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There are 11 species of triatomines in the USA, with seven reported in the American Southwest. These species are capable of transmitting Trypanosoma cruzi, the etiological agent of Chagas disease, but are generally sylvatic and rarely infect humans in the USA. iNaturalist is one of the most popular citizen science data portals, where users record encounters with any individual organism. As of November 2023, iNaturalist reported 722 confirmed triatomine observations in the American Southwest. Maximum entropy ecological niche modelling and bioclimatic environmental variables were used to predict zones of highest human-triatomine interaction. Models fit well for Triatoma protracta (0.85), T. rubida (0.94), and T. recurva (0.96). Precipitation in the warmest quarter was most predictive of T. protracta presence, while precipitation in the driest quarter was most predictive of T. rubida and T. recurva. Locations identified in the American Southwest with highest potential for human-triatomine interaction, and potential T. cruzi transmission, were coastal California, the Sierra Nevada foothills, southern Arizona and border areas of northern Mexico. Study findings can be used for targeted surveillance efforts to address the paucity of contemporary information regarding triatomine species diversity and geographical and ecological associations in the American Southwest., (© 2024. The Author(s).)

Cisplatin is a commonly used chemotherapy agent with a nearly universal side effect of sensorineural hearing loss. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate (STS), while beneficial when used in standard risk hepatoblastoma, is associated with reduced survival in disseminated pediatric malignancy, highlighting the need for more specific drugs without potential tumor protective effects. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo, and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin, and UPR marker gene expression and cell death measured. Treatment with ISRIB (Integrated Stress Response InhIBitor), a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested for its ability to reduce apoptosis in HEK cells, hair-cell death in cochlear cultures, and hearing loss using an in vivo mouse model of cisplatin ototoxicity. Finally, to evaluate whether ISRIB might interfere with cisplatin chemoeffectiveness, we tested it in head and neck squamous cell carcinoma (HNSCC) cell-based assays of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose-response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact cisplatin's cytotoxic effects on HNSCC cell viability, unlike STS. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development., (© 2024. The Author(s).)

All-cause COVID-19 hospitalization ≤ 30 days of infection is a common outcome for severe illness in observational/surveillance studies. Milder COVID-19 disease and COVID-19-specific measurements calls for an evaluation of this endpoint. This was a descriptive, retrospective cohort study of adults ≥ 18 who were established in primary care at Veteran Health Administration (VHA) facilities. The outcome was hospitalization within 30 days of a laboratory-confirmed, symptomatic SARS-CoV-2 infection. Between December 15, 2021 and May 1, 2022, a simple random sample of all VA facilities, excluding Puerto Rico or Philippines, was drawn to identify these hospitalized cases and determine whether hospitalization was due to COVID-19-specific causes. A chart review was conducted to record the inpatient clinical team's diagnosis and whether the inpatient team classified the diagnosis as COVID-19 related or not. These data were used to classify hospitalizations as either due to COVID-19-specific causes (direct manifestations of SARS-CoV-2 infection) or non-COVID-19-specific hospitalizations (incidental SARS-CoV-2 infection), A simple random sample of 9966 (12.3%) all-cause hospitalizations (95% CI: 12.1%, 12.5%) was used to select 300 representative patients. Of these, 226/300 (75.3%) were determined to be COVID-19-specific. COVID-19 pneumonia was most common (147/226, 65.0%). The highest proportion of COVID-19-specific hospitalizations occurred among unvaccinated (85.0%), followed by vaccinated but not boosted (73.7%) and boosted (59.4%) (p < 0.001). The proportion of non-COVID-19-specific hospitalizations was higher in the later period (15-30 days: 55.0%) than the early (0-15 days: 22.5%) (p = 0.003). This study supports the outcome of COVID-19-specific hospitalization instead of all-cause hospitalization in observational studies. The earlier outcome period (0-15 days) was less susceptible to potential measurement bias., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of antigens. In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface antigens that could be targeted by antibodies and chimeric antigen receptor-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas) and 9166 normal tissue samples (from the Genotype-Tissue Expression project), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative antigens. Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue., (© 2024. The Author(s).)

Exposure to both oxidative and shear stress, a condition that the red blood cell (RBC) continuously experiences in the circulation in vivo can be mimicked in a Couette type viscometer and monitored by ektacytometry. RBCs maintain their deformation and orientation under shear stress and oxidative stress until a threshold is reached at which these conditions appear to overwhelm the elaborate and complex pathways that maintain a proper redox environment in the cell. Oxidative stress under shear alters the ability of the cell to deform, changes cell morphology, its orientation in the shear stress field, and appears to alter intracellular and membrane characteristics. The application of the RoxyScan technology allows the comparison of oxidant effects and the role of antioxidant systems. This provides the opportunity to study the ability of RBC to deal with oxidative stress in various conditions, including RBC disorders such as sickle cell disease (SCD)., (© 2024. The Author(s).)

Telomere length (TL) is a marker of biological aging, and shorter telomeres have been associated with several medical and psychiatric disorders, including cardiometabolic dysregulation and Major Depressive Disorder (MDD). In addition, studies have shown shorter TL to be associated with poorer response to certain psychotropic medications, and our previous work suggested shorter TL and higher telomerase activity (TA) predicts poorer response to Selective Serotonin Reuptake Inhibitor (SSRI) treatment. Using a new group of unmedicated medically healthy individuals with MDD (n = 48), we sought to replicate our prior findings demonstrating that peripheral blood mononuclear cell (PBMC) TL and TA predict response to SSRI treatment and to identify associations between TL and TA with biological stress mediators and cardiometabolic risk indices. Our results demonstrate that longer pre-treatment TL was associated with better response to SSRI treatment (β = .407 p = .007). Additionally, we observed that TL had a negative relationship with allostatic load (β = - .320 p = .017) and a cardiometabolic risk score (β = - .300 p = .025). Our results suggest that PBMC TL reflects, in part, the cumulative effects of physiological stress and cardiovascular risk in MDD and may be a biomarker for predicting SSRI response., (© 2023. The Author(s).)

Electroencephalography (EEG) can detect changes in cerebral activity during spaceflight. This study evaluates the effect of spaceflight on brain networks through analysis of the Default Mode Network (DMN)'s alpha frequency band power and functional connectivity (FC), and the persistence of these changes. Five astronauts' resting state EEGs under three conditions were analyzed (pre-flight, in-flight, and post-flight). DMN's alpha band power and FC were computed using eLORETA and phase-locking value. Eyes-opened (EO) and eyes-closed (EC) conditions were differentiated. We found a DMN alpha band power reduction during in-flight (EC: p < 0.001; EO: p < 0.05) and post-flight (EC: p < 0.001; EO: p < 0.01) when compared to pre-flight condition. FC strength decreased during in-flight (EC: p < 0.01; EO: p < 0.01) and post-flight (EC: ns; EO: p < 0.01) compared to pre-flight condition. The DMN alpha band power and FC strength reduction persisted until 20 days after landing. Spaceflight caused electrocerebral alterations that persisted after return to earth. Periodic assessment by EEG-derived DMN analysis has the potential to become a neurophysiologic marker of cerebral functional integrity during exploration missions to space., (© 2023. The Author(s).)

Multiple types and classes of medications are administered in the acute management of traumatic spinal cord injury. Prior clinical studies and evidence from animal models suggest that several of these medications could modify (i.e., enhance or impede) neurological recovery. We aimed to systematically determine the types of medications commonly administered, alone or in combination, in the transition from acute to subacute spinal cord injury. For that purpose, type, class, dosage, timing, and reason for administration were extracted from two large spinal cord injury datasets. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. Across 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in a clinical trial were administered 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Those enrolled in an observational study were administered on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections). To our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, raising the potential to impact neurological recovery. All results can be interactively explored on the R X SCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ )., (© 2023. The Author(s).)

Individuals with autism spectrum disorder (ASD) present difficulties in integrating mental state information in complex moral tasks. Yet, ASD research has not examined whether this process is influenced by emotions, let alone while capturing its neural bases. We investigated how language-induced emotions modulate intent-based moral judgment in ASD. In a fMRI task, 30 adults with ASD and 27 neurotypical controls read vignettes whose protagonists commit harm either accidentally or intentionally, and then decided how much punishment the protagonist deserved. Emotional content was manipulated across scenarios through the use of graphic language (designed to trigger arousing negative responses) vs. plain (just-the-facts, emotionless) language. Off-line functional connectivity correlates of task performance were also analyzed. In ASD, emotional (graphic) descriptions amplified punishment ratings of accidental harms, associated with increased activity in fronto-temporo-limbic, precentral, and postcentral/supramarginal regions (critical for emotional and empathic processes), and reduced connectivity among the orbitofrontal cortex and the angular gyrus (involved in mentalizing). Language manipulation did not influence intentional harm processing in ASD. In conclusion, in arousing and ambiguous social situations that lack intentionality clues (i.e. graphic accidental harm scenarios), individuals with ASD would misuse their emotional responses as the main source of information to guide their moral decisions. Conversely, in face of explicit harmful intentions, they would be able to compensate their socioemotional alterations and assign punishment through non-emotional pathways. Despite limitations, such as the small sample size and low ecological validity of the task, results of the present study proved reliable and have relevant theoretical and translational implications., (© 2023. The Author(s).)

The Trail Making Test (TMT) is one of the most popular neuropsychological tests for executive functions (EFs) assessment. It presents several strengths: it is sensitive to executive dysfunction, it is easy to understand, and has a short administration. However, it has important limitations. First, the underlying EFs articulated during the task are not well discriminated, which makes it a test with low specificity. Second, the pen-and-paper version presents one trial per condition which introduces high variability. Third, only the total time is quantified, which does not allow for a detailed analysis. Fourth, it has a fixed spatial configuration per condition. We designed a computerised version of the TMT to overcome its main limitations and evaluated it in a group of neurotypical adults. Eye and hand positions are measured with high resolution over several trials, and spatial configuration is controlled. Our results showed a very similar performance profile compared to the traditional TMT. Moreover, it revealed differences in eye movements between parts A and B. Most importantly, based on hand and eye movements, we found an internal working memory measure that showed an association to a validated working memory task. Additionally, we proposed another internal measure as a potential marker of inhibitory control. Our results showed that EFs can be studied in more detail using traditional tests combined with powerful digital setups. The cTMT showed potential use in older adult populations and patients with EFs disorders., (© 2022. The Author(s).)

Variability in response to short-acting β 2 -agonists (e.g., albuterol) among patients with asthma from diverse racial/ethnic groups may contribute to asthma disparities. We sought to identify genetic variants associated with bronchodilator response (BDR) to identify potential mechanisms of drug response and risk factors for worse asthma outcomes. Genome-wide association studies of bronchodilator response (BDR) were performed using TOPMed Whole Genome Sequencing data of the Asthma Translational Genomic Collaboration (ATGC), which corresponded to 1136 Puerto Rican, 656 Mexican and 4337 African American patients with asthma. With the population-specific GWAS results, a trans-ethnic meta-analysis was performed to identify BDR-associated variants shared across the three populations. Replication analysis was carried out in three pediatric asthma cohorts, including CAMP (Childhood Asthma Management Program; n = 560), GACRS (Genetics of Asthma in Costa Rica Study; n = 967) and HPR (Hartford-Puerto Rico; n = 417). A genome-wide significant locus (rs35661809; P = 3.61 × 10 -8 ) in LINC02220, a non-coding RNA gene, was identified in Puerto Ricans. While this region was devoid of protein-coding genes, capture Hi-C data showed a distal interaction with the promoter of the DNAH5 gene in lung tissue. In replication analysis, the GACRS cohort yielded a nominal association (1-tailed P < 0.05). No genetic variant was associated with BDR at the genome-wide significant threshold in Mexicans and African Americans. Our findings help inform genetic underpinnings of BDR for understudied minority patients with asthma, but the limited availability of genetic data for racial/ethnic minority children with asthma remains a paramount challenge., (© 2022. The Author(s).)

Our objective was to develop deep learning models with chest radiograph data to predict healthcare costs and classify top-50% spenders. 21,872 frontal chest radiographs were retrospectively collected from 19,524 patients with at least 1-year spending data. Among the patients, 11,003 patients had 3 years of cost data, and 1678 patients had 5 years of cost data. Model performances were measured with area under the receiver operating characteristic curve (ROC-AUC) for classification of top-50% spenders and Spearman ρ for prediction of healthcare cost. The best model predicting 1-year (N = 21,872) expenditure achieved ROC-AUC of 0.806 [95% CI 0.793-0.819] for top-50% spender classification and ρ of 0.561 [0.536-0.586] for regression. Similarly, for predicting 3-year (N = 12,395) expenditure, ROC-AUC of 0.771 [0.750-0.794] and ρ of 0.524 [0.489-0.559]; for predicting 5-year (N = 1779) expenditure ROC-AUC of 0.729 [0.667-0.729] and ρ of 0.424 [0.324-0.529]. Our deep learning model demonstrated the feasibility of predicting health care expenditure as well as classifying top 50% healthcare spenders at 1, 3, and 5 year(s), implying the feasibility of combining deep learning with information-rich imaging data to uncover hidden associations that may allude to physicians. Such a model can be a starting point of making an accurate budget in reimbursement models in healthcare industries., (© 2022. The Author(s).)

Socioeconomic status (SES) negatively impacts cognitive and executive functioning in older adults, yet its effects on socioemotional abilities have not been studied in this population. Also, evidence on neurocognitive processes associated with ageing primarily comes from Western, educated, industrialized, rich, and democratic (WEIRD) populations, hindering the generalization of findings to persons from upper-middle- and low-middle-income countries, such as those of Latin America. Here, we compared the performance of low- and high-SES older adults from Argentina in cognitive state, executive functions, social cognition (emotion recognition and theory of mind), and counter-empathic social emotions (envy and Schadenfreude; displeasure at others' fortune and pleasure at others' misfortune, respectively). Subsequently, we developed a path analysis to test the relationship among those variables in a theoretically plausible model and tested the main paths via multiple regression analyses. Relative to the high-SES group, low-SES older adults showed poorer performance on all assessed domains. Convergent evidence from covariance analysis, path analysis, and linear regressions suggested that low-SES impact on socioemotional processes was not primary but mediated by cognitive and executive impairment. These findings offer the first characterization of SES impacts on cognitive and socioemotional processes in a non-WEIRD population and have relevant equity-related implications for brain health., (© 2022. The Author(s).)

Glioblastoma (GBM) is the most common primary brain tumor with a median survival under two years. Using in silico and in vitro techniques, we demonstrate heterogeneous expression of CD97, a leukocyte adhesion marker, in human GBM. Beyond its previous demonstrated role in tumor invasion, we show that CD97 is also associated with upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways in GBM. While CD97 knockout decreased Akt activation, CD97 targeting did not alter MAPK/Erk activation, did not slow GBM cell proliferation in culture, and increased levels of glycolytic and oxidative phosphorylation metabolites. Treatment with a soluble CD97 inhibitor did not alter activation of the MAPK/Erk and PI3K/Akt pathways. Tumors with high CD97 expression were associated with immune microenvironment changes including increased naïve macrophages, regulatory T cells, and resting natural killer (NK) cells. These data suggest that, while CD97 expression is associated with conflicting effects on tumor cell proliferative and metabolic pathways that overall do not affect tumor cell proliferation, CD97 exerts pro-tumoral effects on the tumor immune microenvironment, which along with the pro-invasive effects of CD97 we previously demonstrated, provides impetus to continue exploring CD97 as a therapeutic target in GBM., (© 2022. The Author(s).)

Mental imagery is the process through which we retrieve and recombine information from our memory to elicit the subjective impression of "seeing with the mind's eye". In the social domain, we imagine other individuals while recalling our encounters with them or modelling alternative social interactions in future. Many studies using imaging and neurophysiological techniques have shown several similarities in brain activity between visual imagery and visual perception, and have identified frontoparietal, occipital and temporal neural components of visual imagery. However, the neural connectivity between these regions during visual imagery of socially relevant stimuli has not been studied. Here we used electroencephalography to investigate neural connectivity and its dynamics between frontal, parietal, occipital and temporal electrodes during visual imagery of faces. We found that voluntary visual imagery of faces is associated with long-range phase synchronisation in the gamma frequency range between frontoparietal electrode pairs and between occipitoparietal electrode pairs. In contrast, no effect of imagery was observed in the connectivity between occipitotemporal electrode pairs. Gamma range synchronisation between occipitoparietal electrode pairs predicted subjective ratings of the contour definition of imagined faces. Furthermore, we found that visual imagery of faces is associated with an increase of short-range frontal synchronisation in the theta frequency range, which temporally preceded the long-range increase in the gamma synchronisation. We speculate that the local frontal synchrony in the theta frequency range might be associated with an effortful top-down mnemonic reactivation of faces. In contrast, the long-range connectivity in the gamma frequency range along the fronto-parieto-occipital axis might be related to the endogenous binding and subjective clarity of facial visual features.

Blood protein concentrations are clinically useful, predictive biomarkers of cardiovascular disease (CVD). Despite a higher burden of CVD among U.S. South Asians, no CVD-related proteomics study has been conducted in this sub-population. The aim of this study is to investigate the associations between plasma protein levels and CVD incidence, and to assess the potential influence of religiosity/spirituality (R/S) on significant protein-CVD associations, in South Asians from the MASALA Study. We used a nested case-control design of 50 participants with incident CVD and 50 sex- and age-matched controls. Plasma samples were analyzed by SOMAscan for expression of 1305 proteins. Multivariable logistic regression models and model selection using Akaike Information Criteria were performed on the proteins and clinical covariates, with further effect modification analyses conducted to assess the influence of R/S measures on significant associations between proteins and incident CVD events. We identified 36 proteins that were significantly expressed differentially among CVD cases compared to matched controls. These proteins are involved in immune cell recruitment, atherosclerosis, endothelial cell differentiation, and vascularization. A final multivariable model found three proteins (Contactin-5 [CNTN5], Low affinity immunoglobulin gamma Fc region receptor II-a [FCGR2A], and Complement factor B [CFB]) associated with incident CVD after adjustment for diabetes (AUC = 0.82). Religious struggles that exacerbate the adverse impact of stressful life events, significantly modified the effect of Contactin-5 and Complement factor B on risk of CVD. Our research is this first assessment of the relationship between protein concentrations and risk of CVD in a South Asian sample. Further research is needed to understand patterns of proteomic profiles across diverse ethnic communities, and the influence of resources for resiliency on proteomic signatures and ultimately, risk of CVD.

There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its receptor tropomyosin receptor kinase A (TrkA) during tibial fracture repair, finding that they peak during the cartilaginous phase. We then tested two injection regimens and found that local β-NGF injections during the endochondral/cartilaginous phase promoted osteogenic marker expression. Gene expression data from β-NGF stimulated cartilage callus explants show a promotion in markers associated with endochondral ossification such as Ihh, Alpl, and Sdf-1. Gene ontology enrichment analysis revealed the promotion of genes associated with Wnt activation, PDGF- and integrin-binding. Subsequent histological analysis confirmed Wnt activation following local β-NGF injections. Finally, we demonstrate functional improvements to bone healing following local β-NGF injections which resulted in a decrease in cartilage and increase of bone volume. Moreover, the newly formed bone contained higher trabecular number, connective density, and bone mineral density. Collectively, we demonstrate β-NGF's ability to promote endochondral repair in a murine model and uncover mechanisms that will serve to further understand the molecular switches that occur during cartilage to bone transformation.

Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate levels of acoustic overstimulation associated with tinnitus and impaired speech perception cause cochlear synaptopathy, characterized physiologically by reduction in wave I of the suprathreshold auditory brainstem response (ABR) and reduced number of synapses between sensory hair cells and auditory neurons. The unfolded protein response (UPR), an endoplasmic reticulum stress response pathway, has been implicated in the pathogenesis and treatment of NIHL as well as neurodegeneration and synaptic damage in the brain. In this study, we used the small molecule UPR modulator Integrated Stress Response InhiBitor (ISRIB) to treat noise-induced cochlear synaptopathy in a mouse model. Mice pretreated with ISRIB prior to noise-exposure were protected against noise-induced synapse loss. Male, but not female, mice also exhibited ISRIB-mediated protection against noise-induced suprathreshold ABR wave-I amplitude reduction. Female mice had higher baseline wave-I amplitudes but greater sensitivity to noise-induced wave-I reduction. Our results suggest that the UPR is implicated in noise-induced cochlear synaptopathy, and can be targeted for treatment.

Whole genome sequencing (WGS) has enabled the discovery of genomic structural variants (SVs), including those targeting intergenic and intronic non-coding regions that eluded previous exome focused strategies. However, the field currently lacks an automated tool that analyzes SV candidates to identify recurrent SVs and their targeted sites (hotspot regions), visualizes these genomic events within the context of various functional elements, and evaluates their potential effect on gene expression. To address this, we developed SV-HotSpot, an automated tool that integrates SV candidates, copy number alterations, gene expression, and genome annotations (e.g. gene and regulatory elements) to discover, annotate, and visualize recurrent SVs and their targeted hotspot regions that may affect gene expression. We applied SV-HotSpot to WGS and matched transcriptome data from metastatic castration resistant prostate cancer patients and rediscovered recurrent SVs targeting coding and non-coding functional elements known to promote prostate cancer progression and metastasis. SV-HotSpot provides a valuable resource to integrate SVs, gene expression, and genome annotations for discovering biologically relevant SVs altering coding and non-coding genome. SV-HotSpot is available at https://github.com/ChrisMaherLab/SV-HotSpot .

Polytraumatic injuries, specifically long bone fracture and traumatic brain injury (TBI), frequently occur together. Clinical observation has long held that TBI can accelerate fracture healing, yet the complexity and heterogeneity of these injuries has produced conflicting data with limited information on underlying mechanisms. We developed a murine polytrauma model with TBI and fracture to evaluate healing in a controlled system. Fractures were created both contralateral and ipsilateral to the TBI to test whether differential responses of humoral and/or neuronal systems drove altered healing patterns. Our results show increased bone formation after TBI when injuries occur contralateral to each other, rather than ipsilateral, suggesting a role of the nervous system based on the crossed neuroanatomy of motor and sensory systems. Analysis of the humoral system shows that blood cell counts and inflammatory markers are differentially modulated by polytrauma. A data-driven multivariate analysis integrating all outcome measures showed a distinct pathological state of polytrauma and co-variations between fracture, TBI and systemic markers. Taken together, our results suggest that a contralateral bone fracture and TBI alter the local neuroinflammatory state to accelerate early fracture healing. We believe applying a similar data-driven approach to clinical polytrauma may help to better understand the complicated pathophysiological mechanisms of healing.