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Objective: The objective of this study was to assess maternal gestational outcomes and offspring growth trajectories following prepregnancy metabolic and bariatric surgery (MBS) compared with non-MBS controls., Methods: Single-center deliveries between January 2020 and March 2023 with prepregnancy Roux-en-Y gastric bypass (herein referred to as "bypass"), sleeve gastrectomy (herein referred to as "sleeve"), and non-MBS controls were included. Offspring growth trajectories were compared with the World Health Organization child growth standards. Linear mixed models assessed MBS-bypass and MBS-sleeve offspring weight, length, and BMI trajectories with a prepregnancy BMI 27 to 37 kg/m 2 and propensity score-matched controls., Results: The study included 440 participants with prepregnancy MBS (MBS-bypass, 185; MBS-sleeve, 225; 76% Hispanic/Latino) and 13,434 non-MBS controls. Gestational weight gain and gestational diabetes mellitus were similar, whereas hypertensive disorders of pregnancy were more common after MBS. The post-MBS offspring had lower birth weight but higher weight gain at 24 months (sleeve, +1.4 kg [95% CI: 1.0-1.9]; bypass, +0.5-0.7 kg [95% CI: 0.0-1.2]) compared with non-MBS groups. Male children had higher weight gain than females. The post-MBS-sleeve but not the post-MBS-bypass offspring had higher BMI z scores., Conclusions: The higher early-life weight gain and sex differences in the post-MBS-sleeve group compared with the post-MBS-bypass group provide a window toward elucidating pathways to mitigate intergenerational metabolic risk transfer., (© 2024 The Obesity Society.)

Reduced nitric oxide (NO) bioavailability is a pathological link between obesity and Alzheimer's disease (AD). Obesity-associated metabolic and mitochondrial bioenergetic dysfunction are key drivers of AD pathology. The hypothalamus is a critical brain region during the development of obesity and dysfunction is an area implicated in the development of AD. NO is an essential mediator of blood flow and mitochondrial bioenergetic function, but the role of NO in obesity-AD is not entirely clear. We investigated diet-induced obesity in female APPswe/PS1dE9 (APP) mouse model of AD, which we treated with two different NO donors (sodium nitrite or L-citrulline). After 26 weeks of a high-fat diet, female APP mice had higher adiposity, insulin resistance, and mitochondrial dysfunction (hypothalamus) than non-transgenic littermate (wild type) controls. Treatment with either sodium nitrite or L-citrulline did not reduce adiposity but improved whole-body energy expenditure, substrate oxidation, and insulin sensitivity. Notably, both NO donors restored hypothalamic mitochondrial respiration in APP mice. Our findings suggest that NO is an essential mediator of whole-body metabolism and hypothalamic mitochondrial function, which are severely impacted by the dual insults of obesity and AD pathology., (© 2024. The Author(s).)

Background: Medications form the basis of treatment for heart failure (HF) and adherence is crucial as untreated HF has a mortality of greater than 30%. As such, specialist HF pharmacists with expertise in prescribing and promoting adherence have become an integral part of the wider HF multidisciplinary team (MDT)., Aim: To implement specialist HF pharmacist prescribing clinics and evaluate their impact., Setting: An integrated HF team at a tertiary London hospital., Development: The clinic was initially developed to facilitate the introduction of sacubitril-valsartan evolving to 6 dedicated clinics/week., Implementation: A dedicated electronic referral pathway was created to channel referrals to the specialist clinic, and referral criteria expanded to all patients requiring optimisation of medical therapy., Evaluation: Data were retrospectively collected for patients with heart failure with reduced ejection fraction seen in the HF pharmacist clinic between September 2021 and July 2022. Overall, 114 patients were seen (mean age 66 years, 78 male). The mean time to medication optimisation was 3 months (averaging 1 appointment/month). The number on optimised doses of guideline-directed medical therapy, increased significantly from 8% at first appointment to 76% on discharge (p < 0.001). The HF pharmacists reviewed all medications and optimised non-HF medications for 17.5% (n = 20) of patients., Conclusion: HF pharmacists can optimise patients' HF and non-HF medical therapy typically within 3 months. By reviewing all prescribed medications, HF pharmacists provide a holistic review of all medications. They can play a vital role in addressing the underutilisation of HF medical therapy and thereby improving patient outcomes., (© 2024. The Author(s).)

Introduction: Long-acting injectable cabotegravir + rilpivirine (CAB + RPV LAI) was approved for use in virally suppressed adults in the England and Wales national health service in November 2021. We describe a service evaluation of delivery processes and outcomes in 12 clinics., Methods: Centres populated a database using information from local policies and clinical records. Services were asked to describe approval processes, clinic pathways, and adherence to national guidelines. Additional data were collected on reasons for regimen choice, treatment discontinuations, and management of viraemia., Results: In total, 518 adults from 12 clinics were approved for CAB + RPV LAI between February 2022 and December 2023. Of the 518 people approved for CAB + RPV LAI, 423 received at least one injection. Median duration on CAB + RPV was 7.5 months (interquartile range 3.7-11.3). In total, 97% of injections were administered within the ±7-day window. Virological failure occurred in 0.7%, and 6% discontinued CAB + RPV., Conclusion: In this large UK-based cohort, robust approval processes and clinic protocols facilitated on-time injections and low rates of both discontinuation and virological failure., (© 2024 The Author(s). HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Aims: In TRED-HF, 40% of patients with recovered dilated cardiomyopathy (DCM) relapsed in the short term after therapy withdrawal. This follow-up investigates the longer-term effects of therapy withdrawal., Methods and Results: TRED-HF was a randomized trial investigating heart failure therapy withdrawal in patients with recovered DCM over 6 months. Those randomized to continue therapy subsequently withdrew treatment between 6 and 12 months. Participants were recommended to restart therapy post-trial and were followed until May 2023. Clinical outcomes are reported in a non-randomized fashion from enrolment and from the end of the trial. The primary outcome was relapse defined as ≥10% reduction in left ventricular ejection fraction to <50%, doubling in N-terminal pro-B-type natriuretic peptide to >400 ng/L, or clinical features of heart failure. From enrolment to the last follow-up (median 6 years, interquartile range 6-7), 33 of 51 patients (65%) relapsed. The 5-year relapse rate from enrolment was 61% (95% confidence interval [CI] 45-73) and from the end of the trial was 39% (95% CI 19-54). Of 20 patients who relapsed during the trial, nine had a recurrent relapse during follow-up. Thirteen relapsed for the first time after the trial; seven had restarted low intensity therapy, four had not restarted therapy and two did not have therapy withdrawn. The mean intensity of therapy was lower after the trial compared to enrolment (mean difference -6 [-8 to -4]; p < 0.001). One third of relapses during follow-up had identifiable triggers (arrhythmia [n = 4], pregnancy [n = 1], hypertension [n = 1], infection [n = 1]). Corrected atrial fibrillation was associated with reduced risk of relapse (hazard ratio 0.33, 95% CI 0.12-0.96; p = 0.042)., Conclusions: The risk of relapse in the 5 years following the TRED-HF trial remained high. Restarting lower doses of heart failure medications at the end of the trial, external triggers and disease progression are likely to have contributed to relapse., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Adenoid cystic carcinoma is a malignancy that is difficult to treat and often metastasizes to the lung. Systemic chemotherapies are not effective for this tumor type, thus local therapies are frequently used. Here, we report a case demonstrating the use of extensive ablative interventions in controlling the progression of metastatic adenoid cystic carcinoma. A patient with adenoid cystic carcinoma developed numerous metastases to his lungs and liver. Local ablative therapies including interstitial brachytherapy and SBRT were used to treat approximately 80 different metastases over the course of a decade. Over 850 brachytherapy seeds were implanted in this patient, and the tumor control and patient outcome were good. As of the most recent follow-up in March 2024, the patient has survived for approximately 12 years since his diagnosis of adenoid cystic carcinoma. To our knowledge, this case represents the most brachytherapy treatments reported in a single patient. It highlights the utility of interstitial brachytherapy and SBRT in treating extensive lung and liver metastases.

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic β-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the β-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N -acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 ( 70 ) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.

People on low-incomes in the UK develop multiple long-term health conditions over 10 years earlier than affluent individuals. Financial diaries -new to public health- are used to explore the lived experiences of financially-vulnerable individuals, diagnosed with at least one long-term condition, living in two inner-city London Boroughs. Findings show that the health status of these individuals is a key barrier to work opportunities, undermining their income. Their precarious and uncertain financial situation, sometimes combined with housing issues, increased stress and anxiety which, in turn, contributed to further deteriorate participants' health. Long-term health conditions limited the strategies to overcome moments of financial crisis and diarists frequently used credit to cope. Restrictions to access reliable services and timely support were connected to the progression of multiple long-term conditions. Models that integrate healthcare, public health, welfare and financial support are needed to slow down the progression from one to many long-term health conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Biosca et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Over the last two decades, inherited cardiac conditions (ICC) centres have emerged with the aim of improving outcomes for patients and their families, through early diagnosis, genetic testing, risk assessment and specialist treatment., Sources of Data: A literature search was performed using PubMed (https://pubmed.ncbi.nlm.nih.gov/). Commissioned ICC service reviews from NHS England, NHS Improvement and PHG Foundation were evaluated., Areas of Agreement: ICC patient management requires a multi-disciplinary approach. ICC services are predominantly based within tertiary centres. Despite expansion, provision of care remains inadequate to meet rising demands. Access to services is inconsistent, partly due to geographic variation and lack of standardized pathways., Areas of Controversy: The optimal ICC care model remains undecided, although there is growing interest in 'hub-and-spoke' networks, which could aid secondary and tertiary service integration and repatriation of care., Growing Points: Genetic mainstreaming is a priority for the Genomic Medicine Service Alliance. The benefits of telehealth and virtual clinics have been validated by their use during the COVID-19 pandemic. Other innovations to improve resource efficiency, such as clinical scientist-led and nurse-led clinics, show promise., Areas Timely for Developing Research: An update for the NHS ICC service specifications is planned that appears well timed given the rapid evolution of the ICC landscape in the decade since last review. This has the potential to address needs including national audit, standardized pathways and ICC networks to improve governance and equity of care. Delegation of commissioning for specialist services to integrated care systems may also provide opportunity for increased regional direction., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background Aims: The successful development of CD19-targeted chimeric antigen receptor (CAR) T-cell therapies has led to an exponential increase in the number of patients recieving treatment and the advancement of novel CAR T products. Therefore, there is a strong need to develop streamlined platforms that allow rapid, cost-effective, and accurate measurement of the key characteristics of CAR T cells during manufacturing (i.e., cell number, cell size, viability, and basic phenotype)., Methods: In this study, we compared the novel benchtop cell analyzer Moxi GO II (ORFLO Technologies), which enables simultaneous evaluation of all the aforementioned parameters, with current gold standards in the field: the Multisizer Coulter Counter (cell counter) and the BD LSRFortessa (flow cytometer)., Results: Our results demonstrated that the Moxi GO II can accurately measure cell number and cell size (i.e., cell volume) while simultaneously assessing simple two-color flow cytometry parameters, such as CAR T-cell viability and CD4 or CAR expression., Conclusions: These measurements are comparable with those of gold standard instruments, demonstrating that the Moxi GO II is a promising platform for quickly monitoring CAR T-cell growth and phenotype in research-grade and clinical samples., Competing Interests: Declaration of Competing Interest MR holds patents related to CAR T cells that are licensed to Novartis, Tmunity (Kite) and viTToria biotherapeutics. MR has served as a consultant for nanoString, BMS, GSK, GLG, GuidePoint, Sana, Bayer and AbClon. MR receives research funding from AbClon, Beckman Coulter, Oxford Nano Imaging, Curiox and viTToria biotherapeutics. MR is the scientific founder of viTToria biotherapeutics. The Ruella laboratory was provided a Moxi GO II device and supplies to perform this study. GD is an employee of ORFLO Technologies. All other authors declare no competing interests., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The burden of screening for inherited cardiac conditions on health services grows ever larger, with each new diagnosis necessitating screening of additional family members. Screening these usually asymptomatic, low-risk individuals is currently performed by consultant cardiologists, consuming vital clinic resources that could otherwise be diverted to sicker patients requiring specialist consultant input. Clinical scientists now constitute a highly skilled and often underutilised group of individuals with training in areas such as clinical evaluation, 12-lead electrocardiography (ECG) interpretation, and echocardiography. These skills place them in a unique position to offer a full screening evaluation in a single consultation. The aim of this study was to implement and evaluate a novel clinical scientist-led screening clinic for first-degree relatives of patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The clinical scientist-led screening clinic was established at a London tertiary centre to allow review of asymptomatic, first-degree relatives of patients with a confirmed diagnosis of HCM or DCM, independent of a cardiology consultant. Patients were evaluated with history, examination, ECG, and echocardiography, with further investigations if deemed necessary. A retrospective review was performed of the first 200 patients seen in the clinic., Results: Of the 200 individuals reviewed between September 2019 and July 2022, 99 had a proband with HCM and 101 a proband with DCM. Overall, 169 individuals (85%) revealed normal screenings and were discharged. Thirty-one individuals (15.5%), all asymptomatic, revealed ECG changes and/or significant echocardiographic findings. Of these, 21 individuals (10.5% of the total cohort) were subsequently diagnosed with a cardiomyopathy or early phenotypic changes consistent with a cardiomyopathy (11 with HCM and 10 with DCM). These individuals were referred on to an inherited cardiac conditions consultant clinic for regular follow-up. Overall, 179 consultant clinic appointments were saved which could instead be allocated to patients requiring specialist consultant input., Conclusions: This is the first description of a clinical scientist-led screening clinic for first-degree relatives of patients with HCM and DCM. The findings demonstrate that implementation of such a service into routine clinical practice is feasible, effective, safe, and can free up capacity in consultant clinics for patients requiring specialist input., (© 2024. The Author(s).)

Modern food technology has given rise to numerous alternative protein sources in response to a growing human population and the negative environmental impacts of current food systems. To aid in achieving global food security, one such form of alternative protein being investigated is cultivated meat, which applies the principles of mechanical and tissue engineering to produce animal proteins and meat products from animal cells. Herein, nonmodified and methacrylated whey protein formed hydrogels with methacrylated alginate as potential tissue engineering scaffolds for cultivated meat. Whey protein is a byproduct of dairy processing and was selected because it is an approved food additive and cytocompatible and has shown efficacy in other biomaterial applications. Whey protein and alginate scaffolds were formed via visible light cross-linking in aqueous solutions under ambient conditions. The characteristics of the precursor solution and the physical-mechanical properties of the scaffolds were quantified; while gelation occurred within the homo- and copolymer hydrogels, the integrity of the network was significantly altered with varying components. Qualitatively, the scaffolds exhibited a three-dimensional (3D) interconnected porous network. Whey protein isolate (WPI)-based scaffolds were noncytotoxic and supported in vitro myoblast adhesion and proliferation. The data presented support the hypothesis that the composition of the hydrogel plays a significant role in the scaffold's performance.

Background: Administration of anti-CD19 chimeric antigen receptor T-cell (CART19) immunotherapy for large B-cell lymphomas (LBCLs), a subset of non-Hodgkin lymphoma (NHL), involves high costs and access to specialized tertiary care centers. We investigated whether minority health populations (MHPs) have equal access to CART19 and whether their outcomes are similar to those of non-MHPs., Methods: We analyzed the prevalence and clinical outcomes of patients treated with commercial CART19 at two geographically and socioeconomically different institutions: the Abramson Cancer Center (ACC, Philadelphia, Pennsylvania) and the Knight Cancer Institute (KCI, Portland, Oregon)., Results: In the ACC catchment area, 8956 patients were diagnosed with NHL between 2015 and 2019 (latest available data from the state registry), including 17.9% MHPs. In the ACC, between 2018 and 2022 (CART became available in 2018), 1492 patients with LBCL were treated, and 194 received CART19. The proportion of MHPs was 15.7% for the entire LBCL cohort but only 6.7% for the CART19 cohort. During the same time, in the KCI catchment area, 4568 patients were diagnosed with NHL, including 4.2% MHPs. In the KCI, 396 patients with LBCL were treated, and 47 received CART19. The proportion of MHPs was 6.6% for the entire LBCL cohort and 4.2% for the CART19 cohort. The 3-month response, survival, and toxicities after CART19 infusion showed similar results, although the number of patients who were treated was limited., Conclusions: This study shows that the access of MHPs to tertiary centers for LBCL care was preserved but appeared reduced for commercial CART19 immunotherapy. Although clinical outcomes of MHPs seemed similar to those of non-MHPs, the small sample size precludes drawing firm conclusions. Further studies are needed. (Funded by the Laffey McHugh Foundation and others.).

Hematologic malignancies disproportionately affect older adults. Hematopoietic cell transplantation (HCT) is potentially curative, but poor overall survival (OS) has limited its use in older adults. Fried's frailty phenotype (FFP) is a geriatric assessment tool that combines objective and subjective performance measures: gait speed, grip strength, activity level, exhaustion, and weight loss. People meeting ≥3 criteria are classified as frail; 1 or 2 criteria, as pre-frail; and 0 criteria, as fit. To evaluate the association of pre-HCT FFP with post-HCT outcomes, we assessed FFP prior to conditioning for 280 HCT recipients age ≥60 years with acute leukemia or a myeloid neoplasm at 3 institutions. When analyzing survival by age group, patients age ≥70 years had inferior OS compared to patients age 60 to 69 years (P = .002), with corresponding OS estimates of 38.9% (95% confidence interval [CI], 27.8% to 49.9%) and 59.3% (95% CI, 51.9% to 65.9%). Nonrelapse mortality (NRM) also was significantly higher in the older patients (P = .0005); the 2-year cumulative incidences of NRM were 38.5% (95% CI, 27.5% to 49.2%) and 17.2% (95% CI, 12.3% to 22.8%), for older and younger recipients, respectively. The cumulative incidences of relapse did not differ by age group (P = .3435). Roughly one-third (35.5%) of the patients were fit, 57.5% were pre-frail, and 7.5% were frail, with corresponding 2-year OS estimates of 68.4% (95% CI, 57.9% to 76.8%), 45.5% (95% CI, 37.4% to 53.2%), and 45.8% (95% CI, 23.4% to 65.8%) (P = .013). FFP was not significantly associated with NRM, but being frail or pre-frail was associated with a higher rate of disease-related deaths (33.3% and 27.3%, respectively, compared with 17.4% for fit patients; P = .043). In univariate modeling of restricted mean survival time with a 3-year horizon (RMST&#95;3y), the factors that were significantly associated were FFP, age, Karnofsky Performance Status (KPS), Disease Risk Index (DRI), and HCT-specific Comorbidity Index (HCT-CI). Of those factors, only FFP (P = .006), age (P = .006), KPS (P = .004), and DRI (P = .005) were significantly associated in multivariate modeling of RMST&#95;3y. Estimates of RMST&#95;3y were computed and 5 risk-groups were created with survival ranging from 31.4 months for those who were age 60 to 69 years, fit, had KPS 90 to 100, and low/intermediate-risk DRI compared to 10.5 months for those who had high-risk features for all the evaluated factors. In univariate and multivariate analyses for restricted mean time to relapse with a 3-year horizon (RMRT&#95;3y), FFP (pre-frail versus fit, P = .007; frail versus fit, P = .061) and DRI (P = .001) were the only significant factors. Predicted RMRT&#95;3y was longest (30.6 months) for those who were fit and had low/intermediate-risk DRI scores and shortest (19.1 months) for those who were frail and had high-risk or very high-risk DRI scores. Both age and FFP impact survival after HCT. Incorporation of FFP into pre-HCT evaluations may improve decision-making and counseling regarding HCT risk for older adults. Our findings support future trials designed to reverse frailty, such as pre-HCT supervised exercise programs, and correlative analyses to unravel the connection of frailty and relapse to generate future targets for intervention. Finally, exploration of novel HCT platforms to reduce relapse in pre-frail and frail patients, as well as reduce NRM in adults age >70 years, are warranted., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Opioids are a key component of pain management among patients with metastatic cancer pain. However, the evidence base available to guide opioid-related decision-making in individuals with advanced cancer is limited. Patients with advanced cancer or cancer that is unlikely to be cured frequently experience pain. Opioids are a key component of pain management among patients with metastatic cancer pain. Many individuals with advanced cancer are now living long enough to experience opioid-related harm. Emerging evidence from chronic noncancer pain literature suggests that longer-term opioid therapy may have limited benefits for pain and function, and opioid-related harms are also a major concern. However, whether these benefits and harms of opioids apply to patients with cancer-related pain is unknown., Objective: This manuscript outlines the protocol for the "Opioid Therapy for Pain in Individuals With Metastatic Cancer: The Benefits, Harms, and Stakeholder Perspectives (BEST) Study." The study aims to better understand opioid decision-making in patients with advanced cancer, along with opioid benefits and harms, through prospective examination of patients' pain experiences and opioid side effects and understanding the decision-making by patients, care partners, and clinicians., Methods: This is a multicenter, prospective cohort study that aims to enroll 630 patients with advanced cancer, 20 care partners, and 20 clinicians (670 total participants). Patient participants must have an advanced solid cancer diagnosis, defined by the American Cancer Society as cancer that is unlikely to be cured. We will recruit patient participants within 12 weeks after diagnosis so that we can understand opioid benefits, harms, and perspectives on opioid decision-making throughout the course of their advanced cancer (up to 2 years). We will also specifically elicit information regarding long-term opioid use (ie, opioids for ≥90 consecutive days) and exclude patients on long-term opioid therapy before an advanced cancer diagnosis. Lived-experience perspectives related to opioid use in those with advanced cancer will be captured by qualitative interviews with a subset of patients, clinicians, and care partners. Our data collection will be grounded in a behavioral decision research approach that will allow us to develop future interventions to inform opioid-related decision-making for patients with metastatic cancer., Results: Data collection began in October 2022 and is anticipated to end by November 2024., Conclusions: Upon successful execution of our study protocol, we anticipate the development of a comprehensive evidence base on opioid therapy in individuals with advanced cancer guided by the behavioral decision research framework. The information gained from this study will be used to guide interventions to facilitate opioid decisions among patients, clinicians, and care partners. Given the limited evidence base about opioid therapy in people with cancer, we envision this study will have significant real-world implications for cancer-related pain management and opioid-related clinical decision-making., International Registered Report Identifier (irrid): DERR1-10.2196/54953., (©Katie Fitzgerald Jones, Gretchen White, Antonia Bennett, Hailey Bulls, Paula Escott, Sarah Orris, Elizabeth Escott, Stacy Fischer, Megan Hamm, Tamar Krishnamurti, Risa Wong, Thomas W LeBlanc, Jane Liebschutz, Salimah Meghani, Cardinale Smith, Jennifer Temel, Christine Ritchie, Jessica S Merlin. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 13.03.2024.)

Background : Locked plating for distal femur fractures is widely recommended and used. We systematically reviewed clinical studies assessing the benefits and harms of fracture fixation with locked plates in AO/OTA Type 32 and 33 femur fractures. Methods : A comprehensive literature search of PubMed, Embase, Cinahl, Web of Science, and the Cochrane Database was performed. The studies included randomized and non-randomized clinical trials, observational studies, and case series involving patients with distal femur fractures. Studies of other fracture patterns, studies conducted on children, pathological fractures, cadaveric studies, animal models, and those with non-clinical study designs were excluded. Results : 53 studies with 1788 patients were found to satisfy the inclusion and exclusion criteria. The most common harms were nonunion (14.8%), malunion (13%), fixation failure (5.3%), infection (3.7%), and symptomatic implant (3.1%). Time to full weight-bearing ranged from 5 to 24 weeks, averaging 12.3 weeks. The average duration of follow-up was 18.18 months, ranging from 0.5 to 108 months. Surgical time ranged between 40 and 540 min, with an average of 141 min. The length of stay in days was 12.7, ranging from 1 to 61. The average plate length was ten holes, ranging from 5 to 20 holes. Conclusion : This review aimed to systematically synthesize the available evidence on the risk associated with locked plating osteosynthesis in distal femur fractures. Nonunion is the most common harm and is the primary cause of reoperation. The overall combined risk of a major and critical complication (i.e., requiring reoperation) is approximately 20%.

Purpose: This trial's purpose was to determine the late toxicity associated with dose escalation to Prostate Imaging Reporting and Data System (PI-RADS) III-V lesions on multiparametric magnetic resonance imaging (MRI) with an image guided combined IMRT-stereotactic body radiation therapy (SBRT) approach in men with localized prostate cancer., Methods and Materials: In this phase 2 trial patients with localized prostate cancer with clinical tumor stage T1-T3bN0 and at least one PIRADS III-V lesion were recruited to receive 45 Gy in 25 fractions to the prostate and seminal vesicles followed by a boost of 18 Gy in 3 fractions to the prostate with a simultaneous integrated boost 21 Gy in 3 fractions to the PI-RADS lesion(s). The primary endpoint was the cumulative incidence of late grade ≥3 genitourinary and gastrointestinal toxicity by 18 months (National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0)., Results: Overall, 50 patients were enrolled in this study, and 43 patients completed at least 18 months of follow-up. The cumulative incidence of grade 1, 2, and 3 late genitourinary toxicity at 18 months was 18%, 53%, and 2%. One patient was noted to have grade 3 hematuria and needed cystoscopy-guided cauterization. No acute grade 3 gastrointestinal or genitourinary toxicities were observed. The cumulative incidence of grade 1, 2, and 3 late gastrointestinal toxicity at 18 months was 31%, 4%, and 0%, respectively. At a median follow-up of 43.5 months, 3 patients developed biochemical recurrence, each with distant bone metastases without local or nodal recurrence. At 3 years, freedom from biochemical failure rate was 95.3% (95% CI, 89.2%-100%)., Conclusions: Multiparametric MRI-guided dose escalation to PI-RADS III-V lesions using a combined image guided IMRT-SBRT approach is associated with an acceptable risk of late gastrointestinal and genitourinary toxicity. The results should be interpreted with caution considering their single institutional nature, small sample size, and short follow-up and should be validated in a larger study., Competing Interests: Disclosures Soumyajit Roy reports research grant from Prostate Cancer Foundation and Swim Across America and speaker honorarium from Varian., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Abstract: Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively treated with axi-cel at the University of Pennsylvania. We also analyzed serum samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (P = .981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% of patients (P = .031). In addition, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results were confirmed both in patients with LBCL and those with FL. Mechanistically, patients with Flu/Cy had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Soil carbon accounting and prediction play a key role in building decision support systems for land managers selling carbon credits, in the spirit of the Paris and Kyoto protocol agreements. Land managers typically rely on computationally complex models fit using sparse datasets to make these accounts and predictions. The model complexity and sparsity of the data can lead to over-fitting, leading to inaccurate results when making predictions with new data. Modellers address over-fitting by simplifying their models and reducing the number of parameters, and in the current context this could involve neglecting some soil organic carbon (SOC) components. In this study, we introduce two novel SOC models and a new RothC-like model and investigate how the SOC components and complexity of the SOC models affect the SOC prediction in the presence of small and sparse time series data. We develop model selection methods that can identify the soil carbon model with the best predictive performance, in light of the available data. Through this analysis we reveal that commonly used complex soil carbon models can over-fit in the presence of sparse time series data, and our simpler models can produce more accurate predictions., (© 2024. The Author(s).)

Background: Agitation is a common clinical problem encountered in the intensive care unit (ICU). Treatment options are based on clinical experience and sparse quality literature., Aim: The aim of this study was to describe the effect of valproic acid (VPA) as adjuvant treatment for agitation in the ICU, identify predictors of response to VPA and evaluate the independent effect of VPA on agitation compared to standard of care (SOC)., Method: This retrospective single center observational study evaluated adult patients admitted to the ICU for whom a psychiatric consultation was requested for agitation management, with agitation defined as a Richmond Agitation Sedation Score of 2 or greater. A descriptive analysis of the proportion of agitation-free patients per day of follow-up, the incidence of agitation-related-events, as well as the evolution of co-medications use over time are presented. A logistic regression model was used to assess predictors of VPA response, defined as being agitation-free on Day 7 and generalized estimating equations were used to evaluate the independent effect of VPA as adjuvant therapy for agitation in the critically ill., Results: One hundred seventy-five patients were included in the study with 78 receiving VPA. The percentage of agitation-free patients on VPA was 6.5% (5/77) on Day 1, 14.1% (11/78) on Day 3 and 39.5% (30/76) on Day 7. Multivariate regression model for clinical and demographic variables identified female gender as predictor of response on Day 7 (OR 6.10 [1.18-31.64], p = 0.03). The independent effect of VPA was non-significant when compared to SOC., Conclusion: Although VPA used as adjuvant treatment was associated with a decrease in agitation, its effect when compared to SOC did not yield significant results., (© 2023. Crown.)

Aim: Heart failure with preserved ejection fraction (HFpEF) remains under-diagnosed in clinical practice despite accounting for nearly half of all heart failure (HF) cases. Accurate and timely diagnosis of HFpEF is crucial for proper patient management and treatment. In this study, we explored the potential of natural language processing (NLP) to improve the detection and diagnosis of HFpEF according to the European Society of Cardiology (ESC) diagnostic criteria., Methods and Results: In a retrospective cohort study, we used an NLP pipeline applied to the electronic health record (EHR) to identify patients with a clinical diagnosis of HF between 2010 and 2022. We collected demographic, clinical, echocardiographic and outcome data from the EHR. Patients were categorized according to the left ventricular ejection fraction (LVEF). Those with LVEF ≥50% were further categorized based on whether they had a clinician-assigned diagnosis of HFpEF and if not, whether they met the ESC diagnostic criteria. Results were validated in a second, independent centre. We identified 8606 patients with HF. Of 3727 consecutive patients with HF and LVEF ≥50% on echocardiogram, only 8.3% had a clinician-assigned diagnosis of HFpEF, while 75.4% met ESC criteria but did not have a formal diagnosis of HFpEF. Patients with confirmed HFpEF were hospitalized more frequently; however the ESC criteria group had a higher 5-year mortality, despite being less comorbid and experiencing fewer acute cardiovascular events., Conclusions: This study demonstrates that patients with undiagnosed HFpEF are an at-risk group with high mortality. It is possible to use NLP methods to identify likely HFpEF patients from EHR data who would likely then benefit from expert clinical review and complement the use of diagnostic algorithms., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Anecdotal evidence indicated some British military dive support boat personnel suffer from uncomfortably cold hands and feet, which could impair their performance and be associated with reductions in core body temperature. This study collected preliminary data on thermal stress and cognitive performance of personnel taking part in a cold-weather training exercise. Six men were monitored during four boat transits in a range of climatic conditions (air temperature +1.2°C to -10.5°C, wind chill -4.5°C to 19.3°C). Core body temperature was measured with a radio pill and 12 skin sites (ISO 9886 plus hand, finger, foot and toe) with iButtons or thermistors. Self-reported thermal comfort and thermal sensation was also recorded. Reaction time and selective attention were measured pre- and post-transit. Participants' physical characteristics and personal clothing ensembles were recorded. No participant became hypothermic. Most participants' hand, foot and digit temperatures fell to below 15°C, indicating a risk of impaired dexterity, in addition to that arising from gloves. During the trial, hand and digit temperatures occasionally fell below 10°C. The limited data collected showed personal clothing choices could provide adequate thermal protection for these conditions and temperatures, and highlighted inter-individual variation and the need to allow for significant variation of day-to-day environmental conditions.

Background: The quality of Registered Nurses' worklife is impacting nurses' mental health, and the standard of care received by clients. Contributing factors to nurses' stress are the trauma of continuous caring for those in great suffering, and adverse working conditions., Objectives: i) to explore the prevalence of work-related stress in a provincial sample of Registered Nurses; ii) to compare the levels of compassion satisfaction, burnout and secondary traumatic stress reported by nurses in hospital, community, non-direct care settings, and, iii) to identify factors that predict levels of nursing work stress., Methods: A descriptive, predictive study with a self-report survey containing demographic questions and the Professional Quality of Life Scale was emailed to over 3,300 Registered Nurses. The scale measured the prevalence of three worklife indicators, compassion satisfaction, burnout and secondary traumatic stress. Multiple linear regression identified factors that predicted the levels of the three indicators. A subgroup analysis explored the quality of worklife based on three practice environments., Findings: Nurses (n  =  661) reported moderate compassion satisfaction, burnout, and secondary traumatic stress. The strongest predictor, satisfaction with one's current job, predicted high compassion satisfaction and lower burnout and secondary stress. The subgroup analysis identified hospital nurses as having the most work-related stress and the lowest level of compassion satisfaction., Conclusion: Innovative, collaborative action can transform nurses' practice environments. Organizational support is essential to bring about needed improvements., 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.

After more than 50 years of studying soldiers in the cold, we are well past the phase of defining the unique problems; the research requirements are known but the solutions have been slow in coming. This requires iterative testing of proposed lab-based solutions with soldiers in the real environment. Representing a renewed effort to produce and implement solutions to human biomedical challenges in Arctic operations, this journal supplement highlights presentations from a three-day NATO Human Factors and Medicine panel-sponsored symposium in Washington DC in October 2022. While technology can certainly aid soldiers in extreme environments, it is ultimately training that is the most important factor for ensuring optimal performance and survival. By investing in the development of specialized Arctic forces training and implementing new solutions to protect their health and performance, we can ensure success in the coldest and harshest of environments.

Context: Somatic EPAS1 variants account for 5% to 8% of all pheochromocytoma and paragangliomas (PPGL) but are detected in over 90% of PPGL in patients with congenital cyanotic heart disease, where hypoxemia may select for EPAS1 gain-of-function variants. Sickle cell disease (SCD) is an inherited hemoglobinopathy associated with chronic hypoxia and there are isolated reports of PPGL in patients with SCD, but a genetic link between the conditions has yet to be established., Objective: To determine the phenotype and EPAS1 variant status of patients with PPGL and SCD., Methods: Records of 128 patients with PPGL under follow-up at our center from January 2017 to December 2022 were screened for SCD diagnosis. For identified patients, clinical data and biological specimens were obtained, including tumor, adjacent non-tumor tissue and peripheral blood. Sanger sequencing of exons 9 and 12 of EPAS1, followed by amplicon next-generation sequencing of identified variants was performed on all samples., Results: Four patients with both PPGL and SCD were identified. Median age at PPGL diagnosis was 28 years. Three tumors were abdominal paragangliomas and 1 was a pheochromocytoma. No germline pathogenic variants in PPGL-susceptibility genes were identified in the cohort. Genetic testing of tumor tissue detected unique EPAS1 variants in all 4 patients. Variants were not detected in the germline, and 1 variant was detected in lymph node tissue of a patient with metastatic disease., Conclusion: We propose that somatic EPAS1 variants may be acquired through exposure to chronic hypoxia in SCD and drive PPGL development. Future work is needed to further characterize this association., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Older adults are the fastest growing sub-group in prisons. They have complex health, social care and custodial needs and often the support they receive is sub-optimal. The Older prisoner Health and Social Care Assessment and Plan (OHSCAP) aimed to better meet these inter-related needs. As part of a wider study, a randomised controlled trial was conducted to evaluate the OHSCAPs effectiveness in meeting older prisoners' health, social care and custodial needs in comparison to treatment as usual. This article describes the nested qualitative study which aimed to explore the barriers and facilitators to the effective implementation of the OHSCAP. Semi-structured interviews were conducted with older adults (n = 14) and staff members t (n = 12). Data was analysed using the framework method. Three overarching key themes were identified. These were: (1) balancing care and custodial requirements; (2) prison, health and social care silos; and (3) rigid prison processes. Prison is an important opportunity to engage residents and improve public health. Cultural and strategic change is required for health, social care and custodial interventions, such as the OHSCAP, to be successfully implemented into prison settings.

Titin is the largest protein found in nature and spans half a sarcomere in vertebrate striated muscle. The protein has multiple functions, including in the organisation of the thick filament and acting as a molecular spring during the muscle contraction cycle. Missense variants in titin have been linked to both cardiac and skeletal myopathies. Titin is primarily composed of tandem repeats of immunoglobulin and fibronectin type III (Fn3) domains in a variety of repeat patterns; however, the vast majority of these domains have not had their high-resolution structure determined experimentally. Here, we present the crystal structures of seven wild type titin Fn3 domains and two harbouring rare missense variants reported in hypertrophic cardiomyopathy (HCM) patients. All domains present the typical Fn3 fold, with the domains harbouring variants reported in HCM patients retaining the wild-type conformation. The effect on domain folding and stability were assessed for five rare missense variants found in HCM patients: four caused thermal destabilization of between 7 and 13 °C and one prevented the folding of its domain. The structures also allowed us to locate the positions of residues whose mutations have been linked to congenital myopathies and rationalise how they convey their deleterious effects. We find no evidence of physiological homodimer formation, excluding one hypothesised mechanism as to how titin variants could exert pathological effects., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the impact of the COVID-19 lockdown measures on HNC, by comparing the stage at presentation and treatment of HNC before and after the most severe COVID-19 restrictions., Design: A retrospective cohort study., Setting: A regional cancer network serving a patient population of 2.4 million., Participants: Newly diagnosed patients with HNC between June and October 2019 (pre-pandemic) and June and October 2021 (post-pandemic)., Main Outcome Measures: Symptom duration before diagnosis, stage at diagnosis, patient performance status (PS) and intent of treatment delivered (palliative vs. curative)., Results: Five hundred forty-five patients were evaluated-250 in the 2019 and 295 in the 2021 cohort. There were no significant differences in symptom duration between the cohorts (p = .359) or patient PS (p = .821). There were no increased odds of presenting with a late (Stage III or IV) AJCC cancer stage in 2021 compared with 2019 (odds ratio [OR] = 0.90; 95% confidence interval [CI]: 0.76-1.08); nor increased odds of receiving palliative rather than curative treatment in 2021 compared with 2019 (OR = 0.68; 95% CI: 0.45-1.03)., Conclusion: The predicted stage shift to more advanced disease at the time of diagnosis of HNC due to the COVID-19 pandemic has not been realised in the longer term. In keeping with this, there was no difference in symptom duration, patient PS, or treatment patterns between the 2019 and 2021 cohorts., (© 2023 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Aims: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by dynamic obstruction of the left ventricular (LV) outflow tract (LVOT). Although this may be mediated by interplay between the hypertrophied septal wall, systolic anterior motion of the mitral valve, and papillary muscle abnormalities, the mechanistic role of LV shape is still not fully understood. This study sought to identify the LV end-diastolic morphology underpinning oHCM., Methods and Results: Cardiovascular magnetic resonance images from 2398 HCM individuals were obtained as part of the NHLBI HCM Registry. Three-dimensional LV models were constructed and used, together with a principal component analysis, to build a statistical shape model capturing shape variations. A set of linear discriminant axes were built to define and quantify (Z-scores) the characteristic LV morphology associated with LVOT obstruction (LVOTO) under different physiological conditions and the relationship between LV phenotype and genotype. The LV remodelling pattern in oHCM consisted not only of basal septal hypertrophy but a combination with LV lengthening, apical dilatation, and LVOT inward remodelling. Salient differences were observed between obstructive cases at rest and stress. Genotype negative cases showed a tendency towards more obstructive phenotypes both at rest and stress., Conclusions: LV anatomy underpinning oHCM consists of basal septal hypertrophy, apical dilatation, LV lengthening, and LVOT inward remodelling. Differences between oHCM cases at rest and stress, as well as the relationship between LV phenotype and genotype, suggest different mechanisms for LVOTO. Proposed Z-scores render an opportunity of redefining management strategies based on the relationship between LV anatomy and LVOTO., Competing Interests: Conflict of interest: P.L. sits at the scientific advisory board of Ultromics. The remaining authors have nothing to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

From an open system perspective non-Markovian effects due to a nearby bath or neighboring qubits are dynamically equivalent. However, there is a conceptual distinction to account for: neighboring qubits may be controlled. We combine recent advances in non-Markovian quantum process tomography with the framework of classical shadows to characterize spatiotemporal quantum correlations. Observables here constitute operations applied to the system, where the free operation is the maximally depolarizing channel. Using this as a causal break, we systematically erase causal pathways to narrow down the progenitors of temporal correlations. We show that one application of this is to filter out the effects of crosstalk and probe only non-Markovianity from an inaccessible bath. It also provides a lens on spatiotemporally spreading correlated noise throughout a lattice from common environments. We demonstrate both examples on synthetic data. Owing to the scaling of classical shadows, we can erase arbitrarily many neighboring qubits at no extra cost. Our procedure is thus efficient and amenable to systems even with all-to-all interactions.

This study examined the associations among race/ethnicity, school climate, and social-normative expectations (expectations about peers' future achievement) in high and low socioeconomic status (SES) schools, with a particular focus on school climate as a process that might influence social-normative expectations. Results showed that more positive perceptions of school climate were significantly associated with higher levels of social-normative expectations in both low and high SES settings. Additionally, identifying as Black was negatively associated with social-normative expectations in both high and low SES schools. School climate significantly moderated the negative relationship between race and social-normative expectations in high SES schools; however, there was no moderation in low SES schools. In both high and low SES schools, school climate was a robust predictor of social-normative expectations, highlighting the importance of social-normative expectations as a metric of school climate improvement in both high and low SES schools. In conclusion, policies related to school culture and climate, school improvement, and turnaround should explicitly focus on the connection of racial and ethnic equity, specifically for Black and Latinx students, to reflect the range and reality of students' social-normative expectations., (© 2022 Wiley Periodicals LLC.)

Objectives: The aim of this study was to investigate the relationship of echocardiographic parameters, laboratory findings and clinical characteristics with in-hospital mortality in adult patients with COVID-19 admitted to the intensive care units (ICU) in two large collaborating tertiary UK centres., Design: Observational retrospective study., Setting: The study was conducted in patients admitted to the ICU in two large tertiary centres in London, UK., Participants: Inclusion criteria were: (1) patients admitted to the ICU with a COVID-19 diagnosis over a period of 16 weeks. and (2) underwent a transthoracic echocardiogram on the first day of ICU admission as clinically indicated.No exclusion criteria applied.Three hundred patients were enrolled and completed the follow-up., Primary and Secondary Outcome Measures: The outcome measure in this study was in-hospital mortality in patients admitted to the ICU with COVID-19 infection., Results: Older age (HR: 1.027, 95% CI 1.007 to 1.047; p=0.008), left ventricular (LV) ejection fraction<35% (HR: 5.908, 95% CI 2.609 to 13.376; p<0.001), and peak C reactive protein (CRP) (HR: 1.002, 95% CI 1.001 to 1.004, p=0.001) were independently correlated with mortality in a multivariable Cox regression model. Following multiple imputation of variables with more than 5% missing values, random forest analysis was applied to the imputed data. Right ventricular (RV) basal diameter (RVD1), RV mid-cavity diameter (RVD2), tricuspid annular plane systolic excursion, RV systolic pressure, hypertension, RV dysfunction, troponin level on admission, peak CRP, creatinine level on ICU admission, body mass index and age were found to have a high relative importance (> 0.7)., Conclusions: In patients with COVID-19 in the ICU, both severely impaired LV function and impaired RV function may have adverse prognostic implications, but older age and inflammatory markers appear to have a greater impact. A combination of echocardiographic and laboratory investigations as well as demographic and clinical characteristics appears appropriate for risk stratification in patients with COVID-19 who are admitted to the ICU., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 ( 41 ) as an oral candidate quality molecule.

Objective: Many patients presenting with suspected acute coronary syndrome (ACS) have high-sensitivity cardiac troponin (hs-cTn) concentrations between rule-in and rule-out thresholds and hence need serial testing, which is time consuming. The Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT) assessed the utility of coronary CT angiography (CCTA) in patients with suspected ACS, non-ischaemic ECG and intermediate initial hs-cTn concentration., Methods: Patients were randomised to CCTA-guided management versus standard of care (SOC). The primary outcome was hospital length of stay (LOS). Secondary outcomes included cost of in-hospital stay and major adverse cardiac events (MACE) at 12 months of follow-up. Data are mean (SD); for LOS harmonic means, IQRs are shown., Results: 250 (aged 55 (14) years, 25% women) patients were randomised. Harmonic mean (IQR) LOS was 7.53 (6.0-9.6) hours in the CCTA arm and 8.14 (6.3-9.8) hours in the SOC arm (p=0.13). Inpatient cost was £1285 (£2216) and £1108 (£3573), respectively, p=0.68. LOS was shorter in the CCTA group in patients with <25% stenosis, compared with SOC; 6.6 (5.6-7.8) hours vs 7.5 (6.1-9.4) hours, respectively; p=0.021. More referrals for cardiology outpatient clinic review and cardiac CT-related outpatient referrals occurred in the SOC arm (p=0.01). 12-month MACE rates were similar between the two arms (7 (5.6%) in the CCTA arm and 8 (6.5%) in the SOC arm-log-rank p=0.78)., Conclusions: CCTA did not lead to reduced hospital LOS or cost, largely because these outcomes were influenced by the detection of ≥25% grade stenosis in a proportion of patients., Trial Registration Number: NCT03583320., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Remote monitoring (RM) is the standard of care for follow up of patients with cardiac implantable electronic devices. The aim of this study was to compare smartphone-based RM (SM-RM) using patient applications (myMerlinPulse™ app) with traditional bedside monitor RM (BM-RM)., Methods and Results: The retrospective study included de-identified US patients who received either SM-RM or BM-RM capable of implantable cardioverter defibrillators or cardiac resynchronization therapy defibrillators (Abbott, USA). Patients in SM-RM and BM-RM groups were propensity-score matched on age and gender, device type, implant year, and month. Compliance with RM was quantified as the proportion of patients enrolling in the RM system (Merlin.net™) and transmitting data at least once. Connectivity was measured by the median number of days between consecutive transmissions per patient. Of the initial 9714 patients with SM-RM and 26 679 patients with BM-RM, 9397 patients from each group were matched. Remote monitoring compliance was higher in SM-RM; significantly more patients with SM-RM were enrolled in RM compared with BM-RM (94.4 vs. 85.0%, P < 0.001), similar number of patients in the SM-RM group paired their device (95.1 vs. 95.0%, P = 0.77), but more SM-RM patients transmitted at least once (98.1 vs. 94.3%, P < 0.001). Connectivity was significantly higher in the SM-RM, with patients transmitting data every 1.2 (1.1, 1.7) vs. every 1.7 (1.5, 2.0) days with BM-RM ( P < 0.001) and remained better over time. Significantly more SM-RM patients utilized patient-initiated transmissions compared with BM-RM (55.6 vs. 28.1%, P < 0.001)., Conclusion: In this large real-world study, patients with SM-RM demonstrated improved compliance and connectivity compared with BM-RM., Competing Interests: Conflict of interest: H.M.: consultant for Abbott. H.B.: speaker fees, institutional fellowship support or research grants from Abbott, Biotronik, Boston Scientific, Medtronic and Microport. R.C.-A.: speaker fees of small amount from Abbott, Johnson and Johnson. N.V.: research/PI/SC member/consultant for Abbott, Biotronik, Boston Scientific, EP Solutions, Medtronic, Impulse Dynamics, Implicity, Pacemate, Cardiologs. C.L.: speaker fees from Bayer, AstraZeneca. D.K.: consultant for Abbott, Biotronik, Boston Scientific, Medtronic. Speaker fees of small amount from Abbott and Medtronic. G.C.-W.: research funding and speaker fees from Pfizer Medtronic BMS and Abbott. K.K., I.R., Y.N.- employment and stock, Abbott. G.B.: speaker fees of small amount from Bayer, Boehringer, Boston, Daiichi., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aim: Exposure to lead can harm a child's health, including damage to the nervous system, delayed growth, hearing loss, and many other adverse health effects, as well as implications for social, economic, educational and social well-being. Lead exposure in children is still a concern and cases require public health management to find the exposure source and interrupt the exposure pathway. Housing characteristics can indicate the presence of lead-contaminated paint and leaded water supply pipes. We aimed to explore the relationship between housing characteristics and elevated blood lead concentration (BLC) in children in England., Methods: We used a retrospective cohort design and included all cases of lead exposure in children reported to the UK Health Security Agency between 2014 and 2020 via surveillance. A case was a child aged under 16 years, resident in England, BLC of ≥ 0.48 μmol/L (10 µg/dL) and referred for public health management. We collected case demographic details and housing characteristics (age and type). We explored associations between elevated BLC and risk factors, using generalised linear mixed effects models and compared cases' housing type to that expected nationally., Results: Two hundred and sixty-six out of 290 cases met the case definition. There was no difference in BLCs between genders, age groups, deprivation, and housing type. After adjusting for reporting source, housing age and type, cases residing in housing built pre-1976 had a BLC of 0.32 (95%CI 0.02, 0.63) µmols/L (6.63 (95%CI 0.42, 13.0) µg/dL) higher than cases living in housing built after this time. Cases were 1.68 times more likely to be living in terraced housing (housing adjoined to one another) than other children and less likely to live in apartments and detached properties., Conclusion: This study suggests an association between housing characteristics and BLC in children. Housing age and type may act as a proxy for lead exposure risk through exposure to leaded paint, lead water pipes, and lead contaminated dust from indoor and outdoor sources. Public health action should consider targeting families more at risk in older housing by raising awareness of the potential presence of lead pipes and paint. Interventions should include working with wider stakeholders including other housing and environmental professionals, the private sector, as well as parents and carers., (© 2022. The Author(s).)

A model needs to make verifiable predictions to have any scientific value. In opinion dynamics, the study of how individuals exchange opinions with one another, there are many theoretical models which attempt to model opinion exchange, one of which is the Martins model, which differs from other models by using a parameter that is easier to control for in an experiment. In this paper, we have designed an experiment to verify the Martins model and contribute to the experimental design in opinion dynamic with our novel method., Competing Interests: The authors have declared that no competing interests exist.

In opinion dynamics, as in general usage, polarisation is subjective. To understand polarisation, we need to develop more precise methods to measure the agreement in society. This paper presents four mathematical measures of polarisation derived from graph and network representations of societies and information-theoretic divergences or distance metrics. Two of the methods, min-max flow and spectral radius, rely on graph theory and define polarisation in terms of the structural characteristics of networks. The other two methods represent opinions as probability density functions and use the Kullback-Leibler divergence and the Hellinger distance as polarisation measures. We present a series of opinion dynamics simulations from two common models to test the effectiveness of the methods. Results show that the four measures provide insight into the different aspects of polarisation and allow real-time monitoring of social networks for indicators of polarisation. The three measures, the spectral radius, Kullback-Leibler divergence and Hellinger distance, smoothly delineated between different amounts of polarisation, i.e. how many cluster there were in the simulation, while also measuring with more granularity how close simulations were to consensus. Min-max flow failed to accomplish such nuance., Competing Interests: The authors have declared that no competing interests exist.

Objective: This study aimed to develop interpretive insights concerning Infection Prevention and Control (IPC) in care homes for older people., Design: This study had a meta-ethnography design., Data Sources: Six bibliographic databases were searched from inception to May 2020 to identify the relevant literature., Review Methods: A meta-ethnography was performed., Results: Searches yielded 652 records; 15 were included. Findings were categorized into groups: The difficulties of enacting IPC measures in the care home environment; workload as an impediment to IPC practice; the tension between IPC and quality of life for care home residents; and problems dealing with medical services located outside the facility including diagnostics, general practice and pharmacy. Infection was revealed as something seen to lie 'outside' the control of the care home, whether according to origins or control measures. This could help explain the reported variability in IPC practice. Facilitators to IPC uptake involved repetitive training and professional development, although such opportunities can be constrained by the ways in which services are organized and delivered., Conclusions: Significant challenges were revealed in implementing IPC in care homes including staffing skills, education, workloads and work routines. These challenges cannot be properly addressed without resolving the tension between the objectives of maintaining resident quality of life while enacting IPC practice. Repetitive staff training and professional development with parallel organisational improvements have prospects to enhance IPC uptake in residential and nursing homes., Patient or Public Contribution: A carer of an older person joined study team meetings and was involved in writing a lay summary of the study findings., (© 2021 The Authors. Health Expectations published by John Wiley & Sons Ltd.)