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BackgroundEndothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well studied in humans.Methods and resultsIn 90 HT patients, plasma ET-1 was measured within 8 weeks after HT (baseline) via a competitive enzyme-linked immunosorbent assay. Three-dimensional volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined with the 75th percentile as a cutoff. Patients were followed beyond the first year after HT for late death or retransplantation. A receiver operating characteristic (ROC) curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year (area under the ROC curve 0.69, 95% confidence interval [CI] 0.57-0.82; P = .007). In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV (odds ratio [OR] 2.13, 95% CI 1.15-3.94; P = .01); this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR 4.88, 95% CI 1.69-14.10; P = .003). Eighteen deaths occurred during a median follow-up period of 3.99 (interquartile range 2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression (hazard ratio [HR] 1.22, 95% CI 0.72-2.05; P = .44). However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (P = .047) and was independently associated with late mortality (HR 2.94, 95% CI 1.12-7.72; P = .02).ConclusionsElevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.

Background and aims Design Setting Participants Measurements Findings Conclusion Opioid dependence is associated with an increased risk of suicide. Drug‐related mortality among people with opioid dependence in Scotland has more than tripled since 2010; less is known about changes in suicide risk. We aimed to determine if opioid agonist therapy (OAT) in Scotland is protective against suicide and to measure trends in suicide rates in those with opioid dependence over time.Retrospective cohort study.Scotland, UK.46 453 individuals in Scotland who received at least one prescription for OAT between 2011 and 2020 with over 304 000 person‐years (pys) of follow‐up.We calculated standardised mortality ratios (SMR) using the age‐ and sex‐specific suicide rates in Scotland for years 2011–2020. We fitted multivariable competing‐risk regression models to estimate suicide rates by OAT exposure and to estimate trends over time, adjusting for potential confounders.There were 575 deaths classed as suicide among the cohort and the overall suicide rate was 1.89 (95% confidence interval [CI] = 1.74–2.05) per 1000 pys. Age and sex SMR for suicide was 7.05 times (95% CI = 6.50–7.65) higher than in the general population. After adjustment, OAT was shown to be highly protective against suicide, with rates more than three times greater (adjusted hazard ratio: 3.07; 95% CI = 2.60–3.62) off OAT compared with on OAT. Suicide rates decreased over time, falling from 2.57 (95% CI = 2.19–3.02) per 1000 pys in 2011–12 to 1.48 (95% CI = 1.21–1.82) in 2019–20.People with opioid dependence in Scotland appear to have a greater risk of suicide than the general population. Treatment is protective, with rates of suicide lower among those on opioid agonist therapy. Suicide rates have decreased over time, during a period in which drug‐related death rates in Scotland have risen to globally high levels. [ABSTRACT FROM AUTHOR]

Among people receiving opioid-agonist treatment (OAT), the risk of COVID-19 infection and disease may be higher owing to underlying health problems and vulnerable social circumstances. We aimed to determine whether recent OAT, when compared with past exposure, affected the risk of (i) testing for SARS-CoV-2, (ii) testing positive for SARS-CoV-2, and (iii) being hospitalized or dying with COVID-19 disease. We included individuals prescribed OAT in Scotland from 2015 to 2020. We performed record linkage to SARS-CoV-2 PCR testing, vaccination, hospitalization, and mortality data, and followed up from March 2020 to December 2021. We used proportional hazards analysis and multivariate logistic regression to estimate associations between recent OAT prescription (in the previous 2 months), compared with past exposure (off treatment for over a year), and COVID-19 outcomes. Models were adjusted for confounders. Among 36 093 individuals prescribed OAT, 19 071 (52.9%) were tested for SARS-CoV-2; 2896 (8.3%) tested positive; and 552 (1.5%) were hospitalized or died with COVID-19. Recent OAT, compared with past exposure, was associated with lower odds of testing positive among those tested (aOR, 0.63; 95% CI, 0.57–0.69). However, among those testing positive, recent OAT was associated with two-fold higher odds of hospitalization or death (aOR, 2.04; 95% CI, 1.60–2.59). We found that recent OAT was associated with lower odds of SARS-CoV-2 infection, but with higher odds of disease once diagnosed. Clinical studies are needed to unravel the role of OAT in these associations. An enhanced effort is warranted to increase vaccine coverage among OAT patients to mitigate the severe consequences of COVID-19. [Display omitted] [ABSTRACT FROM AUTHOR]

With the drive toward high throughput molecular dynamics (MD) simulations involving ever-greater numbers of simulation replicates run for longer, biologically relevant timescales (microseconds), the need for improved computational methods that facilitate fully automated MD workflows gains more importance. Here we report the development of an automated workflow tool to perform AMBER GPU MD simulations. Our workflow tool capitalizes on the capabilities of the Kepler platform to deliver a flexible, intuitive, and user-friendly environment and the AMBER GPU code for a robust and high-performance simulation engine. Additionally, the workflow tool reduces user input time by automating repetitive processes and facilitates access to GPU clusters, whose high-performance processing power makes simulations of large numerical scale possible. The presented workflow tool facilitates the management and deployment of large sets of MD simulations on heterogeneous computing resources. The workflow tool also performs systematic analysis on the simulation outputs and enhances simulation reproducibility, execution scalability, and MD method development including benchmarking and validation.

Background: Lookback investigations are conducted by blood services when a risk of transmission of infection from a donor to a recipient has been identified. They involve tracing transfusion recipients and offering them testing for the relevant infectious agent. Results are relayed to the recipient to provide reassurance that there has been no transmission or to ensure appropriate treatment and care if required, and blood services are able to learn lessons from the planning, delivery, and outcomes of the investigation. A national lookback exercise was conducted in Scotland following the introduction of a test to identify occult hepatitis B infection, as recommended by the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) in 2021. Methods and Materials: This paper outlines the development and delivery of a national lookback program. It discusses the logistical, economic, ethical, regulatory, and scientific issues that were considered during the planning and delivery of the lookback exercise. Results: Development and delivery of a national lookback required robust governance, engagement of all relevant stakeholders and a shared understanding of aims, effective communication, systems, resources, limitations, and project management. Outcomes included a high testing uptake, low levels of reported anxiety, and a comprehensive data set. Conclusion: Key aspects for delivery of a successful large‐scale lookback program include a patient‐centered approach, clear and accessible communication, and whole‐systems multiagency collaboration. Major challenges include stakeholder engagement and capacity. [ABSTRACT FROM AUTHOR]

Background and aims: Drug‐related deaths in Scotland more than doubled between 2011 and 2020. To inform policymakers and understand drivers of this increase, we estimated the number of people with opioid dependence aged 15–64 from 2014/15 to 2019/20. Design: We fitted a Bayesian multi‐parameter estimation of prevalence (MPEP) model, using adverse event rates to estimate prevalence of opioid dependence jointly from Opioid Agonist Therapy (OAT), opioid‐related mortality and hospital admissions data. Estimates are stratified by age group, sex and year. Setting: Scotland, 2014/15 to 2019/20. Participants: People with opioid dependence and potential to benefit from OAT, whether ever treated or not. Using data from the Scottish Public Health Drug Linkage Programme, we identified a baseline cohort of individuals who had received OAT within the last 5 years, and all opioid‐related deaths and hospital admissions (whether among or outside of this cohort). Measurements Rates of each adverse event type and (unobserved) prevalence were jointly modelled. Findings The estimated number and prevalence of people with opioid dependence in Scotland in 2019/20 was 47 100 (95% Credible Interval [CrI] 45 700 to 48 600) and 1.32% (95% CrI 1.28% to 1.37%). Of these, 61% received OAT during 2019/20. Prevalence in Greater Glasgow and Clyde was estimated as 1.77% (95% CrI 1.69% to 1.85%). There was weak evidence that overall prevalence fell slightly from 2014/15 (change −0.07%, 95% CrI ‐0.14% to 0.00%). The population of people with opioid dependence is ageing, with the estimated number of people aged 15–34 reducing by 5100 (95% CrI 3800 to 6400) and number aged 50–64 increasing by 2800 (95% CrI 2100 to 3500) between 2014/15 and 2019/20. Conclusions: The prevalence of opioid dependence in Scotland remained high but was relatively stable, with only weak evidence of a small reduction, between 2014/15 and 2019/20. Increased numbers of opioid‐related deaths can be attributed to increased risk among people with opioid dependence, rather than increasing prevalence. [ABSTRACT FROM AUTHOR]

Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

ImportanceWhole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.ObjectivesTo examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.Design, setting, and participantsAn exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Main outcomes and measuresGenome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.ResultsDepending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P

Background and aims: Direct‐acting antiviral (DAA) treatment has an established positive effect on liver outcomes in people with hepatitis C infection; however, there is insufficient evidence regarding its effects on the 'extra‐hepatic' outcomes of drug‐related hospitalization and mortality (DRM) among people who inject drugs (PWID). We investigated associations between these outcomes and DAA treatment by comparing post‐treatment to baseline periods using a within‐subjects design to minimize selection bias concerns with cohort or case–control designs. Design: This was a self‐controlled case‐series study. Setting Scotland, 1 January 2015–30 November 2020. Participants: The study population of non‐cirrhotic, DAA‐treated PWID was identified using a data set linking Scotland's hepatitis C diagnosis, HCV clinical databases, national inpatient/day‐case hospital records and the national deaths register. Three principal outcomes (drug overdose admission, non‐viral injecting related admission and drug‐related mortality) were defined using ICD codes. Measurements Self‐controlled case‐series methodology was used to estimate the relative incidence (RI) of each outcome associated with time on treatment and up to six 90‐day exposure risk periods thereafter. Findings A total of 6050 PWID were treated with DAAs in the sampling time‐frame. Compared with the baseline period, there was a significantly lowered risk of a drug overdose hospital admission in the second to fifth exposure risk periods only [relative incidence (RI) = 0.86, 95% confidence interval (CI) = 0.80–0.99; 0.89, 95% CI = 0.80–0.99; 0.86, 95% CI = 0.77–0.96; 0.88, 95% CI = 0.78–0.99, respectively]. For non‐viral injecting‐related admission, there was a reduced risk in the first, third and fourth exposure risk periods (RI = 0.76, 95% CI = 0.64–0.90; 0.75, 95% CI = 0.62–0.90; 0.79, 95% CI = 0.66–0.96, respectively). There was no evidence for reduced DRM risk in any period following treatment end. Conclusions: Among people who inject drugs in Scotland, direct‐acting antiviral treatment appears to be associated with a small, non‐durable reduction in the risk of drug‐related hospital admission, but not drug‐related mortality. Direct‐acting antiviral therapy, despite high effectiveness against liver disease, does not appear to offer a panacea for reducing other drug‐related health harms. [ABSTRACT FROM AUTHOR]

ObjectivesWe sought to assess the validity of first-year intravascular ultrasound (IVUS) data as a surrogate marker for long-term outcome after heart transplantation.BackgroundCardiac allograft vasculopathy (CAV) is a major impediment to long-term graft survival. Intravascular ultrasound is more sensitive than coronary angiography and detects intimal thickening (early CAV) in the coronary arteries of the donor heart. Single-center studies have suggested first-year IVUS results might be a surrogate marker for long-term outcome.MethodsFirst-year IVUS results and subsequent five-year clinical follow-up data were reviewed in 125 heart transplant recipients from five institutions. The IVUS tapes (at baseline and one year) were re-analyzed at a core IVUS laboratory. The change in maximal intimal thickness (MIT) from baseline to one year was recorded for several matched sites in the same coronary artery. Patients were classified into two groups: those with >/=0.5 mm in the MIT in any matched site (group 1) and those with MIT /=0.5 mm in the first year after transplantation appears to be a reliable surrogate marker for subsequent mortality, nonfatal major adverse cardiac events, and development of angiographic CAV through five years after heart transplantation.

Transplant vasculopathy significantly limits the survival of cardiac transplant patients and occurs in 50% of patients by 5 years posttransplant. We report our experience with six cardiac transplant patients who underwent intracoronary brachytherapy for in-stent restenosis. At four centers, six patients underwent intracoronary radiation for in-stent restenosis. All patients received extended antiplatelet therapy with clopidogrel and aspirin. Follow-up angiography was performed in all patients. Two of the six patients underwent subsequent target lesion revascularization. Patient 1 presented with total occlusion of her radiated lesion. She had a complex procedure requiring stenting for a dissection after the radiation dwell. Patient 2 had high-grade restenosis following brachytherapy. Patient 3 had a 50% restenotic lesion. Patients 4, 5, and 6 had follow-up angiography that showed no evidence of restenosis. There are few good options to treated accelerated transplant vasculopathy. Radiation therapy may be a viable option in this difficult patient population.