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Abstract Recent failures translating preclinical behavioral treatment effects to positive clinical trial results in humans with Fragile X Syndrome (FXS) support refocusing attention on biological pathways and associated measures, such as electroencephalography (EEG), with strong translational potential and small molecule target engagement. This study utilized guided machine learning to test promising translational EEG measures (resting power and auditory chirp oscillatory variables) in a large heterogeneous sample of individuals with FXS to identify best performing EEG variables for reliably separating individuals with FXS, and genetically-mediated subgroups within FXS, from typically developing controls. Best performing variables included resting relative frontal theta power, all combined posterior-head resting power bands, posterior peak alpha frequency (PAF), combined PAF across all measured regions, combined theta, alpha, and gamma power during the chirp, and all combined chirp oscillatory variables. Sub-group analyses for resting EEG best discriminated non-mosaic FXS males via frontal theta resting relative power (AUC = 0.8759), even with data reduced to a 20-channel clinical montage (AUC = 0.9062). In the chirp task, FXS females and non-mosaic males were nearly perfectly discriminated by combined theta, alpha, and gamma power (AUC = 0.9444) and a combination of all variables (AUC = 0.9610), respectively. Results support use of resting and auditory oscillatory tasks to reliably identify neural deficit in FXS, and to identify specific translational targets for genetically-mediated sub-groups, supporting potential points for stratification.

Abstract Functional electrical stimulation (FES) can support functional restoration of a paretic limb post-stroke. Hebbian plasticity depends on temporally coinciding pre- and post-synaptic activity. A tight temporal relationship between motor cortical (MC) activity associated with attempted movement and FES-generated visuo-proprioceptive feedback is hypothesized to enhance motor recovery. Using a brain–computer interface (BCI) to classify MC spectral power in electroencephalographic (EEG) signals to trigger FES-delivery with detection of movement attempts improved motor outcomes in chronic stroke patients. We hypothesized that heightened neural plasticity earlier post-stroke would further enhance corticomuscular functional connectivity and motor recovery. We compared subcortical non-dominant hemisphere stroke patients in BCI-FES and Random-FES (FES temporally independent of MC movement attempt detection) groups. The primary outcome measure was the Fugl-Meyer Assessment, Upper Extremity (FMA-UE). We recorded high-density EEG and transcranial magnetic stimulation-induced motor evoked potentials before and after treatment. The BCI group showed greater: FMA-UE improvement; motor evoked potential amplitude; beta oscillatory power and long-range temporal correlation reduction over contralateral MC; and corticomuscular coherence with contralateral MC. These changes are consistent with enhanced post-stroke motor improvement when movement is synchronized with MC activity reflecting attempted movement.

Abstract Background We report on our methodological experiences during an investigation of how institutional racism functions in healthcare. We found tension between balancing methodological rigor with the unanticipated consequence of interviewer burden. Methods Semi-structured interviews were conducted with patients. Interviews were recorded, transcribed verbatim, and qualitatively analyzed using thematic content analysis. Interviewers also participated in weekly debriefing sessions and reported experiences with patients. Results Interviewers repeatedly experienced negative encounters with white patients during interviews. Themes included privilege to avoid racism, denial of racism, non-verbal discomfort, falsely claiming Native identities, and intimidation. These experiences were most pronounced with Black interviewers. Discussion Interviewer burden may need to be a consideration taken up in a variety of research contexts.

Abstract Hepatitis C virus (HCV) is a plus-stranded RNA virus that often chronically infects liver hepatocytes and causes liver cirrhosis and cancer. These viruses replicate their genomes employing error-prone replicases. Thereby, they routinely generate a large ‘cloud’ of RNA genomes (quasispecies) which—by trial and error—comprehensively explore the sequence space available for functional RNA genomes that maintain the ability for efficient replication and immune escape. In this context, it is important to identify which RNA secondary structures in the sequence space of the HCV genome are conserved, likely due to functional requirements. Here, we provide the first genome-wide multiple sequence alignment (MSA) with the prediction of RNA secondary structures throughout all representative full-length HCV genomes. We selected 57 representative genomes by clustering all complete HCV genomes from the BV-BRC database based on k-mer distributions and dimension reduction and adding RefSeq sequences. We include annotations of previously recognized features for easy comparison to other studies. Our results indicate that mainly the core coding region, the C-terminal NS5A region, and the NS5B region contain secondary structure elements that are conserved beyond coding sequence requirements, indicating functionality on the RNA level. In contrast, the genome regions in between contain less highly conserved structures. The results provide a complete description of all conserved RNA secondary structures and make clear that functionally important RNA secondary structures are present in certain HCV genome regions but are largely absent from other regions. Full-genome alignments of all branches of Hepacivirus C are provided in the supplement.

Abstract Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

Abstract Vestibular schwannomas (VS) are the most common tumor of the skull base with available treatment options that carry a risk of iatrogenic injury to the facial nerve, which can significantly impact patients’ quality of life. As facial nerve outcomes remain challenging to prognosticate, we endeavored to utilize machine learning to decipher predictive factors relevant to facial nerve outcomes following microsurgical resection of VS. A database of patient-, tumor- and surgery-specific features was constructed via retrospective chart review of 242 consecutive patients who underwent microsurgical resection of VS over a 7-year study period. This database was then used to train non-linear supervised machine learning classifiers to predict facial nerve preservation, defined as House-Brackmann (HB) I vs. facial nerve injury, defined as HB II–VI, as determined at 6-month outpatient follow-up. A random forest algorithm demonstrated 90.5% accuracy, 90% sensitivity and 90% specificity in facial nerve injury prognostication. A random variable (rv) was generated by randomly sampling a Gaussian distribution and used as a benchmark to compare the predictiveness of other features. This analysis revealed age, body mass index (BMI), case length and the tumor dimension representing tumor growth towards the brainstem as prognosticators of facial nerve injury. When validated via prospective assessment of facial nerve injury risk, this model demonstrated 84% accuracy. Here, we describe the development of a machine learning algorithm to predict the likelihood of facial nerve injury following microsurgical resection of VS. In addition to serving as a clinically applicable tool, this highlights the potential of machine learning to reveal non-linear relationships between variables which may have clinical value in prognostication of outcomes for high-risk surgical procedures.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details assessment and management of the child with overweight or obesity. The term “child” is defined as the child between 2 and 12 years of age. Because children are in a continual state of development during this age range, we will specify when our discussion applies to subsets within this age range. For the purposes of this CPS, we will use the following definitions: overweight in the child is a body mass index (BMI) ≥ 85th and

Abstract Recent demonstrations of room-temperature lasing in optically pumped GeSn show promise for future CMOS compatible lasers for Si-photonics applications. However, challenges remain for electrically pumped devices. Investigation of the processes that limit device performance is therefore vital in aiding the production of future commercial devices. In this work, a combined experimental and modelling approach is utilised to explore the dominant loss processes in current devices. By manipulating the band structure of functioning devices using high hydrostatic pressure techniques at low temperature, the dominant carrier recombination pathways are identified. This reveals that 93 $$~\pm ~$$ ± 5% of the threshold current is attributable to defect-related recombination at a temperature, T = 85 K. Furthermore, carrier occupation of L-valley states (carrier leakage) is responsible for 1.1 $$~\pm ~$$ ± 0.3% of the threshold current, but this sharply increases to 50% with a decrease of just 30 meV in the L- $$\Gamma$$ Γ separation energy. This indicates that thermal broadening of a similar order may reproduce these adverse effects, limiting device performance at higher temperatures. Temperature dependent calculations show that carrier occupation of indirect valley L-states strongly affects the transparency carrier density and is therefore very sensitive to the Sn composition, leading to an effective operational temperature range for given Sn compositions and strain values. Recommendations for future device designs are proposed based on band structure and growth optimisations.

Abstract Suppression of threading dislocations (TDs) in thin germanium (Ge) layers grown on silicon (Si) substrates has been critical for realizing high-performance Si-based optoelectronic and electronic devices. An advanced growth strategy is desired to minimize the TD density within a thin Ge buffer layer in Ge-on-Si systems. In this work, we investigate the impact of P dopants in 500-nm thin Ge layers, with doping concentrations from 1 to 50 × 1018 cm−3. The introduction of P dopants has efficiently promoted TD reduction, whose potential mechanism has been explored by comparing it to the well-established Sb-doped Ge-on-Si system. P and Sb dopants reveal different defect-suppression mechanisms in Ge-on-Si samples, inspiring a novel co-doping technique by exploiting the advantages of both dopants. The surface TDD of the Ge buffer has been further reduced by the co-doping technique to the order of 107 cm−2 with a thin Ge layer (of only 500 nm), which could provide a high-quality platform for high-performance Si-based semiconductor devices.

Abstract Background Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders with overlapping behavioral features and genetic etiology. While brain cortical thickness (CTh) alterations have been reported in ASD and ADHD separately, the degree to which ASD and ADHD are associated with common and distinct patterns of CTh changes is unclear. Methods We searched PubMed, Web of Science, Embase, and Science Direct from inception to 8 December 2023 and included studies of cortical thickness comparing youth (age less than 18) with ASD or ADHD with typically developing controls (TDC). We conducted a comparative meta-analysis of vertex-based studies to identify common and distinct CTh alterations in ASD and ADHD. Results Twelve ASD datasets involving 458 individuals with ASD and 10 ADHD datasets involving 383 individuals with ADHD were included in the analysis. Compared to TDC, ASD showed increased CTh in bilateral superior frontal gyrus, left middle temporal gyrus, and right superior parietal lobule (SPL) and decreased CTh in right temporoparietal junction (TPJ). ADHD showed decreased CTh in bilateral precentral gyri, right postcentral gyrus, and right TPJ relative to TDC. Conjunction analysis showed both disorders shared reduced TPJ CTh located in default mode network (DMN). Comparative analyses indicated ASD had greater CTh in right SPL and TPJ located in dorsal attention network and thinner CTh in right TPJ located in ventral attention network than ADHD. Conclusions These results suggest shared thinner TPJ located in DMN is an overlapping neurobiological feature of ASD and ADHD. This alteration together with SPL alterations might be related to altered biological motion processing in ASD, while abnormalities in sensorimotor systems may contribute to behavioral control problems in ADHD. The disorder-specific thinner TPJ located in disparate attention networks provides novel insight into distinct symptoms of attentional deficits associated with the two neurodevelopmental disorders. Trial registration PROSPERO CRD42022370620. Registered on November 9, 2022.

Summary: Background: Controllability analysis is an approach developed for evaluating the ability of a brain region to modulate function in other regions, which has been found to be altered in major depressive disorder (MDD). Both depressive symptoms and cognitive impairments are prominent features of MDD, but the case–control differences of controllability between MDD and controls can not fully interpret the contribution of both clinical symptoms and cognition to brain controllability and linked patterns among them in MDD. Methods: Sparse canonical correlation analysis was used to investigate the associations between resting-state functional brain controllability at the network level and clinical symptoms and cognition in 99 first-episode medication-naïve patients with MDD. Findings: Average controllability was significantly correlated with clinical features. The average controllability of the dorsal attention network (DAN) and visual network had the highest correlations with clinical variables. Among clinical variables, depressed mood, suicidal ideation and behaviour, impaired work and activities, and gastrointestinal symptoms were significantly negatively associated with average controllability, and reduced cognitive flexibility was associated with reduced average controllability. Interpretation: These findings highlight the importance of brain regions in modulating activity across brain networks in MDD, given their associations with symptoms and cognitive impairments observed in our study. Disrupted control of brain reconfiguration of DAN and visual network during their state transitions may represent a core brain mechanism for the behavioural impairments observed in MDD. Funding: National Natural Science Foundation of China (82001795 and 82027808), National Key R&D Program (2022YFC2009900), and Sichuan Science and Technology Program (2024NSFSC0653).

IntroductionThe development of high-quality stated preference (SP) surveys requires a rigorous design process involving engagement with representatives from the target population. However, while transparency in the reporting of the development of SP surveys is encouraged, few studies report on this process and the outcomes. Recommended stages of instrument development includes both steps for stakeholder/end-user engagement and pretesting. Pretesting typically involves interviews, often across multiple waves, with improvements made at each wave; pretesting is therefore resource intensive. The aims of this paper are to report on the outcomes of collaboration with a Lewy body dementia research advisory group during the design phase of a SP survey. We also evaluate an alternative approach to instrument development, necessitated by a resource constrained context.MethodThe approach involved conducting the stages of end-user engagement and pretesting together during a public involvement event. A hybrid approach involving a focus group with breakout interviews was employed. Feedback from contributors informed the evolution of the survey instrument.ResultsChanges to the survey instrument were organized into four categories: attribute modifications; choice task presentation and understanding; information presentation, clarity and content; and best-best scaling presentation. The hybrid approach facilitated group brainstorming while still allowing the researcher to assess the feasibility of choice tasks in an interview setting. However, greater individual exploration and the opportunity to trial iterative improvements across waves was not feasible with this approach.DiscussionInvolvement of the research advisory group resulted in a more person-centered survey design. In a context constrained by time and budget, and with consideration of the capacity and vulnerability of the target population, the approach taken was a feasible and pragmatic mechanism for improving the design of a SP survey.

Abstract Here, we establish a CT-radiomics based method for application in invasive, orthotopic rodent brain tumour models. Twenty four NOD/SCID mice were implanted with U87R-Luc2 GBM cells and longitudinally imaged via contrast enhanced (CE-CT) imaging. Pyradiomics was employed to extract CT-radiomic features from the tumour-implanted hemisphere and non-tumour-implanted hemisphere of acquired CT-scans. Inter-correlated features were removed (Spearman correlation > 0.85) and remaining features underwent predictive analysis (recursive feature elimination or Boruta algorithm). An area under the curve of the receiver operating characteristic curve was implemented to evaluate radiomic features for their capacity to predict defined outcomes. Firstly, we identified a subset of radiomic features which distinguish the tumour-implanted hemisphere and non- tumour-implanted hemisphere (i.e, tumour presence from normal tissue). Secondly, we successfully translate preclinical CT-radiomic pipelines to GBM patient CT scans (n = 10), identifying similar trends in tumour-specific feature intensities (E.g. ‘glszm Zone Entropy’), thereby suggesting a mouse-to-human species conservation (a conservation of radiomic features across species). Thirdly, comparison of features across timepoints identify features which support preclinical tumour detection earlier than is possible by visual assessment of CT scans. This work establishes robust, preclinical CT-radiomic pipelines and describes the application of CE-CT for in-depth orthotopic brain tumour monitoring. Overall we provide evidence for the role of pre-clinical ‘discovery’ radiomics in the neuro-oncology space.

Abstract Background In Ireland, there are currently three educational institutions (recognised institutions- RIs) providing paramedic programmes, accredited by the regulator, the Pre-Hospital Emergency Care Council (PHECC). Each RI assesses their students in-house, and in order to acquire a licence to practice, students must also pass summative assessments provided by PHECC. These assessments comprise multiple choice questions, short answer questions and skills assessments. The objective of this study was to explore the perceptions and experiences of paramedic educators of assessments used within their institution and by the regulator to provide insights that could inform the future design of paramedic assessments. Methods A qualitative study with an interpretivist approach and purposive sampling strategy was performed. Semi-structured interviews were conducted with educators from one RI, across their three sites. Data were analysed using an inductive approach to thematic analysis. Results Four major themes were identified in the data: improving assessments by enhancing authenticity, modifying the current process of assessment, aligning the PHECC and RI examinations and opportunities to use assessment as learning. Conclusions This study identifies perceived deficits and opportunities in the assessments currently used for paramedic students and ways in which these assessments could be improved. While participants were relatively content with their own RI assessments, they identified ways to improve both the RI and PHECC assessments. Modifying some of the current methods could be a useful first step. In particular, assessments used by PHECC could be improved by reflecting ‘real-world’ practice. The inclusion of additional assessment methods by PHECC, a continuous assessment process or devolvement of the entire assessment suite, to the RI/University has the potential to enhance assessments, particularly summative assessments, for paramedic students.

BackgroundEmerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST).Methods and findingsThe primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics.ConclusionsCompared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

BackgroundAdvances in multiple myeloma (MM) treatment have shifted the therapeutic landscape. Understanding patients' perspectives can assist physicians in helping patients make informed decisions. This study aimed to understand the patient decision-making process and gain insights into patient perspectives on B-cell maturation antigen (BCMA)-targeted therapies for MM.MethodsAn 18-question survey was completed by patients with MM enrolled in HealthTree® Cure Hub, an online portal helping patients with plasma cell dyscrasias navigate their disease.ResultsFrom October 28, 2022, to January 12, 2023, 325 patients with MM participated in the survey. The mean age (standard deviation) of the respondents was 66 (8) years; 54% were female and 90% were White. Among 218 patients with complete clinical records in the database, the median (min, max) lines of therapy (LOT) was 2 (1,16). Among 61 (28%) patients who had received ≥4 LOTs, 55 (90%) were triple-class exposed. Of the 290 patients who responded to the question about openness to new therapies, 76 (26%) were open to trying a new therapy immediately and 125 (43%) wanted more information on safety and efficacy. Most respondents reported likely or very likely to try a BCMA CAR T-cell therapy (60%) or a bispecific antibody (74%) and some needed more information to decide (16% for CAR T-cell therapy and 13% for bispecific antibody). The most requested information included efficacy, side effects (SEs), eligibility, and administration process for both CAR T-cell and bispecific therapies. When 2 therapies with the same efficacy and duration of response were offered, 69% of respondents would prefer the therapy with a lower risk of severe SEs but requires continuous dosing with no treatment-free interval, and 31% preferred a therapy given once followed by a treatment-free interval but with a potentially higher risk of severe SEs. To receive an effective therapy, the top acceptable trade-offs included frequent monitoring of SEs and initiating a new therapy in a hospital setting, and the least acceptable compromise was caregiver burden.ConclusionsThis study found a high level of openness in patients with MM to try BCMA-targeted therapies. Information on efficacy, safety, availability, and eligibility may assist patients on decision-making.

Mental ill-health and suicide represent a significant proportion of the burden of global disease among men. Connell’s relational theory of masculinities provides a useful framework to explore how mental health literacy, mental health stigma, and delayed help-seeking and help-offering behaviors are associated with mental ill-health among men, particularly within male-dominated industries. To address the high incidences of mental ill-health in male-dominated industries, several workplace interventions targeting these outcomes have been implemented. No review to date has examined the current state of evidence for these interventions or identified the behavior change techniques used. This review was restricted to empirical, quantitative research reporting on psychosocial interventions targeting mental health literacy, stigma, and help-seeking and help-offering behaviors in male-dominated industries. Quality appraisal was completed using the Effective Public Health Practice Project and a narrative synthesis was conducted. Twelve articles were included for review which reported on four distinct interventions. The methodological quality of two articles was strong, three moderate and seven weak. The strongest evidence of intervention effects related to mental health literacy and help-seeking intentions. There was less evidence relating to help-offering and help-seeking behaviors and mental health stigma. Sixteen behavior change techniques were identified across interventions that are discussed in relation to the wider men’s health literature. The evidence on psychosocial interventions in male-dominated industries is limited due to methodological and conceptual issues. Recommendations for future research include standardized reporting of intervention descriptions, the use of theory to guide intervention development, and utilizing validated and reliable outcome measures.

The current study will explore the post-pandemic bereavement window of widowed caregivers who experienced higher degrees of social isolation and the ways in which leisure was used to cope. A phenomenological multi-case study technique was used to explore the “multiple realities” among female caregivers whose social convoys suffered pre-pandemic because of spousal caregiving and were further impacted by COVID-19 mitigation strategies during the pandemic. Initial analyses utilized the two-cycle approach, as defined by Saldana. In the initial cycle, the researchers independently immersed themselves in the raw data gathered during participant interviews and engaged in open coding to discern concepts, patterns, themes, and categories associated with the multiple realities among the widows whose leisure participation was affected due to the strain of spousal caregiving and exacerbated by COVID-19 mitigation strategies. After completing the first cycle, the researchers then moved to the second phase, thematic analysis, which sought to develop a more structured framework by which to understand the data by identifying, analyzing, and reporting patterns (e.g., themes) within it. A qualitative comparison technique was then employed to deepen our understanding of individuals’ lived experiences. Thematic findings revealed three areas of similarities: Social isolation from caregiving, using leisure to self-focus and explore future possibilities, and core groups.

Abstract Functional MRI (fMRI) of the spinal cord is an expanding area of research with potential to investigate neuronal activity in the central nervous system. We aimed to characterize the functional connectivity features of the human lumbar spinal cord using resting-state fMRI (rs-fMRI) at 3T, using region-based and data-driven analysis approaches. A 3D multi-shot gradient echo resting-state blood oxygenation level dependent-sensitive rs-fMRI protocol was implemented in 26 healthy participants. Average temporal signal-to-noise ratio in the gray matter was 16.35 ± 4.79 after denoising. Evidence of synchronous signal fluctuations in the ventral and dorsal horns with their contralateral counterparts was observed in representative participants using interactive, exploratory seed-based correlations. Group-wise average in-slice Pearson’s correlations were 0.43 ± 0.17 between ventral horns, and 0.48 ± 0.16 between dorsal horns. Group spatial independent component analysis (ICA) was used to identify areas of coherent activity¸ and revealed components within the gray matter corresponding to anatomical regions. Lower-dimensionality ICA revealed bilateral components corresponding to ventral and dorsal networks. Additional separate ICAs were run on two subsets of the participant group, yielding two sets of components that showed visual consistency and moderate spatial overlap. This work shows feasibility of rs-fMRI to probe the functional features and organization of the lumbar spinal cord.

Abstract Background Viral acute respiratory illnesses (viral ARIs) contribute significantly to human morbidity and mortality worldwide, but their successful treatment requires timely diagnosis of viral etiology, which is complicated by overlap in clinical presentation with the non-viral ARIs. Multiple pandemics in the twenty-first century to date have further highlighted the unmet need for effective monitoring of clinically relevant emerging viruses. Recent studies have identified conserved host response to viral infections in the blood. Methods We hypothesize that a similarly conserved host response in nasal samples can be utilized for diagnosis and to rule out viral infection in symptomatic patients when current diagnostic tests are negative. Using a multi-cohort analysis framework, we analyzed 1555 nasal samples across 10 independent cohorts dividing them into training and validation. Results Using six of the datasets for training, we identified 119 genes that are consistently differentially expressed in viral ARI patients (N = 236) compared to healthy controls (N = 146) and further down-selected 33 genes for classifier development. The resulting locked logistic regression-based classifier using the 33-mRNAs had AUC of 0.94 and 0.89 in the six training and four validation datasets, respectively. Furthermore, we found that although trained on healthy controls only, in the four validation datasets, the 33-mRNA classifier distinguished viral ARI from both healthy or non-viral ARI samples with > 80% specificity and sensitivity, irrespective of age, viral type, and viral load. Single-cell RNA-sequencing data showed that the 33-mRNA signature is dominated by macrophages and neutrophils in nasal samples. Conclusion This proof-of-concept signature has potential to be adapted as a clinical point-of-care test (‘RespVerity’) to improve the diagnosis of viral ARIs.

Abstract Traditional diagnostic formulations of psychotic disorders have low correspondence with underlying disease neurobiology. This has led to a growing interest in using brain-based biomarkers to capture biologically-informed psychosis constructs. Building upon our prior work on the B-SNIP Psychosis Biotypes, we aimed to examine whether structural MRI (an independent biomarker not used in the Biotype development) can effectively classify the Biotypes. Whole brain voxel-wise grey matter density (GMD) maps from T1-weighted images were used to train and test (using repeated randomized train/test splits) binary L2-penalized logistic regression models to discriminate psychosis cases (n = 557) from healthy controls (CON, n = 251). A total of six models were evaluated across two psychosis categorization schemes: (i) three Biotypes (B1, B2, B3) and (ii) three DSM diagnoses (schizophrenia (SZ), schizoaffective (SAD) and bipolar (BD) disorders). Above-chance classification accuracies were observed in all Biotype (B1 = 0.70, B2 = 0.65, and B3 = 0.56) and diagnosis (SZ = 0.64, SAD = 0.64, and BD = 0.59) models. However, the only model that showed evidence of specificity was B1, i.e., the model was able to discriminate B1 vs. CON and did not misclassify other psychosis cases (B2 or B3) as B1 at rates above nominal chance. The GMD-based classifier evidence for B1 showed a negative association with an estimate of premorbid general intellectual ability, regardless of group membership, i.e. psychosis or CON. Our findings indicate that, complimentary to clinical diagnoses, the B-SNIP Psychosis Biotypes may offer a promising approach to capture specific aspects of psychosis neurobiology.

Abstract Feline mammary adenocarcinomas (FMA) are aggressive tumours with metastatic capability and limited treatment options. This study aims to investigate whether miRNAs associated with FMA tumours are secreted in extracellular vesicles (EVs) and whether they can potentially be used as a cancer biomarker in EVs from feline plasma. Tumours and matched tumour free margins from 10 felines with FMA were selected. Following a detailed literature search, RT-qPCR analyses of 90 miRNAs identified 8 miRNAs of interest for further investigation. Tumour tissue, margins and plasma were subsequently collected from a further 10 felines with FMA. EVs were isolated from the plasma. RT-qPCR expression analyses of the 8 miRNAs of interest were carried out in tumour tissue, margins, FMA EVs and control EVs. Additionally, proteomic analysis of both control and FMA plasma derived EVs was undertaken. RT-qPCR revealed significantly increased miR-20a and miR-15b in tumours compared to margins. A significant decrease in miR-15b and miR-20a was detected in EVs from FMAs compared to healthy feline EVs. The proteomic content of EVs distinguished FMAs from controls, with the protein targets of miR-20a and miR-15b also displaying lower levels in the EVs from patients with FMA. This study has demonstrated that miRNAs are readily detectable in both the tissue and plasma derived EVs from patients with FMA. These miRNAs and their protein targets are a detectable panel of markers in circulating plasma EVs that may inform future diagnostic tests for FMA in a non-invasive manner. Moreover, the clinical relevance of miR-20a and miR-15b warrants further investigation.

This study investigated the efficacy of various traps differing in colour (green or yellow), presence or absence of decoys (dead Agrilus planipennis) or design (commercial MULTz or multifunnel traps, and homemade bottle- or fan-traps) for monitoring European Buprestidae in deciduous forests and pear orchards. Over two years, we collected 2220 samples on a two-week basis from 382 traps across 46 sites in Belgium and France. None of the traps proved effective for monitoring Agrilus sinuatus in infested pear orchards (17 specimens captured in 2021, 0 in 2022). The decoys did not affect the catch rates whatever the trap model, colour, buprestid species or sex. The fluorescent yellow traps (MULTz and yellow fan-traps) tended to be more attractive than the green traps (green fan-traps and, to a lower extent, multifunnel green traps). Most Agrilus species showed similar patterns in mean trap catches, with the exception of Agrilus biguttatus, which had the largest catches in the green multifunnel traps. Finally, we observed a high variation in catch rates between localities: the site explained 64% of the catches variance, while the tree within the site and the type of trap explained only 6-8.5% each. In many sites, we captured very few specimens, despite the abundance of dying mature trees favourable to the development of Buprestidae. For the early detection of non-native Buprestidae, it therefore seems essential to maximise the number of monitoring sites. Due to their cost-effectiveness, lightweight design, and modularity, fan-traps emerged as promising tools for buprestid monitoring. The study's findings extend beyond European fauna, as a preliminary trial in Canada suggested that yellow fan-traps could also improve captures of non-European buprestid species and catch species of interest such as Agrilus bilineatus (a species on the EPPO A2 list of pests/pathogens recommended for regulation in the EU).

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E−12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

At the end of the 2023 Padua Days of Muscle and Mobility Medicine the next year's meeting was scheduled from 27 February to 2 March 2024 (2024Pdm3). During the summer and autumn the program was confirmed with Scientific Sessions that will take place over five days, starting in the afternoon of February 27, 2024 at the Conference Room of the Hotel Petrarca, Thermae of Euganean Hills (Padua), Italy. As usual, the next day will be spent in Padua, in this occasion at the San Luca Hall of the Santa Giustina monastery in Prato della Valle, Padua, Italy. Collected during Autumn 2023, many more titles and abstracts than expected were submitted, forcing the organization of parallel sessions both on March 1 and March 2 2024 confirming attractiveness of the 2024 Pdm3. The five days will include oral presentations of scientists and clinicians from Argentina, Austria, Belgium, Brazil, Canada, Denmark, Egypt, France, Germany, Iceland, Ireland, Italy, Romania, Russia, Slovenia, Switzerland, UK and USA. Together with the preliminary Program at December 1, 2023, the early submitted Abstracts is e-published in this Issue 33 (4) 2023 of the European Journal of Translational Myology (EJTM). You are invited to join, submitting your Last Minute Abstracts to ugo.carraro@unipd.it by February 1, 2024. Furthermore, with the more generous deadline of May 20, 2024, submit please “Communications” to the European Journal of Translational Myology (Clarivate’s ESCI Impact factor 2.2; SCOPUS Cite Score: 3.2). See you soon at the Hotel Petrarca in Montegrotto Terme, Padua, on February 27, 2024, but the complete program can be followed from home via zoom connection.

Background: Illicitly-manufactured fentanyl and stimulants have replaced prescription opioids as the primary contributors to fatal overdoses in the United States (US), yet the street supply of these substances is challenging to quantify. Building on the foundation of prior research on law enforcement drug reports, the present study compares publicly available forensic laboratory drug report measures to identify which measures account for the most variation in drug overdose mortality between states, within states over time, and in various demographic groups. Methods: Drug reports from the National Forensic Laboratory Information System and drug overdose mortality rates from the Centers for Disease Control and Prevention were examined for all US states and the District of Columbia, 2013–2021 (459 state-years). State- and year- fixed effects models regressed drug overdose mortality rates (in the overall population and subpopulations by sex, age, and race/ethnicity) on various drug report measures, including rates per population and proportional shares of drug reports positive for fentanyl/fentanyl-related compounds, heroin, cocaine, methamphetamine, and xylazine. Results: For drug overdose death rates in the overall population and nearly all subpopulations examined by sex, race/ethnicity, and age, the model including all drug report proportional measures represented the best-performing model (as identified via the lowest Akaike Information Criterion and highest within R-squared value), followed by the model including only the fentanyl/fentanyl-related compounds proportion. Conclusions: Findings support the utility of publicly available drug report composition measures, particularly the proportion of fentanyl/fentanyl-related compounds, as predictors of drug overdose mortality in the US and in various subpopulations.

Abstract Malignant gliomas are a type of primary brain tumour that originates in glial cells. Among them, glioblastoma multiforme (GBM) is the most common and the most aggressive brain tumour in adults, classified as grade IV by the World Health Organization. The standard care for GBM, known as the Stupp protocol includes surgical resection followed by oral chemotherapy with temozolomide (TMZ). This treatment option provides a median survival prognosis of only 16–18 months to patients mainly due to tumour recurrence. Therefore, enhanced treatment options are urgently needed for this disease. Here we show the development, characterization, and in vitro and in vivo evaluation of a new composite material for local therapy of GBM post-surgery. We developed responsive nanoparticles that were loaded with paclitaxel (PTX), and that showed penetration in 3D spheroids and cell internalization. These nanoparticles were found to be cytotoxic in 2D (U-87 cells) and 3D (U-87 spheroids) models of GBM. The incorporation of these nanoparticles into a hydrogel facilitates their sustained release in time. Moreover, the formulation of this hydrogel containing PTX-loaded responsive nanoparticles and free TMZ was able to delay tumour recurrence in vivo after resection surgery. Therefore, our formulation represents a promising approach to develop combined local therapies against GBM using injectable hydrogels containing nanoparticles.

Abstract To successfully establish itself in a novel environment, an animal must make an inherent trade-off between knowledge accumulation and exploitation of knowledge gained (i.e., the exploration–exploitation dilemma). To evaluate how habitat quality affects the spatio-temporal scale of switching between exploration and exploitation during home range establishment, we conducted experimental trials comparing resource selection and space-use of translocated animals to those of reference individuals using reciprocal translocations between habitat types of differing quality. We selected wild pigs (Sus scrofa) as a model species to investigate hypotheses related to the movement behavior of translocated individuals because they are globally distributed large mammals that are often translocated within their introduced range to facilitate recreational hunting. Individuals translocated to higher quality habitat (i.e. higher proportions of bottomland hardwood habitats) exhibited smaller exploratory movements and began exploiting resources more quickly than those introduced to lower quality areas, although those in lower-quality areas demonstrated an increased rate of selection for preferred habitat as they gained knowledge of the landscape. Our data demonstrate that habitat quality mediates the spatial and temporal scale at which animals respond behaviorally to novel environments, and how these processes may determine the success of population establishment.

Leucine-rich repeat kinase 2 (LRRK2) variants associated with Parkinson’s disease (PD) and Crohn’s disease lead to increased phosphorylation of its Rab substrates. While it has been recently shown that perturbations in cellular homeostasis including lysosomal damage can increase LRRK2 activity and localization to lysosomes, the molecular mechanisms by which LRRK2 activity is regulated have remained poorly defined. We performed a targeted siRNA screen to identify regulators of LRRK2 activity and identified Rab12 as a novel modulator of LRRK2-dependent phosphorylation of one of its substrates, Rab10. Using a combination of imaging and immunopurification methods to isolate lysosomes, we demonstrated that Rab12 is actively recruited to damaged lysosomes and leads to a local and LRRK2-dependent increase in Rab10 phosphorylation. PD-linked variants, including LRRK2 R1441G and VPS35 D620N, lead to increased recruitment of LRRK2 to the lysosome and a local elevation in lysosomal levels of pT73 Rab10. Together, these data suggest a conserved mechanism by which Rab12, in response to damage or expression of PD-associated variants, facilitates the recruitment of LRRK2 and phosphorylation of its Rab substrate(s) at the lysosome.

Objective To determine current UK medical students’ career intentions after graduation and on completing the Foundation Programme (FP), and to ascertain the motivations behind these intentions.Design Cross-sectional, mixed-methods survey of UK medical students, using a non-random sampling method.Setting All 44 UK medical schools recognised by the General Medical Council.Participants All UK medical students were eligible to participate. The study sample consisted of 10 486 participants, approximately 25.50% of the medical student population.Outcome measures Career intentions of medical students postgraduation and post-FP, motivations behind these career intentions, characterising the medical student population and correlating demographic factors and propensity to leave the National Health Service (NHS).Results The majority of participating students (8806/10 486, 83.98%) planned to complete both years of the FP after graduation, with under half of these students (4294/8806, 48.76%) intending to pursue specialty training thereafter. A subanalysis of career intentions after the FP by year of study revealed a significant decrease in students’ intentions to enter specialty training as they advanced through medical school. Approximately a third of surveyed students (3392/10 486, 32.35%) intended to emigrate to practise medicine, with 42.57% (n=1444) of those students not planning to return. In total, 2.89% of students intended to leave medicine altogether (n=303). Remuneration, work-life balance and working conditions were identified as important factors in decision-making regarding emigration and leaving the profession. Subgroup analyses based on gender, type of schooling, fee type and educational background were performed. Only 17.26% of surveyed students were satisfied or very satisfied with the overall prospect of working in the NHS.Conclusions The Ascertaining the career Intentions of UK Medical Students study highlights UK students’ views and career intentions, revealing a concerning proportion of those surveyed considering alternative careers or emigration. Addressing factors such as remuneration, work-life balance and working conditions may increase retention of doctors and improve workforce planning efforts.

Abstract Background This window of opportunity trial evaluated the safety of intratumoral Copaxone® and profiled immune markers in biopsies before and after treatment. Methods Patients with percutaneously accessible malignancies scheduled for surgical resection with curative intent were eligible to participate. Adverse events from one, two, or three injections of Copaxone® were monitored leading up to surgical resection. Using RNA sequencing and spatial protein profiling of immune-related targets, changes in mRNA and protein expression patterns, respectively were assessed in tumor biopsy samples pre- and post-treatment. Results Adverse events at the injection site were mild and consistent with historic subcutaneous administration of Copaxone®. Increased intratumoral immune activity was evident in most patients, including the upregulation of genes associated with immune stimulation and targets of checkpoint inhibitor therapy. Conclusions Intratumoral injection of Copaxone® was well tolerated, and immune profile changes in the tumor microenvironment warrant its further evaluation as human intratumoral immunotherapy. Trial registration clinicaltrials.gov, NCT03982212 First posted June 11th, 2019

Abstract Patients with non-small cell lung cancer (NSCLC) who have distant metastases have a poor prognosis. To determine which genomic factors of the primary tumor are associated with metastasis, we analyzed data from 759 patients originally diagnosed with stage I–III NSCLC as part of the AACR Project GENIE Biopharma Collaborative consortium. We found that TP53 mutations were significantly associated with the development of new distant metastases. TP53 mutations were also more prevalent in patients with a history of smoking, suggesting that these patients may be at increased risk for distant metastasis. Our results suggest that additional investigation of the optimal management of patients with early-stage NSCLC harboring TP53 mutations at diagnosis is warranted in light of their higher likelihood of developing new distant metastases.

Abstract Improving maternal nutrition during pregnancy/lactation is a promising strategy to maximise the intestinal health of piglets undergoing abrupt weaning under commercial production conditions. This experiment investigated the effects of maternal supplementation of a casein hydrolysate and yeast β-glucan (CH-YBG) from day 83 of gestation until weaning (day 28) on sow faecal microbial populations and measures of piglet gastrointestinal health parameters at weaning. Sows (n = 10 sows/group) were assigned to: (1) control diet, and (2) control diet + CH-YBG. Maternal supplementation increased the abundance of the phylum Firmicutes, including members Lactobacillus in the sows faeces, with a concomitant increase in the caecal abundance of Lactobacillus in the weaned piglets compared to the controls. Piglets weaned from the supplemented sows had increased villus height in the duodenum (P

Abstract Repetitive transcranial magnetic stimulation (rTMS) is increasingly used to treat neuropsychiatric disorders. Inhibitory and excitatory regimens have been both adopted but the exact mechanism of action remains unclear, and investigating their differential effects on laminar diffusion profiles of neocortex may add important evidence. Twenty healthy participants were randomly assigned to receive a low‐frequency/inhibitory or high‐frequency/excitatory rTMS targeting the left dorsolateral prefrontal cortex (DLPFC). With the brand‐new submillimeter diffusion tensor imaging of whole brain and specialized surface‐based laminar analysis, fractional anisotropy (FA) and mean diffusion (MD) profiles of cortical layers at different cortical depths were characterized before/after rTMS. Inhibitory and excitatory rTMS both showed impacts on diffusion metrics of somatosensory, limbic, and sensory regions, but different patterns of changes were observed—increased FA with inhibitory rTMS, whereas decreased FA with excitatory rTMS. More importantly, laminar analysis indicated laminar specificity of changes in somatosensory regions during different rTMS patterns—inhibitory rTMS affected the superficial layers contralateral to the DLPFC, while excitatory rTMS led to changes in the intermediate/deep layers bilateral to the DLPFC. These findings provide novel insights into acute neurobiological effects on diffusion profiles of rTMS that may add critical evidence relevant to different protocols of rTMS on neocortex.

Objective We sought to compare the incidence of early-onset sepsis (EOS) in infants ≥34 weeks’ gestation identified >24 hours after birth, in hospitals using the Kaiser Permanente Sepsis Risk Calculator (SRC) with hospitals using the National Institute for Health and Care Excellence (NICE) guidance.Design and setting Prospective observational population-wide cohort study involving all 26 hospitals with neonatal units colocated with maternity services across London (10 using SRC, 16 using NICE).Participants All live births ≥34 weeks’ gestation between September 2020 and August 2021.Outcome measures EOS was defined as isolation of a bacterial pathogen in the blood or cerebrospinal fluid (CSF) culture from birth to 7 days of age. We evaluated the incidence of EOS identified by culture obtained >24 hours to 7 days after birth. We also evaluated the rate empiric antibiotics were commenced >24 hours to 7 days after birth, for a duration of ≥5 days, with negative blood or CSF cultures.Results Of 99 683 live births, 42 952 (43%) were born in SRC hospitals and 56 731 (57%) in NICE hospitals. The overall incidence of EOS (24 hours was 2.3/100 000 (n=1) for SRC vs 7.1/100 000 (n=4) for NICE (OR 0.5, 95% CI (0.1 to 2.7)). This corresponded to (1/20) 5% (SRC) vs (4/45) 8.9% (NICE) of EOS cases (χ=0.3, p=0.59). Empiric antibiotics were commenced >24 hours to 7 days after birth in 4.4/1000 (n=187) for SRC vs 2.9/1000 (n=158) for NICE (OR 1.5, 95% CI (1.2 to 1.9)). 3111 (7%) infants received antibiotics in the first 24 hours in SRC hospitals vs 8428 (15%) in NICE hospitals.Conclusion There was no significant difference in the incidence of EOS identified >24 hours after birth between SRC and NICE hospitals. SRC use was associated with 50% fewer infants receiving antibiotics in the first 24 hours of life.

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast skeletal muscle contraction in DMD with a potentially novel, selective, orally active inhibitor of fast skeletal muscle myosin, EDG-5506. Surprisingly, even modest decreases of contraction (

Objective Many children in low-income and middle-income countries are disadvantaged in achieving early developmental potential in childhood as they lack the necessary support from their surroundings, including from parents and caregivers. Digital technologies, such as smartphone apps, coupled with iterative codesign to engage end-users in the technology-delivered content development stages, can help overcome gaps in early child development (ECD). We describe the iterative codesign and quality improvement process that informs the development of content for the Thrive by Five International Program, localised for nine countries in Asia and Africa.Design Between 2021 and 2022, an average of six codesign workshops in each country were conducted in Afghanistan, Indonesia, Kyrgyzstan, Uzbekistan, Cameroon, the Democratic Republic of the Congo, Ethiopia, Kenya and Namibia.ParticipantsA total of 174 parents and caregivers and 58 in-country subject matter experts participated and provided feedback to refine and inform the cultural appropriateness of the Thrive by Five app and its content. Detailed notes from the workshops and written feedback were coded and analysed using established thematic techniques.Results Four themes emerged from the codesign workshops: local realities, barriers to positive parenting, child development and lessons learnt about the cultural context. These themes, as well as various subthemes, informed content development and refinement. For example, childrearing activities were requested and developed to promote inclusion of families from diverse backgrounds, encourage best parenting practices, increase engagement of fathers in ECD, address parents’ mental well-being, educate children about cultural values and help bereaved children with grief and loss. Also, content that did not align with the laws or culture of any country were removed.Conclusions The iterative codesign process informed the development of a culturally relevant app for parents and caregivers of children in the early years. Further evaluation is required to assess user experience and impact in real world settings.

BackgroundSmartphone use has increased dramatically and, in parallel, a market for mobile apps, including health apps, has emerged. The business model of targeted mobile app advertisements allows for the collection of personal and potentially sensitive information, often without user knowledge. Older adults comprise a rapidly growing demographic that is potentially vulnerable to exploitation by those accessing data collected via these apps. ObjectiveThis research examined apps that claimed to be useful to older adults with a goal of (1) classifying the functionality of each app, (2) identifying whether a privacy policy existed and was accessible, and (3) evaluating evidence that could support claims of value to older adults. MethodsAn environmental scan was conducted using the Google search engine and typing “apps for older adults.” The first 25 sites that this search returned comprised the primary data for this study. Data were organized by descriptive features of purpose (eg, health, finance, and utility), the existence of an electronically accessible privacy policy, price, and evidence supporting each recommended mobile app. ResultsA total of 133 mobile apps were identified and promoted as being the best “apps for older adults.” Of these 133 mobile apps, 83% (n=110) included a privacy policy. Fewer apps designated in the “medical” category included a privacy policy than those classified otherwise. ConclusionsThe results suggest that most mobile apps targeting older adults include a privacy policy. Research is needed to determine whether these privacy policies are readable, succinct, and incorporate accessible data use and sharing practices to mitigate potential risks, particularly when collecting potentially sensitive health information.

Summary: Background: Identifying individuals at risk for severe mental illness (SMI) is crucial for prevention and early intervention strategies. While MRI shows potential for case identification even before illness onset, no practical model for mental health risk monitoring has been developed. This study aims to develop an initial version of an efficient and practical model for mental health screening among at-risk populations. Methods: A deep learning model known as Multiple Instance Learning (MIL) was adopted to train and test a SMI detection model with clinical MRI scans of 14,915 patients with SMI (age 32.98 ± 12.01 years, 9102 women) and 4538 healthy controls (age 40.60 ± 10.95 years, 2424 women) in the primary dataset. Validation analysis was conducted in an independent dataset with 290 patients (age 28.08 ± 10.95 years, 169 women) and 310 healthy participants (age 33.55 ± 11.09 years, 165 women). Another three machine learning models of ResNet, DenseNet and EfficientNet were used for comparison. We also recruited 148 individuals receiving high-stress medical school education to characterize the potential real-world utility of the MIL model in detecting risk of mental illness. Findings: Similar performance of successful differentiation of individuals with SMI and healthy controls was observed for the MIL model (AUC: 0.82) and other models (ResNet, DenseNet, EfficientNet, 0.83, 0.81, and 0.80 respectively). MIL had better generalization in the validation test than other models (AUC: 0.82 vs 0.59, 0.66 and 0.59), and less drop-off in performance from 3.0T to 1.5T scanners. The MIL model did better in predicting clinician ratings of distress than self-ratings with questionnaires (84% vs 22%) in the medical student sample. Brain regions that contributed to SMI identification were mainly neocortical, including right precuneus, bilateral temporal regions, left precentral/postcentral gyrus, bilateral medial prefrontal cortex and right cerebellum. Interpretation: Our digital model based on brief clinical MRI protocols identified individual SMI patients with good accuracy and high sensitivity, suggesting that with incremental improvements the approach may offer potentially useful aid for early identification and intervention to prevent illness onset in vulnerable at-risk populations. Funding: This study was supported by the National Natural Science Foundation of China, National Key Technologies R&D Program of China, and Sichuan Science and Technology Program.

House mice (Mus musculus) pose a conservation threat on islands, where they adversely affect native species' distributions, densities, and persistence. On Sand Island of Kuaihelani, mice recently began to depredate nesting adult mōlī (Laysan Albatross, Phoebastria immutabilis). Efforts are underway to eradicate mice from Sand Island, but knowledge of mouse diet is needed to predict ecosystem response and recovery following mouse removal. We used next-generation sequencing to identify what mice eat on Sand Island, followed by stable isotope analysis to estimate the proportions contributed by taxa to mouse diet. We collected paired fecal and hair samples from 318 mice between April 2018 to May 2019; mice were trapped approximately every eight weeks among four distinct habitat types to provide insight into temporal and spatial variation. Sand Island's mice mainly consume arthropods, with nearly equal (but substantially smaller) contributions of C3 plants, C4 plants, and mōlī. Although seabird tissue is a small portion of mouse diet, mice consume many detrital-feeding arthropods in and around seabird carcasses, such as isopods, flesh flies, ants, and cockroaches. Additionally, most arthropods and plants eaten by mice are non-native. Mouse diet composition differs among habitat types but changes minimally throughout the year, indicating that mice are not necessarily limited by food source availability or accessibility. Eradication of house mice may benefit seabirds on Sand Island (by removing a terrestrial, non-native predator), but it is unclear how arthropod and plant communities may respond and change. Non-native and invasive arthropods and plants previously consumed (and possibly suppressed) by mice may be released post-eradication, which could prevent recovery of native taxa. Comprehensive knowledge of target species' diet is a critical component of eradication planning. Dietary information should be used both to identify and to monitor which taxa may respond most strongly to invasive species removal and to assess if proactive, pre-eradication management activities are warranted.

The Clinical and Translational Science Awards (CTSA) Program supports a national network of medical research institutions working to improve the translational process. High-performing translational teams (TTs) are critical for advancing evidence-based approaches that improve human health. When focused on content-appropriate knowledge, skills, and attitudes, targeted training results in the substantial internalization of training content, producing new skills that can be applied to improve team outputs, outcomes, and benefits. More rigorous approaches to develop, test, and evaluate interventions are needed, and we used the Wisconsin Interventions in Team Science framework as a model to systematize our efforts. We designed, built, and tested a five-session TT Training Program for translational researchers. The 90-minute sessions were pilot-tested with 47 postdoctoral fellows and evaluated through a structured evaluation plan. Ninety-five percent of post-session survey respondents indicated that the content and skills provided would make them more effective collaborators, and one hundred percent would recommend the sessions to colleagues. Respondents’ scores increased from pretest to posttest for most learning outcomes. Refinements from participant feedback are described. This work provides a foundation for the continued evolution of evidence-based training programs in the CTSA environment.

While inflammation is an important immune response for protection from infections, excessive or prolonged inflammation can lead to a variety of debilitating diseases including skin disease, diabetes, heart disease, stroke, autoimmune diseases and cancer. Inflammation is a graded response that is typically initiated when resident macrophages sense the presence of pathogens or damage in the tissue and produce inflammatory cytokines and chemokines to kill the pathogen, clear debris and dead tissue, and initiate tissue repair. Here we show that copper-infused fabrics can prevent inflammation by blocking the production of inflammatory cytokines from macrophages after being exposed to LPS, a component of bacterial cell wall. Mechanistically, we show that copper-infused fabrics can significantly reduce the NF-κB and IRF3 activation in LPS-stimulated macrophages. Given the importance of excessive inflammation in diabetes, we show that copper can reduce insulin resistance mediated by inflammatory cytokines in muscle cells. Our data show that copper infused fabrics may be useful to reduce excessive inflammation in macrophages and improve insulin sensitivity in skeletal muscles.

Despite understanding its impact on organizational effectiveness, practical guidance on how to train translational team (TT) leaders is lacking. Previously, we developed an evolutionary learning model of TT maturation consisting of three goal-directed phases: (1). team assembly (Formation); (2). conducting research (Knowledge Generation); and (3). dissemination and implementation (Translation). At each phase, the team acquires group-level knowledge, skills, and attitudes (KSAs) that enhance its performance. Noting that the majority of team-emergent KSAs are promoted by leadership behaviors, we examine the SciTS literature to identify the relevant behaviors for each phase. We propose that effective team leadership evolves from a hierarchical, transformational model early in team Formation to a shared, functional leadership model during Translation. We synthesized an integrated model of TT leadership, mapping a generic “functional leadership” taxonomy to relevant leadership behaviors linked to TT performance, creating an evidence-informed Leadership and Skills Enhancement for Research (LASER) training program. Empirical studies indicate that leadership behaviors are stable across time; to enhance leadership skills, ongoing reflection, evaluation, and practice are needed. We provide a comprehensive multi-level evaluation framework for tracking the growth of TT leadership skills. This work provides a framework for assessing and training relevant leadership behaviors for high-performance TTs.

Introduction: Brief intervention with peer recovery coach support has been used to generate referrals to substance use disorder treatment from the emergency department (ED). This retrospective study evaluated factors associated with successful linkage to treatment following brief intervention in the ED. Methods: Data were extracted from the electronic health record for patients who were referred to substance use treatment from the ED and for whom follow-up data regarding treatment attendance was available (n=666). We examined associations between demographic and insurance variables, substance use, mental health diagnosis, prior abstinence, and stage of change with successful linkage to substance use treatment after ED referral. Results: The sample was majority male (68%), White (62%), and had a mean age of 43 years (SD=12). Medicaid was the most common insurance (49%) followed by employer/private (34%). Multivariable logistic regression determined patients with Medicaid (OR=2.94, 95% CI:2.09-4.13, p=

Abstract Intestinal functions demonstrate circadian rhythms thought to be entrained, in part, by an organisms’ intrinsic feeding and fasting periods as well as by the intestinal microbiome. Circadian disruption as a result of ill-timed nutrient exposure and obesogenic feeding poses an increased risk to disease. As such, the aim of this study was to assess the relationships between dietary timing, composition, and the microbiome with regard to rhythmic small intestinal structure and mucosal immunity. Rodent chow (RC)-mice exhibited time-dependent increases in small intestinal weight, villus height, and crypt depth as well as an increased proportion of CD8αα+ cells and concomitant decrease in CD8αβ+ cells at the onset of the feeding period (p

Invasive bacterial infections remain a major cause of human morbidity. Group B streptococcus (GBS) are Gram-positive bacteria that cause invasive infections in humans. Here, we show that factor XIIIA–deficient (FXIIIA-deficient) female mice exhibited significantly increased susceptibility to GBS infections. Additionally, female WT mice had increased levels of FXIIIA and were more resistant to GBS infection compared with isogenic male mice. We observed that administration of exogenous FXIIIA to male mice increased host resistance to GBS infection. Conversely, administration of a FXIIIA transglutaminase inhibitor to female mice decreased host resistance to GBS infection. Interestingly, male gonadectomized mice exhibited decreased sensitivity to GBS infection, suggesting a role for gonadal androgens in host susceptibility. FXIIIA promoted GBS entrapment within fibrin clots by crosslinking fibronectin with ScpB, a fibronectin-binding GBS surface protein. Thus, ScpB-deficient GBS exhibited decreased entrapment within fibrin clots in vitro and increased dissemination during systemic infections. Finally, using mice in which FXIIIA expression was depleted in mast cells, we observed that mast cell–derived FXIIIA contributes to host defense against GBS infection. Our studies provide insights into the effects of sexual dimorphism and mast cells on FXIIIA expression and its interactions with GBS adhesins that mediate bacterial dissemination and pathogenesis.

BackgroundDigital technologies are widely recognized for their equalizing effect, improving access to affordable health care regardless of gender, ethnicity, socioeconomic status, or geographic region. The Thrive by Five app is designed to promote positive interactions between children and their parents, extended family, and trusted members of the community to support socioemotional and cognitive development in the first 5 years of life and to strengthen connections to culture and community. ObjectiveThis paper aims to describe the iterative co-design process that underpins the development and refinement of Thrive by Five’s features, functions, and content. Minderoo Foundation commissioned this work as a quality improvement activity to support an engaging user experience and inform the development of culturally appropriate and relevant content for parents and caregivers in each country where the app is implemented. MethodsThe app content, referred to as Collective Actions, comprises “The Why,” that presents scientific principles that underpin socioemotional and cognitive development in early childhood. The scientific information is coupled with childrearing activities for parents, extended family, and members of the community to engage in with the children to support their healthy development and to promote positive connections between parents, families, and communities and these young children. Importantly, the initial content is designed and iteratively refined in collaboration with a subject matter expert group from each country (ie, alpha testing). This content is then configured into the app (either a beta version or localized version) for testing (ie, beta testing) by local parents and caregivers as well as experts who are invited to provide their feedback and suggestions for improvements in app content, features, and functions via a brief web-based survey and a series of co-design workshops. The quantitative survey data will be analyzed using descriptive statistics, whereas the analysis of qualitative data from the workshops will follow established thematic techniques. ResultsTo date, the co-design protocol has been completed with subject matter experts, parents, and caregivers from 9 countries, with the first results expected to be published by early 2023. The protocol will be implemented serially in the remaining 21 countries. ConclusionsMobile technologies are the primary means of internet connection in many countries worldwide, which underscores the potential for mobile health programs to improve access to valuable, evidence-based, and previously unavailable parenting information. However, for maximum impact, it is critically important to ensure that mobile health programs are designed in collaboration with the target audience to support the alignment of content with parents’ cultural values and traditions and its relevance to their needs and circumstances. International Registered Report Identifier (IRRID)DERR1-10.2196/39225