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Background: Childhood cancer survivors are at risk for cardiovascular disease. We assessed the burden of potentially modifiable cardiometabolic risk factors (CRF) among survivors compared with population-matched controls. Methods: Survivors previously enrolled on Pediatric Oncology Group protocols 9404, 9425, 9426, 9754, and Dana-Farber Cancer Institute 95-01 from 1996 to 2001 with acute lymphoblastic leukemia/lymphoma, Hodgkin lymphoma, or osteosarcoma were prospectively assessed for the prevalence of CRFs and compared with an age, sex, and race/ethnicity-matched 2013 National Health and Nutrition Examination Survey (NHANES) population. We estimated future predicted cardiovascular risk based on general population (e.g., Framingham) and Childhood Cancer Survivor Study (CCSS) models. Results: Compared with NHANES (n = 584), survivors [n = 164; 44.5% female, median age 28 years (range, 16–38 years); median 17.4 years (range, 13–22 years) since cancer diagnosis; median doxorubicin dose 300 mg/m2; 30.5% chest radiation] had similar rates of obesity, diabetes, and dyslipidemia, but more prehypertension/hypertension (38.4% vs. 30.1%, P = 0.044). Survivors had fewer metabolic syndrome features compared with NHANES (≥2 features: 26.7% vs. 55.9%; P < 0.001). Survivors were more physically active and smoked tobacco less (both P < 0.0001). Therefore, general population cardiovascular risk scores were lower for survivors versus NHANES. However, with CCSS models, 30.5% of survivors were at moderate risk of ischemic heart disease, and >95% at moderate/high risk for heart failure, with a 9% to 12% predicted incidence of these conditions by age 50 years. Conclusions: Childhood cancer survivors exhibited similar or better cardiometabolic and lifestyle profiles compared with NHANES, but nonetheless are at risk for future clinically significant cardiovascular disease. Impact: Further strategies supporting optimal CRF control are warranted in survivors. See related commentary by Mulrooney, p. 515

The aims of this study were to describe the trends in the behavior of pediatric CD during the last decade and to describe the seasonal variation of disease presentation.Patients under 18 years old and diagnosed between 2009 and 2019 were included. The clinical, endoscopic, histological, and laboratory data were collected from the medical records. We analyzed the trends of these parameters according to the year and season of diagnosis.654 patients were included in the study. The number of incident CD cases increased yearly. Patients diagnosed between 2015 and 2019 were younger at diagnosis (OR 2.53, p = 0.02), had more perianal diseases (OR: 2.30, p 0.0001) and more granulomas (OR: 1.61, p = 0.003), but fewer eosinophils (OR: 0.35, p 0.0001) and less chronic lymphoplasmacytic infiltrate (OR: 0.56, p = 0.008) as compared to the 2009-2014 cohort. There was fewer CD diagnosis during winter. Patients diagnosed in the fall had lower PCDAIs, less failure to thrive and less extensive digestive involvement. Colonic disease was significantly more frequent during summer and fall.The clinical and histological phenotype of CD has changed over time and there are important seasonal trends in the frequency and severity on disease behavior suggesting possible disease triggers.

Gay and bisexual men (GBM) who use pre-exposure prophylaxis (PrEP) are at increased risk of sexually transmitted infections (STIs) compared to those who don't use PrEP. Since the implementation of PrEP in Australia, it is possible that attitudes towards STIs have shifted in line with changes in risk and transmission dynamics in the context of increased screening. As the extent to which GBM utilise STI prevention strategies likely depends on their attitudes towards STIs and STI prevention, the aims of this study were to use latent class analysis (LCA) to classify GBM using PrEP on the basis of their attitudes towards STIs and reported risk behaviours, and examine how these categorisations relate to risk of STI acquisition. 1225 GBM who were previously enrolled in a PrEP implementation study (The PrEPX Study) completed a survey focused on sexual behaviours and attitudes towards STIs 1 year post-study follow-up. Data on chlamydia, gonorrhoea and syphilis testing and positivity were available through a sentinel network of participating study clinics. Using LCA, participants were allocated into four classes; Class 1, "Some concern and lowest risk"; Class 2, "Low concern and lower risk"; Class 3, " High concern and higher risk"; and Class 4, "Low concern and highest risk". The majority (78%) of participants were classified into Class 3 or Class 4, two groups which were distinguished by highly disparate attitudes towards STIs but with a similar proportion of participants diagnosed with a bacterial STI in the last 12 months (48% and 57%, respectively). Findings suggest that attitudes towards STIs among GBM using PrEP in Australia vary considerably, and this will likely influence their receptivity to different STI prevention strategies.

Background The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials. Methods P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods. Results In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m2 ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m2 ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2 ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35). Conclusions Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.

Summary Introduction Physical activity increases cortisol-awakening response (CAR) and reduces perceived stress in several pathologies but its impact in morbidly obese subjects, especially women, remains poorly known. Synthesis and results According to their level of physical activity ( 1000 METmin/week), 37 middle-age (41.4 ± 1.7 years) morbidly obese women (BMI: 46.2 ± 0.7 kg/m2) were divided into group 1 (n = 21) and group 2 (n = 16). Saliva samples were taken for cortisol analysis at awakening (coraw) and 30 min after (cor30aw), with (CAR) determination. In parallel, body weight and composition were determined by bioelectrical impedance, whereas quality of life, stress and depression were estimated by specific questionnaires. In group 2 (> 1000MET-min/week) vs. group 1 ( Conclusion The level of physical activity influenced both body composition and CAR as demonstrated in other pathologies, but did not change quality of life, perceived stress and depression in a middle-age morbidly-obese female population. Further studies with a larger number of subjects are necessary to complete these preliminary results and to understand the implicated mechanisms.

Climate change and natural resource extraction are transforming boreal forest landscapes, with effects on Indigenous people’s relationship with the land. Collaborative management could enhance the consideration of Indigenous perspectives and limit negative outcomes of environmental change, but it remains the exception rather than the norm. We addressed barriers to involvement of Indigenous people in land management by developing a method to enhance communication and trust, while favouring bottom-up decision-making. We partnered with the Abitibiwinni and Ouje-Bougoumou First Nations (boreal Quebec, Canada) (i) to develop indicators of Indigenous landscape state, (ii) to create a typology of Indigenous hunting grounds, and (iii) to suggest guidelines for sustainable land management in Indigenous contexts. Through participatory mapping and semidirected interviews with 23 local experts, we identified factors influencing Indigenous landscape value. Using open-access data, we developed indicators to measure landscape state according to those values. We identified four types of hunting grounds with k-means clustering, based upon biophysical factors and disturbance history. Our results suggest that land management should aim to reduce differences between hunting ground states and consider the risk of rapid shifts from one state to another.

BACKGROUND PrEPX was an Australian HIV pre-exposure prophylaxis (PrEP) study conducted between 2016 and 2018. This analysis aimed to estimate hepatitis C (HCV) incidence and explore likely modes of transmission. SETTING Cohort study of PrEP users in Victoria, Australia. METHODS HCV tests were conducted at enrollment and every 12 months thereafter. HCV incident cases were identified from laboratory data. Likely modes of transmission were inferred from computer-assisted self-interviews, medical records, and interviews. RESULTS Among 3202 PrEPX participants tested for HCV at baseline, HCV RNA-positive prevalence was 0.22% (95% confidence interval: 0.09 to 0.45). Among participants testing HCV antibody-negative or RNA-negative at baseline, 2058 had at least one follow-up HCV test. Eight incident HCV cases were identified during 2111 person-years of follow-up (incidence 0.38/100 person-years); all were primary infections in men who had sex with men. Clinical, laboratory, and computer-assisted self-interviews data were available for all, and 6 cases were interviewed. Three cases were attributable to injecting drug use (IDU). A fourth case reported IDU, but his HCV was attributable to sexual transmission. Four other cases reported no IDU and probably acquired HCV sexually. Most cases reported anal trauma in the context of condomless receptive anal intercourse during group sex at sex-on-premises venues. CONCLUSIONS In PrEPX, HCV incidence was low compared to international PrEP studies, and most cases were transmitted sexually. Our findings highlight the need for HCV prevention messaging by clinicians, in sex-on-premises venues, and on digital platforms used to arrange group sex; and the need for HCV screening among some PrEP-using men who have sex with men.

Purpose Since the last Canadian Airway Focus Group (CAFG) guidelines were published in 2013, the literature on airway management has expanded substantially. The CAFG therefore re-convened to examine this literature and update practice recommendations. This first of two articles addresses difficulty encountered with airway management in an unconscious patient. Source Canadian Airway Focus Group members, including anesthesia, emergency medicine, and critical care physicians, were assigned topics to search. Searches were run in the Medline, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL databases. Results were presented to the group and discussed during video conferences every two weeks from April 2018 to July 2020. These CAFG recommendations are based on the best available published evidence. Where high-quality evidence was lacking, statements are based on group consensus. Findings and key recommendations Most studies comparing video laryngoscopy (VL) with direct laryngoscopy indicate a higher first attempt and overall success rate with VL, and lower complication rates. Thus, resources allowing, the CAFG now recommends use of VL with appropriately selected blade type to facilitate all tracheal intubations. If a first attempt at tracheal intubation or supraglottic airway (SGA) placement is unsuccessful, further attempts can be made as long as patient ventilation and oxygenation is maintained. Nevertheless, total attempts should be limited (to three or fewer) before declaring failure and pausing to consider “exit strategy” options. For failed intubation, exit strategy options in the still-oxygenated patient include awakening (if feasible), temporizing with an SGA, a single further attempt at tracheal intubation using a different technique, or front-of-neck airway access (FONA). Failure of tracheal intubation, face-mask ventilation, and SGA ventilation together with current or imminent hypoxemia defines a “cannot ventilate, cannot oxygenate” emergency. Neuromuscular blockade should be confirmed or established, and a single final attempt at face-mask ventilation, SGA placement, or tracheal intubation with hyper-angulated blade VL can be made, if it had not already been attempted. If ventilation remains impossible, emergency FONA should occur without delay using a scalpel-bougie-tube technique (in the adult patient). The CAFG recommends all institutions designate an individual as “airway lead” to help institute difficult airway protocols, ensure adequate training and equipment, and help with airway-related quality reviews.

Lung cancer is the leading cause of cancer death worldwide, with approximately 1.6 million cancer related deaths each year. Prognosis is best in patients with early stage disease, though even then five-year survival is only 55% in some groups. Median survival for advanced non-small cell lung cancer (NSCLC) is 8–12 months with conventional treatment. Immune checkpoint inhibitor (ICI) therapy has revolutionised the treatment of NSCLC with significant long-term improvements in survival demonstrated in some patients with advanced NSCLC. However, only a small proportion of patients respond to ICI, suggesting the need for further techniques to harness the potential of ICI therapy. Thermal ablation utilizes the extremes of temperature to cause tumour destruction. Commonly used modalities are radiofrequency ablation (RFA), cryoablation and microwave ablation (MWA). At present thermal ablation is reserved for curative-intent therapy in patients with localized NSCLC who are unable to undergo surgical resection or stereotactic ablative body radiotherapy (SABR). Limited evidence suggests that thermal ablative modalities can upregulate an anticancer immune response in NSCLC. It is postulated that thermal ablation can increase tumour antigen release, which would initiate and upregulated steps in the cancer immunity cycle required to elicit an anticancer immune response. This article will review the current thermal ablative techniques and their ability to modulate an anti-cancer immune response with a view of using thermal ablation in conjunction with ICI therapy.

We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10–8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10–8) in interaction with colchicine (P = 1.19 × 10–5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.

Objectives To assess the value of effective regurgitant orifice (ERO) in predicting outcome after edge-to-edge transcatheter mitral valve repair (TMVR) for secondary mitral regurgitation (SMR) and identify the optimal cut-off for patients’ selection. Methods Using the EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) registry, that included patients undergoing edge-to-edge TMVR for SMR between November 2008 and January 2019 in 8 experienced European centres, we assessed the optimal ERO threshold associated with mortality in SMR patients undergoing TMVR, and compared characteristics and outcomes of patients according to baseline ERO. Results Among 1062 patients with severe SMR and ERO quantification by proximal isovelocity surface area method in the registry, ERO was 2 in 575 patients (54.1%), who were more symptomatic at baseline (NYHA class ≥ III: 91.4% vs. 86.9%, for ERO 2; P = 0.004). There was no difference in all-cause mortality at 2-year follow-up according to baseline ERO (28.3% vs. 30.0% for ERO 2, P = 0.585). Both patient groups demonstrated significant improvement of at least one NYHA class (61.7% and 73.8%, P = 0.002), resulting in a prevalence of NYHA class ≤ II at 1-year follow-up of 60.0% and 67.4% for ERO 2, respectively (P = 0.05). Conclusion All-cause mortality at 2 years after TMVR does not differ if baseline ERO is 2, and both groups exhibit relevant clinical improvements. Accordingly, TMVR should not be withheld from patients with ERO 2 who remain symptomatic despite optimal medical treatment, if TMVR appropriateness was determined by experienced teams in dedicated valve centres.

IntroductionThe International Association for School Librarianship (IASL) has a reputation for supporting and disseminating research informing school librarianship around the world. Since the organization serves a multi-national and multi-cultural library community, it has the responsibility to promote sound ethical procedures for all research. This can raise serious dilemmas for researchers planning to work in Global South countries with few or different ethical standards for conducting research when, as members of the Global North academic community, we are bound by strict guidelines covering ethical procedures. These dilemmas can include: 1) differing views on what counts as research: 2) differing values and policies on gender, religion, inclusive practices and other social and cultural areas; 3) the insider/outsider phenomenon (white privileged researchers working in non-white communities); and 4) development of culturally sensitive research instruments. These dilemmas present serious challenges as researchers set out to conduct research in school and community libraries in remote/rural areas and large urban centres where frontline staff have little or no experience with, nor knowledge of, educational research. Researchers are charged then to pay serious attention to issues of positionality, paradigms of what is "truth", the use of iterative methods and analyses, as well as an overarching awareness of their reflexivity throughout the research process. Research in this context becomes a continuous process of examining our relationship with fellow researchers and research participants, the dynamics of that relationship, and its relationship to the research that is undertaken. Without a self-critical lens for engaging in the research process, researchers run the risk of placing themselves in the position where "ethical research guidelines {as imposed by Universities} could be yet another western construct that create a global discourse of 'our way' is the 'right way' to do things" (Skelton, 2008, p. 29).Over the past two decades, the ethics of research involving children and youth has become a prominent topic in the literature (Powell, Fitzgerald, Taylor, & Graham, 2012), sparking a proliferation of resources for researchers (Alderson & Morrow, 2011; Childwatch International Research Network, n.d.; Graham, Powell, Taylor, Anderson & Fitzgerald, 2013; Young Lives, n.d.; UNICEF Office of Research, n.d). Spurred by the UN Convention on the Rights of the Child (1989) and the emergence of the sociology of childhood (Mayall, 2002), accordant rights-protecting procedures were instituted and methods of research designed to enable voices of children and youth to be heard in various degrees throughout the research process. However, from an international perspective, this paradigm of research with children and the knowledge generated by it are unbalanced since . . . 'only a little more than 10% of the world's children live in the developed countries of Europe, North America and other European outposts... yet the research is heavily concentrated on children from these places" (Pence & Nsamenang, 2008, p.14).How then should researchers working with children in school and community libraries develop research that assures fair and respectful ethical procedures? What role do children play in the research process - subject, informant or participant? How can Western researchers approach research in developing countries where expectations for ethical research, as defined by Western norms, may or may not exist? This paper takes a critical perspective on these issues by: 1) reflecting on the various stances that researchers take in approaching new research; 2) comparing expectations for ethics in developed and developing countries; and 3) identifying the position children are placed in before, during and after research projects. We begin our discussion by examining some of the current political, economic and ethical challenges facing researchers wishing to work in international contexts. …

Objective To determine the effect of overground walking using a powered exoskeleton on soft tissue body composition in persons with spinal cord injury (SCI). Design A prospective, single group observational pilot study. Setting Medical center. Participants Persons (N=8) with chronic (>6mo) SCI between 18 and 65 years old who weighed less than 100 kg. Interventions Overground ambulation training using a powered exoskeleton (ReWalk) for 40 sessions, with each session lasting up to 2 hours, with participants training 3 times per week. Main Outcome Measure(s) Dual-energy x-ray absorptiometry (DXA) was used to measure lean mass (LM) and fat mass (FM) from the whole body, arms, legs and trunk. DXA was also used to assess visceral adipose tissue (VAT). Walking performance was measured by 6-minute walk test. Results Participants significantly lost total body FM (−1.8±1.2kg, P=.004) with the loss of adiposity distributed over several regional sites. Six of the 8 participants lost VAT, with the average loss in VAT trending toward significance (−0.141kg, P=.06). LM for the group was not significantly changed. Conclusions Sustained and weekly use of powered exoskeletons in persons with SCI has the potential to reduce FM with inferred improvements in health.

Background The pathogenesis of BPD includes inflammation and oxidative stress in the immature lung. Corticosteroids improve respiratory status and outcome, but the optimal treatment regimen for benefit with low systemic effects is uncertain. Methods In a pilot dose escalation trial, we administered ≤5 daily doses of budesonide in surfactant to 24 intubated premature infants (Steroid And Surfactant in ELGANs (SASSIE)). Untargeted metabolomics was performed on dried blood spots using UPLC-MS/MS. Tracheal aspirate IL-8 concentration was determined as a measure of lung inflammation. Results Metabolomics data for 829 biochemicals were obtained on 121 blood samples over 96 h from 23 infants receiving 0.025, 0.05, or 0.1 mg budesonide/kg. Ninety metabolites were increased or decreased in a time- and dose-dependent manner at q ≤ 0.1 with overrepresentation in lipid and amino acid super pathways. Different dose response patterns occurred, with negative regulation associated with highest sensitivity to budesonide. Baseline levels of 22 regulated biochemicals correlated with lung inflammation (IL-8), with highest significance for sphingosine and thiamin. Conclusions Numerous metabolic pathways are regulated in a dose-dependent manner by glucocorticoids, which apparently act via distinct mechanisms that impact dose sensitivity. The findings identify candidate blood biochemicals as biomarkers of lung inflammation and systemic responses to corticosteroids. Impact Treatment of premature infants in respiratory failure with 0.1 mg/kg intra-tracheal budesonide in surfactant alters levels of ~11% of detected blood biochemicals in discrete time- and dose-dependent patterns. A subset of glucocorticoid-regulated biochemicals is associated with lung inflammatory status as assessed by lung fluid cytokine concentration. Lower doses of budesonide in surfactant than currently used may provide adequate anti-inflammatory responses in the lung with fewer systemic effects, improving the benefit:risk ratio.

Background: Marathon participation is becoming increasingly popular among individuals ≥40 years of age. Little is known about the prevalence of subclinical coronary artery disease (CAD) and corresponding ischemia in this patient population. The study objectives are: (1) to characterize the prevalence of silent CAD in marathoners ≥ 40 years old using cardiac computed tomography angiography (CCT); and (2) if subclinical CAD was detected, to determine the functional significance of occult lesions by stress echocardiography (SE). Methods: Marathoners aged ≥ 40 years who completed a full marathon between 2018 and 2019 were recruited to undergo a prospective CCT. Coronary artery stenosis was graded as zero, mild (1%-49%), moderate (50%-69%), or severe (> 70%). All study participants diagnosed with mild-to-severe atherosclerotic CAD on CCT further underwent functional imaging with exercise treadmill SE. Results: A total of 65 individuals (53 ± 7 years, 65% males, 24 ± 3 kg/m2) underwent a prospective CCT within 12 months of marathon completion. Of the total study population, 13 participants (20%) were diagnosed with CAD, of whom 10 (77%) had mild disease, 1 (8%) had moderate disease, and 2 (15%) had severe disease by CCT. Despite the identification of subclinical CAD on CCT, none of the 13 patients had any evidence of inducible ischemia on SE. Conclusions: This is the first study to incorporate both CCT and SE in the evaluation of subclinical CAD in marathoners ≥40 years old. Although the overall prevalence of anatomic CAD was 20%, there was no evidence of functional ischemia in this highly competitive cohort. Résumé: Contexte: Les marathons ont gagné en popularité auprès des individus âgés de 40 ans ou plus. On en sait toutefois peu sur la prévalence de la coronaropathie subclinique et de l’ischémie qui lui est associée dans cette population de patients. L’étude visait à 1) caractériser la prévalence de la coronaropathie silencieuse chez les marathoniens âgés de 40 ans ou plus à l’aide d’une angiographie cardiaque par tomodensitométrie (ACTDM) si une coronaropathie subclinique était détectée, à déterminer l’importance fonctionnelle des lésions occultes par une échocardiographie d’effort (EE). Méthodologie: Des marathoniens âgés de 40 ans ou plus ayant réalisé un marathon entre 2018 et 2019 ont été recrutés et soumis à une ACTDM prospective. Les sténoses des artères coronaires étaient classées selon une échelle allant de zéro, légère (1 à 49 %), modérée (50 à 69 %) à sévère (> 70 %). Tous les participants à l’étude ayant reçu un diagnostic de coronaropathie athéroscléreuse légère à sévère à la suite de l’ACTDM ont été soumis à une imagerie fonctionnelle avec EE sur tapis roulant. Résultats: Au total, 65 sujets (53 ± 7 ans, 65 % d’hommes, 24 ± 3 kg/m2) ont été soumis à une ACTDM prospective dans un délai de 12 mois à la suite de leur dernier marathon. Dans l’ensemble de la population à l’étude, 13 participants (20 %) ont reçu un diagnostic de coronaropathie; 10 (77 %) présentaient une maladie bénigne, 1 (8 %) présentait une maladie modérée et 2 (15 %) présentaient une maladie sévère selon l’ACTDM. Même si une coronaropathie subclinique a été diagnostiquée lors de l’ACTDM, aucun des 13 patients ne présentait de signe d’ischémie inductible à l’EE. Conclusions: Il s’agit de la première étude à utiliser l’ACTDM et l’EE pour évaluer la présence d’une coronaropathie chez des marathoniens âgés de 40 ou plus. Même si la prévalence globale de la coronaropathie anatomique était de 20 %, il n’y avait aucun signe d’ischémie fonctionnelle au sein de cette cohorte hautement compétitive.

BACKGROUND Gay and bisexual men with undiagnosed HIV contribute disproportionately to HIV transmission in Australia. METHODS In 2014 and 2018, we recruited men at gay venues and events in Sydney. Participants self-completed surveys and provided oral fluid samples for HIV testing. We calculated the prevalence of HIV and undiagnosed infection, and assessed changes in behavior, HIV testing, and the use of pre-exposure prophylaxis. We weighted the samples to adjust for differences in where participants were recruited between rounds. Two-sample tests of proportion were used to compare prevalence estimates and χ tests to assess differences between the samples. RESULTS In 2014, 944 men were recruited, and 890 men were recruited in 2018. In 2014, the weighted estimate of HIV prevalence was 6.1% [95% confidence intervals (CI): 4.6 to 7.6], of which 13.8% (95% CI: 5.0 to 22.7) was undiagnosed. In 2018, weighted HIV prevalence was 6.4% (95% CI: 4.8 to 8.0), of which 5.3% (95% CI: 0.5 to 11.1) was undiagnosed. Between 2014 and 2018 among all participants, men reporting at least 10 recent casual partners increased from 22.3% to 27.7% (P = 0.008), condomless anal intercourse with casual partners in the previous 6 months increased from 23.9% to 37.3% (P < 0.001), and sexually transmitted infection diagnoses in the previous year increased from 14.4% to 27.5% (P < 0.001). HIV testing and the use of pre-exposure prophylaxis in the previous 6 months increased from 49.6% to 56.3% (P = 0.004) and 2.0%-21.0% (P < 0.001), respectively. CONCLUSIONS Repeated, bio-behavioral surveillance suggests the prevalence of undiagnosed HIV remains low in Sydney, despite gay and bisexual men reporting more casual sex partners, condomless sex, and sexually transmitted infections.

The participation rate of the Indigenous workforce in the mining industry is significantly lower than that of non-Indigenous people. The purpose of this research was to determine how public and private programs aimed at promoting the recruitment, integration and retention of Indigenous employees in the Canadian mining industry meet the needs of Indigenous employees and mining employers. Five categories of programs were assessed (liaison, work readiness, site readiness, cultural awareness and career progression), according to 50 criteria. A literature review and interviews with 86 participants (43 Indigenous, 27 employers and 16 representatives of public programs in Quebec and Nunavut) showed that only public programs existed in areas not subjected to government/company-Indigenous agreements, meeting 34% of the needs, compared to 76% for private programs in signatory territories. Implementing private programs in non-signatory territories could be beneficial, but would require a mentality change in the industry.

The aim of this study is to develop a tool that is aligned with patients’ and health professionals’ needs to address sexual health in the context of anorectal malformations and Hirschsprung’s disease. A multiphased participatory action–research was conducted. First, an inventory of needs was made through interviews (11 patients, 11 professionals), three online focus groups (4 patients, 20 professionals), and a questionnaire (38 patients). Subsequently, four cocreation sessions with in total four patients and nine professionals were organized to translate the needs into a tool (in the form of a website). The websites’ functionality was assessed via a questionnaire ( n = 34). The website, directed to patients, their parents, and professionals, stimulates awareness, fills knowledge gaps, and shows possibilities for support. The website is expected to change restrictive attitudes toward sexual health and improve the legitimization of the topic needed for the allocation of resources and sexologists’ involvement in current care pathways.

Background: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, and sudden cardiac death represents an important mode of death in these patients. Data evaluating the implantable cardioverter defibrillator (ICD) in this patient population remain scarce. Methods: A Nationwide French Registry including all patients with tetralogy of Fallot with an ICD was initiated in 2010 by the French Institute of Health and Medical Research. The primary time to event end point was the time from ICD implantation to first appropriate ICD therapy. Secondary outcomes included ICD-related complications, heart transplantation, and death. Clinical events were centrally adjudicated by a blinded committee. Results: A total of 165 patients (mean age, 42.2±13.3 years, 70.1% males) were included from 40 centers, including 104 (63.0%) in secondary prevention. During a median (interquartile range) follow-up of 6.8 (2.5–11.4) years, 78 (47.3%) patients received at least 1 appropriate ICD therapy. The annual incidence of the primary outcome was 10.5% (7.1% and 12.5% in primary and secondary prevention, respectively; P =0.03). Overall, 71 (43.0%) patients presented with at least 1 ICD complication, including inappropriate shocks in 42 (25.5%) patients and lead dysfunction in 36 (21.8%) patients. Among 61 (37.0%) patients in primary prevention, the annual rate of appropriate ICD therapies was 4.1%, 5.3%, 9.5%, and 13.3% in patients with, respectively, 0, 1, 2, or ≥3 guidelines-recommended risk factors. QRS fragmentation was the only independent predictor of appropriate ICD therapies (hazard ratio, 3.47 [95% CI, 1.19–10.11]), and its integration in a model with current criteria increased the 5-year time-dependent area under the curve from 0.68 to 0.81 ( P =0.006). Patients with congestive heart failure or reduced left ventricular ejection fraction had a higher risk of nonarrhythmic death or heart transplantation (hazard ratio, 11.01 [95% CI, 2.96–40.95]). Conclusions: Patients with tetralogy of Fallot and an ICD experience high rates of appropriate therapies, including those implanted in primary prevention. The considerable long-term burden of ICD-related complications, however, underlines the need for careful candidate selection. A combination of easy-to-use criteria including QRS fragmentation might improve risk stratification. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03837574.

PURPOSE Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS From 2007 to 2014, Children’s Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005 ) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively ( P = .029). Differences between DFS in a four-arm comparison were significant ( P = .01), with no interactions between the MTX and nelarabine randomizations ( P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.

Aims Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups. Methods and results We performed a case–control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub‐types. We also performed an exploratory genome‐wide study. We included 799 patients with HF and 1529 controls. After adjusting for age, sex, and genetic ancestry, we found that the C allele of rs2234962 in BAG3 was associated with a decreased risk of idiopathic dilated cardiomyopathy (odds ratio 0.42, 95% confidence interval 0.25–0.68, P = 0.0005), consistent with a previous report. No association for the other primary variants or exploratory genome‐wide study was found. Conclusions Our findings provide independent replication for the association between a common coding variant (rs2234962) in BAG3 and the risk of idiopathic dilated cardiomyopathy.

BACKGROUND Although the combination of doxorubicin (DOX) and trastuzumab (TRZ) reduces the progression and recurrence of breast cancer, these anticancer drugs are associated with significant cardiotoxic side effects. OBJECTIVE We investigated whether prophylactic administration of flaxseed (FLX) and its bioactive components, α-linolenic acid (ALA) and secoisolariciresinol diglucoside (SDG), would be cardioprotective against DOX + TRZ-mediated cardiotoxicity in a chronic in vivo female murine model. METHODS Wild-type C57BL/6 female mice (10-12 wk old) received daily prophylactic treatment with one of the following diets: 1) regular control (RC) semi-purified diet; 2) 10% FLX diet; 3) 4.4% ALA diet; or 4) 0.44% SDG diet for a total of 6 wks. Within each arm, mice received 3 weekly injections of 0.9% saline or a combination of DOX [8 mg/(kg.wk)] and TRZ [3 mg/(kg.wk)] starting at the end of week 3. The main outcome was to evaluate the effects of FLX, ALA, and SDG on cardiovascular remodeling and markers of apoptosis, inflammation, and mitochondrial dysfunction. Significance between measurements was determined using a 4 (diet) × 2 (chemotherapy) × 2 (time) mixed factorial design with repeated measures. RESULTS In the RC + DOX + TRZ-treated mice at week 6 of the study, the left ventricular ejection fraction (LVEF) decreased by 50% compared with the baseline LVEF (P

Objective Overexpression of the drug transporter P‐glycoprotein (P‐gp) is thought to be involved in drug‐resistance in epilepsy by extrusion of antiepileptic drugs (AEDs). We used positron emission tomography (PET) and the P‐gp substrate radiotracer (R)‐[11C]verapamil (VPM) together with the third‐generation P‐gp inhibitor tariquidar (TQD) to evaluate P‐gp function in individuals with drug‐resistant epileptogenic developmental lesions. Methods Twelve healthy controls (7 male, median age 45, range 35‐55 years), and two patients with epileptogenic developmental lesions (2 male, aged 24 and 62 years) underwent VPM‐PET scans before and 60 minutes after a 30‐minute infusion of 2 and 3 mg/kg TQD. The influx rate constant, VPM‐K1, was estimated from the first 10 minutes of dynamic data using a single‐tissue compartment model with a VPM plasma input function. Statistical parametric mapping (SPM) analysis was used to compare individual patients with the healthy controls. Results At baseline, SPM voxel‐based analysis revealed significantly lower uptake of VPM corresponding to the area of the epileptogenic developmental lesion compared to 12 healthy controls (P < .048). This was accentuated following P‐gp inhibition with TQD. After TQD, the uptake of VPM was significantly lower in the area of the epileptogenic developmental lesion compared to controls (P < .002). Significance This study provides further evidence of P‐gp overactivity in patients with drug‐resistant epilepsy, irrespective of the type of lesion. Identifying P‐gp overactivity as an underlying contributor to drug‐resistance in individual patients will enable novel treatment strategies aimed at overcoming or reversing P‐gp overactivity.

PURPOSE The benefits and risks of supplementation with antioxidants during cancer therapy have been a controversial area. Few studies have systematically evaluated dietary intake of antioxidants with toxicity and survival in childhood cancer. We sought to determine the role of dietary intake of antioxidants on rates of infections, mucositis, relapse, and disease-free survival during induction and postinduction phases of therapy among children and adolescents with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS We enrolled 794 children in a prospective clinical trial for treatment of ALL. Dietary intake was prospectively evaluated by a food frequency questionnaire. The association between dietary intake of antioxidants and treatment-related toxicities and survival were evaluated with the Benjamini-Hochberg false discovery rate (q) and logistic regression and the Kaplan-Meier method, respectively. RESULTS Dietary surveys were available for analysis from 614 (77%), and 561 (71%) participants at diagnosis and at end of induction, respectively. Of 513 participants who completed the dietary surveys at both time points, 120 (23%) and 87 (16%) experienced a bacterial infection and 22 (4%) and 55 (10%) experienced mucositis during the induction or postinduction phases of treatment, respectively. Increased intake of dietary antioxidants was associated with significantly lower rates of infection and mucositis. No association with relapse or disease-free survival was observed. Supplementation was not associated with toxicity, relapse, or survival. CONCLUSION Consumption of antioxidants through dietary intake was associated with reduced rates of infection or mucositis, with no increased risk of relapse or reduced survival. Dietary counseling on a well-balanced diet that includes an array of antioxidants from food sources alone may confer a benefit from infections and mucositis during treatment of childhood ALL.

Rapid scale-up of preexposure prophylaxis resulted in a redistribution of human immunodeficiency virus and sexually transmitted infection testing across services in Victoria, Australia and did not negatively impact testing among gay and bisexual and other men who have sex with men not using preexposure prophylaxis., Objective Scale-up of human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) has raised concerns regarding its impact on clinic capacity and access to HIV testing. We describe enrolment in PrEPX, a large PrEP implementation study in Victoria, Australia, and the impact of PrEP uptake and maintenance on existing health services. Methods We describe enrolment between July 26, 2016, and March 31, 2018, and trends in HIV testing among PrEPX participating and nonparticipating gay and bisexual and other men who have sex with men (GBM) at 5 study clinics participating in a sentinel surveillance system (ACCESS). We evaluated HIV and STI testing trends using segmented linear regression across the prestudy (January 2015 to June 2016) and PrEPX study (July 2016 to March 2018) periods. Findings There were 2,049 individuals who registered interest in study participation: 72% enrolled into the study. Study clinics enrolled participants rapidly; of 4265 people enrolled in PrEPX (98% GBM), 1000 enrolled by week 3, 88% (n = 876) of whom enrolled at ACCESS sites. Prestudy period HIV testing rates were increasing at all ACCESS sites. In the month PrEPX commenced, there was an additional 247 HIV tests among PrEPX participants (P < 0.01) and no significant change among non-PrEPX GBM (P = 0.72). Across the study period, HIV testing increased by 7.2 (P < 0.01) and 8.9 (P < 0.01) tests/month among PrEPX participants and non-PrEPX GBM, respectively. The HIV testing increased among non-PrEPX GBM at sexual health clinics (18.8 tests/month, P < 0.01) and primary care clinics (7.9 tests/month, P < 0.01). Similar trends were observed across testing for all measured STIs. Conclusions Rapid PrEP scale-up is possible without a reduction in HIV testing among GBM not using PrEP.

The skilled labour shortage in the natural resource sector is a major issue in North America, particularly in the Canadian forestry sector. In the province of Quebec alone, 15 000 positions will need to be filled by 2022. At the same time, many Indigenous communities are seeking to develop employment opportunities, as they have high unemployment rates and a young and growing population. But are forestry employers creating an environment conducive to the recruitment, integration, and retention of an Indigenous workforce? We interviewed 22 directors and human resource managers from 19 forestry businesses (16 non-Indigenous and 3 Indigenous) in Quebec, with a view to answering this question. Employer narratives suggest that they have only just begun to see the potential of the Indigenous workforce and put in place diversity management practices. Partnerships between Indigenous communities and forestry businesses, development of alternative training and skill development methods, and awareness-raising among employees and employers were found to favour recruitment, integration, and retention of Indigenous workers. Conversely, according to participants, stereotypes, discrimination, lack of inclusion measures, drug and alcohol use, and lack of training reduce the potential for Indigenous people to join the forestry workforce.

Funding Acknowledgements Type of funding sources: None. BACKGROUND Epidemiological characteristics and prognostic profiles of patients with newly diagnosed coronary artery disease (CAD) are heterogeneous. Thus, providing individualized cardiovascular (CV) risk stratification and tailored prevention is crucial. PURPOSE Phenotypic unsupervised clustering integrating clinical, coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR) data was used to unveil pathophysiological differences between subgroups of patients with newly diagnosed CAD. METHODS Between 2008 and 2020, consecutive patients with newly diagnosed obstructive CAD on CCTA and further referred for vasodilator stress CMR were followed for the occurrence of major adverse cardiovascular events (MACE), defined by cardiovascular death or nonfatal myocardial infarction. A cluster analysis was performed on clinical, CCTA and CMR variables, and associations between phenogroups and outcomes were assessed. RESULTS Of 2,210 patients who underwent CMR, 2,015 (46% male, mean 70 ± 12 years) completed follow-up (median 6.8[IQR 5.9-9.2] years); 277 experienced a MACE (13.7%). Three mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] CAD in elderly patients with few traditional risk factors; [PG2] women with metabolic syndrome, calcified plaques on CCTA and preserved left ventricular ejection fraction (LVEF); and [PG3] younger male smokers with proximal noncalcified plaques on CCTA, myocardial scar and reduced LVEF. Using survival analysis, the occurrence of MACE, cardiovascular mortality and all-cause mortality (all p CONCLUSIONS Cluster analysis of clinical, CCTA and CMR variables identified 3 phenogroups of patients with newly diagnosed CAD that were associated with distinct clinical and prognostic profiles. Inducible ischemia assessed by stress CMR remained associated with the occurrence of MACE within each phenogroup. Abstract Figure. Cluster analysis: Biplot representation Abstract Figure. Kaplan Meier curves by Phenogroups

Objective Wellness is a challenge for Indigenous peoples, partly because Western services do not adopt a holistic approach. By devaluing traditional knowledge, Indigenous values and beliefs, these services lower Indigenous power and affect cultural identities. Indigenous elders participate in intergenerational solidarity by transmitting knowledge, values, and culture in a holistic approach. Despite widespread acceptance of the importance of Indigenous elders’ contributions to wellness, a rigorous synthesis of knowledge has never been done. This study aimed to provide a comprehensive understanding of how Indigenous elders’ social participation contributes to individual and community wellness. Method A scoping review was conducted with Indigenous elders and stakeholders in Québec (Canada). Sixteen databases were searched with 57 keywords. Data from the documents retrieved were analyzed, organized, and synthesized based on the International Classification of Functioning, Disability and Health. Synthesis A total of 144 documents were examined, comprising 74 scientific papers and 70 sources from the gray literature. Indigenous elders contributed to wellness mainly through relationships and interactions with other community members and non-Indigenous people (72.2%); intergenerational oral and written communications (70.1%); community, social and civic life (45.8%); volunteering and jobs (35.4%); and family life (29.9%). Elders transmit traditional knowledge, strengthen social cohesion, and help to develop positive attitudes such as reciprocity. Their actions favour disease prevention and health promotion, as including traditional approaches increases the acceptability of health and social services. Conclusion This scoping review highlights the need for longitudinal studies with mixed-method designs involving Indigenous communities at all stages of the research to deepen understanding of the contributions of Indigenous elders to individual and community wellness.

BackgroundRegenerating islet-derived protein 3α (REG3α) is an antimicrobial peptide secreted by intestinal Paneth cells. Circulating REG3α has been identified as a gut damage marker in inflammatory bowel diseases. People living with human immunodeficiency virus (PWH) on antiretroviral therapy (ART) present with an abnormal intestinal landscape leading to microbial translocation, persistent inflammation, and development of non-AIDS comorbidities. Herein, we assessed REG3α as a marker of gut damage in PWH.MethodsPlasma from 169 adult PWH, including 30 elite controllers (ECs), and 30 human immunodeficiency virus (HIV)–uninfected controls were assessed. REG3α plasma levels were compared with HIV disease progression, epithelial gut damage, microbial translocation, and immune activation markers.ResultsCross-sectionally, REG3α levels were elevated in untreated and ART-treated PWH compared with controls. ECs also had elevated REG3α levels compared to controls. Longitudinally, REG3α levels increased in PWH without ART and decreased in those who initiated ART. REG3α levels were inversely associated with CD4 T-cell count and CD4:CD8 ratio, while positively correlated with HIV viral load in untreated participants, and with fungal product translocation and inflammatory markers in all PWH.ConclusionsPlasma REG3α levels were elevated in PWH, including ECs. The gut inflammatory marker REG3α may be used to evaluate therapeutic interventions and predict non-AIDS comorbidity risks in PWH.

Study Design Prospective, observational study Objective To explore the effects of exoskeleton-assisted walking (EAW) on bowel function in persons with spinal cord injury (SCI). Setting Ambulatory research facility located in a tertiary care hospital Methods Individuals 18–65 years of age, with thoracic vertebrae one (T1) to T11 motor-complete paraplegia of at least 12 months duration were enrolled. Pre- and post-EAW training, participants were asked to report on various aspects of their bowel function as well as on their overall quality of life (QOL) as related to their bowel function. Results Ten participants completed 25–63 sessions of EAW over a period of 12 to 14 weeks, one participant was lost to follow up due to early withdrawal after 10 sessions. Due to the small sample size, each participant’s results were presented descriptively in a case series format. At least 5/10 participants reported improvements with frequency of bowel evacuations, less time spent on bowel management per bowel day, fewer bowel accidents per month, reduced laxative and/or stool softener use, and improved overall satisfaction with their bowel program post-EAW training. Furthermore, 8/10 reported improved stool consistency and 7/10 reported improved bowel function related QOL. One participant reported worsening of bowel function post-EAW. Conclusion Between 50 and 80% of the participants studied reported improvements in bowel function and/or management post-EAW training. EAW training appeared to mitigate SCI-related bowel dysfunction and the potential benefits of EAW on bowel function after SCI is worthy or further study. Sponsorship N/A

PurposeWhile companies in developed countries are increasingly turning to indigenous employees, integration measures have met with mixed results. Low integration can lead to breach of the psychological contract, i.e. perceived mutual obligations between employee and employer. The purpose of this paper is to identify how leadership and organizational integration measures can be implemented to promote the perceived insider status (PIS) of indigenous employees, thereby fostering fulfillment of the psychological contract.Design/methodology/approachA search for relevant literature yielded 128 texts used to identify integration measures at the level of employee–supervisor relationships (leader-member exchanges, inclusive leadership) and at the level of employee–organization relationships (perceived organizational support, pro-diversity practices).FindingsMeasures related to leadership included recruiting qualified leaders, understanding cultural particularities, integrating diverse contributions and welcoming questions and challenges. Organizational measures included reaching a critical mass of indigenous employees, promoting equity and participation, developing skills, assigning meaningful tasks, maintaining good work relationships, facilitating work-life balance, providing employment security, fostering support from communities and monitoring practices.Originality/valueWhile PIS has been studied in western and culturally diverse contexts, it has received less attention in indigenous contexts. Yet, some indigenous cultural values are incompatible with the basic assumptions of mainstream theories. Furthermore, colonial policies and capitalist development have severely impacted traditional indigenous economic systems. Consequently, indigenous people are facing many barriers to employment in ways that often differ from the experiences of other minority groups.

Objective: To identify T-score values at the total hip (TH) and femoral neck (FN) that correspond to the cutoff value of

Several industries in developed countries are experiencing labor shortages, a particularly acute problem in the mining sector. Indigenous communities have a growing population, and some are interested in participating in mining. However, challenges prevent Indigenous people from entering the workforce. This research aimed to study the attitudes and behaviors of mining sector employers towards the Indigenous workforce, and to identify measures to promote recruitment, integration and retention of Indigenous employees. We conducted semi-structured interviews with 25 non-Indigenous employers occupying managerial positions and representing 17 mining projects located in Quebec and Nunavut (Canada). Eight of these projects were linked by agreements to neighboring Indigenous communities, either by being located on treaty territories or through Impact and Benefit Agreements (IBAs). The mean percentage of Indigenous employees was 23% in projects with an agreement, compared to

Purpose Magnetic resonance imaging (MRI) of the brain allows for the identification of structural lesions typical of Alzheimer's disease (AD), the main cause of dementia. However, to have a clinical impact, it is imperative that acquisition and reporting of this MRI-based evidence be standardized, ensuring the highest possible reliability and reproducibility. Our objective was to validate a systematic radiological MRI acquisition and review process in the context of AD. Methods We included 100 individuals with a suspicion of dementia due to AD for whom MRI were acquired using our proposed protocol of clinically achievable acquisitions and used a unified reading grid to gather semi-quantitative evidence guiding diagnostic. MRIs were read by 3 raters with different experience levels. Interrater reliability was measured using Cohen's kappa statistic. Results Interrater reliability average for lesions occupying space, hemorrhage, or ischemia, was respectively 0.754, 0.715, and 0.501. Average reliability of white matter hyperintensity burden (Fazekas), global cortical atrophy, and temporal lobe atrophy (Scheltens) scales was 0.687, 0.473, and 0.621 (right)/0.599 (left), respectively. The kappas for regional cortical atrophy (frontal, parietal, occipital, temporal, and posterior cingulum) varied from 0.281–0.678. The average MRI reading time varied between 1.43-5.22 minutes. Conclusions The presence of space occupying lesions, hemorrhagic or ischemic phenomena, and radiological scales have a good interrater reproducibility in MRI. Coupled with standardized acquisitions, such a protocol should be used when evaluating possible dementias, especially those due to probable AD.

AimsThe Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomised, double-blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorised according to left ventricular ejection fraction and tolerability to an ACE inhibitor. We conducted a pharmacogenomic study of the CHARM studies to identify genetic predictors of heart failure progression and the efficacy and safety of treatment with candesartan.MethodsWe performed genome-wide association studies (GWAS) with the composite endpoint of cardiovascular death or hospitalisation for heart failure in 2727 patients from CHARM-Overall and stratified by CHARM study according to preserved and reduced ejection fraction. The safety endpoints were hyperkalaemia, renal dysfunction, hypotension, and change in systolic blood pressure. We also conducted a genome-wide gene-level collapsing analysis from whole-exome sequencing data with the composite cardiovascular endpoint.ResultsWe found the genetic variant rs66886237 at 8p21.3 near the gene GFRA2 to be associated with the composite cardiovascular endpoint in 1029 HF patients with preserved ejection fraction from the CHARM-Preserved study [hazard ratio (HR): 1.91, 95% confidence interval (CI): 1.55-2.35; P=1.7×10-9], but not in patients with reduced ejection fraction. None of the GWAS for candesartan safety or efficacy passed the significance threshold.ConclusionsWe have identified a candidate genetic variant potentially predictive of the progression of heart failure in patients with preserved ejection fraction. The findings require further replication and we cannot exclude the possibility that the results may be chance findings.

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Adopting appropriate eligibility criteria for research and clinical programs in which powered exoskeletal-assisted walking devices are used remains a challenge to avoid risk of injury and to encourage the successful use of these devices. Reducing the risk of fracture is a primary concern when establishing eligibility criteria. Evidence from a three-site clinical trial supports the use of screening criteria for bone mineral density at the knee to permit safe use of exoskeletal devices.

The objective of this research was to identify variables (demographic, device, neurological, clinical, and training session dose) that were associated with results of the ten-minute walk test (10MWT) for individuals with a spinal cord injury (SCI) who participated in a large randomized crossover clinical trial of exoskeletal walking. Fifty individuals were randomized into Group AB or BA (A = exoskeleton intervention arm, B = control arm). A generalized linear mixed model was applied to model 10MWT and found that a training dose of 36 sessions and gender were the most significant. These variables were more significant than neurological level of injury or completeness of injury. Understanding the effects of exoskeleton/human interface for different devices is crucial for identifying suitable candidates to use the device and developing effective/efficient clinical training protocols for community ambulation, rehabilitation, and recovery post-SCI.

The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF50) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines., Defined levels of SARS-CoV-2-specific binding and neutralizing antibodies elicited by the COVID-19 vaccine ChAdOx1 nCoV-19 are identified as correlates of protection against symptomatic infection.

We sought to summarize, in a systematic review, the effectiveness of songs to support learning, performance, and recall of quality characteristics of cardiopulmonary resuscitation (CPR) compression rate, and depth. We systematically reviewed the literature from eight academic indexes from the fields of medicine, nursing, allied health, and education, from 2014 to 2020 to identify studies that evaluated an intervention of song use during CPR training against control and reported outcomes of compression rate and depth. There were 185 studies initially identified for review, eight met criteria for inclusion and analysis. For the critical outcome of compression depth, a pooled song group (n=446) when compared to a non-song group (n=443) demonstrated higher odds of being in the recommended range (OR 3.47). All studies, however, performed an average compression depth shallower than recommended guidelines in each arm. The available literature, we found, utilized heterogenous methodology and was at high risk of bias. When pooled, there were trends towards improved CPR metric performance in groups who were exposed to songs during treatment, though this only reached significance when groups were tested at >30 days from initial exposure. Findings of lower compression rates in the song groups suggest that song selection should favor beats per minute closer to the midpoint of the 100-120 ideal range to allow for variation when used as mental metronomes.

Introduction Precise needle puncture of the renal collecting system is an essential step for successful percutaneous nephrolithotomy (PCNL). The use of ultrasound for puncture is receiving increase...

Enclosed you will find the article entitled “A study of two-dimensional single atom-supported MXenes as hydrogen evolution reaction catalysts using DFT and machine learning”. Existing studies predominantly focused on the hydrogen evolution reaction (HER) activities and stabilities of oxygen-terminated MXenes with single-atom loading. However, to the best of our knowledge, two-dimensional (2D) MXenes with different terminations (e.g. Br, I, Se, Te, B, Si, P, and NH) have not yet been investigated for the purposes of HER catalysis. Therefore, in this work, we considered the combined effect of the different surface terminations (B, NH, O, F, Si, P, S, Cl, Se, Br, Te, and I) and single atom loading (Ti, V, Fe, Co, Ni, Cu, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Hf, Ta, W, Re, Os, Ir, Pt, and Au) using DFT calculation. Gibbs free energy of hydrogen adsorption (reflecting activity) and the cohesive energy (a proxy for thermal stability) of these structures (264 in total) were calculated. We demonstrate that 21 uninvestigated 2D single-atom MXene catalysts, among 264 promising candidates, show an electrocatalytic activity surpassing that of platinum and a thermal stability surpassing those of synthesized borophene sheet and MoS2. Moreover, all catalysts examined in this work were further randomly separated into training and test sets with a ratio of 7:3. The HER electrocatalytic performance and thermal stability of the catalysts in the test set were predicted by machine learning algorithms. Most importantly, we present a way to provide a comparable precision (root mean square error values for the activity and thermal stability predictions are 0.158 eV and 0.02 eV, respectively) to the published machine learning works by avoiding their adoption of complex electronic features and the associated high computational cost, and by only using features that are easily available in chemical repositories. The algorithms used in this work are expected to help future researchers quickly screen single atom loaded MXenes HER catalysts at the initial design stage in a cost-effective manner. We have no financial interest in the subject or instrumentation used and there is no known conflict of interest.

Tissue-resident memory T cells (TRM) provide immune defence against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and how the immune pressure exerted by TRM affects developing tumours in humans. We performed deep profiling of lung cancers arising in never-smokers (NS) and ever-smokers (ES), finding evidence of enhanced TRM immunosurveillance in ES lung. Only tumours arising in ES patients underwent clonal immune escape, even when evaluating cancers with similar tumour mutational burden to NS patients, suggesting that the timing of immune pressure exerted by TRM is a critical factor in the evolution of tumour immune evasion. Tumours grown in T cell quiescent NS lungs displayed little evidence of immune evasion and had fewer neoantigens with low diversity, paradoxically making them amenable to treatment with agonist of the costimulatory molecule, ICOS. These data demonstrate local environmental insults enhance TRM immunosurveillance of human tissue, shape the evolution of tumour immunogenicity and that this interplay informs effective immunotherapeutic modalities.

Introduction In a CICO (cannot intubate, cannot oxygenate) situation, anesthesiologists and acute care physicians must be able to perform an emergency surgical cricothyrotomy (front-of-neck airway procedure). CICOs are high-acuity situations with rare opportunities for safe practice. In COVID-19 airway management guidelines, bougie-assisted surgical cricothyrotomy is the recommended emergency strategy for CICO situations. Methods We designed a 4-hour procedural simulation workshop on surgical cricothyrotomy to train 16 medical residents. We provided prerequisite readings, a lecture, and a videotaped demonstration. Two clinical scenarios introduced deliberate practice on partial-task neck simulators and fresh human cadavers. We segmented an evidence-based procedure and asked participants to verbalize the five steps of the procedure on multiple occasions. Results Thirty-two residents who participated in the workshops were surveyed, with a 97% response rate (16 of 16 from anesthesiology, 15 of 16 from emergency medicine). Participants commented positively on the workshop's authenticity, its structure, the quality of the feedback provided, and its perceived impact on improving skills in surgical cricothyrotomy. We analyzed narrative comments related to three domains: preparation for the procedure, performing the procedure, and maintaining the skills. Participants highlighted the importance of performing the procedure many times and mentioned the representativeness of fresh cadavers. Discussion We developed a surgical cricothyrotomy simulation workshop for anesthesiology and emergency medicine residents. Residents in the two specialities uniformly appreciated its format and content. We identified common pitfalls when executing the procedure and provided practical tips and material to facilitate implementation, in particular to face the COVID-19 pandemic.

International audience; Objectives: This study aimed to assess the impact of pulmonary valve replacement (PVR) on ventricular arrhythmias burden in a population of tetralogy of Fallot (TOF) patients with continuous cardiac monitoring by implantable cardioverter-defibrillators (ICDs).Background: Sudden cardiac death is a major cause of death in TOF, and right ventricular overload is commonly considered to be a potential trigger for ventricular arrhythmias.Methods: Data were analyzed from a nationwide French ongoing study (DAI-T4F) including all TOF patients with an ICD since 2000. Survival data with recurrent events were used to compare the burden of appropriate ICD therapies before and after PVR in patients who underwent PVR over the study period.Results: A total of 165 patients (mean age 42.2 ± 13.3 years, 70.1% male) were included from 40 centers. Over a median follow-up period of 6.8 (interquartile range: 2.5 to 11.4) years, 26 patients (15.8%) underwent PVR. Among those patients, 18 (69.2%) experienced at least 1 appropriate ICD therapy. When considering all ICD therapies delivered before (n = 62) and after (n = 16) PVR, the burden of appropriate ICD therapies was significantly lower after PVR (HR: 0.21; 95% confidence interval [CI]: 0.08 to 0.56; p = 0.002). Respective appropriate ICD therapies rates per 100 person-years were 44.0 (95% CI: 35.7 to 52.5) before and 13.2 (95% CI: 7.7 to 20.5) after PVR (p < 0.001). In the overall cohort, PVR before ICD implantation was also independently associated with a lower risk of appropriate ICD therapy in primary prevention patients (HR: 0.29 [95% CI: 0.10 to 0.89]; p = 0.031).Conclusions: In this cohort of high-risk TOF patients implanted with an ICD, the burden of appropriate ICD therapies was significantly reduced after PVR. While optimal indications and timing for PVR are debated, these findings suggest the importance of considering ventricular arrhythmias in the overall decision-making process. (French National Registry of Patients With Tetralogy of Fallot and Implantable Cardioverter Defibrillator [DAI-T4F]; NCT03837574).