Search

Background Cardiopulmonary bypass is known to raise the risk of acute kidney injury (AKI). Previous studies have identified numerous risk factors of cardiopulmonary bypass including the possible impact of perioperative ultrafiltration. However, the association between ultrafiltration (UF) and AKI remains conflicting. Thus, we conducted a meta‐analysis to further examine the relationship between UF and AKI. Hypothesis Ultrafiltration during cardiac surgery increases the risk of developping Acute kidney Injury. Methods We searched PubMed, Web of Science, EBSCO, and SCOPUS through July 2021. The RevMan (version 5.4) software was used to calculate the pooled risk ratios (RRs) and mean differences along with their associated confidence intervals (95% CI). Results We identified 12 studies with a total of 8005 patients. There was no statistically significant difference in the incidence of AKI between the group who underwent UF and the control group who did not (RR = 0.90, 95% CI = 0.64−1). Subgroup analysis on patients with previous renal insufficiency also yielded nonsignificant difference (RR = 0.84, 95% CI = 0.53 −1.33, p = .47). Subgroup analysis based on volume of ultrafiltrate removed (> or

Arterial stiffness is a precursor for the development of hypertension and premature cardiovascular disease (CVD). Physical activity has been associated with lower arterial stiffness among largely White populations, but the types of activity required and whether these findings apply to Black adults remain unknown. We examined whether physical activity levels were associated with arterial stiffness among Black adults in two independent cohorts. In the Morehouse-Emory Cardiovascular (MECA) Center for Health Equity, 378 Black adults (age 52.8 ± 10.3, 39.7% male) without known CVD living in Atlanta, GA were recruited. Arterial stiffness was measured as pulse wave velocity (PWV). Total and domain-specific physical activity were assessed by self-report. Multiple linear regression models were used to investigate differences across physical activity levels after adjusting for age, sex, CVD risk factors, and socioeconomic status. Findings were validated in an independent cohort of Black adults ( n = 55, age 50.4 ± 9.2, 23.6% male). After adjustment for covariates, lower arterial stiffness was associated with higher self-reported levels of sport/exercise (6.92 ± 1.13 vs 7.75 ± 1.14, p < 0.001, highest vs lowest quartile) and home/life activities (7.34 ± 1.24 vs 7.73 ± 1.07, p = 0.04, highest vs lowest quartile), but not work, active living, or the overall physical activity scores. These findings were replicated in the independent cohort where higher levels of sport/exercise remained associated with lower arterial stiffness (6.66 ± 0.57 vs 8.21 ± 0.66, p < 0.001, highest vs lowest quartile). Higher levels of sport/exercise and home/life-related physical activities (in comparison to occupational physical activity) are associated with lower arterial stiffness in Black adults.

BACKGROUND AND AIMS: Opioid agonist treatment is effective but resource intensive to administer safely in custodial settings, leading to significant under-treatment of opioid dependence in these settings world-wide. This study assessed the safety of subcutaneous slow-release depot buprenorphine in custody. SETTING: This is an open-label, non-randomized trial conducted in correctional centres in New South Wales, Australia. Sixty-seven men and women, aged ≥ 18 years of various security classifications with a diagnosis of moderate to severe DSM-5 opioid use disorder currently serving a custodial sentence of ≥ 6 months were recruited between November 2018 and July 2019. Patients not in opioid agonist treatment at recruitment commenced depot buprenorphine; patients already stable on oral methadone treatment were recruited to the comparison arm. INTERVENTION AND COMPARATOR: Depot buprenorphine (CAM2038 weekly for 4 weeks then monthly) and daily oral methadone. Safety was assessed by adverse event (AE) monitoring and physical examinations at every visit. Participants were administered a survey assessing self-reported diversion and substance use at baseline and weeks 4 and 16. FINDINGS: Retention in depot buprenorphine treatment was 92.3%. Ninety-four per cent of patients reported at least one adverse event, typically mild and transient. No diversion was identified. The prevalence of self-reported non-prescribed opioid use among depot buprenorphine patients decreased significantly between baseline (97%) and week 16 (12%, odds ratio = 0.0035, 95% confidence interval = 0.0007-0.018, P

Uveitis is a heterogeneous collection of diseases. We tested the hypothesis that despite the diversity of uveitides, there could be common mechanisms shared by multiple subtypes, and that evidence of these common mechanisms may be detected as gene expression profiles in whole blood.Cohort study.Ninety subjects with uveitis including axial spondyloarthritis (n = 17), sarcoidosis (n = 13), inflammatory bowel disease (n = 12), tubulointerstitial nephritis with uveitis (n = 10), or idiopathic uveitis (n = 38) as well as 18 healthy controls were enrolled, predominantly at Oregon HealthScience University. RNA-Seq data generated from peripheral, whole blood identified 19,859 unique transcripts. We analyzed gene expression pathways via Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO). We validated our list of upregulated genes by comparison to a previously published study on peripheral blood gene expression among 50 subjects with diverse forms of uveitis.Both the Kyoto Encyclopedia of Genes and Genomes and GO analysis identified multiple shared pathways or GO terms with a P value of.0001. Almost all pathways related to the immune response and/or response to an infection. A total of 119 individual transcripts were upregulated by at least 1.5-fold and false discovery rate.05, and 61 were downregulated by similar criteria. Comparing mRNA from our study with a false discovery rate.05 and the prior report, we identified 10 common gene transcripts: ICAM1, IL15RA, IL15, IRF1, IL10RB, GSK3A, TYK2, MEF2A, MEF2B, and MEF2D.Many forms of uveitis share overlapping mechanisms. These data support the concept that a single therapeutic approach could benefit diverse forms of this disease.

PURPOSE: To test the hypothesis that idiopathic uveitis can be categorized into subtypes based on gene expression from blood. DESIGN: Case control study METHODS: We applied RNA-Seq to peripheral blood from patients with uveitis associated with one of four systemic diseases, including axial spondyloarthritis (n=17), sarcoidosis (n=13), inflammatory bowel disease (n=12), tubulo-interstitial nephritis with uveitis (n=10), or idiopathic uveitis (n=38) as well as 18 healthy controls evaluated predominantly at Oregon Health & Science University. A high dimensional negative binomial regression model implemented in the edgeR R package compared each disease group against the controls. The 20 most distinctive genes for each diagnosis were extracted. Out of 80 genes, there were 75 unique genes. A classification algorithm was developed by fitting a gradient boosting tree with 5-fold cross-validation. mRNA from subjects with idiopathic uveitis was analyzed to see if any fit clinically and by gene expression pattern with one of the diagnosable entities. RESULTS: For uveitis associated with a diagnosable systemic disease, gene expression profiling achieved an overall accuracy of 85% (balanced average of sensitivity plus specificity, p-value < 0.001). Although the majority of patients with idiopathic uveitis presumably have none of these four associated systemic diseases, gene expression profiles helped to reclassify 11 of 38 subjects. CONCLUSIONS: Peripheral blood gene expression profiling is a potential adjunct in accurate differential diagnosis of the cause of uveitis. Validation of these results and characterization of the gene expression profile from additional discrete diagnoses could enhance the value of these observations.

Background: To determine the effectiveness of sacubitril/valsartan 97/103 mg twice daily (b.i.d.) on tolerability, safety, and quality of life (QoL) in Canadian patients with heart failure with reduced ejection fraction in a real-life setting. Methods: In Prospective, Multicenter, Open Label, Post-Approval Study Aimed at Characterizing the Use of LCZ696 at 97 mg Sacubitril/103 mg Valsartan bid in Patients With HFrEF (PARASAIL), an open-label, prospective, phase IV, multicentre study, outpatients with heart failure with reduced ejection fraction and New York Heart Association functional class II-III were followed up for 12 months. The suggested starting dose of sacubitril/valsartan was 24/26 mg b.i.d. replacing angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, with an uptitration to 97/103 mg b.i.d. or as per clinical judgement. The primary endpoint was the proportion of patients achieving the target dose of sacubitril/valsartan 97/103 mg b.i.d. after 6 months of treatment. Results: For the 302 patients included, the mean age was 64.47 years, and a majority of patients (82.8%) belonged to New York Heart Association class II. Overall, 195 (64.6%) patients were on maximum dose of sacubitril/valsartan 97/103 mg b.i.d. after 6 months and 62.3% remained on this dose at month 12. Using patient global assessment, patients experienced an improvement in QoL. For Minnesota Living with Heart Failure Questionnaire scores, a significant decrease from the baseline was observed at weeks 4, 12, and 24 (P

“Big data” approaches in the form of large-scale human genomic studies have led to striking advances in autism spectrum disorder (ASD) genetics. Similar to many other psychiatric syndromes, advances in genotyping technology, allowing for inexpensive genome-wide assays, has confirmed the contribution of polygenic inheritance involving common alleles of small effect, a handful of which have now been definitively identified. However, the past decade of gene discovery in ASD has been most notable for the application, in large family-based cohorts, of high-density microarray studies of submicroscopic chromosomal structure as well as high-throughput DNA sequencing—leading to the identification of an increasingly long list of risk regions and genes disrupted by rare, de novo germline mutations of large effect. This genomic architecture offers particular advantages for the illumination of biological mechanisms but also presents distinctive challenges. While the tremendous locus heterogeneity and functional pleiotropy associated with the more than 100 identified ASD-risk genes and regions is daunting, a growing armamentarium of comprehensive, large, foundational -omics databases, across species and capturing developmental trajectories, are increasingly contributing to a deeper understanding of ASD pathology.

CA extern - Weitere Nicht-UDE-Autoren sind nicht genannt. Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007. © 2020 Hellenic Society of Cardiology

BackgroundMelanoma patients who develop immunotherapy-related adverse events often have durable responses to treatment. We previously identified that long-term melanoma survivors presenting with the autoimmune adverse event, vitiligo, developed long lived CD8+ resident memory T cell (TRM) responses in skin and tumor with circulating memory T cell (TCIRC) clonal counterparts in blood.1 Despite the focus on CD8+ T cells in prior studies, CD4+ T cell features remain largely in the background.MethodsUsing the same patient cohort, we performed parallel single-cell RNA sequencing (scRNAseq) and single-cell TCR sequencing (scTCRseq) on CD4+ T cells sorted from matched skin, tumor, and blood using the 10X Genomics platform. The UMI counts-based gene expression matrix was processed using the R package Seurat (v.3.0).ResultsEleven distinct CD4+ T cell clusters were identified. The FOXP3 expressing regulatory T cell (Treg) cluster was comprised of cells from skin, tumor, and blood, and could be further sub-clustered into 3 distinct populations with one having transcripts associated with Treg activation. Of the T helper-like clusters, we identified subsets with transcripts associated with cytotoxicity (GZMA, GNLY, CX3CR1; TCYTO), exhaustion (PDCD1, HAVCR2, TOX; TEX), and three clusters that were excluded from blood with clear resident memory characteristics (high CD69, low KLF2, S1PR1). These three clusters were differentiated by expression of IL2 (TRM-IL2); ID2 and CD40LG (TRM-ACTIVATED) and CD28 (TRM-CD28). Paired scTCRseq revealed a high level of clonal overlap between the TCYTO and the TRM-ACTIVATED clusters, with RNA velocity analysis supporting a potential differentiation trajectory from TRM-ACTIVATED to TCYTO. Integrating our previously published CD8+ TRM and TCIRC profiles, we identified a core TRM signature and core TCIRC signature from both the CD4+ and CD8+ TRM and TCIRC cells, respectively, in melanoma patients. The core TRM signature predicted better overall survival of advanced melanoma patients in TCGA, while the core TCIRC signature did not.ConclusionsThis study supports the crucial anti-tumor role of TRM in cancer patients and extends this important observation to CD4+ T cells.ReferenceHan JC, Zhao YD, Shirai K, Molodtsov A, Kolling FW, Fisher JL, Zhang PS, Yan SF, Searles TG, Bader JM, Gui J, Cheng C, Ernstoff MS, Turk MJ, Angeles CV. Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy. Nature Cancer 2021;2(3).Ethics ApprovalIRB-approved written informed consent was obtained from patients with advanced melanoma, to perform skin and tumor biopsies, draw blood, and to access historical banked tissue and blood samples for analysis. All human studies were performed in accordance with ethical regulation, and pre-approved by the Committee for the Protection of Human Subjects at Dartmouth-Hitchcock Medical Center IRB (#00029821).

Background Formalin-fixed, paraffin-embedded (FFPE) tissues for RNA-seq have advantages over fresh frozen tissue including abundance and availability, connection to rich clinical data, and association with patient outcomes. However, FFPE-derived RNA is highly degraded and chemically modified, which impacts its utility as a faithful source for biological inquiry. Methods True archival FFPE breast cancer cases (n = 58), stored at room temperature for 2–23 years, were utilized to identify key steps in tissue selection, RNA isolation, and library choice. Gene expression fidelity was evaluated by comparing FFPE data to public data obtained from fresh tissues, and by employing single-gene, gene set and transcription network-based regulon analyses. Results We report a single 10 μm section of breast tissue yields sufficient RNA for RNA-seq, and a relationship between RNA quality and block age that was not linear. We find single-gene analysis is limiting with FFPE tissues, while targeted gene set approaches effectively distinguish ER+ from ER- breast cancers. Novel utilization of regulon analysis identified the transcription factor KDM4B to associate with ER+ disease, with KDM4B regulon activity and gene expression having prognostic significance in an independent cohort of ER+ cases. Conclusion Our results, which outline a robust FFPE-RNA-seq pipeline for broad use, support utilizing FFPE tissues to address key questions in the breast cancer field, including the delineation between indolent and life-threatening disease, biological stratification and molecular mechanisms of treatment resistance.

Chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are a group of rare and heterogeneous myeloid disorders. There is strong morphologic resemblance among these distinct diagnostic entities as well as a lack of specific molecular markers and limited understanding of disease pathogenesis, which has made diagnosis challenging in certain cases. The treatment has remained empirical, resulting in dismal outcomes. We, therefore, performed whole-exome and RNA sequencing of these rare hematologic malignancies and present the most complete survey of the genomic landscape of these diseases to date. We observed a diversity of combinatorial mutational patterns that generally do not cluster within any one diagnosis. Gene expression analysis reveals enrichment, but not cosegregation, of clinical and genetic disease features with transcriptional clusters. In conclusion, these groups of diseases represent a continuum of related diseases rather than discrete diagnostic entities.

Background:Early trauma (general, emotional, physical, and sexual abuse before age 18 years) has been associated with both cardiovascular disease risk and lifestyle-related risk factors for cardiovascular disease, including smoking, obesity, and physical inactivity. Despite higher prevalence, the association between early trauma and cardiovascular health (CVH) has been understudied in Black Americans, especially those from low-income backgrounds, who may be doubly vulnerable. Therefore, we investigated the association between early trauma and CVH, particularly among low-income Black Americans.Methods:We recruited 457 Black adults (age 53±10, 38% male) without known cardiovascular disease from the Atlanta, GA, metropolitan area using personalized, community-based recruitment methods. The Early Trauma Inventory was administered to assess overall early traumatic life experiences which include physical, sexual, emotional abuse, and general trauma. Our primary outcome was the American Heart Association Life’s Simple 7, which is a set of 7 CVH metrics, including 4 lifestyle-related factors (smoking, body mass index, physical activity, and diet) and three physiologically measured health factors (blood pressure, total blood cholesterol, and blood glucose). We used linear regression models adjusting for age, sex, socioeconomic status, and depression to test the association between early trauma and CVH and tested the early trauma by household income (Results:Higher levels of early trauma were associated with lower Life’s Simple 7 scores (β, −0.05 [95% CI, −0.09 to −0.01],P=0.02, per 1 unit increase in the Early Trauma Inventory score) among lower, but not higher, income Black participants (Pvalue for interaction=0.04). Subtypes of early trauma linked to Life’s Simple 7 were general trauma, emotional abuse, and sexual abuse. Exploratory analyses demonstrated that early trauma was only associated with the body mass index and smoking components of Life’s Simple 7.Conclusions:Early trauma, including general trauma, emotional abuse, and sexual abuse, may be associated with worse CVH among low-, but not higher-income Black adults.

While T-cell responses to cancer immunotherapy have been avidly studied, long-lived memory has been poorly characterized. In a cohort of metastatic melanoma survivors with exceptional responses to immunotherapy, we probed memory CD8+ T-cell responses across tissues, and across several years. Single-cell RNA sequencing revealed three subsets of resident memory T (TRM) cells shared between tumors and distant vitiligo-affected skin. Paired T-cell receptor sequencing further identified clonotypes in tumors that co-existed as TRM in skin and as effector memory T (TEM) cells in blood. Clonotypes that dispersed throughout tumor, skin and blood preferentially expressed an IFNG/TNF-high signature, which had a strong prognostic value for patients with melanoma. Remarkably, clonotypes from tumors were found in patient skin and blood up to 9 years later, with skin maintaining the most focused tumor-associated clonal repertoire. These studies reveal that cancer survivors can maintain durable memory as functional, broadly distributed TRM and TEM compartments. Turk and colleagues analyze exceptional responders to checkpoint blockade for melanoma, and detect tissue-resident memory and effector memory T-cell clonotypes in skin and blood, respectively, up to 9 years after treatment.

Background There is significant opportunity to improve the nutritional quality of foods packed in children’s school lunchboxes. Interventions that are effective and scalable targeting the school and home environment are therefore warranted. Objective This study aimed to assess the effectiveness of a multicomponent, mobile health–based intervention, SWAP IT, in reducing the energy contribution of discretionary (ie, less healthy) foods and drinks packed for children to consume at school. Methods A type I effectiveness–implementation hybrid cluster randomized controlled trial was conducted in 32 primary schools located across 3 local health districts in New South Wales, Australia, to compare the effects of a 6-month intervention targeting foods packed in children’s lunchboxes with those of a usual care control. Primary schools were eligible if they were not participating in other nutrition studies and used the required school communication app. The Behaviour Change Wheel was used to co-design the multicomponent SWAP IT intervention, which consisted of the following: school lunchbox nutrition guidelines, curriculum lessons, information pushed to parents digitally via an existing school communication app, and additional parent resources to address common barriers to packing healthy lunchboxes. The primary outcome, mean energy (kilojoules) content of discretionary lunchbox foods and drinks packed in lunchboxes, was measured via observation using a validated school food checklist at baseline (May 2019) and at 6-month follow-up (October 2019). Additional secondary outcomes included mean lunchbox energy from discretionary foods consumed, mean total lunchbox energy packed and consumed, mean energy content of core lunchbox foods packed and consumed, and percentage of lunchbox energy from discretionary and core foods, all of which were also measured via observation using a validated school food checklist. Measures of school engagement, consumption of discretionary foods outside of school hours, and lunchbox cost were also collected at baseline and at 6-month follow-up. Data were analyzed via hierarchical linear regression models, with controlling for clustering, socioeconomic status, and remoteness. Results A total of 3022 (3022/7212, 41.90%) students consented to participate in the evaluation (mean age 7.8 years; 1487/3022, 49.22% girls). There were significant reductions between the intervention and control groups in the primary trial outcome, mean energy (kilojoules) content of discretionary foods packed in lunchboxes (–117.26 kJ; 95% CI –195.59 to –39.83; P=.003). Relative to the control, the intervention also significantly reduced secondary outcomes regarding the mean total lunchbox energy (kilojoules) packed (–88.38 kJ; 95% CI –172.84 to –3.92; P=.04) and consumed (–117.17 kJ; 95% CI –233.72 to –0.62; P=.05). There was no significant difference between groups in measures of student engagement, consumption of discretionary foods outside of school hours, or cost of foods packed in children’s lunchboxes. Conclusions The SWAP IT intervention was effective in reducing the energy content of foods packed for and consumed by primary school–aged children at school. Dissemination of the SWAP IT program at a population level has the potential to influence a significant proportion of primary school–aged children, impacting weight status and associated health care costs. Trial Registration Australian Clinical Trials Registry ACTRN12618001731280; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376191&isReview=true International Registered Report Identifier (IRRID) RR2-10.1186/s12889-019-7725-x

Background Exposure to occupational manganese (Mn) is associated with neurotoxic brain injury, manifesting primarily as parkinsonism. The association between environmental Mn exposure and parkinsonism is unclear. To characterize the association between environmental Mn exposure and parkinsonism, we performed population-based sampling of residents older than 40 in Meyerton, South Africa (N = 621) in residential settlements adjacent to a large Mn smelter and in a comparable non-exposed settlement in Ethembalethu, South Africa (N = 95) in 2016–2020. Methods A movement disorders specialist examined all participants using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3). Participants also completed an accelerometry-based kinematic test and a grooved pegboard test. We compared performance on the UPDRS3, grooved pegboard, and the accelerometry-based kinematic test between the settlements using linear regression, adjusting for covariates. We also measured airborne PM2.5-Mn in the study settlements. Results Mean PM2.5-Mn concentration at a long-term fixed site in Meyerton was 203 ng/m3 in 2016–2017 – approximately double that measured at two other neighborhoods in Meyerton. The mean Mn concentration in Ethembalethu was ~ 20 times lower than that of the long-term Meyerton site. UPDRS3 scores were 6.6 (CI 5.2, 7.9) points higher in Meyerton than Ethembalethu residents. Mean angular velocity for finger-tapping on the accelerometry-based kinematic test was slower in Meyerton than Ethembalethu residents [dominant hand 74.9 (CI 48.7, 101.2) and non-dominant hand 82.6 (CI 55.2, 110.1) degrees/second slower]. Similarly, Meyerton residents took longer to complete the grooved pegboard, especially for the non-dominant hand (6.9, CI -2.6, 16.3 s longer). Conclusions Environmental airborne Mn exposures at levels substantially lower than current occupational exposure thresholds in the United States may be associated with clinical parkinsonism.

Background: The prevalence of parkinsonism in developing countries is largely unknown due to difficulty in ascertainment because access to neurologists is often limited.Objective: Develop and validate a parkinsonism screening tool using objective motor task-based tests that can be administered by non-clinicians.Methods: In a cross-sectional population-based sample from South Africa, we evaluated 315 adults, age >40, from an Mn-exposed (smelter) community, using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3), Purdue grooved pegboard, and kinematic-UPDRS3-based motor tasks. In 275 participants (training dataset), we constructed a linear regression model to predict UPDRS3. We selected motor task summary measures independently associated with UPDRS3 (p < 0.05). We validated the model internally in the remaining 40 participants from the manganese-exposed community (test dataset) using the area under the receiver operating characteristic curve (AUC), and externally in another population-based sample of 90 participants from another South African community with only background levels of environmental Mn exposure.Results: The mean UPDRS3 score in participants from the Mn-exposed community was 9.1 in both the training and test datasets (standard deviation = 6.4 and 6.1, respectively). Together, 57 (18.1%) participants in this community had a UPDRS3 ≥ 15, including three with Parkinson's disease. In the non-exposed community, the mean UPDRS3 was 3.9 (standard deviation = 4.3). Three (3.3%) had a UPDRS3 ≥ 15. Grooved pegboard time and mean velocity for hand rotation and finger tapping tasks were strongly associated with UPDRS3. Using these motor task summary measures and age, the UPDRS3 predictive model performed very well. In the test dataset, AUCs were 0.81 (95% CI 0.68, 0.94) and 0.91 (95% CI 0.81, 1.00) for cut points for neurologist-assessed UPDRS3 ≥ 10 and UPDRS3 ≥ 15, respectively. In the external validation dataset, the AUC was 0.85 (95% CI 0.73, 0.97) for UPDRS3 ≥ 10. AUCs were 0.76–0.82 when excluding age.Conclusion: A predictive model based on a series of objective motor tasks performs very well in assessing severity of parkinsonism in both Mn-exposed and non-exposed population-based cohorts.

BackgroundIn contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity.Methods and resultsCLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure.Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest.ConclusionIn patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes.ClinicalTrials identifierISRCTN43070564

Supplemental Digital Content is available in the text., Objectives: Coronavirus disease 2019 is associated with high mortality rates and multiple organ damage. There is increasing evidence that these patients are at risk for various cardiovascular insults; however, there are currently no guidelines for the diagnosis and management of such cardiovascular complications in patients with coronavirus disease 2019. We share data and recommendations from a multidisciplinary team to highlight our institution’s clinical experiences and guidelines for managing cardiovascular complications of coronavirus disease 2019. Design, Setting, and Patients: This was a retrospective cohort study of patients admitted to one of six ICUs dedicated to the care of patients with coronavirus disease 2019 located in three hospitals within one academic medical center in Atlanta, Georgia. Measurements/Interventions: Chart review was conducted for sociodemographic, laboratory, and clinical data. Rates of specific cardiovascular complications were assessed, and data were analyzed using a chi-square or Wilcoxon rank-sum test for categorical and continuous variables. Additionally, certain cases are presented to demonstrate the sub committee’s recommendations. Main Results: Two-hundred eighty-eight patients were admitted to the ICU with coronavirus disease 2019. Of these, 86 died (29.9%), 242 (84.03%) had troponin elevation, 70 (24.31%) had dysrhythmias, four (1.39%) had ST-elevation myocardial infarction, eight (2.78%) developed cor pulmonale, and 190 (65.97%) with shock. There was increased mortality risk in patients with greater degrees of troponin elevation (p < 0.001) and with the development of arrhythmias (p < 0.001), cor pulmonale (p < 0.001), and shock (p < 0.001). Conclusions: While there are guidelines for the diagnosis and management of pulmonary complications of coronavirus disease 2019, there needs to be more information regarding the management of cardiovascular complications as well. These recommendations garnered from the coronavirus disease 2019 cardiology subcommittee from our institution will add to the existing knowledge of these potential cardiovascular insults as well as highlight suggestions for the diagnosis and management of the range of cardiovascular complications of coronavirus disease 2019. Additionally, with the spread of coronavirus disease 2019, our case-based recommendations provide a bedside resource for providers newly caring for patients with coronavirus disease 2019.

The advents of early detection and advances in surgical procedures have made possible for most patients of congenital heart disease to survive to their adulthood to have further cardiac or non-cardiac surgeries. In this chapter, basic cardiac anatomic abnormal diseases and their pathophysilogy are presented to guilde to easier understand and better clinical treat these diseases during the peri-operative anesthesia management. Congenital heart disease (CHD) encompasses a range of both structural and conduction abnormalities. The annual incidence of CHD is about 1% of births per year in the United States (approximately 40,000). Of these roughly 40,000 cases, about 7000 are considered critical congenital heart conditions, such as coarctation of the aorta, large septal defects, Ebstein’s anomaly, tetralogy of Fallot (TOF), patent ductus arteriosus (PDA), aortic stenosis, transposition of the great vessels (TGV), aortopulmonary shunts, Eisenmenger’s anomaly, and rhythm disturbances such as Wolff-Parkinson-White (WPW) syndrome. The advents of earlier detection and advances in surgical procedures have made it possible for many of these patients to survive to adulthood; in fact, approximately 68% reach 18 years of age. With such a growing population of adults with CHD, the need for anesthesia practitioners to manage this population is more pertinent than ever.

Introduction: Arterial stiffness is a precursor for development of hypertension and premature cardiovascular disease (CVD). Physical activity has been associated with lower arterial stiffness among largely White populations, but the types of activity required and whether these findings apply to Blacks remain unknown. We examined whether physical activity levels were associated with arterial stiffness among Blacks in two independent cohorts. Methods: In the Morehouse-Emory Cardiovascular (MECA) Center for Health Equity, 458 Black adults (age 53 ± 10, 39% male) without known CVD living in Atlanta, GA were recruited. Arterial stiffness was measured as pulse wave velocity (PWV) using applanation tonometry (Sphygmocor Inc). Total and domain specific physical activity (work, active living, household, and sport/exercise) were assessed by self-report using the Jackson Heart Study Physical Activity Questionnaire. Multiple linear regression models were used to investigate differences after adjusting for age, gender, blood pressure, diabetes, and smoking. Change in the Framingham Risk Score (FRS) was tested as a potential mediator. Findings were validated in the Emory-Morehouse Partnership to Reduce Cardiovascular Health Disparities (META-Health) --another independent cohort of Black adults (n=60, age 50 ± 10, 25% male). Results: Lower arterial stiffness was associated with higher self-reported levels of sport/exercise (Beta = -0.54 [-1.03, -0.05], p=0.03, highest versus lowest quartile), but not work, active living, household-related physical activities, or the overall physical activity scores. 26.9% of this improvement appeared to be mediated through changes in FRS factors. These findings were confirmed in an independent group of Blacks in META-Health where higher levels of sport/exercise remained associated with lower arterial stiffness (Beta = -1.46 [-2.80, -0.12], p=0.03, highest versus lowest quartile). Conclusion: Higher sport/exercise related physical activity is associated with lower arterial stiffness in Blacks, an association that is only partially attributable to a lower traditional CVD risk factor burden.

Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here we tested the hypothesis that the unfolded protein response (UPR) links mechanistically aneuploidy and local immune dysregulation. Using a single somatic copy-number alteration (SCNA) score inclusive of whole-chromosome, arm and focal chromosome alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages. Co-expression patterns of UPR genes changed substantially between SCNAlow and SCNAhigh groups. Pathway activity scores showed increased activity by multiple branches of the UPR in response to aneuploidy. The PERK branch showed the strongest association with a reduced CYT score. The conditioned medium of aneuploid cells transmitted XBP1 splicing and caused IL-6 and Arginase1 transcription in receiver bone marrow-derived macrophages. We propose the UPR as a mechanistic link between aneuploidy and immune dysregulation in the tumor microenvironment.Statement of SignificanceAneuploidy accumulates over the life of a tumor and is associated with poor prognosis. Tumor progression is also associated with a progressive immune dysregulation. To explain these complex and concurrent disorders we tested the hypothesis that the unfolded protein could represent the link between aneuploidy and a dysregulation of local immunity favoring tumor progression.

OBJECTIVE: To understand the neurotoxic effects of manganese (Mn) exposure on monoaminergic function, utilizing [(11)C]dihydrotetrabenazine (DTBZ) positron emission tomography (PET) to measure vesicular monoamine transporter 2 (VMAT2). METHODS: Basal ganglia and thalamic DTBZ binding potentials (BPND) were calculated on 56 PETs from 41 Mn-exposed workers. Associations between cumulative Mn exposure, regional BPND, and parkinsonism were examined by mixed linear regression. RESULTS: Thalamic DTBZ BPND was inversely associated with exposure in workers with less than 3 mg Mn/m(3)-yrs, but subsequently remained stable. Pallidal DTBZ binding increased in workers with less than 2 mg Mn/m(3)-yrs of exposure, but decreased thereafter. Thalamic DTBZ binding was inversely associated with parkinsonism (P = 0.003). CONCLUSION: Mn-dose-dependent associations with thalamic and pallidal DTBZ binding indicate direct effects on monoaminergic VMAT2. Thalamic DTBZ binding was also associated with parkinsonism, suggesting potential as an early biomarker of Mn neurotoxicity.

Background: Asthma exacerbations in pregnancy are associated with adverse perinatal outcomes. FENO-based management in pregnancy reduced asthma exacerbations in a previous trial. BLT examined whether FENO-based asthma management would improve perinatal outcomes. Methods: BLT was a multi-centre, parallel group, RCT of asthma management guided by a FENO algorithm versus usual care. 1200 pregnant women with doctor diagnosed asthma and symptoms, or medication use for asthma in the previous year, were randomised to usual care (baseline assessment of asthma and no treatment changes) or FENO-based management. In the intervention group, a modified FENO algorithm was applied each 6-12 weeks (FENO used to adjust ICS dose, long acting beta agonist added when symptoms uncontrolled). A composite adverse perinatal outcome (preterm birth, intrauterine growth restriction, perinatal mortality, neonatal hospitalisation) was assessed from hospital records (primary outcome). Exacerbations in pregnancy (admission, emergency department visit, unscheduled doctor visit or oral steroid course) were assessed postpartum. Results: Baseline characteristics were similar between usual care (n=599) and FENO (n=601) groups. Intention to treat analysis found no significant difference between groups for the composite perinatal outcome (25.6% usual care, 29.4% FENO, OR 1.21 [0.94, 1.56]), all components of the composite outcome, and maternal exacerbations (19.2% usual care, 16.1% FENO, OR 0.80 [0.58, 1.10]). Conclusion: FENO-guided asthma management had no effect on perinatal outcomes. Funding: NHMRC Australia

Objective To evaluate whether a safe medication strategy compared with usual care, provided to people with dementia during an unplanned admission, reduces readmissions to hospital and re-presentation to emergency departments within three months. Methods A prospective, controlled pre-/post-trial conducted at two regional hospitals in New South Wales, Australia. Results No treatment effect was seen for time to first re-presentation or readmission within three months (P = .3). Compliance with six strategies applicable for all participants in the intervention phase was 58%. There was no treatment effect for secondary outcomes including dose administration aid use, home medicines review (HMR) requests by general practitioners and completed HMRs; however, they were significantly higher at the intervention site in both phases. Conclusion A bundle of care to improve medication safety in people with dementia did not reduce re-presentations or readmissions within three months.

Background People with dementia (PWD) are at risk for medication related harm due to their impaired cognition and frequently being prescribed many medications. Few previous studies of PWD inpatients have been focused on medication safety interventions.This study aimed to evaluate an intervention designed to improve medication safety for people with dementia (PWD) and their carers during an unplanned admission to hospital. This article reports the effect of the intervention on potentially inappropriate medications (PIMs), polypharmacy and anticholinergic burden scores for PWD in the study. Methods A quasi-experimental pre-post design using an intervention site and a control site was conducted in 2017-2019, in a regional area in New South Wales, Australia. PIMs, polypharmacy and anticholinergic burden were measured at admission, discharge and three months after discharge. In addition, medication reconciliation at admission and scoring of pharmacists recommendations using severity and relevance scores were measured. Results There were 628 participants including 350 in the post-intervention phase. Polypharmacy for these admissions was high, and there was approximately 30% reduction in the number of medications at discharge. PIMs at admission were also high, and decreased significantly at discharge however there was no treatment effect associated with the intervention. The mean anticholinergic burden score also decreased significantly between admission and discharge, however, no treatment effect was seen. Conclusions High rates of polypharmacy and PIMs in this study indicate this study population was admitted with multiple comorbidities. Reduced PIMs at discharge were correlated with reduced anticholinergic burden. Medication reconciliation resulted in many recommendations that contributed to the reductions in medications. Although the study did not report a treatment effect, reductions in the number of medications and PIMs reduced medication related risk for PWD. Reduced risks associated with inappropriate or unnecessary medications can reduce hospital admissions and adverse events for PWD. This intervention was feasible to implement, and future multisite studies should be designed to recruit larger study samples to evaluate interventions for improving medication safety for PWD. They should also adopt routine screening for cognitive impairment to identify PWD at admission.

Background: The treat-to-target (T2T) strategy has become established in several medical specialties as a key guidance to optimal therapeutic decision making. T2T may be effective in the assessment of the biologic class of agents called interleukin (IL)-17 inhibitors, which are emerging as a safe and effective treatment option for autoimmune inflammatory conditions such as plaque psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Objective: The objective of this article is to use a T2T approach for the evaluation of the effectiveness and safety of IL-17 inhibitors in the management of patients with plaque psoriasis, PsA, and AS. Methods: Following a comprehensive literature search, a full-day meeting was convened to discuss and identify the T2T targets for psoriasis, PsA, and AS. Clinical trial evidence was presented for the approved IL-17 inhibitors—secukinumab, ixekizumab, and brodalumab—to assess whether these data meet T2T safety and efficacy targets. Results: All 3 approved agents were significantly superior to placebo and active controls in the achievement of T2T targets for psoriasis. Secukinumab and ixekizumab were likewise associated with significantly better outcomes than controls in the PsA targets, and secukinumab resulted in significant AS target improvements vs placebo. The IL-17 inhibitors were also associated with low rates of serious adverse events and exacerbations of common comorbid conditions. Conclusion: Phase III trial results support the T2T benefit and safety of IL-17 inhibitors according to their specific indications for the management of patients with plaque psoriasis, PsA, and AS.

Introduction: Herpesviruses might play a role in the pathogenesis of neurodegenerative disorders. We sought to examine a possible association between alpha herpesvirus infections and Parkinson’s disease. Methods: We conducted a population-based case-control study of incident Parkinson’s disease in 2009 Medicare beneficiaries age 66–90 years (89,790 cases, 118,095 randomly selected comparable controls). We classified beneficiaries with any diagnosis code for “herpes simplex” and/or “herpes zoster” in the previous 5 years as having had the respective alpha herpesviruses. In beneficiaries with Part D prescription coverage, we also identified those prescribed anti-herpetic medications. We calculated odds ratios (OR) and 95% CI between alpha herpesvirus diagnosis/treatment and Parkinson’s disease with logistic regression, with adjustment for age, sex, race/ethnicity, smoking, and use of medical care. Results: Parkinson’s disease risk was inversely associated with herpes simplex (OR 0.79, 95% CI 0.74–0.84), herpes zoster (OR 0.88, 95% CI 0.85–0.91), and anti-herpetic medications (OR 0.87, 95% CI 0.80–0.96). Conclusion: Herpesvirus infection or treatment might reduce risk of Parkinson’s disease, but future studies will be required to explore whether this inverse association is causal.

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity. FLT3 is commonly mutated in acute myeloid leukaemia and treatment with FLT3 inhibitors often ends with relapse. Here, the authors perform exome sequencing of samples from patients treated with the FLT3 inhibitor, crenolanib, to show that resistance occurs due to diverse molecular mechanisms, not primarily due to secondary FLT3 mutations.

This review summarizes the proceedings of a symposium presented at the "Alcoholism and Stress: A Framework for Future Treatment Strategies" conference held in Volterra, Italy on May 9-12, 2017. Psychiatric diseases, including alcohol-use disorders (AUDs), are influenced through complex interactions of genes, neurobiological pathways, and environmental influences. A better understanding of the common neurobiological mechanisms underlying an AUD necessitates an integrative approach, involving a systematic assessment of diverse species and phenotype measures. As part of the World Congress on Stress and Alcoholism, this symposium provided a detailed account of current strategies to identify mechanisms underlying the development and progression of AUDs. Dr. Sean Farris discussed the integration and organization of transcriptome and postmortem human brain data to identify brain regional- and cell type-specific differences related to excessive alcohol consumption that are conserved across species. Dr. Brien Riley presented the results of a genome-wide association study of DSM-IV alcohol dependence; although replication of genetic associations with alcohol phenotypes in humans remains challenging, model organism studies show that COL6A3, KLF12, and RYR3 affect behavioral responses to ethanol, and provide substantial evidence for their role in human alcohol-related traits. Dr. Rob Williams expanded upon the systematic characterization of extensive genetic-genomic resources for quantifying and clarifying phenotypes across species that are relevant to precision medicine in human disease. The symposium concluded with Dr. Robert Hitzemann's description of transcriptome studies in a mouse model selectively bred for high alcohol ("binge-like") consumption and a non-human primate model of long-term alcohol consumption. Together, the different components of this session provided an overview of systems-based approaches that are pioneering the experimental prioritization and validation of novel genes and gene networks linked with a range of behavioral phenotypes associated with stress and AUDs.

The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML. Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.

BACKGROUND The US Preventive Services Task Force (USPSTF) endorses routine screening for genetic risk of breast and/or ovarian cancer as a component of primary health care. Implementation of this recommendation may prove challenging, especially in clinics serving disadvantaged communities. METHODS The authors tested the feasibility of implementing the USPSTF mandate at a federally qualified health center (FQHC) to identify women who were eligible for genetic counseling (GC). A 12-month usual-care phase was followed by a 12-month intervention phase, during which time cancer genetic risk assessment (CGRA) was systematically performed for all women aged 25 to 69 years who presented for an annual examination. Women who were eligible for GC were recruited to participate in the study. RESULTS After initiating CGRA, 112 women who were eligible for GC consented to study participation, and 56% of them received a referral for GC from their primary care physician. A subgroup of 50 participants were seen by the same primary care physician during both the usual-care and intervention phases. None of these patients was referred for GC during usual care, compared with 64% after the initiation of CGRA (P

Background Endotoxin, a contaminant of cotton dust, is an experimental model for parkinsonism (PS). Methods We investigated associations between exposures to endotoxin, solvents, magnetic fields, and night shift work, and neurologist-determined PS among Shanghai women textile workers, including 537 retired cotton factory workers ages ≥50 years and an age-matched reference group of 286 retired textile workers not exposed to cotton dust. Repeat exams were conducted 2.5 years after enrollment among 467 cotton workers and 229 reference workers. Results We identified 39 prevalent PS cases and 784 non-cases. No consistent or statistically significant associations were observed for endotoxin, solvents, magnetic fields, or shift work with PS risk, severity, or progression. Conclusions Despite the null findings, additional studies of endotoxin exposure and risk of PS in other well-characterized occupational cohorts are warranted in view of toxicological evidence that endotoxin is a pathogenic agent and its widespread occurrence in multiple industries worldwide.

Fracture liaison services (FLS) are an accepted approach to lowering rates of osteoporotic refractures. However, resource allocations to FLS are open to challenge, as most relevant cost analyses are based on anticipated, rather than observed, benefits. To support informed decision making, we have estimated the cost of operating an FLS, from the perspective of the Australian health system, with real life costs. On the basis of hospital records, we compared total costs of two cohorts of patients presenting with minimal trauma fractures (MTFs) at two hospital emergency departments (EDs) across a 6‐month period (July to December 2010). The treatment cohort (FLS Cohort, n = 515) attended an ED at a hospital offering FLS post‐fracture care; the Usual Care Cohort (n = 416) attended an ED at a hospital without an FLS. Hospital records were reviewed for further attendance of both groups at their respective hospitals’ EDs with refractures for the subsequent 3 years. Costs were constructed from “bottom up” with a “microcosting” approach. Total costs for both cohorts included any FLS and the costs of refractures. Cohort costs were estimated for every 1000 patients over the 3 observed years. Compared with the Usual Care Cohort, the FLS Cohort had 62 fewer fractures per 1000 patients and $617,275 lower costs over 3 years. In a sensitivity analysis, where 20% of the Usual Care Cohort received FLS preventative treatment, FLS Cohort costs were lower by $880,154. As both hospitals consistently process around 2000 patients per year, the estimated annual saving is $1.2 million to $1.8 million (Australian dollars). From the perspective of the Australian public health system, investment in FLS can be a financially effective way of reducing the cost of osteoporotic fracture management. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Occupational manganese (Mn) exposure is associated with the development of parkinsonism; however, the mechanism of neurotoxicity is unknown. Brain positron emission tomography (PET) imaging provides a non-invasive method of assessing dopamineric neuronal function. 6-[18F]fluoro-L-DOPA (FDOPA) PET reflects in-vivo nigrostriatal function, but results in Mn exposure are conflicting. The objective of this study was to investigate the association between Mn exposure secondary to occupational welding, FDOPA striatal uptake, and clinical parkinsonism as measured by Unified Parkinson Disease Rating Scale motor subscore 3 (UPDRS3) scores. FDOPA PET scans were acquired on 72 subjects (27 Mn-exposed welders, 14 other Mn-exposed workers, and 31 non-exposed subjects). We estimated cumulative welding exposure from detailed work histories, and a movement disorders specialist examined all subjects. Striatal volumes of interest were identified on aligned magnetic resonance imaging (MRI) for each subject. Specific striatal FDOPA uptake was calculated with a graphical analysis method. We used linear regression while adjusting for age to assess the association between welding exposure and FDOPA uptake in the caudate, anterior putamen, and posterior putamen. Compared to the non-exposed subjects, mean caudate FDOPA uptake was 0.0014 min−1 (95% confidence interval [CI] 0.0008, 0.0020) lower in Mn-exposed welders and 0.0012 min−1 (95% CI 0.0005, 0.0019) lower in other Mn-exposed workers (both p ≤ 0.001). There was no clear dose-response association between caudate FDOPA uptake and Mn exposure or UPDRS3 scores. Mn-exposed welders and workers demonstrated lower caudate FDOPA uptake, indicating pre-synaptic dopaminergic dysfunction in Mn-exposed subjects that was not associated with clinical parkinsonism.

Evolution often deals in genomic trade-offs: changes in the genome that are beneficial overall persist even though they also produce disease in a subset of individuals. Here, we explore the possibility that such trade-offs have occurred as part of the evolution of the human brain. Specifically, we provide support for the possibility that the same key genes that have been major contributors to the rapid evolutionary expansion of the human brain and its exceptional cognitive capacity also, in different combinations, are significant contributors to autism and schizophrenia. Furthermore, the model proposes that one of the primary genes behind this trade-off may not technically be “a gene” or “genes” but rather are the highly duplicated sequences that encode the Olduvai protein domain family (formerly called DUF1220). This is not an entirely new idea. Others have proposed that the same genes involved in schizophrenia were also critical to the rapid expansion of the human brain, a view that has been expressed as “the same ‘genes’ that drive us mad have made us human”. What is new is that a “gene”, or more precisely a protein domain family, has been found that may satisfy these requirements.

Cell-cell fusion describes the process by which two cells combine their plasma membranes and become a single cell, possessing and retaining certain genetic information from each parent cell. Here, using a Cre-loxP-based method initially developed to investigate extracellular vesicle targeting, we found that cancer cells spontaneously and rapidly deliver DNA to non-cancer cells in vitro via a cell-cell fusion event. The resulting hybrid cells were aneuploid and possessed enhanced clonal diversity and chemoresistance compared to non-hybrid cancer cells. We also observed cell-cell fusion to occur in vivo between melanoma cells and non-cancer cells of both hematopoietic and non-hematopoietic lineages. These findings suggest that cell-cell fusion occurs during the natural progression of cancer and show that this mechanism has the potential to cause massive genomic alterations that are observed in cancer. Furthermore, these findings somewhat contradict recent publications suggesting that the Cre-loxP method measures only extracellular vesicle-mediated intercellular communication.

The purpose of this review is to explore immune-mediated mechanisms of stress surveillance in cancer, with particular emphasis on the idea that all cancers have classical hallmarks (Hanahan and Weinberg in Cell 100:57-70, 67; Cell 144:646-674, 68) that could be interrelated. We postulate that hallmarks of cancer associated with cellular stress pathways (Luo et al. in Cell 136:823-837, 101) including oxidative stress, proteotoxic stress, mitotic stress, DNA damage, and metabolic stress could define and modulate the inflammatory component of cancer. As such, the overarching goal of this review is to define the types of cellular stress that cancer cells undergo, and then to explore mechanisms by which immune cells recognize, respond to, and are affected by each stress response.

Examine associations between pesticide exposure and signs or symptoms of parkinsonism.Prior to the 2014 pesticide spray season, the authors examined 38 active pesticide handlers aged 35 to 65 (median: 43.5) who participated in the State of Washington's cholinesterase monitoring program in the Yakima Valley, where cholinesterase-inhibiting insecticides are applied in fruit orchards. A movement disorder specialist assessed the workers using the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscore 3 (UPDRS3). Participants also self-reported work and medical histories, including the UPDRS activities of daily living subscore 2 (UPDRS2). The authors explored the relation between these scores and lifetime occupational pesticide exposure while accounting for age.All participants were Hispanic men born in Mexico who had worked in agriculture for 4 to 43 years (median: 21 years, including 11 years applying pesticides, mostly in the United States). Ten participants (26%) reported difficulty with one or more UPDRS2 activities of daily living (maximum = 2), and nine (24%) had a UPDRS30 (maximum = 10). The most common symptom and sign, respectively, were excess saliva (n = 6) and action tremor (n = 5). UPDRS2 and UPDRS3 scores were unrelated to the number of years applying pesticides, but UPDRS3, especially action tremor, was positively associated with living on or by a farm.Symptoms and signs of parkinsonism were absent to mild in this small sample of active workers who apply cholinesterase-inhibiting insecticides in Washington State, USA. Future studies should be larger and examine older, retired workers with greater cumulative exposure to agricultural pesticides at work and home, including other types of agricultural pesticides.

BackgroundA priority area in the field of substance dependence treatment is reducing the rates of relapse. Previous research has demonstrated that telephone delivered continuing care interventions are both clinically and cost effective when delivered as a component of outpatient treatment. This protocol describes a NSW Health funded study that assesses the effectiveness of delivering a telephone delivered continuing care intervention for people leaving residential substance treatment in Australia.Methods/designAll participants will be attending residential alcohol and other drug treatment provided by The Salvation Army or We Help Ourselves. The study will be conducted as a randomised controlled trial, where participants will be randomised to one of three treatment arms. The treatment arms will be: (i) 12-session continuing care telephone intervention; (ii) 4-session continuing care telephone intervention, or (iii) continuing care plan only. Baseline assessment batteries and development of the participants’ continuing care plan will be completed prior to participants being randomised to a treatment condition. Research staff blind to the treatment condition will complete follow-up assessments with participants at 3-months and 6-months after they have been discharged from their residential service.DiscussionThis study will provide comprehensive data on the effect of delivering the continuing care intervention for people exiting residential alcohol and other drug treatment. If shown to be effective, this intervention can be disseminated to improve the rates of relapse among people leaving residential alcohol and other drug treatment.Trial registrationAustralian New Zealand Clinical Trials Registry, ACTRN12618001231235. Registered on 23rd July 2018.https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375621&isReview=true

Background: Opioid agonist treatment (OAT) is effective but resource intensive to administer safely in custodial settings, leading to significant under-treatment of opioid dependence in these settings worldwide. Methods: This open-label trial compared depot buprenorphine, CAM2038 (weekly for 4 weeks then monthly) to oral methadone ( https://www.anzctr.org.au ACTRN12618000942257). Modelled treatment costs included a comparison group on sublingual buprenorphine-naloxone. Men and women, aged>18 years of various security classifications with a diagnosis of moderate to severe DSM-5 opioid use disorder and a custodial sentence of at least six months were recruited from correctional centres in New South Wales, Australia. Findings: Between November 2018 and July 2019, 67 patients not in OAT treatment at recruitment commenced depot buprenorphine. Sixty-two patients already stable on oral methadone treatment were recruited to the comparison arm. Patients treated with depot buprenorphine commonly reported at least one adverse event related to study drug (63/67, 94%), typically mild and transient. No diversion of depot buprenorphine was identified. Retention in depot buprenorphine treatment was 92%. Self-reported use of non-prescribed opioids (primarily buprenorphine-naloxone) and injecting drug use decreased significantly among depot buprenorphine patients by 16 weeks (p

Introduction Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark. Methods Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2. Results Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p –5), but none were statistically significant after adjusting for multiple testing (p –8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10–4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10–3). Conclusion The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.

We read with interest the recent study by Silverman et al. ([1][1]) that investigated circulating plasma miRNA as a biomarker of sudden cardiac death. We have a serious concern with regard to their blood and plasma processing protocol. They reported that “venous blood was collected via peripheral

Background At a population level, small reductions in energy intake have the potential to contribute to a reduction in the prevalence of childhood obesity. In many school systems, there is the potential to achieve a reduction in energy intake through modest improvements in foods packed in children’s school lunchboxes. This study will assess the effectiveness and cost-effectiveness of a multi-component intervention that uses an existing school-based communication application to reduce the kilojoule content from discretionary foods and drinks consumed by children from school lunchboxes whilst at school. Methods A Type I hybrid effectiveness-implementation cluster randomised controlled trial will be conducted in up to 36 primary schools in the Hunter New England, Central Coast and Mid North Coast regions of New South Wales, Australia. Designed using the Behaviour Change Wheel, schools will be randomly allocated to receive either a 5-month (1.5 school terms) multi-component intervention that includes: 1) school lunchbox nutrition guidelines; 2) curriculum lessons; 3) information pushed to parents via an existing school-based communication application and 4) additional parent resources to address common barriers to packing healthy lunchboxes or a control arm (standard school practices). The study will assess both child level dietary outcomes and school-level implementation outcomes. The primary trial outcome, mean energy (kJ) content of discretionary lunchbox foods packed in children’s lunchboxes, will be assessed at baseline and immediately post intervention (5 months or 1.5 school terms). Analyses will be performed using intention to treat principles, assessing differences between groups via hierarchical linear regression models. Discussion This study will be the first fully powered randomised controlled trial internationally to examine the impact of an m-health intervention to reduce the mean energy from discretionary food and drinks packed in the school lunchbox. The intervention has been designed with scalability in mind and will address an important evidence gap which, if shown to be effective, has the potential to be applied at a population level. Trial registration Australian Clinical Trials Registry ACTRN:12618001731280 registered on 17/10/2018. Protocol Version 1.

Background Manganese (Mn) neurotoxicity is associated with parkinsonism; the associated motor deficits can affect individuals' quality of life (QoL). We investigated associations between Mn exposure, parkinsonian signs, and QoL in Mn mine workers. Methods We assessed parkinsonian signs and QoL in 187 black South African Mn mine workers, using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3) and the Parkinson Disease Questionnaire (PDQ-39), respectively. We estimated cumulative Mn exposure in mg Mn/m3 -years using complete occupational histories and a job-exposure matrix. We investigated the cross-sectional association between cumulative Mn exposure and UPDRS3 score, and the UPDRS3 score and PDQ-39, adjusting for age, using linear regression. Results Participants' mean age was 41.8 years (range, 21-67 years); 97.3% were male. Estimated mean cumulative Mn exposure at the time of examination was 5.4 mg Mn/m3 -years, with a mean of 14.0 years working in a Mn mine. The mean UPDRS3 score was 10.1 and 25.7% of the workers had a UPDRS3 score greater than or equal to 15. There was a U-shaped dose-response relation between cumulative Mn exposure and UPDRS3 score, with a positive association up to 15 mg Mn/m3 -years of exposure and an inverse association thereafter. Greater UPDRS3 scores were associated with poorer self-reported QoL. Conclusion In this cohort of employed Mn mine workers, parkinsonian signs were common and were associated with both estimated cumulative Mn exposure and poorer QoL.

Objective T1-weighted brain magnetic resonance imaging (MRI) of the basal ganglia provides a noninvasive measure of manganese (Mn) exposure, and may also represent a biomarker for clinical neurotoxicity. Methods We acquired T1-weighted MRI scans in 27 Mn-exposed welders, 12 other Mn-exposed workers, and 29 nonexposed participants. T1-weighted intensity indices were calculated for four basal ganglia regions. Cumulative Mn exposure was estimated from work history data. Participants were examined using the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3). Results We observed a positive dose-response association between cumulative Mn exposure and the pallidal index (PI) (β = 2.33; 95% confidence interval [CI], 0.93 to 3.74). There was a positive relationship between the PI and UPDRS3 (β = 0.15; 95% CI, 0.03 to 0.27). Conclusion The T1-weighted pallidal signal is associated with occupational Mn exposure and severity of parkinsonism.

ObjectiveTo examine the association between fractures and Parkinson disease (PD) during the 5-year prodromal phase as compared to controls.MethodsWe performed a population-based case–control study of Medicare beneficiaries in the United States from 2004 to 2009. We identified 89,632 incident PD cases and 117,760 comparable controls 66–90 years of age in 2009. PD case status was the outcome, and noncranial fracture the independent variable. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for association between fracture and PD in yearly time intervals prior to PD diagnosis/control reference date, after adjusting for covariates.ResultsThere were 39,606 total fractures (25.4% cases, 14.3% controls) over the 5 years prior to the PD diagnosis/control reference date. PD was positively associated with fractures even after adjusting for age, sex, race/ethnicity, Charlson comorbidity index, alcohol use, tobacco use, and osteoporosis. The association between PD and fracture was evident at yearly time windows prior to PD diagnosis/control reference date. The association between PD and each type of fracture strengthened as the PD diagnosis/control reference date approached (all time interaction p values ≤0.02). Among beneficiaries with a mechanism of injury, the majority were attributed to falls (74.6% cases, 72.8% controls).ConclusionFractures occur more commonly during the prodromal period of PD compared to controls, especially as diagnosis date approached, suggesting that patients with PD may experience unrecognized motor and nonmotor symptoms.

Background Diabetes is increasing in incidence, morbidity and treatment costs globally, hence prevention strategies need to be explored. Animal studies and some human data have shown that zinc can improve glycaemic control, but the impact of this effect in a pre-diabetic population remains uncertain. This study is designed to investigate whether zinc gluconate and lifestyle coaching can improve glucose handling and ultimately reduce diabetes incidence in an at-risk pre-diabetic population in Australia. Methods/design The study will be a randomised, placebo-controlled, double-blind clinical trial. The study will be conducted at the Hunter New England Local Health District New South Wales (NSW), Australia. Pre-diabetic (haemoglobin A1c [HbA1c] 5.7–6.4) male and female participants (n = 410) aged 40–70 years will be recruited through the Diabetes Alliance Network, a collaboration of diabetes specialists and general practitioner practices. All participants will be given routine care to encourage healthy lifestyle changes using a telephone coaching service (Get Healthy Information and Coaching Service, NSW Health) and then randomised to receive a supplement, either zinc gluconate (equivalent to 30 mg of elemental zinc) or placebo of identical appearance for 12 months. The identity of the supplements will be blinded to both research personnel and the participants. Participants will be asked to complete medical, lifestyle and dietary surveys and will have baseline and final visits at their general practitioner practice. Primary outcomes will be HbA1c and insulin sensitivity collected at baseline and at 1, 6 and 12 months; secondary outcomes will include fasting blood glucose, fasting cholesterol, blood pressure and body mass index. The primary efficacy endpoint will be judged at 6 months. Discussion This study will generate new evidence about the potential for health coaching, with or without zinc supplementation, to improve glucose handling and ultimately to reduce progression from pre-diabetes to diabetes. Trial registration Australian and New Zealand Clinical Trials Registry, ACTRN12618001120268. Registered on 6 July 2018. Electronic supplementary material The online version of this article (10.1186/s13063-019-3317-4) contains supplementary material, which is available to authorized users.