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The contribution of sex hormones to cardiovascular disease, including arterial stiffness, is established; however, the role of sex chromosome interaction with sex hormones, particularly in women, is lagging. Arterial stiffness depends on the intrinsic properties and transmural wall geometry that comprise a network of cells and extracellular matrix (ECM) proteins expressed in a sex-dependent manner. In this study, we used four-core genotype (FCG) mice to determine the relative contribution of sex hormones versus sex chromosomes or their interaction with arterial stiffness. Gonadal intact FCG mice included females (F) and males (M) with either XX or XY sex chromosomes ( n = 9-11/group). We isolated the thoracic aorta, and a tissue puller was used to assess structural resistance to changes in shape under control, collagenase, or elastase conditions. We determined histological collagen area fraction and evaluated aortic ECM genes by PCR microarrays followed by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Stress-strain curves showed higher elastic modulus ( P < 0.001), denoting decreased distensibility in XXF compared with XYF aortas, which were significantly reversed by collagenase and elastase treatments ( P < 0.01). Aortic gene expression analysis indicated a significant reduction in Emilin1 , Thbs2 , and Icam1 in the XXF versus XYF aorta ( P < 0.05). Uniaxial stretching of XXF aortic vascular smooth muscle cells indicated decreased Thbs2 , Ctnna1 , and Ecm1 genes. We observed a significant ( P < 0.05) reduction in Masson's trichrome staining in collagenase but not elastase-treated aortic rings compared with the control. The increased aortic elastic modulus in XXF compared with XYF mice suggests a decrease in aortic distensibility mediated by a reduction in ECM genes. NEW & NOTEWORTHY FCG mice model can segregate vascular phenotypes by sex hormones, sex chromosomes, and their interaction. We show increased aortic stiffening in XX versus XY female mice and decreased ECM genes, suggesting decreased distensibility and impaired mechanotransduction in XXF versus XYF mice aortas. Therefore, the XX versus XY differences imply a unique role for sex chromosomes in regulating aortic integrity and ECM genes in female mice.

Background: Military-civilian partnerships (MCP) provide a bidirectional exchange of information and trauma best practices. In 2021, Penn Presbyterian Medical Center and the U.S. Navy signed a 3-year memorandum of understanding to embed active duty trauma providers into the Trauma Division to facilitate the training and sustainment of combat casualty care (CCC) skills. To date, there is little evidence to demonstrate the efficacy of military-civilian partnerships in maintaining combat casualty readiness in non-physician trauma providers., Methods: We evaluated the impact of combat casualty readiness for non-physician providers by mapping clinical experiences in an urban Level I trauma center against the Defense Health Agency's Joint Trauma Systems (JTS) Clinical Practice Guidelines (CPG). The JTS CPGs provide best practices for CCCand highlight the critical skills providers need to know before deploying to an austere environment. Patient acuity data and specific JTS CPG skills performed by a non-physician providers were collected in their respective specialties for each patient seen between January 2023 to January 2024. Analyses were performed using descriptive statistics via Redcap., Results: A sample of 6 Navy personnel in different specialties: 1 Physician Assistant, 3 Registered Nurses (emergency medicine, perioperative, critical care), and 2 corpsmen (scrub tech and search & rescue/prehospital medic) completed 1299 records on patients treated. In all, 685 (52.7%) were trauma patients and 614 (47.3%) were non-trauma patients. Categories of injuries seen, listed from the most frequent to the least, were as follows: Other (764), Falls (250), Motor Vehicle Crashes (164), Gunshot Wound (126), Stab-related injuries (41). Category 1 skills, defined as "essential to know," were performed in 921 (36.1%) of the patients treated. In Category 2, skills described as "important to know" were performed in 889 (34.8%) of the patients treated. Category 3 skills, identified as "less urgent" as they are rare among trauma patients, were performed in 486 (19.0%) of the patients treated, and 252 (9.8%) required none of the JTS CPG skills. These categories were further broken down based on the frequency of the skills performed. Analysis revealed strengths and identified opportunities to direct clinical experience for underperforming skills., Conclusion: Military-civilian partnerships support CCC readiness. The data presented and the continuation of mapping personnel's clinical experience to military CPGs can gauge readiness in non-physician trauma providers. Notably, several skills in each category were identified as opportunities to modify the clinical exposure of the military provider. These findings indicate that modifications in clinical assignments could enhance active duty combat casualty readiness in these critical skills., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Introduction: The definition of pulmonary hypertension (PH) was recently changed and led to a new subset of PH patients with mildly impaired pulmonary haemodynamics, characterised by a mean pulmonary artery pressure (mPAP) of 21-24 mmHg and with a pulmonary vascular resistance (PVR) >2 WU. We evaluated the association of PH-targeted therapy and outcome in mild precapillary PH using the PVRI GoDeep meta-registry., Methods: All patients with mild precapillary PH (mPAP 21-24 mmHg, pulmonary arterial wedge pressure ≤15 mmHg and PVR >2 WU) diagnosed with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) were enrolled. Patients were considered as "treated" if PH-targeted therapy was initiated within 6 months of diagnostic right heart catheterisation. Various statistical models, including in-depth sensitivity analyses, were used to examine the association between PH-targeted therapy and transplant-free survival., Results: 132 patients with group 1 or group 4 mild PH were identified, of whom 34 patients received PH-targeted therapy. There were no differences in baseline haemodynamics between untreated and treated groups, whereas treated patients suffered more frequently from renal comorbidities and required long-term oxygen treatment more often. Most prescribed were phosphodiesterase-5-inhibitors. PH-targeted therapy was associated with significantly higher survival rates. Cox-regression analyses revealed significantly reduced hazard ratios among treated patients adjusted for various confounders. Subgroup analyses in PAH (n=78) similarly indicated higher survival rates and reduced hazard ratios in treated patients., Conclusion: PH-targeted therapy may be associated with improved survival in PAH and CTEPH patients with mild PH. To mitigate potential bias of the results due to the retrospective study design, randomised controlled trials are warranted., Competing Interests: Conflict of interest: A. Yogeswaran reports nonfinancial support from the University of Giessen during the conduct of the study, and personal fees from MSD outside the submitted work. P.M. Hassoun reports personal fees from Merck Co., outside the submitted work. M.R. Wilkins reports personal fees from MorphogenIX, Janssen, Chiesi and Aerami, grants from the British Heart Foundation and the NIHR, personal fees from MSD, Benevolent AI and Tiakis Biotech, outside the submitted work; in addition, M.R. Wilkins has a patent Zip12 as a drug target issued. Dr Howard reports personal fees and nonfinancial support from Janssen, personal fees from MSD, personal fees from Gossamer, personal fees from Altavant, outside the submitted work. H.A. Ghofrani reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the study, and personal fees from Bayer, Actelion, Pfizer, Merck, GSK and Takeda, grants and personal fees from Novartis, Bayer HealthCare and Encysive/Pfizer, and grants from Aires, the German Research Foundation, Excellence Cluster Cardiopulmonary Research and the German Ministry for Education and Research, outside the submitted work. W. Seeger reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the study, and personal fees from Pfizer and Bayer Pharma AG outside the submitted work. K. Tello reports nonfinancial support from the University of Giessen during the conduct of the current study and speaker honoraria from Actelion and Bayer outside the submitted work. All other authors declare no conflicts of interest., (Copyright ©The authors 2025.)

Background: As the lifespan of people with cystic fibrosis (pwCF) improves, more individuals are pursuing pregnancy. Historically, pregnancy was not recommended in this population; however, more recent evidence has revealed inconsistent survival and lung function outcomes. Our aim was to assess the differences in survival and lung function between pregnant and never-pregnant pwCF and to provide updated recommendations for contemporary clinical practice., Methods: In this retrospective matched parallel cohort study, data was collected from the American Cystic Fibrosis Foundation Patient Registry (CFFPR) from 1999 to 2019. 1743 adult pwCF with a reported pregnancy were matched with 1743 never-pregnant patients. Regression models were developed to estimate associations between patient characteristics, pregnancy, and outcomes. The primary endpoint was the probability of survival comparing pregnant and never-pregnant pwCF, while the secondary endpoint was lung function over time., Results: The study cohort (n = 3486) had a mean age of 24.96 years. There was no significant difference in survival probabilities between pregnant and never-pregnant pwCF (56.2 %, CI 95 % : 51.3 %-61.5 % vs. 55.8 %, CI 95 % : 52.1 %-59.7 %, p = 0.5). The multivariable time-dependent Cox regression analysis resulted in a significantly lower mortality hazard rate for pregnant cohorts (HR:0.78, p < 0.01). There was no significant association between pregnancy and lung function over time (0.99, p = 0.21)., Conclusion: Pregnancy was associated with a reduced hazard of death compared to never-pregnant pwCF and did not demonstrate a significant impact on lung function. Therefore, pregnancy should not be generally discouraged in pwCF and clinicians should evaluate pregnancy risks and benefits on an individualized basis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Over the past few decades, the gonadotropin-releasing hormone agonist goserelin has been evaluated in ovarian function suppression (OFS) with adjuvant endocrine therapy and ovarian function preservation (OFP) during chemotherapy., Objective: The goal of this systematic literature review was to assess the efficacy of goserelin in OFS and OFP in combination with endocrine therapies and chemotherapy, respectively, in pre- and perimenopausal women with early-stage breast cancer., Design: This study is a systematic review., Data Sources and Methods: The literature search was conducted using PubMed. Prospective clinical studies evaluating the efficacy of goserelin in OFS or OFP in pre- or perimenopausal breast cancer were identified by four reviewers working in teams of two., Results: Twenty-nine studies were included in this systematic review. The addition of goserelin as OFS to adjuvant endocrine therapy generally resulted in significant benefits in disease-free survival. Studies have shown better OFP results among women 40 years or younger compared with older patients. Chemotherapy in association with goserelin for OFP resulted in a higher recovery rate of menses within 6-24 months, a shorter time for menstrual recovery, and significantly higher pregnancy rates when compared with cytotoxic therapy without goserelin. Hormonal recovery with higher anti-Müllerian hormone and estradiol levels, and lower follicle-stimulating hormone and luteinizing hormone levels occurred more frequently among women who received goserelin during chemotherapy as compared with those receiving cytotoxic therapy alone. The benefits of goserelin in OFP were more substantial among women 40 years or younger than in older patients., Conclusion: The findings of this systematic review highlight the benefits of adding goserelin to endocrine therapies for OFS and chemotherapy for OFP in early-stage breast cancer. Additionally, scientific data supporting OFS (including goserelin) in combination with newer agents such as cyclin-dependent kinase 4 and 6 inhibitors and bone-modifying agents are emerging., Competing Interests: N.C. reports advisory roles for Novartis, Stemline Therapeutics, Seagen, and Guardant Health. She reports institutional research funding from Eli Lilly. D.A.B. received a grant from Conquer Cancer, The ASCO Foundation. H.J.K. received a research fund from Patient-Centered Clinical Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea. S.S., J.C., and N.O. are employees of TerSera Therapeutics, LLC. R.M. was an employee of TerSera Therapeutics, LLC at the time the systematic literature review was initiated. M.L. reports advisory role for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, Menarini; speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Takeda, Menarini, AstraZeneca; travel grants from Gilead, Daiichi Sankyo, Roche; research funding (to the Institution) from Gilead all outside the submitted work., (© The Author(s), 2025.)

Background: Previous studies have demonstrated the safety of pulmonary endarterectomy (PEA) across body mass index (BMI) strata. However, long-term survival and patient-reported outcome measures by BMI strata remain unknown. We examined the impact of preoperative BMI on long-term survival, QOL, and functional outcomes for patients undergoing PEA for chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: Retrospective review of 2,004 patients from the UK National Cohort between 2007 and 2021 undergoing PEA for CTEPH (mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance >160 dynes). Patients were stratified into BMI<20, 20 to 29, 30 to 39, 40 to 49, and 50+. All-cause mortality was the primary outcome measure. Secondary outcome measures were 3- to 6-month postoperative hemodynamics, 6-minute walk distance (6MWD), New York Heart Association (NYHA) class, and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) scores., Results: Hemodynamics and 6MWD at 3 to 6 months were similar across BMI strata. Patients with BMI 50+ reported the highest incidence of postoperative NYHA III/IV limitation (53.3%, p < 0.001) and the highest residual symptom burden by CAMPHOR (p < 0.001). Five-year survival was lowest in patients with BMI 50+ (70.2%) and BMI<20 (73.4%), while highest in BMI 30 to 39 (88.2%, p = 0.008). Ten-year Kaplan-Meier estimates predicted the lowest survival in BMI 50+ and BMI<20., Conclusions: PEA remains safe and effective for all patients regardless of BMI. Despite similar hemodynamic outcomes, patients with BMI 50+ are at the greatest risk of long-term all-cause mortality, and patients with BMI 50+ experience residual symptomatic limitation., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: People with dementia and carers can face many barriers, or inequalities, in accessing a diagnosis or care. These barriers are unjust and can be addressed by the right interventions, to ensure that everyone receives equitable access to diagnosis and care. A lack of knowledge about dementia in the health and social care workforce is a recognised barrier. The Dementia Inequalities Game was co-produced with people with personal, professional, and voluntary sector experiences of dementia, and offers an educational tool to educate people about dementia and associated inequalities and overcome this knowledge gap in the current and future (in training) workforce. Aims: The aim of this study was to assess the impact of playing the co-produced Dementia Inequalities Game on knowledge about dementia and associated inequalities in health care, allied health professional, nursing and psychology students. Methods: We conducted 11 game play workshops as part of regular teaching in undergraduate and postgraduate courses in psychology, nursing, occupational therapy, physiotherapy, orthoptics, and radiography at one University in the North of England. Students did not have to partake in the workshops. Participating students completed a brief before and after knowledge questionnaire about dementia and inequalities. Paired samples t-tests were used to compare ratings of knowledge of dementia and associated inequalities before and after game play. Findings: Three-hundred-and-eighteen students took part in the workshops, with 312 fully completed questionnaires. The largest cohort of students (49%) were studying for a degree in nursing. Playing the game significantly increased knowledge about dementia ( p < .001) and dementia inequalities ( p < .001). Implications: Playing the Dementia Inequalities Game is an effective tool to improve knowledge about dementia and associated inequalities in health care and psychology students. Using the game as an educational and sociable intervention in health and social care professionals is a next avenue to test., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Risk prediction tools are routinely utilised in cardiothoracic surgery but have not been developed for pulmonary endarterectomy (PEA). There is no data on whether patients undergoing PEA may benefit from a tailored risk modelling approach. We develop and validate a clinically-usable tool to predict PEA 90-day mortality (90 DM) with the secondary aim of informing factors that may influence five-year mortality (5 YM) and improvement in patient-reported outcomes (PROchange) using common clinical assessment parameters. Derived model predictions were compared to those of the currently most widely implemented cardiothoracic surgery risk tool, EuroSCORE II., Methods: Consecutive patients undergoing PEA for chronic thromboembolic pulmonary hypertension (CTEPH) between 2007 and 2018 (n=1334) were included in a discovery dataset. Outcome predictors included an intentionally broad array of variables, incorporating demographic, functional and physiological measures. Three statistical models (linear regression, penalised linear regression and random forest) were considered per outcome, each calibrated, fitted and assessed using cross-validation, ensuring internal consistency. The best predictive models were incorporated into an open-source PEA risk tool and validated using a separate prospective PEA cohort from 2019 to 2021 (n=443) at the same institution., Results: Random forest models had the greatest predictive accuracy for all three outcomes. Novel risk models had acceptable discriminatory ability for outcome 90 DM (AUROC 0.82) outperforming that of EuroSCORE II (AUROC 0.65). CTEPH related factors were important for outcome 90 DM but 5 YM was driven by non-CTEPH factors, dominated by generic cardiovascular risk. We were unable to accurately predict a positive improvement in PRO status (AUROC 0.47)., Conclusions: Operative mortality from PEA can be predicted pre-operatively to a potentially clinically useful degree. Our validated models enable individualised risk stratification at clinician point-of-care to better inform shared decision making., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Burns are one of the most common injuries in both civilian and combat settings and are difficult to treat. This is particularly true when the wounds are infected with antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). A new generation of safe, broadly effective, and easily applied anti-infection agents is needed to successfully prevent and treat infections. Nanoemulsions (NEs) are nanometer-sized particles with a positively charged surfactant at their oil-water interface. In the current study, we further investigated antimicrobial NEs as a treatment to address burn wounds infected by MRSA. Specifically, using a porcine skin model, we infected partial thickness thermal burn wounds with MRSA and then treated it with the nanoemulsion formulation (NB-201) or placebo controls. Bacterial viability after treatment was determined, and inflammation indexes in wounds were scored by histopathology. Topical treatment of infected wounds with NB-201 resulted in reduced colony-forming units (CFUs) compared to placebo treatment. In addition, NB-201 was effective in significantly alleviating inflammation in the treated wounds and promoting wound healing. These results indicate that NB-201 is a promising new agent to treat skin burn wounds infected with MRSA., Importance: The findings of this study are focused on therapeutic applications of nanotechnology. In the current study, we demonstrated that a nanoemulsion formulation could effectively kill methicillin-resistant Staphylococcus aureus (MRSA) infection in porcine skin burn wounds. Infection of MRSA in burn wound is a common threat to public health and is usually difficult to treat due to limited therapies available. NB-201 was effective in significantly alleviating inflammation in the treated wounds and promoting wound healing. Therefore, the finding of this study has a great potential to make this formulation a novel antimicrobial agent against MRSA., Competing Interests: The authors declare no conflict of interest.

Background: The Mettler-Toledo 7000RMS analyzer is a bio-fluorescent particle counter (BFPC) used to monitor real-time bioburden results from purified water (PW)., Objective: Validation of the analyzer using 13 microorganisms and a low-intensity, fluorescent, polystyrene bead., Methods: During the execution of the validation, a laboratory water system that met PW quality standards was connected to the 7000RMS, and a syringe pump was used to introduce various concentrations of microorganisms and fluorescent polystyrene beads to the analyzer. Samples were collected and tested via the traditional membrane filtration (MF) method and the colony-forming unit (CFU) plate count results were compared to the auto-fluorescent unit (AFU) of the 7000RMS analyzer. The validation study was designed to follow the guidance in United States Pharmacopeia (USP) Chapter <1223>, European Pharmacopeia (EP) Chapter 5.1.6, and parenteral drug association (PDA) Technical Report 33. Concepts and strategies were adapted from EP Chapter 2.6.12 Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests, EP Chapter 10.2, EP Chapter 2.6.1 Sterility, USP Chapter <61> Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests, USP Chapter <71> Sterility Tests, and Japanese Pharmacopoeia (JP) General Information Chapter G8 Water: Quality Control of Water for Pharmaceutical Use., Results: All pre-determined validation acceptance criteria for accuracy, specificity, precision, LOD, LOQ, linearity, and range were met., Conclusions: The 7000RMS demonstrated performance equivalence to the MF method per USP <1223> but characteristically lacked correlation to the CFU., Highlights: This validation approach highlights the superior capabilities of the 7000RMS when compared against the traditional compendial MF testing method for PW., (© The Author(s) 2024. Published by Oxford University Press on behalf of AOAC INTERNATIONAL.)

Several steps in the abattoir can influence the presence of microbes and associated resistance genes (ARGs) on the animal carcasses used for further meat processing. We investigated how these processes influence the resistome-microbiome of groups of pigs with different on-farm antimicrobial exposure status, from the moment they entered the abattoir until the end of carcass processing. Using a targeted enrichment metagenomic approach, we identified 672 unique ARGs conferring resistance to 43 distinct AMR classes from pooled skin (N = 42) and carcass swabs (N = 63) collected sequentially before, during, and after the slaughter process and food safety interventions. We observed significant variations in the resistome and microbial profiles of pigs before and after slaughter, as well as a significant decline in ARG counts, diversity, and microbial DNA load during slaughter and carcass processing, irrespective of prior antimicrobial treatments on the farm. These results suggest that existing interventions in the abattoir are effective in reducing not only the pathogen load but also the overall bacterial burden, including ARGs on pork carcasses. Concomitant with reductions in microbial and ARG counts, we observed an increase in the relative abundance of non-drug-specific ARGs, such as those conferring resistance to metals and biocides, and in particular mercury. Using a strict colocalization procedure, we found that most mercury ARGs were associated with genomes from the Pseudomonadaceae and Enterobacteriaceae families. Collectively, these findings demonstrate that slaughter and processing practices within the abattoir can shape the microbial and ARG profiles of pork carcasses during the transition from living muscle to meat., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The golf swing has been associated with mechanical injury risk factors at many joints. One swing, the Minimalist Golf Swing, was hypothesised to reduce lumbar spine, lead hip, and lead knee ranges of motion and peak net joint moments, while affecting swing performance, compared to golfers' existing swings. Existing and MGS swings of 15 golfers with handicaps ranging from +2 to -20 were compared. During MGS downswing, golfers had 18.3% less lumbar spine transverse plane ROM, 40.7 and 41.8% less lead hip sagittal and frontal plane ROM, and 39.2% less lead knee sagittal plane ROM. MGS reduced lead hip extensor, abductor, and internal rotator moments by 17.8, 19.7 and 43%, while lead knee extensor, abductor, adductor and external rotator moments were reduced by 24.1, 26.6, 37 and 68.8% respectively. With MGS, club approach was 2° shallower, path 4° more in-to-out and speed 2 m/s slower. MGS reduced certain joint ROM and moments that are linked to injury risk factors, while influencing club impact factors with varying effect. Most golf injuries are from overuse, so reduced loads per cycle with MGS may extend the healthy life of joints, and permit golfers to play injury-free for more years.

Objective This study aims to describe the pattern and trends in acute rheumatic fever (ARF)/rheumatic heart disease (RHD)-related hospitalisations and costs for Australians aged <65 years. Methods This retrospective linked data study measured trends in hospitalisations and costs for ARF, RHD and complications of ARF/RHD in Northern Territory, South Australia, Western Australia, Queensland and New South Wales between 1 July 2012 and 30 June 2017. Persons with ARF/RHD were identified from RHD registers and/or hospital records. Results Over the 5-year study period, 791 children, aged <16years (86.3% Indigenous), and 2761 adults, aged 16-64years (44.8% Indigenous), were hospitalised for ARF, RHD or associated complications. On average there were 296 paediatric admissions per year, increasing 6.1% annually (95% CI: 2.4-9.6%, P =0.001) and 1442 adult admissions per year, increasing 1.7% annually (95% CI: 0.1-3.4%, P =0.03). Total 5-year costs were AU$130.6m (AU$17.6m paediatric, AU$113.0m adult). Paediatric costs were mostly for ARF-related admissions whereas adult costs mostly involved valvular surgery. Emergency admissions and air ambulance transfers were common, particularly for non-metropolitan residents. Conclusions Successful ARF/RHD prevention would deliver significant hospital cost savings. Investment in primary and specialist health care in regional areas may reduce emergency admissions and regional transfers, further reducing hospital burden.

Group A Streptococcus (Strep A) skin infections (impetigo) can contribute to the development of acute rheumatic fever (ARF) and rheumatic heart disease (RHD). This is of particular concern for Indigenous residents of remote communities, where rates of ARF and RHD are much higher than their urban and non-Indigenous counterparts. There are three main potential Strep A transmission pathways: skin to skin, surface to skin, and transmission through the air (via droplets or aerosols). Despite a lack of scientific certainty, the physical environment may be modified to prevent Strep A transmission through environmental health initiatives in the home, identifying a strong role for housing. This research sought to provide an outline of identified household-level environmental health initiatives to reduce or interrupt Strep A transmission along each of these pathways. The identified initiatives addressed the ability to wash bodies and clothes, to increase social distancing through improving the livability of yard spaces, and to increase ventilation in the home. To assist with future pilots and evaluation, an interactive costing tool was developed against each of these initiatives. If introduced and evaluated to be effective, the environmental health initiatives are likely to also interrupt other hygiene-related infections.

Background and Purpose: Healthcare is responsible for 5.4% of greenhouse gas emissions in the UK. Emissions in surgery is a relatively unexplored area; in particular, this hasn't yet been looked at as a whole in ENT in the UK. The purpose of the study was to quantify the amount of greenhouse gas (GHG) emission from a tonsillectomy and assess the proportion of each source's contribution., Methods: Operational data from tonsillectomies performed at a large university teaching hospital in the UK were gathered and converted to global warming potential using established conversion factors and data from existing healthcare-focused carbon footprint studies. The domains considered were waste, pharmaceuticals, surgical instrument decontamination, transportation, consumables use and utilities. This study used a process-based carbon footprint approach based on the "Greenhouse Gas Protocol: Product Life Cycle Accounting and Reporting Standard"., Main Findings: The carbon footprint of a typical case was 41 kgCO2e which is equivalent to driving a car for approximately 150 miles. Consumables were responsible for 17% of this; 14% came from transport, 5.4% from decontamination, 4.8% from pharmaceuticals and 4% from waste. However, the largest GHG was from utilities, of which heating, ventilation and air conditioning was the overwhelming contributor., Conclusions: While the largest sources of GHG emissions require hospital-wide initiatives, there are aspects of consumables and waste streams we can improve on in ENT surgery. These include the use of disposable vs reusable instruments as well as increased availability and use of recycling waste streams in theatres. Additionally, this study provides a template that can be applied to other ENT procedures., Competing Interests: Declaration of competing interest No conflicts exist for all authors., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: With no approved therapies for pulmonary hypertension (PH) associated with interstitial lung disease (PH-ILD) in Europe, we surveyed clinician perceptions on PH-ILD management and unmet need to understand current real-world practices., Methods: An online clinician survey on PH-ILD management was conducted in France, Germany, Italy, Spain and the UK., Results: 55 clinicians (78% pulmonologists), each managing a median 20 PH-ILD patients (interquartile range (IQR) 10-50), participated. Upon PH suspicion, clinicians referred a median 50% (IQR 20-73%) of patients for echocardiography alone and 35% (IQR 20-78%) for echocardiography, followed by right heart catheterisation. Upon diagnosis, a median 20% (IQR 9-30%), 40% (IQR 20-50%) and 35% (IQR 20-55%) of patients fell under the pulmonary arterial pressure ranges of 21-24 mmHg, 25-34 mmHg and >35 mmHg, respectively. 50% of patients received off-label treatment for their PH and, of those, off-label phosphodiesterase-5 inhibitor (PDE-5i), endothelin receptor antagonist (ERA) and prostacyclin analogues were prescribed first-line by 78%, 9% and 7% of clinicians, respectively. Upon PDE-5i non-response, 35% of clinicians proceed with an ERA, 35% with no further therapy. 55% of clinicians used dual-therapy. Yearly median inpatient admissions and emergency visits were 2.0 (IQR 1.3-2.9) and 1.5 (IQR 1.0-2.0), respectively (n=31 responses). Most clinicians (69%) highlighted lack of efficacy or evidence for current therapies as a key gap in PH-ILD management., Conclusions: This study gives insight into real-world European PH-ILD diagnosis and management. With significant use of off-label treatment, there is a large unmet need due to lack of approved therapies. Despite updated guidelines, more evidence is needed to standardise PH-ILD management., Competing Interests: Conflict of interest: S. Ghio, H. Nunes, J.M. Cifrián, R.P. Rojo and A. Guenther report no conflict of interest. D. Montani reports receiving grants and personal fees from Actelion, Bayer, GSK, Pfizer, MSD, Chiesi, Boehringer and Acceleron. F. Meloni reports having participated in advisory boards for Zambon and Boehringer. J. Cannon reports having received honorarium for attending and speaking at Janssen and Ferrer advisory boards and international conferences. L. Howard reports having received honoraria from Ferrer. H.G. García, M.F. Delgado and G.B. Jeanneret are employed by Ferrer Pharma Ltd., (Copyright ©The authors 2024.)

Recent results suggest that autistic individuals exhibit reduced accuracy compared to non-autistic peers in temporally coordinating their actions with predictable external cues, e.g., synchronizing finger taps to an auditory metronome. However, it is not yet clear whether these difficulties are driven primarily by motor differences or extend into perceptual rhythmic timing tasks. We recruited autistic and non-autistic participants for an online study testing both finger tapping synchronization and continuation as well as rhythmic time perception (anisochrony detection). We fractionated each participant's synchronization results into parameters representing error correction, motor noise, and internal time-keeper noise, and also investigated error-correcting responses to small metronome timing perturbations. Contrary to previous work, we did not find strong evidence for reduced synchronization error correction. However, we found compelling evidence for noisier internal rhythmic timekeeping in the synchronization, continuation, and perceptual components of the experiment. These results suggest that noisier internal rhythmic timing processes underlie some sensorimotor coordination challenges in autism., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Pawan Sinha reports financial support was provided by Simons Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objectives: For many people with dementia and unpaid carers, using technology for care and support has become essential. Rapid proliferation of technology highlights the need to understand digital access to health and social care services for dementia. This mixed-methods systematic review aims to explore digital access to health and social care services for dementia, from the perspective of people with dementia and unpaid carers., Methods: Nine electronic databases were searched in May 2023 for qualitative, quantitative, or mixed-method studies, published in English or German, focused on experiences of using technology-delivered health and social care services for people with dementia and unpaid carers. After removal of duplicates and screening, 44 empirical papers were included., Results: From the 44 studies, findings were grouped into five categories, highlighting experiences for people with dementia and unpaid carers: (1) Adapting to technology, (2) Inequalities and variations in outcomes, (3) Impact on caring, (4) Impact on health, and (5) Impact on relationships. Proliferation of technology in care access emphasised the need for quick adaptation to technology and examination of its impact. The impact of such service delivery has evidenced mixed findings. There were improvements in the health and wellbeing of people with dementia and unpaid carers, and benefits for their dyadic relationship. However, using technology for health and social care access is not always possible and is often reliant on unpaid carers for support. Lower tech-literacy, lack of equipment or money to buy equipment and poor internet connection can impact the potential for positive outcomes., Conclusions: Technology can bring great benefits: social inclusion, improved service access and care. However, using technology in service delivery in dementia needs careful thought. Professionals and service providers need to be cognizant of the complex nature of dementia, and the benefits and challenges of hybrid service delivery., (© 2024 The Author(s). International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Areas Covered: This paper outlines the selection of NAMs, including in vitro assays using primary rat cortical neurons, zebrafish embryos, and Caenorhabditis elegans . These assays aim to assess neurotoxic endpoints such as neuronal activity and behavioral responses. Microelectrode array recordings of rat cortical neurons provide insights into the impact of botanical extracts on neuronal function, while the zebrafish embryos and C. elegans assays evaluate neurobehavioral responses. The paper also provides an account of the selection of botanical case studies based on expert judgment and existing neuroactivity/toxicity information. The proposed battery of assays will be tested with these case studies to evaluate their utility for neurotoxicity screening., Expert Opinion: The complexity of botanicals necessitates the use of multiple NAMs for effective neurotoxicity screening. This paper discusses the evaluation of methodologies to develop a robust framework for evaluating botanical safety, including complex neuronal models and key neurodevelopmental process assays. It aims to establish a comprehensive screening framework.

Objective: To assess asymptomatic rates and severity of SARS-CoV-2 infection in people with epilepsy and their healthcare workers in a long-term care facility which had implemented weekly surveillance testing between April 2020 and June 2022., Methods: Questionnaires focused on objective and subjective COVID-19 symptoms for people with epilepsy residing in and their healthcare workers at the Chalfont Centre for Epilepsy in June 2022. Demographic information, comorbidities, and seizure frequency were gathered from medical records. We also collected responses on objective and subjective COVID-19 symptoms from healthcare workers who participated in a prospective study assessing the reaction to COVID-19 vaccinations (SAFER)., Results: Fifty-five out of 89 (62%) residents tested positive at least once on weekly PCR testing for SARS-CoV-2 during the period of interest; 20 of those (37%) were asymptomatic. In comparison, of those 63 healthcare workers who tested positive at least once on weekly testing during the same period, only four (6%) were asymptomatic. Of the 159 healthcare workers who also participated in the SAFER study, 41 tested positive at least once, and seven (17%) were completely asymptomatic during infection with SARS-CoV-2., Significance: People with epilepsy living in a long-term care facility were more likely to present with asymptomatic SARS-CoV-2 infections than healthcare workers at the same facility. Despite possible bias in the reporting of subjective symptoms due to management-by-proxy, there is no evidence that vulnerable people living in an epilepsy long-term care facility showed reduced resilience towards infections., Plain Language Summary: People with epilepsy living in care home facilities had a surprisingly high degree of asymptomatic infections with SARS-CoV-2. Very few residents had severe or fatal outcomes. This is in stark contrast to the widely reported bad outcomes for people without epilepsy in other care homes. People with epilepsy reported significantly less symptoms than their healthcare workers. No changes in seizure frequency during or after infection were observed., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Purpose: Predictions are complex, multisensory, and dynamic processes involving real-time adjustments based on environmental inputs. Disruptions to prediction abilities have been proposed to underlie characteristics associated with autism. While there is substantial empirical literature related to prediction, the field lacks a self-assessment measure of prediction skills related to daily tasks. Such a measure would be useful to better understand the nature of day-to-day prediction-related activities and characterize these abilities in individuals who struggle with prediction., Methods: An interdisciplinary mixed-methods approach was utilized to develop and validate a self-report questionnaire of prediction skills for adults, the Prediction-Related Experiences Questionnaire (PRE-Q). Two rounds of online field testing were completed in samples of autistic and neurotypical (NT) adults. Qualitative feedback from a subset of these participants regarding question content and quality was integrated and Rasch modeling of the item responses was applied., Results: The final PRE-Q includes 19 items across 3 domains (Sensory, Motor, Social), with evidence supporting the validity of the measure's 4-point response categories, internal structure, and relationship to other outcome measures associated with prediction. Consistent with models of prediction challenges in autism, autistic participants indicated more prediction-related difficulties than the NT group., Conclusions: This study provides evidence for the validity of a novel self-report questionnaire designed to measure the day-to-day prediction skills of autistic and non-autistic adults. Future research should focus on characterizing the relationship between the PRE-Q and lab-based measures of prediction, and understanding how the PRE-Q may be used to identify potential areas for clinical supports for individuals with prediction-related challenges., (© 2024. The Author(s).)

Some theories have proposed that autistic individuals have difficulty learning predictive relationships. We tested this hypothesis using a serial reaction time task in which participants learned to predict the locations of a repeating sequence of target locations. We conducted a large-sample online study with 61 autistic and 71 neurotypical adults. The autistic group had slower overall reaction times, but demonstrated sequence-specific learning equivalent to the neurotypical group, consistent with other findings of typical procedural memory in autism. The neurotypical group, however, made significantly more prediction-related errors early in the experiment when the stimuli changed from repeated sequences to random locations, suggesting certain limited behavioural differences in the learning or utilization of predictive relationships for autistic adults., (© 2023. The Author(s).)

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac ventricular wall stress that is incorporated into pulmonary hypertension (PH) risk stratification models. Sendaway sampling may enable patients to perform NT-proBNP tests remotely. This UK-wide study aimed to assess the agreement of sendaway NT-proBNP with standard venous NT-proBNP and to assess the effect of delayed processing., Methods: Reference venous NT-proBNP was collected from PH patients. Samples for capillary and venous sendaway tests were collected contemporaneously, mailed to a reference laboratory and processed at 3 and 7 days using a Roche Cobas e411 device. Differences in paired measurements were analysed with Passing-Bablok regression, percentage difference plots and the % difference in risk strata., Results: 113 patients were included in the study. 13% of day 3 capillary samples were insufficient. Day 3 capillary samples were not equivalent to reference samples (Passing Bablok analysis slope of 0.91 (95% CI 0.88 to 0.93) and intercept of 6.0 (95% CI 0.2 to 15.9)). The relative median difference was -7% and there were acceptable limits of agreement. Day 3 capillary NT-proBNP accurately risk stratified patients in 93.5% of cases. By comparison, day 3 venous results accurately risk stratified patients in 90.1% of cases and were equivalent by Passing-Bablok regression. Delayed sampling of sendaway tests led to an unacceptable level of agreement and systematically underestimated NT-proBNP., Conclusions: Sendaway NT-proBNP sampling may provide an objective measure of right ventricular strain for virtual PH clinics. Results must be interpreted with caution in cases of delayed sampling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches., Competing Interests: Dr Frances Varian: MRC clinical fellow, travel and conference funding from Janssen Ltd. Dr Jennifer Dick, Mr Christian Battersby, Mr Stefan Roman, Miss Jenna Ablott, Dr Lisa Watson, Mrs Sarah Bizmahfooz, and Dr Hamza Zafar: none declared. Dr Gerry Colgan: no direct conflicts, has undertaken consultancy work & honoraria for Janssen Ltd, Bayer Ltd, MSD. Received research funding from Janssen Ltd. Dr John Cannon: support to attend conferences from Janssen and been paid for advisory boards by Janssen and Ferrer. Jay Suntharalingam and Dr Jim Lordan: none declared. Professor Luke Howard: I have received honoraria for advisory boards, steering committees, and speaking from Janssen. My department has received research funding support from Janssen. I have received personal support for travel, accommodation, and registration at international meetings. I have received honoraria for advisory boards and speaking from MSD. I have received honoraria for advisory boards from Endotronix. Colm McCabe: none declared. Dr John Wort: I have received honoraria from Janssen, MSD, Ferrer, and Acceleron, research grants from Janssen and Ferrer and travel and accommodation grants from Janssen. Laura Price and Dr Colin Church: none declared. Dr Neil Hamilton: Honoraria from MSD and Janssen, travel and accommodation grants from Janssen, participation on advisory boards for Bayer, MSD, Janssen, and Vifor, and is a board member on the NHS Specialist respiratory clinical reference group. Dr Abdul Hameed: none declared. Dr Judith Hurdman, Dr Iain Armstrong and Dr Charlie Elliot: none declared. Prof Robin Condliffe: No COI. Received honoraria for speaking and advisory boards from Janssen and MS. Prof Martin Wilkins: support from NIHR for clinical research facility and biomedical research center infrastructure support BHF center support (RE/18/4/34215), consulting fees for MorphogenIX, Janssen and Janssen, Kinaset, Chiesi, Aerami, BenevolentAI, Novartis, and VIVS, participation on data safety monitoring board for Acceleron and GSK. Associate Professor Alastair Webb: none declared. Dr David Adlam: none declared. Professor Ray L Benza: steering and adjudication committees ABBOTT. Professor Kazem Rahimi: receives grants from the Oxford Martin School and the British Heart Foundation. He is an associate editor of Heart and a specialty editor of PLOS Medicine. And he is a cofounder of Zeesta and sits on the advisory board of Medtronic. Dr Moha Shojaei, Dr Nan Lin, Prof James Wason, Dr Alasdair McIntosh, Prof Alex McConnachie, and Dr Jennifer Middleton: none declared. Dr Roger Thompson: I have received honoraria, travel support, and grant funding from Janssen. Prof David Kiely: Support and grants received from NIHR Sheffield Biomedical Research Centre, Janssen Pharmaceuticals; additional grants from Ferrer; consulting fees, honoraria payments, and supports for attending meetings received from Janssen Pharmaceuticals, Ferrer, Altavant, MSD, and united Therapeutics, participants on advisory boards with Janssen and MSD; members of clinical reference group for specialist respiratory medicine (NHS England) and lead of UK national audit of pulmonary hypertension. Dr Mark Toshner: funding from NIHR Cambridge BRC, NIHR HTA; consulting fees from MorphogenIX and Jansen; participation on data safety monitoring board/advisory board with ComCov and FluCov. Dr Alex Rothman: research funding: Wellcome Trust Clinical Research Career Development Fellowship (206632/Z/17/Z), Medical Research Council (UK) Experimental Medicine Award (MR/W026279/1), NIHR Biomedical Research Center Sheffield, Contribution in kind: Medtronic, Abbott, Endotronix, Novartis, Janssen. Research support and consulting: NXT Biomedical, Endotronix, SoniVie, Neptune, Gradient., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

KRAS mutations occur commonly in the lung and can lead to the development of non-small cell lung cancer (NSCLC). While the mutated KRAS protein is a neoantigen, it usually does not generate an effective anti-tumor immune response on mucosal/epithelial surfaces. Despite this, mutated KRAS remains a potential target for immunotherapy since immune targeting of this protein in animal models has been effective at eliminating tumor cells. We attempted to develop a KRAS vaccine using mutated and wild-type KRAS peptides in combination with a nanoemulsion (NE) adjuvant. The efficacy of this approach was tested in an inducible mutant KRAS-mouse lung tumor model. Animals were immunized intranasally using NE with KRAS peptides. These animals had decreased CD4 + FoxP3 + T cells in both lymph nodes and spleen. Immunized animals also showed higher IFN-γ and IL-17a levels to mutated KRAS that were produced by CD8 + T cells and enhancement in KRAS-specific Th1 and Th17 responses that persisted for 3 months after the last vaccination. Importantly, the immunized animals had significantly decreased tumor incidence compared to control animals. In conclusion, a mucosal approach to KRAS vaccination demonstrated the ability to induce local KRAS-specific immune responses in the lung and resulted in reduced tumor incidence., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Parkinson's Disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of midbrain dopaminergic neurons in the substantia nigra part of the brain. Pathology spread to numerous brain regions and cell types suggests that intercellular communication is essential to PD progression. Exosomes mediate intercellular communication between neurons, glia, and other cell types throughout PD-relevant brain regions. However, the mechanism remains unclear, and its implication in PD pathology, is not well understood. In the current study, we explored the role of exosomes in modulating the response to PD-relevant toxicants. In cellular models of PD, neuronal cell-derived exosomes are readily internalized by recipient neuronal cells as intact vesicles. Internalized exosomes in bystander neuronal cells localize to mitochondria and dysregulate mitochondrial functions, leading to cell death under PD stress conditions. NGS analysis of exosomes released by neuronal cells subjected to PD stress conditions showed that levels of specific miRNAs were altered in exosomes under PD stress conditions. Bioinformatic analysis of the miRNA targets revealed enriched pathways related to neuronal processes and morphogenesis, apoptosis and ageing. Levels of two miRNAs, hsa-miR-30a-5p and hsa-miR-181c-5p, were downregulated in exosomes under PD stress conditions. Expression of the identified miRNAs in neuronal cells led to their enrichment in exosomes, and exosome uptake in neuronal cells ameliorated mitochondrial dysfunction induced by PD stress conditions and rescued cell death. In conclusion, loss of enrichment of specific miRNAs, including miR-30a-5p and miR-181c-5p, under PD stress conditions causes mitochondrial dysfunction and neuronal death, and hence may lead to progression of PD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Infusion-related reactions (IRRs) are a recognized concern for chemotherapy, biologic agents, and newer immunotherapies. Antihistamines are frequently recommended to prevent or manage these reactions. For over 60 years, diphenhydramine has been the only H 1 antihistamine for intravenous (IV) administration. It has been considered the standard of care as part of premedication regimens to prevent IRRs associated with these therapies despite the lack of a US Food and Drug Administration (FDA)-approved indication and no evidence of efficacy data. Intravenous cetirizine was approved in 2019 for acute urticaria treatment, making it the only second-generation H 1 antihistamine that can be administered intravenously. Compared with diphenhydramine, cetirizine has an improved safety profile with less sedation, fewer contraindications, lower incidence of anticholinergic side effects, and minimal risk of adverse events in elderly patients. A head-to-head study demonstrated that IV cetirizine is as effective as IV diphenhydramine in reducing IRRs and may decrease chair time, treatment center visits, and the need for rescue medication. Over the past 3 decades, the FDA has addressed the issue of IRRs by mandating language regarding the requirement or recommendation for premedication in the label of over 50 FDA-approved infusion products. As more therapeutics have premedication required or recommended, IV cetirizine should be considered an antihistamine for preventing and treating IRRs. In this article, we describe a patient whose IRR was successfully managed with IV cetirizine and discuss first- vs. second-generation H 1 antihistamines and their use in treating and preventing IRRs., Competing Interests: Dr. Tyler is a consultant to TerSera Therapeutics, AstraZeneca, Sandoz, and Urogen, and on the speakers bureaus for Bristol-Myers Squibb, Amgen, Pfizer, Sanofi, Incyte, G1 Therapeutics, and Pharmacosmos. Drs. Stojanoff, Cannon, Um, Young, Brent, and Martin are employed by TerSera Therapeutics. Dr. Holmes was a principal investigator for the phase II study of IV cetirizine for the prevention of hypersensitivity IRRs, and has been a paid consultant for TerSera Therapeutics., (© 2024 BroadcastMed LLC.)

Background: The use of Zone 1 REBOA for life-threatening trauma has increased dramatically., Study Design: The Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery database was queried for blunt and penetrating trauma between 2013 and 2021. Outcomes were examined both for mechanisms of injury combined and separately and for combinations of abdominal injury with and without traumatic brain injury and chest injuries (Abbreviated Injury Scale [AIS] score >2)., Results: A total of 531 patients underwent REBOA (408 with blunt injury and 123 with penetrating injury) and 1,603 (595 with blunt injury and 1,008 with penetrating injury) underwent resuscitative thoracotomy (RT). Mean age was 38.5 ± 16 years and mean injury severity score was 34.5 ± 21; 57.7% had chest AIS score of more than 2, 21.8% had head AIS score of more than 2, and 37.3% had abdominal AIS score of more than 2. Admission Glasgow Coma Scale was 4.9 + 4, and systolic blood pressure at aortic occlusion (AO) was 22 + 40 mmHg. No differences in outcomes in REBOA or RT patients were identified between institutions (p > 0.5). After inverse probability weighting, Glasgow Coma Scale, age, injury severity score, systolic blood pressure at AO, CPR at AO, and blood product transfusion, REBOA was superior to RT in both blunt (odds ratio [OR] 4.7, 95% CI 1.9 to 11.7) and penetrating (OR 4.9, 95% CI 1.7 to 14) injuries, across all spectrums of injury (p < 0.01). Overall mortality was significantly higher for AO more than 90 minutes compared with less than 30 minutes in blunt (OR 4.6, 95% CI 1.5 to 15) and penetrating (OR 5.4, 95% CI 1.1 to 25) injuries. Duration of AO more than 60 minutes was significantly associated with mortality after penetrating abdominal injury (OR 5.1, 95% CI 1.1 to 22) and abdomen and head (OR 5.3, 95% CI 1.6 to 18)., Conclusions: In-hospital survival is higher for patients undergoing REBOA than RT for all injury patterns. Complete AO by REBOA or RT should be limited to less than 30 minutes. Neither hospital and procedure volume nor trauma verification level impacts outcomes for REBOA or RT., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Receiving and accessing care after a diagnosis of dementia, both for the person and their carer, are fraught with inequalities. The aim of this public engagement activity was to co-produce a board game about dementia inequalities to facilitate learning, dialogue and educate about different barriers, and facilitators, to diagnosis and care and to test the game's impact on dementia knowledge with the general public., Methods: Two virtual and two face-to-face workshops with people with dementia, unpaid carers, health and social care professionals and Third Sector representatives were held between October 2022 and June 2023. Virtual workshops involved discussions of inequalities and how a board game may feature inequalities. The first face-to-face workshop was split into the same activities, aided by outcomes from workshops 1 and 2. Workshop 4 attendees tested the prototype. The impact of the game on knowledge about dementia and inequalities was tested at a game play workshop in October 2023., Results: Forty stakeholders attended four workshops. Workshops provided step-by-step thoughts on how the game could be designed or modified. The final game, prototype tested in workshop 4, consists of a one-sided, two-half board depicting the prediagnosis process (left half) and postdiagnosis process (right half). Fifty-two members of the general public participated in the game play workshop, which led to significant improvements in knowledge about dementia (p < .001) and inequalities (p < .001)., Discussion: The game can be used to improve knowledge about dementia inequalities for health and social care professionals, carers, people living with dementia, decision makers and the general public., Patient or Public Contribution: This engagement activity fully involved people with dementia, unpaid carers, health and social care professionals and Third Sector representatives throughout, with two unpaid carers as public advisers on the team., (© 2024 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Concerns over the harmful effects of social media have directed public attention to media literacy as a potential remedy. Current conceptions of media literacy are frequently based on mass media, focusing on the analysis of common content and evaluation of the content using common values. This article initiates a new conceptual framework of social media literacy (SoMeLit). Moving away from the mass media-based assumptions of extant approaches, SoMeLit centers on the user's self in social media that is in dynamic causation with their choices of messages and networks. The foci of analysis in SoMeLit, therefore, are one's selections and values that influence and are influenced by the construction of one's reality on social media; and the evolving characteristics of social media platforms that set the boundaries of one's social media reality construction. Implications of the new components and dimensions of SoMeLit for future research, education, and action are discussed., (© The Author(s) 2022.)

The spectrum of diseases caused by Streptococcus pyogenes (Strep A) ranges from superficial to serious life-threatening invasive infections. We conducted a scoping review of published articles between 1980 and 2021 to synthesize evidence of state transitions across the Strep A disease spectrum. We identified 175 articles reporting 262 distinct observations of Strep A disease state transitions. Among the included articles, the transition from an invasive or toxin-mediated disease state to another disease state (i.e., to recurrent ARF, RHD or death) was described 115 times (43.9% of all included transition pairs) while the transition to and from locally invasive category was the lowest (n = 7; 0.02%). Transitions from well to any other state was most frequently reported (49%) whereas a relatively higher number of studies (n = 71) reported transition from invasive disease to death. Transitions from any disease state to locally invasive, Strep A pharyngitis to invasive disease, and chronic kidney disease to death were lacking. Transitions related to severe invasive diseases were more frequently reported than superficial ones. Most evidence originated from high-income countries and there is a critical need for new studies in low- and middle-income countries to infer the state transitions across the Strep A disease spectrum in these high-burden settings., (© 2024. The Author(s).)

Adopting emerging microbiological methods is often desirable because it enables more advantageous, real-time monitoring practices. However, when the newer method measures contamination based on a different detection principle and provides results that are based on different units of measure, a paradigm shift is necessary. That shift can be one of the most difficult challenges in any such project and requires careful consideration. In this article, we explore the challenges presented by the bio-fluorescent particle counting (BFPC) technology, when considering that the traditional colony-forming unit (CFU) is the gold standard that any change is measured against. We examine why attempts to correlate newer units of measure used by biofluorescent particle counters, namely the auto-fluorescent units (AFUs), to the traditional CFUs are not necessarily appropriate. The article explores in depth why there is no consistent correlation factor between the two units of measure, and why that should not be a barrier to fully leveraging, implementing, and using such modern technologies in routine monitoring., (© PDA, Inc. 2023.)

Aim: Acute rheumatic fever (ARF), a serious inflammatory condition, often leads to rheumatic heart disease (RHD). Between 2011 and 2016, Aotearoa New Zealand implemented a rheumatic fever prevention programme (RFPP) to reduce high rates of ARF through improved community access to timely diagnosis and early treatment of group A streptococcal (GAS) pharyngitis, which has been shown to prevent subsequent ARF. This study aimed to quantify the change in penicillin antibiotic dispensing rates among children aged 18 years or younger during the RFPP., Method: This retrospective analysis utilised administrative data from the National Pharmaceutical Collection. Using a controlled, interrupted time series analysis, the effect of the RFPP on antibiotic dispensing rates was explored. Poisson regression models were used to assess the change in dispensing rates during the RFPP among control regions (those not in the RFPP) and regions participating in the RFPP. The primary measure was rate ratio (RR) for the difference between the observed versus counterfactual rates of penicillin dispensing., Result: A total of 12,154,872 dispensing records between 2005 and 2018 were included. Amoxicillin was the most frequently dispensed penicillin (57.7%), followed by amoxicillin-clavulanate (23.4%). Amoxicillin dispensing increased by 4.3% in regions operating the RFPP compared to the increase in control regions (p<0.001). The overall rate of penicillin dispensing decreased, driven by a rapid decline in amoxicillin-clavulanate dispensing., Conclusion: During the RFPP an increase in amoxicillin dispensing was seen in regions participating in the programme and regions outside of the programme, indicating the programmatic approach led to improved adherence to recommended first-line antibiotics., Competing Interests: The authors have no conflict of interest to declare. This research was funded by the Health Research Council (HRC) of New Zealand (18-079)., (© PMA.)

Group A Streptococcus causes a wide range of diseases from relatively mild infections including pharyngitis to more severe illnesses such as invasive diseases and rheumatic heart disease (RHD). Our aim is to estimate the cost-effectiveness of a hypothetical Strep A vaccine on multiple disease manifestations at the global-level. Cost-effectiveness analyses were carried out by building on the potential epidemiological impact of vaccines that align with the WHO's Preferred Product Characteristics for Strep A vaccines. Maximum vaccination costs for a cost-effective vaccination strategy were estimated at the thresholds of 1XGDP per capita and health opportunity costs. The maximum cost per fully vaccinated person for Strep A vaccination to be cost-effective was $385-$489 in high-income countries, $213-$312 in upper-income-income countries, $74-$132 in lower-middle-income countries, and $37-$69 in low-income countries for routine vaccination at birth and 5 years of age respectively. While the threshold costs are sensitive to vaccine characteristics such as efficacy, and waning immunity, a cost-effective Strep A vaccine will lower morbidity and mortality burden in all income settings., (© 2023. Springer Nature Limited.)

BACKGROUNDFood allergy (FA) is a growing health problem requiring physiologic confirmation via the oral food challenge (OFC). Many OFCs result in clinical anaphylaxis, causing discomfort and risk while limiting OFC utility. Transepidermal water loss (TEWL) measurement provides a potential solution to detect food anaphylaxis in real time prior to clinical symptoms. We evaluated whether TEWL changes during an OFC could predict anaphylaxis onset.METHODSPhysicians and nurses blinded to the TEWL results conducted and adjudicated the results of all 209 OFCs in this study. A study coordinator measured TEWL throughout the OFC and had no input on the OFC conduct. TEWL was measured 2 ways in 2 separate groups. First, TEWL was measured using static, discrete measurements. Second, TEWL was measured using continuous monitoring. Participants who consented provided blood samples before and after the OFCs for biomarker analyses.RESULTSTEWL rose significantly (2.93 g/m2/h) during reactions and did not rise during nonreacting OFCs (-1.00 g/m2/h). Systemic increases in tryptase and IL-3 were also detected during reactions, providing supporting biochemical evidence of anaphylaxis. The TEWL rise occurred 48 minutes earlier than clinically evident anaphylaxis. Continuous monitoring detected a significant rise in TEWL that presaged positive OFCs, but no rise was seen in the OFCs that resulted in no reaction, providing high predictive specificity (96%) for anaphylaxis against nonreactions 38 minutes prior to anaphylaxis onset.CONCLUSIONSDuring OFCs, a TEWL rise anticipated a positive clinical challenge. TEWL presents a monitoring modality that may predict food anaphylaxis and facilitate improvements in OFC safety and tolerability.

The objective of the study was to explore the feasibility of a new drug delivery system using laponite (LAP) and cyclic poly(ethylene glycol) (cPEG). Variously shaped and flexible hybrid nanocrystals were made by both the covalent and physical attachment of chemically homogeneous cyclized PEG to laponite nanodisc plates. The size of the resulting, nearly spherical particles ranged from 1 to 1.5 µm, while PEGylation with linear methoxy poly (ethylene glycol) (mPEG) resulted in fragile sheets of different shapes and sizes. When infused with 10% doxorubicin (DOX), a drug commonly used in the treatment of various cancers, the LAP-cPEG/DOX formulation was transparent and maintained liquid-like homogeneity without delamination, and the drug loading efficiency of the LAP-cPEG nano system was found to be higher than that of the laponite-poly(ethylene glycol) LAP-mPEG system. Furthermore, the LAP-cPEG/DOX formulation showed relative stability in phosphate-buffered saline (PBS) with only 15% of the drug released. However, in the presence of human plasma, about 90% of the drug was released continuously over a period of 24 h for the LAP-cPEG/DOX, while the LAP-mPEG/DOX formulation released 90% of DOX in a 6 h burst. The results of the cell viability assay indicated that the LAP-cPEG/DOX formulation could effectively inhibit the proliferation of A549 lung carcinoma epithelial cells. With the DOX concentration in the range of 1-2 µM in the LAP-cPEG/DOX formulation, enhanced drug effects in both A549 lung carcinoma epithelial cells and primary lung epithelial cells were observed compared to LAP-mPEG/DOX. The unique properties and effects of cPEG nanoparticles provide a potentially better drug delivery system and generate interest for further targeting studies and applications.

Purpose: The retinal pigment epithelium (RPE) is an important tissue for maintaining a healthy retina. Retinal pigment epithelial cells help regulate nutrient transport to photoreceptors and are heavily pigmented to prevent light scattering. These cells also have junction proteins to form monolayers. Monolayers are key players in pathologies such as age-related macular degeneration (AMD), a leading cause of vision loss in older adults. During AMD, RPE cell detachment can occur, resulting in a loss of junctions. Losing junctions can increase the expression of pro-angiogenic vascular endothelial growth factor (VEGF). This overexpression can cause abnormal blood vessel growth or angiogenesis in the retina. Age-related macular degeneration treatments target VEGF to slow angiogenesis progression. However, other proteins, such as angiopoietin-2 (Ang-2) and the tissue inhibitor of metalloproteinase-1 (TIMP-1), may also play important roles, making them potential targets for treatment. Controlling RPE junction formation will help elucidate the relationship between RPE cell detachment and additional angiogenic factor secretion, lead to more therapeutics, and increase the efficacy of current treatments., Methods: Micropatterning was used to control the spatial arrangement of primary porcine RPE cells using polydimethylsiloxane (PDMS) stencils. Patterns were formed into PDMS stencils to mimic 10%, 25%, and 50% overall detachment of the RPE monolayer. Zonula-occludens-1 (ZO-1), Ang-2, and VEGF were visualized using immunocytochemical (ICC) staining. An enzyme-linked immunosorbent assay (ELISA) was used to quantify extracellular Ang-2, VEGF, TIMP-1, and TIMP-2 levels. A rod outer segment (OS) phagocytosis assay was performed to determine how RPE junction loss directly affects photoreceptor support., Results: The growth of primary porcine RPE cells was successfully controlled using stencils. Morphological changes and a decrease in pigmentation were observed, showing a decline in barrier and light absorption functions as degeneration increased. One day after stencil removal, junction proteins were delocalized, and angiogenic factor secretions were correlated with increased levels of detachment. Secretion levels of Ang-2 and TIMP-1 were significantly increased, whereas VEGF and TIMP-2 concentrations were not as affected by varying levels of detachment. OS phagocytosis appeared lower in RPE cells when ZO-1 was affected., Conclusions: These results suggest a correlation between loss of junctions, abnormal angiogenic protein secretion, and reduced OS phagocytosis. Furthermore, Ang-2 and TIMP-1 proteins might be beneficial targets for AMD treatments, and their roles in retinal diseases deserve further investigation., (Copyright © 2023 Molecular Vision.)

Introduction: Hemorrhagic pericardial effusion (HPE) is a rare but life-threatening diagnosis that may occur after thoracic trauma. Previous reports have concentrated on delayed HPE in those who did not require initial surgical intervention for their traumatic injuries. In this report, we identify and characterize the phenomenon of HPE after emergent thoracic surgery for trauma., Methods: This is a retrospective review of patients who required emergent thoracic surgery for trauma at a level 1 trauma center from 2017 to 2021. Using the institutional trauma database, demographics, injury characteristics, and outcomes were compared between patients with HPE and those without HPE after thoracic surgery for trauma., Results: Ninety-one patients were identified who underwent emergent thoracic surgery for trauma. Most were young men who sustained a penetrating thoracic injury. Seven patients (7.7%) went on to develop HPE. Patients who developed HPE were younger (18 vs. 32 years, p=0.034), required bilateral anterolateral thoracotomy (85% vs. 7%, p<0.001), and were more likely to have pulmonary injuries (100% vs. 52.4%, p<0.001). Five patients with HPE survived to hospital discharge. The two patients with HPE who died were both coagulopathic and had HPE diagnosed within 4 days of injury. The median time to HPE diagnosis in survivors was 24 days with four of five HPE survivors on therapeutic anticoagulation at the time of diagnosis., Conclusions: HPE may occur after emergent thoracic surgery for trauma. Those at highest risk of HPE include younger patients with bilateral thoracotomy incisions and pulmonary injuries. Early HPE, clinical signs of tamponade, and/or coagulopathy in patients with HPE portend a worse prognosis. Surgeons and trauma team members caring for patients after emergent thoracic exploration for trauma should be aware of this potentially devastating complication and should consider postoperative echocardiography in high-risk patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Femoroacetabular impingement is characterized by premature contact between the proximal femur and acetabulum. The loss of femoral head-neck concavity associated with cam morphology leads to mechanical impingement during hip flexion and internal rotation. Other femoral and acetabular features have been linked with mechanical impingement but have not been comprehensively investigated. This study sought to determine which bony features are most influential in contributing to mechanical impingement in persons with a cam morphology., Methods: Twenty individuals (10 female, 10 male) with a cam morphology participated. Finite element analyses incorporating subject-specific bony geometry derived from computed tomography scans were used to determine which femoral (alpha angle and femoral neck-shaft angle) and acetabular (anteversion angle, inclination angle, depth, and lateral center-edge angle) features accentuate acetabular contact pressure with increasing degrees of hip internal rotation with the hip flexed to 90°. To determine the best predictors of acetabular contact pressure sensitivity to internal rotation, all morphological variables were included in a stepwise regression with the final model subjected to a bootstrapping procedure., Findings: The stepwise regression revealed that femoral neck-shaft angle, acetabular anteversion angle, acetabular inclination angle, and acetabular depth were the best combination of variables to predict contact pressure sensitivity to internal rotation, explaining 55% of the variance. Results of the bootstrap analysis revealed that a median value of 65% [37%, 89%] variance in sensitivity could be explained by these morphological variables., Interpretation: Mechanical impingement and the concomitant acetabular contact pressure are modulated by multiple femoral and acetabular features in persons with a cam morphology., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Rhythmicity permeates large parts of human experience. Humans generate various motor and brain rhythms spanning a range of frequencies. We also experience and synchronize to externally imposed rhythmicity, for example from music and song or from the 24-h light-dark cycles of the sun. In the context of music, humans have the ability to perceive, generate, and anticipate rhythmic structures, for example, "the beat." Experimental and behavioral studies offer clues about the biophysical and neural mechanisms that underlie our rhythmic abilities, and about different brain areas that are involved but many open questions remain. In this paper, we review several theoretical and computational approaches, each centered at different levels of description, that address specific aspects of musical rhythmic generation, perception, attention, perception-action coordination, and learning. We survey methods and results from applications of dynamical systems theory, neuro-mechanistic modeling, and Bayesian inference. Some frameworks rely on synchronization of intrinsic brain rhythms that span the relevant frequency range; some formulations involve real-time adaptation schemes for error-correction to align the phase and frequency of a dedicated circuit; others involve learning and dynamically adjusting expectations to make rhythm tracking predictions. Each of the approaches, while initially designed to answer specific questions, offers the possibility of being integrated into a larger framework that provides insights into our ability to perceive and generate rhythmic patterns., Competing Interests: EL and JK hold ownership interest in Oscillo Biosciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Large, Roman, Kim, Cannon, Pazdera, Trainor, Rinzel and Bose.)

Introduction: While windlass-rod style tourniquets stop bleeding in limbs when used by skilled responders, they are less successful in the hands of the untrained or not recently trained public. To improve usability, an academic-industry partnership developed the Layperson Audiovisual Assist Tourniquet (LAVA TQ). The LAVA TQ is novel in design and technology and addresses known challenges in public tourniquet application. A previously published multisite, randomized controlled trial of 147 participants showed that the LAVA TQ is much easier for the lay public to use compared to the Combat Application Tourniquet (CAT). This study evaluates the LAVA TQ's ability to occlude blood flow in humans compared to the CAT., Methods: This study was a prospective, blinded, randomized controlled trial to demonstrate the non-inferiority of the LAVA TQ to occlude blood flow when applied by expert users compared to the CAT. The study team enrolled participants in Bethesda, Maryland, in 2022. The primary outcome was the proportion of blood flow occlusion by each tourniquet. The secondary outcome was surface application pressure for each device., Results: The LAVA TQ and CAT occluded blood flow in all limbs (21 LAVA TQ, 100%; 21 CAT, 100%). The LAVA TQ was applied at a mean pressure of 366 millimeters of mercury (mm Hg) (SD 20 mm Hg), and the CAT at a mean pressure of 386 mm Hg (SD 63 mm Hg) (P = 0.14)., Conclusion: The novel LAVA TQ is non-inferior to the traditional windlass-rod CAT in occluding blood flow in human legs. The application pressure of LAVA TQ is similar to that used in the CAT. The findings of this study, coupled with LAVA TQ's demonstrated superior usability, make the LAVA TQ an acceptable alternative limb tourniquet.

Individuals with autism spectrum disorder (ASD) may show secondary sensory and cognitive characteristics, including differences in auditory processing, attention, and, according to a prominent hypothesis, the formulation and utilization of predictions. We explored the overlap of audition, attention, and prediction with an online auditory "temporal orienting" task in which participants utilized predictive timing cues (both rhythmic and interval-based) to improve their detection of faint sounds. We compared an autistic (n = 78) with a nonautistic (n = 83) group, controlling for nonverbal IQ, and used signal detection measures and reaction times to evaluate the effect of valid temporally predictive cues. We hypothesized that temporal orienting would be compromised in autism, but this was not supported by the data: the boost in performance induced by predictability was practically identical for the two groups, except for the small subset of the ASD group with co-occurring attention deficit hyperactivity disorder, who received less benefit from interval-based cueing. However, we found that the presence of a rhythm induced a significantly stronger bias toward reporting target detections in the ASD group at large, suggesting weakened response inhibition during rhythmic entrainment., (© 2023 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)