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The effect of IFITM3 on viral pathogenesis is poorly understood. Here, the authors show that IFITM3 restricts cytomegalovirus pathogenesis by reducing Nogo-B-mediated inflammation in response to viral stimuli.

Abstract Background Face-to-face group-based diabetes prevention programmes have been shown to be effective in many settings. Digital delivery may suit some patients, but research comparing the effectiveness of digital with face-to-face delivery is scarce. The aim was to assess if digital delivery of the English National Health Service Diabetes Prevention Programme (NHS DPP) is non-inferior to group-based face-to-face delivery in terms of weight change, and evaluate factors associated with differential change. Methods The study included those recruited to the NHS DPP in 2017–2018. Individual-level data from a face-to-face cohort was compared to two cohorts on a digital pilot who (i) were offered no choice of delivery mode, or (ii) chose digital over face-to-face. Changes in weight at 6 and 12 months were analysed using mixed effects linear regression, having matched participants from the digital pilot to similar participants from face-to-face. Results Weight change on the digital pilot was non-inferior to face-to-face at both time points: it was similar in the comparison of those with no choice (difference in weight change: -0.284 kg [95% CI: -0.712, 0.144] at 6 months) and greater in digital when participants were offered a choice (-1.165 kg [95% CI: -1.841, -0.489]). Interactions between delivery mode and sex, ethnicity, age and deprivation were observed. Conclusions Digital delivery of the NHS DPP achieved weight loss at least as good as face-to-face. Patients who were offered a choice and opted for digital experienced better weight loss, compared to patients offered face-to-face only.

Introduction WHO guidelines on iron supplementation among children call for further research to identify the optimal schedule, duration, dose and cosupplementation regimen.Methods A systematic review and meta-analysis of randomised controlled trials was undertaken. Randomised controlled trials providing ≥30 days of oral iron supplementation versus placebo or control to children and adolescents aged 0.05), although serum ferritin levels and (after adjustment for baseline anaemia) haemoglobin levels increased more with frequent supplementation. Shorter (1–3 months) versus longer (7+ months) durations of supplementation generally showed similar benefits after controlling for baseline anaemia status, except for ferritin which increased more with longer duration of supplementation (p=0.04). Moderate-dose and high-dose supplements were more effective than low-dose supplements at improving haemoglobin (p=0.004), ferritin (p=0.008) and iron deficiency anaemia (p=0.02), but had similar effects to low-dose supplements for overall anaemia. Iron supplementation provided similar benefits when administered alone or in combination with zinc or vitamin A, except for an attenuated effect on overall anaemia when iron was cosupplemented with zinc (p=0.048).Conclusions Weekly and shorter duration iron supplementation at moderate or high doses might be optimal approaches for children and adolescents at risk of deficiency.Trial registration number CRD42016039948.

Background: Hemorrhage is a leading cause of preventable death in trauma. Accurately predicting a patient's blood transfusion requirement is essential but can be difficult. Machine learning (ML) is a field of artificial intelligence that is emerging within medicine for accurate prediction modeling. This systematic review aimed to identify and evaluate all ML models that predict blood transfusion in trauma., Methods: This systematic review was registered on the International Prospective register of Systematic Reviews (CRD4202237110). MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were systematically searched. Publications reporting an ML model that predicted blood transfusion in injured adult patients were included. Data extraction and risk of bias assessment were performed using validated frameworks. Data were synthesized narratively because of significant heterogeneity., Results: Twenty-five ML models for blood transfusion prediction in trauma were identified. Models incorporated diverse predictors and varied ML methodologies. Predictive performance was variable, but eight models achieved excellent discrimination (area under the receiver operating characteristic curve, >0.9) and nine models achieved good discrimination (area under the receiver operating characteristic curve, >0.8) in internal validation. Only two models reported measures of calibration. Four models have been externally validated in prospective cohorts: the Bleeding Risk Index, Compensatory Reserve Index, the Marsden model, and the Mina model. All studies were considered at high risk of bias often because of retrospective data sets, small sample size, and lack of external validation., Discussion: This review identified 25 ML models developed to predict blood transfusion requirement after injury. Seventeen ML models demonstrated good to excellent performance in silico, but only four models were externally validated. To date, ML models demonstrate the potential for early and individualized blood transfusion prediction, but further research is critically required to narrow the gap between ML model development and clinical application., Level of Evidence: Systematic Review Without Meta-analysis; Level IV., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Hemorrhage is the most common cause of preventable death after injury. Most deaths occur early, in the prehospital phase of care., Objective: To establish whether prehospital zone 1 (supraceliac) partial resuscitative endovascular balloon occlusion of the aorta (Z1 P-REBOA) can be achieved in the resuscitation of adult trauma patients at risk of cardiac arrest and death due to exsanguination., Design, Setting, and Participants: This was a prospective observational cohort study (Idea, Development, Exploration, Assessment and Long-term follow-up [IDEAL] 2A design) with recruitment from June 2020 to March 2022 and follow-up until discharge from hospital, death, or 90 days evaluating a physician-led and physician-delivered, urban prehospital trauma service in the Greater London area. Trauma patients aged 16 years and older with suspected exsanguinating subdiaphragmatic hemorrhage, recent or imminent hypovolemic traumatic cardiac arrest (TCA) were included. Those with unsurvivable injuries or who were pregnant were excluded. Of 2960 individuals attended by the service during the study period, 16 were included in the study., Exposures: ZI REBOA or P-REBOA., Main Outcomes and Measures: The main outcome was the proportion of patients in whom Z1 REBOA and Z1 P-REBOA were achieved. Clinical end points included systolic blood pressure (SBP) response to Z1 REBOA, mortality rate (1 hour, 3 hours, 24 hours, or 30 days postinjury), and survival to hospital discharge., Results: Femoral arterial access for Z1 REBOA was attempted in 16 patients (median [range] age, 30 [17-76] years; 14 [81%] male; median [IQR] Injury Severity Score, 50 [39-57]). In 2 patients with successful arterial access, REBOA was not attempted due to improvement in clinical condition. In the other 14 patients (8 [57%] of whom were in traumatic cardiac arrest [TCA]), 11 successfully underwent cannulation and had aortic balloons inflated in Z1. The 3 individuals in whom cannulation was unsuccessful were in TCA (failure rate = 3/14 [21%]). Median (IQR) pre-REBOA SBP in the 11 individuals for whom cannulation was successful (5 [46%] in TCA) was 47 (33-52) mm Hg. Z1 REBOA plus P-REBOA was associated with a significant improvement in BP (median [IQR] SBP at emergency department arrival, 101 [77-107] mm Hg; 0 of 10 patients were in TCA at arrival). The median group-level improvement in SBP from the pre-REBOA value was 52 (95% CI, 42-77) mm Hg (P < .004). P-REBOA was feasible in 8 individuals (8/11 [73%]) and occurred spontaneously in 4 of these. The 1- and 3-hour postinjury mortality rate was 9% (1/11), 24-hour mortality was 27% (3/11), and 30-day mortality was 82% (9/11). Survival to hospital discharge was 18% (2/11). Both survivors underwent early Z1 P-REBOA., Conclusions and Relevance: In this study, prehospital Z1 P-REBOA is feasible and may enable early survival, but with a significant incidence of late death., Trial Registration: ClinicalTrials.gov Identifier: NCT04145271.

There are no licensed vaccines for human cytomegalovirus (HCMV), and current antiviral drugs that target viral proteins are toxic and prone to resistance. Targeting host pathways essential for virus replication provides an alternate strategy that may reduce opportunities for drug resistance to occur. Oxidative stress is triggered by numerous viruses including HCMV. Peroxynitrite is a reactive nitrogen species that is formed during oxidative stress. Herein, we identified that HCMV rapidly induces the generation of intracellular peroxynitrite upon infection in a manner partially dependent upon xanthine oxidase generation. Peroxynitrite promoted HCMV infection in both cell-free and cell-associated infection systems in multiple cell types. Inhibiting peroxynitrite within the first 24 hours of infection prevented HCMV replication and peroxynitrite promoted cell entry and pp65 translocation into the host cell nuclei. Furthermore, using the murine cytomegalovirus model, we demonstrated that antagonizing peroxynitrite significantly reduces cytomegalovirus replication and pathogenesis in vivo . Overall, our study highlights a proviral role for peroxynitrite in CMV infection and implies that RNS and/or the mechanisms that induce their production could be targeted as a novel strategy to inhibit HCMV infection., Importance: Human cytomegalovirus (HCMV) causes significant disease in individuals with impaired or immature immune systems, such as transplant patients and after congenital infection. Antiviral drugs that target the virus directly are toxic and are susceptible to antiviral drug resistance due to virus mutations. An alternate strategy is to target processes within host cells that are required by the virus for replication. Herein, we show that HCMV infection triggers a highly reactive molecule, peroxynitrite, during the initial stages of infection. Peroxynitrite was required for the initial entry of the virus into the cell and promotes virus replication in multiple cell types, suggesting a broad pro-viral function. Importantly, targeting peroxynitrite dramatically inhibited cytomegalovirus replication in cells in the laboratory and in mice, suggesting that therapeutic targeting of this molecule and/or the cellular functions it regulates could represent a novel strategy to inhibit HCMV infection., Competing Interests: The authors declare no conflict of interest.

Background: Non-suicidal self-injury (NSSI) presents an increasingly prevalent problem for young people; however, there remains a scarce evidence base for effective, scalable treatments for adolescents. This study aimed to assess the feasibility and acceptability of a brief, cognitive analytic therapy (CAT)-informed intervention for young people who engage in NSSI (CATCH-Y)., Methods: A case series design recruited 13 young people who met the inclusion and exclusion criteria to participate in the five-session intervention. Eligible participants were aged 13-17 years (M = 15.15, SD = 1.28) and had engaged in NSSI at least once in the previous 6 months. Feasibility and acceptability were measured via recruitment, retention, qualitative feedback and missing data. The secondary outcome measures of personal recovery and motivation were administered pre- and post-assessment, with measures of depressive symptoms and urges to self-injure., Results: The intervention was found to be largely feasible and acceptable with high rates of recruitment, retention and pre-/post-assessment data completeness. Measures showed preliminary support for positive change in rates of NSSI, urges to self-harm, low mood and personal recovery, although results were mixed. Completion rates for remote assessments were low., Conclusions: The findings of this study support further evaluation of the CATCH-Y intervention on a larger scale. In-person assessments may be preferable to remote to ensure good completion rates., (© 2024 The Authors. Clinical Psychology & Psychotherapy published by John Wiley & Sons Ltd.)

Introduction: Trauma contributes to the greatest loss of disability-adjusted life-years for adolescents and young adults worldwide. In the context of global abdominal trauma, the trauma laparotomy is the most commonly performed operation. Variation likely exists in how these patients are managed and their subsequent outcomes, yet very little global data on the topic currently exists. The objective of the GOAL-Trauma study is to evaluate both patient and injury factors for those undergoing trauma laparotomy, their clinical management and postoperative outcomes., Methods: We describe a planned prospective multicentre observational cohort study of patients undergoing trauma laparotomy. We will include patients of all ages who present to hospital with a blunt or penetrating injury and undergo a trauma laparotomy within 5 days of presentation to the treating centre. The study will collect system, patient, process and outcome data, following patients up until 30 days postoperatively (or until discharge or death, whichever is first). Our sample size calculation suggests we will need to recruit 552 patients from approximately 150 recruiting centres., Discussion: The GOAL-Trauma study will provide a global snapshot of the current management and outcomes for patients undergoing a trauma laparotomy. It will also provide insight into the variation seen in the time delays for receiving care, the disease and patient factors present, and patient outcomes. For current standards of trauma care to be improved worldwide, a greater understanding of the current state of trauma laparotomy care is paramount if appropriate interventions and targets are to be identified and implemented., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Selective aortic arch perfusion (SAAP) is a novel endovascular technique that combines thoracic aortic occlusion with extracorporeal perfusion of the brain and heart. SAAP may have a role in both haemorrhagic shock and in cardiac arrest due to coronary ischaemia. Despite promising animal studies, no data is available that describes SAAP in humans. The primary aim of this study was to assess the feasibility of selective aortic arch perfusion in humans. The secondary aim of the study was to assess the feasibility of achieving direct coronary artery access via the SAAP catheter as a potential conduit for salvage percutaneous coronary intervention., Methods: Using perfused human cadavers, a prototype SAAP catheter was inserted into the descending aorta under fluoroscopic guidance via a standard femoral percutaneous access device. The catheter balloon was inflated and the aortic arch perfused with radio-opaque contrast. The coronary arteries were cannulated through the SAAP catheter., Results: The procedure was conducted four times. During the first two trials the SAAP catheter was passed rapidly and without incident to the intended descending aortic landing zone and aortic arch perfusion was successfully delivered via the device. The SAAP catheter balloon failed on the third trial. On the fourth trial the left coronary system was cannulated using a 5Fr coronary guiding catheter through the central SAAP catheter lumen., Conclusions: For the first time using a perfused cadaveric model we have demonstrated that a SAAP catheter can be easily and safely inserted and SAAP can be achieved using conventional endovascular techniques. The SAAP catheter allowed successful access to the proximal aorta and permitted retrograde perfusion of the coronary and cerebral circulation., (© 2023. Crown.)

Purpose of Review: The use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) to temporarily control bleeding and improve central perfusion in critically injured trauma patients remains a controversial topic. In the last decade, select trauma services around the world have gained experience with REBOA. We discuss the recent observational data together with the initial results of the first randomized control trial and provide a view on the next steps for REBOA in trauma resuscitation., Recent Findings: While the observational data continue to be conflicting, the first randomized control trial signals that in the UK, in-hospital REBOA is associated with harm. Likely a result of delays to haemorrhage control, views are again split on whether to abandon complex interventions in bleeding trauma patients and to only prioritize transfer to the operating room or to push REBOA earlier into the post injury phase, recognizing that some patients will not survive without intervention., Summary: Better understanding of cardiac shock physiology provides a new lens in which to evaluate REBOA through. Patient selection remains a huge challenge. Invasive blood pressure monitoring, combined with machine learning aided decision support may assist clinicians and their patients in the future. The use of REBOA should not delay definitive haemorrhage control in those patients without impending cardiac arrest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The appropriate use of regulatory agilities has the potential to accelerate regulatory review, utilize resources more efficiently and deliver medicines and vaccines more rapidly, all without compromising quality, safety and efficacy. This was clearly demonstrated during the COVID-19 pandemic where regulators and industry rapidly adapted to ensure continued supply of existing critical medicines and review and approve new innovative medicines. In this retrospective study, we analyze the impact of regulatory agilities on the review and approval of Pfizer/BioNTech's BNT162b2 mRNA COVID-19 Vaccine globally using regulatory approval data from 73 country/regional approvals. We report on the critical role of reliance and provide evidence that demonstrates reliance approaches and certain regulatory agilities reduced review times for the COVID-19 vaccine. These findings support the case for more widespread implementation of regulatory agilities and demonstrate the important role of such approaches to improve public health outcomes., Competing Interests: PP, JM, JB, MM, MZ, JR, HC, JC, SR, JO’B, and DB are full-time employees, and hold stock or stock options in Pfizer. KI-L was employed by Pfizer during the development of the manuscript and hold no stock or stock-options. RR is a full-time employee of BioNTech SE and holds stock or stock options in BioNTech., (Copyright © 2023 Patel, Macdonald, Boobalan, Marsden, Rizzi, Zenon, Ren, Chu, Cappelleri, Roychoudhury, O’Brien, Izaki-Lee and Boyce.)

Inhibitory CD4 + T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity. However, the mechanisms that underpin the development of these regulatory cells, especially in the context of ongoing antigen exposure, have remained obscure. To address this knowledge gap, we undertook a comprehensive functional, phenotypic, and transcriptomic analysis of interleukin (IL)-10-producing CD4 + T cells induced by chronic infection with murine cytomegalovirus (MCMV). We identified these cells as clonally expanded and highly differentiated T H 1-like cells that developed in a T-bet-dependent manner and coexpressed arginase-1 (Arg1), which promotes the catalytic breakdown of L-arginine. Mice lacking Arg1-expressing CD4 + T cells exhibited more robust antiviral immunity and were better able to control MCMV. Conditional deletion of T-bet in the CD4 + lineage suppressed the development of these inhibitory cells and also enhanced immune control of MCMV. Collectively, these data elucidated the ontogeny of IL-10-producing CD4 + T cells and revealed a previously unappreciated mechanism of immune regulation, whereby viral persistence was facilitated by the site-specific delivery of Arg1., Competing Interests: MC, KL, KM, MM, LC, AC, JS, RA, SC, VK, KL, OB, DW, SJ, DC, DP, IH No competing interests declared, (© 2023, Clement et al.)

Purpose: The burden of major trauma within the UK is ever increasing. There is a need to establish research priorities within the field. Delphi methodology can be used to develop consensus opinion amongst a group of stakeholders. This can be used to prioritise clinically relevant, patient-centred research questions to guide future funding allocations. The aim of our study was to identify key future research priorities pertaining to the management of major trauma in the UK., Methods: A three-phased modified Delphi process was undertaken. Phase 1 involved the submission of research questions by members of the trauma community using an online survey (Phase 1). Phases 2 and 3 involved two consecutive rounds of prioritisation after questions were subdivided into 6 subcategories: Brain Injury, Rehabilitation, Trauma in Older People, Pre-hospital, Interventional, and Miscellaneous (Phases 2 and 3). Cut-off points were agreed by consensus amongst the steering subcommittees. This established a final prioritised list of research questions., Results: In phase 1, 201 questions were submitted by 65 stakeholders. After analysis and with consensus achieved, 186 questions were taken forward for prioritisation in phase 2 with 114 included in phase 3. 56 prioritised major trauma research questions across the 6 categories were identified with a clear focus on long-term patient outcomes. Research priorities across the patient pathway from roadside to rehabilitation were deemed of importance., Conclusions: Consensus within the major trauma community has identified 56 key research questions across 6 categories. Dissemination of these questions to funding bodies to allow for the development of high-quality research is now required. There is a clear indication for targeted multi-centre multi-disciplinary research in major trauma., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)