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Novel antimalarial compounds targeting both the pathogenic and transmissible stages of the human malaria parasite, Plasmodium falciparum, would greatly benefit malaria elimination strategies. However, most compounds affecting asexual blood stage parasites show severely reduced activity against gametocytes. The impact of this activity loss on a compound's transmission-blocking activity is unclear. Here, we report the systematic evaluation of the activity loss against gametocytes and investigate the confounding factors contributing to this. A threshold for acceptable activity loss between asexual blood stage parasites and gametocytes was defined, with near-equipotent compounds required to prevent continued gametocyte maturation and onward transmission. Target abundance is not predictive of gametocytocidal activity, but instead, lipoidal uptake is the main barrier of dual activity and is influenced by distinct physicochemical properties. This study provides guidelines for the required profiles of potential dual-active antimalarial agents and facilitates the development of effective transmission-blocking compounds., Competing Interests: Competing interests D.L. is a senior director in drug discovery at the Medicines for Malaria Venture (M.M.V.). M.M.V. funded part of this study. The other authors declare no competing interest., (© 2024. The Author(s).)

Purpose: This cross-sectional monocentric study aims to utilize the Early Childhood Attention Battery to investigate early attention patterns in young preterm children and ascertain the extent to which their attentional abilities diverge from those of term peers., Methods: Inclusion criteria encompassed gestational age < 34 weeks, with assessments conducted between 3 and 5 years 11 months. Exclusion criteria included major brain lesions, significant motor or behavioral disorders, and intellectual functioning with IQ < 70. Preterm raw scores converted to scaled scores and percentiles. Frequency analysis compared preterm scores to norms. Non-parametric tests assessed significance between scaled scores and subgroups (age, gestational age, sex, birth weight)., Results: One hundred nineteen preterm patients were enrolled in the study between November 2016 and June 2023. Comparisons with published norms showed lower mean scores across all subtests and domains for preterm children. A notable proportion of assessments (13-40%) fell below the 5th percentile, with the dual task item in sustained attention being the highest (40%). Sex did not predict differences, except for auditory sustained and visual search subtests. Gestational age did not correlate with abnormal scores, consistent with previous studies. The prevalence of assessments below the 5th percentile highlights preterm children's vulnerability to attention issues. The test's sensitivity to attention deficits in preterm populations suggests its potential in identifying at-risk children early for tailored interventions., Conclusions: The battery effectively detects attentional deficits in preterm children. Early detection and targeted insights support tailored educational interventions. By focusing on specific attention skills, the battery guides clinicians in choosing individualized or group activities based on areas most affected., What Is Known: • Attention is often impaired in preterm children but it is not systematically investigated before school age. The ECAB is a tool specifically designed for preschool children., What Is New: • Using the ECAB we evidenced a different level of attention between pre-term and term-born children at preschool age., Competing Interests: Declarations Conflict of interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aim: Testicular cancers, particularly seminomas and non-seminomas, generally have a favorable prognosis, although a small subset of patients experience mortality. Current knowledge of clinical markers associated with relapse and poor prognosis in seminoma is limited. Chemokines, key proteins in the tumor microenvironment, are underexplored in seminoma prognosis. Additionally, tumor-infiltrating lymphocytes (TILs), which play a critical role in cancer prognosis, require further investigation in the context of seminoma., Patients and Methods: Samples from 25 seminoma patients and 24 control patients who underwent orchiectomy were immunohistochemically (IHC) stained for chemokines CXCR4, CXCR5, and their ligands CXCL12, CXCL13, and the proliferation marker Ki-67. The associations between IHC results and clinical presentations were examined., Results: Chemokine profiles differed between seminoma and normal testis. The expression of chemokines in TILs in seminoma samples was especially over-expressed. The cytoplasmic expression of CXCL13 in TILs multiplied by the percentage of TILs in each sample, appeared to approach statistical significance concerning the likelihood of relapse., Conclusion: The involvement of TILs in seminoma biology warrants further investigation, especially their role in the tumor micro-environment and pathogenesis. Chemokine and Ki-67 expression in TILs could serve as potential markers for assessing seminoma prognosis., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Pediatric trauma centers have had challenges meeting the American College of Surgeons criteria for screening and intervening for alcohol with adolescent trauma patients. The study objective was to conduct an implementation trial to evaluate the effectiveness of the Science to Service Laboratory (SSL) implementation strategy in improving alcohol and other drugs (AOD) screening, brief intervention, and referral to treatment (SBIRT) delivery at pediatric trauma centers., Methods: Using a stepped wedge cross-over cluster randomized design, 10 US pediatric trauma centers received the SSL implementation strategy to deliver SBIRT with admitted adolescent (12-17 years old) trauma patients. The strategy adapted three core SSL elements: didactic training, performance feedback, and facilitation. The main outcome measured was SBIRT reach. Data were collected from each center's electronic health record (EHR) during pre- and post-implementation wedges (2018-2022)., Results: EHR data from 8461 adolescent patients were extracted. Aggregated across all sites, the reach of screening with a validated AOD screening tool increased significantly from 25.2% (95% CI: 23.9, 26.5%) of adolescents during pre-implementation to 47.7% (95% CI: 46.3%, 49.2%) post-implementation. There was variability of change across centers. Brief interventions continued to be delivered at high levels to identified adolescents. Referral to primary care providers for further AOD discussion or referral to specialty service for adolescents with high risk use did not improve post-implementation and remained low., Conclusions: The SSL implementation strategy can be successfully utilized by pediatric trauma centers to improve AOD screening, but challenges exist in connecting adolescents for continuation of AOD discussions after discharge., Level of Evidence: Level II, Therapeutic., Competing Interests: Conflicts of interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Bereaved care partner surveys typically focus on the experience with care in the final days of life. We sought to develop and pilot a novel bereaved care partner survey to understand experiences with ALS supportive care provided throughout the illness and identify opportunities for quality improvement., Methods: We developed the survey using a multisite, interdisciplinary consensus process involving ALS and palliative care clinicians as well as patient advocates. We then piloted the survey at a single site via video interviews with care partners of patients who died from ALS between three and 15 months prior. Qualitative findings were analyzed using Rapid Qualitative Analysis., Results: The survey includes 17 core questions and nine demographic items. Questions inquire about whether the patient and care partner received adequate help with physical symptoms, emotional and practical needs, education about the illness and how to provide hands-on care, preparing for what was to come, and bereavement. They also query whether care was person-centered and consistent with the patient's values and preferences. During the pilot with 18 bereaved care partners, the tool generated detailed feedback about aspects of care to preserve as well as how to improve ALS supportive care., Discussion: We developed and piloted a bereaved care partner survey to understand and improve the quality of ALS supportive care, which was found to be feasible and acceptable. Next steps include testing it at additional centers in order to generate learnings that can advance ALS supportive care in ways that are meaningful to patients and care partners., (Published by Elsevier Inc.)

The complete genome sequence of the opportunistic pathogen Nocardia vulneris is reported. The strain N. vulneris LPB4002 was isolated from a clinical sample of a patient with actinomycetoma. The reported genome comprises a single 9,489-Kb closed chromosome, with 8,584 protein-coding genes and 68% GC content.

Background: Disparities in time to hospital presentation and prehospital stroke care may be important drivers in inequities in acute stroke treatment rates, functional outcomes, and mortality. It is unknown how patient-level factors, such as race and ethnicity and county-level socioeconomic status, affect these aspects of prehospital stroke care., Methods: Cross-sectional study of patients with ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage in the Get With the Guidelines-Stroke registry, presenting from July 2015 to December 2019, with symptom onset ≤24 hours. Multivariable logistic regression and quantile regression were used to investigate the outcomes of interest: emergency medical services (EMS) transport (versus private vehicle), EMS prehospital notification (versus no prehospital notification), and stroke symptom onset to time of arrival at the emergency department. Prespecified covariates included patient-level, hospital-level, and county-level characteristics., Results: The inclusion criteria was met by the 606 369 patients. Of the patients, 51.2% were men and 69.9% White, with a median National Institutes of Health Stroke Severity of 4 (IQR, 2-10), and median social deprivation index (SDI) of 51 (IQR, 27-75). Median symptom onset to arrival time was 176 minutes (IQR, 64-565). Black race was significantly associated with prolonged symptom onset to emergency department arrival time (+28.21 minutes [95% CI, 25.59-30.84]), and decreased odds of EMS prehospital notification (OR, 0.80 [95% CI, 0.78-0.82]). SDI was not associated with differences in EMS use but was associated with lower odds of EMS prehospital notification (upper SDI tercile versus lowest, OR, 0.79 [95% CI, 0.78-0.81]). SDI was also significantly associated with stroke symptom onset to emergency department arrival time (upper SDI tercile versus lowest +2.56 minutes [95% CI, 0.58-4.53])., Conclusions: In this national cross-sectional study, Black race was associated with prolonged symptom onset to time of arrival intervals and significantly decreased odds of EMS prehospital notification, despite similar use of EMS transport. Greater county-level deprivation was also associated with reduced odds of EMS prehospital notification and slightly prolonged stroke symptom onset to emergency department arrival time. Efforts to reduce place-based disparities in stroke care must address significant inequities in prehospital care of acute stroke and continue to address health inequities associated with race and ethnicity., Competing Interests: IQVIA (Parsippany, NJ) serves as the data collection and coordination center. Data analysis was performed on the AHA Precision Medicine Platform. The Get With The Guidelines–Stroke (GWTG-Stroke) program is provided by the AHA/American Stroke Association. GWTG-Stroke is sponsored, in part, by Novartis, Novo Nordisk, AstraZeneca, Bayer, Tylenol, and HCA Healthcare. This project was part of the 2023 GWTG-Stroke Data Challenge.

Abstract: Over the past two decades, there has been increasing interest in the diagnosis and management of schwannomas of the inner ear including hearing rehabilitation with cochlear implants. However, tumor nomenclature and classification within the literature have been variable and oftentimes cumbersome. The term "intralabyrinthine schwannoma" is in common use when describing these tumors but is a potential source of confusion given that people often use the term "labyrinth" or "labyrinthine" to refer to the vestibular component of the inner ear only (i.e., labyrinthectomy or the translabyrinthine approach).During the Ninth Quadrennial Conference on Vestibular Schwannoma and Other Cerebellopontine Angle Lesions in Bergen, Norway, in May 2023, a multidisciplinary group of conference participants met and discussed issues pertaining to current terminology and classifications to enhance clarity and to reflect recent advances in tumor management and hearing rehabilitation.Although a variety of terms have been previously used to describe inner ear schwannomas, consensus was achieved on the term "inner ear schwannoma (IES)" to describe eighth nerve schwannomas of the cochlea, vestibule, or semicircular canals. Subgroups under this term comprise intravestibular, intracochlear, or intravestibulocochlear inner ear schwannomas (low complexity tumors), inner ear schwannomas with transfundal extension into the internal auditory canal but without modiolar involvement (intermediate complexity tumors), and inner ear schwannomas with transfundal extension with modiolar involvement (high complexity tumors).The details of the recommendations for an updated and simplified tumor nomenclature centered around tumor control and hearing rehabilitation with cochlear implantation are presented., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

GABA (γ-aminobutyric acid) receptors are constituents of many inhibitory synapses within the central nervous system. They are formed by 5 subunits out of 19 various subunits: α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3. Two main subtypes of GABA receptors have been identified, namely GABAA and GABAB. The GABAA receptor (GABAAR) is formed by a variety of combinations of five subunits, although both α and β subunits must be included to produce a GABA-gated ion channel. Other subunits are γ, δ, ε, π, and ϴ. GABAAR has many isoforms, that dictate, among other properties, their differing affinities and conductance. Drugs acting on GABAAR form the cornerstone of anesthesia and sedation practice. Some such GABAAR agonists used in anesthesia practice are propofol, etomidate, methohexital, thiopental, isoflurane, sevoflurane, and desflurane. Ketamine, nitrous oxide, and xenon are not GABAR agonists and instead inhibit glutamate receptors-mainly NMDA receptors. Inspite of its many drawbacks such as pain in injection, quick and uncontrolled conversion from sedation to general anesthesia and dose-related cardiovascular depression, propofol remains the most popular GABAR agonist employed by anesthesia providers. In addition, being formulated in a lipid emulsion, contamination and bacterial growth is possible. Literature is rife with newer propofol formulations, aiming to address many of these drawbacks, and with some degree of success. A nonemulsion propofol formulation has been developed with cyclodextrins, which form inclusion complexes with drugs having lipophilic properties while maintaining aqueous solubility. Inhalational anesthetics are also GABA agonists. The binding sites are primarily located within α + /β - and β + /α - subunit interfaces, with residues in the α + /γ - interface. Isoflurane and sevoflurane might have slightly different binding sites providing unexpected degree of selectivity. Methoxyflurane has made a comeback in Europe for rapid provision of analgesia in the emergency departments. Penthrox (Galen, UK) is the special device designed for its administration. With better understanding of pharmacology of GABAAR agonists, newer sedative agents have been developed, which utilize "soft pharmacology," a term pertaining to agents that are rapidly metabolized into inactive metabolites after producing desired therapeutic effect(s). These newer "soft" GABAAR agonists have many properties of ideal sedative agents, as they can offer well-controlled, titratable activity and ultrashort action. Remimazolam, a modified midazolam and methoxycarbonyl-etomidate (MOC-etomidate), an ultrashort-acting etomidate analog are two such examples. Cyclopropyl methoxycarbonyl metomidate is another second-generation soft etomidate analog that has a greater potency and longer half-life than MOC-etomidate. Additionally, it might not cause adrenal axis suppression. Carboetomidate is another soft analog of etomidate with low affinity for 11β-hydroxylase and is, therefore, unlikely to have clinically significant adrenocortical suppressant effects. Alphaxalone, a GABAAR agonist, is recently formulated in combination with 7-sulfobutylether-β-cyclodextrin (SBECD), which has a low hypersensitivity profile., (© 2024. The Author(s).)

Objective: To describe and compare the characteristics of people with SUD and their use of healthcare services in two ways: 1) across varying levels of marginalization and 2) before and during the pandemic., Methods: We conducted a population-based cross-sectional study using administrative data from Ontario, Canada. We included individuals age 16+ with a recorded diagnosis of SUD between June 2018-2019 (pre-pandemic) and June 2021-2022 (during-pandemic). Baseline sociodemographic and clinical characteristics and use of healthcare services were enumerated across the five quintiles of the Ontario Marginalization Index., Results: 259,497 pre-pandemic and 276,459 during-pandemic people with SUD were identified. Over 40% belonged to the two highest marginalization quintiles (Q4/Q5). Most had an outpatient visit with similar percentages across quintiles, however the number of visits increased with increasing marginalization (pre-pandemic: mean 8.5 visits in Q1 vs 13.0 visits in Q5; during-pandemic: mean 9.5 in Q1 vs 13.4 in Q5). There was no consistent pattern in percent of people who sought alcohol-related outpatient care, however more marginalized people sought drug-related outpatient care (pre-pandemic: 19.1% in Q1 vs 31.7% in Q5; during-pandemic: 18.7% in Q1 vs 32.5% in Q5). Almost half of people with SUD had an emergency department (ED) visit, of which more belonged to higher marginalization quintiles (pre-pandemic: 43.5% in Q1 vs 49.8% in Q5; during-pandemic: 41.4% in Q1 vs 49.3% in Q5)., Conclusions: SUD prevalence and most health service utilization remained similar from pre- to during-pandemic. Increasing marginalization was associated with increased use of healthcare among people with SUD. Future research should aim to further explore the complex relationship between marginalization and substance use., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chu 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: Poor adherence to photoprotection in Xeroderma Pigmentosum (XP) increases morbidity and shortens lifespan due to skin cancers., Objective: To test a highly personalised intervention (XPAND) to reduce the dose of ultraviolet radiation (UVR) reaching the face in adults with XP, designed using known psychosocial determinants of poor photoprotection., Methods: A two-arm parallel group randomised controlled trial, including patients with sub-optimal photoprotection to receive XPAND or a delayed intervention control arm that received XPAND the following year. XPAND comprises seven one-to-one sessions targeting photoprotection barriers (e.g., misconceptions about UVR) supported by personalised text messages, activity sheets, and educational materials incorporating behaviour change techniques. The primary outcome, mean daily UVR dose-to-face across 21 days in June-July 2018, was calculated by combining UVR exposure at the wrist with a face photoprotection activity diary. Secondary outcomes were UVR dose-to-face across 21 days in August 2018, time spent outside, photoprotective measures used outside, mood, automaticity, confidence-to-photoprotect. Financial costs and quality-adjusted life years (QALYs) were calculated., Results: 16 patients were randomised, 13 provided sufficient data for primary outcome analysis. The XPAND group (n=8) had lower mean daily UVR dose-to-face [0.03 SED (SD 0.02] compared to control (n=7) [0.36 SED (SD 0.16)] (adjusted difference=-0.25, p<0.001, Hedge's g=2.2). No significant between-group differences were observed in time spent outside, photoprotection outside, mood, or confidence. The delayed intervention control showed improvements in UVR dose-to-face (adjusted difference=-0.05, Hedge's g=-0.1) , time outside (adjusted difference=-69.9, Hedge's g=-0.28), and photoprotection (adjusted difference=-0.23, Hedge's g=0.45), after receiving XPAND. XPAND was associated with lower treatment costs (£-2642; 95% CI: -£8715 to £3873) and fewer QALYs (-0.0141; 95% CI: -0.0369 to 0.0028)., Conclusions: XPAND was associated with a lower UVR dose-to-face in XP patients and was cost-effective., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Objectives: Female athletes who experience childbirth during their athletic careers can expect to return to elite sports postpartum and perform at a comparable or improved level. However, mothering athletes often encounter significant barriers when re-entering elite sports. The aim of this study was to explore the experiences of a geographically diverse group of mothering athletes who returned to elite sports after childbirth., Design: Qualitative phenomenological research design using semi-structured interviews., Methods: In-depth one-on-one interviews were conducted with nineteen mothering elite running athletes hailing from fourteen different countries. Interviews were recorded, transcribed verbatim, and analyzed using thematic analysis., Results: Findings were generated into five main themes: (1) Deciding to become a mother, (2) revealing pregnancy to stakeholders, (3) experience of pregnancy, (4) combining motherhood and elite running, and (5) improvement strategies to support athlete mothers. The findings revealed that participants experienced stress regarding their pregnancy announcements due to concerns about potential repercussions on their careers. These concerns included the impact on sponsorship deals, relationships with governing bodies, and interactions with their coaches. Participants felt their elite coaches and health practitioners had insufficient education to support them throughout their pregnancies and postpartum return to elite running. Finally, athletes express a sense of diminished pressure and increased motivation in races upon resuming their elite careers, attributing their improved athletic performance postpartum to their shift in focus from themselves to their child., Conclusions: This study illuminates challenges and offers valuable insights to coaches, sponsors, health practitioners, exercise professionals, researchers, race organizers, and governing athletic bodies in better supporting mothering athletes., Competing Interests: Declaration of interest statement No potential conflict of interest was reported by the authors., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background: The purpose of this project was to measure satisfaction with virtual comprehensive geriatric assessments (CGA) among older Veterans (OVs)., Methods: The CGA involved five different healthcare providers and four one-hour VA Video Connect (VVC) calls. Using specific enrollment criteria, OVs were recruited in four cohorts separated by time. After completing the CGA, participants were asked to complete a 10-statement telephone questionnaire. Before analyses, responses to each statement were dichotomized as Agree (Agree/Strongly agree) or Do not Agree (Neutral/Disagree/Strongly Disagree). Descriptive statistics and Binomial generalized linear models (GLMs) were used to analyze the data., Results: All 269 enrolled OVs completed all components of the CGA. This included 79, 57, 61, and 72 Veterans in cohorts 1 to 4, respectively. Their average age was 76.0 ± 5.9 years, and they were predominately white (82%), male (94%), and residents of rural settings (64%). Of the 236 (88%) OVs who completed the telephone survey, 57% indicated they were comfortable using VVC and 57% expressed willingness to use VVC again; 44% felt that VVC was easier than going to in-person visits. The OVs in Cohort 1 were more likely to agree with these statements than those in the remaining cohorts, especially Cohorts 2 and 4. Differences in demographics partially explained some of these findings. The majority (89% or higher) of survey participants agreed with the remaining seven survey statements indicating they were satisfied with the CGA program., Conclusion: OVs were very satisfied with their participation in a program of CGA, although not necessarily the mode of delivery. The percentage of participants who indicated discomfort using VVC for the CGA visits appeared to increase with time. Further work is needed to determine which OVs would be the best candidates to use VVC to complete all or part of a CGA., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Despite exercise intolerance being predictive of outcomes in pulmonary arterial hypertension (PAH), its underlying cardiac mechanisms are not well described. The aim of the study was to explore the biventricular response to exercise and its associations with cardiorespiratory fitness in children with PAH. Participants underwent incremental cardiopulmonary exercise testing and simultaneous exercise echocardiography on a recumbent cycle ergometer. Linear mixed models were used to assess cardiac function variance and associations between cardiac and metabolic parameters during exercise. Eleven participants were included with a mean age of 13.4 ± 2.9 yr old. Right ventricle (RV) systolic pressure (RVsp) increased from a mean of 59 ± 25 mmHg at rest to 130 ± 40 mmHg at peak exercise ( P < 0.001), whereas RV fractional area change (RV-FAC) and RV-free wall longitudinal strain (RVFW-S l ) worsened (35.2 vs. 27%, P = 0.09 and -16.6 vs. -14.6%, P = 0.1, respectively). At low- and moderate-intensity exercise, RVsp was positively associated with stroke volume and O 2 pulse ( P < 0.1). At high-intensity exercise, RV-FAC, RVFW-S l , and left ventricular longitudinal strain were positively associated with oxygen uptake and O 2 pulse ( P < 0.1), whereas stroke volume decreased toward peak ( P = 0.04). In children with PAH, the increase of pulmonary pressure alone does not limit peak exercise, but rather the concomitant reduced RV functional reserve, resulting in RV to pulmonary artery (RV-PA) uncoupling, worsening of interventricular interaction and LV dysfunction. A better mechanistic understanding of PAH exercise physiopathology can inform stress testing and cardiac rehabilitation in this population. NEW & NOTEWORTHY In children with pulmonary arterial hypertension, there is a marked increase in pulmonary artery pressure during physical activity, but this is not the underlying mechanism that limits exercise. Instead, right ventricle-to-pulmonary artery uncoupling occurs at the transition from moderate to high-intensity exercise and correlates with lower peak oxygen uptake. This highlights the more complex underlying pathological responses and the need for multiparametric assessment of cardiac function reserve in these patients when feasible.

Background and Purpose: Inhibitors of voltage-gated sodium channels (Na V s) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Na v channels as a means of informing the development of improved antiseizure drugs., Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of Na V 1.6 alone or together with Na V 1.2. These novel Na V inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding Na V 1.6) and in wild-type mice., Key Results: Pharmacologic inhibition of Na V 1.6 in Scn8a N1768D/+ mice prevented seizures evoked by a 6-Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. Na V 1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS Na V isoforms., Conclusions and Implications: Our data suggest Na V 1.6 inhibition is a driver of efficacy for Na V inhibitor anti-seizure medicines. Sparing the Na V 1.1 channels of inhibitory interneurons did not compromise efficacy. Selective Na V 1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives: To evaluate radiomics features' reproducibility using inter-package/inter-observer measurement analysis in renal masses (RMs) based on MRI and to employ machine learning (ML) models for RM characterization., Methods: 32 Patients (23M/9F; age 61.8 ± 10.6 years) with RMs (25 renal cell carcinomas (RCC)/7 benign masses; mean size, 3.43 ± 1.73 cm) undergoing resection were prospectively recruited. All patients underwent 1.5 T MRI with T2-weighted (T2-WI), diffusion-weighted (DWI)/apparent diffusion coefficient (ADC), and pre-/post-contrast-enhanced T1-weighted imaging (T1-WI). RMs were manually segmented using volume of interest (VOI) on T2-WI, DWI/ADC, and T1-WI pre-/post-contrast imaging (1-min, 3-min post-injection) by two independent observers using two radiomics software packages for inter-package and inter-observer assessments of shape/histogram/texture features common to both packages (104 features; n = 26 patients). Intra-class correlation coefficients (ICCs) were calculated to assess inter-observer and inter-package reproducibility of radiomics measurements [good (ICC ≥ 0.8)/moderate (ICC = 0.5-0.8)/poor (ICC < 0.5)]. ML models were employed using reproducible features (between observers and packages, ICC > 0.8) to distinguish RCC from benign RM., Results: Inter-package comparisons demonstrated that radiomics features from T1-WI-post-contrast had the highest proportion of good/moderate ICCs (54.8-58.6% for T1-WI-1 min), while most features extracted from T2-WI, T1-WI-pre-contrast, and ADC exhibited poor ICCs. Inter-observer comparisons found that radiomics measurements from T1-WI pre/post-contrast and T2-WI had the greatest proportion of features with good/moderate ICCs (95.3-99.1% T1-WI-post-contrast 1-min), while ADC measurements yielded mostly poor ICCs. ML models generated an AUC of 0.71 [95% confidence interval = 0.67-0.75] for diagnosis of RCC vs. benign RM., Conclusion: Radiomics features extracted from T1-WI-post-contrast demonstrated greater inter-package and inter-observer reproducibility compared to ADC, with fair accuracy for distinguishing RCC from benign RM., Clinical Relevance: Knowledge of reproducibility of MRI radiomics features obtained on renal masses will aid in future study design and may enhance the diagnostic utility of radiomics models for renal mass characterization., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Little is known about colorectal cancer screening in 9/11 World Trade Center (WTC)-exposed populations. We utilized survey data from the WTC Health Registry (WTCHR) to examine associations between enrollees' characteristics and colorectal cancer (CRC) screening., Methods: We studied 22,061 enrollees aged 50-75 who completed the WTCHR follow-up survey in 2015-2016. Those with a history of CRC were excluded. Screening was defined as a self-reported, routine colonoscopy or sigmoidoscopy during the 12-month period prior to the survey. Multivariable log binomial regression identified factors associated with screening in the 12 months preceding the survey. We also stratified by age group., Results: Of 22,061 enrollees, 23% were screened, with largely similar rates across age groups. Higher screening percentages were seen in selected groups including non-Hispanic Black enrollees (26.4%), males (24.3%), those married/living with a partner (24.1%), those with a higher household income (≥ $150 k, 25.4%), those who received services from the WTC Health Program (25.6%), and those with greater perceived social support (24.4%). On multivariable analyses, non-Hispanic Black enrollees [adjusted relative risk (aRR) = 1.30, 95% confidence interval (CI) 1.19-1.42] were significantly more likely to report screening, even after stratifying by age group. Hispanic enrollees, those with a higher household income, those with increased perceived social support, and those with diagnosed medical conditions under 70 years old were also associated with screening., Conclusion: We found that non-Hispanic Black compared with non-Hispanic White enrollees were more likely to obtain screening for CRC. Continued efforts to promote health and wellness of WTC-exposed population is essential., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Tumor necrosis has been reported to represent an independent prognostic factor in colorectal cancer, but its evaluation methods have not been described in sufficient detail to introduce tumor necrosis evaluation into clinical use. To study the potential of tumor necrosis as a prognostic indicator in colorectal cancer, criteria for 3 methods for its evaluation were defined: the average percentage method (tumor necrosis percentage of the whole tumor), the hotspot method (tumor necrosis percentage in a single hotspot), and the linear method (the diameter of the single largest necrotic focus). Cox regression models were used to calculate cancer-specific mortality hazard ratios (HRs) for tumor necrosis categories in 2 colorectal cancer cohorts with more than 1800 cases. For reproducibility assessment, 30 cases were evaluated by 9 investigators, and Spearman's rank correlation coefficients and Cohen's kappa coefficients were calculated. We found that all 3 methods predicted colorectal cancer-specific survival independent of other prognostic parameters, including disease stage, lymphovascular invasion, and tumor budding. The greatest multivariable HRs were observed for the average percentage method (cohort 1: HR for ≥ 40% vs. <3% 3.03, 95% CI, 1.93-4.78; cohort 2: HR for ≥ 40% vs. < 3% 2.97; 95% CI, 1.63-5.40). All 3 methods had high reproducibility, with the linear method showing the highest mean Spearman's correlation coefficient (0.91) and Cohen's kappa (0.70). In conclusion, detailed criteria for tumor necrosis evaluation were established. All 3 methods showed good reproducibility and predictive ability. The findings pave the way for the use of tumor necrosis as a prognostic factor in colorectal cancer., Competing Interests: Conflicts of Interest and Source of Funding: This study was funded by Cancer Foundation Finland (59-5619 to J.P.V.), Finnish Medical Foundation (6021 to J.P.V.; 6259 to M.K.), Oulu Medical Research Foundation (to M.K.), Sigrid Jusélius Foundation (230229 to J.P.V.), and Finnish State Research Funding (to M.J.M. and J.P.V.). T.T. Seppälä reports consultation fees from Amgen Finland, Tillots Pharma, and Nouscom, being a co-owner and CEO of Healthfund Finland Ltd, and a position in the Clinical Advisory Board and a minor shareholder of LS Cancer Diag Ltd. For the remaining authors, none were declared., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To conduct an exhaustive scoping search of existing literature, incorporating diverse bibliographic sources to elucidate the relationships between metabolite biomarkers in human fluids and dietary intake., Background: The search for biomarkers linked to specific dietary food intake holds immense significance for precision health and nutrition research. Using objective methods to track food consumption through metabolites offers a more accurate way to provide dietary advice and prescriptions on healthy dietary patterns by healthcare professionals. An extensive investigation was conducted on biomarkers associated with the consumption of several food groups and consumption patterns. Evidence is integrated from observational studies, systematic reviews, and meta-analyses to achieve precision nutrition and metabolism personalization., Methods: Tailored search strategies were applied across databases and gray literature, yielding 158 primary research articles that met strict inclusion criteria. The collected data underwent rigorous analysis using STATA and Python tools. Biomarker-food associations were categorized into 5 groups: cereals and grains, dairy products, protein-rich foods, plant-based foods, and a miscellaneous group. Specific cutoff points (≥3 or ≥4 bibliographic appearances) were established to identify reliable biomarkers indicative of dietary consumption., Results: Key metabolites in plasma, serum, and urine revealed intake from different food groups. For cereals and grains, 3-(3,5-dihydroxyphenyl) propanoic acid glucuronide and 3,5-dihydroxybenzoic acid were significant. Omega-3 fatty acids and specific amino acids showcased dairy and protein foods consumption. Nuts and seafood were linked to hypaphorine and trimethylamine N-oxide. The miscellaneous group featured compounds like theobromine, 7-methylxanthine, caffeine, quinic acid, paraxanthine, and theophylline associated with coffee intake., Conclusions: Data collected from this research demonstrate potential for incorporating precision nutrition into clinical settings and nutritional advice based on accurate estimation of food intake. By customizing dietary recommendations based on individualized metabolic profiles, this approach could significantly improve personalized food consumption health prescriptions and support integrating multiple nutritional data.This article is part of a Nutrition Reviews special collection on Precision Nutrition., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Standardised nursing terminologies (SNTs) support the visibility of nursing work and documentation, enabling data sharing and comparison. An online survey assessed the knowledge and use of SNTs and revealed barriers and enablers to their use by Australian nurses. Just over half of the respondents were familiar with SNTs before the survey, a quarter reported a reasonable understanding of SNTs, just under half reported previous use of a SNT, and less than 14% indicated a current use of a SNT in their workplace. Perceived benefits to SNTs identified by respondents included a reduction in variation and the ability to evaluate the effectiveness of nursing care by measuring outcomes. Both barriers and enablers to the use of SNTs included education and training, standardisation and contextualisation across Australia, and integration into any electronic medical record system. Nurses are poorly informed on what SNTs are and how they can be leveraged to support their work and documentation. There is a need for an Australia-wide strategic approach to ensure the future of nurses' work is visible, and SNTs are purposefully and correctly implemented across the country.

Purpose: Lesbian, gay, bisexual, trans, queer, and intersex (LGBTQI) people face unique challenges in cancer care. This mixed methods study examined LGBTQI patients' satisfaction with cancer care and factors associated with satisfaction, including experiences of LGBTQI disclosure. The study also explored what helps to facilitate safe disclosure and improve satisfaction with care for this population., Methods: We used a mixed methods approach, involving 430 surveys and 104 semi-structured interviews with LGBTQI people with cancer (16-92 years) with various cancer types, sexuality and gender identities, ages, and people with intersex variations., Results: Most participants reported being satisfied with their cancer care (n = 300, 76.3%) and had disclosed their LGBTQI sexuality or gender identity or intersex variations to at least some of their cancer healthcare professionals (HCPs) (n = 357, 87.1%). Satisfaction with care was higher with more disclosure to HCPs, HCP acknowledgment of partner/s and support people, and the ability to find LGBTQI specific information about cancer; it was lower with reports of discrimination in cancer care. Qualitative analysis identified that some participants were always out to HCPs, but others felt burdened with the responsibility and emotion work of disclosure and feared negative responses. Same-gender intimate partners facilitated disclosure and need to be respected within cancer care., Conclusions: HCPs need to take the lead in facilitating LGBTQI disclosure in cancer care. Targeted interventions and training for HCPs, including reception and administration staff, are crucial to ensure equitable, affirming cancer care for all LGBTQI patients, ultimately leading to improved satisfaction with cancer care., Implications for Cancer Survivors: Creating safe and inclusive environments for LGBTQI cancer patients is essential to encourage disclosure and improve satisfaction with cancer care., (© 2024. The Author(s).)

Introduction : During the COVID-19 pandemic, hospitals in North America were overwhelmed with COVID-19 patients and had limited capacity to admit patients. Remote patient monitoring (RPM) programs were developed to monitor COVID-19 patients at home and reduce disease transmission and the demand on hospitals. A critical component of RPM programs is effective escalation pathways. The purpose of this review is to synthesize the implementation of escalation pathways of RPM programs for COVID-19 patients in Canada and the United States. Methods: The search identified 563 articles from Embase, PubMed, and Scopus. Following title and abstract screening, 131 were selected for full-text review, and 26 articles were included. Data were extracted on study location, patient eligibility and program size, data collection, monitoring team, escalation criteria, and escalation response. Results: The included studies were published between 2020 and 2022; 3 in Canada and 23 in the United States. The RPM programs collected physiological vital signs and symptom data, which were inputted manually by patients and health care workers or synced automatically. Escalations were triggered automatically or following manual review by nurses and physicians when signs and symptoms were concerning or reached a specific threshold. Escalations included emergency department referrals, physician appointments, and increased monitoring. Conclusion: Many decisions are required when designing RPM escalation pathways for patients with COVID-19, which is crucial to promptly address patients' changing health statuses and clinical needs. Future research is needed to evaluate the effectiveness of escalation pathways for COVID-19 patients through performance metrics and patient and health care worker experience.

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC 50 ) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

Background: AbobotulinumtoxinA has become well established as a treatment option for moderate to severe glabellar lines since its first aesthetic approval in 2009., Objective: Pivotal trials leading to regulatory approval showed that abobotulinumtoxinA treatment was associated with high responder rates when defined as achievement of none or mild glabellar lines (0 or 1 on the glabellar line severity scale) and a duration of action of up to 5 months. More recently, the goals for treatment of glabellar lines have shifted toward not only achieving a decrease in glabellar line severity but also ensuring that patients are satisfied with their experience., Materials and Methods: Patients seek an improvement in the appearance of their glabellar lines while maintaining a "natural look," fast onset of effect, and long duration of response., Results: Trial designs have evolved to meet these new targets, including expanding the definition of responders to those having at least 1-grade improvement in the glabellar line severity scale score from baseline coupled with the use of subject satisfaction and psychological well-being questionnaires., Conclusion: The findings demonstrate that abobotulinumtoxinA remains a well-tolerated and consistently effective treatment option associated with a rapid onset of effect, duration of efficacy lasting up to 6 months, and high, long-lasting levels of patient satisfaction., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: The use of botulinum toxins for facial rejuvenation and improvement of dynamic wrinkles has become a mainstay in the aesthetic treatment armamentarium. However, using these same neuromodulators (NMs) for lifting the structures of the face, is a newer addition to antiaging protocols. The muscles of facial animation all interplay with each other. Lifting can be accomplished by treating those muscles that are responsible for depression, leaving the elevators unopposed and resulting in a rejuvenated, lifted outcome. Brow lifting, cheek lifting, and even contouring of the lower face and jawline are all possibilities using NMs., Objective: To review the literature and current practices in techniques for lifting the different anatomic facial zones., Methods: The authors present and discuss the published data and personal experiences of using NM for lifting and retraining of the facial musculature. This article will discuss the effects and approaches to lifting with botulinum toxin injections, including the potential success and side effects associated with these off-label injections., Results/conclusions: The use of botulinum toxins has expanded beyond its traditional use as a reducer of dynamic wrinkles. A significant amount of published data now exists for the off-label use of botulinum toxins for lifting and shaping the face. These can be considered advanced techniques as each region has its own anatomic intricacies and side effects can occur. More placebo-controlled objective data would also help elucidate exact dosing strategies for each region., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Point-of-care ultrasound (POCUS) is a pivotal diagnostic tool for emergent conditions, yet the variable proficiency of emergency physicians (EPs) poses challenges. Inadequate skills may lead to care delays and suboptimal patient evaluation. This manuscript explores an innovative educational intervention deploying a Registered Diagnostic Medical Sonographer (RDMS) credentialed sonographer educator (SE) in a large academic Emergency Department (ED). We sought to evaluate the feasibility of using a SE to address POCUS skills deficiencies and attrition., Methods: The study involved 26 EPs voluntarily participating in hands-on training with the SE between July 2021-June 2022. The educational sessions addressed machine operation, image acquisition, image interpretation, and electronic medical record documentation of POCUS results. Subjects who consented completed a survey on their comfort level with POCUS before and after the intervention.  Results: Survey data indicated increased comfort and competence among participants with basic machine operation, resident POCUS supervision, and ordering and documenting POCUS exams. Post-training, 44% of providers reported performing more POCUS exams, 44% reported documenting their POCUS in the EMR more often clinically, 57% were more likely to encourage residents to perform scans, and 14% were more likely to perform a POCUS before ordering a comprehensive ultrasound. The study also observed an increase in the number of scans performed post-intervention (more than double). The SE intervention addressed challenges such as resource limitations, and feedback from participants highlighted the program's positive impact, particularly in reducing intimidation and fostering a desire for further training. While self-reported data and limited survey completion pose limitations, the increase in POCUS scans and positive feedback underscore the intervention's potential.  Conclusions: This pilot study demonstrates the feasibility and initial impact of integrating a SE into an academic ED setting. Further research is warranted to assess the specific effects on provider comfort and clinical decision-making with POCUS. The findings support the value of a dedicated SE in enhancing EPs' POCUS proficiency, promoting ongoing education, and ultimately improving patient care.

Objective: An American Psychiatric Nurses Association (APNA) task force reviewed current staffing research to revise and update the 2011 APNA "Staffing inpatient psychiatric units" position paper and provide recommendations to the APNA Board of Directors on how psychiatric mental health (PMH) nurses might champion the staffing needs of inpatient psychiatric units., Methods: Current research on staffing and nursing practice in inpatient psychiatric units was reviewed as well as variables believed to influence staffing and nursing practice, such as consumer needs and workplace culture. Since current nurse staffing principles emphasize nursing value and how that value is connected to outcomes, the literature search included a focus on staffing and related patient outcomes., Results: PMH nurses are critical to the safety and quality of care in inpatient psychiatric units. However, there are little existing data on the relationship between staffing levels and even common adverse events such as staff injury and restraint of patients. Furthermore, there is scant research conducted on inpatient psychiatric units that informs optimal staffing models or establishes links between staffing and patient outcomes., Conclusions: Consistent with current evidence, the universal use of a single method or model of determining staffing needs (e.g., nursing hours per, case mix index, or mandatory ratios) is not recommended. PMH nurses should champion systematic evaluation of staffing on their inpatient units against select patient, nurse, and system outcomes. A data repository of PMH nurse-sensitive outcomes is necessary to benchmark unit performance and staffing., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Overdose remains a pressing public health concern in the United States, particularly with the emergence of fentanyl and other potent synthetic opioids in the drug supply. We evaluated trends in recurrent overdose and opioid use disorder (OUD) treatment initiation following emergency department (ED) visits for opioid overdose to inform response efforts., Methods: This retrospective cohort study used electronic health record and statewide administrative data from Rhode Island residents who visited EDs for opioid overdose between July 1, 2016, and June 30, 2021, a period with fentanyl predominance in the local drug supply. The primary outcome was recurrent overdose in the 365 days following the initial ED visit. OUD treatment initiation within 180 days following the initial ED visit was considered as a secondary outcome. Trends in study outcomes were summarized by year of the initial ED visit., Results: Among 1745 patients attending EDs for opioid overdose, 20 % (n=352) experienced a recurrent overdose within 365 days, and this percentage was similar by year (p=0.12). Among patients who experienced any recurrent overdose, the median time to first recurrent overdose was 88 days (interquartile range=23-208), with 85 % (n=299/352) being non-fatal. Among patients not engaged in OUD treatment at their initial ED visit, 33 % (n=448/1370) initiated treatment within 180 days; this was similar by year (p=0.98)., Conclusions: Following ED visits for opioid overdose in Rhode Island from 2016-2021, the one-year risk of recurrent overdose and six-month treatment initiation rate remained stable over time. Innovative prevention strategies and improved treatment access are needed., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

The United States Pharmacopeial Convention (USP) is a nonprofit, scientific, standard-setting organization, and world leader in establishing quality, purity, and testing standards for medicines, foods, and dietary supplements. USP quality standards are used in more than 140 countries and are legally recognized by more than 40 countries. Currently, there is renewed interest in herbal medicines globally, and health policies are being implemented worldwide for the use of complementary and traditional medicine. In response, USP has developed a robust body of monographs that can be used to guide industry and regulators in ensuring the quality and safety of botanical ingredients used in dietary supplements and herbal medicines. Throughout the Pan American regions, there is a strong tradition of using botanicals as herbal medicines and, as in other regions, a growing desire for botanical dietary supplements. This underscores the need for public quality standards to ensure quality, reduce the flow of substandard and adulterated products, and ensure public health and safety. In April 2022, USP launched the Pan America Botanical Dietary Supplements and Herbal Medicines Expert Panel, with experts representing 12 different countries. The Expert Panel's work focuses on developing quality control standards for the most important botanical ingredients used in the respective countries, ingredients that are also of global importance. This article provides an overview of the state of botanical dietary supplements and herbal medicines in different Pan American regions with a focus on the regulatory status of herbal products, the development of national quality and research initiatives, and policies related to agriculture conservation and sustainability, among other topics., Competing Interests: Author MF was employed by Pharmavite LLC. Author EF was employed by Native Botanicals Inc. Author WP was employed by CAMAG Scientific Inc. 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 © 2024 Upton, Agudelo, Cabrera, Caceres, Calderón, Calzada, Camacho, da Costa, Dobrecky, Enciso, Escobar, Fakhary, Fletcher, Gao, Lock, Mata, Parada, Perera, Pombo, Reich, Sanchez, Simirgiotis, Sood, Amiguet, Villar, Ghelman, Schveitzer, Portella, Wolffenbüttel, Ruppelt, Frickmann, Gavillan-Suarez, Allen, Alvarado, Sarma, Marles, Monagas and Navarro-Hoyos.)

Background: Early-stage upper gastrointestinal (UGI) cancer patients, after surgery, have altered gastrointestinal functions, compromising their nutritional status and health outcomes. Nutritional care provision to UGI survivors rarely focuses on long-term survivorship. Here, we explore recommendations for surveillance of micronutrient deficiency and supplementation for UGI cancer survivors after surgery., Methods: A scoping review, based on the Joanna Briggs Institute methodology for scoping reviews. Six databases (Medline, Embase, CINAHL, Cochrane, Scopus, and PsycINFO) and 21 cancer-related organisation websites were searched. Publications between 2010 and March 2024 with recommendations aimed at adult UGI cancer (oesophageal, gastric, pancreatic, small bowel, and biliary tract) survivors were included., Results: Twenty-six publications met the selection criteria: 11 reviews (8 narrative reviews, 2 systematic, 1 meta-analysis), 7 expert opinions, 6 guidelines, and 2 consensus papers. Twenty-two publications recommended monitoring of micronutrient deficiencies, and 23 suggested supplementation, with 8 lacking details. Most were targeted at patients with gastric cancer (n = 19), followed by pancreatic cancer (n = 7) and oesophageal cancer (n = 3) with none for biliary tract and small bowel cancers. Vitamin B12 and iron were the most consistently recommended micronutrients across the three tumour groups., Conclusion: Limited publications recommend surveillance of micronutrient status in UGI cancer survivors during the survivorship phase, especially for oesophageal and pancreatic cancer survivors; most were narrative reviews. These recommendations lacked details, and information was inconsistent., Implications for Cancer Survivors: Long-term UGI cancer survivors are at risk of micronutrient deficiency after surgery. A standardised approach to prevent, monitor, and treat micronutrient deficiencies is needed., (© 2024. The Author(s).)

Background: Longitudinal studies highlight the importance of early intervention and timely device fitting for language development in children with congenital or early acquired hearing loss. Due to the variability in hearing loss, comorbidities, family circumstances, and service access, individualised monitoring of listening development is essential to inform decision-making. The Functional Listening Index-Paediatric (FLI-P), a 64-item hierarchical checklist of listening skills, has been validated for children with hearing loss aged 0-6 years. This study aimed to develop benchmarks for the FLI-P in typically hearing children, allowing for comparison with individual children with hearing loss., Methods: FLI-P scores were obtained from parents/caregivers of 561 typically hearing children aged 0-72 months. Each child's FLI-P score was categorised into a 6-month age block, with a minimum of 36 data points per block. Quantile regression was employed to establish percentiles of FLI-P scores by age., Results: FLI-P scores were successfully recorded for all 561 children. Regression analysis determined that the 16th and 84th percentiles of FLI-P scores corresponded to approximately ±1 standard deviation from the median score for each age group. A graphical representation of these percentile trajectories was created to facilitate comparison between children with hearing loss and the normative data., Conclusion: A normative dataset of FLI-P scores from typically hearing children has been established, allowing for comparisons with the scores and developmental trajectories of individual children with hearing loss. The study demonstrates how FLI-P can guide early intervention decisions and effectively monitor progress.

Aims: Complete ruptures of the ulnar collateral ligament (UCL) of the thumb are a common injury, yet little is known about their current management in the UK. The objective of this study was to assess the way complete UCL ruptures are managed in the UK., Methods: We carried out a multicentre, survey-based cross-sectional study in 37 UK centres over a 16-month period from June 2022 to September 2023. The survey results were analyzed descriptively., Results: A total of 37 centres participated, of which nine were tertiary referral hand centres and 28 were district general hospitals. There was a total of 112 respondents (69 surgeons and 43 hand therapists). The strongest influence on the decision to offer surgery was the lack of a firm 'endpoint' to stressing the metacarpophalangeal joint (MCPJ) in either full extension or with the MCPJ in 30° of flexion. There was variability in whether additional imaging was used in managing acute UCL injuries, with 46% routinely using additional imaging while 54% did not. The use of a bone anchor was by far the most common surgical option for reconstructing an acute ligament avulsion (97%, n = 67) with a transosseous suture used by 3% (n = 2). The most common duration of immobilization for those managed conservatively was six weeks (58%, n = 65) and four weeks (30%, n = 34). Most surgeons (87%, n = 60) and hand therapists (95%, n = 41) would consider randomizing patients with complete UCL ruptures in a future clinical trial., Conclusion: The management of complete UCL ruptures in the UK is highly variable in certain areas, and there is a willingness for clinical trials on this subject., Competing Interests: B. J. F. Dean and M.Mikhail report a British Society for Surgery of the Hand (BSSH) pump priming grant for this study. B. J. F. Dean also reports a British Medical Association Doris Hillier grant which was unrelated to this study. B. J. F. Dean is also a member of the BSSH research committee. D. J. Beard holds a Senior Investigator grant from the National Institute for Health and Care Research, unrelated to this study. M. Mikhail reports a BSSH grant to the ULCTEAR steering group for this study, allocated under his name. N. Riley reports consulting fees from Acumend, Arthrex, and Meshworks, unrelated to this study., (© 2024 Mikhail et al.)

Objective: Screening, brief intervention, and referral to treatment (SBIRT) for adolescent alcohol and drug (AOD) use is recommended to occur with adolescents admitted to pediatric trauma centers. Most metrics on SBIRT service delivery only reference medical record documentation. In this analysis we examined changes in adolescents' perception of SBIRT services and concordance of adolescent-report and medical record data, among a sample of adolescents admitted before and after institutional SBIRT implementation., Methods: We implemented SBIRT for adolescent AOD use using the Science to Service Laboratory implementation strategy and enrolled adolescents at 9 pediatric trauma centers. The recommended clinical workflow was for nursing to screen, social work to provide adolescents screening positive with brief intervention and referral to their PCP for continued AOD discussions with those. Adolescents screening as high-risk also referred to specialty services. Adolescents were enrolled and contacted 30 days after discharge and asked about their perception of any SBIRT services received. Data were also extracted from enrolled patient's medical record., Results: There were 430 adolescents enrolled, with 424 that were matched to their EHR data and 329 completed the 30-day survey. In this sample, EHR documented screening increased from pre-implementation to post-implementation (16.3%-65.7%) and brief interventions increased (27.1%-40.7%). Adolescents self-reported higher rates of being asked about alcohol or drug use than in EHR data both pre- and post-implementation (80.7%-81%). Both EHR data and adolescent self-reported data demonstrated low referral back to PCP for continued AOD discussions., Conclusions: Implementation of SBIRT at pediatric trauma centers was not associated with change in adolescent perceptions of SBIRT, despite improved documentation of delivery of AOD screening and interventions. Adolescents perceived being asked about AOD use more often than was documented. Referral to PCP or specialty care for continued AOD discussion remains an area of needed attention., Trial Registration: Clinicaltrials.gov NCT03297060., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Extending the duration of effect of botulinum toxins-by administering doses beyond those of the approved labels-has been an area of increasing interest in the field of aesthetics., Objectives: The aim of this study was to investigate the safety and duration of effect of 40-unit (U) prabotulinumtoxinA-xvfs (twice the approved dose and concentration) for the treatment of moderate-to-severe glabellar lines., Methods: A total of 154 adult patients were randomized 1:1:1 to a single treatment of either 40 U prabotulinumtoxinA-xvfs (PRA 40, 5 injections of 8 U/0.05 mL), or 20 U of either prabotulinumtoxinA-xvfs (PRA 20) or onabotulinumtoxinA (ONA 20). Both 20-U controls were administered as 5 injections of 4 U/0.1 mL. Efficacy and safety were assessed on days 2, 7 (by telephone), 30, and every 30 days thereafter up to 365 days or until the patient had returned to baseline. The primary effectiveness endpoint was the duration of effect (estimated by Kaplan-Meier analysis), defined as the number of days from treatment day (baseline) to the day that glabellar line severity at maximum frown by investigator assessment returned to the baseline value., Results: Patients had a mean age of 47 years (20-72 years); 69.5% had severe glabellar lines at baseline. Of the 36 adverse events, 32 (88.9%) were mild and 4 (11.1%) were moderate in severity; none were serious. The median durations of effect were estimated to be 183, 149, and 148 days for PRA 40-, PRA 20-, and ONA 20-treated patients, respectively., Conclusions: In this phase 2 pilot study, 40 U prabotulinumtoxinA-xvfs was observed to be safe and had a duration of 6 months., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Aesthetic Society.)

Eicosanoids are a family of bioactive lipids, including derivatives of the ubiquitous fatty acid arachidonic acid (AA). The intimate involvement of eicosanoids in inflammation motivates the development of predictive in silico models for a systems-level exploration of disease mechanisms, drug development and replacement of animal models. Using an ensemble modelling strategy, we developed a computational model of the AA cascade. This approach allows the visualisation of plausible and thermodynamically feasible predictions, overcoming the limitations of fixed-parameter modelling. A quality scoring method was developed to quantify the accuracy of ensemble predictions relative to experimental data, measuring the overall uncertainty of the process. Monte Carlo ensemble modelling was used to quantify the prediction confidence levels. Model applicability was demonstrated using mass spectrometry mediator lipidomics to measure eicosanoids produced by HaCaT epidermal keratinocytes and 46BR.1N dermal fibroblasts, treated with stimuli (calcium ionophore A23187), (ultraviolet radiation, adenosine triphosphate) and a cyclooxygenase inhibitor (indomethacin). Experimentation and predictions were in good qualitative agreement, demonstrating the ability of the model to be adapted to cell types exhibiting differences in AA release and enzyme concentration profiles. The quantitative agreement between experimental and predicted outputs could be improved by expanding network topology to include additional reactions. Overall, our approach generated an adaptable, tuneable ensemble model of the AA cascade that can be tailored to represent different cell types and demonstrated that the integration of in silico and in vitro methods can facilitate a greater understanding of complex biological networks such as the AA cascade.

This contribution presents the results of research focused on changes in selected properties of organic-coated steel sheets in a corrosive environment of salt mist. The aim of this study was to characterise coated sheets and to analyse the influence of elevated temperature on changes in their selected properties. The methodology and experiments were chosen to simulate the accelerated ageing and to evaluate the surface of organic-coated steel sheets. During the research, the effect of artificial ageing due to increased temperature on changes in mechanical properties of coated sheets was monitored, which were determined by tensile testing according to STN EN 10002-1. The fracture surface of the test samples was analysed using a SEM. The following observations were made for the evaluation of coating by cross-cut tests according to EN ISO 2409. Corrosion tests were carried out by conducting salt spray corrosion tests according to EN ISO 9227. The test specimens were artificially sectioned using a laser beam. The results of the research experiments confirmed the assumption that the utilisation of the laser beam was convenient for the creation cross-cut test of the material. After the ageing test, only small significant changes in the basic mechanical properties of the tested materials were observed. It is necessary to take into account that there were changes in the appearance of the coating. The cross-cut test confirmed the results that the plastic-coated sheets could be utilised in salt corrosion environments.

Background and Objectives: Electronic media (e-media) has become a universal part of young children's daily lives. Previous studies have found an association between increased screen time and children's psychosocial symptoms. We investigated whether parents' psychological distress and parenting style dimensions explain the association between children's screen time and psychosocial symptoms. Moreover, we investigated whether parents' mental well-being and parenting style dimensions moderate this association., Methods: We used data from the Finnish CHILD-SLEEP birth cohort study. Parents and the child were assessed when the child was 5 years old (N = 671). The measure of screen time included program viewing from TV and other devices. Child's psychosocial problems and parents' depression, stress and parenting style dimensions were assessed by self-reports., Results: A high level of screen time in children was associated with attention and concentration difficulties, hyperactivity and impulsivity symptoms as well as internalizing and externalizing symptoms among 5-year-olds. For the most part, the associations remained significant despite controlling for parents' mental health, parenting style dimensions and multiple background factors, especially associations relating to attention and concentration difficulties and hyperactivity symptoms were robust. Maternal stress and depression moderated the association between children's screen time and psychosocial symptoms, indicating a more pronounced association among stressed or depressed mothers., Conclusion: There is an independent association between children's screen time and psychosocial symptoms which is especially pronounced among those children whose mothers had poorer mental well-being. In clinical practice, the length of screen time should be inquired already at a young age and parents should be offered guidance to reduce the possible ill effects of excessive screen time, as well as help with their own mental health problems., (© 2024. The Author(s).)

Introduction: Despite growing efforts to increase diversity in recruitment and to teach principles of diversity, equity, and inclusion (DEI), representation of individuals underrepresented in medicine continues to fall short. This demonstrates a need for efforts that target the work environment and culture to increase retention alongside existing recruitment initiatives. We designed this interactive allyship workshop with a focus on building skills necessary for being an ally that has been missing in existing allyship curricula., Methods: This workshop was led by multidepartmental faculty with experience in DEI training. Participants engaged in a number of interactive activities to reflect on their own identities and privilege and practiced ways to engage in difficult conversations. Prior to the workshop, participants completed a survey that was repeated at the workshop's completion to evaluate their perspective change and understanding of allyship. We also collected responses to a self-reflective exercise during the workshop., Results: Participants included 68 anesthesia and surgery attendees, 53 of whom (78%) completed the postsurvey. Participants strongly agreed that this workshop was important to the workplace and medical training. Themes from the self-reflective exercises included endorsement of sponsorship and mentorship activities, community support, and advocacy., Discussion: Interactive skill-building activities are important and effective at helping trainees develop as allies. Long-term follow-up is needed to assess longitudinal knowledge retention and translation into behavioral change to create a more inclusive and supportive work environment., (© 2024 Tang et al.)

Background: Renal cell carcinoma is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced renal cell carcinoma are the focus of this National Institute for Health and Care Excellence multiple technology appraisal. A patient's risk of disease progression depends on a number of prognostic risk factors; patients are categorised as having intermediate/poor risk or favourable risk of disease progression., Objectives: The objectives of this multiple technology appraisal were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus relevant comparators listed in the final scope issued by the National Institute for Health and Care Excellence: sunitinib, pazopanib, tivozanib, cabozantinib and nivolumab plus ipilimumab., Methods: The assessment group carried out clinical and economic systematic reviews and assessed the clinical and cost-effectiveness evidence submitted by Eisai, Hatfield, Hertfordshire, UK (the manufacturer of lenvatinib) and Merck Sharp & Dohme, Whitehouse Station, NJ, USA (the manufacturer of pembrolizumab). The assessment group carried out fixed-effects network meta-analyses using a Bayesian framework to generate evidence for clinical effectiveness. As convergence issues occurred due to sparse data, random-effects network meta-analysis results were unusable. The assessment group did not develop a de novo economic model, but instead modified the partitioned survival model provided by Merck Sharp & Dohme., Results: The assessment group clinical systematic review identified one relevant randomised controlled trial (CLEAR trial). The CLEAR trial is a good-quality, phase III, multicentre, open-label trial that provided evidence for the efficacy and safety of lenvatinib plus pembrolizumab compared with sunitinib. The assessment group progression-free survival network meta-analysis results for all three risk groups should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons owing to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. The assessment group overall survival network meta-analysis results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the overall survival for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption, the assessment group overall survival network meta-analysis results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. Only one cost-effectiveness study was included in the assessment group review of cost-effectiveness evidence. The study was limited to the all-risk population, undertaken from the perspective of the US healthcare system and included comparators that are not recommended by the National Institute for Health and Care Excellence for patients with untreated advanced renal cell carcinoma. Therefore, the extent to which resource use and results are generalisable to the NHS is unclear. The assessment group cost-effectiveness results from the modified partitioned survival model focused on the intermediate-/poor-risk and favourable-risk subgroups. The assessment group cost-effectiveness results, generated using list prices for all drugs, showed that, for all comparisons in the favourable-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated fewer benefits than all other treatments available to NHS patients. For the intermediate-/poor-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated more benefits than treatment with cabozantinib and nivolumab plus ipilimumab., Conclusions: Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab with sunitinib is available from the CLEAR trial. For most of the assessment group Bayesian hazard ratio network meta-analysis comparisons, it is difficult to reach conclusions due to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the economic model are relevant to NHS clinical practice and can be used to inform National Institute for Health and Care Excellence decision-making. The assessment group cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options., Study Registration: This study is registered as PROSPERO CRD4202128587., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment ; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information.

Background: Lung cancer is one of the most common types of cancer in the United Kingdom. It is often diagnosed late. The 5-year survival rate for lung cancer is below 10%. Early diagnosis may improve survival. Software that has an artificial intelligence-developed algorithm might be useful in assisting with the identification of suspected lung cancer., Objectives: This review sought to identify evidence on adjunct artificial intelligence software for analysing chest X-rays for suspected lung cancer, and to develop a conceptual cost-effectiveness model to inform discussion of what would be required to develop a fully executable cost-effectiveness model for future economic evaluation., Data Sources: The data sources were MEDLINE All, EMBASE, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, Epistemonikos, ACM Digital Library, World Health Organization International Clinical Trials Registry Platform, clinical experts, Tufts Cost-Effectiveness Analysis Registry, company submissions and clinical experts. Searches were conducted from 25 November 2022 to 18 January 2023., Methods: Rapid evidence synthesis methods were employed. Data from companies were scrutinised. The eligibility criteria were (1) primary care populations referred for chest X-ray due to symptoms suggestive of lung cancer or reasons unrelated to lung cancer; (2) study designs that compared radiology specialist assessing chest X-ray with adjunct artificial intelligence software versus radiology specialists alone and (3) outcomes relating to test accuracy, practical implications of using artificial intelligence software and patient-related outcomes. A conceptual decision-analytic model was developed to inform a potential full cost-effectiveness evaluation of adjunct artificial intelligence software for analysing chest X-ray images to identify suspected lung cancer., Results: None of the studies identified in the searches or submitted by the companies met the inclusion criteria of the review. Contextual information from six studies that did not meet the inclusion criteria provided some evidence that sensitivity for lung cancer detection (but not nodule detection) might be higher when chest X-rays are interpreted by radiology specialists in combination with artificial intelligence software than when they are interpreted by radiology specialists alone. No significant differences were observed for specificity, positive predictive value or number of cancers detected. None of the six studies provided evidence on the clinical effectiveness of adjunct artificial intelligence software. The conceptual model highlighted a paucity of input data along the course of the diagnostic pathway and identified key assumptions required for evidence linkage., Limitations: This review employed rapid evidence synthesis methods. This included only one reviewer conducting all elements of the review, and targeted searches that were conducted in English only. No eligible studies were identified., Conclusions: There is currently no evidence applicable to this review on the use of adjunct artificial intelligence software for the detection of suspected lung cancer on chest X-ray in either people referred from primary care with symptoms of lung cancer or people referred from primary care for other reasons., Future Work: Future research is required to understand the accuracy of adjunct artificial intelligence software to detect lung nodules and cancers, as well as its impact on clinical decision-making and patient outcomes. Research generating key input parameters for the conceptual model will enable refinement of the model structure, and conversion to a full working model, to analyse the cost-effectiveness of artificial intelligence software for this indication., Study Registration: This study is registered as PROSPERO CRD42023384164., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135755) and is published in full in Health Technology Assessment ; Vol. 28, No. 50. See the NIHR Funding and Awards website for further award information.

Purpose: In this study, we explored the role of apoptosis as a potential biomarker for cardiac failure using functional micro-CT and fluorescence molecular tomography (FMT) imaging techniques in Ercc1 mutant mice. Ercc1 is involved in multiple DNA repair pathways, and its mutations contribute to accelerated aging phenotypes in both humans and mice, due to the accumulation of DNA lesions that impair vital DNA functions. We previously found that systemic mutations and cardiomyocyte-restricted deletion of Ercc1 in mice results in left ventricular (LV) dysfunction at older age., Procedures and Results: Here we report that combined functional micro-CT and FMT imaging allowed us to detect apoptosis in systemic Ercc1 mutant mice prior to the development of overt LV dysfunction, suggesting its potential as an early indicator and contributing factor of cardiac impairment. The detection of apoptosis in vivo was feasible as early as 12 weeks of age, even when global LV function appeared normal, underscoring the potential of apoptosis as an early predictor of LV dysfunction, which subsequently manifested at 24 weeks., Conclusions: This study highlights the utility of combined functional micro-CT and FMT imaging in assessing cardiac function and detecting apoptosis, providing valuable insights into the potential of apoptosis as an early biomarker for cardiac failure., (© 2024. The Author(s).)

Background: MRI-Linac systems enable daily diffusion-weighed imaging (DWI) MRI scans for assessing glioblastoma tumor changes with radiotherapy treatment., Purpose: Our study assessed the image quality of echoplanar imaging (EPI)-DWI scans compared with turbo spin echo (TSE)-DWI scans at 0.35 Tesla (T) and compared the apparent diffusion coefficient (ADC) values and distortion of EPI-DWI on 0.35 T MRI-Linac compared to high-field diagnostic MRI scanners., Methods: The calibrated National Institute of Standards and Technology (NIST)/Quantitative Imaging Biomarkers Alliance (QIBA) Diffusion Phantom was scanned on a 0.35 T MRI-Linac, and 1.5 T and 3 T MRI with EPI-DWI. Five patients were scanned on a 0.35 T MRI-Linac with a TSE-DWI sequence, and five other patients were scanned with EPI-DWI on a 0.35 T MRI-Linac and a 3 T MRI. The quality of images was compared between the TSE-DWI and EPI-DWI on the 0.35 T MRI-Linac assessing signal-to-noise ratios and presence of artifacts. EPI-DWI ADC values and distortion magnitude were measured and compared between 0.35 T MRI-Linac and high-field MRI for both phantom and patient studies., Results: The average ADC differences between EPI-DWI acquired on the 0.35 T MRI-Linac, 1.5 T and 3 T MRI scanners and published references in the phantom study were 1.7%, 0.4% and 1.0%, respectively. Comparing the ADC values based on EPI-DWI in glioblastoma tumors, there was a 3.36% difference between 0.35 and 3 T measurements. Susceptibility-induced distortions in the EPI-DWI phantoms were 0.46 ± 1.51 mm for 0.35 MRI-Linac, 0.98 ± 0.51 mm for 1.5 T MRI and 1.14 ± 1.88 mm for 3 T MRI; for patients -0.47 ± 0.78 mm for 0.35 T and 1.73 ± 2.11 mm for 3 T MRIs. The mean deformable registration distortion for a phantom was 1.1 ± 0.22 mm, 3.5 ± 0.39 mm and 4.7 ± 0.37 mm for the 0.35 T MRI-Linac, 1.5 T MRI, and 3 T MRI scanners, respectively; for patients this distortion was -0.46 ± 0.57 mm for 0.35 T and 4.2 ± 0.41 mm for 3 T. EPI-DWI 0.35 T MRI-Linac images showed higher SNR and lack of artifacts compared with TSE-DWI, especially at higher b-values up to 1000 s/mm 2 ., Conclusion: EPI-DWI on a 0.35 T MRI-Linac showed superior image quality compared with TSE-DWI, minor and less distortions than high-field diagnostic scanners, and comparable ADC values in phantoms and glioblastoma tumors. EPI-DWI should be investigated on the 0.35 T MRI-Linac for prediction of early response in patients with glioblastoma., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To report a validation of the Riester Big Ben Square Desk Aneroid Sphygmomanometer according to the international protocol developed by the Working Group on Blood Pressure Monitoring of the European Society of Hypertension 2002 (ESH-IP 2002) in the interest of transparency. This legacy publication is intended to assure users that the device satisfied the requirements in place at that time., Methods: Performance of the device was assessed by participants' age, sex, arm circumference and entry SBP/DBP. Validation was performed in 33 participants. The sphygmomanometer was assessed according to the ESH-IP, which defines zones of accuracy compared to the mercury standard as ≤5, ≤10, ≤15 mmHg or more., Results: The mean (± SD) age was 50.5 ± 13.0 years, range 29-71 years, entry SBP 142.6 ± 23.7 mmHg, entry DBP 89.0 ± 17.8 mmHg. The device passed all the requirements listed and the validation protocol. The Riester Big Ben Square Desk aneroid sphygmomanometer slightly underestimated the observer-measured SBP, yet slightly overestimated DBP. The observer-device disagreement was -0.8 ± 6.4 mmHg SBP and +0.6 ± 4.0 mmHg DBP., Conclusion: These data show that the Riester Big Ben Square Desk aneroid sphygmomanometer fulfilled the ESH-IP 2002 requirements for the validation of BP monitors. It was on this basis that the British and Irish Hypertension Society recommended it for clinical use in the adult population., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This study examined lesbian, gay, bisexual, transgender, queer and intersex (LGBTQI) cancer patients' sexual well-being post-cancer, and the associations between sexual well-being and social support, physical concerns, distress, quality of life (QOL), and coping. We used a mixed-methods approach, including 430 surveys and 103 interviews, representing a range of tumor types, sexual and gender identities, age groups, and intersex status. The findings indicated that LGBTQI people with cancer experience declines in sexual well-being following cancer, which are associated with reduced QOL, greater physical concerns, and lower social support. The perceived helpfulness of coping mechanisms was associated with greater sexual well-being across genders, with cisgender men reporting the sharpest declines in sexual well-being and highest use of coping mechanisms. Across all groups, searching for information online was the most frequently used coping mechanism, with support groups and counseling the most under-utilized. Qualitative findings facilitated interpretation of these results, providing examples of ways in which cancer impacted sexual well-being and how physical changes influence sexual embodiment or desire to engage in sex. Concerns about reduced sexual desire and activity, associated with changes to breasts, vulva, vagina, penis, erectile dysfunction, incontinence, scarring, and stoma, reflect previous findings in the non-LGBTQI cancer population. Unique to this population are the impact of physical changes on LGBTQI embodiment, including disruption to sexual and gender identities, and feelings of disconnection from queer communities. Addressing LGBTQI sexual well-being within oncology healthcare is a matter of sexual and reproductive justice, for a population whose needs are often overlooked within cancer care.

Remimazolam was derived from its parent compound by adding an ester linkage into its structure so that the drug becomes a substrate for ester metabolism. As a result, it undergoes organ-independent ester hydrolysis, although the clinical benefits in terms of shorter recovery are not uniformly observed in clinical practice. Remimazolam is mainly tested in procedural sedation. In comparison to propofol, the current gold standard for procedural sedation, its proposed attractiveness is shorter wake-up times and a clear-headed recovery. Its clear advantages over propofol are better hemodynamic stability, lack of pain on injection and availability of a reversal agent in the form of flumazenil. Data on patient and proceduralist satisfaction are lacking. Remimazolam is also used for induction and maintenance of general anesthesia in Japan (where it is approved for this purpose). In this scenario, it is not clear if it can achieve the same degree of lack of recall as propofol. The use of remimazolam in obstetrics, pediatrics and high-risk populations is an emerging area.

Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens are capable of inducing efficacious humoral and cellular immune responses in nonhuman primates. Several studies have evaluated the use of immune modulators to further enhance vaccine-induced T-cell responses. The hematopoietic growth factor Flt3L drives the expansion of various bone marrow progenitor populations, and administration of Flt3L was shown to promote expansion of dendritic cell populations in spleen and blood, which are targets of arenaviral vectors. Therefore, we evaluated the potential of Flt3 signaling to enhance the immunogenicity of arenaviral vaccines encoding SIV immunogens (SIV SME543 Gag, Env, and Pol) in rhesus macaques, with a rhesus-specific engineered Flt3L-Fc fusion protein. In healthy animals, administration of Flt3L-Fc led to a 10- to 100-fold increase in type 1 dendritic cells 7 days after dosing, with no antidrug antibody (ADA) generation after repeated dosing. We observed that administration of Flt3L-Fc fusion protein 7 days before arenaviral vaccine increased the frequency and activation of innate immune cells and enhanced T-cell activation with no treatment-related adverse events. Flt3L-Fc administration induced early innate immune activation, leading to a significant enhancement in magnitude, breadth, and polyfunctionality of vaccine-induced T-cell responses. The Flt3L-Fc enhancement in vaccine immunogenicity was comparable to a combination with αCTLA-4 and supports the use of safe and effective variants of Flt3L to augment therapeutic vaccine-induced T-cell responses.IMPORTANCEInduction of a robust human immunodeficiency virus (HIV)-specific CD4 + and CD8 + T-cell response through therapeutic vaccination is considered essential for HIV cure. Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens have demonstrated strong immunogenicity and efficacy in nonhuman primates. Here, we demonstrate that the immunogenicity of arenaviral vectors encoding SIV immunogens can be enhanced by administration of Flt3L-Fc fusion protein 7 days before vaccination. Flt3L-Fc-mediated increase in dendritic cells led to robust improvements in vaccine-induced T- and B-cell responses compared with vaccine alone, and Flt3L-Fc dosing was not associated with any treatment-related adverse events. Importantly, immune modulation by either Flt3L-Fc or αCTLA-4 led to comparable enhancement in vaccine response. These results indicate that the addition of Flt3L-Fc fusion protein before vaccine administration can significantly enhance vaccine immunogenicity. Thus, safe and effective Flt3L variants could be utilized as part of a combination therapy for HIV cure., Competing Interests: A.V.B., J.S., D.J., B.S., S.N., S.L., S. Suthram, M.H., B.C., C.C., R.G., M.K., and B.F. are Gilead employees and shareholders. A.N. is contracted by and works at Gilead. S.A.-E., H.L., K.K.O., R.W., S. Schulha, and S. Schmidt are employees of Hookipa Pharm Inc. and its subsidiary Hookipa Biotech GmbH and shareholders.

Background and Objectives: Correct child car restraint use significantly reduces risk of death and serious injury in motor vehicle crashes, but millions of US children ride with improper restraints. We created a tablet-based car restraint educational intervention using Computer Intervention Authoring Software (CIAS) and examined its impact on knowledge and behaviours among parents in the paediatric emergency department (PED)., Methods: This was a non-blinded, randomised controlled trial of parents of PED patients ages 0-12 years. Participants were evaluated for baseline car restraint knowledge and behaviour. The intervention group completed an interactive tablet-based module, while the control group received printed handouts on car restraint safety. After 1 week, both groups received a follow-up survey assessing changes in car restraint knowledge and behaviour. Logistic regressions determined predictors of knowledge retention and behavioural changes. Parents in the CIAS group were also surveyed on programme acceptability., Results: 211 parents completed the study with follow-up data. There was no significant difference in baseline car restraint knowledge (74.3% correct in intervention, 61.8% in control, p=0.15), or increase in follow-up restraint knowledge. Significantly more intervention-group caregivers reported modifying their child's car restraint at follow-up (52.5% vs 31.8%,p=0.003), and 93.7% of them found CIAS helpful in learning to improve car safety., Conclusion: Parents had overall high levels of car restraint knowledge. Using CIAS led to positive behavioural changes regarding child car restraint safety, with the vast majority reporting positive attitudes towards CIAS. This novel, interactive, tablet-based tool is a useful PED intervention for behavioural change in parents., Trial Registration Number: NCT03799393., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)