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Background The reported survival of tetralogy of Fallot (TOF) is > 97%. Patients with pulmonary atresia and/or genetic conditions have worse outcomes, but long-term estimates of survival and morbidity for these TOF subgroups are scarce. The objective of this study was to describe the 30-year outcomes of TOF according to native anatomy and the coexistence of genetic conditions. Methods The TRIVIA (Tetralogy of Fallot Research for Improvement of Valve Replacement Intervention: A Bridge Across the Knowledge Gap) study is a retrospective population-based cohort including all TOF subjects born from 1980 to 2015 in Quebec. We evaluated all-cause mortality by means of Cox proportional hazards regression, and cumulative mean number of cardiovascular interventions and unplanned hospitalisations with the use of marginal means/rates models. We computed 30-year estimates of outcomes according to TOF types, ie, classic TOF (cTOF) and TOF with pulmonary atresia (TOF-PA), and the presence of genetic conditions. Results We included 960 subjects. The median follow-up was 17 years (interquartile range, 8-27). Nonsyndromic cTOF subjects had a 30-year survival of 95% and had undergone a mean of 2.8 interventions and 0.5 hospitalisations per subject. In comparison, TOF-PA subjects had a lower 30-year survival of 78% and underwent a mean of 8.1 interventions, with 4 times as many hospitalisations. The presence of a genetic condition was associated with lower survival ( Conclusions The anatomic types and the presence of genetic conditions strongly influence the long-term outcomes of TOF. We provided robust 30-year estimates for key markers of prognosis that may be used to improve risk stratification and provide more informed counselling to families.

Background Bone quality influences humeral implant selection for shoulder arthroplasty. However, little is known about how well bone near the humeral resection represents more distal cancellous bone. This investigation aimed to quantify the correlations between the apparent density of sites near the humeral head resection plane and cancellous sites throughout the metaphysis. Methods Using computed tomography data from 98 subjects, apparent bone density was quantified in 65 regions throughout the proximal humerus. Pearson's correlation coefficient was determined comparing the density between samples from the humeral resection and all supporting regions beneath the resection. Mean correlation coefficients were compared for (i) each sample region with all support regions, (ii) pooling all sample regions within a slice, and (iii) considering sample regions correlated with only the support regions in the same anatomic section. Results Stronger correlations existed for bone sampled beneath the resection (0.33 ± 0.10≤ r ≤ 0.88 ± 0.10), instead of from the resected humeral head (0.22 ± 0.10≤ r ≤ 0.66 ± 0.14). None of sample region correlated strongly with all support regions; however, strong correlations existed when sample and support regions both came from the same anatomic section. Discussion Assessments of cancellous bone quality in the proximal humerus should be made beneath the humeral resection not in the resected humeral head; and each anatomic quadrant should be assessed independently.

Chimeric antigen receptors (CARs) are fusion proteins that contain antigen-recognition domains and T cell signaling domains. Signaling lymphocytic-activation molecule F7 (SLAMF7) is a promising target for CAR T cell therapies of the plasma cell malignancy multiple myeloma (MM) because SLAMF7 is expressed by MM but not normal nonhematopoietic cells. We designed CARs targeting SLAMF7. We transduced human T cells with anti-SLAMF7 CARs containing either CD28 or 4-1BB costimulatory domains. T cells expressing CD28-containing CARs or 4-1BB-containing CARs recognized SLAMF7 in vitro. SLAMF7-specific cytokine release was higher for T cells expressing CARs with CD28 versus 4-1BB domains. In murine solid tumor and disseminated tumor models, anti-tumor activity of T cells was superior with CD28-containing CARs versus 4-1BB-containing CARs. Because of SLAMF7 expression on some normal leukocytes, especially natural killer cells that control certain viral infections, the inclusion of a suicide gene with an anti-SLAMF7 CAR is prudent. We designed a construct with a CD28-containing anti-SLAMF7 CAR and a suicide gene. The suicide gene encoded a dimerization domain fused to a caspase-9 domain. T cells expressing the anti-SLAMF7 CAR plus suicide-gene construct specifically recognized SLAMF7 in vitro and eliminated tumors from mice. T cells expressing this construct were eliminated on demand by administering the dimerizing agent AP1903 (rimiducid).

PURPOSE Anti-CD19 chimeric antigen receptors (CARs) are artificial fusion proteins that cause CD19-specific T-cell activation. Durability of remissions and incidence of long-term adverse events are critical factors determining the utility of anti-CD19 CAR T-cell therapy, but long-term follow-up of patients treated with anti-CD19 CAR T cells is limited. This work provides the longest follow-up of patients in remission after anti-CD19 CAR T-cell therapy. METHODS Between 2009 and 2015, we administered 46 CAR T-cell treatments to 43 patients (ClinicalTrials.gov identifier: NCT00924326 ). Patients had relapsed B-cell malignancies of the following types: diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma (DLBCL/PMBCL; n = 28), low-grade B-cell lymphoma (n = 8), or chronic lymphocytic leukemia (CLL; n = 7). This report focuses on long-term outcomes of these patients. The CAR used was FMC63-28Z; axicabtagene ciloleucel uses the same CAR. Cyclophosphamide plus fludarabine conditioning chemotherapy was administered before CAR T cells. RESULTS The percentages of CAR T-cell treatments resulting in a > 3-year duration of response (DOR) were 51% (95% CI, 35% to 67%) for all evaluable treatments, 48% (95% CI, 28% to 69%) for DLBCL/PMBCL, 63% (95% CI, 25% to 92%) for low-grade lymphoma, and 50% (95% CI, 16% to 84%) for CLL. The median event-free survival of all 45 evaluable treatments was 55 months. Long-term adverse effects were rare, except for B-cell depletion and hypogammaglobulinemia. Median peak blood CAR-positive cell levels were higher among patients with a DOR of > 3 years (98/µL; range, 9-1,217/µL) than among patients with a DOR of < 3 years (18/µL; range, 0-308/μL, P = .0051). CONCLUSION Complete remissions of a variety of B-cell malignancies lasting ≥ 3 years occurred after 51% of evaluable anti-CD19 CAR T-cell treatments. Remissions of up to 9 years are ongoing. Late adverse events were rare.

Trajectory modelling techniques have been developed to determine subgroups within a given population and are increasingly used to better understand intra- and inter-individual variability in health outcome patterns over time. The objectives of this narrative review are to explore various trajectory modelling approaches useful to epidemiological research and give an overview of their applications and differences. Guidance for reporting on the results of trajectory modelling is also covered. Trajectory modelling techniques reviewed include latent class modelling approaches, ie, growth mixture modelling (GMM), group-based trajectory modelling (GBTM), latent class analysis (LCA), and latent transition analysis (LTA). A parallel is drawn to other individual-centered statistical approaches such as cluster analysis (CA) and sequence analysis (SA). Depending on the research question and type of data, a number of approaches can be used for trajectory modelling of health outcomes measured in longitudinal studies. However, the various terms to designate latent class modelling approaches (GMM, GBTM, LTA, LCA) are used inconsistently and often interchangeably in the available scientific literature. Improved consistency in the terminology and reporting guidelines have the potential to increase researchers' efficiency when it comes to choosing the most appropriate technique that best suits their research questions.

Summary Background Health care administrative databases are increasingly used for health studies and public health surveillance. Cases of individuals with obesity are selected using case‐identification methods. However, the validity of these methods is fragmentary and particularly challenging for obesity case identification. Objective The objectives of this systematic review are to (1) determine the case‐identification methods used to identify individuals with obesity in health care administrative databases and (2) to summarize the validity of these case‐identification methods when compared with a reference standard. Methods A systematic literature search was conducted in six bibliographic databases for the period January 1980 to June 2019 for all studies evaluating obesity case‐identification methods compared with a reference standard. Results Seventeen articles met the inclusion criteria. International Classification of Diseases (ICD) codes were the only case‐identification method utilized in selected articles. The performance of obesity‐identification methods varied widely across studies, with positive predictive value ranging from 19% to 100% while sensitivity ranged from 3% to 92%. The sensitivity of these methods was usually low while the specificity was higher. Conclusion When obesity is reported in health care administrative databases, it is usually correctly reported; however, obesity tends to be highly underreported in databases. Therefore, case‐identification methods to monitor the prevalence and incidence of obesity within health care administrative databases are not reliable. In contrast, the use of these methods remains relevant for the selection of individuals with obesity for cohort studies, particularly when identifying cohorts of individuals with severe obesity or cohorts where obesity is associated with comorbidities.

Background: Guidelines for surgical management of tetralogy of Fallot (TOF) are often based on low-quality evidence due to the many challenges of congenital heart disease: heterogeneous cardiac anatomy, consequences from surgical interventions arising years later, and scarcity of hard outcomes. The overarching goal of the Tetralogy of Fallot Research for Improvement of Valve replacement Intervention: A Bridge Across the Knowledge Gap (TRIVIA) study is to evaluate the long-term impact of the surgical management strategies in TOF. The specific objectives are: (1) to describe the long-term outcomes of TOF according to the native anatomy and the presence of genetic conditions, (2) to evaluate the long-term outcomes of surgical repair according to associated residual lesions, and (3) to evaluate the impact of paediatric pulmonary valve replacements on the long-term outcomes. Methods: The TRIVIA study is a population-based cohort including all subjects with TOF in the province of Québec between 1980 and 2017. It links patient-level granular clinical data with long-term administrative health care data. We will evaluate mortality, cardiovascular interventions, and hospitalizations for adverse cardiovascular events using survival Cox models and marginal mean/rates models for recurrent events, respectively. Multivariate multilevel models will correct for potential confounders, and risk score matching will mitigate the potential of confounding by indication. Results: The current TRIVIA cohort includes 1001 eligible subjects with TOF with complete lifelong follow-up for > 98%. The median follow-up is 17.1 years, totalling > 17,000 patient-years. Conclusions: Universal health insurance data combined with granular clinical data enable the development of population-based cohorts, to which contemporary statistical methods are applied to address important research questions in congenital heart disease research. Résumé: Contexte: Les lignes directrices pour la prise en charge chirurgicale de la tétralogie de Fallot (TdF) sont souvent basées sur des données de faible qualité en raison des nombreux défis posés par les maladies cardiaques congénitales : anatomie cardiaque hétérogène, répercussions des interventions chirurgicales survenant des années plus tard et rareté de conclusions solides. L'objectif principal de l’étude TRIVIA (Tetralogy of Fallot Research for Improvement of Valve replacement Intervention: A Bridge Across the Knowledge Gap) est d'évaluer l'impact à long terme des stratégies de prise en charge chirurgicale dans les TdF. Les objectifs spécifiques sont les suivants : (1) décrire les issues à long terme de la TdF en fonction de l'anatomie native et de la présence de conditions génétiques, (2) évaluer les conséquences à long terme de la chirurgie réparatrice en fonction des lésions résiduelles associées, et (3) évaluer l'impact des remplacements valvulaires pulmonaires pédiatriques sur le pronostic à long terme. Méthodes: L'étude TRIVIA est une étude de cohorte basée sur une population comprenant tous les sujets atteints de TdF dans la province du Québec entre 1980 et 2017. Elle fait le lien entre les données cliniques détaillées des patients et les données administratives des soins de santé à long terme. Nous évaluerons la mortalité, les interventions cardiovasculaires et les hospitalisations pour troubles cardiovasculaires en utilisant respectivement des analyses de survie par les modèles de Cox et des modèles de moyennes/taux marginaux pour les événements récurrents. Des modèles multivariés à plusieurs niveaux permettront de corriger les facteurs de confusion potentiels, et l'appariement par des scores de risque atténuera le potentiel de confusion par indication. Résultats: La cohorte de l’étude TRIVIA comprend actuellement 1001 sujets admissibles atteints de TdF avec un suivi complet tout au long de la vie pour > 98 %. Le suivi médian est de 17,1 ans, pour un total de > 17 000 patients-années. Conclusions: Les données de l'assurance maladie universelle combinées à des données cliniques détaillées permettent la mise en place de cohortes populationnelles, auxquelles les méthodes statistiques contemporaines pourront être appliquées afin de répondre aux questions importantes pour la recherche portant sur les maladies cardiaques congénitales.

Background Published methods to describe and visualize Care Trajectories (CTs) as patterns of healthcare use are very sparse, often incomplete, and not intuitive for non-experts. Our objectives are to propose a typology of CTs one year after a first hospitalization for Chronic Obstructive Pulmonary Disease (COPD), and describe CT types and compare patients’ characteristics for each CT type. Methods This is an observational cohort study extracted from Quebec’s medico-administrative data of patients aged 40 to 84 years hospitalized for COPD in 2013 (index date). The cohort included patients hospitalized for the first time over a 3-year period before the index date and who survived over the follow-up period. The CTs consisted of sequences of healthcare use (e.g. ED-hospital-home-GP-respiratory therapists, etc.) over a one-year period. The main variable was a CT typology, which was generated by a ‘tailored’ multidimensional State Sequence Analysis, based on the “6W” model of Care Trajectories. Three dimensions were considered: the care setting (“where”), the reason for consultation (“why”), and the speciality of care providers (“which”). Patients were grouped into specific CT types, which were compared in terms of care use attributes and patients’ characteristics using the usual descriptive statistics. Results The 2581 patients were grouped into five distinct and homogeneous CT types: Type 1 (n = 1351, 52.3%) and Type 2 (n = 748, 29.0%) with low healthcare and moderate healthcare use respectively; Type 3 (n = 216, 8.4%) with high healthcare use, mainly for respiratory reasons, with the highest number of urgent in-hospital days, seen by pulmonologists and respiratory therapists at primary care settings; Type 4 (n = 100, 3.9%) with high healthcare use, mainly cardiovascular, high ED visits, and mostly seen by nurses in community-based primary care; Type 5 (n = 166, 6.4%) with high healthcare use, high ED visits and non-urgent hospitalisations, and with consultations at outpatient clinics and primary care settings, mainly for other reasons than respiratory or cardiovascular. Patients in the 3 highest utilization CT types were older, and had more comorbidities and more severe condition at index hospitalization. Conclusions The proposed method allows for a better representation of the sequences of healthcare use in the real world, supporting data-driven decision making.

BackgroundSecondary analysis of health administrative databases is indispensable to enriching our understanding of health trajectories, health care utilization, and real-world risks and benefits of drugs among large populations.ObjectivesThis systematic review aimed at assessing evidence about the validity of algorithms for the identification of individuals suffering from nonarthritic chronic noncancer pain (CNCP) in administrative databases.MethodsStudies reporting measures of diagnostic accuracy of such algorithms and published in English or French were searched in the Medline, Embase, CINAHL, AgeLine, PsycINFO, and Abstracts in Social Gerontology electronic databases without any dates of coverage restrictions up to March 1, 2018. Reference lists of included studies were also screened for additional publications.ResultsOnly six studies focused on commonly studied CNCP conditions and were included in the review. Some algorithms showed a ≥60% combination of sensitivity and specificity values (back pain disorders in general, fibromyalgia, low back pain, migraine, neck/back problems studied together). Only algorithms designed to identify fibromyalgia cases reached a ≥80% combination (without replication of findings in other studies/databases).ConclusionsIn summary, the present investigation informs us about the limited amount of literature available to guide and support the use of administrative databases as valid sources of data for research on CNCP. Considering the added value of such data sources, the important research gaps identified in this innovative review provide important directions for future research. The review protocol was registered with PROSPERO (CRD42018086402).

Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are an effective treatment for B-cell lymphoma, but often cause neurologic toxicity. We treated 20 patients with B-cell lymphoma on a phase I, first-in-human clinical trial of T cells expressing the new anti-CD19 CAR Hu19-CD828Z ( NCT02659943 ). The primary objective was to assess safety and feasibility of Hu19-CD828Z T-cell therapy. Secondary objectives included assessments of blood levels of CAR T cells, anti-lymphoma activity, second infusions and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remission. Hu19-CD828Z T cells had clinical anti-lymphoma activity similar to that of T cells expressing FMC63-28Z, an anti-CD19 CAR tested previously by our group, which contains murine binding domains and is used in axicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% of patients who received Hu19-CD828Z T cells, whereas 50% of patients who received FMC63-28Z T cells experienced this degree of toxicity (P = 0.0017). T cells expressing Hu19-CD828Z released lower levels of cytokines than T cells expressing FMC63-28Z. Lower levels of cytokines were detected in blood from patients who received Hu19-CD828Z T cells than in blood from those who received FMC63-28Z T cells, which could explain the lower level of neurologic toxicity associated with Hu19-CD828Z. Levels of cytokines released by CAR-expressing T cells particularly depended on the hinge and transmembrane domains included in the CAR design. In a first-in-human, phase I trial in patients with B-cell lymphoma, CD19 CAR T cells with fully human binding domains exhibit lower neurologic toxicity, but similar clinical activity, to previously tested CD19 CAR T cells with murine binding domains.

Background Chronic conditions such as diabetes and chronic obstructive pulmonary disease (COPD) are common and burdensome diseases primarily managed in primary care. Yet, evidence points to suboptimal quality of care for these conditions in primary care settings. Quality improvement collaboratives (QICs) are organized, multifaceted interventions that can be effective in improving chronic disease care processes and outcomes. In Quebec, Canada, the Institut national d’excellence en santé et en services sociaux (INESSS) has developed a large-scale QIC province-wide program called COMPAS+ that aims to improve the prevention and management of chronic diseases in primary care. This paper describes the protocol for our study, which aims to evaluate implementation and impact of COMPAS+ QICs on the prevention and management of targeted chronic diseases like diabetes and COPD. Methods This is a mixed-methods, integrated knowledge translation study. The quantitative component involves a controlled interrupted time series involving nine large integrated health centres in the province. Study sites will receive one of two interventions: the multifaceted COMPAS+ intervention (experimental condition) or a feedback only intervention (control condition). For the qualitative component, a multiple case study approach will be used to achieve an in-depth understanding of individual, team, organizational and contextual factors influencing implementation and effectiveness of the COMPAS+ QICs. Discussion COMPAS+ is a QI program that is unique in Canada due to its integration within the governance of the Quebec healthcare system and its capacity to reach many primary care providers and people living with chronic diseases across the province. We anticipate that this study will address several important gaps in knowledge related to large-scale QIC projects and generate strong and useful evidence (e.g., on leadership, organizational capacity, patient involvement, and implementation) having the potential to influence the design and optimisation of future QICs in Canada and internationally.

Objectives Growing attention has been given to considering sex and gender in health research. However, this remains a challenge in the context of retrospective studies where self-reported gender measures are often unavailable. This study aimed to create and validate a composite gender index using data from the Canadian Community Health Survey (CCHS). Methods According to scientific literature and expert opinion, the GENDER Index was built using several variables available in the CCHS and deemed to be gender-related (e.g., occupation, receiving child support, number of working hours). Among workers aged 18–50 years who had no missing data for our variables of interest (n = 29,470 participants), propensity scores were derived from a logistic regression model that included gender-related variables as covariates and where biological sex served as the dependent variable. Construct validity of propensity scores (GENDER Index scores) were then examined. Results When looking at the distribution of the GENDER Index scores in males and females, they appeared related but partly independent. Differences in the proportion of females appeared between groups categorized according to the GENDER Index scores tertiles (p p p = 0.0309), and ability to handle unexpected/difficult problems (p = 0.0375). Conclusion The GENDER Index could be useful to enhance the capacity of researchers using CCHS data to conduct gender-based analysis among populations of workers.

BACKGROUND A small fraction of patients use a disproportionately large amount of emergency department (ED) resources. Identifying these patients, especially those with ambulatory care sensitive conditions (ACSC), would allow health care professionals to enhance their outpatient care. OBJECTIVE The objectives of the study were to determine predictive factors associated with frequent ED use in a Quebec adult population with ACSCs and to compare several models predicting the risk of becoming an ED frequent user following an ED visit. RESEARCH DESIGN This was an observational population-based cohort study extracted from Quebec's administrative data. SUBJECTS The cohort included 451,775 adult patients, living in nonremote areas, with an ED visit between January 2012 and December 2013 (index visit), and previously diagnosed with an ACSC but not dementia. MEASURES The outcome was frequent ED use (≥4 visits) during the year following the index visit. Predictors included sociodemographics, physical and mental comorbidities, and prior use of health services. We developed several logistic models (with different sets of predictors) on a derivation cohort (2012 cohort) and tested them on a validation cohort (2013 cohort). RESULTS Frequent ED users represented 5% of the cohort and accounted for 36% of all ED visits. A simple 2-variable prediction model incorporating history of hospitalization and number of previous ED use accurately predicted future frequent ED use. The full model with all sets of predictors performed only slightly better than the simple model (area under the receiver-operating characteristic curve: 0.786 vs. 0.759, respectively; similar positive predictive value and number needed to evaluate curves). CONCLUSIONS The ability to identify frequent ED users based only on previous ED and hospitalization use provides an opportunity to rapidly target this population for appropriate interventions.

BackgroundAdoptive cell therapy with tumor-infiltrating lymphocytes (TILs) has demonstrated tremendous promise in clinical trials for patients with solid or metastatic tumors.1 However, current TIL therapy requires systemic administration of IL-2 to promote TIL survival, and IL-2-associated toxicities greatly limit patient eligibility and reduce the long-term clinical benefit of TIL therapy.2 3 Unlike IL-2, which promotes T cell exhaustion, IL-15 maintains antigen-independent TIL persistence through homeostatic proliferation and supports CD8+ T cell anti-tumor activity without stimulating regulatory T cells. We designed genetically engineered TILs to express a regulated form of membrane-bound IL-15 (mbIL15) for tunable long-term persistence, leading to enhanced efficacy and safety for the treatment of patients with solid tumors.MethodsObsidian’s cytoDRiVE™ platform includes small human protein sequences called drug responsive domains (DRD)s that enable regulated expression of a fused target protein under control of FDA-approved, bioavailable small molecule ligands. cytoTIL15 contains TILs engineered with mbIL15 under the control of a carbonic-anhydrase-2 DRD, controlled by the ligand acetazolamide (ACZ). After isolation from tumors, TILs were transduced and expanded in vitro through a proprietary TIL expansion process. cytoTIL15 were immunophenotyped and assessed for in vitro antigen-independent survival and co-cultured with tumor cells to assess polyfunctionality and cytotoxicity. In vivo TIL persistence and anti-tumor efficacy was evaluated through adoptive transfer of TILs into immunodeficient NSG mice, either naïve or implanted with subcutaneous patient-derived-xenograft (PDX) tumors.Results cytoTIL15 and conventional IL2-dependent TILs isolated from melanoma tumor samples expanded to clinically relevant numbers over 14 days. Throughout expansion, cytoTIL15 were enriched for CD8+ T cells and acquired enhanced memory-like characteristics, while maintaining diverse TCRVβ sub-family representation. cytoTIL15 demonstrated enhanced potency over conventional TILs, as measured by increased polyfunctionality and cytotoxicity against tumor and PDX lines in vitro (figure 1A). In a 10-day antigen-independent in vitro assay, cytoTIL15 persisted at greater frequencies than conventional TILs in the absence of IL-2 (figure 1B; *p30 days following adoptive cell transfer (figure 1C). Importantly, cytoTIL15 achieved significant tumor control in a human PDX model (figure 1D), which correlated with increased TIL accumulation in secondary lymphoid organs.Abstract 166 Figure 1cytoTIL15 demonstrate superior persistence. cytoTIL15 is an engineered TIL product expressing regulatable mbIL15. (A) cytoTIL15 demonstrate enhanced in vitro cytotoxicity after co-culture with melanoma tumor lines (representative data from 3 TIL donors). (B) cytoTIL15 have improved persistence in antigen- and IL2- independent culture conditions in vitro compared to conventional TILs cultured in the absence of IL-2 as well as (C) in vivo compared to conventional TILs supplemented with IL-2, when engrafted into NSG mice (in vitro: representative data from 1 TIL donor, performed in >3 replicate donors, in vivo: n=5/group, representative of 1 TIL donor, performed in >3 replicate donors). (D) cytoTIL15 (with 200mg/kg ACZ PO QD) demonstrate enhanced anti-tumor efficacy in a xenograft melanoma model as compared to conventional TILs (with 50000 IU IL-2 q8h BID, IP for 5 days) (n=8/group, representative of 1 TIL donor, performed in >2 replicate donors; ACT = adoptive cell transfer).ConclusionsTaken together, the superior persistence and potency of cytoTIL15 in the complete absence of IL-2 highlights the clinical potential of cytoTIL15 as a novel TIL product with enhanced safety and efficacy for patients with melanomas, and other solid tumors.AcknowledgementsThe authors wish to acknowledge the Cooperative Human Tissue Network for the their supply of human tumor tissue, and the MD Anderson Cancer Center for technical support; schematic created with BioRender.com.ReferencesChandran SS, Somerville RPT, Yang JC, Sherry RM, Klebanoff CA, Goff SL, Wunderlich JR, Danforth DN, Zlott D, Paria BC, Sabesan AC, Srivastava AK, Xi L, Pham TH, Raffeld M, White DE, Toomey MA, Rosenberg SA, Kammula US. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study. Lancet Oncol 2017 Jun;18(6):792–802. doi: 10.1016/S1470-2045(17)30251-6. Epub 2017 Apr 7. PMID: 28395880; PMCID: PMC5490083.Yang JC. Toxicities associated with adoptive T-cell transfer for Cancer. Cancer J 2015;21:506–9.Schwartz RN, Stover L, Dutcher JP. Managing toxicities of high-dose interleukin-2. Oncology (Williston Park) 2002 Nov;16(11 Suppl 13):11–20. PMID: 12469935.

Objective: During shoulder arthroplasty, surgeons must select the optimal implant for each patient. The metaphyseal bone properties affect this decision; however, the typical resection “thumb test” lacks objectivity. This investigation's purposes were to determine the correlation strength between the indentation depth of a handheld mechanism and the density, compressive strength, and modulus of a bone surrogate; as well as to assess how changing the indenter tip shape and impact energy may affect the correlation strengths. Methods: A spring-loaded indenter was developed. Four tip shapes (needle, tapered, flat, and radiused cylinders) and four spring energies (0.13 J–0.76J) were assessed by indenting five cellular foam bone surrogates of varying density, every five times. After each indentation, the indentation depth was measured with a separate probe and correlated with manufacturer specifications of the apparent density, compressive strength, and modulus. Results: indentation depth plateaued as the bone surrogate's material properties increased, particularly for indentation tips with larger footprints and the 0.13 J spring. All tip shapes produced strong (R2≥0.7) power-law relationships between the indentation depth metric and the bone surrogate's material properties (density: 0.70 ≤ R2 ≤ 0.95, strength: 0.75 ≤ R2 ≤ 0.97, modulus: 0.70 ≤ R2 ≤ 0.93); though the use of the needle tip yielded the widest indentation depth scale. Interpretation: these strong correlations suggest that a handheld indenter may provide objective intra-operative evidence of cancellous material properties. Further investigations are warranted to study indenter tip shape and spring energy in human tissue; though the needle tip with spring energy between 0.30 J and 0.76 J seems the most promising.

Gold nanoparticles are a potential method for enhancing radiation therapy, causing extra damage to tumors when irradiated through the Auger effect. One of the major obstacles to using gold nanoparticles in human trials is the relatively large amount of gold required. This paper details an experiment where a relatively small amount of gold (200 μg) was used to significantly reduce tumor volume in mice, as well as the results of an inter-tissue biodistribution experiment. Using a longitudinal analysis, tumor size as a function of time was found to be significantly reduced when mice were given 200 μg of gold nanoparticles and 20 Gray of radiation, compared to radiation alone. 200 μg in a 20-gram mouse would be mass equivalent to 750 mg of gold in a 75 kg person. Biodistribution measurements demonstrated that gold nanoparticles stayed in the tumor for at least one week after injection when targeted to tumors using pH-Low Insertion Peptide and intratumoral injections. These results show gold nanoparticles to be effective at one of the smallest amounts of gold ever attempted in a mouse, and showed that tumor targeting has the potential to keep gold nanoparticles available in tumors long enough to be beneficial to fractionated radiation treatments (a key component of radiation therapy in the clinic).

Photodynamic therapy (PDT), a treatment that uses a photosensitizer, molecular oxygen, and light to kill target cells, is a promising cancer treatment method. However, a limitation of PDT is its dependence on light that is not highly penetrating, precluding the treatment of tumors located deep in the body. Copper-cysteamine nanoparticles are a new type of photosensitizer that can generate cytotoxic singlet oxygen molecules upon activation by X-rays. In this paper, we report on the use of copper-cysteamine nanoparticles, designed to be targeted to tumors, for X-ray–induced PDT. In an in vivo study, results show a statistically significant reduction in tumor size under X-ray activation of pH-low insertion peptide–conjugated, copper-cysteamine nanoparticles in mouse tumors. This work confirms the effectiveness of copper-cysteamine nanoparticles as a photosensitizer when activated by radiation and suggests that these Cu-Cy nanoparticles may be good candidates for PDT in deeply seated tumors when combined with X-rays and conjugated to a tumor-targeting molecule.

Background Previous studies indicate that youth with posttraumatic stress disorder (PTSD) have abnormal activation in brain regions important for emotion processing. It is unknown whether symptom improvement is accompanied by normative changes in these regions. This study identified neural changes associated with symptom improvement with the long-term goal of identifying malleable targets for interventions. Methods A total of 80 functional magnetic resonance imaging (fMRI) scans were collected, including 20 adolescents with PTSD (ages 9–17) and 20 age- and sex-matched healthy control subjects, each scanned before and after a 5-month period. Trauma-focused cognitive behavioral therapy was provided to the PTSD group to ensure improvement in symptoms. Whole brain voxel-wise activation and region of interest analyses of facial expression task data were conducted to identify abnormalities in the PTSD group versus HC at baseline (BL), and neural changes correlated with symptom improvement from BL to EOS of study (EOS). Results At BL, the PTSD group had abnormally elevated activation in the cingulate cortex, hippocampus, amygdala, and medial frontal cortex compared to HC. From BL to EOS, PTSD symptoms improved an average of 39%. Longitudinal improvement in symptoms of PTSD was associated with decreasing activation in posterior cingulate, mid-cingulate, and hippocampus, while improvement in dissociative symptoms was correlated with decreasing activation in the amygdala. Conclusions Abnormalities in emotion-processing brain networks in youth with PTSD normalize when symptoms improve, demonstrating neural plasticity of these regions in young patients and the importance of early intervention.

PIM447, a novel pan-PIM inhibitor, has shown preclinical activity in multiple myeloma (MM). In the multicenter, open-label, first-in-human study, patients with relapsed and/or refractory MM were enrolled to determine the maximum-tolerated dose (MTD) or recommended dose (RD), safety, pharmacokinetics, and preliminary anti-myeloma activity of PIM447. PIM447 was administered in escalating oral doses of 70-700 mg once daily (q.d.) for 28-day continuous cycles. Seventy-nine patients with a median of four prior therapies were enrolled. Seventy-seven patients (97.5%) had an adverse event (AE) suspected as treatment related, with treatment-related grade 3/4 AEs being mostly hematologic. Eleven dose-limiting toxicities occurred, and an MTD of 500 mg q.d. and an RD of 300 mg q.d. were established. The main reason for discontinuation was disease progression in 54 patients (68.4%). In the entire study population, a disease control rate of 72.2%, a clinical benefit rate of 25.3%, and an overall response rate of 8.9% were observed per modified International Myeloma Working Group criteria. Median progression-free survival at the RD was 10.9 months. PIM447 was well tolerated and demonstrated single-agent antitumor activity in relapsed/refractory MM patients, providing proof of principle for Pim (Proviral Insertions of Moloney Murine leukemia virus) kinase inhibition as a novel therapeutic approach in MM.

Chronic obstructive pulmonary disease (COPD) yields a high rate of failures such as hospital readmission and death in the United States, Canada and worldwide. COPD failure imposes a significant social and economic burden on society, and predicting such failure is crucial to early intervention and decision-making, making this a very important research issue. Current analysis methods address all risk factors in medical records indiscriminately and therefore generally suffer from ineffectiveness in real applications, mainly because many of these factors relate weakly to prediction. Numerous studies have been done on selecting factors for survival analysis, but their inherent shortcomings render these methods inapplicable for failure prediction in the context of unknown and intricate correlation patterns among risk factors. These difficulties have prompted us to design a new Cox-based learning machine that embeds the feature weighting technique into failure prediction. In order to improve predictive accuracy, we propose two weighting criteria to maximize the area under the ROC curve (AUC) and the concordance index (C-index), respectively. At the same time, we perform a Dirichlet-based regularization on weights, making differences between factor relevance clearly visible while maintaining the model's high predictive ability. The experimental results on real-life COPD data collected from patients hospitalized at the Centre Hospitalier Universitaire de Sherbrooke (CHUS) demonstrate the effectiveness of our learning machine and its great promise in clinical applications.

A cell-based assay employing Madin–Darby canine kidney cells stably expressing human neonatal Fc receptor (FcRn) heavy chain and β2-microglobulin genes was developed to measure transcytosis...

L’objectif de cet article est d’estimer la prévalence et le taux d’incidence du trouble du spectre de l’autisme (TSA) diagnostiqué chez les enfants et les adolescents à partir de données médico-administratives jumelées de quatre provinces canadiennes. Un objectif secondaire est de comparer les résultats obtenus afin d’établir si les fichiers administratifs peuvent servir de système d’information pour la surveillance du TSA au Canada.Les estimations ont été produites à partir des données provenant des provinces du Manitoba, de l’Ontario, du Québec et de la Nouvelle-Écosse. La population à l’étude est composée de tous les résidents âgés de 24 ans et moins admissibles au régime d’assurance maladie en vertu de la loi provinciale entre 1999 à 2012. Pour être considéré comme ayant un TSA, l’individu devra avoir eu au moins une visite médicale ou une hospitalisation avec un diagnostic principal de TSA (codes 299 de la CIM-9 ou leurs équivalents CIM-10-CA). La prévalence annuelle et le taux d’incidence sont mesurés pour la période allant de 1999-2000 à 2011-2012, et présentés selon le sexe et par groupes d’âge.La prévalence du TSA entre 1999 et 2012 a connu une forte progression dans toutes les provinces et pour tous les groupes d’âge. Le taux d’incidence a suivi la même tendance d’accroissement dans le temps. La prévalence et le taux d’incidence du TSA n’ont pas augmenté de façon similaire dans toutes les provinces du Canada. L’Ontario semble afficher les plus fortes proportions, suivi de la Nouvelle-Écosse.Nos résultats permettent non seulement de dresser un portrait du TSA dans quatre provinces canadiennes, mais soulèvent aussi de nombreuses pistes pour de futures recherches. Cette étude discute également de l’utilité, de la fiabilité et du potentiel des fichiers médico-administratifs en matière de recherche., Objective The prevalence of diagnosed autism spectrum disorders (ASD) has risen steadily over time. There is therefore a need for the monitoring of treated ASD for timely policy making. The objective of this study is to report and compare over a 10-year period the prevalence and incidence rate of diagnosed ASD in four Canadian provinces.Methods This study utilized data from the provinces of Manitoba, Ontario, Quebec and Nova Scotia with access to linked administrative database sources used in the Canadian Chronic Diseases Surveillance Systems to assess the prevalence and incidence rate of a physician diagnosis of ASD. Estimates were produced using health datasets for outpatient and inpatient care (Med-Echo in Quebec, the Canadian Institute of Health Information Discharge Abstract Database in the three other provinces, plus the Ontario Mental Health Reporting System). Dates of service, diagnosis, and physician specialty were extracted. The target population consisted of all residents aged 24 and under eligible for healthcare coverage under provincial law between 1999 and 2012. To be considered as having ASD, an individual had to have at least one physician claim or hospital discharge abstract indicating one of the following: ICD-9 codes 299.0 to 299.9 or their ICD-10 equivalents, F84.0 to F84.9. The estimates were presented in yearly brackets between 1999-2000 and 2011-2012 by sex and age groups. The main analyses focused on those aged 17 years or less, with the 18 to 24 years group added to show the subsequent progression of the disorder.Results Our findings show that the annual prevalence of ASD rose steadily between 1999 and 2012 in all provinces and for all age groups although this increase varied across Canadian provinces. There were higher annual prevalence estimates in Ontario (4.8 per 1,000) and Nova Scotia (4.2 per 1,000) compared to Quebec (3.0 per 1,000) and Manitoba (2.5 per 1,000), among persons aged 17 years and younger in 2011. As compared to 1999, Quebec and Ontario reported a fivefold and fourfold increase in 2010-2012, the highest among provinces. The prevalence was four times higher in boys than in girls. By age group, the highest prevalence was observed in those aged between 1 to 4 and 5 to 9 years depending on the province. ASD was generally diagnosed before age 10. Incident cases were more frequently diagnosed by pediatricians followed by either psychiatrists or general practitioners depending on the province.Conclusion Our research confirms that ASD has risen steadily in terms of prevalence and incidence rate and that it varies considerably across provinces. It also demonstrates that health administrative databases can be used as registers for ASD. Information derived from these databases could support and monitor development of improved coordination and shared care to meet the continuous and changing needs of patients and families over time. Implication for future research include exploring the etiology of ASD in more recent cohorts as well as investigating the association between variations in health service availability and the prevalence of ASD.

Purpose The impacts of high blood eosinophil count (HBEC) at admission for COPD exacerbation on posthospitalization outcomes are still unclear. Previous studies have focused on its associations with first readmission rates; yet, its impacts on longitudinal outcomes such as subsequent readmissions still have to be explored. The main objective of this study is to investigate outcomes associated with HBEC following a first hospitalization for COPD exacerbation. Patients and methods This is an observational cohort study design. We retrospectively analyzed data of patients with a first hospitalization within 5 years for COPD exacerbation between April 2006 and March 2013. Patients were stratified into the HBEC group if the blood eosinophil count at admission was ≥200 cells/µL and/or ≥2% of the total white blood cells. With information on exact dates of subsequent hospitalizations and death, we modeled readmissions and death as states in a multi-state Markov model and estimated transition probabilities to the next states. Sensitivity analyses were performed by varying thresholds for the definition of HBEC (≥300 cells/µL and/or ≥3%). Results A total of 479 patients were included, of which 173 had HBEC. The transition probabilities for a first readmission was 74% (95% CI, 66%-83%) for patients with HBEC vs 70% (95% CI, 63%-77%) for patients with normal blood eosinophil count (NBEC). The transition probabilities for a second readmission were 91% (95% CI, 84%-100%) for HBEC patients in contrast with 83% (95% CI, 74%-92%) for NBEC patients. Meanwhile, transition probability for death was lower in patients with HBEC. The differences enlarged in sensitivity analyses with higher cutoff. Conclusion Greater blood eosinophil cell counts during a first hospitalization for COPD predict increased susceptibility to up to two readmissions. These patients may however have a lower risk of death.

Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer's disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence of target engagement in vivo, with increases in systemic tau concentrations observed in tau transgenic mice, nonhuman primates, and humans. Higher concentrations of systemic tau were observed after dosing in AD participants compared to healthy control participants. No concerning safety signals were observed in the phase 1 clinical trial at single doses up to 16,800 mg and multiple doses totaling 33,600 mg in a month.

Network architecture is a brain-organizational motif present across spatial scales from cell assemblies to distributed systems. Structural pathology in some neurodegenerative disorders selectively afflicts a subset of functional networks, motivating the network degeneration hypothesis (NDH). Recent evidence suggests that structural pathology recapitulating physiology may be a general property of neuropsychiatric disorders. To test this possibility, we compared functional and structural network meta-analyses drawing upon the BrainMap database. The functional meta-analysis included results from >7,000 experiments of subjects performing >100 task paradigms; the structural meta-analysis included >2,000 experiments of patients with >40 brain disorders. Structure-function network concordance was high: 68% of networks matched (pFWE, Peter Fox & Thomas Vanasse et al. compare atrophy patterns in 40+ brain disorders with healthy task-activation networks across 100+ behavioral domains. Their analyses demonstrate strong spatial correspondence between disease-related structural coalterations and functional networks, an observation that greatly extends the scope of the network-degeneration hypothesis. Further, the metabolic cost of network hubs (nodal stress) is implicated as a common mechanism across a wide range of brain disorders.

An amendment to this paper has been published and can be accessed via the original article.

Purpose: The JAK1/2 inhibitor ruxolitinib has demonstrated significant benefits for patients with myeloproliferative neoplasms (MPN). However, patients often lose response to ruxolitinib or suffer disease progression despite therapy with ruxolitinib. These observations have prompted efforts to devise treatment strategies to improve therapeutic efficacy in combination with ruxolitinib therapy. Activation of JAK–STAT signaling results in dysregulation of key downstream pathways, notably increased expression of cell-cycle mediators including CDC25A and the PIM kinases. Experimental Design: Given the involvement of cell-cycle mediators in MPNs, we sought to examine the efficacy of therapy combining ruxolitinib with a CDK4/6 inhibitor (LEE011) and a PIM kinase inhibitor (PIM447). We utilized JAK2-mutant cell lines, murine models, and primary MPN patient samples for these studies. Results: Exposure of JAK2-mutant cell lines to the triple combination of ruxolitinib, LEE011, and PIM447 resulted in expected on-target pharmacodynamic effects, as well as increased apoptosis and a decrease in the proportion of cells in S-phase, compared with ruxolitinib. As compared with ruxolitinib monotherapy, combination therapy led to reductions in spleen and liver size, reduction of bone marrow reticulin fibrosis, improved overall survival, and elimination of disease-initiating capacity of treated bone marrow, in murine models of MPN. Finally, the triple combination reduced colony formation capacity of primary MPN patient samples to a greater extent than ruxolitinib. Conclusions: The triple combination of ruxolitinib, LEE011, and PIM447 represents a promising therapeutic strategy with the potential to increase therapeutic responses in patients with MPN.

Ferrari, Andrea/0000-0002-4724-0517; Pellegrini, Cristina/0000-0003-2168-8097; Migliano, Emilia/0000-0002-5316-8937; Maisonneuve, Patrick/0000-0002-5309-4704; Guida, Stefania/0000-0002-8221-6694; Pastorino, Lorenza/0000-0002-2575-8331; CARRERA, CRISTINA/0000-0003-1608-8820; Paillerets, Brigitte Bressac-de/0000-0003-0245-8608; Sekulovic, Lidija Kandolf/0000-0002-5221-5068; Caini, Saverio/0000-0002-2262-1102; Potrony, Miriam/0000-0003-2766-0765; Pizzichetta, Maria Antonietta/0000-0002-4201-8490; Little, Julian/0000-0001-5026-5531; Nagore, Eduardo/0000-0003-3433-8707; Polsky, David/0000-0001-9554-5289; Demenais, Florence/0000-0001-8361-0936; Nazzaro, Gianluca/0000-0001-8534-6497; gandini, sara/0000-0002-1348-4548; Cornelius, Lynn A/0000-0002-6329-2819; Palmieri, Giuseppe/0000-0002-4350-2276; Cotignola, Javier/0000-0003-4473-9854; Ghiorzo, Paola/0000-0002-3651-8173; Autier, Philippe/0000-0003-1538-5321; Bishop, Tim/0000-0002-8752-8785; Sera, Francesco/0000-0002-8890-6848; Newton-Bishop, Julia/0000-0001-9147-6802; Litchfield, Melisa/0000-0003-0002-7724, WOS: 000464254100018, PubMed: 30872112, Background Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. Methods in this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. Findings We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1.54, 95% CI 1.02-2.33), including when analysis was restricted to patients aged 18 years or younger (1.80, 1.06-3.07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1.60, 95% CI 1.05-2.44; p=0.04) and Asp294His (2.15, 1.05-4.40; p=0.04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. Interpretation Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies. Copyright (c) 2019 Elsevier Ltd. All rights reserved., [AIRC-MFAG-11831]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086] Funding Source: NIH RePORTER, SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.

To review the available evidence supporting the validity of algorithms to identify asthma patients in healthcare administrative databases. A systematic literature search was conducted on multiple d...

Background Early identification of patients with chronic conditions and complex health needs in emergency departments (ED) would enable the provision of services better suited to their needs, such as case management. A case-finding tool would ultimately support ED teams to this end and could reduce the cost of services due to avoidable ED visits and hospitalizations. The aim of this study was to develop and validate a short self-administered case-finding tool in EDs to identify patients with chronic conditions and complex health needs in an adult population. Methods This prospective development and initial validation study of a case-finding tool was conducted in four EDs in the province of Quebec (Canada). Adult patients with chronic conditions were approached at their third or more visit to the ED within 12 months to complete a self-administered questionnaire, which included socio-demographics, a comorbidity index, the reference standard INTERMED self-assessment, and 12 questions to develop the case-finding tool. Significant variables in bivariate analysis were included in a multivariate logistic regression analysis and a backward elimination procedure was applied. A receiver operating characteristic (ROC) curve was developed to identify the most appropriate threshold score to identify patients with complex health needs. Results Two hundred ninety patients participated in the study. The multivariate analysis yielded a six-question tool, COmplex NEeds Case-finding Tool – 6 (CONECT-6), which evaluates the following variables: low perceived health; limitations due to pain; unmet needs; high self-perceived complexity; low income; and poor social support. With a threshold of two or more positive answers, the sensitivity was 90% and specificity 66%. The positive and negative predictive values were 49 and 95% respectively. Conclusions The case-finding process is the essential characteristic of case management effectiveness. This study presents the first case-finding tool to identify adult patients with chronic conditions and complex health needs in ED.

The Copper-cysteamine (Cu-Cy) nanoparticle is a novel sensitizer with a potential to increase the effectiveness of radiation therapy for cancer treatment. In this work, the effect of nanoparticle size and the energy of X-rays on the effectiveness of radiation therapy are investigated. The effect of the particle size on their performance is very complicated. The nanoparticles with an average size of 300 nm have the most intense photoluminescence, the nanoparticles with the average size of 100 nm have the most reactive oxygen species production upon X-ray irradiation, while the nanoparticles with the average size of 40 nm have the best outcome in the tumor suppression in mice upon X-ray irradiation. For energy, 90 kVp radiation resulted in smaller tumor sizes than 250 kVp or 350 kVp radiation energies. Overall, knowledge of the effect of nanoparticle size and radiation energy on radiation therapy outcomes could be useful for future applications of Cu-Cy nanoparticles.

BackgroundRecent studies suggest that hydroxychloroquine (HCQ) could be effective against COVID-19. It is reasonable to expect that if HCQ can prevent or reduce the adverse effects of influenza, it may also reduce the effects of COVID-19 in humans. The objective of this study was to test whether HCQ can prevent or reduce the risk and severity of influenza.MethodsThis is an observational cohort study using medico-administrative data from Québec. Patients included had at least one emergency department (ED) visit in 2012 or 2013, with a prior diagnosis of chronic conditions, and were admissible to the public drug insurance plan. Two sub-cohorts were considered depending on reasons for ED visit: other than influenza or pneumonia (primary prevention) and influenza or pneumonia (secondary prevention).ResultsIn the primary prevention analysis (n=417,353), patients taking HCQ (n=3,659) had an increased risk of hospitalization for pneumonia in the following year compared to those who did not (5.2% vs. 2.9%; adjusted OR=1.25, p=0.0079). In the secondary prevention analysis (n=27,152), patients taking HCQ (n=392), compared to those who did not had a modest and non-significant increased risk of hospitalization for pneumonia after 30 days (25.8% vs. 22.6%; adjusted OR=1.14, p=0.3177).InterpretationBased on the assumption that HCQ has similar effects on the COVID-19 as those observed on influenza, we can infer that it will not have positive effects on COVID-19. We should therefore act cautiously before initiating prospective interventional studies on the use of HCQ to reduce adverse effects of COVID-19.

Since the introduction of the combined antiretroviral therapy, HIV-1 infection has become a manageable chronic disease in which patients display a life expectancy almost identical to the general population. Nevertheless, various age-related pathologies such as neurocognitive disorders have emerged as serious complications. A "shock and kill" strategy using latency-reversing agents (LRA) to reactivate HIV-1 has been proposed to eliminate the viral reservoir in such chronically infected patients. However, the impact of LRA on the central nervous system remains elusive. Given that an increased amyloid beta (Aβ) deposition is a feature of HIV-1-infected brains, we investigated the consequences of HIV-1 infection and treatment with two LRA (bryostatin-1 and JQ1) on the capacity of human astrocytes to engulf and clear Aβ. We show here that HIV-1-infected astrocytes accumulate a very high amount of Aβ compared to uninfected cells, but the engulfed peptide in degraded very slowly. The LRA bryostatin-1 induces a reduction in Aβ endocytosis, whereas JQ1 treatment results in a very slow degradation of the ingested material associated with a reduced expression of the endopeptidase neprilysin. An exposure to JQ1 also induces a sustained release of Aβ-loaded microvesicles. Thus, both HIV-1 infection and treatment with some LRA could contribute to the reported Aβ accumulation in the brain of HIV-1-infected persons.

HIV-1 infection in the central nervous system (CNS) causes the release of neurotoxic products from infected cells which trigger extensive neuronal loss. Clinically, this results in HIV-1-associated neurocognitive disorders (HAND). However, the effects on neuroprotective factors in the brain remain poorly understood and understudied in this situation. HAND is a multifactorial process involving several players, and the complex cellular mechanisms have not been fully elucidated yet. In this study, we reported that HIV-1 infection of astrocytes limits their potential to express the protective chemokine fractalkine in response to an inflammatory environment. We next confirmed that this effect was not due to a default in its shedding from the cell surface. We then investigated the biological mechanism responsible for this reduced fractalkine expression and found that HIV-1 infection specifically blocks the interaction of transcription factor NF-κB on its promoter with no effect on other cytokines. Moreover, we demonstrated that fractalkine production in astrocytes is regulated in response to immune factors secreted by infected/activated microglia and macrophages. In contrast, we observed that conditioned media from these infected cells also trigger neuronal apoptosis. At last, we demonstrated a strong neuroprotective action of fractalkine on human neurons by reducing neuronal damages. Taken together, our results indicate new relevant interactions between HIV-1 and fractalkine signaling in the CNS. This study provides new information to broaden the understanding of HAND and possibly foresee new therapeutic strategies. Considering its neuro-protective functions, reducing its production from astrocytes could have important outcomes in chronic neuroinflammation and in HIV-1 neuropathogenesis.

CACNA1A deletions cause epilepsy, ataxia, and a range of neurocognitive deficits, including inattention, impulsivity, intellectual deficiency and autism. To investigate the underlying mechanisms, we generated mice carrying a targeted Cacna1a deletion restricted to parvalbumin-expressing (PV) neurons (PVCre;Cacna1ac/+) or to cortical pyramidal cells (PC) (Emx1Cre;Cacna1ac/+). GABA release from PV-expressing GABAergic interneurons (PV-INs) is reduced in PVCre;Cacna1ac/+ mutants, resulting in impulsivity, cognitive rigidity and inattention. By contrast, the deletion of Cacna1a in PCs does not impact cortical excitability or behaviour in Emx1Cre;Cacna1ac/+ mutants. A targeted Cacna1a deletion in the orbitofrontal cortex (OFC) results in reversal learning deficits while a medial prefrontal cortex (mPFC) deletion impairs selective attention. These deficits can be rescued by the selective chemogenetic activation of cortical PV-INs in the OFC or mPFC of PVCre;Cacna1ac/+ mutants. Thus, Cacna1a haploinsufficiency disrupts perisomatic inhibition in frontal cortical circuits, leading to a range of potentially reversible neurocognitive deficits.

Background Frequent emergency department users are patients cumulating at least four visits per year. Few studies have focused on persistent frequent users, who maintain their frequent user status for multiple consecutive years. This study targets an adult population with chronic conditions, and its aims are: 1) to estimate the prevalence of persistent frequent ED use; 2) to identify factors associated with persistent frequent ED use (frequent use for three consecutive years) and compare their importance with those associated with occasional frequent ED use (frequent use during the year following the index date); and 3) to compare characteristics of “persistent frequent users” to “occasional frequent users” and to “users other than persistent frequent users”. Methods This is a retrospective cohort study using Quebec administrative databases. All adult patients who visited the emergency department in 2012, diagnosed with chronic conditions, and living in non-remote areas were included. Patients who died in the three years following their index date were excluded. The main outcome was persistent frequent use (≥4 visits per year during three consecutive years). Potential predictors included sociodemographic characteristics, physical and mental comorbidities, and prior healthcare utilization. Odds ratios were computed using multivariable logistic regression. Results Out of 297,182 patients who visited ED at least once in 2012, 3,357 (1.10%) were persistent frequent users. Their main characteristics included poor socioeconomic status, mental and physical comorbidity, and substance abuse. Those characteristics were also present for occasional frequent users, although with higher percentages for the persistent user group. The number of previous visits to the emergency department was the most important factor in the regression model. The occasional frequent users’ attrition rate was higher between the first and second year of follow-up than between the second and third year. Conclusions Persistent frequent users are a subpopulation of frequent users with whom they share characteristics, such as physical and mental comorbidities, though the former are poorer and younger. More research is needed in order to better understand what factors can contribute to persistent frequent use.

OBJECTIVE The Adverse Childhood Experiences (ACE) study is one of the largest studies ever conducted that has examined the relationship of childhood abuse, neglect, and family dysfunction to subsequent health and well-being later in life. Questions from the ACE study evolved into the ACE Study Questionnaire, a measure used for assessing individuals' self-reported experiences of childhood adversity. The ACE measure is widely available and the Centers for Disease Control and Prevention (CDC) recommends it as a tool for assessing one's lifetime risk of mental and physical health problems and other negative social problems. Despite the extensive dissemination of the ACE Study Questionnaire, to date there has been only one article published about its psychometric properties. The current study examined the test-retest reliability of the ACE-SQ in a sample of nonservice seeking college athletes (N = 141). METHOD Time 1 and Time 2 of data collection were approximately one year apart. Pearson's correlations were computed to observe a level of agreement between Time 1 and Time 2 responses. RESULTS The overall measure yielded a modest test-retest coefficient, r = .71, p < .001. Household dysfunction items demonstrated a higher stability coefficient, r = .65, p < .001 than did abuse and neglect items, r = .52, p < .001. CONCLUSIONS These findings suggest that further research is needed on the psychometric properties of this questionnaire in different age populations. (PsycINFO Database Record

Background: Data on treatment expectation and perception towards vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs), and low molecular weight heparins (LMWH) for the management of venous thromboembolism (VTE) are sparse.Methods: Prospective observational study including subjects admitted to the hospital with a diagnosis of VTE and a prescription of VKA, DOAC, or a LMWH. Treatment expectations, convenience and satisfaction were assessed using the Perception of anticoagulant treatment questionnaire (PACT-Q) at baseline and at three months.Results: A total of 140 patients were included. Treatment expectations regarding ease of use and the ability to self-manage anticoagulation therapy were higher in patients on DOACs. However, overall treatment satisfaction scores were similar at three months between the groups.Conclusion: Patients with VTE who are prescribed an anticoagulant have different expectations at baseline, but appear to have similar treatment satisfaction regardless of the type of anticoagulant prescribed.

This cohort study compares the long-term outcomes associated with valve-sparing procedures vs transannular patches for correction of tetralogy of Fallot., Key Points Question Do valve-sparing (VS) operations have better long-term outcomes than transannular patches (TAP) for correction of tetralogy of Fallot (TOF) when stratifying for residual lesions after surgical treatment? Findings In this cohort study of 528 patients with repaired TOF in the province of Quebec, Canada, from 1980 to 2015, individuals who underwent a VS procedure had statistically significantly increased 30-year survival compared with individuals who underwent TAP. Moreover, individuals who underwent a VS procedure had statistically significantly fewer reinterventions, even in the presence of moderate residual pulmonary stenosis. Meaning These findings suggest that it is beneficial to perform a VS procedure for correction of TOF, even in the presence of moderate residual stenosis, compared with TAP repair., Importance The choice of the right surgical technique for correction of tetralogy of Fallot (TOF) is contentious for patients with a moderate to severe right outflow tract obstruction. The use of a transannular patch (TAP) exposes patients to chronic pulmonary regurgitation, while valve-sparing (VS) procedures may incompletely relieve pulmonary obstruction. Objective To compare 30-year outcomes of TOF repair after a VS procedure vs TAP. Design, Setting, and Participants This retrospective population-based cohort study was conducted among all patients with TOF born in the province of Quebec, Canada, from 1980 to 2015 who underwent complete surgical repair. Patients who received a TAP or VS procedure were matched using a propensity score based on preoperative factors in a 1:1 ratio. Data were analyzed from March 2020 through April 2021. Exposures The study groups were individuals who received TAP and those who received VS. The VS group was further stratified by the presence of residual pulmonary stenosis. Main Outcomes and Measures The primary outcome was all-cause mortality, with 30-year survival evaluated using Cox proportional-hazards models. Secondary outcomes included the cumulative mean number of cardiovascular interventions, pulmonary valve replacements (PVRs), and cardiovascular hospitalizations were evaluated using marginal means/rates regressions. Results Among 683 patients with TOF (401 patients who underwent TAP [58.7%] and 282 patients who underwent a VS procedure [41.3%]), adequate propensity score matching was achieved for 528 patients (264 patients who underwent a VS procedure and 264 patients who underwent TAP). Among this study cohort, 307 individuals (58.1%) were men. The median (interquartile range [IQR]) follow-up was 16.0 (8.1-25.4) years, for a total of 8881 patient-years, including 63 individuals (11.9%) followed up for more than 30 years. Individuals who received a VS procedure had an increased 30-year survival of 99.1% compared with 90.4% for individuals who received TAP (hazard ratio [HR], 0.09 [95% CI, 0.02-0.41]; P = .002). Patients who underwent TAP had an increased 30-year cumulative mean number of cardiovascular interventions compared with patients who underwent a VS procedure without residual pulmonary stenosis (2.0 interventions [95% CI, 1.5-2.7 interventions] vs 0.7 interventions [95% CI, 0.5-1.1 interventions]; mean ratio [MR], 0.36 [95% CI, 0.25-0.50]; P

Objective: To estimate the prevalence, comorbidities, and service use of people with autism spectrum disorders (ASDs) based on data from Quebec Integrated Chronic Diseases Surveillance System (QICDSS). Methods: We included all residents up to age 24 eligible for health plan coverage who were in Quebec for at least 1 day from January 1, 1996, to March 31, 2015. To be considered as having an ASD, an individual had to have had at least 1 physician claim or hospital discharge abstract from 2000 to 2015 indicating one of the following ASD diagnosis codes: ICD-9 codes 299.0 to 299.9 or their ICD-10 equivalents. Results: The QICDSS shows that the prevalence of ASD has risen steadily over the past decade to approximately 1.2% ( n = 16,940) of children and youths aged 1 to 17 years in 2014 to 2015. The same prevalence was obtained using Ministry of Education data. Common medical comorbidities included congenital abnormalities of the nervous system, particularly in the first year of life. Psychiatric comorbidity was much more highly prevalent, especially common mental disorders like anxiety and attention-deficit/hyperactivity disorder. Children and youths with ASDs made on average 2.3 medical visits per year compared with 0.2 in the general population. Between 18 and 24 years old, the mental health needs of individuals with ASDs were met less by medical specialists and more by general practitioners. Conclusion: Information derived from this database could support and monitor development of better medical services coordination and shared care to meet the continuous and changing needs of patients and families over time.