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Platelets are small, anucleate entities that bud from megakaryocytes in the bone marrow. Among circulating cells, platelets are the most abundant cell, traditionally involved in regulating the balance between thrombosis (the terminal event of platelet activation) and hemostasis (a protective response to tissue injury). Although platelets lack the precise cellular control offered by nucleate cells, they are in fact very dynamic cells, enriched in preformed RNA that allows them the capability of de novo protein synthesis which alters the platelet phenotype and responses in physiological and pathological events. Antiplatelet medications have significantly reduced the morbidity and mortality for patients afflicted with thrombotic diseases, including stroke and myocardial infarction. However, it has become apparent in the last few years that platelets play a critical role beyond thrombosis and hemostasis. For example, platelet-derived proteins by constitutive and regulated exocytosis can be found in the plasma and may educate distant tissue including blood vessels. First, platelets are enriched in inflammatory and anti-inflammatory molecules that may regulate vascular remodeling. Second, platelet-derived microparticles released into the circulation can be acquired by vascular endothelial cells through the process of endocytosis. Third, platelets are highly enriched in mitochondria that may contribute to the local reactive oxygen species pool and remodel phospholipids in the plasma membrane of blood vessels. Lastly, platelets are enriched in proteins and phosphoproteins which can be secreted independent of stimulation by surface receptor agonists in conditions of disturbed blood flow. This so-called biomechanical platelet activation occurs in regions of pathologically narrowed (atherosclerotic) or dilated (aneurysmal) vessels. Emerging evidence suggests platelets may regulate the process of angiogenesis and blood flow to tumors as well as education of distant organs for the purposes of allograft health following transplantation. This review will illustrate the potential of platelets to remodel blood vessels in various diseases with a focus on the aforementioned mechanisms.

Purpose: Malignancy after heart transplantation is associated with poor outcomes. At present, no prediction model exists for any malignancy within the first year after transplant. Methods: We studied adults who underwent heart transplantation included in the multicenter, national Scientific Registry of Transplant Recipients from January 2000 through April 2021. Possible predictors of malignancy were identified based on their known association with malignancy. Multiple imputations were conducted for missing values using predictive mean matching. A multivariable logistic regression model for predicting malignancy development within the first year after transplant was developed and internally validated via 500 bootstrapped samples to estimate the optimism-corrected measures of model accuracy and performance. Results: Among the 47 212 recipients comprising 16% females, 76% whites, 7% with prior malignancy, and a median age of 56 years; 865 (2.3% of those with non-missing data) developed malignancy within the first year after transplant. Prior malignancy, older age at heart transplantation, white race, and nonischemic heart failure etiology were the strongest predictors of new malignancy. The optimism-corrected model had modest discrimination (C-statistic: 0.70, 95% CI: 0.69-0.72) and good calibration and performance (calibration slope: 0.96; Cox-Snell R2: 0.063), particularly at lower predicted risk. A nomogram for the practicing clinician was developed. Conclusions: Using selection variables previously linked to cutaneous malignancy, our model was modestly predictive of the development of any malignancy in the first year after heart transplantation. Future research could identify factors that may improve malignancy prediction, including incorporation of time-to-event data.

Diagnostic guidelines for compulsive sexual behavior disorder note that moral distress related to sexual behavior is not sufficient to receive the diagnosis. Recent work has questioned the uniqueness of moral distress in predicting self-reported feelings of sexual addiction, demonstrating that other so-called addictive behaviors (e.g., gaming and internet use) are well-predicted by moral disapproval of those behaviors. The present work tested if moral incongruence (the interaction of behavioral frequency and moral disapproval of a behavior) is uniquely related to sexual behavior, or if it generalizes to other addictions as well.This work used a large sample (The interaction of behavioral frequency and behavioral disapproval (i.e., moral incongruence) predicted self-reported feelings of addiction to pornography and gambling. Moral incongruence was consistently unrelated to self-reported feelings of addiction to tobacco, illicit substances, and prescription drugs. Results regarding alcohol and marijuana were inconclusive.Moral incongruence is clearly a salient factor in understanding compulsive sexual behavior, and it appears to also be salient to gambling disorder. Though moral incongruence does not seem relevant to some substances (i.e., nicotine, prescription drug misuse, or illicit drug use), further research is needed regarding the effect of moral incongruence on self-reported feelings of addiction to alcohol and marijuana. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Numerous debates surround the recent inclusion of compulsive sexual behavior disorder (CSBD) in the International Classification of Diseases (11th ed.), such as the appropriate classification of this construct and what symptom criteria best capture this syndrome. Although controversy surrounding CSBD abounds, there is general agreement that researchers should examine this syndrome in diverse groups, such as lesbian, gay, bisexual, and transgender populations. However, there have been few investigations into how diverse sociocultural contexts may influence the assessment and treatment of CSBD. Therefore, we propose several differential diagnosis considerations when working with sexual and gender diverse clients to avoid CSBD misdiagnosis.

With the implementation of the new heart transplant (HT) allocation system, patients requiring biventricular support systems have the highest priority, a shorter waitlist time, and a higher frequency of HT. However, the short-term and long-term outcomes of such patients are often disputed. Hence, we examined the outcomes of these patients who underwent HT before change in allocation scheme. Additionally, we compared post-HT outcomes of extracorporeal membrane oxygenation (ECMO) with other nondischargeable biventricular (BiVAD) supported patients. We identified adult ECMO or BiVAD supported HT recipients between 2000 and 2018 in the Scientific Registry of Transplant Recipients database. We compared survival with the Kaplan-Meier method. Using overlap propensity score weighting, we constructed Cox proportional hazards regression models to determine the risk-adjusted influence of BiVAD versus ECMO on survival. Of the 730 patients HT recipients; 528 (72.3%) and 202 (27.7%) were bridged with BiVAD and ECMO, respectively. For BiVAD versus ECMO patients, the 30-day, 1-year, 3-year, and 5-year mortality rates were 8.0% versus 14.4%, 16.3% versus 21.3%, 22.4% versus 25.3%, and 26.3% versus 25.7%, respectively. Risk-adjusted post-HT survival of BiVAD and ECMO patients at 30-day (HR 1.24 [95% CI, 0.68-2.27]; P = 0.4863), 1-year (HR 1.29 [95% CI, 0.80-2.09]; P = 0.3009), 3-year (HR 1.27 [95% CI, 0.83-1.94]; P = 0.2801), and 5-year (HR 1.35, 95% CI, 0.90-2.05; P = 0.1501) were similar. Around three-fourth of the ECMO or BiVAD supported patients were alive at 5-years post-HT. The short-term and long-term post-HT survivals of groups were comparable.

Background Releasing timely and relevant clinical guidelines is challenging for organizations globally. Priority-setting is crucial, as guideline development is resource-intensive. Our aim, as a national organization responsible for developing cardiovascular clinical guidelines, was to develop a method for generating and prioritizing topics for future clinical guideline development in areas where guidance was most needed. Methods Several novel processes were developed, adopted and evaluated, including (1) initial public consultation for health professionals and the general public to generate topics; (2) thematic and qualitative analysis, according to the International Classification of Diseases (ICD-11), to aggregate topics; (3) adapting a criteria-based matrix tool to prioritize topics; (4) achieving consensus through a modified-nominal group technique and voting on priorities; and (5) process evaluation via survey of end-users. The latter comprised the organization’s Expert Committee of 12 members with expertise across cardiology and public health, including two citizen representatives. Results Topics (n = 405; reduced to n = 278 when duplicates removed) were identified from public consultation responses (n = 107 respondents). Thematic analysis synthesized 127 topics that were then categorized into 37 themes using ICD-11 codes. Exclusion criteria were applied (n = 32 themes omitted), resulting in five short-listed topics: (1) congenital heart disease, (2) valvular heart disease, (3) hypercholesterolaemia, (4) hypertension and (5) ischaemic heart diseases and diseases of the coronary artery. The Expert Committee applied the prioritization matrix to all five short-listed topics during a consensus meeting and voted to prioritize topics. Unanimous consensus was reached for the topic voted the highest priority: ischaemic heart disease and diseases of the coronary arteries, resulting in the decision to update the organization’s 2016 clinical guidelines for acute coronary syndromes. Evaluation indicated that initial public consultation was highly valued by the Expert Committee, and the matrix tool was easy to use and improved transparency in priority-setting. Conclusion Developing a multistage, systematic process, incorporating public consultation and an international classification system led to improved transparency in our clinical guideline priority-setting processes and that topics chosen would have the greatest impact on health outcomes. These methods are potentially applicable to other national and international organizations responsible for developing clinical guidelines.

Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and guide treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD.We used aptamer-based proteomics to measure 4,783 proteins in 2 cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modeling-logistic regression assessed the ability of candidate proteins to classify fibrosis.From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n = 62) and B (n = 98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n = 71) and D (n = 84). The A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) protein accurately distinguished non-alcoholic fatty liver (NAFL)/non-alcoholic steatohepatitis (NASH) with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4, with AUROCs of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3), with AUROCs of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROCs 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROCs 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and fibrosis-4 score.The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis; they exhibited superior diagnostic performance compared to standard of care fibrosis scores.Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in the blood which may identify fibrosis without the need for a liver biopsy.

With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein’s genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease., Circulating proteins have been linked to many conditions, and understanding their genetic control can lead to understanding of disease. Here, the authors associate common genetic variants with protein levels, finding overlap of genetic associations with circulating proteins and complex disease.

Supplementary Appendix, Table 1, Figure Legends 1-4 from Serial Magnetic Resonance Spectroscopy Reveals a Direct Metabolic Effect of Cediranib in Glioblastoma

Supplementary Methods, Figures 1-4 from Serial Magnetic Resonance Spectroscopy Reveals a Direct Metabolic Effect of Cediranib in Glioblastoma

Proton magnetic resonance spectroscopy is increasingly used in clinical studies of brain tumor to provide information about tissue metabolic profiles. In this study, we evaluated changes in the levels of metabolites predominant in recurrent glioblastoma multiforme (rGBM) to characterize the response of rGBM to antiangiogenic therapy. We examined 31 rGBM patients treated with daily doses of cediranib, acquiring serial chemical shift imaging data at specific time points during the treatment regimen. We defined spectra from three regions of interest (ROI)—enhancing tumor (ET), peritumoral tissue, and normal tissue on the contralateral side (cNT)—in post-contrast T1-weighted images, and normalized the concentrations of N-acetylaspartate (NAA) and choline (Cho) in each ROI to the concentration of creatine in cNT (norCre). We analyzed the ratios of these normalized metabolites (i.e., NAA/Cho, NAA/norCre, and Cho/norCre) by averaging all patients and categorizing two different survival groups. Relative to pretreatment values, NAA/Cho in ET was unchanged through day 28. However, after day 28, NAA/Cho significantly increased in relation to a significant increase in NAA/norCre and a decrease in Cho/norCre; interestingly, the observed trend was reversed after day 56, consistent with the clinical course of GBM recurrence. Notably, receiver operating characteristic analysis indicated that NAA/Cho in tumor shows a high prediction to 6-month overall survival. These metabolic changes in these rGBM patients strongly suggest a direct metabolic effect of cediranib and might also reflect an antitumor response to antiangiogenic treatment during the first 2 months of treatment. Further study is needed to confirm these findings. Cancer Res; 71(11); 3745–52. ©2011 AACR.

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

Induction in heart transplant (HT) patients is non-uniform, with center-specific protocols often dictating use and selection of agents according to patient-specific immunologic risk factors. Data regarding the evolution of induction practice patterns after the 2018 allocation system change are not available. We evaluated whether the new allocation system altered induction practice patternsaffected outcomes in adult HT recipients.We included adults (18+ years of age) who had undergone HT and received induction immunosuppression and were stratified based on surgery being before (January 1st 2015-May 31st 2018) and after (May 1st 2018-December 31st, 2021) the UNOS allocation policy change. Outcomes of 30-day mortality, 1-year mortality, and 1-year graft failure were compared between those transplanted before and after the policy change through risk-adjusted Cox proportional hazards models while drug-treated rejection in the first year was compared using multiple logistic regression.Of the 7,845 HT recipients who received induction therapy, 5,070 (64.6%) were transplanted before and 2,775 (35.4%) after the UNOS policy change. The most used induction agents were basiliximab (56.0%) and thymoglobulin (39.3%), with thymoglobulin used more often in the new (43.1%) than old system (37.2%; p0.001). Among adult HT recipients who received induction, risk-adjusted hazards of 30-day mortality (HR 0.89, 95% CI 0.67-1.18), 1-year mortality (HR 1.00, 95% CI 0.84-1.19), and 1-year graft failure (HR 0.83, 95% CI 0.60-1.15) were similar between the old and new systems. Conversely, the adjusted odds of drug-treated rejection in the first year was lower in the new system (OR 0.52, 95% CI 0.38-0.72).HT recipients in the new allocation system were more likely to receive thymoglobulin induction, which may be associated with a reduced risk of drug-treated rejection.

Indigenous Peoples have historically been targets of extractive research that has led to little to no benefit. In genomics, such research not only exposes communities to harms and risks of misuse, but also deprives such communities of potential benefits. Tribes in the US have been exercising their sovereignty to limit this extractive practice by adopting laws and policies to govern research on their territories and with their citizens. Federally and state recognized tribes are in the strongest position to assert research oversight. Other tribes lack the same authority, given that federal and state governments do not recognize their rights to regulate research, resulting in varying levels of oversight by tribes. These governance measures establish collective protections absent from the US federal government’s research oversight infrastructure, while setting expectations regarding benefits to tribes as political collectives. Using a legal epidemiology approach, the paper discusses findings from a review of Tribal research legislation, policy, and administrative materials from 26 tribes in the US. The discussion specifies issues viewed by tribes as facilitators and barriers to securing benefits from research for their nations and members/citizens, and describes preemptive and mitigating strategies pursued by tribes in response. These strategies are set within the framing of the CARE Principles for Indigenous Data Governance (Collective Benefit, Authority to Control, Responsibility, Ethics), a set of standards developed to ensure that decisions made about data pertaining to Indigenous communities at the individual and tribal levels are responsive to their values and collective interests. Our findings illustrate gaps to address for benefit sharing and a need to strengthen Responsibility and Ethics in tribal research governance.

Introduction The differentiation of Lewy body dementia from other common dementia types clinically is difficult, with a considerable number of cases only being found post-mortem. Consequently, there is a clear need for inexpensive and accurate diagnostic approaches for clinical use. Electroencephalography (EEG) is one potential candidate due to its relatively low cost and non-invasive nature. Previous studies examining the use of EEG as a dementia diagnostic have focussed on the eyes closed (EC) resting state; however, eyes open (EO) EEG may also be a useful adjunct to quantitative analysis due to clinical availability. Methods We extracted spectral properties from EEG signals recorded under research study protocols (1024 Hz sampling rate, 10:5 EEG layout). The data stems from a total of 40 dementia patients with an average age of 74.42, 75.81 and 73.88 years for Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), respectively, and 15 healthy controls (HC) with an average age of 76.93 years. We utilised k-nearest neighbour, support vector machine and logistic regression machine learning to differentiate between groups utilising spectral data from the delta, theta, high theta, alpha and beta EEG bands. Results We found that the combination of EC and EO resting state EEG data significantly increased inter-group classification accuracy compared to methods not using EO data. Secondly, we observed a distinct increase in the dominant frequency variance for HC between the EO and EC state, which was not observed within any dementia subgroup. For inter-group classification, we achieved a specificity of 0.87 and sensitivity of 0.92 for HC vs dementia classification and 0.75 specificity and 0.91 sensitivity for AD vs DLB classification, with a k-nearest neighbour machine learning model which outperformed other machine learning methods. Conclusions The findings of our study indicate that the combination of both EC and EO quantitative EEG features improves overall classification accuracy when classifying dementia types in older age adults. In addition, we demonstrate that healthy controls display a definite change in dominant frequency variance between the EC and EO state. In future, a validation cohort should be utilised to further solidify these findings.

Mycophenolate mofetil (MMF) is the gold-standard immunosuppressive agent in heart transplantation (HT), but dose-dependent toxicities (e.g., neutropenia) are frequent. Gut bacteria β-d-glucuronidases (GUS) modulate MMF bioavailability, and changes in the intestinal flora may influence the pharmacokinetics of MMF. The objective of this study was to evaluate the safety and efficacy of MMF 1.5 g every 12 h (q12) [high-dose, HD] versus 1 g q12 [low-dose, LD] and explore the association between neutropenia and GUS.We compared the incidence of acute cellular rejection (ACR) and neutropenia during the first 6 months post-HT. The association between neutropenia and GUS was investigated in an exploratory analysis on a subset of patients with prospectively collected stool data. Stool samples were analyzed using 16S rRNA sequencing.A total of 168 patients (120 MMF-HD, 48 MMF-LD; mean age 55.7 years, 79% male) were studied. Neutropenia occurred in 38.6% of patients at a median of 106 [64-143] days. Freedom from neutropenia was lower in MMF-HD compared with MMF-LD (57% vs. 73%, p = 0.03). ACR (≥1R/1B) occurred in 37.5% of patients at a median of 20 [10-96] days, while high-grade ACR (≥2R/3A) occurred in 11.3% at a median of 14 [9-89] days. Freedom from ACR was similar between groups. MMF-LD was associated with more high-grade ACR (hazard ratio [HR] 3.47, 95% confidence interval [CI] 1.09-11.08, p = 0.03) during the first month, but less neutropenia (HR 0.54, 95% CI 0.29-1.00, p = 0.05) between 1 and 6 months. GUS-producing bacteria were more abundant in neutropenic patients.MMF-LD was associated with higher rates of early high-grade ACR and lower rates of later neutropenia. Further studies are warranted to test whether temporal MMF dose adjustments and gut microbial composition could improve clinical outcomes post-HT.

OBJECTIVE To examine if older age (>70 years) should be a relative contraindication for heart transplantation, we evaluated the characteristics and outcomes of patients with age ≥70 years listed for heart transplantation; and whether post-transplantation survival was inferior to younger counterparts. DESIGN Retrospective cohort analysis. SETTING The scientific registry of transplant recipients (SRTR). PARTICIPANTS Adults (≥18 years) listed for heart transplantation in the SRTR between 2000 and 2018. INTERVENTIONS Heart transplantation. MEASUREMENTS Characteristics and outcomes were compared for adults ≥70 years and

PURPOSE Effect of pre-transplant amiodarone use on post-heart transplant (HT) survival is not well established. We therefore sought to examine the effect of amiodarone use on post-HT survival. METHODS We stratified adults who underwent HT between January 2000 and August 2018 in the Scientific Registry of Transplant Recipients according to pre-transplant amiodarone use and used recipient and donor characteristics to calculate propensity scores. We then used overlap propensity score weighting to construct Cox proportional hazards regression models (adjusted for Index for Mortality Prediction After Cardiac Transplantation [IMPACT] score and donor/recipient predicted heart mass [PHM] ratio) for mortality outcomes. Logistic regression was used to compare the odds of primary graft failure and drug-treated rejection. RESULTS 25,394 adult HT recipients were included; median (inter-quartile range) age was 55 (46, 62) years and 75.5% were men. Compared with nonusers, amiodarone users had a significantly higher prevalence of hypertension (46.7% vs. 50.2%; p

Maximal oxygen uptake (VO2max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO2max, and of increases of VO2max in response to exercise training (ΔVO2max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO2max and ΔVO2max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual’s ΔVO2max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans. Plasma proteomic profiles from 650 adult humans are measured before and after a 20-week exercise regimen to determine proteins associated with baseline cardiorespiratory fitness and improvements in response to exercise.