Causes of death among people who use illicit opioids in England between 2001 and 2018:a matched cohort study

BACKGROUND: In many countries, the average age of people who use illicit opioids, such as heroin, is increasing. This has been suggested to be a reason for increasing numbers of opioid-related deaths seen in surveillance data. We aimed to describe causes of death among people who use illicit opioids in England, how causes of death have changed over time, and how they change with age. METHODS: In this matched cohort study, we studied patients in the Clinical Practice Research Datalink with recorded illicit opioid use (defined as aged 18–64 years, with prescriptions or clinical observations that indicate use of illicit opioids) in England between Jan 1, 2001, and Oct 30, 2018. We also included a comparison group, matched (1:3) for age, sex, and general practice with no records of illicit opioid use before cohort entry. Dates and causes of death were obtained from the UK Office for National Statistics. The cohort exit date was the earliest of date of death or Oct 30, 2018. We described rates of death and calculated cause-specific standardised mortality ratios. We used Poisson regression to estimate associations between age, calendar year, and cause-specific death. FINDINGS: We collected data for 106 789 participants with a history of illicit opioid use, with a median follow-up of 8·7 years (IQR 4·3–13·5), and 320 367 matched controls with a median follow-up of 9·5 years (5·0–14·4). 13 209 (12·4%) of 106 789 participants in the exposed cohort had died, with a standardised mortality ratio of 7·72 (95% CI 7·47–7·97). The most common causes of death were drug poisoning (4375 [33·1%] of 13 209), liver disease (1272 [9·6%]), chronic obstructive pulmonary disease (COPD; 681 [5·2%]), and suicide (645 [4·9%]). Participants with a history of illicit opioid use had higher mortality rates than the comparison group for all causes of death analysed, with highest standardised mortality ratios being seen for viral hepatitis (103·5 [95% CI 61·7–242·6]), HIV (16·7 [9·5–34·9]), and COPD (14·8 [12·6–17·6]). In the exposed cohort, at age 20 years, the rate of fatal drug poisonings was 271 (95% CI 230–313) per 100 000 person-years, accounting for 59·9% of deaths at this age, whereas the mortality rate due to non-communicable diseases was 31 (16–45) per 100 000 person-years, accounting for 6·8% of deaths at this age. Deaths due to non-communicable diseases increased more rapidly with age (1155 [95% CI 880–1431] deaths per 100 000 person-years at age 50 years; accounting for 52·0% of deaths at this age) than did deaths due to drug poisoning (507 (95% CI 452–562) per 100 000 person-years at age 50 years; accounting for 22·8% of deaths at this age). Mirroring national surveillance data, the rate of fatal drug poisonings in the exposed cohort increased from 345 (95% CI 299–391) deaths per 100 000 person-years in 2010–12 to 534 (468–600) per 100 000 person-years in 2016–18; an increase of 55%, a trend that was not explained by ageing of participants. INTERPRETATION: People who use illicit opioids have excess risk of death across all major causes of death we analysed. Our findings suggest that population ageing is unlikely to explain the increasing number of fatal drug poisonings seen in surveillance data, but is associated with many more deaths due to non-communicable diseases. FUNDING: National Institute for Health Research

Design, synthesis, and evaluation of substituted nicotinamide adenine dinucleotide (NAD+) synthetase inhibitors as potential antitubercular agents

Nicotinamide adenine dinucleotide (NAD+) synthetase catalyzes the last step in NAD+ biosynthesis. Depletion of NAD+ is bactericidal for both active and dormant Mycobacterium tuberculosis (Mtb). By inhibiting NAD+ synthetase (NadE) from Mtb, we expect to eliminate NAD+ production which will result in cell death in both growing and nonreplicating Mtb. NadE inhibitors have been investigated against various pathogens, but few have been tested against Mtb. Here, we report on the expansion of a series of urea-sulfonamides, previously reported by Brouillette et al. Guided by docking studies, substituents on a terminal phenyl ring were varied to understand the structure-activity-relationships of substituents on this position. Compounds were tested as inhibitors of both recombinant Mtb NadE and Mtb whole cells. While the parent compound displayed very weak inhibition against Mtb NadE (IC50=1000µM), we observed up to a 10-fold enhancement in potency after optimization. Replacement of the 3,4-dichloro group on the phenyl ring of the parent compound with 4-nitro yielded 4f, the most potent compound of the series with an IC50 value of 90µM against Mtb NadE. Our modeling results show that these urea-sulfonamides potentially bind to the intramolecular ammonia tunnel, which transports ammonia from the glutaminase domain to the active site of the enzyme. This hypothesis is supported by data showing that, even when treated with potent inhibitors, NadE catalysis is restored when treated with exogenous ammonia. Most of these compounds also inhibited Mtb cell growth with MIC values of 19-100µg/mL. These results improve our understanding of the SAR of the urea-sulfonamides, their mechanism of binding to the enzyme, and of Mtb NadE as a potential antitubercular drug target

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: Health-related quality of life outcomes, resource utilization, and cost-effectiveness analysis

BackgroundThe Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial showed that survival in patients with severe lower limb ischemia (rest pain, tissue loss) who survived postintervention for >2 years after initial randomization to bypass surgery (BSX) vs balloon angioplasty (BAP) was associated with an improvement in subsequent amputation-free and overall survival of about 6 and 7 months, respectively. We now compare the effect on hospital costs and health-related quality of life (HRQOL) of the BSX-first and BAP-first revascularization strategies using a within-trial cost-effectiveness analysis.MethodsWe measured HRQOL using the Vascular Quality of Life Questionnaire (VascuQol), the Short Form 36 (SF-36), and the EuroQol (EQ-5D) health outcome measure up to 3 years from randomization. Hospital use was measured and valued using United Kingdom National Health Service hospital costs over 3 years. Analysis was by intention-to-treat. Incremental cost-effectiveness ratios were estimated for cost per quality-adjusted life-year (QALY) gained. Uncertainty was assessed using nonparametric bootstrapping of incremental costs and incremental effects.ResultsNo significant differences in HRQOL emerged when the two treatment strategies were compared. During the first year from randomization, the mean cost of inpatient hospital treatment in patients allocated to BSX ($34,378) was estimated to be about$8469 (95% confidence interval, $2,417-$14,522) greater than that of patients allocated to BAP ($25,909). Owing to increased costs subsequently incurred by the BAP patients, this difference decreased at the end of follow-up to$5521 ($45,322 for BSX vs$39,801 for BAP) and was no longer significant. The incremental cost-effectiveness ratio of a BSX-first strategy was $184,492 per QALY gained. The probability that BSX was more cost-effective than BAP was relatively low given the similar distributions in HRQOL, survival, and hospital costs.ConclusionsAdopting a BSX-first strategy for patients with severe limb ischemia does result in a modest increase in hospital costs, with a small positive but insignificant gain in disease-specific and generic HRQOL. However, the real-world choice between BSX-first and BAP-first revascularization strategies for severe limb ischemia due to infrainguinal disease cannot depend on costs alone and will require a more comprehensive consideration of individual patient preferences conditioned by expectations of survival and other health outcomes

Social Complexity and Nesting Habits Are Factors in the Evolution of Antimicrobial Defences in Wasps

Microbial diseases are important selective agents in social insects and one major defense mechanism is the secretion of cuticular antimicrobial compounds. We hypothesized that given differences in group size, social complexity, and nest type the secretions of these antimicrobials will be under different selective pressures. To test this we extracted secretions from nine wasp species of varying social complexity and nesting habits and assayed their antimicrobial compounds against cultures of Staphylococcus aureus. These data were then combined with phylogenetic data to provide an evolutionary context. Social species showed significantly higher (18x) antimicrobial activity than solitary species and species with paper nests showed significantly higher (11x) antimicrobial activity than those which excavated burrows. Mud-nest species showed no antimicrobial activity. Solitary, burrow-provisioning wasps diverged at more basal nodes of the phylogenetic trees, while social wasps diverged from the most recent nodes. These data suggest that antimicrobial defences may have evolved in response to ground-dwelling pathogens but the most important variable leading to increased antimicrobial strength was increase in group size and social complexity

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia

Chronic limb-threatening ischemia (CLTI)is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG)are focused on definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD)in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI)is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR)hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP)and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen)has not been established. Regenerative medicine approaches (eg, cell, gene therapies)for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative. © 2019 Society for Vascular Surgery and European Society for Vascular Surger

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

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