Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality.

BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).

The circularly permuted globin domain of androglobin exhibits atypical heme stabilization and nitric oxide interaction.

In the decade since the discovery of androglobin, a multi-domain hemoglobin of metazoans associated with ciliogenesis and spermatogenesis, there has been little advance in the knowledge of the biochemical and structural properties of this unusual member of the hemoglobin superfamily. Using a method for aligning remote homologues, coupled with molecular modelling and molecular dynamics, we have identified a novel structural alignment to other hemoglobins. This has led to the first stable recombinant expression and characterization of the circularly permuted globin domain. Exceptional for eukaryotic globins is that a tyrosine takes the place of the highly conserved phenylalanine in the CD1 position, a critical point in stabilizing the heme. A disulfide bond, similar to that found in neuroglobin, forms a closed loop around the heme pocket, taking the place of androglobin's missing CD loop and further supporting the heme pocket structure. Highly unusual in the globin superfamily is that the heme iron binds nitric oxide as a five-coordinate complex similar to other heme proteins that have nitric oxide storage functions. With rapid autoxidation and high nitrite reductase activity, the globin appears to be more tailored toward nitric oxide homeostasis or buffering. The use of our multi-template profile alignment method to yield the first biochemical characterisation of the circularly permuted globin domain of androglobin expands our knowledge of the fundamental functioning of this elusive protein and provides a pathway to better define the link between the biochemical traits of androglobin with proposed physiological functions.

Effect of Rural Trauma Team Development on the Outcomes of Motorcycle Accident-Related Injuries (Motor Registry Project): Protocol for a Multicenter Cluster Randomized Controlled Trial.

BACKGROUND: Injury is a global health concern, and injury-related mortality disproportionately impacts low- and middle-income countries (LMICs). Compelling evidence from observational studies in high-income countries shows that trauma education programs, such as the Rural Trauma Team Development Course (RTTDC), increase clinician knowledge of injury care. There is a dearth of such evidence from controlled clinical trials to demonstrate the effect of the RTTDC on process and patient outcomes in LMICs. OBJECTIVE: This multicenter cluster randomized controlled clinical trial aims to examine the impact of the RTTDC on process and patient outcomes associated with motorcycle accident-related injuries in an African low-resource setting. METHODS: This is a 2-arm, parallel, multi-period, cluster randomized, controlled, clinical trial in Uganda, where rural trauma team development training is not routinely conducted. We will recruit regional referral hospitals and include patients with motorcycle accident-related injuries, interns, medical trainees, and road traffic law enforcement professionals. The intervention group (RTTDC) and control group (standard care) will include 3 hospitals each. The primary outcomes will be the interval from the accident to hospital admission and the interval from the referral decision to hospital discharge. The secondary outcomes will be all-cause mortality and morbidity associated with neurological and orthopedic injuries at 90 days after injury. All outcomes will be measured as final values. We will compare baseline characteristics and outcomes at both individual and cluster levels between the intervention and control groups. We will use mixed effects regression models to report any absolute or relative differences along with 95% CIs. We will perform subgroup analyses to evaluate and control confounding due to injury mechanisms and injury severity. We will establish a motorcycle trauma outcome (MOTOR) registry in consultation with community traffic police. RESULTS: The trial was approved on August 27, 2019. The actual recruitment of the first patient participant began on September 01, 2019. The last follow-up was on August 27, 2023. Posttrial care, including linkage to clinical, social support, and referral services, is to be completed by November 27, 2023. Data analyses will be performed in Spring 2024, and the results are expected to be published in Autumn 2024. CONCLUSIONS: This trial will unveil how a locally contextualized rural trauma team development program impacts organizational efficiency in a continent challenged with limited infrastructure and human resources. Moreover, this trial will uncover how rural trauma team coordination impacts clinical outcomes, such as mortality and morbidity associated with neurological and orthopedic injuries, which are the key targets for strengthening trauma systems in LMICs where prehospital care is in the early stage. Our results could inform the design, implementation, and scalability of future rural trauma teams and trauma education programs in LMICs. TRIAL REGISTRATION: Pan African Clinical Trials Registry (PACTR202308851460352); https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=25763. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55297.

Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids.

Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.

An autoantibody signature predictive for multiple sclerosis.

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes.

Approaches to Engaging Men During Primary Healthcare Encounters: A scoping review.

Gender-responsive healthcare is critical to advancing men's health given that masculinities intersect with other social determinants to impact help-seeking, engagement with primary healthcare, and patient outcomes. A scoping review was undertaken with the aim to synthesize gender-responsive approaches used by healthcare providers (HCPs) to engage men with primary healthcare. MEDLINE, PubMed, CINAHL, and PsycINFO databases were searched for articles published between 2000 and February 2024. Titles and abstracts for 15,659 citations were reviewed, and 97 articles met the inclusion criteria. Data were extracted and analyzed thematically. Thirty-three approaches were synthesized from across counseling/psychology, general practice, social work, nursing, psychiatry, pharmacy, and unspecified primary healthcare settings. These were organized into three interrelated themes: (a) tailoring communication to reach men; (b) purposefully structuring treatment to meet men's health needs, and (c) centering the therapeutic alliance to retain men in care. Strength-based and asset-building approaches focused on reading and responding to a diversity of masculinities was reinforced across the three findings. While these approaches are recommended for the judicious integration into health practitioner education and practice, this review highlighted that the evidence remains underdeveloped, particularly for men who experience health inequities. Critical priorities for further research include intersectional considerations and operationalizing gender-responsive healthcare approaches for men and its outcomes, particularly at first point-of-contact encounters.

Differences in expression of male aggression between wild bonobos and chimpanzees.

Researchers investigating the evolution of human aggression look to our closest living relatives, bonobos (Pan paniscus) and chimpanzees (Pan troglodytes), as valuable sources of comparative data.1,2 Males in the two species exhibit contrasting patterns: male chimpanzees sexually coerce females3,4,5,6,7,8 and sometimes kill conspecifics,9,10,11,12 whereas male bonobos exhibit less sexual coercion13,14 and no reported killing.13 Among the various attempts to explain these species differences, the self-domestication hypothesis proposes negative fitness consequences of male aggression in bonobos.2,15,16 Nonetheless, the extent to which these species differ in overall rates of aggression remains unclear due to insufficiently comparable observation methods.17,18,19,20,21,22,23 We used 14 community-years of focal follow data-the gold standard for observational studies24-to compare rates of male aggression in 3 bonobo communities at the Kokolopori Bonobo Reserve, Democratic Republic of Congo, and 2 chimpanzee communities at Gombe National Park, Tanzania. As expected, given that females commonly outrank males, we found that bonobos exhibited lower rates of male-female aggression and higher rates of female-male aggression than chimpanzees. Surprisingly, we found higher rates of male-male aggression among bonobos than chimpanzees even when limiting analyses to contact aggression. In both species, more aggressive males obtained higher mating success. Although our findings indicate that the frequency of male-male aggression does not parallel species difference in its intensity, they support the view that contrary to male chimpanzees, whose reproductive success depends on strong coalitions, male bonobos have more individualistic reproductive strategies.25.

A systematic assessment of the impact of rare canonical splice site variants on splicing using functional and in silico methods.

BACKGROUND/OBJECTIVES: Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function (LoF) and are assigned very strong evidence of pathogenicity (according to ACMG criterion PVS1). The exact nature and predictability of splicing effects of unselected rare CSSVs in blood-expressed genes is poorly understood. METHODS: 168 rare CSSVs in unselected blood-expressed genes were identified by genome sequencing in 112 individuals, and their impact on splicing was interrogated manually in RNA sequencing (RNA-seq) data. Blind to these RNA-seq data, we attempted to predict the precise impact of CSSVs by applying in silico tools and the ClinGen Sequence Variant Interpretation Working Group 2018 guidelines for applying PVS1 criterion. RESULTS: There was no evidence of a frameshift nor of reduced expression consistent with nonsense-mediated decay for 25.6% of CSSVs: 17.9% had wildtype splicing only and normal junction depths, 3.6% resulted in cryptic splice site usage and in-frame indels, 3.6% resulted in full exon skipping (in-frame), and 0.6% resulted in full intron inclusion (in-frame). The predicted impact on splicing using (i) SpliceAI, (ii) MaxEntScan, and (iii) AutoPVS1, an automatic classification tool for PVS1 interpretation of null variants that utilizes Ensembl Variant Effect Predictor and MaxEntScan, was concordant with RNA-seq analyses for 65%, 63% and 61% of CSSVs, respectively. CONCLUSION: Approximately 1 in 4 rare CSSVs may not cause LoF based on analysis of RNA-seq data. Predictions from in silico methods were often discordant with findings from RNA-seq. More caution may be warranted in applying PVS1-level evidence to CSSVs in the absence of functional data.

Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

Purpose: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). Methods: We coupled phenotyping with exome or genome sequencing of 467 pedigrees with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. Results: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. Conclusion: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

Earth at risk: An urgent call to end the age of destruction and forge a just and sustainable future.

Human development has ushered in an era of converging crises: climate change, ecological destruction, disease, pollution, and socioeconomic inequality. This review synthesizes the breadth of these interwoven emergencies and underscores the urgent need for comprehensive, integrated action. Propelled by imperialism, extractive capitalism, and a surging population, we are speeding past Earth's material limits, destroying critical ecosystems, and triggering irreversible changes in biophysical systems that underpin the Holocene climatic stability which fostered human civilization. The consequences of these actions are disproportionately borne by vulnerable populations, further entrenching global inequities. Marine and terrestrial biomes face critical tipping points, while escalating challenges to food and water access foreshadow a bleak outlook for global security. Against this backdrop of Earth at risk, we call for a global response centered on urgent decarbonization, fostering reciprocity with nature, and implementing regenerative practices in natural resource management. We call for the elimination of detrimental subsidies, promotion of equitable human development, and transformative financial support for lower income nations. A critical paradigm shift must occur that replaces exploitative, wealth-oriented capitalism with an economic model that prioritizes sustainability, resilience, and justice. We advocate a global cultural shift that elevates kinship with nature and communal well-being, underpinned by the recognition of Earth's finite resources and the interconnectedness of its inhabitants. The imperative is clear: to navigate away from this precipice, we must collectively harness political will, economic resources, and societal values to steer toward a future where human progress does not come at the cost of ecological integrity and social equity.

Critical assessment of variant prioritization methods for rare disease diagnosis within the rare genomes project.

BACKGROUND: A major obstacle faced by families with rare diseases is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years and causal variants are identified in under 50%, even when capturing variants genome-wide. To aid in the interpretation and prioritization of the vast number of variants detected, computational methods are proliferating. Knowing which tools are most effective remains unclear. To evaluate the performance of computational methods, and to encourage innovation in method development, we designed a Critical Assessment of Genome Interpretation (CAGI) community challenge to place variant prioritization models head-to-head in a real-life clinical diagnostic setting. METHODS: We utilized genome sequencing (GS) data from families sequenced in the Rare Genomes Project (RGP), a direct-to-participant research study on the utility of GS for rare disease diagnosis and gene discovery. Challenge predictors were provided with a dataset of variant calls and phenotype terms from 175 RGP individuals (65 families), including 35 solved training set families with causal variants specified, and 30 unlabeled test set families (14 solved, 16 unsolved). We tasked teams to identify causal variants in as many families as possible. Predictors submitted variant predictions with estimated probability of causal relationship (EPCR) values. Model performance was determined by two metrics, a weighted score based on the rank position of causal variants, and the maximum F-measure, based on precision and recall of causal variants across all EPCR values. RESULTS: Sixteen teams submitted predictions from 52 models, some with manual review incorporated. Top performers recalled causal variants in up to 13 of 14 solved families within the top 5 ranked variants. Newly discovered diagnostic variants were returned to two previously unsolved families following confirmatory RNA sequencing, and two novel disease gene candidates were entered into Matchmaker Exchange. In one example, RNA sequencing demonstrated aberrant splicing due to a deep intronic indel in ASNS, identified in trans with a frameshift variant in an unsolved proband with phenotypes consistent with asparagine synthetase deficiency. CONCLUSIONS: Model methodology and performance was highly variable. Models weighing call quality, allele frequency, predicted deleteriousness, segregation, and phenotype were effective in identifying causal variants, and models open to phenotype expansion and non-coding variants were able to capture more difficult diagnoses and discover new diagnoses. Overall, computational models can significantly aid variant prioritization. For use in diagnostics, detailed review and conservative assessment of prioritized variants against established criteria is needed.

Chromosome-scale genome assembly of bread wheat's wild relative Triticum timopheevii.

Wheat (Triticum aestivum) is one of the most important food crops with an urgent need for increase in its production to feed the growing world. Triticum timopheevii (2n = 4x = 28) is an allotetraploid wheat wild relative species containing the At and G genomes that has been exploited in many pre-breeding programmes for wheat improvement. In this study, we report the generation of a chromosome-scale reference genome assembly of T. timopheevii accession PI 94760 based on PacBio HiFi reads and chromosome conformation capture (Hi-C). The assembly comprised a total size of 9.35 Gb, featuring a contig N50 of 42.4 Mb and included the mitochondrial and plastid genome sequences. Genome annotation predicted 166,325 gene models including 70,365 genes with high confidence. DNA methylation analysis showed that the G genome had on average more methylated bases than the At genome. In summary, the T. timopheevii genome assembly provides a valuable resource for genome-informed discovery of agronomically important genes for food security.

REPAIRS Delphi: A UK and Ireland Consensus Statement on the Management of Infected Arterial Pseudoaneurysms Secondary to Groin Injecting Drug Use.

OBJECTIVE: Consensus guidelines on the optimal management of infected arterial pseudoaneurysms secondary to groin injecting drug use are lacking. This pathology is a problem in the UK and globally, and operative management options remain contentious. This study was designed to establish consensus to promote better management of these patients, drawing on the expert experience of those in a location with a high prevalence of illicit drug use. METHODS: A three round modified Delphi was undertaken, systematically surveying consultant vascular surgeons in the UK and Ireland using an online platform. Seventy five vascular surgery units were invited to participate, with one consultant providing the unit consensus practice. Round one responses were thematically analysed to generate statements for round two. These statements were evaluated by participants using a five point Likert scale. Consensus was achieved at a threshold of 70% or more agreement or disagreement. Those statements not reaching consensus were assessed and modified for round three. The results of the Delphi process constituted the consensus statement. RESULTS: Round one received 64 (86%) responses, round two 59 (79%) responses, and round three 62 (83%) responses; 73 out of 75 (97%) units contributed. Round two comprised 150 statements and round three 24 statements. Ninety one statements achieved consensus agreement and 15 consensus disagreement. The Delphi statements covered sequential management of these patients from diagnosis and imaging, antibiotics and microbiology, surgical approach, wound management, follow up, and additional considerations. Pre-operative imaging achieved consensus agreement (97%), with computerised tomography angiogram being the modality of choice (97%). Ligation and debridement without arterial reconstruction was the preferred approach at initial surgical intervention (89%). Multidisciplinary management, ensuring holistic care and access to substance use services, also gained consensus agreement. CONCLUSION: This comprehensive consensus statement provides a strong insight into the standard of care for these patients.

The landscape of regional missense mutational intolerance quantified from 125,748 exomes.

Missense variants can have a range of functional impacts depending on factors such as the specific amino acid substitution and location within the gene. To interpret their deleteriousness, studies have sought to identify regions within genes that are specifically intolerant of missense variation 1-12 . Here, we leverage the patterns of rare missense variation in 125,748 individuals in the Genome Aggregation Database (gnomAD) 13 against a null mutational model to identify transcripts that display regional differences in missense constraint. Missense-depleted regions are enriched for ClinVar 14 pathogenic variants, de novo missense variants from individuals with neurodevelopmental disorders (NDDs) 15,16 , and complex trait heritability. Following ClinGen calibration recommendations for the ACMG/AMP guidelines, we establish that regions with less than 20% of their expected missense variation achieve moderate support for pathogenicity. We create a missense deleteriousness metric (MPC) that incorporates regional constraint and outperforms other deleteriousness scores at stratifying case and control de novo missense variation, with a strong enrichment in NDDs. These results provide additional tools to aid in missense variant interpretation.

Rural trauma team development training amongst medical trainees and traffic law enforcement professionals in a low-income country: a protocol for a prospective multicenter interrupted time series.

Background: Road traffic injuries and their resulting mortality disproportionately affect rural communities in low-middle-income countries (LMICs) due to limited human and infrastructural resources for postcrash care. Evidence from high-income countries show that trauma team development training could improve the efficiency, care, and outcome of injuries. A paucity of studies have evaluated the feasibility and applicability of this concept in resource constrained settings. The aim of this study protocol is to establish the feasibility of rural trauma team development and training in a cohort of medical trainees and traffic law enforcement professionals in Uganda. Methods: Muticenter interrupted time series of prospective interventional trainings, using the rural trauma team development course (RTTDC) model of the American College of Surgeons. A team of surgeon consultants will execute the training. A prospective cohort of participants will complete a before and after training validated trauma related multiple choice questionnaire during September 2019-November 2023. The difference in mean prepost training percentage multiple choice questionnaire scores will be compared using ANOVA-test at 95% CI. Time series regression models will be used to test for autocorrelations in performance. Acceptability and relevance of the training will be assessed using 3 and 5-point-Likert scales. All analyses will be performed using Stata 15.0. Ethical approval was obtained from Research and Ethics Committee of Mbarara University of Science and Technology (Ref: MUREC 1/7, 05/05-19) and Uganda National Council for Science and Technology (Ref: SS 5082). Retrospective registration was accomplished with Research Registry (UIN: researchregistry9490).

Molecular identification of Crimean-Congo haemorrhagic fever virus in Hyalomma rufipes and Amblyomma variegatum in the Upper East Region of Ghana.

Sampled ticks were screened for Crimean-Congo haemorrhagic fever virus (CCHFV) using an assay that targets the nucleoprotein gene region of the S segment, a conserved region of the CCHFV genome. Minimum infection rates of 0.34% and 0.10% were obtained when testing pools of Hyalomma rufipes and Amblyomma variegatum, respectively. Next-generation sequencing and phylogenetic analysis showed that the S and L segments of the CCHFV isolate clustered with those of similar isolates of genotype III. However, analysis of the M segment showed that reassortment had occurred, causing this segment to cluster with those of isolates of genotype I, providing the first evidence of such an occurrence in Ghana.

Neurosyphilis is characterized by a compartmentalized and robust neuroimmune response but not by neuronal injury.

BACKGROUND: Neurosyphilis is increasing in prevalence but its pathophysiology remains incompletely understood. This study assessed for CNS-specific immune responses during neurosyphilis compared to syphilis without neurosyphilis and compared these immune profiles to those observed in other neuroinflammatory diseases. METHODS: Participants with syphilis were categorized as having neurosyphilis if their cerebrospinal fluid (CSF)-venereal disease research laboratory (VDRL) test was reactive and as having syphilis without neurosyphilis if they had a non-reactive CSF-VDRL test and a white blood cell count <5/µL. Neurosyphilis and syphilis without neurosyphilis participants were matched by rapid plasma reagin titer and HIV status. CSF and plasma were assayed for markers of neuronal injury and glial and immune cell activation. Bulk RNA sequencing was performed on CSF cells, with results stratified by the presence of neurological symptoms. FINDINGS: CSF neopterin and five CSF chemokines had levels significantly higher in individuals with neurosyphilis compared to those with syphilis without neurosyphilis, but no markers of neuronal injury or astrocyte activation were significantly elevated. The CSF transcriptome in neurosyphilis was characterized by genes involved in microglial activation and lipid metabolism and did not differ in asymptomatic versus symptomatic neurosyphilis cases. CONCLUSIONS: The CNS immune response observed in neurosyphilis was comparable to other neuroinflammatory diseases and was present in individuals with neurosyphilis regardless of neurological symptoms, yet there was minimal evidence for neuronal or astrocyte injury. These findings support the need for larger studies of the CSF inflammatory response in asymptomatic neurosyphilis. FUNDING: This work was funded by the National Institutes of Health, grants K23MH118999 (S.F.F.) and R01NS082120 (C.M.M.).

"I'd have no idea how to go about this " - a survey of Australian medical students' perspectives on their men's health education.

BACKGROUND: While there have been calls over the last 15 years for the inclusion of training in sex and gender-based medicine in medical school curricula and to sustain such improvements through a more gender responsive health system, little progress has been made. A related objective of the Australian National Men's Health Strategy (2020-30) is to improve practitioner core learning competencies in men's health as a critical step to reducing the burden of disease in men and disparities between men in health care access and outcomes. The aim of this study was therefore to obtain Australian medical student perspectives on the extent to which men's health and sex and gender-based medicine education is delivered in their curricula, their preparedness for engaging with men in clinical practice, and the men's health content they would have found useful during their training. METHODS: Eighty-three students (48% male) from 17 accredited medical schools, and in at least their fourth year of training, completed an online survey. The survey was co-designed by a multidisciplinary team of men's health researchers and clinicians, alongside a student representative. A mix of quantitative and qualitative survey items inquired about students' preparedness for men's health clinical practice, and coverage of men's health and sex- and gender-based medicine in their curricula. RESULTS: Most students reported minimal to no men's health coverage in their medical school education (65%). While few were offered optional men's health units (10.5%), the majority would have liked more formal training on the topic (78%). Accompanying qualitative findings substantiated a lack of preparedness among medical students to engage male patients, likely stemming from minimal coverage of men's health in their medical education. CONCLUSIONS: Australian medical students may feel underprepared for contemporary men's health clinical practice, as well as, albeit to a lesser extent, women's health clinical practice. There is a clear need and desire amongst medical students to enhance curricula with sex and gender-based medicine training.

Rapid Operationalization of COVID-19 Immunization Clinics With Medical and Physician Assistant Students Serving as Vaccinators.

Introduction: In anticipation of institutional and community-wide COVID-19 immunization clinics, an educational program for the administration of COVID-19 vaccines was developed, collaborating with the Virginia Department of Health to train doctor of medicine and physician assistant students to serve as vaccinators. Faculty and students also worked with state legislatures to propose and enact a bill that would enable such students to vaccinate patients. Methods: Between January 2021 and August 2022, 263 student volunteers completed 3,685 person-hours, administering 48,279 doses. On the basis of community need, the majority of vaccines were administered at mass vaccination clinics in Chesapeake (47%) and Norfolk (22%) in Virginia. One year after the first COVID-19 immunization clinic, the authors surveyed students who assisted with clinics, utilizing a Likert scale and free-text responses to elicit feedback about the training and volunteer experience. Results: Volunteers ranked the vaccination clinics among the top third of established volunteer experiences offered at Eastern Virginia Medical School, and 75% of respondents believed that this training should be a permanent part of their program curriculum. Conclusions: This paper presents a strategy for preparing students to serve as vaccinators during public health emergencies and show how other institutions of medical education can prepare for and engage student participation in vaccination campaigns and emergent health initiatives.

Retraining transplant pharmacy staff to reduce Medicare Part B prescription billing errors post-transplant.

BACKGROUND: Medicare Part B (MedB) imposes penalties for certain errors in prescription billing of post-transplant medications, which can greatly affect pharmacy revenue. To prevent MedB billing fines, pharmacy staff must be cognizant of specific MedB requirements. OBJECTIVE: This quality improvement project aimed to retrain certified pharmacy technicians (CPhTs) on common billing errors and evaluate changes in error rates and potential fines after retraining. We aimed to determine whether retraining CPhTs minimizes MedB prescription billing errors and reduces potential fines owed by the Vanderbilt Transplant Pharmacy (VTP) to the Centers for Medicare and Medicaid Services (CMS). METHODS: This was a single-center, quality improvement study including post-transplant patients with at least one MedB prescription billing error who filled prescriptions through VTP. All CPhTs involved in MedB prescription billing received retraining focused on the top 3 errors in MedB billing identified at VTP: early refills, missing relationship of caller to patient and residence of patient on order documentation, or no day supply remaining recorded on the order file. Retraining consisted of developing a training checklist, testing current knowledge levels, individualized nonpunitive coaching based on technician specific errors, and retesting for knowledge retention. Outcomes included the number of prescriptions with at least one MedB prescription billing error and the projected amount of dollars fined owing to errors recorded during the 3 months before and 3 months after retraining. RESULTS: Fourteen CPhTs received retraining. Average refill too soon errors decreased by 37.5% (10.7% vs. 6.7%), average missing relationship by 21.7% (7.7% vs. 6%), and day supply errors by 39.7% (1.7% vs. 1%). Error reductions equaled a 28.2% decrease (approximately $12,700) in potential fines. CONCLUSION: Retraining focused on MedB billing error successfully reduced error frequency and fines from CMS. MedB billing error fines can be costly for pharmacies dispensing high-cost medications; therefore, identifying common errors and training staff can be useful and financially prudent.