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Leukotriene C4 synthase (LTC4S) is a glutathione S -transferase that mediates the biosynthesis of cysteinyl leukotriene C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that drive type 2 inflammation, bronchoconstriction, and itch. Thus, LTC4S represents an attractive drug target for the treatment of allergic inflammatory diseases, but to date, no LTC4S inhibitor has been tested in patients. Herein, we disclose the discovery and preclinical profiling of the highly selective, oral LTC4S inhibitor GJG057 (compound 1 ), which exhibits 20-fold improved potency (IC 50 = 44 nM) versus clinical candidate AZD9898 (IC 50 = 900 nM) in a human whole blood LTC4 release assay. GJG057 showed efficacy in a murine asthma exacerbation model as well as in a mastoparan-induced skin challenge PK/PD model and was profiled in GLP toxicology studies. Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug. Its potential as a topical drug is currently being evaluated.

Objectives: Digitally native university students face challenges to their well-being and up to a third develop mental health problems. "Whitu: seven ways in seven days" is an app based on positive psychology, cognitive behaviour therapy (CBT) and psychoeducation principles., Methods: Ninety-first year university students (45 per arm) participated in a randomised controlled trial of Whitu against a university self-help website ("Be Well"). Primary outcomes were changes in well-being on the World Health Organisation 5-item well-being index (WHO-5) and the short Warwick-Edinburgh mental well-being scale (SWEMWBS). Secondary outcomes were changes in depression, anxiety, self-compassion, stress, sleep and self-reported acceptability of the app., Results: At 4 weeks (primary endpoint), participants in the intervention group experienced significantly higher mental well-being (mean difference: 2.53 (95%CI: 0.53, 4.52); p  = 0.013) and significantly lower depression (-4.23 (-8.32, -0.15); p  = 0.042), compared to controls. Emotional well-being was greater in the intervention group at 3 months (12.23 (3.93, 20.54; p  = 0.004). Other outcomes were similar between groups. User feedback was positive, with 88% saying they would recommend the app to a friend., Conclusions: Whitu is an acceptable, effective, scalable and multi-modal means of improving some aspects of well-being and mental health among university students., Trial Registration: This study was registered with the Australian New Zealand Clinical Trials Network Registry: ACTRN12622000053729.

The past decade has seen a huge increase in clinical research with psychedelic drugs and 3,4-methylenedioxymethamphetamine (MDMA), which have revealed great potential for treating mental health conditions. Given this progress in research, as well as the current unmet clinical need of millions of patients, in 2023, the Australian Therapeutic Goods Administration (TGA) approved the use of psilocybin for treatment-resistant depression and MDMA for PTSD to take effect from 1 July 2023. The campaign for TGA approval was led by a coalition comprising the Australian charity Mind Medicine Australia with support from Professor David Nutt, Drug Science, Professor Arthur Christopolous, Professor Chris Langmead (both from Monash University) and from large numbers of clinical, academic and patient groups. Under the rescheduling, current prescribing rights are limited to psychiatrists who have become authorised prescribers under the TGA's Authorised Prescriber Scheme, and psilocybin can only be used for treatment resistant depression and MDMA can only be used for PTSD. This paper reviews the background for this decision, its implications for approvals in other jurisdictions, as well as for the development pathways for other psychedelic drugs., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Using educational frameworks for learner assessment in genetic counseling (GC) training may help students and supervisors articulate developmentally appropriate clinical skills-based objectives and tasks that align with various stages of training as students work toward achieving entry-level competency. This professional issues case study describes how two GC programs adapted and implemented the RIME (Reporter-Interpreter-Manager-Educator) learner assessment framework, originally designed for medical education, to support and assess students' acquisition of practice-based competencies (PBCs) during clinical fieldwork placements. Each RIME level describes a different set of expectations regarding the skills students should be able to demonstrate based on the level of training they have achieved up to that point in time. In early training, students work mainly on gathering and reporting clinical information (Reporter level). In early to mid-training, students have learned what information to collect from clients and begin to apply the information to generate differential diagnoses (Interpreter level). When students reach the Manager level (typically by mid- to late-training), they can independently develop and implement case management plans tailored to individual cases. The Educator level, which may not be fully attained until after graduation, involves critically evaluating evidence and educating others about new evidence. The following paper describes our experiences incorporating the RIME framework into two GC graduate programs and explains the development of corresponding RIME-based assessment forms that align with the Accreditation Council of Genetic Counseling's 2023 PBCs. Overall, we find that using the RIME framework fosters a growth mindset by enabling students and supervisors to create developmentally appropriate goals and expectations, thereby facilitating assessment and guidance of trainee progress. Despite these perceived benefits, we acknowledge the need for research to evaluate the efficacy of the RIME framework or other learner assessment models in supporting student progression in achieving the GC PBCs., (© 2024 National Society of Genetic Counselors.)

Mass casualty events (MASCAL) do not follow the same rules as typical major incidents. In the West at least, the latter often occur in stable, networked trauma systems, whereas MASCAL are characterised by overwhelming numbers of patients, compounded by protracted scene and transport times, decompensated response systems and significant disruption to infrastructure, command and control.This paper describes the 8Ds approach being taken by the UK Defence Medical Services and the North Atlantic Treaty Organization Emergency Medicine Panel framework to approach MASCAL. The eight domains were derived from literature about management of casualties in the World Wars, and also from approaches taken by civilian health systems as they struggle to manage increasing demand. They are: distribute ; decompress ; delay ; delegate ; deliver faster and deliver better ; dynamic levels of care ; and de-escalate These domains will allow a structured approach to research and innovate around MASCAL, informing better guidelines for their management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic viral infections are ubiquitous in humans, with individuals harboring multiple latent viruses that can reactivate during acute illnesses. Recent studies have suggested that SARS-CoV-2 infection can lead to reactivation of latent viruses such as Epstein-Barr Virus (EBV) and cytomegalovirus (CMV), yet, the extent and impact of viral reactivation in COVID-19 and its effect on the host immune system remain incompletely understood. Here we present a comprehensive multi-omic analysis of viral reactivation of all known chronically infecting viruses in 1,154 hospitalized COVID-19 patients, from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, who were followed prospectively for twelve months. We reveal significant reactivation of Herpesviridae , Enteroviridae , and Anelloviridae families during acute stage of COVID-19 (0-40 days post-hospitalization), each exhibiting distinct temporal dynamics. We also show that viral reactivation correlated with COVID-19 severity, demographic characteristics, and clinical outcomes, including mortality. Integration of cytokine profiling, cellular immunophenotyping, metabolomics, transcriptomics, and proteomics demonstrated virus-specific host responses, including elevated pro-inflammatory cytokines (e.g. IL-6, CXCL10, and TNF), increased activated CD4+ and CD8+ T-cells, and upregulation of cellular replication genes, independent of COVID-19 severity and SARS-CoV-2 viral load. Notably, persistent Anelloviridae reactivation during convalescence (≥3 months post-hospitalization) was associated with Post-Acute Sequelae of COVID-19 (PASC) symptoms, particularly physical function and fatigue. Our findings highlight a remarkable prevalence and potential impact of chronic viral reactivation on host responses and clinical outcomes during acute COVID-19 and long term PASC sequelae. Our data provide novel immune, transcriptomic, and metabolomic biomarkers of viral reactivation that may inform novel approaches to prognosticate, prevent, or treat acute COVID-19 and PASC., Competing Interests: IMPACC Network Competing Interests The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays and NDV-based SARS-CoV-2 vaccines which list Florian Krammer as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. Florian Krammer has consulted for Merck and Pfizer (before 2020), and is currently consulting for Pfizer, Seqirus, 3rd Rock Ventures, Merck and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS-CoV-2. Viviana Simon is a co-inventor on a patent filed relating to SARS-CoV-2 serological assays (the “Serology Assays”). Ofer Levy is a named inventor on patents held by Boston Children’s Hospital relating to vaccine adjuvants and human in vitro platforms that model vaccine action. His laboratory has received research support from GlaxoSmithKline (GSK) and is a co-founder of and advisor to Ovax, Inc. Charles Cairns serves as a consultant to bioMerieux and is funded for a grant from Bill & Melinda Gates Foundation. James A Overton is a consultant at Knocean Inc. Jessica Lasky-Su serves as a scientific advisor of Precion Inc. Scott R. Hutton, Greg Michelloti and Kari Wong are employees of Metabolon Inc. Vicki Seyfert-Margolis is a current employee of MyOwnMed. Nadine Rouphael reports grants or contracts with Merck, Sanofi, Pfizer, Vaccine Company, Quidel, Lilly and Immorna, and has participated on data safety monitoring boards for Moderna, Sanofi, Seqirus, Pfizer, EMMES, ICON, BARDA, Imunon, CyanVac and Micron. Nadine Rouphael has also received support for meetings/travel from Sanofi and Moderna and honoraria from Virology Education. Adeeb Rahman is a current employee of Immunai Inc. Steven Kleinstein is a consultant related to ImmPort data repository for Peraton. Nathan Grabaugh is a consultant for Tempus Labs and the National Basketball Association. Akiko Iwasaki is a consultant for 4BIO, Blue Willow Biologics, Revelar Biotherapeutics, RIGImmune, Xanadu Bio, Paratus Sciences. Monika Kraft receives research funds paid to her institution from NIH, ALA; Sanofi, Astra-Zeneca for work in asthma, serves as a consultant for Astra-Zeneca, Sanofi, Chiesi, GSK for severe asthma; is a co-founder and CMO for RaeSedo, Inc, a company created to develop peptidomimetics for treatment of inflammatory lung disease. Esther Melamed received research funding from Babson Diagnostics and honorarium from Multiple Sclerosis Association of America and has served on the advisory boards of Genentech, Horizon, Teva, and Viela Bio. Carolyn Calfee receives research funding from NIH, FDA, DOD, Roche-Genentech and Quantum Leap Healthcare Collaborative as well as consulting services for Janssen, Vasomune, Gen1e Life Sciences, NGMBio, and Cellenkos. Wade Schulz was an investigator for a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; is a technical consultant to Hugo Health, a personal health information platform; cofounder of Refactor Health, an AI-augmented data management platform for health care; and has received grants from Merck and Regeneron Pharmaceutical for research related to COVID-19. Grace A McComsey received research grants from Redhill, Cognivue, Pfizer, and Genentech, and served as a research consultant for Gilead, Merck, Viiv/GSK, and Jenssen. Linda N. Geng received research funding paid to her institution from Pfizer, Inc.

Deep Eutectic Solvents (DESs) have recently been shown to be part of a dense ionic fluid continuum between ionic liquids and concentrated aqueous brines. Charge transport was shown to be governed by fluidity, with no discontinuity between molar conductivity and fluidity irrespective of cation, charge density or ionic radius. By adjusting the activity of water and chloride ions, mass transport, speciation and reactivity can be altered. It has been shown that while brines provide a high chloride content at a lower viscosity than DESs, unlike DESs, brines are unable to prevent metal passivation due to their high water content. This results in the possibility to impart a level of selectivity towards metal dissolution (or passivation) when processing mixed metal materials. Forced convection can be used to avoid the issue of slow mass transport in viscous media, and the use of jets or targeted ultrasound are effective methods for overcoming this issue. High-powered ultrasound was applied to copper, cobalt, and aluminium electrodes undergoing anodic dissolution, and linear sweep voltammetry showed a linear current-voltage response at potentials anodic of the oxidation potential under sonication, with total charge passed being 5 to 134 times greater than under silent conditions. Application of ultrasound to silver and nickel electrodes displayed an initial linear current-voltage response, but the increased water content of the brines resulted in passivation. Mass transport throughout the bulk solution is governed by the forced convection imparted by the ultrasound and ionic species must only migrate across the electrical double layer. It is shown that the anodic dissolution of a range of metals classically expected to passivate, e.g. aluminium, can be significantly accelerated under insonation conditions.

Competing Interests: The 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.

Objective: Assess the safety of ambulatory surgery performed for obstructive sleep apnea., Study Design: Retrospective chart review., Setting: Tertiary care hospital., Methods: Demographic data including age, gender, race, body mass index, insurance status, socioeconomic status, and distance traveled for surgery was collected, as well as comorbidities, and apnea-hypopnea index (AHI). Outcome variables included continuous positive airway pressure reinitiation, planned/unplanned postoperative admission, emergency department (ED) presentation, or readmission within 7 and 14 days of surgery., Results: A total of 601 patients were included, who underwent sleep surgery between 2017 and 2022. The median age was 55 years [interquartile range: 19]. A total of 437 patients (73%) were male, 502 (84%) were Caucasian, and the median distance traveled was 20 miles [27]. The median AHI was 27.1 [26]. A total of 286 hypoglossal nerve stimulators, 12 tonsillectomies, 160 expansion sphincteroplasties (ESP), and 201 nasal procedures were performed. There were 9 (1%) planned and 23 (4%) total admissions postoperatively. Sixteen patients (2%) presented to ED within 7 days, and 22 (3%) within 14 days. Nine (1%) were readmitted within 7 days, and 12 (2%) within 14 days. There were significantly more planned admissions, unplanned admissions, ED presentations, and readmissions for ESP. There were no significant differences in demographic or clinical data between patients who underwent single versus multiple surgeries., Conclusion: Outpatient sleep surgery is generally safe. Close postoperative monitoring is necessary and overnight observation should be considered in those with very severe sleep apnea and/or significant comorbidities. The distance a patient travels should also be considered for overnight admission., (© 2024 The Authors. Otolaryngology–Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

A Variant of Uncertain Significance (VUS) is a difference in the DNA sequence with uncertain consequences for gene function. A VUS in a hereditary cancer gene should not change medical care, yet some patients undergo medical procedures based on their VUS result, highlighting the unmet educational needs among patients and healthcare providers. To address this need, we developed, evaluated, and refined novel educational materials to explain that while VUS results do not change medical care, it remains important to share any personal or family history of cancer with family members given that their personal and family medical history can guide their cancer risk management. We began by reviewing the prior literature and transcripts from interviews with six individuals with a VUS result to identify content and design considerations to incorporate into educational materials. We then gathered feedback to improve materials via a focus group of multidisciplinary experts and multiple rounds of semi-structured interviews with individuals with a VUS result. Themes for how to improve content, visuals, and usefulness were used to refine the materials. In the final round of interviews with an additional 10 individuals with a VUS result, materials were described as relatable, useful, factual, and easy to navigate, and also increased their understanding of cancer gene VUS results.

Competing Interests: Competing interests: CH—RCEM Toxicology Advisory Group. AAB—president, RCEM. JF—chair, Quality in Emergency Care Committee, RCEM. PH—chair, Best Practice Committee, RCEM.

In programmes of assessment with both high and low-stakes assessments, the inclusion of open-ended long answer questions in the high-stakes examination can contribute to driving deeper learning among students. However, in larger institutions, this would generate a seemingly insurmountable marking workload. In this study, we use a focused ethnographic approach to explore how such a marking endeavour can be tackled efficiently and pragmatically. In marking parties, examiners come together to individually mark student papers. This study focuses on marking parties for two separate tasks assessing written clinical communication in medical school finals at Southampton, UK. Data collected included field notes from 21.3 h of marking parties, details of demographics and clinical and educational experience of examiners, examiners' written answers to an open-ended post-marking party questionnaire, an in-depth interview and details of the actual marks assigned during the marking parties. In a landscape of examiners who are busy clinicians and rarely interact with each other educationally, marking parties represent a spontaneous and sustainable community of practice, with functions extending beyond the mere marking of exams. These include benchmarking, learning, managing biases and exam development. Despite the intensity of the work, marking parties built camaraderie and were considered fun and motivating.

Background: Steatohepatitis is common in persons living with HIV and may be associated with gut microbial translocation (MT). However, few studies have evaluated the gut-liver axis in persons living with HIV. In the Women's Interagency HIV Study, we examined the associations of HIV and circulating biomarkers linked to MT and gut damage using the FibroScan-aspartate aminotransferase (FAST) score, a noninvasive surrogate for steatohepatitis with advanced fibrosis., Methods: Among 883 women with HIV and 354 without HIV, we used multivariable regression to examine the associations of HIV and serum biomarkers linked to MT and gut damage (kynurenine and tryptophan ratio, intestinal fatty acid-binding protein, soluble CD14, and soluble CD163) with a log-transformed FAST score after adjusting for key covariates. We used a path analysis and mediation models to determine the mediating effect of each biomarker on the association of HIV with FAST., Results: HIV infection was associated with a 49% higher FAST score. MT biomarker levels were higher in women with HIV than women without HIV ( P < .001 for each). MT biomarkers mediated 13% to 32% of the association of HIV and FAST score., Conclusions: Biomarkers linked to MT and gut damage are associated with a higher FAST score and mediate the association of HIV with a higher FAST score. Our findings suggest that MT may be an important mechanism by which HIV increases the risk of steatohepatitis with advanced fibrosis., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in Caenorhabditis elegans, Drosophila and rodents, but its mechanism is not well defined. Here, we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril-hypersensitive mutants. We identified a missense mutation that causes a partial loss of function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNA interference promoted dauer larvae formation, suggesting that acn-1 is a daf gene. Captopril-mediated lifespan extension was abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 influence lifespan by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

The use of artificial intelligence (AI)-based tools to guide prescribing decisions is full of promise and may enhance patient outcomes. These tools can perform actions such as choosing the 'safest' medication, choosing between competing medications, promoting de-prescribing or even predicting non-adherence. These tools can exist in a variety of formats; for example, they may be directly integrated into electronic medical records or they may exist in a stand-alone website accessible by a web browser. One potential impact of these tools is that they could manipulate our understanding of the benefit-risk of medicines in the real world. Currently, the benefit risk of approved medications is assessed according to carefully planned agreements covering spontaneous reporting systems and planned surveillance studies. But AI-based tools may limit or even block prescription to high-risk patients or prevent off-label use. The uptake and temporal availability of these tools may be uneven across healthcare systems and geographies, creating artefacts in data that are difficult to account for. It is also hard to estimate the 'true impact' that a tool had on a prescribing decision. International borders may also be highly porous to these tools, especially in cases where tools are available over the web. These tools already exist, and their use is likely to increase in the coming years. How they can be accounted for in benefit-risk decisions is yet to be seen., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Aims: Serum prolactin levels may be elevated by venepuncture stress. We investigated the utility of a rested prolactin sample, obtained through an indwelling venous cannula, in preventing the overdiagnosis of hyperprolactinaemia., Methods: Patients at our institution undergo serial prolactin sampling, usually over 40 min, when investigating hyperprolactinaemia. We retrospectively reviewed all serial prolactin sampling performed during a 3-year period. Patients with possible medication-induced hyperprolactinaemia and macroprolactin interference were excluded. We assessed the effect of venepuncture-associated stress on hyperprolactinaemia with the main outcome being normalisation of serum prolactin at the end of serial sampling., Results: Ninety-three patients with documented hyperprolactinaemia (range 360-1690 mU/L) were included in the analysis. Prolactin decreased during serial sampling in 73 patients (78%), suggesting a prevalent effect of venepuncture stress. The final prolactin sample was normal in 50 patients (54%), consistent with stress hyperprolactinaemia rather than pathological hyperprolactinaemia. Patients with a referral prolactin result greater than two times the upper reference limit (URL) were less likely (15%) to have a normal prolactin result on serial sampling. Measurement of a single rested prolactin sample from an indwelling cannula showed the same diagnostic utility as serial sampling., Conclusion: Serum prolactin results are frequently elevated by the stress of venepuncture. Confirmation of pathological hyperprolactinaemia in a rested sample obtained from an indwelling venous cannula is recommended in patients with mild hyperprolactinaemia, particularly when the referral prolactin is less than two times the URL., (© 2023 Royal Australasian College of Physicians.)

Context: The American College of Radiology Thyroid Image Reporting and Data System (ACR TI-RADS) was developed to predict malignancy risk in thyroid nodules using ultrasound features. TI-RADS was derived from a database of patients already selected for fine-needle aspiration (FNA), raising uncertainty about applicability to unselected patients., Objective: We aimed to assess the effect of ACR TI-RADS reporting in unselected patients presenting for thyroid ultrasound in a real-world setting., Methods: Records for all patients presenting for thyroid ultrasonography in Canterbury, New Zealand, were reviewed across two 18-month periods, prior to and after implementation of TI-RADS reporting. Patient outcomes were compared between the 2 periods. Malignancy rates were calculated for nodules 10 mm or larger with a definitive FNA or histology result., Results: A total of 1210 nodules were identified in 582 patients prior to implementation of TI-RADS; 1253 nodules were identified in 625 patients after implementation of TI-RADS. TI-RADS category was associated with malignancy rate (0% in TR1 and TR2, 3% in TR3, 5% in TR4, 12% in TR5; P = .02); however, 63% of nodules were graded TR3 or TR4, for which malignancy rate did not meaningfully differ from baseline risk. After implementation of TI-RADS there was a small reduction in the proportion of patients proceeding to FNA (49% vs 60%; P < .01) or surgery (14% vs 18%; P < .05), with no difference in cancer diagnoses (3% vs 4%, not significant)., Conclusion: TI-RADS category is associated with malignancy rate and may alter clinical decision-making in a minority of patients; however, it is nondiscriminatory in the majority of nodules. In this study of unselected patients, nodules classified as TR5 and thus considered "highly suspicious" for cancer had only a modest risk of malignancy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: In sub-Saharan Africa, increased antiretroviral therapy (ART) availability has improved survival after diagnosis of Kaposi sarcoma (KS) compared to the pre-ART era, but mortality among patients with KS is still considerably higher than HIV-infected persons without KS. Furthermore, among those patients with KS who are treated initially with ART without adjunct chemotherapy and who do survive, little is known about how well they function and feel - quality of life (QOL) - compared to those without KS., Methods: Among HIV-infected adults initiating ART in two prospective studies in Uganda, we compared those presenting with KS to those without KS. QOL was measured using the Medical Outcomes Survey-HIV instrument prior to ART initiation and at 16, 32, and 48 weeks thereafter; higher scores indicate better QOL. To ascertain the independent effect of KS versus non-KS on 11 domains of QOL and two summary scores, we created mixed effects models adjusted for directed acyclic graph-informed confounders., Results: We examined 224 participants with KS and 730 without KS, among whom 64% were women and median age was 34 years. Prior to ART initiation, participants had a median CD4+ T count of 159 cells/mm 3 and plasma HIV RNA of 5.1 log 10 copies/ml. In adjusted analyses prior to ART initiation, those with KS had lower mean scores in 8 of 11 QOL domains and both physical and mental health summary scores compared to those without KS. After 48 weeks of ART, those with KS had higher mean QOL scores compared those without KS in 4 domains and the mental health summary score, and lower scores in only one domain. There was no significant difference in 6 domains and the physical health summary score., Conclusions: Amongst HIV-infected adults in East Africa, at time of ART initiation, those with KS had worse mean QOL compared to those without KS. Over the first year of ART, those with KS became comparable to or exceeded those without KS in most QOL domains. The findings indicate that some patients with KS can be treated with ART alone and further emphasize the need to predict those who will do well with ART alone versus those who need additional initial therapy.

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in C. elegans , Drosophila , and rodents, but its mechanism is not well defined. Here we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril hypersensitive mutants. We identified a missense mutation that causes a partial loss-of-function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNAi promoted dauer larvae formation, suggesting acn-1 is a daf gene. Captopril-mediated lifespan extension xwas abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 control aging by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control., Summary Statement: Captopril and acn-1 control aging. By demonstrating they regulate dauer formation and interact with daf genes, including a new DAF-2(A261V) mutant corresponding to a human disease variant, we clarified the mechanism.

Long-term consequences of human immunodeficiency virus (HIV) are likely the result of persistent inflammation and immune dysfunction of which cytomegalovirus (CMV) is a known contributor. We leveraged 2 AIDS Clinical Trials Group clinical trials exploring the effects of immune modulators (ruxolitinib and sirolimus) on inflammation in people with HIV on antiretroviral therapy to determine whether these interventions affected CMV shedding at various mucosal sites. Analyzing 635 mucosal samples collected, we found no significant difference in CMV levels across study arms or time points. Men had more CMV shedding than women. We did confirm an association between higher CMV DNA and immune markers associated with HIV persistence and HIV-associated mortality rates., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: To determine if there is a recovery time difference between patients with and without obstructive sleep apnea (OSA) when using total intravenous anesthesia (TIVA) compared to volatile gas inhalational anesthesia., Patients and Methods: OSA and Non-OSA patients were identified at a tertiary institution between January 2019 and November 2020. Non-OSA patients were defined as those who have not been formerly diagnosed with OSA. A modified STOP-BANG score (MSBS) was performed to screen Non-OSA patients for OSA. Recovery was measured by Phase I recovery time, or time it took a patient to reach ≥9/10 on the Aldrete scoring system., Results: A total of 334 patients were included with 142 in the OSA cohort (59 TIVA, 83 inhalational anesthesia) and 192 in the Non-OSA cohort (119 TIVA, 73 inhalational anesthesia). In OSA patients, there was a 41.29-minute recovery time reduction when using TIVA versus sevoflurane ( P  < .0001). Non-OSA patients recovered faster than OSA patients when undergoing inhalational anesthesia by 46.76 minutes and TIVA by 18.58 minutes ( P  < .0001 and P  = .0907, respectively). Non-OSA patients with a MSBS < 3 and ≥3 had a shorter recovery time compared to OSA patients when both underwent sevoflurane anesthesia (57.27 minutes, P  < .0001 and 56.23 minutes, P  = .040, respectively). Non-OSA patients with a MSBS of <3 had a decrease in recovery time of 26.68 minutes when compared to OSA patients who underwent TIVA ( P  = .0004)., Conclusions: When utilizing TIVA over inhalational anesthesia, patients with OSA have significantly increased benefit in terms of reduced Phase I recovery times as compared to Non-OSA patients.

Background: Exclusion criteria that are treatment effect modifiers (TEM) decrease RCTs results generalisability and the potentials of effectiveness estimation. In "augmented RCTs", a small proportion of otherwise-excluded patients are included to allow for effectiveness estimation. In Hodgkin Lymphoma (HL) RCTs, older age and comorbidity are common exclusion criteria, while also TEM. We simulated HL RCTs augmented with age or comorbidity, and explored in each scenario the impact of augmentation on effectiveness estimation accuracy., Methods: Simulated data with a population of HL individuals initiating drug A or B was generated. There were drug-age and drug-comorbidity interactions in the simulated data, with a greater magnitude of the former compared to the latter. Multiple augmented RCTs were simulated by randomly selecting patients with increasing proportions of older, or comorbid patients. Treatment effect size was expressed using the between-group Restricted Mean Survival Time (RMST) difference at 3 years. For each augmentation proportion, a model estimating the "real-world" treatment effect (effectiveness) was fitted and the estimation error measured (Root Mean Square Error, RMSE)., Results: In simulated RCTs including none (0%), or the real-world proportion (30%) of older patients, the interquartile range of RMST difference was 0.4-0.5 years and 0.2-0.3 years, respectively, and RMSE were 0.198 years (highest possible error) and 0.056 years (lowest), respectively. Augmenting RCTs with 5% older patients decreased estimation error substantially (RMSE = 0.076 years). Augmentation with comorbid patients proved less useful for effectiveness estimation., Conclusion: In augmented RCTs aiming to inform the effectiveness of drugs, augmentation should concern in priority those exclusion criteria of suspected important TEM magnitude, so as to minimie the proportion of augmentation necessary for good effectiveness estimations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Inc.)

Objective: Specific guidelines regarding an optimal general anesthesia (GA) approach to obstructive sleep apnea (OSA) patients remain undefined. Literature comparing the efficacy of total intravenous anesthesia (TIVA) and inhalational anesthesia in this population is sparse. We hypothesize that OSA patients receiving TIVA will experience reduced recovery times and other improved post-surgical outcomes., Study Design: Randomized controlled trial., Methods: Adult OSA patients undergoing upper airway surgery (hypoglossal nerve stimulation [HNS], nasal, or palate surgery) from February 2020-December 2020 were included. A post-anesthesia care unit (PACU) nursing survey documented patients' alertness, pain, oxygen supplementation, and postoperative nausea and vomiting from PACU arrival to 2 hours. Perioperative timepoints from the electronic medical record (EMR) and a nurse-estimated Phase I recovery time were collected., Results: One hundred eleven patients were included (46 TIVA and 65 inhalational anesthesia). Per EMR-recorded timepoints, TIVA patients undergoing HNS and palate surgery experienced Phase I Time reductions of 12.5 min (p = 0.042) and 27.5 min (p = 0.016), respectively. Per the PACU survey, TIVA patients undergoing any surgery, HNS, or palate surgery experienced nurse-estimated Phase I Time reductions of 16.5 min (p = 0.004), 12.5 min (p = 0.031), and 38.5 min (p = 0.024), respectively. Overall, TIVA patients experienced higher alertness and pain ratings, and lower oxygen supplementation requirements from PACU arrival to 30 min (p < 0.05)., Conclusion: Patients with OSA receiving TIVA for GA maintenance during upper airway procedures experienced reduced recovery times and oxygen supplementation requirements, and a more rapid return to alertness. Future work toward developing optimized anesthetic guidelines for OSA patients is merited., Level of Evidence: 3 Laryngoscope, 133:984-992, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Here we describe the isolation and characterization of stictamycin, a new aromatic polyketide with activity against Staphylococcus aureus . Stictamycin was identified following metabolic profiling and bioactivity guided fractionation of organic extracts from Streptomyces sp. 438-3, an isolate from the New Zealand lichen Sticta felix . Comprehensive 1D and 2D NMR analyses were performed to determine the planar structure of stictamycin and relative configurations of stereo centers, with subsequent comparison of experimental and theoretical ECD spectra allowing elucidation of the absolute configuration. Whole-genome sequencing and biosynthetic gene cluster (BGC) analysis revealed that the Streptomyces sp. 438-3 strain contains an atypical type II polyketide (T2PKS) BGC capable of assembling polycyclic-aromatic ring skeletons. Cloning and knockout studies of this T2PKS BGC were used to confirm that it is responsible for the biosynthesis of stictamycin and elucidate a plausible biosynthetic scheme.

Ionic liquids are attractive liquid materials for many advanced applications. For targeted design, in-depth knowledge about their structure-property-relations is urgently needed. We prepared a set of novel protic ionic liquids (PILs) with a guanidinium cation with either an ether or alkyl side chain and different anions. While being a promising cation class, the available data is insufficient to guide design. We measured thermal and transport properties, nuclear magnetic resonance (NMR) spectra as well as liquid and crystalline structures supported by ab initio computations and were able to obtain a detailed insight into the influence of the anion and the ether substitution on the physical and spectroscopic properties. For the PILs, hydrogen bonding is the main interaction between cation and anion and the H-bond strength is inversely related to the proton affinity of the constituting acid and correlated to the increase of 1 H and 15 N chemical shifts. Using anions from acids with lower proton affinity leads to proton localization on the cation as evident from NMR spectra and self-diffusion coefficients. In contrast, proton exchange was evident in ionic liquids with triflate and trifluoroacetate anions. Using imide-type anions and ether side groups decreases glass transitions as well as fragility, and accelerated dynamics significantly. In case of the ether guanidinium ionic liquids, the conformation of the side chain adopts a curled structure as the result of dispersion interactions, while the alkyl chains prefer a linear arrangement.

The presence of macroscopic fat on computed tomography (CT) imaging has been traditionally regarded as an indication that an adrenal lesion is likely to be a benign myelolipoma, for which further investigation is not usually required. Two cases are described where an adrenal lesion was eventually found to be malignant on histology (adrenocortical carcinoma in the first case, undifferentiated sarcoma in the second case), despite the presence of macroscopic fat on CT. In both cases there were other clinical and radiological indicators of potential malignant pathology. These cases add to increasing awareness in the literature that malignant adrenal tumors may rarely contain macroscopic fat, emphasizing a need for clinical vigilance., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Aims: Exposure to corticosteroids is known to increase the risk of developing type 2 diabetes. We estimated the risk of incident type 2 diabetes in selected patient groups exposed to systemic corticosteroids., Materials and Methods: In a retrospective, observational cohort study, using real-world data from UK primary care, patients were selected who had at least one episode of exposure to oral or intravenous corticosteroids for any indication. Corticosteroid-exposed patients were matched with non-exposed patients. Relative dosage was estimated as a weight-based, prednisolone-equivalent dose. Crude rates of progression to type 2 diabetes were determined for patient groups defined by relevant steroid-related and phenotypic characteristics present at corticosteroid exposure., Results: Overall, rates of incidence of type 2 diabetes were 12.5 and 6.7 events per thousand person-years' (pkpy) exposure, respectively, in those who received at least one dose of corticosteroids versus those never exposed. This represented a rate ratio of 1.85 (95% CI 1.74-1.97). The incidence of type 2 diabetes was found to be associated with several of the selected characteristics, both individually and multi-dimensionally. The highest rate of incident type 2 diabetes was observed in very severely obese men aged 46-55 years having had the longest corticosteroid exposure and highest corticosteroid dose (190 incident events pkpy exposure)., Conclusions: Corticosteroid exposure increased the risk of incident type 2 diabetes, and there was evidence of both a dose-response and a duration response. The impact of corticosteroid exposure upon the rate of incident type 2 diabetes appeared, however, to involve a complex, multi-dimensional interaction between the selected characteristics, some of which might be impacted by reverse causality., (© 2022 John Wiley & Sons Ltd.)

Polymer-induced drag reduction (DR) in fluids was studied using a rotational rheometer with double-gap concentric cylinder geometry. Although both polymers (polyacrylamide (PAM) and 2-acrylamido-2-methylpropane sulfonic acid (SPAM)) had molecular weights of several MDa, the contrasting polymer charge, nonionic and anionic, led to different polymer overlap concentrations ( c *), PAM ≫ SPAM, and fluid rheology, with PAM fluids mostly Newtonian and SPAM fluids non-Newtonian (shear-thinning). Based on these differences, it was important to account for the infinite shear viscosity and normalize the polymer concentration by the intrinsic concentration ( c int ) so that the DR performance of the two polymer fluids could be accurately compared. Both polymers induced DR, and the maximum DR by SPAM (DR% = 28) was slightly higher than that by PAM (DR% = 22) when Re p ∼ 1700. For PAM, the loss of DR with time diminished at higher polymer concentrations (≥100 ppm, at Re p = 3149) but was found to be sensitive to high Re p , with polymer chain scission the likely cause of the reduced performance. For the semi-dilute SPAM fluids, the shear stability contrasted that of PAM, showing negligible dependence on the polymer concentration and Re p . The apparent rapid loss of DR was predominantly attributed to a time-dependent effect and not polymer degradation. In pipe flow, the maximum DR for SPAM was higher than that measured by rheometry and was attributed to differences in the flow conditions. However, changes in the normalized DR/c with polymer concentration were found to be consistent between the two flow geometries. Furthermore, the high fluid stresses in pipe flow (at high Re p ) led to drag reduction losses consistent with PAM, as the time-dependent effect was not seen., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Lysil oxidase like enzyme-2 (LOXL-2) and TNC-C play important roles in organ fibrosis. We assessed circulating LOXL-2 and TNC-C levels and their relationship to fibrosis severity in HIV- and/or HCV-infected individuals. Methods: Healthy controls (n = 22), HIV mono- (n = 15), HCV mono- (n = 52) and HCV/HIV-co-infected (n = 92) subjects were included. Results: LOXL-2 and TNC-C levels were significantly higher in HCV mono- and HCV/HIV-co-infected individuals with F0 compared to healthy controls. In addition, in HCV/HIV-co-infected individuals, LOXL-2 levels were higher in intermediate fibrosis compared to no/mild fibrosis. Conclusion: In HCV/HIV-co-infected study participants, both LOXL-2 and TNC-C were significantly higher in intermediate fibrosis compared to no/mild fibrosis, but did not further increase with advanced fibrosis. Furthermore, both markers were elevated among HCV/HIV-positive individuals with mild/no fibrosis.

Background: Understanding the spectrum of COVID-19 in people with HIV (PWH) is critical to provide clinical guidance and risk reduction strategies., Setting: Centers for AIDS Research Network of Integrated Clinic System, a US multisite clinical cohort of PWH in care., Methods: We identified COVID-19 cases and severity (hospitalization, intensive care, and death) in a large, diverse HIV cohort during March 1, 2020-December 31, 2020. We determined predictors and relative risks of hospitalization among PWH with COVID-19, adjusted for disease risk scores., Results: Of 16,056 PWH in care, 649 were diagnosed with COVID-19 between March and December 2020. Case fatality was 2%; 106 (16.3%) were hospitalized, and 12 died. PWH with current CD4 count <350 cells/mm 3 [aRR 2.68; 95% confidence interval (CI): 1.93 to 3.71; P < 0.001] or lowest recorded CD4 count <200 cells/mm 3 (aRR 1.67; 95% CI: 1.18 to 2.36; P < 0.005) had greater risks of hospitalization. HIV viral load and antiretroviral therapy status were not associated with hospitalization, although most of the PWH were suppressed (86%). Black PWH were 51% more likely to be hospitalized with COVID-19 compared with other racial/ethnic groups (aRR 1.51; 95% CI: 1.04 to 2.19; P = 0.03). Chronic kidney disease, chronic obstructive pulmonary disease, diabetes, hypertension, obesity, and increased cardiovascular and hepatic fibrosis risk scores were associated with higher hospitalization risk. PWH who were older, not on antiretroviral therapy, and with current CD4 count <350 cells/mm 3 , diabetes, and chronic kidney disease were overrepresented among PWH who required intubation or died., Conclusions: PWH with CD4 count <350 cells/mm 3 , and a history of CD4 count <200 cells/mm 3 , have a clear excess risk of severe COVID-19, accounting for comorbidities associated with severe outcomes. PWH with these risk factors should be prioritized for COVID-19 vaccination and early treatment and monitored closely for worsening illness., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To compare cost and time spent in surgical and postoperative courses in patients with obstructive sleep apnea (OSA) undergoing surgery with either total intravenous anesthesia (TIVA) or inhalational anesthesia., Study Design: Retrospective chart review., Methods: Retrospective review on patients undergoing surgery for OSA under general anesthesia from January 2019 to October 2020. Cost per service was acquired for the day of surgery., Results: A total of 230 patients were included: 95 received TIVA; 135 received inhalation anesthesia. Total cost was significantly higher in the TIVA nasal surgery group by $286 (P = .035). TIVA produced significantly higher pharmacy and operating room costs across all surgeries and OSA severities. These increased costs were offset by significantly lower supply costs in upper airway stimulator (UAS, -$419.50; P = .007) and uvulopalatopharyngoplasty (UPPP, -$115.16; P = .015) patients receiving TIVA. In the TIVA cohort, there was a trend toward lower recovery room costs after UAS (-$111.09; P = .063) and nasal surgery (-$64.45; P = .096) and anesthesia costs after nasal surgery (-$36.67; P = .054). Total recovery time was reduced by 18 minutes (P = .004) for nasal surgery, 25 minutes (P = .043) for UAS, and 27 minutes (P = .147) for UPPP patients receiving TIVA., Conclusion: When used in an outpatient setting for patients with OSA, TIVA adds to pharmacy and operating room costs, but this is usually offset by lower supply, anesthesia, and recovery room costs. We found decreased recovery times in the TIVA cohort. TIVA has proven benefits in patient outcomes and can be cost-effective in OSA surgery., Level of Evidence: 3 Laryngoscope, 132:1487-1494, 2022., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Surveys suggest that the general public (i.e., adults or parents) supports sexual health education in schools. However, the number of schools providing sex education continues to decline in the United States. The purpose of this study is to conduct a meta-analysis of U.S.-based representative surveys to provide a pooled estimate of public support for sexual health education delivered in schools., Methods: A systematic search of three databases (Medline, PsycInfo, and ERIC) was conducted to identify survey measuring adult and parent attitudes toward sexual health education in school between 2000 and 2016. Meta-analyses were conducted in OpenMetaAnalyst via the metaphor package in R using a DerSimonian-Laird random effect models to account for heterogeneity between surveys., Results: A total of 23 citations met study inclusion and exclusion criteria, representing 15 unique probability surveys conducted with the public. Among the included surveys, 14 were nationwide and 11 included parents or an overrepresentation of parents. Across all survey findings, 88.7% (95% confidence interval = 86.2-91.2) of respondents supported sexual health education. Among surveys that only included parents or oversampled for parents, 90.0% (95% confidence interval = 86.5-93.4) supported sexual health education, and among nationally representative surveys, 87.7% (95% confidence interval = 85.1-90.6) of respondents supported sexual health education., Conclusion: These findings demonstrate overwhelming support for sexual health education delivered in schools. Additional research is needed to determine individual differences in support for specific sexual health education topics and skills delivered through classroom-based instruction., (Published by Elsevier Inc.)

Background: School health education, including sexual health education, plays a crucial role in shaping adolescents' protective health behaviors, experiences, and outcomes. Adolescents need functional knowledge and skills to practice, adopt, and maintain healthy behaviors for preventing sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), and unintended pregnancy., Methods: The US Centers for Disease Control and Prevention's Division of Adolescent and School Health (CDC/DASH) has advanced school-based approaches to STI/HIV and pregnancy prevention through surveillance, research and evaluation, and program partnership and collaboration for over 3 decades., Results: CDC/DASH uses systematic and innovative strategies to identify the breadth of adolescent sexual health evidence; characterize key elements of effective educational curricula; and provide practical guidance to support school-based delivery. CDC/DASH's approach to effective health and sexual health education in schools has changed dramatically over the past 30 years and must continue to progress., Conclusion: This paper describes how and why that approach has evolved and outlines directions for the future., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Understanding the spectrum of SARS-CoV-2 infection and COVID-19 disease in people with HIV (PWH) is critical to provide clinical guidance and implement risk-reduction strategies., Objective: To characterize COVID-19 in PWH in the United States and identify predictors of disease severity., Design: Observational cohort study., Setting: Geographically diverse clinical sites in the CFAR Network of Integrated Clinical Systems (CNICS)., Participants: Adults receiving HIV care through December 31, 2020., Measurements: COVID-19 cases and severity (hospitalization, intensive care, death)., Results: Of 16,056 PWH in care, 649 were diagnosed with COVID-19 between March-December 2020. Case fatality was 2%; 106 (16.3%) were hospitalized and 12 died. PWH with current CD4 count <350 cells/mm 3 (aRR 2.68; 95%CI 1.93-3.71; P<.001) or lowest recorded CD4 count <200 (aRR 1.67; 95%CI 1.18-2.36; P<.005) had greater risk of hospitalization. HIV viral load suppression and antiretroviral therapy (ART) status were not associated with hospitalization, although the majority of PWH were suppressed (86%). Black PWH were 51% more likely to be hospitalized with COVID-19 compared to other racial/ethnic groups (aRR 1.51; 95%CI 1.04-2.19, P=.03). Chronic kidney disease (CKD), chronic obstructive pulmonary disease, diabetes, hypertension, obesity, and increased cardiovascular and hepatic fibrosis risk scores were associated with higher risk of hospitalization. PWH who were older, not on ART, with current CD4 <350, diabetes, and CKD were overrepresented amongst PWH who required intubation or died., Limitations: Unable to compare directly to persons without HIV; underestimate of total COVID-19 cases., Conclusions: PWH with CD4 <350 cells/mm 3 , low CD4/CD8 ratio, and history of CD4 <200, have a clear excess risk of severe COVID-19, after accounting for comorbidities also associated with severe outcomes. PWH with these risk factors should be prioritized for COVID-19 vaccination, early treatment, and monitored closely for worsening illness.

Background: Teacher instructional competency, the set of essential knowledge and skills needed to guide teaching practice, is critical to the successful implementation of school health education. The purpose of this paper is to introduce the Health Education Teacher Instructional Competency (HETIC) framework, a new conceptualization describing teacher characteristics, essential knowledge, and essential skills, which can influence instructional practice and improve student learning outcomes in health education., Methods: Data from 17 publicly available guidance documents, professional standards, published reports, and empirical studies relevant to the fields of public education, school health education, and sexual health education were abstracted and analyzed using qualitative thematic content analysis., Results: The framework describes 3 domains: personal characteristics, essential knowledge, and essential skills, which are believed to contribute to teachers' instructional competencies in delivering health education. The knowledge domain asserts 5 key categories, while the essential skills domain includes 3 categories (learning environments, content and delivery, and collaboration and learning) and contains 11 unique skills. Collectively, these domains are influenced by the learner, school/community, and policy-level factors that shape health education curriculum and instruction., Conclusions: The HETIC framework presents a conceptual roadmap to guide quality health education preparation, job-embedded training, and delivery. Improving teachers' instructional competencies strengthens learning and prosocial environments that are inclusive, responsive, and affirming of students' health and learning needs. Teacher who demonstrate instructional competency can help students to achieve desired education and health outcomes, specifically acquiring the knowledge and skills needed to adapt, practice, and maintain healthy behaviors throughout their lifetime., (© 2021, American School Health Association This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Ionic liquids are modern liquid materials with potential and actual implementation in many advanced technologies. They combine many favourable and modifiable properties but have a major inherent drawback compared to molecular liquids - slower dynamics. In previous studies we found that the dynamics of ionic liquids are significantly accelerated by the introduction of multiple ether side chains into the cations. However, the origin of the improved transport properties, whether as a result of the altered cation conformation or due to the absence of nanostructuring within the liquid as a result of the higher polarity of the ether chains, remained to be clarified. Therefore, we prepared two novel sets of methylammonium based ionic liquids; one set with three ether substituents and another set with three butyl side chains, in order to compare their dynamic properties and liquid structures. Using a range of anions, we show that the dynamics of the ether-substituted cations are systematically and distinctly accelerated. Liquefaction temperatures are lowered and fragilities increased, while at the same time cation-anion distances are slightly larger for the alkylated samples. Furthermore, pronounced liquid nanostructures were not observed. Molecular dynamics simulations demonstrate that the origin of the altered properties of the ether substituted ionic liquids is primarily due to a curled ether chain conformation, in contrast to the alkylated cations where the alkyl chains retain a linear conformation. Thus, the observed structure-property relations can be explained by changes in the geometric shape of the cations, rather than by the absence of a liquid nanostructure. Application of quantum chemical calculations to a simplified model system revealed that intramolecular hydrogen-bonding is responsible for approximately half of the stabilisation of the curled ether-cations, whereas the other half stems from non-specific long-range interactions. These findings give more detailed insights into the structure-property relations of ionic liquids and will guide the development of ionic liquids that do not suffer from slow dynamics.

Objectives/hypothesis: There is currently no standard of care in terms of anesthesia modality for patients receiving upper airway surgery with comorbid obstructive sleep apnea (OSA). Although both total intravenous anesthesia (TIVA) and volatile gas anesthesia are commonly utilized in ambulatory otolaryngology surgery, it is currently unclear if there are any advantages with one modality over the other. We hypothesize that patients receiving upper airway surgery with comorbid OSA will have quicker recovery times with TIVA., Study Design: Retrospective chart review from January 2019 to December 2019., Methods: All patients aged 18 and older receiving upper airway surgery (upper airway stimulation, nasal surgery, modified uvulopalatopharyngoplasty) were included. Patients were excluded when there was incomplete or missing data in the electronic medical record., Results: Eighty-six patients received gas anesthesia and 62 patients received TIVA. Phase I recovery times were significantly reduced by surgery and by severity of OSA: nasal surgery, upper airway stimulation, and modified uvulopalatopharyngoplasty had a reduction of 35.5 minutes (P < .001), 42.5 minutes (P < .001), and 36 minutes (P = .022), respectively. In terms of severity, mild, moderate, and severe OSA had reductions of 23.5 minutes (P = .004), 52 minutes (P = .004), and 47 minutes (P < .001), respectively. The severity of OSA generally correlated with increased time spent in Phase I: as severity increased, Phase I time increased by 16.8 minutes for the gas cohort (P < .001), whereas in the TIVA cohort, it increased only 4.3 minutes (P = .489)., Conclusion: Patients having upper airway surgery with comorbid OSA that received TIVA (propofol and remifentanil) spent significantly less time in Phase I and the recovery room overall compared to those receiving volatile gas anesthesia in the form of sevoflurane, and this correlated with the severity of OSA., Level of Evidence: 3. Laryngoscope, 131:925-931, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Aims: THEMIS (NCT01991795) demonstrated cardioprotective benefits of ticagrelor plus acetylsalicylic acid (ASA) compared with placebo plus ASA in patients with type 2 diabetes (T2D), stable coronary artery disease (CAD) and no history of myocardial infarction (MI) or stroke. To complement these findings, we assessed clinical outcomes and healthcare costs in commercially insured US patients similar to those in THEMIS., Methods: This retrospective, observational study used data from Optum. The T2D-CAD cohort (n = 154,369) included patients (≥50 years old) either with high cardiovascular risk or taking a P2Y 12 inhibitor. The THEMIS-like cohort (n = 126,938) comprised patients (≥50 years old) at high cardiovascular risk; the THEMIS-PCI-like cohort comprised a subset of these patients with prior percutaneous coronary intervention (PCI) (n = 18,394)., Results: Mean follow-up was 2.4-2.5 years. Incidence rates of the composite outcome (death, MI, and stroke) were 6.56 (95% CI 6.50-6.63), 6.21 (6.14-6.28), and 5.57 (5.39-5.74) per 100 person-years, and annualized healthcare costs per patient were US$15,848, US$16,044, and US$20,934 for the T2D-CAD, THEMIS-like, and THEMIS-PCI-like cohorts, respectively., Conclusions: Commercially insured patients similar to those in THEMIS had high cardiovascular event rates and healthcare costs, highlighting a need for improved preventive strategies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: E.W., N.B., K.A.S., P.H., M.K., and C.M. are employees of AstraZeneca. N.W. is a consultant for AstraZeneca., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Failure of homologous chromosomes to recombine is arguably the most important cause of human meiotic nondisjunction, having been linked to numerous autosomal and sex chromosome trisomies of maternal origin. However, almost all information on these "exchangeless" homologs has come from genetic mapping studies of trisomic conceptuses, so the incidence of this defect and its impact on gametogenesis are not clear. If oocytes containing exchangeless homologs are selected against during meiosis, the incidence may be much higher in developing germ cells than in zygotes. To address this, we initiated studies of exchangeless chromosomes in fetal ovarian samples from elective terminations of pregnancy. In total, we examined more than 7,000 oocytes from 160 tissue samples, scoring for the number of foci per cell of the crossover-associated protein MLH1. We identified a surprisingly high level of recombination failure, with more than 7% of oocytes containing at least one chromosome pair that lacked an MLH1 focus. Detailed analyses indicate striking chromosome-specific differences, with a preponderance of MLH1-less homologs involving chromosomes 21 or 22. Further, the effect was linked to the overall level of recombination in the cell, with the presence of one or two exchangeless chromosomes in a cell associated with a 10%-20% reduction in the total number of crossovers. This suggests individuals with lower rates of meiotic recombination are at an increased risk of producing aneuploid offspring., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The novel coronavirus (SARS-CoV-2 or COVID-19) pandemic has impacted nearly every aspect of otolaryngologic practice. The transition from office-based evaluation to telemedicine and the number of postponed elective surgical cases is unprecedented. There is a significant need to resume elective surgical care for these patients at the appropriate time. As practices begin to move towards resuming elective and same day ambulatory surgery, safety of both the patient and healthcare team is of paramount importance. Usage of total intravenous anesthesia (propofol and remifentanil) over volatile gas anesthesia (e.g., sevoflurane) may increase the number of patients able to safely receive care by reducing potential spread of the virus through reduction in coughing and significantly decreasing the time spent in the recovery room., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Students work in fast-paced environments that do not allow them the time to thumb through books for needed clinical information. At times such as these, just-in-time training using mobile technology comes to the rescue. Apps, tweets, and the Internet are all in the hands of nursing students and can decrease their cognitive load while enhancing clinical learning.

Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. We previously explored whether there was an association of ASD with any analyte measured in the first newborn screening blood test. Here we explore the second screen. Our matched case-control study examined data on 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Subjects were linked to their 2007-2009 newborn screening blood test data, which included values for 36 analytes or analyte ratios. Data were available for 3,005 cases and 6,212 controls. The most compelling associations were evident for fatty acid oxidation analytes octanoylcarnitine (C8) and octanoylcarnitine/acetylcarnitine (C8/C2). Their adjusted odds ratios comparing 10th versus first analyte deciles were between 1.42 and 1.54 in total births, term births, and males. C8 was consistent with first screen results. Adipylcarnitine (C6DC), an organic acid analyte, showed opposite results in the two screens. Several other analytes exhibiting significant associations in the first screen did not in the second. Our results provide evidence that abnormal newborn blood levels of some carnitines may be associated with risk of later ASD, possibly related to their involvement with mitochondrial function in the developing brain., (© 2020 Wiley Periodicals LLC.)

The acid dissociation constant (p K ) has an important influence on molecular properties crucial to compound development in synthesis, formulation, and optimization of absorption, distribution, metabolism, and excretion properties. We will present a method that combines quantum mechanical calculations, at a semi-empirical level of theory, with machine learning to accurately predict p a for a diverse range of mono- and polyprotic compounds. The resulting model has been tested on two external data sets, one specifically used to test p K a for a diverse range of mono- and polyprotic compounds. The resulting model has been tested on two external data sets, one specifically used to test p K a prediction methods (SAMPL6) and the second covering known drugs containing basic functionalities. Both sets were predicted with excellent accuracy (root-mean-square errors of 0.7-1.0 log units), comparable to other methodologies using a much higher level of theory and computational cost.

Background: THEMIS (NCT01991795) showed that in patients with type 2 diabetes (T2D) and stable coronary artery disease (CAD) but with no prior myocardial infarction (MI) or stroke, ticagrelor plus acetylsalicylic acid (ASA) decreased the incidence of ischaemic cardiovascular events compared with placebo plus ASA. To complement these findings, we assessed disease burden and healthcare resource utilization (HRU) in US patients with CAD and T2D, but without a prior MI or stroke., Methods: This observational study used 2013-2014 data from the Diabetes Collaborative Registry linked to Medicare administrative claims. Two cohorts of patients with T2D were studied: patients at high cardiovascular risk (THEMIS-like cohort; N = 56 040) and patients at high cardiovascular risk or taking P2Y12 inhibitors (CAD-T2D cohort; N = 69 790). Outcomes included the composite of all-cause death, MI and stroke; the individual events from the composite endpoint; HRU; and costs., Results: Median age was 73.0 years, and median follow-up was 1.3 years in both cohorts. Event rates of the composite outcome were 16.34 (95% confidence interval: 16.31-16.37) and 17.64 (17.61-17.67) per 100 person-years for the THEMIS-like and CAD-T2D cohorts, respectively. The incidence rate of bleeding events was 0.13 events per 100 person-years in both cohorts. Healthcare costs per patient-year were USD 8741 and USD 9150 in the THEMIS-like and CAD-T2D cohorts, respectively., Conclusions: Patients in the THEMIS-like cohort and the broader CAD-T2D population had similarly substantial cardiovascular event rates and healthcare costs, indicating that patients with CAD and T2D similar to the THEMIS population are at an increased cardiovascular risk., Competing Interests: Eric Wittbrodt, Narinder Bhalla, Karolina Andersson Sundell, Phillip Hunt and Carl Mellström are employees of AstraZeneca (significant relationships). Qi Gao and Liyan Dong are employees of the Baim Institute for Clinical Research (significant relationships). Nathan Wong is a consultant for AstraZeneca (modest relationship). Matthew Cavender has received research support (nonsalary) from AstraZeneca, Bristol‐Myers Squibb, Chiesi, GlaxoSmithKline, Novartis, Takeda and The Medicines Company, and research support with salary from Novo Nordisk; he has also received modest consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Edwards Lifesciences, Janssen, Merck and Sanofi‐Aventis., (© 2020 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

This is the third paper in a three-part series detailing the lessons identified during the National Health Service (NHS) England clinical debrief meetings which followed the response to the 2017 Manchester and London terrorist incidents. It covers the postincident and recovery phases including rehabilitation, bereavement support, psychological support, network and regional lessons, NHS communications and supply organisations. It also summarises the military application of these lessons and outlines the next steps for further development., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2020. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)