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Background: Obesity-associated asthma results in increased morbidity and mortality. We report one-year asthma outcomes with the Counterweight-Plus weight management programme (CWP) compared to usual care (UC) in a single-centre, randomised, controlled trial in patients with difficult-to-treat asthma and obesity., Research Question: Can CWP use result in improved asthma control and quality of life compared to UC at one-year in patients with difficult-to-treat asthma and obesity?, Study Design and Methods: We randomised (1:1 CWP:UC) adults with difficult-to-treat asthma and body mass index ≥30kg/m 2 . CWP with dietitian support: 12-week total diet replacement phase (850kcal/day low-energy formula); food reintroduction and maintenance phases up to one-year. Outcomes include Asthma Control Questionnaire (ACQ-6), Asthma Quality of Life Questionnaire (AQLQ) and healthcare usage. Minimal clinically important difference (MCID) is 0.5 for ACQ-6 and AQLQ., Results: Of 36 recruited, 29 attended at 52-weeks: 13 CWP, 16 UC. CWP resulted in greater weight change (median -14kg [IQR -15, -9]) compared to UC (2kg [-7, 8]; p=0.015) at 52-weeks. A greater proportion achieved MCID with CWP vs UC in AQLQ (71% vs 6% respectively; p<0.001). No between-group differences were observed in ACQ-6. Median exacerbation frequency reduced over 52-weeks with CWP from 4 (IQR 2, 5) to 0 (0, 2) (p<0.001), though no between-group difference was observed. 70% of the CWP group lost ≥10% body weight and had improvement in ACQ-6 (mean difference -1.1, 95%CI -1.9, -0.3; p=0.018) and AQLQ (1.2, 95%CI 0.4, 2.1; p=0.011) across 52-weeks., Interpretation: Use of a dietitian-supported weight management programme results in sustained weight-loss and is a potential treatment for obesity in asthma. CWP resulted in a higher proportion achieving MCID improvement in AQLQ compared to UC. Within group differences in AQLQ and exacerbation frequency suggest potential with CWP. These encouraging signals justify a larger sample study to further assess asthma-related outcomes., (Copyright © 2024. Published by Elsevier Inc.)

High-throughput phenotypic screens using biochemical perturbations and high-content readouts are constrained by limitations of scale. To address this, we establish a method of pooling exogenous perturbations followed by computational deconvolution to reduce required sample size, labor and cost. We demonstrate the increased efficiency of compressed experimental designs compared to conventional approaches through benchmarking with a bioactive small-molecule library and a high-content imaging readout. We then apply compressed screening in two biological discovery campaigns. In the first, we use early-passage pancreatic cancer organoids to map transcriptional responses to a library of recombinant tumor microenvironment protein ligands, uncovering reproducible phenotypic shifts induced by specific ligands distinct from canonical reference signatures and correlated with clinical outcome. In the second, we identify the pleotropic modulatory effects of a chemical compound library with known mechanisms of action on primary human peripheral blood mononuclear cell immune responses. In sum, our approach empowers phenotypic screens with information-rich readouts to advance drug discovery efforts and basic biological inquiry., (© 2024. The Author(s).)

Significant variations have been observed in viral copies generated during SARS-CoV-2 infections. However, the factors that impact viral copies and infection dynamics are not fully understood, and may be inherently dependent upon different viral and host factors. Here, we conducted virus whole genome sequencing and measured viral copies using RT-qPCR from 9,902 SARS-CoV-2 infections over a 2-year period to examine the impact of virus genetic variation on changes in viral copies adjusted for host age and vaccination status. Using a genome-wide association study (GWAS) approach, we identified multiple single-nucleotide polymorphisms (SNPs) corresponding to amino acid changes in the SARS-CoV-2 genome associated with variations in viral copies. We further applied a marginal epistasis test to detect interactions among SNPs and identified multiple pairs of substitutions located in the spike gene that have non-linear effects on viral copies. We also analyzed the temporal patterns and found that SNPs associated with increased viral copies were predominantly observed in Delta and Omicron BA.2/BA.4/BA.5/XBB infections, whereas those associated with decreased viral copies were only observed in infections with Omicron BA.1 variants. Our work showcases how GWAS can be a useful tool for probing phenotypes related to SNPs in viral genomes that are worth further exploration. We argue that this approach can be used more broadly across pathogens to characterize emerging variants and monitor therapeutic interventions., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: NDG is a paid consultant for BioNTech, DMW has received consulting fees from Pfizer, Merck, and GSK, unrelated to this manuscript, and has been PI on research grants from Pfizer and Merck to Yale, unrelated to this manuscript., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: There are no large studies reporting oncological or survival outcomes for patients diagnosed with perineural spread (PNS) of cutaneous squamous cell carcinoma (cSCC) via the ophthalmic nerve (V 1 ). Where orbital exenteration may be necessary for curative treatment, it is critical to have survival data with which the morbidity associated with surgical treatment can be justified. Furthermore, with the emerging treatment option of immunotherapy, current standard of care outcomes are needed to help guide future trial design and eventually changed management guidelines., Objective: To determine the oncological and survival outcomes observed in patients with PNS of cSCC via V 1 ., Materials and Methods: Retrospective analysis of prospectively maintained cohort of patients with PNS of cSCC via V1 treated in a tertiary Australian head and neck oncology/skull base referral center. Consecutive sample of 53 patients managed between March 1, 1999 and April 30, 2020. Follow-up closure date was September 1, 2021. Curative-intent surgery, curative-intent radiotherapy, or palliative care was undertaken. Endpoints included five-year overall, disease-specific, and disease-free survival from the date of treatment., Results: Five-year Kaplan-Meier overall survival was 61.9% (95% CI 46.2%-74.3%), with disease-specific survival of 74.6% (95% CI 58.8%-85.3%), and disease-free survival 62.1% (95% CI 46.5%-74.3%). Survival was superior in patients treated via surgery and adjuvant radiotherapy than in those receiving surgery alone or definitive radiotherapy. Survival was superior among patients with less advanced disease as assessed by the Williams zonal staging system; patients with Zone 1 disease had disease-specific survival of 94.1% at 5 years with 82.5% disease-free survival., Discussion: Five-year oncological and survival outcomes in this cohort were favorable. Superior survival was observed in patients treated with curative-intent surgery and adjuvant radiotherapy. Less extensive disease as delineated by the Williams zonal staging system was associated with improved survival., Conclusion: Surgical resection with adjuvant radiotherapy confers favourable oncological and survival outcome in patients with V1 PNS, particularly with early disease limited to Zone 1., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Background: Assigning trauma team activation (TTA) levels for trauma patients is a classification task that machine learning models can help optimize. However, performance is dependent on the "ground-truth" labels used for training. Our purpose was to investigate 2 ground truths, the Cribari matrix and the Need for Trauma Intervention (NFTI), for labeling training data., Study Design: Data were retrospectively collected from the institutional trauma registry and electronic medical record, including all pediatric patients (age <18 years) who triggered a TTA (January 2014 to December 2021). Three ground truths were used to label training data: (1) Cribari (Injury Severity Score >15 = full activation), (2) NFTI (positive for any of 6 criteria = full activation), and (3) the union of Cribari+NFTI (either positive = full activation)., Results: Of 1,366 patients triaged by trained staff, 143 (10.47%) were considered undertriaged using Cribari, 210 (15.37%) using NFTI, and 273 (19.99%) using Cribari+NFTI. NFTI and Cribari+NFTI were more sensitive to undertriage in patients with penetrating mechanisms of injury (p = 0.006), specifically stab wounds (p = 0.014), compared with Cribari, but Cribari indicated overtriage in more patients who required prehospital airway management (p < 0.001), CPR (p = 0.017), and who had mean lower Glasgow Coma Scale scores on presentation (p < 0.001). The mortality rate was higher in the Cribari overtriage group (7.14%, n = 9) compared with NFTI and Cribari+NFTI (0.00%, n = 0, p = 0.005)., Conclusions: To prioritize patient safety, Cribari+NFTI appears best for training a machine learning algorithm to predict the TTA level., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

In this paper, we aim to build a platform that will help bridge the gap between high-dimensional computation and wet-lab experimentation by allowing users to interrogate genomic signatures at multiple molecular levels and identify best next actionable steps for downstream decision making. We introduce Multioviz: a publicly accessible R package and web application platform to easily perform in silico hypothesis testing of generated gene regulatory networks. We demonstrate the utility of Multioviz by conducting an end-to-end analysis in a statistical genetics application focused on measuring the effect of in silico perturbations of complex trait architecture. By using a real dataset from the Wellcome Trust Centre for Human Genetics, we both recapitulate previous findings and propose hypotheses about the genes involved in the percentage of immune CD8+ cells found in heterogeneous stocks of mice. Source code for the Multioviz R package is available at https://github.com/lcrawlab/multio-viz and an interactive version of the platform is available at https://multioviz.ccv.brown.edu/ ., (© 2024. The Author(s).)

Up to 20% of orthopedic surgeons still avoid the use of cephalosporins in patients with penicillin allergies despite its reported safety in the adult and general surgery pediatric population. The primary objective is to determine the incidence of adverse effects and allergic reactions when using cephalosporins in pediatric orthopedic patients labeled as penicillin-allergic as compared to those without previously reported penicillin allergy. A multicenter retrospective chart review was performed across three level 1 trauma centers from January 2013 to February 2020 to identify penicillin-allergic as well as non-penicillin-allergic pediatric patients treated for orthopedic injuries. Data were collected regarding patient demographics, antibiotic administered, timing of antibiotic administration, reported drug allergy, and described allergic reaction. Postoperative or intraoperative allergic reactions to antibiotics, surgical site infections, and complications were recorded. A total of 2289 surgeries performed by four fellowship-trained surgeons were evaluated. Eighty-five patients diagnosed with penicillin allergy were identified and underwent 95 surgeries and 95 patients without previously reported penicillin allergy underwent 95 surgeries. One patient, with a documented history of anaphylaxis to cefazolin, sustained an anaphylactic reaction intraoperatively to cefazolin. There were no other reported reactions, surgical site infections, or complications. There was no statistically significant difference in rate of allergic reaction in patients with previously reported penicillin allergy treated with cefazolin and those with no previous reported reaction ( P > 0.05). Prophylaxis with cephalosporins is not associated with increased risk for allergic reaction. Cephalosporins can be safely administered to pediatric patients with penicillin allergy undergoing orthopedic intervention. Level of evidence: Level II, Multicenter Retrospective Prognostic Study., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The concept of functional localization within the brain and the associated risk of resecting these areas during removal of infiltrating tumors, such as diffuse gliomas, are well established in neurosurgery. Global efficiency (GE) is a graph theory concept that can be used to simulate connectome disruption following tumor resection. Structural connectivity graphs were created from diffusion tractography obtained from the brains of 80 healthy adults. These graphs were then used to simulate parcellation resection in every gross anatomical region of the cerebrum by identifying every possible combination of adjacent nodes in a graph and then measuring the drop in GE following nodal deletion. Progressive removal of brain parcellations led to patterns of GE decline that were reasonably predictable but had inter-subject differences. Additionally, as expected, there were deletion of some nodes that were worse than others. However, in each lobe examined in every subject, some deletion combinations were worse for GE than removing a greater number of nodes in a different region of the brain. Among certain patients, patterns of common nodes which exhibited worst GE upon removal were identified as "connectotypes". Given some evidence in the literature linking GE to certain aspects of neuro-cognitive abilities, investigating these connectotypes could potentially mitigate the impact of brain surgery on cognition., (© 2024. The Author(s).)

LD score regression (LDSC) is a method to estimate narrow-sense heritability from genome-wide association study (GWAS) summary statistics alone, making it a fast and popular approach. In this work, we present interaction-LD score (i-LDSC) regression: an extension of the original LDSC framework that accounts for interactions between genetic variants. By studying a wide range of generative models in simulations, and by re-analyzing 25 well-studied quantitative phenotypes from 349,468 individuals in the UK Biobank and up to 159,095 individuals in BioBank Japan, we show that the inclusion of a cis -interaction score (i.e. interactions between a focal variant and proximal variants) recovers genetic variance that is not captured by LDSC. For each of the 25 traits analyzed in the UK Biobank and BioBank Japan, i-LDSC detects additional variation contributed by genetic interactions. The i-LDSC software and its application to these biobanks represent a step towards resolving further genetic contributions of sources of non-additive genetic effects to complex trait variation., Competing Interests: SP, GD, DU, JS, AH, SR, LC No competing interests declared, (© 2024, Pattillo Smith, Darnell et al.)

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples., Competing Interests: DECLARATION OF INTERESTS S.R.M., R.J.K., M.M.S., and D.M.W. disclose equity ownership in Travera. A.K.S. reports compensation for consulting and/or SAB membership from Honeycomb Biotechnologies, Cellarity, Bio-Rad Laboratories, Fog Pharma, Passkey Therapeutics, Ochre Bio, Relation Therapeutics, IntrECate biotherapeutics, and Dahlia Biosciences unrelated to this work. P.S.W receives research funding from Microsoft. S.R. holds equity in Amgen and receives research funding from Microsoft. D.M.W. is an employee of Merck and Co., owns equity in Merck and Co., Bantam, Ajax, and Travera, received consulting fees from Astra Zeneca, Secura, Novartis, and Roche/Genentech, and received research support from Daiichi Sankyo, Astra Zeneca, Verastem, Abbvie, Novartis, Abcura, and Surface Oncology. P.S.W., A.K.S., M.A.M., S.R.M., and D.M.W. have filed a patent related to this work. Other authors – none.

Introduction: Percutaneous nephrolithotripsy (PCNL) is a minimally invasive procedure for treating large and complex kidney stones, often resulting in significant post-operative pain and increased opioid use. This study aims to compare pain scores between patients undergoing PCNL who did and did not receive a preoperative single-shot thoracic paravertebral block (PVB) at the post-anesthesia care unit (PACU) as the primary outcome. Secondary outcomes were patient-controlled analgesia (PCA) usage on post-operative day 1 (POD 1), total opioid consumption on PACU and POD 1, and post-operative nausea and vomiting (PONV)., Methods: A retrospective cohort study was conducted on the medical records of 341 patients who underwent PCNL from July 2014 to April 2016 in a single major academic center. PVB was administered at thoracic levels T7-9 using a volume of 20 cc of bupivacaine, ranging from 0.25% to 0.5%, to achieve the desired analgesic effect., Results: After excluding 34 patients, the study included 123 in the no block (NB) group and 149 in the regional anesthesia (RA) group. There were no differences in demographics, including age, sex, weight and height, BMI, and indication for PCNL. The results revealed that the RA group experienced a statistically significant reduction in PCA usage in both crude and adjusted models (adjusted logistic regression analysis: OR = 0.19, 95% CI = 0.05-0.60; p = 0.008). However, there were no significant changes in total opioid consumption, pain scores, or incidents of PONV., Conclusion: The retrospective analysis did not reveal any discernible advantage in pain management associated with the use of PVB for post-PCNL analgesia, except for reducing the percentage of PCA narcotics used. Future investigations with larger sample sizes and meticulous control for surgical indications and complexity are imperative to accurately assess the efficacy of this block in the context of post-PCNL surgery., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, JS Medeiros et al.)

Enhanced recovery after surgery (ERAS) has an increasingly important role in the perioperative management of thoracic surgical patients. It has been extensively studied in multiple surgical specialties, particularly colorectal surgery, where ERAS protocols have been shown to reduce postoperative length of stay and postoperative complications. Electronic searches of two research databases were performed: PubMed (1972 to October 2023) and Ovid MEDLINE (1946 to October 2023). The literature search was completed on January 4, 2024. Search terms included: "thoracic surgery" and "ERAS" or "Enhanced Recovery After Surgery". The search was limited to studies evaluating humans undergoing thoracic surgery for any indication. The primary outcome was overall morbidity, with secondary outcomes including mortality, length of stay, and pulmonary complications. The search yielded a total of 794 records, of which 30 (four meta-analyses and 26 observational trials) met the relevant inclusion and exclusion criteria. This review suggested the implementation of ERAS protocols can lead to a reduction in postoperative morbidity; however, this was not a consistent finding. The majority of studies included demonstrated a reduction in the length of stay with the implementation of ERAS. Overall, ERAS/ERATS is an important adjunct to the management of patients requiring thoracic surgery, consistently leading to shorter lengths of stay and likely contributing to reduced rates of postoperative morbidity. Further research will be required to determine the impact of the recently released ERATS guidelines., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Goldblatt et al.)

Objectives: The aim of this study was to assess the early outcomes and risk factors of paediatric patients requiring extracorporeal membrane oxygenation after cardiac surgery (post-cardiotomy)., Methods: Retrospective binational cohort study from the Australia and New Zealand Congenital Outcomes Registry for Surgery database. All patients younger than 18 years of age who underwent a paediatric cardiac surgical procedure from 1 January 2013 to 31 December 2021 and required post-cardiotomy extracorporeal membrane oxygenation (PC-ECMO) in the same hospital admission were included in the study., Results: Of the 12 290 patients included in the study, 376 patients required post-cardiotomy ECMO (3%). Amongst these patients, hospital mortality was 35.6% and two-thirds of patients experienced a major complication. Hypoplastic left heart syndrome was the most common diagnosis (17%). The Norwood procedure and modified Blalock-Taussig shunts had the highest incidence of requiring PC-ECMO (odds ratio of 10 and 6.8 respectively). Predictors of hospital mortality after PC-ECMO included single-ventricle physiology, intracranial haemorrhage and chylothorax., Conclusions: In the current era, one-third of patients who required PC-ECMO after paediatric cardiac surgery in Australia and New Zealand did not survive to hospital discharge. The Norwood procedure and isolated modified Blalock-Taussig shunt had the highest incidence of requiring PC-ECMO. Patients undergoing the Norwood procedure had the highest mortality (48%). Two-thirds of patients on PC-ECMO developed a major complication., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Frailty, social isolation, and loneliness have individually been associated with adverse health outcomes. This study examines how frailty in combination with loneliness or social isolation is associated with socioeconomic deprivation and with all-cause mortality and hospitalisation rate in a middle-aged and older population. Baseline data from 461,047 UK Biobank participants (aged 37-73) were used to assess frailty (frailty phenotype), social isolation, and loneliness. Weibull models assessed the association between frailty in combination with loneliness or social isolation and all-cause mortality adjusted for age/sex/smoking/alcohol/socioeconomic-status and number of long-term conditions. Negative binomial regression models assessed hospitalisation rate. Frailty prevalence was 3.38%, loneliness 4.75% and social isolation 9.04%. Frailty was present across all ages and increased with age. Loneliness and social isolation were more common in younger participants compared to older. Co-occurrence of frailty and loneliness or social isolation was most common in participants with high socioeconomic deprivation. Frailty was associated with increased mortality and hospitalisation regardless of social isolation/loneliness. Hazard ratios for mortality were 2.47 (2.27-2.69) with social isolation and 2.17 (2.05-2.29) without social isolation, 2.14 (1.92-2.38) with loneliness and 2.16 (2.05-2.27) without loneliness. Loneliness and social isolation were associated with mortality and hospitalisation in robust participants, but this was attenuated in the context of frailty. Frailty and loneliness/social isolation affect individuals across a wide age spectrum and disproportionately co-occur in areas of high deprivation. All were associated with adverse outcomes, but the association between loneliness and social isolation and adverse outcomes was attenuated in the context of frailty. Future interventions should target people living with frailty or loneliness/social isolation, regardless of age., (© 2024. The Author(s).)

Background: Almost no research has been published reporting on evaluations of the effectiveness of psychological interventions for people with severe to profound intellectual disabilities and depression. This paper describes the development and initial feasibility testing of an adapted Behavioural Activation therapy (BeatIt2) for this population., Method: Phase 1 of the study examined participant recruitment and willingness to be randomised in the context of a planned Randomised Controlled Trial (RCT). Phase 2 examined the feasibility of delivering the intervention., Results: Twenty adults with a severe or profound intellectual disability and clinically significant depression were recruited to Phase 1 of the study. In Phase 2, there was 100% participant retention for those recruited to the study at 6-month follow-up. The BeatIt2 therapy was reported to be acceptable for participants., Conclusion: COVID disruption meant that it was not possible to complete the planned feasibility RCT. The positive findings suggest that additional evaluation of BeatIt2 is warranted., (© 2024 The Authors. Journal of Applied Research in Intellectual Disabilities published by John Wiley & Sons Ltd.)

Background: Critically ill pediatric patients are frequently initiated methicillin-resistant Staphylococcus aureus (MRSA) active antibiotics during infection evaluation even though MRSA infections are rare in many patient populations. The MRSA nasal swab polymerase chain reaction assay (MRSA-NS-PCR) is a test that has been shown to have a high negative predictive value (NPV) for MRSA infection in adults. This study evaluated the diagnostic test characteristics of the MRSA-NS-PCR in predicting the presence of MRSA infection in critically ill pediatric patients., Study Design: A retrospective cohort study was performed in a 44-bed pediatric intensive care unit (PICU) between 2013 and 2017. 3860 pediatric patients (54% male, median age 4 years [IQR 1-11 years]) admitted to the PICU who met pediatric systemic inflammatory response syndrome (pSIRS) criteria, were screened with a MRSA-NS-PCR, and had cultures obtained within seven days of MRSA-NS-PCR collection were included. Predictive values and post-test probabilities of the MRSA-NS-PCR for MRSA infection were calculated., Results: MRSA-NS-PCR was positive in 8.6% of patients. MRSA infection was identified in 40 patients, equaling an incidence rate of 2 per 1000 patient days. The MRSA-NS-PCR demonstrated a positive predictive value (PPV) of 9.7%, a NPV of 99.8%, and a post-test probability for a negative test of 0.2% for MRSA infection., Conclusions: The MRSA-NS-PCR has a poor PPV but a high NPV for MRSA infection in PICU patients when the incidence of MRSA infection is low. Creation of protocols to guide antimicrobial selection based on MRSA-NS-PCR results may lead to improved antimicrobial stewardship and significant risk reduction., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite the implementation of lifesaving newborn screening programs and a galactose-restricted diet, many patients with classic galactosemia develop long-term debilitating neurological deficits and primary ovarian insufficiency. Previously, we showed that the administration of human GALT mRNA predominantly expressed in the GalT gene-trapped mouse liver augmented the expression of hepatic GALT activity, which decreased not only galactose-1 phosphate (gal-1P) in the liver but also peripheral tissues. Since each peripheral tissue requires distinct methods to examine the biomarker and/or GALT effect, this highlights the necessity for alternative strategies to evaluate the overall impact of therapies. In this study, we established that whole-body galactose oxidation (WBGO) as a robust, noninvasive, and specific method to assess the in vivo pharmacokinetic and pharmacodynamic parameters of two experimental gene-based therapies that aimed to restore GALT activity in a mouse model of galactosemia. Although our results illustrated the long-lasting efficacy of AAVrh10-mediated GALT gene transfer, we found that GALT mRNA therapy that targets the liver predominantly is sufficient to sustain WBGO. The latter could have important implications in the design of novel targeted therapy to ensure optimal efficacy and safety., Competing Interests: The authors declare the following competing interests: X.Y., F.W., J.T., L.C., R.D., S.C., S.M., Y.W., M.Z., J.S., P.G.V.M., and P.F.F. are employees of Moderna and hold equities from the company., (© 2024 The Author(s).)

Per/polyfluoroalkyl substances (PFASs) are ubiquitous, highly persistent anthropogenic chemicals that bioaccumulate and biomagnify in aquatic food webs and are associated with adverse health effects, including liver and kidney diseases, cancers, and immunosuppression. We investigated the accumulation of PFASs in a marine apex predator, the white shark ( Carcharodon carcharias ). Muscle ( N = 12) and blood plasma ( N = 27) samples were collected from 27 sharks during 2018-2021 OCEARCH expeditions along the eastern coast of North America from Nova Scotia to Florida. Samples were analyzed for 47 (plasma) and 43 (muscle) targeted PFASs and screened for >2600 known and novel PFASs using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Perfluoroalkyl carboxylates with carbon chain-length C11 to C14 were frequently detected above the method reporting limits in plasma samples, along with perfluorooctanesulfonate and perfluorodecanesulfonate. Perfluoropentadecanoate was also detected in 100% of plasma samples and concentrations were estimated semiquantitatively as no analytical standard was available. Total concentrations of frequently detected PFASs in plasma ranged from 0.56 to 2.9 ng mL -1 (median of 1.4 ng mL -1 ). In muscle tissue, nine targeted PFASs were frequently detected, with total concentration ranging from 0.20 to 0.84 ng g -1 ww. For all frequently detected PFASs, concentrations were greater in plasma than in muscle collected from the same organism. In both matrices, perfluorotridecanoic acid was the most abundant PFAS, consistent with several other studies. PFASs with similar chain-lengths correlated significantly among the plasma samples, suggesting similar sources. Total concentrations of PFASs in plasma were significantly greater in sharks sampled off of Nova Scotia than all sharks from other locations, potentially due to differences in diet. HRMS suspect screening tentatively identified 13 additional PFASs in plasma, though identification confidence was low, as no MS/MS fragmentation was collected due to low intensities. The widespread detection of long-chain PFASs in plasma and muscle of white sharks highlights the prevalence and potential biomagnification of these compounds in marine apex predators., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: The assignment of trauma team activation levels can be conceptualized as a classification task. Machine learning models can be used to optimize classification predictions. Our purpose was to demonstrate proof-of-concept for a machine learning tool for predicting trauma team activation levels in pediatric patients with traumatic injuries., Methods: Following IRB approval, we retrospectively collected data from the institutional trauma registry and electronic medical record at our Pediatric Trauma Center for all patients (age <18 y) who triggered a trauma team activation (1/2014-12/2021), including: demographics, mechanisms of injury, comorbidities, pre-hospital interventions, numeric variables, and the six "Need for Trauma Intervention (NFTI)" criteria. Three machine learning models (Logistic Regression, Random Forest, Support Vector Machine) were tested 1000 times in separate trials using the union of the Cribari and NFTI metrics as ground-truth (Injury Severity Score >15 or positive for any of 6 NFTI criteria = full activation). Model performance was quantified and compared to emergency department (ED) staff., Results: ED staff had 75% accuracy, an area under the curve (AUC) of 0.73 ± 0.04, and an F1 score of 0.49. The best performing of all machine learning models, the support vector machine, had 80% accuracy, AUC 0.81 ± 4.1e -5 , F1 Score 0.80, with less variance compared to other models and ED staff., Conclusions: All machine learning models outperformed ED staff in all performance metrics. These results suggest that data-driven methods can optimize trauma team activations in the ED, with potential improvements in both patient safety and hospital resource utilization., Type of Study: Economic/Decision Analysis or Modeling Studies., Level of Evidence: II., (Copyright © 2023 Elsevier Inc. All rights reserved.)