Matrix Gla protein and the long-term incidence and progression of coronary artery and aortic calcification in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Matrix Gla protein (MGP) is an inhibitor of calcification that requires carboxylation by vitamin K for activity. The inactive form of MGP, dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP), has been associated with increased calcification. However, it is not known whether there is a longitudinal relationship between dephosphorylated-uncarboxylated matrix Gla protein levels and coronary and aortic calcification in large population cohorts. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) followed participants with serial cardiac computed tomography (CT) measures of vascular calcification. Dp-ucMGP was measured at baseline in a subset of participants who completed baseline and follow-up CTs approximately 10 years later and had available plasma specimens (n = 2663). Linear mixed effects models (LMMs) were used to determine the association of dp-ucMGP with the simultaneous incidence and progression of coronary artery, ascending thoracic aortic, or descending thoracic aortic calcification (CAC, ATAC, DTAC)]. RESULTS: For every one standard deviation (SD, 178 pmol/L) increment in dp-ucMGP, CAC increased by 3.44 ([95% CI = 1.68, 5.21], p < 0.001) Agatston units/year (AU/year), ATAC increased by 0.63 ([95% CI = 0.27, 0.98], p = 0.001) AU/year, and DTAC increased by 8.61 ([95% CI = 4.55, 12.67], p < 0.001) AU/year. The association was stronger for DTAC in those ≥65 years and with diabetes. CONCLUSIONS: We found a positive association of the inactive form of matrix Gla protein, dp-ucMGP, and long-term incidence/progression of CAC, ATAC, and DTAC. Future studies should investigate dp-ucMGP as a calcification regulator and MGP as a possible therapeutic target to slow progression of calcification in the vasculature.

HIV, HIV-specific Factors and Myocardial Disease in Women.

BACKGROUND: People with HIV (PWH) have an increased risk of cardiovascular disease (CVD). Cardiac magnetic resonance (CMR) has documented higher myocardial fibrosis, inflammation and steatosis in PWH, but studies have mostly relied on healthy volunteers as comparators and focused on men. METHODS: We investigated the associations of HIV and HIV-specific factors with CMR phenotypes in female participants enrolled in the Women's Interagency HIV Study's New York and San Francisco sites. Primary phenotypes included myocardial native (n) T1 (fibro-inflammation), extracellular volume fraction (ECV, fibrosis) and triglyceride content (steatosis). Associations were evaluated with multivariable linear regression, and results pooled or meta-analyzed across centers. RESULTS: Among 261 women with HIV (WWH, total n = 362), 76.2% had undetectable viremia at CMR. For the 82.8% receiving continuous antiretroviral therapy (ART) in the preceding 5 years, adherence was 51.7%, and 71.3% failed to achieve persistent viral suppression (42.2% with peak viral load < 200 cp/mL). Overall, WWH showed higher nT1 than women without HIV (WWOH) after full adjustment. This higher nT1 was more pronounced in those with antecedent or current viremia or nadir CD4+ count < 200 cells/µL, the latter also associated with higher ECV. WWH and current CD4+ count < 200 cells/µL had less cardiomyocyte steatosis. Cumulative exposure to specific ART showed no associations. CONCLUSIONS: Compared with sociodemographically similar WWOH, WWH on ART exhibit higher myocardial fibro-inflammation, which is more prominent with unsuppressed viremia or CD4+ lymphopenia. These findings support the importance of improved ART adherence strategies, along with better understanding of latent infection, to mitigate cardiac end-organ damage in this population.

Metabolomic Profiling of Cardiac Fibrosis and Steatosis in Women With or at Risk for HIV.

BACKGROUND: Heart failure is a prevalent disorder whose prognosis remains poor despite advances in treatment. Women with or at risk for HIV may be particularly susceptible, yet the metabolic pathways that promote myocardial disease and heart failure in this context remain incompletely characterized. METHODS: To evaluate the metabolomic signatures of cardiac magnetic resonance measured phenotypes, we used available plasma metabolomic measures from participants in the Women's Interagency HIV Study who underwent cardiac magnetic resonance imaging. Our primary outcomes were myocardial extracellular volume fraction (MECV) and intramyocardial triglyceride content (IMTG). We applied partial least squares and identified the top 10 lipid and polar metabolites associated with MECV and IMTG. We used multivariable linear regression to evaluate these metabolites' individual associations with each phenotype. RESULTS: The mean age of participants (n = 153) was 53 ± 7, 93% were Black or Hispanic, and 74% were HIV positive. Phenylacetylglutamine, a microbial metabolite, was positively associated with MECV after full adjustment and false discovery rate correction. Three phosphatidylcholine species, N-acetylaspartic acid, and a lysophosphatidylcholine species were inversely associated with IMTG, while prolylglycine, methionine sulfoxide, sphingosine, taurine, and phosphorylcholine were positively associated with this phenotype. We found no evidence of interaction by HIV for the observed associations, but there was effect modification by hepatitis C virus of taurine's and phosphorylcholine's associations with IMTG. CONCLUSION: Among women with or at risk for HIV, we related various lipid and polar metabolites to cardiac fibrosis or steatosis, of which phenylacetylglutamine, N-acetylaspartic acid, and prolylglycine are novel. These findings implicate plausible mechanisms that could be targetable for therapeutics.

Predictors of shortages of opioid analgesics in the US: Are the characteristics of the drug company the missing puzzle piece?

BACKGROUND: Shortages of opioid analgesics are increasingly common, interfere with patient care and increase healthcare cost. This study characterized the incidence of shortages of opioid analgesics in the period 2015-2019 and evaluated potential predictors to forecast the risk of shortages. METHODS: This was an observational retrospective study using the US Food and Drug Administration (FDA) drug shortages data. All FDA approved opioids were included in the study. Opioid analgesics were identified using the FDA National Drug Codes (NDC) and classified according to the Drug Enforcement Administration (DEA) schedule. We conducted Least Absolute Shrinkage and Selection Operator logistic regression analysis to assess direction of the association between risk of shortage and potential predictors. We used multivariable penalized logistic regression analysis to model predictors of shortages. We split the dataset into training and validation sets to evaluate the performance of the model. FINDINGS: The FDA approved 8,207 unique NDCs for opioid analgesics; 3,017 (36.8%) were in the market as of April 30, 2019 and 91(3.0%) of them were listed as in shortage by the FDA. All NDCs in shortage were schedule II opioids; 86 (94.5%) were injectable and 84 (92.3%) generics. There were 418 companies with at least one opioid NDC listed by the FDA. Three companies accounted for more than 4 in 5 of the schedule II active injectable opioids. For each unit increase in the number of prior instances of shortages of a company, the likelihood of an NDC shortage for that company increased by 3.4%. For each unit increase in number of NDCs marketed by a company, the odds of an NDC shortage for that company decreased by 1%. CONCLUSIONS: In the period 2015-2019, shortages of opioid analgesics disproportionally impacted schedule II and injectable opioids. The risk of shortage of opioid analgesics significantly increased with the incidence of previous instances of shortages of a manufacturing company and decreased with the number of NDCs marketed by a company. The characteristics of the manufacturing company, rather than the number of companies, might be the missing piece to the complex puzzle of drug shortages in the US.

Perioperative Prescribing Practices of Extended-Release Opioids in Noncancer Surgical Patients, 2015-2018.

BACKGROUND: Extended-release (ER) opioids are indicated for the management of persistent moderate to severe pain in patients requiring around-the-clock opioid analgesics for an extended period of time. Concerns have been raised regarding safety of ER opioids due to its potential for abuse and dependence. However, little is known about perioperative prescribing practices of ER opioids. This study assessed perioperative prescribing practices of ER opioids in noncancer surgical patients stratified by type of opioid exposure prior to admission and examined predictors of postoperative opioid administration in oral morphine equivalents (OME). METHODS: This was a retrospective cohort study using the University of California San Francisco Medical Center electronic health record data. This study included 25,396 adult noncancer patients undergoing elective surgery under general anesthesia in the period 2015-2018. The primary study outcome was predictors of postoperative administration of opioids in hospitalized surgical patients. Secondary outcomes included patients discontinued and initiated on ER opioids during their hospital stay. RESULTS: substance use disorder diagnosis and use of opioids, surgery type, and postoperative administration of nonopioid analgesics were associated with postoperative administration of opioids (P < .0001). The estimated adjusted mean (95% confidence interval [CI]) of postoperative administration of OME prior to admission in ER opioid users (170.08 mg; 147.08-196.67) was twice the amount for opioid-naïve patients (81.36 mg; 70.7-93.63; P < .0001). One in 5 prior to admission ER opioid users were weaned off ER opioids while hospitalized without adversely affecting their postoperative pain or hospital length of stay (LOS). Four of 5 patients who used ER opioids prior to admission also received ER opioids after surgery, whereas, 1 in 100 opioid-naïve patients received ER opioids during their hospital stay. CONCLUSIONS: We found significant variability in the perioperative prescribing practices of ER opioids in hospitalized noncancer surgical patients by use of opioids prior to admission and surgery type. Pain medicine practitioners and surgeons may play a significant role tackling the surgery-related risk of exposure to ER opioids and decreasing opioid-related complications.

Estimating the basic reproductive ratio for the Ebola outbreak in Liberia and Sierra Leone.

BACKGROUND: Ebola virus disease has reemerged as a major public health crisis in Africa, with isolated cases also observed globally, during the current outbreak. METHODS: To estimate the basic reproductive ratio R0, which is a measure of the severity of the outbreak, we developed a SEIR (susceptible-exposed-infected-recovered) type deterministic model, and used data from the Centers for Disease Control and Prevention (CDC), for the Ebola outbreak in Liberia and Sierra Leone. Two different data sets are available: one with raw reported data and one with corrected data (as the CDC suspects under-reporting). RESULTS: Using a deterministic ordinary differential equation transmission model for Ebola epidemic, the basic reproductive ratio R0 for Liberia resulted to be 1.757 and 1.9 for corrected and uncorrected case data, respectively. For Sierra Leone, R0 resulted to be 1.492 and 1.362 for corrected and uncorrected case data, respectively. In each of the two cases we considered, the estimate for the basic reproductive ratio was initially greater than unity leading to an epidemic outbreak. CONCLUSION: We obtained robust estimates for the value of R0 associated with the 2014 Ebola outbreak, and showed that there is close agreement between our estimates of R0. Analysis of our model also showed that effective isolation is required, with the contact rate in isolation less than one quarter of that for the infected non-isolated population, and that the fraction of high-risk individuals must be brought to less than 10% of the overall susceptible population, in order to bring the value of R0 to less than 1, and hence control the outbreak.