Biological markers of brain network connectivity and pain sensitivity distinguish low coping from high coping Veterans with persistent post-traumatic headache.

Headache is the most common type of pain following mild traumatic brain injury. Roughly half of those with persistent post-traumatic headache (PPTH) also report neck pain which is associated with greater severity and functional impact of headache. This observational cohort study aimed to identify biological phenotypes to help inform mechanism-based approaches in the management of PPTH with and without concomitant neck pain. Thirty-three military Veterans (mean (SD) = 37±16 years, 29 males) with PPTH completed a clinical assessment, quantitative sensory testing, and magnetic resonance imaging of the brain and cervical spine. Multidimensional phenotyping was performed using a Random Forest analysis and Partitioning Around Medoids (PAM) clustering of input features from three biologic domains: 1) resting state functional connectivity (rsFC) of the periaqueductal gray (PAG), 2) quality and size of cervical muscles, and 3) mechanical pain sensitivity and central modulation of pain. Two subgroups were distinguished by biological features that included forehead pressure pain threshold and rsFC between the PAG and selected nodes within the default mode, salience, and sensorimotor networks. Compared to the High Pain Coping group, the Low Pain Coping group exhibited higher pain-related anxiety (p=0.009), higher pain catastrophizing (p=0.004), lower pain self-efficacy (p=0.010), and greater headache-related disability (p=0.012). Findings suggest that greater functional connectivity of pain modulation networks involving the PAG combined with impairments in craniofacial pain sensitivity, but not cervical muscle health, distinguish a clinically important subgroup of individuals with PPTH who are less able to cope with pain and more severely impacted by headache.

Individualized pretest risk estimates to guide treatment decisions in patients with clinical high risk for psychotic disorders.

INTRODUCTION: Clinical high risk for psychosis (CHR) states are associated with an increased risk of transition to psychosis. However, the predictive value of CHR screening interviews is dependent on pretest risk enrichment in referred patients. This poses a major obstacle to CHR outreach campaigns since they invariably lead to risk dilution through enhanced awareness. A potential compensatory strategy is to use estimates of individual pretest risk as a 'gatekeeper' for specialized assessment. We aimed to test a risk stratification model previously developed in London, UK (OASIS) and to train a new predictive model for the Swiss population. METHOD: The sample was composed of 513 individuals referred for CHR assessment from six Swiss early psychosis detection services. Sociodemographic variables available at referral were used as predictors whereas the outcome variable was transition to psychosis. RESULTS: Replication of the risk stratification model developed in OASIS resulted in poor performance (Harrel's c=0.51). Retraining resulted in moderate discrimination (Harrel's c=0.67) which significantly differentiated between different risk groups. The lowest risk group had a cumulative transition incidence of 6.4% (CI: 0-23.1%) over two years. CONCLUSION: Failure to replicate the OASIS risk stratification model might reflect differences in the public health care systems and referral structures between Switzerland and London. Retraining resulted in a model with adequate discrimination performance. The developed model in combination with CHR assessment result, might be useful for identifying individuals with high pretest risk, who might benefit most from specialized intervention.

Pathways to care in youth and young adults at clinical high risk for psychosis in Switzerland: Current situation and clinical implementation of the PsyYoung project.

AIM: We aim to give an insight into the current situation in Switzerland concerning the pathways to care of young people with clinical high risk of psychosis. In a second step we propose a procedure of optimizing pathways to care developed within the project PsyYoung. METHODS: A qualitative survey derived and adapted from Kotlicka-Antczak et al. (2020) was conducted in large early detection services of three Swiss cantons (Geneva, Basel-Stadt, Vaud) focusing on pathways to care. More specifically, using questionnaires delivered to the heads of participating services, information was collected on referral sources, on activities to implement outreach campaigns and on the use of a pre-screening tool. RESULTS: Main results on referral source indicated that sources were variable but seemed to come primarily from the medical sector and more so from the psychiatric sector. Very few referrals came from non-medical sectors. Outreach activities included the contact to other clinics as well as through brochures and posters. All services but one used the Prodromal Questionnaire - 16 as pre-screening tool. CONCLUSIONS: All in all, the results indicate a referral and care pathway system implemented mostly within the medical and particularly mental health sector. Accordingly, the PsyYoung project proposes a procedure for pathways to care which could help overcome the obstacle of referrals being restrained to a narrow field of mental health and to harmonize the referral process within services dedicated to the same aim of helping young people at high risk of developing a psychosis.

Identifying Clinical Phenotypes in People Who Are Hispanic/Latino With Chronic Low Back Pain: Use of Sensor-Based Measures of Posture and Movement, Pain, and Psychological Factors.

OBJECTIVE: The aim of this study was to identify clinical phenotypes using sensor-based measures of posture and movement, pain behavior, and psychological factors in Hispanic/Latino people with chronic low back pain (CLBP). METHODS: Baseline measures from an ongoing clinical trial were analyzed for 81 Hispanic/Latino people with CLBP. Low back posture and movement were measured using commercial sensors during in-person testing and 8 hours of ecological monitoring. Magnitude, frequency, and duration of lumbar movements, sitting and standing postures were measured. Movement-evoked pain was assessed during in-person movement testing. Psychological measures included the Pain Catastrophizing Scale and the Fear Avoidance Beliefs Questionnaire. Random forest analysis was conducted to generate 2 groups and identify important variables that distinguish groups. Group differences in demographics, pain, psychological, and posture and movement variables were examined using t-tests and chi-square analyses. RESULTS: Two subgroups of Hispanic/Latino people with CLBP were identified with minimal error (7.4% misclassification ["out-of-bag" error]). Ecological posture and movement measures best distinguished groups, although most movement-evoked pain and psychological measures did not. Group 1 had greater height and weight, lower movement frequency, more time in sitting, and less time in standing. Group 2 had a greater proportion of women than men, longer low back pain duration, higher movement frequency, more time in standing, and less time in sitting. CONCLUSION: Two distinct clinical phenotypes of Hispanic/Latino people with CLBP were identified. One group was distinguished by greater height and weight and more sedentary posture and movement behavior; the second group had more women, longer duration of low back pain, higher lumbar spine movement frequency, and longer duration of standing postures. IMPACT: Ecological measures of posture and movement are important for identifying 2 clinical phenotypes in Hispanic/Latino people with CLBP and may provide a basis for a more personalized plan of care. LAY SUMMARY: Wearable sensors were used to measure low back posture and movement in Hispanic/Latino people with chronic low back pain. These posture and movement measures helped to identify 2 different clinical subgroups that will give physical therapists more information to better personalize treatment for chronic low back pain in Hispanic/Latino patients.

Assessing Predictive Ability of Dynamic Time Warping Functional Connectivity for ASD Classification.

Functional connectivity MRI (fcMRI) is a technique used to study the functional connectedness of distinct regions of the brain by measuring the temporal correlation between their blood oxygen level-dependent (BOLD) signals. fcMRI is typically measured with the Pearson correlation (PC), which assumes that there is no lag between time series. Dynamic time warping (DTW) is an alternative measure of similarity between time series that is robust to such time lags. We used PC fcMRI data and DTW fcMRI data as predictors in machine learning models for classifying autism spectrum disorder (ASD). When combined with dimension reduction techniques, such as principal component analysis, functional connectivity estimated with DTW showed greater predictive ability than functional connectivity estimated with PC. Our results suggest that DTW fcMRI can be a suitable alternative measure that may be characterizing fcMRI in a different, but complementary, way to PC fcMRI that is worth continued investigation. In studying different variants of cross validation (CV), our results suggest that, when it is necessary to tune model hyperparameters and assess model performance at the same time, a K-fold CV nested within leave-one-out CV may be a competitive contender in terms of performance and computational speed, especially when sample size is not large.

Improving Pathways to Care for Patients at High Psychosis Risk in Switzerland: PsyYoung Study Protocol.

AIMS: Psychotic disorders are one of the main causes of chronic disability in young people. An at-risk mental state (ARMS) is represented by subclinical symptoms that precede the first episode of psychosis (FEP). The PsyYoung project aims to optimize the detection of an ARMS while reducing unnecessary psychiatric treatments. It investigates the effects of service changes on the referrals and outcomes of young people with ARMS or a FEP. METHODS: Six psychiatric outpatient clinics in three cantons (Basel-Stadt, Vaud, and Geneva) participated in the project. They passed through an implementation phase including service changes and the adaptation of a standardized stepped care model for diagnosis and assessment, in addition to measures for increasing the awareness, networking and training of local professionals. PRELIMINARY RESULTS: All participating cantons had entered the implementation phase. By March 2023, there were 619 referrals to participating sites. A total of 163 patients (37% FEP and 31% ARMS) and 15 close relatives had participated in individual longitudinal assessments, and 26 patients participated in qualitative interviews. CONCLUSION: This national collaborative project addresses the issue of early intervention for emerging psychoses, and creates spaces for fruitful reflections and collaboration in Switzerland. The ultimate aim of PsyYoung is to harmonize clinical practices in early intervention of psychosis on a national level.

Race-Specific Spirometry Equations Do Not Improve Models of Dyspnea and Quantitative Chest CT Phenotypes.

BACKGROUND: Race-specific spirometry reference equations are used globally to interpret lung function for clinical, research, and occupational purposes, but inclusion of race is under scrutiny. RESEARCH QUESTION: Does including self-identified race in spirometry reference equation formation improve the ability of predicted FEV1 values to explain quantitative chest CT abnormalities, dyspnea, or Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification? STUDY DESIGN AND METHODS: Using data from healthy adults who have never smoked in both the National Health and Nutrition Survey (2007-2012) and COPDGene study cohorts, race-neutral, race-free, and race-specific prediction equations were generated for FEV1. Using sensitivity/specificity, multivariable logistic regression, and random forest models, these equations were applied in a cross-sectional analysis to populations of individuals who currently smoke and individuals who formerly smoked to determine how they affected GOLD classification and the fit of models predicting quantitative chest CT phenotypes or dyspnea. RESULTS: Race-specific equations showed no advantage relative to race-neutral or race-free equations in models of quantitative chest CT phenotypes or dyspnea. Race-neutral reference equations reclassified up to 19% of Black participants into more severe GOLD classes, while race-neutral/race-free equations may improve model fit for dyspnea symptoms relative to race-specific equations. INTERPRETATION: Race-specific equations offered no advantage over race-neutral/race-free equations in three distinct explanatory models of dyspnea and chest CT scan abnormalities. Race-neutral/race-free reference equations may improve pulmonary disease diagnoses and treatment in populations highly vulnerable to lung disease.

Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion.

Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson's r = 0.794-0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4-9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient's tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.

Viral predation pressure on coral reefs.

BACKGROUND: Predation pressure and herbivory exert cascading effects on coral reef health and stability. However, the extent of these cascading effects can vary considerably across space and time. This variability is likely a result of the complex interactions between coral reefs' biotic and abiotic dimensions. A major biological component that has been poorly integrated into the reefs' trophic studies is the microbial community, despite its role in coral death and bleaching susceptibility. Viruses that infect bacteria can control microbial densities and may positively affect coral health by controlling microbialization. We hypothesize that viral predation of bacteria has analogous effects to the top-down pressure of macroorganisms on the trophic structure and reef health. RESULTS: Here, we investigated the relationships between live coral cover and viruses, bacteria, benthic algae, fish biomass, and water chemistry in 110 reefs spanning inhabited and uninhabited islands and atolls across the Pacific Ocean. Statistical learning showed that the abundance of turf algae, viruses, and bacteria, in that order, were the variables best predicting the variance in coral cover. While fish biomass was not a strong predictor of coral cover, the relationship between fish and corals became apparent when analyzed in the context of viral predation: high coral cover (> 50%) occurred on reefs with a combination of high predator fish biomass (sum of sharks and piscivores > 200 g m-2) and high virus-to-bacteria ratios (> 10), an indicator of viral predation pressure. However, these relationships were non-linear, with reefs at the higher and lower ends of the coral cover continuum displaying a narrow combination of abiotic and biotic variables, while reefs at intermediate coral cover showed a wider range of parameter combinations. CONCLUSIONS: The results presented here support the hypothesis that viral predation of bacteria is associated with high coral cover and, thus, coral health and stability. We propose that combined predation pressures from fishes and viruses control energy fluxes, inhibiting the detrimental accumulation of ecosystem energy in the microbial food web.

Cystic Fibrosis Screen Positive, Inconclusive Diagnosis Genotypes in People with Cystic Fibrosis from the U.S. Patient Registry.

Rationale: Variants within the cystic fibrosis (CF) transmembrane conductance regulator gene, CFTR, that are of unknown significance or are categorized as non-CF causing may be observed in persons with CF. These variants are frequently detected in children with inconclusive newborn screen results and, in some cases, may be associated with a benign presentation in early childhood that progresses to a CF phenotype later in life. Objectives: To analyze data from individuals enrolled in the U.S. Cystic Fibrosis Foundation Patient Registry who have received a diagnosis of CF and who have variants found in a population of children with a CF screen positive, inconclusive diagnosis (CFSPID). Methods: This retrospective review analyzed registry data from individuals with a diagnosis of CF who also harbor one or more variants of interest because of their frequency within a CFSPID population and/or their interpretation as non-CF causing. Three groups were defined by the number of CF-causing variants identified (CF-Cx2, CF-Cx1, and CF-Cx0), which were reported in addition to the variant(s) of interest. Multivariate quantile regression modeling of the outcome for forced expiratory volume in 1 second (FEV1) generated a disease severity score for each person determined by six selected variables. Median scores were calculated for the three groups. Results: Patients carrying one CF-causing variant and at least one variant of interest (CF-Cx1) had higher median disease severity scores compared with those carrying CF-Cx2, suggesting a milder phenotype (P < 0.05). However, there was no statistically significant difference in scores between CF-Cx2 and the two other groups combined (CF-Cx1 and CF-Cx0; P = 0.33). Analysis revealed that the CF-Cx1 and CF-Cx0 groups, when compared with the CF-Cx2 group, had later median diagnoses (8 years vs. newborn; P < 0.0001), lower median sweat chloride (48 mmol/L vs. 94.5 mmol/L; P < 0.0001), lower prevalence of pancreatic insufficiency (29% vs. 78%; P < 0.0001), and higher median FEV1% predicted (95% vs. 87%; P = 0.0002). Conclusions: Individuals with CF who have specific variants frequently identified in children with CFSPID have a similar range of disease severity scores compared with those who have two CF-causing variants, but a milder phenotype overall. Variants that should be given careful scrutiny because of their high prevalence are G576A+R668C, T854T, R75Q, F1052V, R1070W, R31C, and L967S.

Characterization and Function of Cryopreserved Bone Marrow from Deceased Organ Donors: A Potential Viable Alternative Graft Source.

Despite the readily available graft sources for allogeneic hematopoietic cell transplantation (alloHCT), a significant unmet need remains in the timely provision of suitable unrelated donor grafts. This shortage is related to the rarity of certain HLA alleles in the donor pool, nonclearance of donors owing to infectious disease or general health status, and prolonged graft procurement and processing times. An alternative hematopoietic progenitor cell (HPC) graft source obtained from the vertebral bodies (VBs) of deceased organ donors could alleviate many of the obstacles associated with using grafts from healthy living donors or umbilical cord blood (UCB). Deceased organ donor-derived bone marrow (BM) can be preemptively screened, cryogenically banked for on-demand use, and made available in adequate cell doses for HCT. We have developed a good manufacturing practice (GMP)-compliant process to recover and cryogenically bank VB-derived HPCs from deceased organ donor (OD) BM. Here we present results from an analysis of HPCs from BM obtained from 250 deceased donors to identify any substantial difference in composition or quality compared with HPCs from BM aspirated from the iliac crests of healthy living donors. BM from deceased donor VBs was processed in a central GMP facility and packaged for cryopreservation in 5% DMSO/2.5% human serum albumin. BM aspirated from living donor iliac crests was obtained and used for comparison. A portion of each specimen was analyzed before and after cryopreservation by flow cytometry and colony-forming unit potential. Bone marrow chimerism potential was assessed in irradiated immunocompromised NSG mice. Analysis of variance with Bonferroni correction for multiple comparisons was used to determine how cryopreservation affects BM cells and to evaluate indicators of successful engraftment of BM cells into irradiated murine models. The t test (with 95% confidence intervals [CIs]) was used to compare cells from deceased donors and living donors. A final dataset of complete clinical and matched laboratory data from 226 cryopreserved samples was used in linear regressions to predict outcomes of BM HPC processing. When compared before and after cryopreservation, OD-derived BM HPCs were found to be stable, with CD34+ cells maintaining high viability and function after thawing. The yield from a single donor is sufficient for transplantation of an average of 1.6 patients (range, 1.2 to 7.5). CD34+ cells from OD-derived HPCs from BM productively engrafted sublethally irradiated immunocompromised mouse BM (>44% and >67% chimerism at 8 and 16 weeks, respectively). Flow cytometry and secondary transplantation confirmed that OD HPCs from BM is composed of long-term engrafting CD34+CD38-CD45RA-CD90+CD49f+ HSCs. Linear regression identified no meaningful predictive associations between selected donor-related characteristics and OD BM HPC quality or yield. Collectively, these data demonstrate that cryopreserved BM HPCs from deceased organ donors is potent and functionally equivalent to living donor BM HPCs and is a viable on-demand graft source for clinical HCT. Prospective clinical trials will soon commence in collaboration with the Center for International Blood and Marrow Research to assess the feasibility, safety, and efficacy of Ossium HPCs from BM (ClinicalTrials.gov identifier NCT05068401).

Pan-Arctic soil moisture control on tundra carbon sequestration and plant productivity.

Long-term atmospheric CO2 concentration records have suggested a reduction in the positive effect of warming on high-latitude carbon uptake since the 1990s. A variety of mechanisms have been proposed to explain the reduced net carbon sink of northern ecosystems with increased air temperature, including water stress on vegetation and increased respiration over recent decades. However, the lack of consistent long-term carbon flux and in situ soil moisture data has severely limited our ability to identify the mechanisms responsible for the recent reduced carbon sink strength. In this study, we used a record of nearly 100 site-years of eddy covariance data from 11 continuous permafrost tundra sites distributed across the circumpolar Arctic to test the temperature (expressed as growing degree days, GDD) responses of gross primary production (GPP), net ecosystem exchange (NEE), and ecosystem respiration (ER) at different periods of the summer (early, peak, and late summer) including dominant tundra vegetation classes (graminoids and mosses, and shrubs). We further tested GPP, NEE, and ER relationships with soil moisture and vapor pressure deficit to identify potential moisture limitations on plant productivity and net carbon exchange. Our results show a decrease in GPP with rising GDD during the peak summer (July) for both vegetation classes, and a significant relationship between the peak summer GPP and soil moisture after statistically controlling for GDD in a partial correlation analysis. These results suggest that tundra ecosystems might not benefit from increased temperature as much as suggested by several terrestrial biosphere models, if decreased soil moisture limits the peak summer plant productivity, reducing the ability of these ecosystems to sequester carbon during the summer.

Cannabis Use: A New Risk Behaviour Among Adults With Congenital Heart Disease.

Background: Cannabis use has increased in Canada and can be associated with adverse cardiovascular events. Given increased use and accessibility to cannabis, there is a need among clinicians to better understand cannabis use in adults with congenital heart disease. Methods: A cross-sectional survey (May to September 2018) was used to investigate cannabis use among 252 patients with adult congenital heart disease in a quaternary care centre. Results: Of the 252 patients, 53 (21%) reported using cannabis. The majority of cannabis users were men (62%), between the ages of 25 and 39 years (mean age = 32 ± 16 years), and more likely to use tobacco (n = 9, 17%; P = 0.001) and alcohol (n = 37, 60%; P = 0.001). Significant differences (P = 0.011) were found between the age of onset for tobacco use among cannabis users (mean age: 16 ± 8 years) and non-cannabis users (mean age: 20 ± 3 years). Users reported consuming cannabis for recreational purposes (n = 29, 55%), anxiety (n = 22, 42%), depression (n = 15, 28%), and pain management (n = 4, 8%). Conclusions: This study supports our clinical experience that a high proportion of patients with adult congenital heart disease use cannabis. Cannabis users represent a patient population who may demonstrate less optimal health behaviours, including tobacco and alcohol use. Assessment of cannabis use should be an integral part of risk behaviour and cardiovascular risk profile at each clinic visit. Given the current legalization of cannabis in Canada and the growing increase of cannabis use, educational support should be provided to patients and caregivers.

Contexte: La consommation de cannabis, en hausse au Canada, a été associée à des manifestations cardiovasculaires indésirables. Puisque l'usage et la disponibilité du cannabis ont augmenté, il est nécessaire pour les cliniciens de mieux comprendre cet usage chez les adultes qui présentent une cardiopathie congénitale. Méthodologie: Nous avons mené une enquête transversale (mai à septembre 2018) sur l'usage du cannabis auprès de 252 adultes atteints d'une cardiopathie congénitale dans un centre de soins quaternaires. Résultats: Cinquante-trois patients sur 252 (21 %) ont indiqué consommer du cannabis. Les utilisateurs de cannabis étaient en majorité des hommes (62 %), ils étaient âgés de 25 à 39 ans (âge moyen de 32 ans ± 16), et ils étaient plus susceptibles de consommer du tabac (n = 9; 17 %; p = 0,001) et de l'alcool (n = 37; 60 %; p = 0,001). Une différence significative a été notée entre l'âge au moment de commencer l'usage de tabac chez les utilisateurs de cannabis (âge moyen de 16 ± 8 ans) et chez les non-utilisateurs (âge moyen de 20 ± 3 ans). Les personnes consommaient du cannabis pour un usage récréatif (n = 29; 55 %), ou pour la prise en charge de l'anxiété (n = 22; 42 %), de la dépression (n = 15; 28 %) ou de la douleur (n = 4; 8 %). Conclusion: Notre étude corrobore notre expérience clinique, selon laquelle une proportion importante des adultes atteints d'une cardiopathie congénitale consomment du cannabis. Les patients qui font usage de cannabis constituent une population qui pourrait adopter des comportements moins favorables pour la santé, comme la consommation d'alcool et de produits de tabac. Une évaluation de l'usage de cannabis devrait faire partie intégrante du profil de comportements à risque et du risque cardiovasculaire réalisé à chacune des visites des patients. Étant donné la légalisation du cannabis au Canada et l'augmentation constante de son usage, un soutien éducatif devrait être offert aux patients et à leurs proches.

Crime and Building Rehabilitation or Demolition: A Dose-Response Analysis.

Thousands of buildings in Cleveland, Ohio were demolished or rehabilitated since the Great Recession in the 2000s. Recent evidence suggests removing vacant and decaying buildings reduces violent and firearm-involved crime. This study examines the dose-response relationship between demolitions, rehabilitations, and crime. We use Bayesian spatiotemporal models to estimate the association of interest for five types of crime outcomes: violent crimes, violent crimes involving a firearm, drug crimes, and crimes often associated with building vacancy. We estimate associations in quarterly time periods from 2012 through 2017 in 569 hexagons approximately the size of a neighborhood (2000 feet, approximately 610 m, in diameter), stratified by vacancy level. Across vacancy levels, the majority of our models do not identify statistically significant associations between demolition and rehabilitation dose and crime incidence. However, in some cases, we identify positive associations between demolition and crime. These associations generally appeared at higher levels of demolition (2 or 3 or more demolitions) in areas characterized by medium to high levels of vacancy. We also find that the presence of a property rehabilitation is associated with an increase in drug crimes in areas with medium levels of vacancy.

Precision Medicine Highlights Dysregulation of the CDK4/6 Cell Cycle Regulatory Pathway in Pediatric, Adolescents and Young Adult Sarcomas.

Despite improved therapeutic and clinical outcomes for patients with localized diseases, outcomes for pediatric and AYA sarcoma patients with high-grade or aggressive disease are still relatively poor. With advancements in next generation sequencing (NGS), precision medicine now provides a strategy to improve outcomes in patients with aggressive disease by identifying biomarkers of therapeutic sensitivity or resistance. The integration of NGS into clinical decision making not only increases the accuracy of diagnosis and prognosis, but also has the potential to identify effective and less toxic therapies for pediatric and AYA sarcomas. Genome and transcriptome profiling have detected dysregulation of the CDK4/6 cell cycle regulatory pathway in subpopulations of pediatric and AYA OS, RMS, and EWS. In these patients, the inhibition of CDK4/6 represents a promising precision medicine-guided therapy. There is a critical need, however, to identify novel and promising combination therapies to fight the development of resistance to CDK4/6 inhibition. In this review, we offer rationale and perspective on the promise and challenges of this therapeutic approach.

Earlier snowmelt may lead to late season declines in plant productivity and carbon sequestration in Arctic tundra ecosystems.

Arctic warming is affecting snow cover and soil hydrology, with consequences for carbon sequestration in tundra ecosystems. The scarcity of observations in the Arctic has limited our understanding of the impact of covarying environmental drivers on the carbon balance of tundra ecosystems. In this study, we address some of these uncertainties through a novel record of 119 site-years of summer data from eddy covariance towers representing dominant tundra vegetation types located on continuous permafrost in the Arctic. Here we found that earlier snowmelt was associated with more tundra net CO2 sequestration and higher gross primary productivity (GPP) only in June and July, but with lower net carbon sequestration and lower GPP in August. Although higher evapotranspiration (ET) can result in soil drying with the progression of the summer, we did not find significantly lower soil moisture with earlier snowmelt, nor evidence that water stress affected GPP in the late growing season. Our results suggest that the expected increased CO2 sequestration arising from Arctic warming and the associated increase in growing season length may not materialize if tundra ecosystems are not able to continue sequestering CO2 later in the season.

Stress and emotional arousal in urban environments: A biosocial study with persons having experienced a first-episode of psychosis and persons at risk.

This article examines the entanglement between feelings of stress and discomfort, physiological arousal and urban experiences of persons living with early psychosis. It adopts a biosocial approach, using mixed methods combining ambulatory skin conductance monitoring, mobile interviews and contextual data, collected through GPS and video recordings. The study draws on and strives to cross-fertilize two recent strands of research. The first relates to the use of digital phenotyping in mental health research. The second explores stress and emotional arousal in cities using ambulatory physiological measures. Empirically, the paper is based on fieldwork in Basel, Switzerland, with nine participants recruited within the Basel Early Treatment Service (BEATS), and four controls. We focus on three salient elements in our results: visual perception of moving bodies, spatial transitions and openness and enclosure of the built environment. The analysis shows how these elements elicit physiological responses of arousal and expressed feelings of discomfort. In the concluding section we discuss the methodological implications of these results and suggest the notion of regime of attention as a focus for future biosocial research on urban mental health.

Integrative Multi-OMICs Identifies Therapeutic Response Biomarkers and Confirms Fidelity of Clinically Annotated, Serially Passaged Patient-Derived Xenografts Established from Primary and Metastatic Pediatric and AYA Solid Tumors.

Establishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-naïve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug−gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p < 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy.

Practice Patterns of Nurse Practitioners in a Multi-Site Academic Healthcare Setting.

OBJECTIVE: The objective of this paper is to describe the day-to-day activities, known as practice patterns, of nurse practitioners (NPs) across a four-site academic healthcare network in Ontario, which comprises acute, primary, rehabilitation and complex continuing care. BACKGROUND: Information regarding NP practice patterns is available from other jurisdictions and practice settings, but information specific to large, urban and multi-site organizations is available to a lesser extent. This information can inform and support leaders' decisions about NP roles and responsibilities. METHOD: A cross-sectional online survey was sent to the 125 NPs employed in this healthcare network. RESULTS: Respondents (n = 45) were primarily experienced, graduate-prepared NPs, who work with specialized populations and support the education of healthcare professional trainees. The majority of these NPs' activities focused on direct and indirect care, with fewer activities centred on leadership/administration, education, research and personal breaks. Clinical care activities varied among NPs and were contextual to the population and program. CONCLUSION: While direct and indirect care are vital components of NP practice, the overwhelming emphasis on these components indicates that the organization and the healthcare system are losing opportunities to capitalize on advanced nursing practice knowledge and skills in the domains of leadership, research and education.

[PsyYoung: A transcantonal project for facilitating access to care for young people at risk for psychotic disorders]. / PsyYoung†: un projet pluri-cantonal pour faciliter l'accès aux soins des jeunes à risque de développer une psychose.

Approximately 2% of adolescents and young adults display symptoms indicating a high risk for psychotic disorders. Apart from a risk of 20-35% of developing a psychotic disorder, these individuals show high rates of persisting mental health problems and functional impairment, even in the absence of a psychotic transition. Treatment in specialized centers can improve outcomes in these patients, but the need to provide timely access to care needs to be balanced against the risks of premature psychiatrization, stigmatization and unnecessary medication treatment. The transcantonal project PsyYoung aims to optimize early detection in young people, while at the same time minimizing unnecessary psychiatrization. This will be achieved through improved networking across the entire care chain and a stepped-care intervention approach.

Près de 2 % des adolescents et jeunes adultes présentent des symptômes indiquant un risque élevé de développer une psychose. Outre ce risque se situant entre 20 et 35 %, ces individus présenteront des taux élevés d'autres troubles psychiques et déficits fonctionnels, même en l'absence de transition vers la psychose. Le traitement dans des centres spécialisés peut améliorer l'évolution de ces patients mais les besoins de fournir un accès rapide aux soins doivent être mis en perspective des risques de psychiatrisation prématurée, stigmatisation, et médication inutile. Le projet pluri-cantonal PsyYoung vise à optimiser la détection précoce pour les jeunes, tout en minimisant la psychiatrisation inutile. Ceci sera atteint en améliorant le réseautage de l'ensemble de la chaîne de soins et la mise en œuvre d'un modèle de soins par étapes.