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Background: Hospitalisation can be a traumatic experience, where inpatients are exposed to an abundance of physical and psychological stressors. Evidence suggests that these hospital-related stressors negatively impact health: a phenomenon known as post-hospital syndrome. The current study aimed to identify hospital-related stressors, and to develop and provide initial validation for a new measure of in-hospital stress.Methods: Measure development occurred in three stages: (i) semi-structured interviews, (ii) item generation, and (iii) pilot testing. Twenty-one patients were interviewed regarding their recent hospital experiences, and a list of hospital-related stressors was produced. These stressors were compiled into a questionnaire and piloted on 200 recent inpatients to provide initial evidence of internal consistency and construct validity.Results: Stressors identified from the interviews captured all relevant questions from three previous hospital stress measures, plus 12 more. The most reported stressor was ‘poor sleep’. These hospital-related stressors were developed into 67 questions, forming the Hospital Stress Questionnaire (HSQ). The HSQ showed excellent internal consistency and construct validity, and correlated with feelings of vulnerability and being unprepared to go home.Conclusion: The HSQ is a promising self-report tool for measuring in-hospital stress. Future research ought to investigate its psychometric properties further in larger and more diverse samples. The measure has potential to be used to monitor patient risk of post-hospital syndrome.

With the generation of spatially resolved transcriptomics of microbial biofilms, computational tools can be used to integrate this data to elucidate the multi-scale mechanisms controlling heterogeneous biofilm metabolism. This work presents a Multi-scale model of Metabolism In Cellular Systems (MiMICS) which is a computational framework that couples a genome-scale metabolic network reconstruction (GENRE) with Hybrid Automata Library (HAL), an existing agent-based model and reaction-diffusion model platform. A key feature of MiMICS is the ability to incorporate multiple -omics-guided metabolic models, which can represent unique metabolic states that yield different metabolic parameter values passed to the extracellular models. We used MiMICS to simulate Pseudomonas aeruginosa regulation of denitrification and oxidative stress metabolism in hypoxic and nitric oxide (NO) biofilm microenvironments. Integration of P. aeruginosa PA14 biofilm spatial transcriptomic data into a P. aeruginosa PA14 GENRE generated four PA14 metabolic model states that were input into MiMICS. Characteristic of aerobic, denitrification, and oxidative stress metabolism, the four metabolic model states predicted different oxygen, nitrate, and NO exchange fluxes that were passed as inputs to update the agent's local metabolite concentrations in the extracellular reaction-diffusion model. Individual bacterial agents chose a PA14 metabolic model state based on a combination of stochastic rules, and agents sensing local oxygen and NO. Transcriptome-guided MiMICS predictions suggested microscale denitrification and oxidative stress metabolic heterogeneity emerged due to local variability in the NO biofilm microenvironment. MiMICS accurately predicted the biofilm's spatial relationships between denitrification, oxidative stress, and central carbon metabolism. As simulated cells responded to extracellular NO, MiMICS revealed dynamics of cell populations heterogeneously upregulating reactions in the denitrification pathway, which may function to maintain NO levels within non-toxic ranges. We demonstrated that MiMICS is a valuable computational tool to incorporate multiple -omics-guided metabolic models to mechanistically map heterogeneous microbial metabolic states to the biofilm microenvironment.

Abstract Background The opioid crisis continues in full force, as physicians and caregivers are desperate for resources to help patients with opioid use and chronic pain disorders find safer and more accessible non-opioid tools. Main body The purpose of this article is to review the current state of the opioid epidemic; the shifting picture of cannabinoids; and the research, policy, and current events that make opioid risk reduction an urgent public health challenge. The provided table contains an evidence-based clinical framework for the utilization of cannabinoids to treat patients with chronic pain who are dependent on opioids, seeking alternatives to opioids, and tapering opioids. Conclusion Based on a comprehensive review of the literature and epidemiological evidence to date, cannabinoids stand to be one of the most interesting, safe, and accessible tools available to attenuate the devastation resulting from the misuse and abuse of opioid narcotics. Considering the urgency of the opioid epidemic and broadening of cannabinoid accessibility amidst absent prescribing guidelines, the authors recommend use of this clinical framework in the contexts of both clinical research continuity and patient care.

In biliary tract cancer HER2 alterations correlate with poor prognosis. Here, the authors present the results of a phase II clinical trial reporting the efficacy and safety of the tyrosine kinase inhibitor neratinib in patients with HER2-mutation positive advanced biliary tract cancers.

Long COVID (LongC) is associated with a myriad of symptoms including cognitive impairment. We reported at the beginning of the COVID-19 pandemic that neuronal-enriched or L1CAM+ extracellular vesicles (nEVs) from people with LongC contained proteins associated with Alzheimer’s disease (AD). Since that time, a subset of people with prior COVID infection continue to report neurological problems more than three months after infection. Blood markers to better characterize LongC are elusive. To further identify neuronal proteins associated with LongC, we maximized the number of nEVs isolated from plasma by developing a hybrid EV Microfluidic Affinity Purification (EV-MAP) technique. We isolated nEVs from people with LongC and neurological complaints, AD, and HIV infection with mild cognitive impairment. Using the OLINK platform that assesses 384 neurological proteins, we identified 11 significant proteins increased in LongC and 2 decreased (BST1, GGT1). Fourteen proteins were increased in AD and forty proteins associated with HIV cognitive impairment were elevated with one decreased (IVD). One common protein (BST1) was decreased in LongC and increased in HIV. Six proteins (MIF, ENO1, MESD, NUDT5, TNFSF14 and FYB1) were expressed in both LongC and AD and no proteins were common to HIV and AD. This study begins to identify differences and similarities in the neuronal response to LongC versus AD and HIV infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1β was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.

In kilonovae, freshly synthesized r -process elements imprint features on optical spectra, as observed in AT2017gfo, the counterpart to the GW170817 binary neutron star merger. However, measuring the r -process compositions of the merger ejecta is computationally challenging. Vieira et al. introduced Spectroscopic r -process Abundance Retrieval for Kilonovae ( SPARK ), a software tool to infer elemental abundance patterns of the ejecta and associate spectral features with particular species. Previously, we applied SPARK to the 1.4-day spectrum of AT2017gfo and inferred its abundance pattern for the first time, characterized by electron fraction Y _e = 0.31, a substantial abundance of strontium, and a dearth of lanthanides and heavier elements. This ejecta is consistent with wind from a remnant hypermassive neutron star and/or accretion disk. We now extend our inference to spectra at 2.4 and 3.4 days and test the need for multicomponent ejecta, where we stratify the ejecta in composition. The ejecta at 1.4 and 2.4 days is described by the same single blue component. At 3.4 days, a new redder component with lower Y _e = 0.16 and a significant abundance of lanthanides emerges. This new redder component is consistent with dynamical ejecta and/or neutron-rich ejecta from a magnetized accretion disk. As expected from photometric modeling, this component emerges as the ejecta expands, the photosphere recedes, and the earlier bluer component dims. At 3.4 days, we find an ensemble of lanthanides, with the presence of cerium most concrete. This presence of lanthanides has important implications for the contribution of kilonovae to the r -process abundances observed in the Universe.

Kilonovae are likely a key site of heavy r -process element production in the Universe, and their optical/infrared spectra contain insights into both the properties of the ejecta and the conditions of the r -process. However, the event GW170817/AT2017gfo is the only kilonova so far with well-observed spectra. To understand the diversity of absorption features that might be observed in future kilonovae spectra, we use the TARDIS Monte Carlo radiative transfer code to simulate a suite of optical spectra spanning a wide range of kilonova ejecta properties and r -process abundance patterns. To identify the most common and prominent absorption lines, we perform dimensionality reduction using an autoencoder, and we find spectra clusters in the latent space representation using a Bayesian Gaussian Mixture model. Our synthetic kilonovae spectra commonly display strong absorption by strontium _38 Sr ii , yttrium _38 Y ii , and zirconium _40 Zr i–ii , with strong lanthanide contributions at low electron fractions ( Y _e ≲ 0.25). When a new kilonova is observed, our machine-learning framework will provide context on the dominant absorption lines and key ejecta properties, helping to determine where this event falls within the larger “zoo” of kilonovae spectra.

Background The Autism Spectrum Quotient is a popular autism screening tool recommended for identifying potential cases of autism. However, many women with autism demonstrate a different presentation of traits to those currently captured by screening measures and assessment methods, such as the Autism Spectrum Quotient. Aims Different models of the Autism Spectrum Quotient have been proposed in the literature, utilising different items from the original 50-item scale. Within good-fitting models, the current study aimed to explore whether these items assess autistic traits similarly across men and women. Method Seventeen Autism Spectrum Quotient models were identified from the literature. Using the responses of a large sample of adults from the UK general population (5246 women, 1830 men), confirmatory factor analysis was used to evaluate the fit of each model. Measurement invariance with respect to gender, adjusting for age, was explored in the 11 model frameworks that were found to have satisfactory fit to our data. Results It emerged that only two items were gender invariant (non-biased), whereas for the remaining items, the probability of endorsement was influenced by gender. In particular, women had a higher probability of endorsing items relating to social skills and communication. Conclusions If the items of the Autism Spectrum Quotient indeed reflect autism-related traits, those items should be rephrased to ensure they do not present a gender-related bias. This is vital for ensuring more timely diagnoses and support for all people with autism.

Since its discovery six decades ago, the predatory bacterium Bdellovibrio bacteriovorus has sparked recent interest as a potential remedy to the antibiotic resistance crisis. Here we give a comprehensive historical overview from discovery to progressive developments in microscopy and molecular mechanisms. Research on B. bacteriovorus has moved from curiosity to a new model organism, revealing over time more details on its physiology and fascinating predatory life cycle with the help of a variety of methods. Based on recent findings in cryo-electron tomography, we recapitulate on the intricate molecular details known in the predatory life cycle including how this predator searches for its prey bacterium, to how it attaches, grows, and divides all from within the prey cell. Finally, the newly developed B. bacteriovorus progeny leave the prey cell remnants in the exit phase. While we end with some unanswered questions remaining in the field, new imaging technologies and quantitative, systematic advances will likely help to unravel them in the next decades.

Protected areas (PA) to conserve wildlife are the cornerstone of biodiversity conservation but they can also result in increased human-wildlife conflict (HWC), which poses a serious challenge to jointly achieving sustainable development goals of food security and biodiversity conservation, particular in regions with high conservation values and subsistence farmers. In the Himalayan Kingdom of Bhutan, expanding PAs and other conservation efforts have led to increased wildlife populations that are causing more damage to crop and livestock and impacting on the livelihoods of subsistence farmers and herders. In this study, we used a social-ecological systems framework to quantify the intensity this impact and associated economic losses with identified wildlife species and compared differences between livelihood types (crop farming versus livestock husbandry) and land tenure (inside versus outside protected areas). Results indicated that Meso-scale wildlife species that are not the focus of conservation caused higher economic losses. Approximately 43% of total economic loss through crop depredation was attributed to wild pig (Sus scrofa) and 56% of the total economic loss through livestock predation was caused by wild dogs (Cuon alpinus). Losses borne by respondents whose livelihoods depend mainly on livestock were significantly higher, with a mean loss equivalent to US$1328 per household per annum, than those depending on crop production (US$171 per household per annum). Economic losses incurred through crop and livestock depredation were significantly higher for the respondents residing inside PAs, which is attributed by those households to a perceived increase in wildlife populations because of conservation policies. Interventions for prevention and mitigation of these impacts should recognize these varying unintended effects of wildlife and be better targeted at groups living in different parts of the landscape. These include expanding compensation scheme to losses caused by wild dogs and pigs, supporting ecotourism ventures within PAs to diversify income options and introducing control measures for these animals.

Background Hospital inpatients are exposed to high levels of stress during hospitalisation that may increase susceptibility to major adverse health events post-hospitalisation (known as post-hospital syndrome). However, the existing evidence base has not been reviewed and the magnitude of this relationship remains unknown. Therefore, the aim of the current systematic review and meta-analysis was to: 1) synthesise existing evidence and to determine the strength of the relationship between in-hospital stress and patient outcomes, and 2) determine if this relationship differs between (i) in-hospital vs post-hospital outcomes, and (ii) subjective vs objective outcome measures. Methods A systematic search of MEDLINE, EMBASE, PsychINFO, CINAHL, and Web of Science from inception to February 2023 was conducted. Included studies reported a measure of perceived and appraised stress while in hospital, and at least one patient outcome. A random-effects model was generated to pool correlations (Pearson’s r), followed by sub-group and sensitivity analyses. The study protocol was preregistered on PROSPERO (CRD42021237017). Results A total of 10 studies, comprising 16 effects and 1,832 patients, satisfied the eligibility criteria and were included. A small-to-medium association was found: as in-hospital stress increased, patient outcomes deteriorated (r = 0.19; 95% CI: 0.12–0.26; I2 = 63.6; p < 0.001). This association was significantly stronger for (i) in-hospital versus post-hospital outcomes, and (ii) subjective versus objective outcome measures. Sensitivity analyses indicated that our findings were robust. Conclusions Higher levels of psychological stress experienced by hospital inpatients are associated with poorer patient outcomes. However, more high-quality, larger scale studies are required to better understand the association between in-hospital stressors and adverse outcomes.

Brain functional networks identified from resting functional magnetic resonance imaging (fMRI) data have the potential to reveal biomarkers for brain disorders, but studies of complex mental illnesses such as schizophrenia (SZ) often yield mixed results across replication studies. This is likely due in part to the complexity of the disorder, the short data acquisition time, and the limited ability of the approaches for brain imaging data mining. Therefore, the use of analytic approaches which can both capture individual variability while offering comparability across analyses is highly preferred. Fully blind data-driven approaches such as independent component analysis (ICA) are hard to compare across studies, and approaches that use fixed atlas-based regions can have limited sensitivity to individual sensitivity. By contrast, spatially constrained ICA (scICA) provides a hybrid, fully automated solution that can incorporate spatial network priors while also adapting to new subjects. However, scICA has thus far only been used with a single spatial scale (ICA dimensionality, i.e., ICA model order). In this work, we present an approach using multi-objective optimization scICA with reference algorithm (MOO-ICAR) to extract subject-specific intrinsic connectivity networks (ICNs) from fMRI data at multiple spatial scales, which also enables us to study interactions across spatial scales. We evaluate this approach using a large N (N > 1,600) study of schizophrenia divided into separate validation and replication sets. A multi-scale ICN template was estimated and labeled, then used as input into scICA which was computed on an individual subject level. We then performed a subsequent analysis of multiscale functional network connectivity (msFNC) to evaluate the patient data, including group differences and classification. Results showed highly consistent group differences in msFNC in regions including cerebellum, thalamus, and motor/auditory networks. Importantly, multiple msFNC pairs linking different spatial scales were implicated. The classification model built on the msFNC features obtained up to 85% F1 score, 83% precision, and 88% recall, indicating the strength of the proposed framework in detecting group differences between schizophrenia and the control group. Finally, we evaluated the relationship of the identified patterns to positive symptoms and found consistent results across datasets. The results verified the robustness of our framework in evaluating brain functional connectivity of schizophrenia at multiple spatial scales, implicated consistent and replicable brain networks, and highlighted a promising approach for leveraging resting fMRI data for brain biomarker development.

Background: Individual variation in brain aging trajectories is linked with several physical and mental health outcomes. Greater stress levels, worry, and rumination correspond with advanced brain age, while other individual characteristics, like mindfulness, may be protective of brain health. Multiple lines of evidence point to advanced brain aging in schizophrenia (i.e., neural age estimate > chronological age). Whether psychological dimensions such as mindfulness, rumination, and perceived stress contribute to brain aging in schizophrenia is unknown. Methods: We estimated brain age from high-resolution anatomical scans in 54 healthy controls (HC) and 52 individuals with schizophrenia (SZ) and computed the brain predicted age difference (BrainAGE-diff), i.e., the delta between estimated brain age and chronological age. Emotional well-being summary scores were empirically derived to reflect individual differences in trait mindfulness, rumination, and perceived stress. Core analyses evaluated relationships between BrainAGE-diff and emotional well-being, testing for slopes differences across groups. Results: HC showed higher emotional well-being (greater mindfulness and less rumination/stress), relative to SZ. We observed a significant group difference in the relationship between BrainAge-diff and emotional well-being, explained by BrainAGE-diff negatively correlating with emotional well-being scores in SZ, and not in HC. That is, SZ with younger appearing brains (predicted age

BackgroundCerebellar structural and functional abnormalities underlie widespread deficits in clinical, cognitive, and motor functioning that are observed in schizophrenia. Consequently, the cerebellum is a promising target for novel schizophrenia treatments. Here we conducted an updated systematic review examining the literature on cerebellar stimulation efficacy and tolerability for mitigating symptoms of schizophrenia. We discuss the purported mechanisms of cerebellar stimulation, current methods for implementing stimulation, and future directions of cerebellar stimulation for intervention development with this population.MethodsTwo independent authors identified 20 published studies (7 randomized controlled trials, 7 open-label studies, 1 pilot study, 4 case reports, 1 preclinical study) that describe the effects of cerebellar circuitry modulation in patients with schizophrenia or animal models of psychosis. Published studies up to October 11, 2022 were identified from a search within PubMed, Scopus, and PsycInfo.ResultsMost studies stimulating the cerebellum used transcranial magnetic stimulation or transcranial direct-current stimulation, specifically targeting the cerebellar vermis/midline. Accounting for levels of methodological rigor across studies, these studies detected post-cerebellar modulation in schizophrenia as indicated by the alleviation of certain clinical symptoms (mainly negative and depressive symptoms), as well as increased frontal-cerebellar connectivity and augmentation of canonical neuro-oscillations known to be abnormal in schizophrenia. In contrast to a prior review, we did not find consistent evidence for cognitive improvements following cerebellar modulation stimulation. Modern cerebellar stimulation methods appear tolerable for individuals with schizophrenia, with only mild and temporary side effects.ConclusionCerebellar stimulation is a promising intervention for individuals with schizophrenia that may be more relevant to some symptom domains than others. Initial results highlight the need for continued research using more methodologically rigorous designs, such as additional longitudinal and randomized controlled trials.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022346667].

Background: The COVID-19 pandemic has had significant impacts on health care access and delivery, with disparate effects across social and racial lines. Federally Qualified Health Centers (FQHCs) provide critical primary care services to the nation’s most underserved populations, including many communities hardest hit by COVID-19. Methods: We conducted an ecological analysis that aimed to examine FQHC penetration, COVID-19 mortality, and socio-demographic factors in 4 major United States cities: New York, New York; Chicago, Illinois; Detroit, Michigan; and Seattle, Washington. Results: We found the distribution of COVID-19 cases and mortality varied spatially and in magnitude by city. COVID-19 mortality was significantly higher in communities with higher percentages of low-income residents and higher percentages of racial/ethnic minority residents. FQHC penetration was protective against increased COVID-19 mortality, after model adjustment. Conclusions: Our study underpins the critical role of safety-net health care and policymakers must ensure investment in long-term sustainability of FQHCs, through strategic deployment of capital, workforce development, and reimbursement reform.

Abstract Background Treatment on risk adapted intensive pediatric protocols has improved outcome for teenagers and young adults (TYA) with T‐cell acute lymphoblastic leukemia (T‐ALL). Understanding the biology of disease in this age group and the genetic basis of relapse is a key goal as patients with relapsed/refractory disease have poor outcomes with conventional chemotherapy and novel molecular targets are required. This study examines the question of whether TYA T‐ALL has a specific biological‐molecular profile distinct from pediatric or adult T‐ALL. Methods Genomic characterization was undertaken of a retrospective discovery cohort of 80 patients aged 15–26 years with primary or relapsed T‐ALL, using a combination of Genome‐Wide Human SNP Array 6.0, targeted gene mutation and promoter methylation analyses. Findings were confirmed by MLPA, real‐time quantitative PCR, and FISH. Whole Exome Sequencing was performed in 4 patients with matched presentation and relapse to model clonal evolution. A prevalence analysis was performed on a final data set of 1,792 individual cases to identify genetic lesions with age specific frequency patterns, including 972 pediatric (1–14 years), 439 TYA (15–24 years) and 381 adult (≥25 years) cases. These cases were extracted from 19 publications with comparable genomic data identified through a PubMed search. Results Genomic characterization of this large cohort of TYA T‐ALL patients identified recurrent isochromosome 7q i(7q) in our discovery cohort (n = 3). Prevalence analysis did not identify any age specific genetic abnormalities. Genomic analysis of 6 pairs of matched presentation – relapsed T‐ALL established that all relapses were clonally related to the initial leukemia. Whole exome sequencing analysis revealed recurrent, targetable, mutations disrupting NOTCH, PI3K/AKT/mTOR, FLT3, NRAS as well as drug metabolism pathways. Conclusions All genetic aberrations in TYA T‐ALL occurred with an incidence similar or intermediate to that reported in the pediatric and adult literature, demonstrating that overall TYA T‐ALL exhibits a transitional genomic profile. Analysis of matched presentation – relapse supported the hypothesis that relapse is driven by the Darwinian evolution of sub‐clones associated with drug resistance (NT5C2 and TP53 mutations) and re‐iterative mutation of known key T‐ALL drivers, including NOTCH1.

Abstract As surface water resources in the U.S. continue to be pressured by excess nutrients carried by agricultural runoff, the need to assess runoff risk at the field scale continues to grow in importance. Most landscape hydrologic models developed at regional scales have limited applicability at finer spatial scales. Hybrid models can be used to address the scale mismatch between model simulation and applicability, but could be limited by their ability to generalize over a large domain with heterogeneous hydrologic characteristics. To assist the generalization, we develop a regionalization approach based on the principal component analysis and K‐means clustering to identify the clusters with similar runoff potential over the Great Lakes region. For each cluster, hybrid models are developed by combining National Oceanic and Atmospheric Administration's National Water Model and a data‐driven model, eXtreme gradient boosting with field‐scale measurements, enabling prediction of daily runoff risk level at the field scale over the entire region.

OBJECTIVES/GOALS: A negative circumferential resection margin (CRM) after surgical resection of rectal cancer decreases local recurrence and increases overall survival. While MRI is used to predict this risk, there is no predictive model that incorporates clinical factors to predict the risk of CRM positivity. METHODS/STUDY POPULATION: Utilizing the National Cancer Database from 2010-2014, we performed a retrospective study evaluating factors predictive for positive CRM after surgical resection of rectal cancer. The primary outcome was positive CRM (tumor≤1 mm from the surgical margin). Our population included patients with clinical stage I-III rectal cancer who underwent total mesorectal excision. For the primary outcome, multivariable logistic models were used to estimate the probability of a positive CRM. Model performance was evaluated by using the area under the receiver operating characteristic curve (AUC). Model calibration was assessed by examining the calibration plot. Bootstrapping method (300-iteration) was used to internally validate and estimate optimism-adjusted measures of discrimination and overall model fit. RESULTS/ANTICIPATED RESULTS: There were 28,790 patients included. 2,245 (7.8%) had positive CRM. Older age, race, larger tumor size, higher tumor grade, mucinous and signet tumor histology, APR, open operative approach, facility location, higher T stage, lymphovascular invasion, lack of neoadjuvant chemotherapy/radiation, and perineural invasion were all significantly associated with positive CRM (p DISCUSSION/SIGNIFICANCE: An objective model that predicts positive CRM and associated poor clinical outcomes is possible to be used in conjunction with MRI. Positive CRM is associated with specific patient demographics, tumor characteristics, and operative approach. These factors can be used to predict CRM positivity in the preoperative period and plan accordingly.

Abstract Surveying cryptic, sparsely distributed taxa using autonomous recording units, although cost‐effective, provides imperfect knowledge about species presence. Summertime bat acoustic surveys in North America exemplify the challenges with characterizing sources of uncertainty: observation error, inability to census populations, and natural stochastic variation. Statistical uncertainty, if not considered thoroughly, hampers determining rare species presence accurately and/or estimating rangewide status and trends with suitable precision. Bat acoustic data are processed using an automated workflow in which proprietary or open‐source algorithms assign a species label to each recorded high‐frequency echolocation sequence. A false‐negative occurs, if a species is actually present but not recorded and/or all recordings from the species are of such poor quality that a correct species identity cannot be assigned to any observation. False positives for a focal species are a direct result of the presence and incorrect identification of a recording from another species. We compare four analytical approaches in terms of parameter estimation and their resulting (in)correct decisions regarding species presence or absence using realistic data‐generating scenarios for bat acoustic data within a simulation study. The current standard for deciding species presence or absence uses a multinomial likelihood‐ratio test p value (maximum likelihood estimate [MLE]‐metric) that accounts for known species misidentifications, but not imperfect detection and only returns a binary outcome (evidence of presence or not). We found that the MLE‐metric had estimated median correct decisions less than 60% for presence and greater than 85% for absence. Alternatively, a multispecies count detection model was equivalent to or better than the MLE‐metric for correct claims of rare species presence or absence using the posterior probability a species was present at a site and, importantly, provided unbiased estimates of relative activity and probability of occurrence, creating opportunities for reducing posterior uncertainty through the inclusion of meaningful covariates. Single‐species occupancy models with and without false‐positive detections removed were insufficient for determining local presence because of substantially biased occurrence and detection probabilities. We propose solutions to potential barriers for integrating local, short‐term and rangewide, long‐term acoustic surveys within a cohesive statistical framework that facilitates determining local species presence with uncertainty concurrent with estimating species–environment relationships.

Abstract Background There are limited data on the prevalence of Lynch syndrome (LS) in women with primary ovarian cancer with mismatch repair deficiency (MMR‐D) by immunohistochemistry (IHC). Materials and Methods Three hundred and eight cases of primary ovarian, fallopian, and peritoneal cancer between January 2012 and December 2019 were evaluated for MMR‐D by IHC. The incidence of LS in this cohort was evaluated. Results MMR‐D by IHC was identified in 16 of 308 (5.2%) (95% CI: 3.2%–8.3%) primary ovarian‐related cancers. Most cases with MMR‐D were endometrioid (n = 11, 68.7%); (95% CI: 44.2%–86.1%). MSH2/MSH6 protein loss was detected in eight cases (50.0%); (95% CI: 28.0%–72.0%) and MLH1/PMS2 protein loss was detected in four cases (25.0%); (95% CI: 9.7%–50.0%). MSH6 protein loss was detected in two cases (12.5%); (95% CI: 2.2%–37.3%) and PMS2 protein loss was detected in two cases (12.5%); (95% CI: 2.2%–37.3%). All four cases with MLH1/PMS2 protein loss had MLH1 promotor hypermethylation. All 12 women with ovarian cancer suggestive of LS underwent germline testing and 8 (66.6%); (95% CI: 38.8%–86.5%) were confirmed to have LS. Conclusions Most ovarian cancers with somatic MMR‐D were confirmed to have LS in this cohort. Germline testing for LS in addition to BRCA1/2 for all women with an epithelial ovarian cancer would be efficient and would approach 100% sensitivity for identifying Lynch syndrome. Utilization of a multigene panel should also be considered, given the additional non‐Lynch germline mutation identified in this cohort.

Abstract Adjuvant ultrasound at 2 MHz with or without an ultrasound contrast agent improves the rate of thrombus resolution by recombinant tissue plasminogen activator (rt-PA) in laboratory and clinical studies. A sub-megahertz approach can further expand this therapy to a subset of patients with an insufficient temporal bone window, improving efficacy in unselected patient populations. The aim of this study was to determine if a clinical ultrasound contrast agent (UCA), Definity, and 220 kHz pulsed ultrasound accelerated rt-PA thrombolysis in a preclinical animal model of vascular occlusion. The effect of Definity and ultrasound on thrombus clearance was first investigated in vitro and subsequently tested in a xenographic porcine cerebral thromboembolism model in vivo. Two different microcatheter designs (end-hole, multi-side-hole) were used to infuse rt-PA and Definity at the proximal edge or directly into clots, respectively. Sonothrombolysis with Definity increased clot mass loss relative to saline or rt-PA alone in vitro, only when rt-PA was administered directly into clots via a multi-side-hole microcatheter. Combined treatment with rt-PA, Definity, and ultrasound in vivo increased the rate of reperfusion up to 45 min faster than clots treated with rt-PA or saline. In this porcine cerebral thromboembolism model employing retracted human clots, 220 kHz ultrasound, in conjunction with Definity increased the probability of early successful reperfusion with rt-PA.

Motivation and pleasure deficits are common in schizophrenia, strongly linked with poorer functioning, and may reflect underlying alterations in brain functions governing reward processing and goal pursuit. While there is extensive research examining cognitive and reward mechanisms related to these deficits in schizophrenia, less attention has been paid to psychological characteristics that contribute to resilience against, or risk for, motivation and pleasure impairment. For example, psychological tendencies involving positive future expectancies (e.g., optimism) and effective affect management (e.g., reappraisal, mindfulness) are associated with aspects of reward anticipation and evaluation that optimally guide goal-directed behavior. Conversely, maladaptive thinking patterns (e.g., defeatist performance beliefs, asocial beliefs) and tendencies that amplify negative cognitions (e.g., rumination), may divert cognitive resources away from goal pursuit or reduce willingness to exert effort. Additionally, aspects of sociality, including the propensity to experience social connection as positive reinforcement may be particularly relevant for pursuing social goals. In the current review, we discuss the roles of several psychological characteristics with respect to motivation and pleasure in schizophrenia. We argue that individual variation in these psychological dimensions is relevant to the study of motivation and reward processing in schizophrenia, including interactions between these psychological dimensions and more well-characterized cognitive and reward processing contributors to motivation. We close by emphasizing the value of considering a broad set of modulating factors when studying motivation and pleasure functions in schizophrenia.

Deep learning techniques have been applied to electroencephalogram (EEG) signals, with promising applications in the field of psychiatry. Schizophrenia is one of the most disabling neuropsychiatric disorders, often characterized by the presence of auditory hallucinations. Auditory processing impairments have been studied using EEG-derived event-related potentials and have been associated with clinical symptoms and cognitive dysfunction in schizophrenia. Due to consistent changes in the amplitude of ERP components, such as the auditory N100, some have been proposed as biomarkers of schizophrenia. In this paper, we examine altered patterns in electrical brain activity during auditory processing and their potential to discriminate schizophrenia and healthy subjects. Using deep convolutional neural networks, we propose an architecture to perform the classification based on multi-channels auditory-related EEG single-trials, recorded during a passive listening task. We analyzed the effect of the number of electrodes used, as well as the laterality and distribution of the electrical activity over the scalp. Results show that the proposed model is able to classify schizophrenia and healthy subjects with an average accuracy of 78% using only 5 midline channels (Fz, FCz, Cz, CPz, and Pz). The present study shows the potential of deep learning methods in the study of impaired auditory processing in schizophrenia with implications for diagnosis. The proposed design can provide a base model for future developments in schizophrenia research.

Abstract Recurring glacial cycles through the Quaternary period drastically altered the size and distribution of natural populations of North American flora and fauna. The “southerly refugia model” has been the longstanding framework for testing the effects of glaciation on contemporary genetic patterns; however, insights from ancient DNA have contributed to the reconstruction of more complex histories for some species. The American badger, Taxidea taxus, provides an interesting species for exploring the genetic legacy of glacial history, having been hypothesized to have postglacially emerged from a single, southerly refugium to recolonize northern latitudes. However, previous studies have lacked genetic sampling from areas where distinct glacial refugia have been hypothesized, including the Pacific Northwest and American Far North (Yukon, Alaska). In order to further investigate the phylogeographic history of American badgers, we collected mitochondrial DNA sequence data from ancient subfossil material collected within the historical range (Alaska, Yukon) and combined them with new and previously published data from across the species' contemporary distribution (n = 1,207). We reconstructed a mostly unresolved phylogenetic tree and star‐like haplotype network indicative of emergence from a largely panmictic glacial refugium and recent population expansion, the latter further punctuated by significantly negative Tajima's D and Fu's Fs values. Although directionality of migration cannot be unequivocally inferred, the moderate to high levels of genetic variation exhibited by American badgers, alongside the low frequency of haplotypes with indels in the Midwest, suggest a potential recolonization into central North America after the hypothesized ice‐free corridor reopened ~13,000 years ago. Overall, the expanded reconstruction of phylogeographic history of American badgers offers a broader understanding of contemporary range‐wide patterns and identifies unique genetic units that can likely be used to inform conservation of at‐risk populations at the northern periphery.

The hallmark of resting EEG spectra are distinct rhythms emerging from a broadband, aperiodic background. This aperiodic neural signature accounts for most of total EEG power, although its significance and relation to functional neuroanatomy remains obscure. We hypothesized that aperiodic EEG reflects a significant metabolic expenditure and therefore might be associated with the default mode network while at rest. During eyes-open, resting-state recordings of simultaneous EEG-fMRI, we find that aperiodic and periodic components of EEG power are only minimally associated with activity in the default mode network. However, a whole-brain analysis identifies increases in aperiodic power correlated with hemodynamic activity in an auditory-salience-cerebellar network, and decreases in aperiodic power are correlated with hemodynamic activity in prefrontal regions. Desynchronization in residual alpha and beta power is associated with visual and sensorimotor hemodynamic activity, respectively. These findings suggest that resting-state EEG signals acquired in an fMRI scanner reflect a balance of top-down and bottom-up stimulus processing, even in the absence of an explicit task.

Type VI Secretion Systems (T6SSs) are widespread in bacteria and can dictate the development and organisation of polymicrobial ecosystems by mediating contact dependent killing. In Neisseria species, including Neisseria cinerea a commensal of the human respiratory tract, interbacterial contacts are mediated by Type four pili (Tfp) which promote formation of aggregates and govern the spatial dynamics of growing Neisseria microcolonies. Here, we show that N. cinerea expresses a plasmid-encoded T6SS that is active and can limit growth of related pathogens. We explored the impact of Tfp on N. cinerea T6SS-dependent killing within a colony and show that pilus expression by a prey strain enhances susceptibility to T6SS compared to a non-piliated prey, by preventing segregation from a T6SS-wielding attacker. Our findings have important implications for understanding how spatial constraints during contact-dependent antagonism can shape the evolution of microbial communities.

BackgroundA number of studies in recent years have explored whole-brain dynamic connectivity using pairwise approaches. There has been less focus on trying to analyze brain dynamics in higher dimensions over time.MethodsWe introduce a new approach that analyzes time series trajectories to identify high traffic nodes in a high dimensional space. First, functional magnetic resonance imaging (fMRI) data are decomposed using spatial ICA to a set of maps and their associated time series. Next, density is calculated for each time point and high-density points are clustered to identify a small set of high traffic nodes. We validated our method using simulations and then implemented it on a real data set.ResultsWe present a novel approach that captures dynamics within a high dimensional space and also does not use any windowing in contrast to many existing approaches. The approach enables one to characterize and study the time series in a potentially high dimensional space, rather than looking at each component pair separately. Our results show that schizophrenia patients have a lower dynamism compared to healthy controls. In addition, we find patients spend more time in nodes associated with the default mode network and less time in components strongly correlated with auditory and sensorimotor regions. Interestingly, we also found that subjects oscillate between state pairs that show opposite spatial maps, suggesting an oscillatory pattern.ConclusionOur proposed method provides a novel approach to analyze the data in its native high dimensional space and can possibly provide new information that is undetectable using other methods.

Abstract Background Germline mutations in the BRCA1 and BRCA2 genes predispose carriers to breast and ovarian cancer, and there remains a need to identify the specific genomic mechanisms by which cancer evolves in these patients. Here we present a systematic genomic analysis of breast tumors with BRCA1 and BRCA2 mutations. Methods We analyzed genomic data from breast tumors, with a focus on comparing tumors with BRCA1/BRCA2 gene mutations with common classes of sporadic breast tumors. Results We identify differences between BRCA-mutated and sporadic breast tumors in patterns of point mutation, DNA methylation and structural variation. We show that structural variation disproportionately affects tumor suppressor genes and identify specific driver gene candidates that are enriched for structural variation. Conclusions Compared to sporadic tumors, BRCA-mutated breast tumors show signals of reduced DNA methylation, more ancestral cell divisions, and elevated rates of structural variation that tend to disrupt highly expressed protein-coding genes and known tumor suppressors. Our analysis suggests that BRCA-mutated tumors are more aggressive than sporadic breast cancers because loss of the BRCA pathway causes multiple processes of mutagenesis and gene dysregulation.

Severe congenital Factor XI (FXI) deficiency (