damage. The main objective of this study was to compare the oxidative and antioxidant profiles in mule and horse neonates immediately post-parturition, as well as at subsequent time points (1, 6, 12, and 24 h, 7 and 30 days) during their extrauterine existence. The parameters assessed included the systemic concentrations of Thiobarbituric Acid Reactive Substances (TBARS) and carbonyl groups; the activities of the antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx); and the levels of the total, indirect, and direct bilirubin. Our results showed no interaction effect between the neonatal groups and the assessed time points for the variables under investigation. Notably, the concentrations of TBARS, as a marker of lipid peroxidation, and bilirubin were consistently lower in the mules, whereas the glutathione peroxidase (GPx) activity exhibited higher levels in this group. The bilirubin levels were notably reduced in the mule neonates. The TBARS demonstrated a progressive decrease over the observation period in both groups, while the GPx activity remained relatively stable from birth to 7 days, with a substantial increase evident at the 30-day mark. Protein oxidation was not affected by the group and time, while for the SOD values, all times were statistically similar, except for the lower activity at T1h. Consequently, our findings lead us to the conclusion that neonatal mules and horses manifest distinct patterns of oxidative activity and antioxidant capacity during the initial month of their extrauterine existence, potentially indicative of different adaptation mechanisms to the extrauterine environment.

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [-0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.

Patients exposed to trauma often experience high rates of adverse post-traumatic neuropsychiatric sequelae (APNS). The biological mechanisms promoting APNS are currently unknown, but the microbiota-gut-brain axis offers an avenue to understanding mechanisms as well as possibilities for intervention. Microbiome composition after trauma exposure has been poorly examined regarding neuropsychiatric outcomes. We aimed to determine whether the gut microbiomes of trauma-exposed emergency department patients who develop APNS have dysfunctional gut microbiome profiles and discover potential associated mechanisms. We performed metagenomic analysis on stool samples (n = 51) from a subset of adults enrolled in the Advancing Understanding of RecOvery afteR traumA (AURORA) study. Two-, eight- and twelve-week post-trauma outcomes for post-traumatic stress disorder (PTSD) (PTSD checklist for DSM-5), normalized depression scores (PROMIS Depression Short Form 8b) and somatic symptom counts were collected. Generalized linear models were created for each outcome using microbial abundances and relevant demographics. Mixed-effect random forest machine learning models were used to identify associations between APNS outcomes and microbial features and encoded metabolic pathways from stool metagenomics. Microbial species, including Flavonifractor plautii, Ruminococcus gnavus and, Bifidobacterium species, which are prevalent commensal gut microbes, were found to be important in predicting worse APNS outcomes from microbial abundance data. Notably, through APNS outcome modeling using microbial metabolic pathways, worse APNS outcomes were highly predicted by decreased L-arginine related pathway genes and increased citrulline and ornithine pathways. Common commensal microbial species are enriched in individuals who develop APNS. More notably, we identified a biological mechanism through which the gut microbiome reduces global arginine bioavailability, a metabolic change that has also been demonstrated in the plasma of patients with PTSD.

Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.

ImportanceUniversal nasal mupirocin plus chlorhexidine gluconate (CHG) bathing in intensive care units (ICUs) prevents methicillin-resistant Staphylococcus aureus (MRSA) infections and all-cause bloodstream infections. Antibiotic resistance to mupirocin has raised questions about whether an antiseptic could be advantageous for ICU decolonization.ObjectiveTo compare the effectiveness of iodophor vs mupirocin for universal ICU nasal decolonization in combination with CHG bathing.Design, setting, and participantsTwo-group noninferiority, pragmatic, cluster-randomized trial conducted in US community hospitals, all of which used mupirocin-CHG for universal decolonization in ICUs at baseline. Adult ICU patients in 137 randomized hospitals during baseline (May 1, 2015-April 30, 2017) and intervention (November 1, 2017-April 30, 2019) were included.InterventionUniversal decolonization involving switching to iodophor-CHG (intervention) or continuing mupirocin-CHG (baseline).Main outcomes and measuresICU-attributable S aureus clinical cultures (primary outcome), MRSA clinical cultures, and all-cause bloodstream infections were evaluated using proportional hazard models to assess differences from baseline to intervention periods between the strategies. Results were also compared with a 2009-2011 trial of mupirocin-CHG vs no decolonization in the same hospital network. The prespecified noninferiority margin for the primary outcome was 10%.ResultsAmong the 801 668 admissions in 233 ICUs, the participants' mean (SD) age was 63.4 (17.2) years, 46.3% were female, and the mean (SD) ICU length of stay was 4.8 (4.7) days. Hazard ratios (HRs) for S aureus clinical isolates in the intervention vs baseline periods were 1.17 for iodophor-CHG (raw rate: 5.0 vs 4.3/1000 ICU-attributable days) and 0.99 for mupirocin-CHG (raw rate: 4.1 vs 4.0/1000 ICU-attributable days) (HR difference in differences significantly lower by 18.4% [95% CI, 10.7%-26.6%] for mupirocin-CHG, P

In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the National Institutes of Health (NIH) initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program's goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science.

Wearable optics have a broad range of uses, for example, in refractive spectacles and augmented/virtual reality devices. Despite the long-standing and widespread use of wearable optics in vision care and technology, user discomfort remains an enduring mystery. Some of this discomfort is thought to derive from optical image minification and magnification. However, there is limited scientific data characterizing the full range of physical and perceptual symptoms caused by minification or magnification during daily life. In this study, we aimed to evaluate sensitivity to changes in retinal image size introduced by wearable optics. Forty participants wore 0%, 2%, and 4% radially symmetric optical minifying lenses binocularly (over both eyes) and monocularly (over just one eye). Physical and perceptual symptoms were measured during tasks that required head movement, visual search, and judgment of world motion. All lens pairs except the controls (0% binocular) were consistently associated with increased discomfort along some dimension. Greater minification tended to be associated with greater discomfort, and monocular minification was often-but not always-associated with greater symptoms than binocular minification. Furthermore, our results suggest that dizziness and visual motion were the most reported physical and perceptual symptoms during naturalistic tasks. This work establishes preliminary guidelines for tolerances to binocular and monocular image size distortion in wearable optics.

Considerable racial/ethnic disparities persist in exposure to life stressors and socioeconomic resources that can directly affect threat neurocircuitry, particularly the amygdala, that partially mediates susceptibility to adverse posttraumatic outcomes. Limited work to date, however, has investigated potential racial/ethnic variability in amygdala reactivity or connectivity that may in turn be related to outcomes such as post-traumatic stress disorder (PTSD). Participants from the AURORA study (n = 283), a multisite longitudinal study of trauma outcomes, completed functional magnetic resonance imaging and psychophysiology within approximately two-weeks of trauma exposure. Seed-based amygdala connectivity and amygdala reactivity during passive viewing of fearful and neutral faces were assessed during fMRI. Physiological activity was assessed during Pavlovian threat conditioning. Participants also reported the severity of posttraumatic symptoms 3 and 6 months after trauma. Black individuals showed lower baseline skin conductance levels and startle compared to White individuals, but no differences were observed in physiological reactions to threat. Further, Hispanic and Black participants showed greater amygdala connectivity to regions including the dorsolateral prefrontal cortex (PFC), dorsal anterior cingulate cortex, insula, and cerebellum compared to White participants. No differences were observed in amygdala reactivity to threat. Amygdala connectivity was associated with 3-month PTSD symptoms, but the associations differed by racial/ethnic group and were partly driven by group differences in structural inequities. The present findings suggest variability in tonic neurophysiological arousal in the early aftermath of trauma between racial/ethnic groups, driven by structural inequality, impacts neural processes that mediate susceptibility to later PTSD symptoms.

Chemical genetic approaches have had a transformative impact on discovery of drug targets for malaria but have primarily been used for parasite targets. To identify human pathways required for intrahepatic development of parasite, we implemented multiplex cytological profiling of malaria infected hepatocytes treated with liver stage active compounds. Some compounds, including MMV1088447 and MMV1346624, exhibited profiles similar to cells treated with nuclear hormone receptor (NHR) agonist/antagonists. siRNAs targeting human NHRs, or their signaling partners identified eight genes that were critical for Plasmodium berghei infection. Knockdown of NR1D2, a host NHR, significantly impaired parasite growth by downregulation of host lipid metabolism. Importantly, treatment with MMV1088447 and MMV1346624 but not other antimalarials, phenocopied the lipid metabolism defect of NR1D2 knockdown. Our data underlines the use of high-content imaging for host-cellular pathway deconvolution, highlights host lipid metabolism as a drug-able human pathway and provides new chemical biology tools for studying host-parasite interactions.

BACKGROUND: Disparities in physical and mental health among Black, Indigenous, and People of Color (BIPOC) are well-documented and mirrored in the Veteran population. Chronic stress due to racism and discrimination is one possible mechanism driving these negative health outcomes. The Race-Based Stress and Trauma Empowerment (RBSTE) group is a novel, manualized, health promotion intervention designed to address the direct and indirect impacts of racism among Veterans of Color. This paper describes the protocol of the first pilot randomized controlled trial (RCT) of RBSTE. This study will examine the feasibility, acceptability, and appropriateness of RBSTE compared to an active control (an adaptation of Present-Centered Therapy; PCT) in a Veterans Affairs (VA) healthcare setting. A secondary aim is to identify and optimize strategies for holistic evaluation. METHODS: Veterans of Color (N = 48) endorsing perceived discrimination and stress will be randomized to RBSTE or PCT; both groups will be delivered in 8 weekly, 90-min virtual group sessions. Outcomes will include measures of psychological distress, discrimination and ethnoracial identity, holistic wellness, and allostatic load. Measures will be administered at baseline and post-intervention. CONCLUSION: This study will inform future interventions targeting identity-based stressors and represents an important step in advancing equity for BIPOC in medicine and research. CLINICAL TRIAL REGISTRATION NUMBER: NCT05422638.

STUDY OBJECTIVE: To derive and initially validate a brief bedside clinical decision support tool that identifies emergency department (ED) patients at high risk of substantial, persistent posttraumatic stress symptoms after a motor vehicle collision. METHODS: Derivation (n=1,282, 19 ED sites) and validation (n=282, 11 separate ED sites) data were obtained from adults prospectively enrolled in the Advancing Understanding of RecOvery afteR traumA study who were discharged from the ED after motor vehicle collision-related trauma. The primary outcome was substantial posttraumatic stress symptoms at 3 months (Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-5 ≥38). Logistic regression derivation models were evaluated for discriminative ability using the area under the curve and the accuracy of predicted risk probabilities (Brier score). Candidate posttraumatic stress predictors assessed in these models (n=265) spanned a range of sociodemographic, baseline health, peritraumatic, and mechanistic domains. The final model selection was based on performance and ease of administration. RESULTS: Significant 3-month posttraumatic stress symptoms were common in the derivation (27%) and validation (26%) cohort. The area under the curve and Brier score of the final 8-question tool were 0.82 and 0.14 in the derivation cohort and 0.76 and 0.17 in the validation cohort. CONCLUSION: This simple 8-question tool demonstrates promise to risk-stratify individuals with substantial posttraumatic stress symptoms who are discharged to home after a motor vehicle collision. Both external validation of this instrument, and work to further develop more accurate tools, are needed. Such tools might benefit public health by enabling the conduct of preventive intervention trials and assisting the growing number of EDs that provide services to trauma survivors aimed at promoting psychological recovery.

In this editorial we ask key questions about what it means to publish ‘a journal’ in a world of publishing which is driven by individual article metrics and online access. Seeing the value of journals as venues for intellectual debate, we therefore set out a renewed vision as to how the Transactions of the Institute of British Geographers can provide space for more collective and collaborative approaches to geographical debate. This approach revolves around the idea of ‘transactions’ itself and creating spaces in the journal for more commentary, debate and dialogue, alongside continuing to publish landmark papers.

IntroductionThe coronavirus disease 19 (COVID-19) pandemic has disrupted healthcare delivery including elective endoscopy. We aimed to determine the prevalence of endoscopy cancellations in the COVID-19 era and identify patient characteristics associated with cancellation due to the pandemic.MethodsMedical charts were reviewed for adults who cancelled an outpatient endoscopic procedure from 5/2020 to 8/2020. The association of patient characteristics with cancellation of endoscopy due to COVID-19 was assessed using logistic regression.ResultsThere were 652 endoscopy cancelations with 211 (32%) due to COVID-19, 384 (59%) due to non-COVID reasons, and 57 (9%) undetermined. Among COVID-19 related cancellations, 75 (36%) were COVID-19 testing logistics related, 121 (57%) were COVID-19 fear related, and 15 (7%) were other. On adjusted analysis, the odds of cancellation due to COVID-19 was significantly higher for black patients (OR 2.04, 95% CI 1.07-3.88, p = 0.03), while patients undergoing EGD (OR 0.56, 95% CI 0.31-0.99, p = 0.05) or advanced endoscopy (OR 0.18, 95% CI 0.07-0.49, p = 0.001) had lower odds of cancellation. The odds of cancelling due to COVID-19 testing logistics was significantly higher among black patients (OR 3.12, 95% CI 1.03-9.46, p = 0.05) and patients with Medi-Cal insurance (OR 2.89, 95% CI 1.21-6.89, p = 0.02).ConclusionBlack race is associated with an increased risk of COVID-19 related cancellation. Specifically, black patients and those with Medi-Cal are at increased risk of cancellation related to logistics of obtaining pre-endoscopy COVID-19 testing. Racial and socioeconomic disparities in access to endoscopy may be further amplified by the COVID-19 pandemic and warrant further study.

Adverse Childhood Experiences (ACEs) are associated with poor health yet, we know little about how distinct patterns of ACE types are associated with cardiovascular (cardiovascular (CVD)) risk factors. The current study 1) examined associations of latent ACE classes with modifiable CVD risk factors including high cholesterol, smoking, diabetes, hypertension, high triglycerides, physical inactivity, overweight/obesity, and lifetime depression; and 2) examined the impact of socioeconomic status-related (SES) factors on these relationships. Using a cross-sectional analysis of the National Epidemiologic Survey of Alcohol and Related Conditions-III (n = 36,309) data, four latent classes of ACEs were previously identified: 1) low adversity, 2) primarily household dysfunction, 3) primarily maltreatment, and 4) multiple adversity types. We examined the association of these classes with CVD risk factors in adulthood and subsequently, the same model accounting for SES-related factors. Tobacco smoking, overweight/obesity, and lifetime depression were each associated with higher odds of being in classes 2, 3, and 4 than class 1, respectively. These relationships held after adjusting for SES-related factors. Class 4 was associated with the most CVD risk factors, including high triglycerides and high cholesterol after controlling for SES-related factors. The consistent associations between tobacco smoking, overweight/obesity, and lifetime depression with each adverse ACE profile, even after controlling for SES, suggest behavioural CVD prevention programs should target these CVD risk factors simultaneously.

AIMS: Childhood adversities (CAs) predict heightened risks of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) among people exposed to adult traumatic events. Identifying which CAs put individuals at greatest risk for these adverse posttraumatic neuropsychiatric sequelae (APNS) is important for targeting prevention interventions. METHODS: Data came from n = 999 patients ages 18-75 presenting to 29 U.S. emergency departments after a motor vehicle collision (MVC) and followed for 3 months, the amount of time traditionally used to define chronic PTSD, in the Advancing Understanding of Recovery After Trauma (AURORA) study. Six CA types were self-reported at baseline: physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect and bullying. Both dichotomous measures of ever experiencing each CA type and numeric measures of exposure frequency were included in the analysis. Risk ratios (RRs) of these CA measures as well as complex interactions among these measures were examined as predictors of APNS 3 months post-MVC. APNS was defined as meeting self-reported criteria for either PTSD based on the PTSD Checklist for DSM-5 and/or MDE based on the PROMIS Depression Short-Form 8b. We controlled for pre-MVC lifetime histories of PTSD and MDE. We also examined mediating effects through peritraumatic symptoms assessed in the emergency department and PTSD and MDE assessed in 2-week and 8-week follow-up surveys. Analyses were carried out with robust Poisson regression models. RESULTS: Most participants (90.9%) reported at least rarely having experienced some CA. Ever experiencing each CA other than emotional neglect was univariably associated with 3-month APNS (RRs = 1.31-1.60). Each CA frequency was also univariably associated with 3-month APNS (RRs = 1.65-2.45). In multivariable models, joint associations of CAs with 3-month APNS were additive, with frequency of emotional abuse (RR = 2.03; 95% CI = 1.43-2.87) and bullying (RR = 1.44; 95% CI = 0.99-2.10) being the strongest predictors. Control variable analyses found that these associations were largely explained by pre-MVC histories of PTSD and MDE. CONCLUSIONS: Although individuals who experience frequent emotional abuse and bullying in childhood have a heightened risk of experiencing APNS after an adult MVC, these associations are largely mediated by prior histories of PTSD and MDE.

The authors sought to characterize adverse posttraumatic neuropsychiatric sequelae (APNS) symptom trajectories across ten symptom domains (pain, depression, sleep, nightmares, avoidance, re-experiencing, anxiety, hyperarousal, somatic, and mental/fatigue symptoms) in a large, diverse, understudied sample of motor vehicle collision (MVC) survivors. More than two thousand MVC survivors were enrolled in the emergency department (ED) and completed a rotating battery of brief smartphone-based surveys over a 2-month period. Measurement models developed from survey item responses were used in latent growth curve/mixture modeling to characterize homogeneous symptom trajectories. Associations between individual trajectories and pre-trauma and peritraumatic characteristics and traditional outcomes were compared, along with associations within and between trajectories. APNS across all ten symptom domains were common in the first two months after trauma. Many risk factors and associations with high symptom burden trajectories were shared across domains. Both across and within traditional diagnostic boundaries, APNS trajectory intercepts, and slopes were substantially correlated. Across all domains, symptom severity in the immediate aftermath of trauma (trajectory intercepts) had the greatest influence on the outcome. An interactive data visualization tool was developed to allow readers to explore relationships of interest between individual characteristics, symptom trajectories, and traditional outcomes ( http://itr.med.unc.edu/aurora/parcoord/ ). Individuals presenting to the ED after MVC commonly experience a broad constellation of adverse posttraumatic symptoms. Many risk factors for diverse APNS are shared. Individuals diagnosed with a single traditional outcome should be screened for others. The utility of multidimensional categorizations that characterize individuals across traditional diagnostic domains should be explored.

Heterogeneity and comorbidity are two interwoven challenges associated with various healthcare problems that greatly hampered research on developing effective treatment and understanding of the underlying neurobiological mechanism. Very few studies have been conducted to investigate heterogeneous causal effects (HCEs) in graphical contexts due to the lack of statistical methods. To characterize this heterogeneity, we first conceptualize heterogeneous causal graphs (HCGs) by generalizing the causal graphical model with confounder-based interactions and multiple mediators. Such confounders with an interaction with the treatment are known as moderators. This allows us to flexibly produce HCGs given different moderators and explicitly characterize HCEs from the treatment or potential mediators on the outcome. We establish the theoretical forms of HCEs and derive their properties at the individual level in both linear and nonlinear models. An interactive structural learning is developed to estimate the complex HCGs and HCEs with confidence intervals provided. Our method is empirically justified by extensive simulations and its practical usefulness is illustrated by exploring causality among psychiatric disorders for trauma survivors. Code implementing the proposed algorithm is open-source and publicly available at: https://github.com/richard-watson/ISL.

Degenerative Suspensory Ligament Desmitis (DSLD) negatively impacts connective tissues in horses, which often leads to progressive chronic pain and lameness. DSLD has been shown to be a systemic disorder that affects multiple body systems, including tendons, sclerae, and the aorta. Currently, the diagnosis is confirmed by post mortem histological examination of a tendon or suspensory ligament. Histology reveals inappropriate accumulations of proteoglycans in the tendons and other tissues in DSLD-affected horses. Unfortunately, there is no reliable method to diagnose DSLD in living horses. Recently, bone morphogenetic protein 2 (BMP2) was identified in active DSLD lesions. In addition, recent data from RNA sequencing (RNA-seq) showed overexpression of numerous genes, among them BMP2, FOS and genes for keratins in DSLD skin biopsies-derived RNA. We hypothesized that some of these genes can be used as biomarkers for diagnosis of DSLD in a panel. Overexpression of some of them was verified in quantitative real time PCR. Immunohistochemistry and RNAscope in-situ hybridization (ISH) assays were used to determine the level of overexpression of specific genes in skin biopsies from control and DSLD-affected horses. The RNAscope ISH assay has shown to be more reliable and more specific that immunohistochemistry. ISH confirmed a significant increase in KRT83 and BMP-2 in hair follicles in DSLD cases, as well as abnormally high expression of FOS in the epidermis, especially in aging horses. Because statistically relevant specificity and sensitivity was documented only for FOS and BMP2, but not KRT83 we recommend the use of FOS and BMP2 panel to diagnose DSLD. We conclude that a panel of two markers from the studied group (BMP2 and FOS) can serve as an additional diagnostic tool for DSLD in living horses, especially in older animals. Further studies are necessary to confirm if this biomarker panel could be used as a prospective tool to identify DSLD in horses as they age.

ObjectiveThe presence of macroscopic residual disease after primary cytoreductive surgery (PCS) is an important factor influencing survival for patients with high-grade serous ovarian cancer (HGSC). More research is needed to identify factors associated with having macroscopic residual disease. We analyzed 12 lifestyle and personal exposures known to be related to ovarian cancer risk or inflammation to identify those associated with having residual disease after surgery.MethodsThis analysis used data on 2054 patients with advanced stage HGSC from the Ovarian Cancer Association Consortium. The exposures were body mass index, breastfeeding, oral contraceptive use, depot-medroxyprogesterone acetate use, endometriosis, first-degree family history of ovarian cancer, incomplete pregnancy, menopausal hormone therapy use, menopausal status, parity, smoking, and tubal ligation. Logistic regression models were fit to assess the association between these exposures and having residual disease following PCS.ResultsMenopausal estrogen-only therapy (ET) use was associated with 33% lower odds of having macroscopic residual disease compared to never use (OR = 0.67, 95%CI 0.46-0.97, p = 0.033). Compared to nulliparous women, parous women who did not breastfeed had 36% lower odds of having residual disease (OR = 0.64, 95%CI 0.43-0.94, p = 0.022), while there was no association among parous women who breastfed (OR = 0.90, 95%CI 0.65-1.25, p = 0.53).ConclusionsThe association between ET and having no macroscopic residual disease is plausible given a strong underlying biologic hypothesis between this exposure and diagnosis with HGSC. If this or the parity finding is replicated, these factors could be included in risk stratification models to determine whether HGSC patients should receive PCS or neoadjuvant chemotherapy.

A central question in neuroscience is how sensory inputs are transformed into percepts. At this point, it is clear that this process is strongly influenced by prior knowledge of the sensory environment. Bayesian ideal observer models provide a useful link between data and theory that can help researchers evaluate how prior knowledge is represented and integrated with incoming sensory information. However, the statistical prior employed by a Bayesian observer cannot be measured directly, and must instead be inferred from behavioral measurements. Here, we review the general problem of inferring priors from psychophysical data, and the simple solution that follows from assuming a prior that is a Gaussian probability distribution. As our understanding of sensory processing advances, however, there is an increasing need for methods to flexibly recover the shape of Bayesian priors that are not well approximated by elementary functions. To address this issue, we describe a novel approach that applies to arbitrary prior shapes, which we parameterize using mixtures of Gaussian distributions. After incorporating a simple approximation, this method produces an analytical solution for psychophysical quantities that can be numerically optimized to recover the shapes of Bayesian priors. This approach offers advantages in flexibility, while still providing an analytical framework for many scenarios. We provide a MATLAB toolbox implementing key computations described herein.

BackgroundFailure of Alzheimer's disease and related diseases (ADRD) research studies to include and engage Black participants is a major issue, which limits the impact and generalizability of research findings. Little is known about participation of Black adults in online ADRD-related research registries.ObjectivesAs part of the Community Engaged Digital Alzheimer's Research (CEDAR) Study, this study aims to increase our understanding of facilitators and barriers of Black adults to participating in ADRD-related online registries, as well as to understand their preferences for communication channels.Design, setting, participants, measurementsWe invited all Black participants enrolled in the Brain Health Registry (BHR) to complete a cross-sectional online survey. The survey consisted of rating scales and open-text questions asking about their attitudes towards brain health research, reasons for joining and continuing to participate in BHR, difficulties with participating, and preferences for modes of contact and website usage.ResultsOf all invited Black BHR participants (N=3,636), 198 (5.5%) completed the survey. The mean age was 58.4 (SD=11.3), mean years of education were 16.3 (SD=2.4), and 85.5% identified as female. Reported facilitators for joining and continuing to participate in BHR were personal interest (e.g., learning more about own brain health) and altruism (e.g., helping research). Among additional registry features which could encourage return, receiving feedback or scores about BHR tasks was rated the highest. Of those who found BHR participation difficult (21%), the most frequent reason was time burden. The most preferred way of receiving study information was via email. Participants reported that the websites that they used the most were YouTube and Facebook.DiscussionThe results of our study can inform the development of culturally-responsive registry features and engagement efforts to improve inclusion and participation of Black adults in online ADRD research. Providing participants with feedback about their registry performance and reducing the number of registry tasks are among the recommended strategies.

Recent approval of transdermal flunixin meglumine (FM) (Banamine®) in cattle has opened the door for the drug's potential application in other species. Transdermal FM could provide a safe and effective form of pain relief in donkeys. In order to evaluate the pharmacokinetics and effects of FM on anti-inflammatory biomarkers in donkeys, a three-way crossover study design was employed. In total, 6 healthy donkeys were administered transdermal (TD) FM at a dosage of 3.3 mg/kg, and oral (PO) and intravenous (IV) doses of 1.1 mg/kg body weight. Blood samples were collected over 96 h to determine the concentration of flunixin, 5OH flunixin, and eicosanoids (TXB2 and PGF2 alpha) using LC-MS/MS. The results indicated that both flunixin and 5OH flunixin were detectable in blood samples collected during TD. The elimination of the drug was slower following the TD route compared to PO and IV. TD administration significantly decreased TXB2 levels in non-stimulated serum from 1 to 96 h post-administration, while IV and PO resulted in TXB2 reduction for 1 to 8 h. A significant reduction in PGF2 alpha was observed in PO and IV 1 h after administration, while TD resulted in a gradual decline from 4 to 72 h. The study concluded that the off-label use of transdermal FM at 3.3 mg/kg could be effective in controlling inflammation in donkeys.

Biological age, distinct from an individual's chronological age, has been studied extensively through predictive aging clocks. However, these clocks have limited accuracy in short time-scales. Here we trained deep learning models on fundus images from the EyePACS dataset to predict individuals' chronological age. Our retinal aging clocking, 'eyeAge', predicted chronological age more accurately than other aging clocks (mean absolute error of 2.86 and 3.30 years on quality-filtered data from EyePACS and UK Biobank, respectively). Additionally, eyeAge was independent of blood marker-based measures of biological age, maintaining an all-cause mortality hazard ratio of 1.026 even when adjusted for phenotypic age. The individual-specific nature of eyeAge was reinforced via multiple GWAS hits in the UK Biobank cohort. The top GWAS locus was further validated via knockdown of the fly homolog, Alk, which slowed age-related decline in vision in flies. This study demonstrates the potential utility of a retinal aging clock for studying aging and age-related diseases and quantitatively measuring aging on very short time-scales, opening avenues for quick and actionable evaluation of gero-protective therapeutics.

Introduction: Hospitals have implemented various wellness interventions to offset the negative effects of coronavirus disease 2019 (COVID-19) on emergency physician morale and burnout. There is limited high quality evidence regarding effectiveness of hospital-directed wellness interventions, leaving hospitals without guidance on best practices. We sought to determine intervention effectiveness and frequency of use in the spring/summer 2020. The goal was to facilitate evidence-based guidance for hospital wellness program planning.  Methods: This cross-sectional observational study we used a novel survey tool piloted at a single hospital and then distributed throughout the United States via major emergency medicine (EM) society listservs and closed social media groups. Subjects reported their morale levels using a slider scale from 1 (lowest) to 10 (highest) at the time of the survey and, retrospectively, at their respective COVID-19 peak in 2020. Subjects also rated effectiveness of wellness interventions using a Likert scale from 1 (not at all effective) to 5 (very effective). Subjects indicated their hospital’s usage frequency of common wellness interventions. We analyzed results using descriptive statistics and t-tests. Results: Of 76,100 EM society and closed social media group members, 522 (0.69%) subjects were enrolled. Study population demographics were similar to the national emergency physician population. Morale at the time of the survey was worse (mean [M] 4.36, SD 2.29) than the spring/summer 2020 peak (M 4.57, SD 2.13) [t(458)=-2.27, P=0.024]. The most effective interventions were hazard pay (M 3.59, SD 1.12), staff debriefing groups (M 3.51, SD 1.16), and free food (M 3.34, SD 1.14). The most frequently used interventions were free food (350/522, 67.1%), support sign display (300/522, 57.5%), and daily email updates (266/522, 51.0%). Infrequently used were hazard pay (53/522, 10.2%) and staff debriefing groups (127/522, 24.3%). Conclusion: There is discordance between the most effective and most frequently used hospital-directed wellness interventions. Only free food was both highly effective and frequently used. Hazard pay and staff debriefing groups were the two most effective interventions but were infrequently used. Daily email updates and support sign display were the most frequently used interventions but were not as effective. Hospitals should focus effort and resources on the most effective wellness interventions.

BackgroundThis study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic.MethodsCHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality.ResultsThis study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121).ConclusionCHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic.

Anxiety sensitivity, or fear of anxious arousal, is cross-sectionally associated with a wide array of adverse posttraumatic neuropsychiatric sequelae, including symptoms of posttraumatic stress disorder, depression, anxiety, sleep disturbance, pain, and somatization. The current study utilizes a large-scale, multi-site, prospective study of trauma survivors presenting to emergency departments. Hypotheses tested whether elevated anxiety sensitivity in the immediate posttrauma period is associated with more severe and persistent trajectories of common adverse posttraumatic neuropsychiatric sequelae in the eight weeks posttrauma. Participants from the AURORA study (n = 2,269 recruited from 23 emergency departments) completed self-report assessments over eight weeks posttrauma. Associations between heightened anxiety sensitivity and more severe and/or persistent trajectories of trauma-related symptoms identified by growth mixture modeling were analyzed. Anxiety sensitivity assessed two weeks posttrauma was associated with severe and/or persistent posttraumatic stress, depression, anxiety, sleep disturbance, pain, and somatic symptoms in the eight weeks posttrauma. Effect sizes were in the small to medium range in multivariate models accounting for various demographic, trauma-related, pre-trauma mental health-related, and personality-related factors. Anxiety sensitivity may be a useful transdiagnostic risk factor in the immediate posttraumatic period identifying individuals at risk for the development of adverse posttraumatic neuropsychiatric sequelae. Further, considering anxiety sensitivity is malleable via brief intervention, it could be a useful secondary prevention target. Future research should continue to evaluate associations between anxiety sensitivity and trauma-related pathology.

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q

Background and aimUp to a third of patients with inflammatory bowel disease (IBD) have elevated liver enzymes (ELE). We evaluated the incidence, predictors, and outcomes associated with ELE in a diverse and vulnerable IBD cohort.MethodsWe retrospectively evaluated 336 IBD patients receiving care at the San Francisco safety net gastroenterology clinics between June 1996 and December 2019. Baseline characteristics were captured at first visit, then patients were followed until last clinic activity or death. Testing and etiology, pattern of ELE defined as transient (

Nanotechnology-based approaches have demonstrated encouraging results for sustainable agriculture production, particularly in the field of fertilizers and pesticide innovation. It is essential to evaluate the economic and environmental benefits of these nanoformulations. Here we estimate the potential revenue gain/loss associated with nanofertilizer and/or nanopesticide use, calculate the greenhouse gas emissions change from the use of nanofertilizer and identify feasible applications and critical issues. The cost-benefit analysis demonstrates that, while current nanoformulations show promise in increasing the net revenue from crops and lowering the environmental impact, further improving the efficiency of nanoformulations is necessary for their widescale adoption. Innovating nanoformulation for targeted delivery, lowering the greenhouse gas emissions associated with nanomaterials and minimizing the content of nanomaterials in the derived nanofertilizers or pesticides can substantially improve both economic and environmental benefits.

Trauma-exposed veterans receiving mental health care may have an elevated risk of experiencing COVID-19-related difficulties. Using data from several ongoing clinical trials (N = 458), this study examined exposure to COVID-19-related stressors and their associations with key sociodemographic factors and mental health outcomes. The results showed that exposure to COVID-19-related stressors was common, higher among veterans who were racial/ethnic minorities d = 0.32, and associated with elevated posttraumatic stress disorder (PTSD), r = .288, and depressive symptom severity, r = .246. Women veterans experienced more difficulty accessing social support, d = 0.31, and higher levels of COVID-19-related distress, d = 0.31, than men. Qualitative data were consistent with survey findings and highlighted the broader societal context in veterans' experience of COVID-19-related distress. These findings may inform future research on the impact of the pandemic on veterans, particularly those who are women and members of minoritized racial/ethnic groups, as well as mental health treatment planning for this population.

The strong interaction is not well understood at low energies or for interactions with low momentum transfer. Chiral perturbation theory gives testable predictions for the nucleonic generalized polarizabilities, which are fundamental quantities describing the nucleon’s response to an external field. We report a measurement of the proton’s generalized spin polarizabilities extracted with a polarized electron beam and a polarized solid ammonia target in the region where chiral perturbation theory is expected to be valid. The investigated structure function g2 characterizes the internal spin structure of the proton. From its moments, we extract the longitudinal–transverse spin polarizability δLT and twist-3 matrix element and polarizability d2¯. Our results provide discriminating power between existing chiral perturbation theory calculations and will help provide a better understanding of this strong quantum chromodynamics regime.

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Necrosis of the nipple-areolar complex (NAC) is a major complication of breast surgery that most commonly results from venous congestion. Several conservative rescue therapies have been proposed for relieving NAC congestion, but each carries certain drawbacks, including cost and side effect profile. In this study, we evaluated the effectiveness of topical dimethyl sulfoxide (DMSO), an inexpensive compound with vasodilatory, free radical scavenging, and antiinflammatory properties in rescuing congested NACs.MethodsWe conducted a review of all 15 patients treated with DMSO for NAC congestion at our institution between May 2019 and October 2020. DMSO was applied in liquid form on a soaked gauze pad in the hospital; patients were instructed to apply a DMSO cream to the NAC twice a day following discharge. Patient characteristics and data related to DMSO treatment and NAC healing were compared via univariate analysis.ResultsEighteen congested NACs from 15 patients who underwent mastectomy, breast reduction, mastopexy, or breast reconstruction were treated with DMSO. Of the 18 treated NACs, 15 healed with DMSO treatment alone. The average length of DMSO treatment was 9.4 ± 8.5 days (mean ± standard deviation); NAC healing took place over 9.9 ± 9.6 days. There were no complications related to DMSO treatment.ConclusionsThis pilot study shows that DMSO may be an effective topical treatment for NAC congestion following breast surgery. Given its low cost, ease of application, and lack of side effects, future studies should prospectively compare DMSO against other topical treatments, like nitroglycerin ointment.

Trophic niche partitioning is observed in many adaptive radiations and is hypothesized to be a central process underlying species divergence. However, patterns of dietary niche partitioning are inconsistent across radiations and there are few studies of niche partitioning in putative examples of sympatric speciation. Here, we conducted the first quantitative study of dietary niche partitioning using stomach contents and stable isotope analyses in one of the most celebrated examples of sympatric speciation: the cichlid radiation from crater lake Barombi Mbo, Cameroon. We found little evidence for trophic niche partitioning among cichlids, including the nine species coexisting in the narrow littoral zone. Stable isotope analyses supported these conclusions of substantial dietary overlap. Our data, however, did reveal that five of eleven species consume rare dietary items, including freshwater sponge, terrestrial ants, and nocturnal foraging on shrimp. Stomach contents of the spongivore (Pungu maclareni) were 20% freshwater sponge, notable considering that only 0.04% of all fishes consume sponges. Overall, we conclude that cichlid species in lake Barombi Mbo overlap considerably in broad dietary niches-in part due to the large proportion of detritus in the stomach contents of all species-but there is evidence for divergence among species in their diet specializations on unique resources. We speculate that these species may utilize these additional specialized resources during periods of low resource abundance in support of Liem's paradox.

Understanding variation of traits within and among species through time and across space is central to many questions in biology. Many resources assemble species-level trait data, but the data and metadata underlying those trait measurements are often not reported. Here, we introduce FuTRES (Functional Trait Resource for Environmental Studies; pronounced few-tress), an online datastore and community resource for individual-level trait reporting that utilizes a semantic framework. FuTRES already stores millions of trait measurements for paleobiological, zooarchaeological, and modern specimens, with a current focus on mammals. We compare dynamically derived extant mammal species' body size measurements in FuTRES with summary values from other compilations, highlighting potential issues with simply reporting a single mean estimate. We then show that individual-level data improve estimates of body mass-including uncertainty-for zooarchaeological specimens. FuTRES facilitates trait data integration and discoverability, accelerating new research agendas, especially scaling from intra- to interspecific trait variability.