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Coronaviruses have caused three severe epidemics since the start of the 21st century: SARS, MERS and COVID-19. The severity of the ongoing COVID-19 pandemic and increasing likelihood of future coronavirus outbreaks motivates greater understanding of factors leading to severe coronavirus disease. We screened ten strains from the Collaborative Cross mouse genetic reference panel and identified strains CC006/TauUnc (CC006) and CC044/Unc (CC044) as coronavirus-susceptible and resistant, respectively, as indicated by variable weight loss and lung congestion scores four days post-infection. We generated a genetic mapping population of 755 CC006xCC044 F2 mice and exposed the mice to one of three genetically distinct mouse-adapted coronaviruses: clade 1a SARS-CoV MA15 (n=391), clade 1b SARS-CoV-2 MA10 (n=274), and clade 2 HKU3-CoV MA (n=90). Quantitative trait loci (QTL) mapping in SARS-CoV MA15- and SARS-CoV-2 MA10-infected F2 mice identified genetic loci associated with disease severity. Specifically, we identified seven loci associated with variation in outcome following infection with either virus, including one, HrS43, that is present in both groups. Three of these QTL, including HrS43, were also associated with HKU3-CoV MA outcome. HrS43 overlaps with a QTL previously reported by our lab that is associated with SARS-CoV MA15 outcome in CC011xCC074 F2 mice and is also syntenic with a human chromosomal region associated with severe COVID-19 outcomes in humans GWAS. The results reported here provide: (a) additional support for the involvement of this locus in SARS-CoV MA15 infection, (b) the first conclusive evidence that this locus is associated with susceptibility across the Sarbecovirus subgenus, and (c) demonstration of the relevance of mouse models in the study of coronavirus disease susceptibility in humans.

Coronavirus (CoV) cause considerable morbidity and mortality in humans and other mammals, as evidenced by the emergence of Severe Acute Respiratory CoV (SARS-CoV) in 2003, Middle East Respiratory CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. Although poorly characterized, natural genetic variation in human and other mammals modulate virus pathogenesis, as reflected by the spectrum of clinical outcomes ranging from asymptomatic infections to lethal disease. Using multiple human epidemic and zoonotic Sarbecoviruses, coupled with murine Collaborative Cross genetic reference populations, we identify several dozen quantitative trait loci that regulate SARS-like group-2B CoV pathogenesis and replication. Under a Chr4 QTL, we deleted a candidate interferon stimulated gene, Trim14 which resulted in enhanced SARS-CoV titers and clinical disease, suggesting an antiviral role during infection. Importantly, about 60 % of the murine QTL encode susceptibility genes identified as priority candidates from human genome-wide association studies (GWAS) studies after SARS-CoV-2 infection, suggesting that similar selective forces have targeted analogous genes and pathways to regulate Sarbecovirus disease across diverse mammalian hosts. These studies provide an experimental platform in rodents to investigate the molecular-genetic mechanisms by which potential cross mammalian susceptibility loci and genes regulate type-specific and cross-SARS-like group 2B CoV replication, immunity, and pathogenesis in rodent models. Our study also provides a paradigm for identifying susceptibility loci for other highly heterogeneous and virulent viruses that sporadically emerge from zoonotic reservoirs to plague human and animal populations.

Summary: The response to infection is generally heterogeneous and diverse, with some individuals remaining asymptomatic while others present with severe disease or a diverse range of symptoms. Here, we address the role of host genetics on immune phenotypes and clinical outcomes following viral infection by studying genetically diverse mice from the Collaborative Cross (CC), allowing for use of a small animal model with controlled genetic diversity while maintaining genetic replicates. We demonstrate variation by deeply profiling a broad range of innate and adaptive immune cell phenotypes at steady-state in 63 genetically distinct CC mouse strains and link baseline immune signatures with virologic and clinical disease outcomes following infection of mice with herpes simplex virus 2 (HSV-2) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This work serves as a resource for CC strain selection based on steady-state immune phenotypes or disease presentation upon viral infection, and further, points to possible pre-infection immune correlates of survival and early viral clearance upon infection.

Postoperative implant-associated spine infection remains poorly understood. Currently there is no large animal model using biofilm as initial inocula to study this challenging clinical entity. The purpose of the present study was to develop a sheep model for implant-associated spine infection using clinically relevant biofilm inocula and to assess the in vivo utility of methylene blue (MB) for visualizing infected tissues and guiding debridement. This 28-day study used five adult female Rambouillet sheep, each with two non-contiguous surgical sites– in the lumbar and thoracic regions– comprising randomized positive and negative infection control sites. A standard mini-open approach to the spine was performed to place sterile pedicle screws and Staphylococcus aureus biofilm-covered (positive control), or sterile (negative control) spinal fusion rods. Surgical site bioburden was quantified at the terminal procedure. Negative and positive control sites were stained with MB and staining intensity quantified from photographs. Specimens were analyzed with x-ray, micro-CT and histologically. Inoculation rods contained ∼10.44 log10 colony forming units per rod (CFU/rod). Biofilm inocula persisted on positive-control rod explants with ∼6.16 log10 CFU/rod. There was ∼6.35 log10 CFU/g of tissue in the positive controls versus no identifiable bioburden in the negative controls. Positive controls displayed hallmarks of deep spine infection and osteomyelitis, with robust local tissue response, bone resorption, and demineralization. MB staining was more intense in infected, positive control sites. This work presents an animal-efficient sheep model displaying clinically relevant implant-associated deep spine infection.

Studying changes in cortical oscillations can help elucidate the mechanistic link between receptor physiology and the clinical effects of anaesthetic drugs. Propofol, a GABA-ergic drug produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing evoked responses. Dexmedetomidine, an α2- adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deep sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations. Sixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visuomotor task. The key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the Mv100 (visual M100) (27%) and Mv150 (52%) visual evoked fields (VEF), whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on movement related gamma synchrony (MRGS), movement related beta de-synchronisation (MRBD) or Mm100 (movement-related M100) movement-related evoked fields (MEF), although dexmedetomidine slowed the Mm300. Dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%, statistically non- significant). Overall, dexmedetomidine and propofol, at equi-sedative doses, produce contrasting effects on visual induced GBR, VEF, PMBR and MEF. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs with their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness.

Summary: Genetically diverse mouse populations are powerful tools for characterizing the regulation of the proteome and its relationship to whole-organism phenotypes. We used mass spectrometry to profile and quantify the abundance of 6,798 proteins in liver tissue from mice of both sexes across 58 Collaborative Cross (CC) inbred strains. We previously collected liver proteomics data from the related Diversity Outbred (DO) mice and their founder strains. We show concordance across the proteomics datasets despite being generated from separate experiments, allowing comparative analysis. We map protein abundance quantitative trait loci (pQTLs), identifying 1,087 local and 285 distal in the CC mice and 1,706 local and 414 distal in the DO mice. We find that regulatory effects on individual proteins are conserved across the mouse populations, in particular for local genetic variation and sex differences. In comparison, proteins that form complexes are often co-regulated, displaying varying genetic architectures, and overall show lower heritability and map fewer pQTLs. We have made this resource publicly available to enable quantitative analyses of the regulation of the proteome.

Anthropogenic nitrogen (N) and sulfur (S) deposition can negatively affect ecosystem functions and lichen biomonitors can be a cost-effective way to monitor air pollution exposure across the landscape. Interior dry forests of the southwestern United States face increasing development pressures; however, this region differs from others with well-developed biomonitoring programs in having drier climates and a greater fraction of deposition delivered in dry forms. We measured throughfall N and S deposition at 12 sites in Utah and 10 in New Mexico and co-located collection of 6 lichen species. Throughfall N deposition ranged from 0.76 to 6.96 kg/ha/year and S deposition from 0.57 to 1.44 kg/ha/year with elevated levels near human development that were not predicted by commonly used simulation models. Throughfall N was 4.6 and 1.6 times higher in summer compared with fall-spring in Utah and New Mexico and S deposition was 3.9 and 1.8 times higher in summer. Lichen N and S concentrations ranged from 0.97 to 2.7% and 0.09 to 0.33%. Replicate samples within plots showed high variability in N and S concentrations with within-plot coefficients of variation for N ranging between 5 and 10% and for S between 7 and 15%. In Utah, N and S concentrations in lichen species were correlated with each other in most cases, with R2 ranging from 0.52 to 0.85. N concentrations in Melanohalea exasperatula and Melanohalea subolivacea could be correlated with average annual throughfall N deposition in Utah (R2 = 0.58 and 0.31). Those relationships were improved by focusing on deposition in fall-spring prior to lichen sampling in Utah (R2 for M. exasperatula, M. subolivacea, and X. montana = 0.59, 0.42, and 0.28). In New Mexico, lichens exhibited greater coefficients of variability within plots than between plots and could not be correlated with throughfall N deposition. In neither study area was S correlated between lichens and throughfall deposition, which may be the result of low S deposition over a narrow deposition range or complex lichen assimilation of S. Lichen biomonitoring for N deposition in the region shows promise, but could potentially be improved by sampling more thalli to reduce within-plot variability, repeated lichen collection synchronized with throughfall changeouts to explore temporal variability, and washing lichen collections to distinguish N and S that has been incorporated by the thalli from dry deposition that may accumulate on lichen surfaces.

Cortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model (TCM) capable of recapitulating broadband spectral responses. Compared with an existing cortex-only 4-population model, Bayesian Model Selection preferred the TCM. The model was able to accurately and significantly recapitulate ketamine-induced reductions in alpha amplitude and increases in gamma amplitude. Parameter analysis revealed no change in receptor time-constants but significant increases in select synaptic connectivity with ketamine. Significantly increased connections included both AMPA and NMDA mediated connections from layer 2/3 superficial pyramidal cells to inhibitory interneurons and both GABAA and NMDA mediated within-population gain control of layer 5 pyramidal cells. These results support the use of extended generative models for explaining oscillatory data and provide in silico support for ketamine's ability to alter local coupling mediated by NMDA, AMPA and GABA-A.

Spinocerebellar Ataxia type 3 (SCA3, also known as Machado-Joseph disease) is a neurodegenerative disorder caused by a CAG repeat expansion encoding an abnormally long polyglutamine (polyQ) tract in the disease protein, ataxin-3 (ATXN3). No preventive treatment is yet available for SCA3. Because SCA3 is likely caused by a toxic gain of ATXN3 function, a rational therapeutic strategy is to reduce mutant ATXN3 levels by targeting pathways that control its production or stability. Here, we sought to identify genes that modulate ATXN3 levels as potential therapeutic targets in this fatal disorder. We screened a collection of siRNAs targeting 2742 druggable human genes using a cell-based assay based on luminescence readout of polyQ-expanded ATXN3. From 317 candidate genes identified in the primary screen, 100 genes were selected for validation. Among the 33 genes confirmed in secondary assays, 15 were validated in an independent cell model as modulators of pathogenic ATXN3 protein levels. Ten of these genes were then assessed in a Drosophila model of SCA3, and one was confirmed as a key modulator of physiological ATXN3 abundance in SCA3 neuronal progenitor cells. Among the 15 genes shown to modulate ATXN3 in mammalian cells, orthologs of CHD4, FBXL3, HR and MC3R regulate mutant ATXN3-mediated toxicity in fly eyes. Further mechanistic studies of one of these genes, FBXL3, encoding a F-box protein that is a component of the SKP1-Cullin-F-box (SCF) ubiquitin ligase complex, showed that it reduces levels of normal and pathogenic ATXN3 in SCA3 neuronal progenitor cells, primarily via a SCF complex-dependent manner. Bioinformatic analysis of the 15 genes revealed a potential molecular network with connections to tumor necrosis factor-α/nuclear factor-kappa B (TNF/NF-kB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways. Overall, we identified 15 druggable genes with diverse functions to be suppressors or enhancers of pathogenic ATXN3 abundance. Among identified pathways highlighted by this screen, the FBXL3/SCF axis represents a novel molecular pathway that regulates physiological levels of ATXN3 protein.

Objective: To use multiple perspectives to identify the key components of pediatric primary care conversations for motivating parents to utilize parenting programs. We aim to develop an actionable framework that primary care clinicians (PCCs) can follow for effective conversations with parents., Methods: We conducted focus groups and interviews with researchers (n = 6) who have experience delivering parenting interventions through primary care, clinical personnel in federally qualified health centers (FQHCs) (n = 9), parents of 3-5-year olds who receive services at a FQHC pediatric clinic (n = 6), and parent educators (n = 5). Groups and interviews were informed by nominal group technique, and researchers triangulated consolidated strategies across the groups., Results: Key strategies for PCCs to motivate parents to utilize parenting programs followed three steps: 1) learning about a parent's questions and concerns, 2) sharing resources, and 3) following up. PCCs can learn about parents' needs by empathizing, listening and responding, and asking questions that acknowledge parents' expertise. When sharing resources, PCCs can motivate participation in parenting programs by explaining each resource and its benefits, providing options that support parents' autonomy, and framing resources as strengthening rather than correcting parents' existing strategies or skills. Finally, PCCs can continue to engage parents by scheduling follow-up conversations or designating a staff member to check-in with parents. We provide examples for each strategy., Conclusions: Findings provide guidance from multiple perspectives on strategies to motivate parents in pediatric primary care setting for utilizing parenting programs., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Limiting the negative impact of climate change on nature and humans is one of the most pressing issues of the 21st century. Meanwhile, people in modern society spend most of the day indoors. It is therefore surprising that comparatively little attention has been paid to indoor human exposure in relation to climate change. Heat action plans have now been designed in many regions to protect people from thermal stress in their private homes and in public buildings. However, in order to be able to plan effectively for the future, reliable information is required about the long-term effects of climate change on indoor air quality and climate. The Indoor Air Quality Climate Change (IAQCC) model is an expediant tool for estimating the influence of climate change on indoor air quality. The model follows a holistic approach in which building physics, emissions, chemical reactions, mold growth and exposure are combined with the fundamental parameters of temperature and humidity. The features of the model have already been presented in an earlier publication, and it is now used for the expected climatic conditions in Central Europe, taking into account various shared socioeconomic pathway (SSP) scenarios up to the year 2100. For the test house examined in this study, the concentrations of pollutants in the indoor air will continue to rise. At the same time, the risk of mold growth also increases (the mold index rose from 0 to 4 in the worst case for very sensitive material). The biggest problem, however, is protection against heat and humidity. Massive structural improvements are needed here, including insulation, ventilation, and direct sun protection. Otherwise, the occupants will be exposed to increasing thermal discomfort, which can also lead to severe heat stress indoors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To describe the new Royal Adelaide Hospital (RAH) design and infrastructure features that helped mitigate the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission within the hospital during the pre-vaccination and pre-antiviral period., Method: The RAH infrastructure, design and initial pandemic response was assessed. A retrospective review of all confirmed or suspected coronavirus disease 2019 (COVID-19) patients admitted from 1 February 2020 to 30 May 2020 was also performed to assess risk of transmission. Outbreak response reports were reviewed to identify episodes of nosocomial COVID-19., Results: Key infrastructure features include single-bed overnight rooms with dedicated bathrooms, creation of pandemic areas accessible only to pandemic staff, and sophisticated air-handling units with improved ventilation. A total of 264 COVID-19 related admission occurred, with 113 confirmed cases and 1579 total cumulative bed days. Despite a limited understanding of SARS-CoV-2 transmission, no vaccination or anti-viral therapy, global shortages of particulate filter respirators and restricted testing during this period, only one probable nosocomial COVID-19 case occurred in a healthcare worker, with no nosocomial cases involving patients., Conclusions: The RAH design and pandemic features complimented existing infection control interventions and was important in limiting nosocomial spread of SARS-CoV-2., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Plastic products are ubiquitous in our homes, but we know very little about emissions from these products and their subsequent impact on indoor air quality. This is the first study to systematically determine temperature-dependent emissions of volatile organic compounds from commonly used plastic consumer products found in the home. The plastic types included high-density polyethylene (HDPE), polypropylene (PP), polyethylene terephthalate (PET), polystyrene (PS) and polyester rubber. Plastic samples were exposed to increasing temperatures (between 18 and 28 °C) in controlled environmental chambers, connected to a proton-transfer-reaction time-of-flight mass-spectrometer (PTR-ToF-MS), where real-time emissions were detected. Average emission rates were determined and used to initialise an indoor air chemistry model (INCHEM-Py) at the highest and lowest experimental temperatures, to explore the impact these product emissions have on the indoor air chemistry. The PS tubing plastic proved to be the highest emitting polymer per surface area. Almost all selected VOC emissions were found to have a linear relationship with temperature. Upon observing the impacts of primary VOC emissions from plastics in modelled simulations, the hydroxyl radical concentration decreased by an average of 1.6 and 10 % relative to the baseline (with no plastics included) at 18 °C and 28 °C respectively. On the other hand, formaldehyde concentrations increased by 29 and 31.6 % relative to the baseline conditions at 18 °C and 28 °C respectively. The presence of plastic products indoors, therefore, has the potential to impact the indoor air quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Asthma is one of the most common chronic non-communicable diseases worldwide and is characterised by variable airflow obstruction, causing dyspnoea and wheezing. Highly effective therapies are available; asthma morbidity and mortality have vastly improved in the past 15 years, and most patients can attain good asthma control. However, undertreatment is still common, and improving patient and health-care provider understanding of when and how to adjust treatment is crucial. Asthma management consists of a cycle of assessment of asthma control and risk factors and adjustment of medications accordingly. With the introduction of biological therapies, management of severe asthma has entered the precision medicine era-a shift that is driving clinical ambitions towards disease remission. Patients with severe asthma often have co-existing conditions contributing to their symptoms, mandating a multidimensional management approach. In this Seminar, we provide a clinically focused overview of asthma; epidemiology, pathophysiology, diagnosis, and management in children and adults., Competing Interests: Declaration of interests CP declares research grants from AstraZeneca, GSK, Novartis, Teva Pharmaceuticals, Sanofi, Chiesi Farmaceutici, and ALK-Abelló; consulting fees from AstraZeneca, GSK, Novartis, Teva Pharmaceuticals, Sanofi, Chiesi Farmaceutici, and ALK-Abelló; honoraria for lectures from AstraZeneca, GSK, Novartis, Teva Pharmaceuticals, Sanofi, Chiesi Farmaceutici, and ALK-Abelló; and fees for being on the advisory board for AstraZeneca, Novartis, Teva Pharmaceuticals, Sanofi, and ALK-Abelló. EM declares consulting fees from ALK-Abelló, AstraZeneca, Chiesi Farmaceutici, Novartis, and Sanofi. EM is a member of the European Respiratory Society Environmental Health Committee. LL declares consulting fees from ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia Group, GSK, Menarini, Novartis, Orion, and Sanofi; honoraria for lectures from ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia Group, GSK, Menarini, Novartis, Orion, and Sanofi; and fees for being on the advisory board for ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia Group, GSK, Menarini, Novartis, Orion, and Sanofi. LL owns shares of Ausculthing OY. DS declares consulting fees from GSK and Novartis; honoraria for lectures from Teva Pharmaceuticals and Chiesi; and travel fees from Chiesi., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Re-aligning eating patterns with biological rhythm can reduce the burden of metabolic syndrome in older adults with overweight or obesity. Time-restricted eating (TRE) has been shown to result in weight loss and improved cardiometabolic health while being less challenging than counting calories. The New York Time-Restricted EATing study (NY-TREAT) is a two-arm, randomized clinical trial (RCT) that aims to examine the efficacy and sustainability of TRE (eating window ≤10 h/day) vs. a habitual prolonged eating window (HABIT, ≥14 h/day) in metabolically unhealthy midlife adults (50-75 years) with overweight or obesity and prediabetes or type 2 diabetes (T2D). Our primary hypothesis is that the TRE will result in greater weight loss compared to HABIT at 3 months. The efficacy of the TRE intervention on body weight, fat mass, energy expenditure, and glucose is tested at 3 months, and the sustainability of its effect is measured at 12 months, with ambulatory assessments of sleep and physical activity (ActiGraph), eating pattern (smartphone application), and interstitial glucose (continuous glucose monitoring). The RCT also includes state-of-the-art measurements of body fat (quantitative magnetic resonance), total energy expenditure (doubly-labelled water), insulin secretion, insulin resistance, and glucose tolerance. Adherence to self-monitoring and reduced eating window are monitored remotely in real-time. This RCT will provide further insight into the effects of TRE on cardiometabolic health in individuals with high metabolic risk. Sixty-two participants will be enrolled, and with estimated 30% attrition, 42 participants will return at 12 months. This protocol describes the design, interventions, methods, and expected outcomes. Clinical trial registration:NCT04465721 IRB: AAAS7791., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CJP is a Sports Nutrition Consultant for Renaissance Periodization, LLC., (Copyright © 2022. Published by Elsevier Inc.)

Background: We aimed to assess whether asymptomatic ("happy") hypoxia was an identifiable physiological phenotype of COVID-19 acute respiratory distress syndrome (ARDS), and associated with need for ICU admission., Methods: We performed an observational cohort study of all adult patients admitted with hypoxaemic respiratory failure to a large acute hospital Trust serving the East Midlands, UK. Patients with confirmed COVID-19 were compared to those without. Physiological response to hypoxaemia was modelled using a linear mixed effects model., Results: Of 1,586 patients included, 75% tested positive for SARS-CoV-2. The ROX index was 2.08 min -1 lower (1.56-2.61, p < 0.001) in the COVID-19 cohort when adjusted for age and ethnicity, suggesting an enhanced respiratory response to hypoxia compared to the non-Covid-19 patients. There was substantial residual inter- and intra-patient variability in the respiratory response to hypoxaemia. 33% of the infected cohort required ICU, and of these 31% died within 60 days. ICU admission and mortality were both associated with an enhanced respiratory response for all degrees of hypoxaemia., Conclusions: Patients with COVID-19 display a more symptomatic phenotype in response to hypoxaemia than those with other causes of hypoxaemic respiratory failure, however individual patients exhibit a wide range of responses. As such although asymptomatic hypoxaemia may be a phenomenon in any individual patient with hypoxaemic respiratory failure, it is no more frequently observed in those with SARS-CoV-2 infection than without., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To provide Canadian surgeons and other providers who offer female genital cosmetic surgery (FGCS) and procedures, and their referring practitioners, with evidence-based direction in response to increasing requests for, and availability of, vaginal and vulvar surgeries and procedures that fall outside the traditional realm of medically indicated reconstructions., Target Population: Women of all ages seeking FGCS or procedures., Benefits, Harms, and Costs: Health care providers play an important role in educating women about their anatomy and helping them appreciate individual variations. Most women requesting FGCS and procedures have normal genitalia, and up to 87% are reassured by counselling. At this time, due to lack of rigorous clinical or scientific evidence of short- and long-term efficacy and safety, FGCS and procedures for non-medical indications cannot be supported. FGCS and procedures are typically provided in the private sector, where costs are borne by the patient., Evidence: Literature was retrieved through searches of MEDLINE, Scopus, and The Cochrane Library using appropriate controlled vocabulary and keywords. The selected search terms represented keywords for FGCS (labiaplasty, surgery, vaginal laser therapy, laser vaginal tightening, vaginal laser, vaginal rejuvenation, vaginal relaxation syndrome, hymenoplasty, vaginal cosmetic procedures) combined with female genital counselling, consent, satisfaction, follow-up, adolescent, and body dysmorphic or body dysmorphia. The search was restricted to publications after 2012 in order to update the literature since the previous guideline on this topic. Results were restricted to systematic reviews, randomized controlled trials, and observational studies. Studies were restricted to those involving humans, and no language restrictions were applied. The search was completed on May 20, 2020, and updated on November 10, 2020., Validation Methods: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations)., Intended Audience: Gynaecologists, primary care providers, surgeons performing FGCS and/or procedures., (Copyright © 2021 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Shortened duration therapy for acute and recent HCV infection has been shown to be highly effective in several small non-randomised studies with direct-acting antiviral regimens; however, large randomised studies are lacking., Methods: REACT was an NIH-funded multicentre international, open-label, randomised, phase IV non-inferiority trial examining the efficacy of short course (6-week) vs. standard course (12-week) therapy with sofosbuvir-velpatasvir for recent HCV infection (estimated duration of infection ≤12 months). Randomisation occurred at week 6. The primary endpoint was sustained virological response 12 weeks after treatment end (SVR12) in the intention-to treat (ITT) population. A total of 250 participants were due to be enrolled, but on advice of the data safety and monitoring board the study was halted early., Results: The primary analysis population consisted of 188 randomised participants at termination of study enrolment; short arm (n = 93), standard arm (n = 95). Ninety-seven percent were male and 69% HIV positive. ITT SVR12 was 76/93, 81.7% (95% CI 72.4-89.0) in the short arm and 86/95, 90.5% (95% CI 82.7-95.6) in the standard arm. The difference between the arms was -8.8 (95% CI -18.6 to 1.0). In modified ITT analysis, wherein non-virological reasons for failure were excluded (death, reinfection, loss to follow-up), SVR12 was 76/85, 89.4% (95% CI 80.8-95.0) in the short arm and 86/88, 97.7% in the standard arm (95% CI 92.0-99.7; difference -8.3%, p = 0.025)., Conclusions: In this randomised study in recent HCV infection, a 6-week course of sofosbuvir-velpatasvir did not meet the criteria for non-inferiority to standard 12-week therapy., Lay Summary: In this randomised trial, 188 people with recently acquired hepatitis C infection were randomly assigned to treatment using either a short 6-week course (93 people) or standard 12-week course (95 people) of the hepatitis C treatment sofosbuvir/velpatasvir. There were 9 cases of relapse after treatment with the short course and 2 following the standard course. A shortened course of 6-week therapy for hepatitis C infection appeared to be less effective than a standard 12-week course in people with recently acquired hepatitis C infection. CLINICALTRIALS., Gov Identifier: NCT02625909., Competing Interests: Conflict of interest GVM: grants from Gilead Sciences and AbbVie Inc, outside the submitted work; SB: grants from Gilead Sciences, outside the submitted work; personal fees for Advisory Boards and lectures/presentations from Gilead Sciences, outside the submitted work; MvDW: grants and personal fees from AbbVie, grants and personal fees from Gilead, grants and personal fees from Johnson & Johnson, grants and personal fees from MSD, grants and personal fees from ViiV, outside the submitted work; JR: personal fees from Gilead Sciences, Janssen, Merck, Theratechnologies and ViiV, outside the submitted work; JF: grants and personal fees from Gilead Sciences, grants and personal fees from AbbVie, personal fees from GSK, personal fees from Roche, grants from Janssen, grants from Eiger, grants and personal fees from Enanta, personal fees from Arubutus, outside the submitted work; AR: Advisory boards: MSD, Gilead Sciences, Travel grants: Gilead Sciences, Pfizer, AbbVie; Research support: Investigator initiated trial grant from Gilead Sciences. All remuneration went to his home institution and not to Dr. Rauch personally; CT: Gilead Advisory board (Remdesivir) 2020; MSD Advisory board (HCV) 2018; educational grants from Gilead and AbbVie (Annual Preceptorship on HCV in PWID), outside the submitted work; JB: grants from NIH, during the conduct of the study; personal fees from AbbVie, grants and personal fees from Gilead, outside the submitted work; AK: grants from PCORI, grants from NIH/NIAID, grants from NIH/NIA, grants from UpToDate, Inc., personal fees from Biomarin, Inc., personal fees for lectures/presentations: CME companies, Clinical Care Options companies, Mentor Planning and Practice Point, personal fees from DKBMed for communications, personal fees for academic work from Geisinger Health Systems and St. Luke’s/Roosevelt, personal fees from Ken Krayesek Law Offices, personal fees from Duke University, outside the submitted work; MH: grants from Gilead Sciences, grants from AbbVie, outside the submitted work; EG: personal fees from Gilead Scientific Advisory Board, personal fees from AbbVie Scientific Advisory Board, personal fees from Janssen Scientific Advisory Board, outside the submitted work; MN: grants, personal fees and non-financial support from AbbVie, grants, personal fees and non-financial support from MSD, grants, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from Gilead Sciences, payment or honoraria: Gilead, AbbVie, BMS and MSD, travel support: Gilead, AbbVie, BMS and MSD, personal fees from MBS DMSB or equivalent, outside the submitted work; PI: grants and personal fees from Gilead Sciences, personal fees from AbbVie, personal fees from ViiV, outside the submitted work; JG: grants and personal fees from AbbVie, grants and personal fees from Gilead Sciences, grants and personal fees from Merck, grants and personal fees from Cepheid, grants from Hologic, grants from Indivior, payment or honoraria: AbbVie, Gilead Sciences and Cepheid, travel support: AbbVie, Gilead Sciences and Cepheid, receipt of testing equipment and cartridges from Cepheid, receipt of testing reagents from Hologic, outside the submitted work; KP: grants from Gilead sciences Australia and ViiV Healthcare Australia, outside the submitted work; GD: grants, personal fees and non-financial support from Gilead Sciences, AbbVie and Merck, grants from Bristol-Myers Squibb, outside the submitted work; DS, MM, TA and PM: nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021. Published by Elsevier B.V.)

Understanding the abiotic and biotic variables affecting tick populations is essential for studying the biology and health risks associated with vector species. We conducted a study on the phenology of exotic Haemaphysalis longicornis (Asian longhorned tick) at a site in Albemarle County, Virginia, United States. We also assessed the importance of wildlife hosts, habitats, and microclimate variables such as temperature, relative humidity, and wind speed on this exotic tick's presence and abundance. In addition, we determined the prevalence of infection with selected tick-borne pathogens in host-seeking H. longicornis. We determined that the seasonal activity of H. longicornis in Virginia was slightly different from previous studies in the northeastern United States. We observed nymphal ticks persist year-round but were most active in the spring, followed by a peak in adult activity in the summer and larval activity in the fall. We also observed a lower probability of collecting host-seeking H. longicornis in field habitats and the summer months. In addition, we detected H. longicornis on several wildlife hosts, including coyote (Canis latrans), eastern cottontail (Sylvilagus floridanus), raccoon (Procyon lotor), Virginia opossum (Didelphis virginiana), white-tailed deer (Odocoileus virginianus), woodchuck (Marmota monax), and a Peromyscus sp. mouse. This latter record is the first detection of a larval H. longicornis on a North American rodent host important to the enzootic maintenance of tick-borne pathogens of humans and animals. Finally, we continued to detect the exotic piroplasm parasite, Theileria orientalis Ikeda, in H. longicornis as well as other pathogens, including Rickettsia felis, Anaplasma phagocytophilum (AP-1), and a Hepatozoon sp. previously characterized in Amblyomma americanum. These represent some of the first detections of arthropod-borne pathogens native to the United States in host-seeking H. longicornis. These data increase our understanding of H. longicornis biology in the United States and provide valuable information into the future health risks associated with this tick and pathogens., (Copyright © 2021. Published by Elsevier GmbH.)

Competing Interests: The authors declare that they have no conflicts of interest.

Objective: The interview process for applying to general surgery residency is burdened by a high volume of applicants, resulting in unprofessional behavior by both applicants and programs. Sharing more information regarding interview scheduling with applicants may limit fourth year medical student educational disruptions, minimized late cancellations to interview, and improve overall satisfaction with the process. Thus, we set out to determine what information is currently available to applicants., Design: We used publicly accessible sources to determine what information was shared by US general surgery residency programs with applicants. Specifically, we looked at the deadline for applications, United States Medical Licensing Examination Step 1 and 2 score cutoffs, number of interview dates available, specific interview dates, a stated policy to not offering more interviews than slots, dates when applicants can expect to be notified of interview offers, notification of decision to decline, and International Medical Graduate and visa policies., Setting: This study took place at Maine Medical Center in Portland, Maine, an academic medical center with a general surgery residency program., Participants: Not applicable., Results: Three hundred seventeen programs were examined. Seventy-six percent of programs specified an application deadline, 65% of programs specified a Step 1 cut-off score, 50% of programs specified a Step 2 cut-off score, 61% of programs stated a visa policy, and 50% of programs stated an International Medical Graduate policy. Twenty-five percent of programs disclosed the number of interview dates, 23% disclosed what those interview dates were. About 3.4% of programs gave interview release dates, 2.8% of programs notify applicants of decline to interview, and 0.63% of programs explicitly describe a policy of offering only as many interviews as slots available. Thirty-two percent of programs provided conflicting information., Conclusions: The information available to applicants from public access sources regarding interview scheduling is minimal, unstandardized, and unreliable. Notably lacking were policies that only offer as many interviews as slots available, dates when applicants can expect to be notified of interview offers, and notification of declines. Providing such information to applicants in a standardized way may improve satisfaction with the interview scheduling process., (Published by Elsevier Inc.)

Objective: This study aims to assess information needs and information sources and seeks to illustrate what at-risk individuals consider motivators of and barriers to information-seeking before and after genetic testing for cancer predisposition., Methods: Semi-structured interviews with people seeking genetic counseling in Switzerland were analyzed qualitatively using thematic analysis. Wilson's model of information behavior was the theoretical framework., Results: We identified four themes that illustrate motivators of and barriers to information-seeking: attitudes and emotions; knowledge; social environment; and demographic factors. We also elucidated information needs and collected participants' information sources., Conclusion: This study£s empirical approach helps healthcare professionals to understand their patients' behaviors and wishes concerning information-seeking more concretely than theoretical models alone. The study also identifies information gaps, especially outside the genetic counseling setting., Practice Implications: Genetic counselors and other healthcare professionals need to purposefully assist patients in finding trustworthy and accessible information. Healthcare professionals in all disciplines need to be educated about predictive genetic testing., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The Asian longhorned tick, Haemaphysalis longicornis, has recently become established in the United States. In East Asia, Australia, and New Zealand, the native and previously introduced ranges, this tick is a vector of an important pathogen of cattle, Theileria orientalis. In 2017, the pathogenic Ikeda genotype of T. orientalis was associated with cattle mortalities in Virginia and in 2018 the exotic H. longicornis was detected at this same site. To investigate the possible role of this exotic tick in the epidemiology of theileriosis in Virginia, we tested host-seeking H. longicornis for piroplasm infections. We document the detection of exotic Theileria orientalis Ikeda genotype in 12.7 % (15/118) environmentally collected H. longicornis using both the 18S rRNA and major piroplasm surface protein (MPSP) gene targets. This is the first detection of a pathogen in H. longicornis in its introduced range in the United States and offers new insight into the animal health risks associated with the introduction of this exotic tick species to North America., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Objectives: There is a need to improve efficiency in healthcare delivery without compromising quality of care. One approach is the development and evaluation of behavioural strategies to reduce unnecessary use of common tests. However, there is an absence of evidence on patient attitudes to the use of such approaches in the delivery of care. Our objective was to explore patient acceptability of a nudge-type intervention that aimed to modify blood test requests by hospital doctors., Study Design: Single-centre qualitative study., Methods: The financial costs of common blood tests were presented to hospital doctors on results reports for 1 year at a hospital. Focus group discussions were conducted with recent inpatients at the hospital using a semi-structured question schedule. Discussions were transcribed and analysed using qualitative content analysis to identify and prioritise common themes explaining attitudes to the intervention approach., Results: Three focus groups involving 17 participants were conducted. Patients were generally apprehensive about the provision of blood test cost feedback to doctors. Attitudes were organised around themes representing beliefs about blood tests, the impact on doctors and their autonomy, and beliefs about unnecessary testing. Patients thought that blood tests were important, powerful and inexpensive, and cost information could place doctors under additional pressure., Conclusion: The findings identify predominantly positive beliefs about testing and negative attitudes to the use of financial costs in the decision-making of hospital doctors. Public discussion and education about the possible overuse of common tests may allow more resources to be allocated to evidence-based healthcare, by reducing the perception that such strategies to improve healthcare efficiency negatively impact on quality of care., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We examined associations between parental IPV exposure, perceived social support, and adolescent relationship abuse (ARA) victimization, specifically in a group of marginalized youth., Methods: Data were drawn from surveys administered to marginalized youth as part of the Healthy Allegheny Teen Survey. Logistic regression examined (1) the association between IPV exposure and social support and (2) how social support influences the association between IPV exposure and ARA victimization., Results: IPV-exposed youth reported lower perceived social support (adjusted odds ratio: .54, confidence interval [CI]: .31-.96). There was a significant association between IPV exposure and ARA victimization (odds ratio: 3.5, CI: 1.5-8.1). However, among youth with higher social support, the association between IPV exposure and ARA victimization attenuated and lost significance (odds ratio: 1.9, CI: .57-6.5)., Conclusions: IPV-exposed youth reported less social support; however, social support may buffer the association between IPV exposure and ARA. Interventions may consider bolstering social support for IPV-exposed youth., (Copyright © 2020 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)