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Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious drug-related adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate therapy, we conducted a genomewide association study (GWAS) meta-analysis followed by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates, which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls). Discovery GWAS was performed in randomly selected 70% of the patients with cancer and replication GWAS was performed in the remaining 30% of the patients with cancer treated with intravenous bisphosphonates followed by meta-analysis of all 3,639 patients with cancer. GWAS was also performed in 1,369 patients with osteoporosis treated with oral bisphosphonates. The lead single-nucleotide polymorphism (SNP), rs2736308 on chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR) of 2.71 and 95% confidence interval (CI) of 1.90–3.86 (P=3.57*10−8) in the meta-analysis of patients with cancer. This SNP was validated in the MRONJ GWAS in patients with osteoporosis (OR: 2.82, 95% CI: 1.55–4.09, P=6.84*10−4). The meta-analysis combining patients with cancer and patients with osteoporosis yielded the same lead SNP rs2736308 on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09–3.39, P=9.65*10−11). This locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been associated with bone mineral density. FDFT1 encodes a membrane-associated enzyme, which is implicated in the bisphosphonate pathway. This study provides insights into the potential mechanism of MRONJ.

Pharmacogenetics (PGx) association studies are used to discover, replicate, and validate the association between an inherited genotype and a treatment outcome. The objective of this tutorial is to provide trainees and novice PGx researchers with an overview of the major decisions that need to be made when designing and conducting a PGx association study. The first critical decision is to determine whether the objective of the study is discovery, replication, or validation. Next, the researcher must identify a patient cohort that has all of the data necessary to conduct the intended analysis. Then, the investigator must select and define the treatment outcome, or phenotype, that will be analyzed. Next, the investigator must determine what genotyping approach and genetic data will be included in the analysis. Finally, the association between the genotype and phenotype is tested using some statistical analysis methodology. This tutorial is divided into five sections; each section describes commonly used approaches and provides suggestions and resources for designing and conducting a PGx association study. Successful PGx association studies are necessary to discover and validate associations between inherited genetic variation and treatment outcomes, which enable clinical translation to improve efficacy and reduce toxicity of treatment.

Advances in cancer treatment have significantly improved the survival of patients with cancer, but, unfortunately, many of these treatments also have long‐term complications. Cancer treatment‐related cardiotoxicities are becoming a significant clinical problem that a new discipline, Cardio‐Oncology, was established to advance the cardiovascular care of patients with growing cancer populations. Anthracyclines are a class of chemotherapeutic agents used to treat many cancers in adults and children. Their clinical use is limited by anthracycline‐induced cardiotoxicity (AIC), which can lead to heart failure. Early‐onset cardiotoxicity appears within a year of treatment, whereas late‐onset cardiotoxicity occurs > 1 year and even up to decades after treatment completion. The pathophysiology of AIC was hypothesized to be caused by generation of reactive oxygen species that lead to lipid peroxidation, defective mitochondrial biogenesis, and DNA damage of the cardiomyocytes. The accumulation of anthracycline metabolites was also proposed to cause mitochondrial damage and the induction of cardiac cell apoptosis, which induces arrhythmias, contractile dysfunction, and cardiomyocyte death. This paper will provide a general overview of cardiotoxicity focusing on the effect of anthracyclines and their epigenetic molecular mechanisms on cardiotoxicity.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug reaction. Our previous whole-exome sequencing study found SIRT1 intronic region single-nucleotide polymorphism (SNP) rs7896005 to be associated with MRONJ in cancer patients treated with intravenous (iv) bisphosphonates (BPs). This study aimed to identify causal variants for this association. In silico analyses identified three SNPs (rs3758391, rs932658, and rs2394443) in the SIRT1 promoter region that are in high linkage disequilibrium (r2 > 0.8) with rs7896005. To validate the association between these SNPs and MRONJ, we genotyped these three SNPs on the germline DNA from 104 cancer patients of European ancestry treated with iv BPs (46 cases and 58 controls). Multivariable logistic regression analysis showed the minor alleles of these three SNPs were associated with lower odds for MRONJ. The odds ratios (95% confidence interval) and p values were 0.351 (0.164-0.751; p = 0.007) for rs3758391, 0.351 (0.164-0.751; p = 0.007) for rs932658, and 0.331 (0.157-0.697; p = 0.0036) for rs2394443, respectively. In the reporter gene assays, constructs containing rs932658 with variant allele A had higher luciferase activity than the reference allele, whereas constructs containing SNP rs3758391 and/or rs2394443 did not significantly affect activity. These results indicate that the promoter SNP rs932658 regulates the expression of SIRT1 and presumably lowers the risk of MRONJ by increasing SIRT1 expression. © 2020 American Society for Bone and Mineral Research (ASBMR).

Introduction In intensive care unit (ICU) patients, delirium is frequent, occurs early in ICU admission, and is associated with poor outcomes. Risk models based on clinical factors have shown variable performance in terms of predictive ability. Identification of a candidate biomarker that associates with delirium may lead to a better understanding of disease mechanism, validation biomarker studies, and the ability to develop targeted interventions for prevention and treatment of delirium. This study analyzed metabolite concentrations early in the course of ICU admission to assess the association with delirium onset. Methods Within 24 hours of ICU admission, blood samples for global and targeted metabolomics analyses in adult surgical ICU patients were collected prospectively. Metabolites were determined using mass spectrometry/ultra-high-pressure liquid chromatography and analyzed in patients with delirium and a group of controls matched on age, sex, and admission Sequential Organ Function Assessment (SOFA) score. Results Patients in the study (65 per group) were a mean age of 59 years, had a median SOFA score of 6, and were most commonly admitted to the ICU following major trauma. In the delirium group, median onset of delirium was 3 (interquartile range 1-6) days, and the most common delirium subtype was mixed (56%). Kynurenic acid was significantly increased, and tryptophan concentration was significantly decreased in the delirium group (p=0.04). The ratio of kynurenine-to-tryptophan concentration was significantly higher in the delirium group (p=0.005). Conclusions Evidence of upregulation was found in the tryptophan metabolic pathway in delirious patients because tryptophan concentrations were lower, tryptophan metabolites were higher, and the kynurenine-to-tryptophan ratio was increased. These findings suggest a role of increased inflammation and accumulation of neurotoxic metabolites in the pathogenesis of ICU delirium. Future studies should target this pathway to validate metabolites in the tryptophan pathway as risk biomarkers in patients with ICU delirium.

Purpose Monoclonal gammopathy of undetermined significance (MGUS) is a prevalent yet largely asymptomatic precursor to multiple myeloma. Patients with MGUS must undergo regular surveillance and testing, with few known predictors of progression. We developed an algorithm to identify MGUS patients in electronic health data to facilitate large-scale, population-based studies of this premalignant condition. Methods We developed a four-step algorithm using electronic health record and health claims data from men and women aged 50 years or older receiving care from a large, multispecialty medical group between 2007 and 2015. The case definition required patients to have at least two MGUS ICD-9 diagnosis codes within 12 months, at least one serum and/or urine protein electrophoresis and one immunofixation test, and at least one in-office hematology/oncology visit. Medical charts for selected cases were abstracted then adjudicated independently by two physicians. We assessed algorithm validity by positive predictive value (PPV). Results We identified 833 people with at least two MGUS diagnosis codes; 429 (52%) met all four algorithm criteria. We randomly selected 252 charts for review, including 206 from patients meeting all four algorithm criteria. The PPV for the 206 algorithm-identified charts was 76% (95% CI, 70%-82%). Among the 49 cases deemed to be false positives (24%), 33 were judged to have multiple myeloma or another lymphoproliferative condition, such as lymphoma. Conclusions We developed a simple algorithm that identified MGUS cases in electronic health data with reasonable accuracy. Inclusion of additional steps to eliminate cases with malignant disease may improve algorithm performance.

Purpose Two previously validated algorithms to identify sudden cardiac death using administrative data showed high positive predictive value. We evaluated the agreement between the algorithms using data from a common source population. Methods We conducted a cross-sectional study to assess the percent agreement between deaths identified by two sudden cardiac death algorithms using Tennessee Medicaid and death certificate data from 2007 through 2014. The source population included all deceased patients aged 18 to 64 years with Medicaid enrollment in the 6 months prior to death. To identify sudden cardiac deaths, algorithm 1 used only hospital/emergency department (ED) claims from encounters at the time of death, and algorithm 2 required death certificates and used claims data for specific exclusion criteria. Results We identified 34 107 deaths in the source population over the study period. The two algorithms identified 4372 potential sudden cardiac deaths: Algorithm 1 identified 3117 (71.3%) and algorithm 2 identified 1715 (39.2%), with 460 (10.5%) deaths identified by both algorithms. Of the deaths identified by algorithm 1, 1943 (62.3%) had an underlying cause of death not specified in algorithm 2. Of the deaths identified by algorithm 2, 1053 (61.4%) had no record of a hospital or ED encounter at the time of death, and 202 (11.8%) had a discharge diagnosis code not specified in algorithm 1. Conclusions We found low agreement between the two algorithms for identification of sudden cardiac deaths because of differences in sudden cardiac death definitions and data sources.

Objectives To determine the efficacy and safety of statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) events in older adults, especially those aged 80 and older and with multimorbidity. Methods The National Institute on Aging and the National Heart, Lung and Blood Institute convened A multidisciplinary expert panel from July 31 to August 1, 2017, to review existing evidence, identify knowledge gaps, and consider whether statin safety and efficacy data in persons aged 75 and older without ASCVD are sufficient; whether existing data can inform the feasibility, design, and implementation of future statin trials in older adults; and clinical trial options and designs to address knowledge gaps. This article summarizes the presentations and discussions at that workshop. Results There is insufficient evidence regarding the benefits and harms of statins in older adults, especially those with concomitant frailty, polypharmacy, comorbidities, and cognitive impairment; a lack of tools to assess ASCVD risk in those aged 80 and older; and a paucity of evidence of the effect of statins on outcomes of importance to older adults, such as statin‐associated muscle symptoms, cognitive function, and incident diabetes mellitus. Prospective, traditional, placebo‐controlled, randomized clinical trials (RCTs) and pragmatic RCTs seem to be suitable options to address these critical knowledge gaps. Future trials have to consider greater representation of very old adults, women, underrepresented minorities, and individuals of differing health, cognitive, socioeconomic, and educational backgrounds. Feasibility analyses from existing large healthcare networks confirm appropriate power for death and cardiovascular outcomes for future RCTs in this area. Conclusion Existing data cannot address uncertainties about the benefits and harms of statins for primary ASCVD prevention in adults aged 75 and older, especially those with comorbidities, frailty, and cognitive impairment. Evidence from 1 or more RCTs could address these important knowledge gaps to inform person‐centered decision‐making. J Am Geriatr Soc 66:2188–2196, 2018.

Aims Since 2005, several glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been approved to treat people with type 2 diabetes. These agents are considered for use at the same point in the treatment paradigm as basal insulins. A comprehensive comparison of these drug classes, therefore, can help inform treatment decisions. This systematic review and meta-analysis assessed the clinical efficacy and safety of GLP-1 RAs compared with basal insulins. Materials and methods MEDLINE, EMBASE, CENTRAL and PubMed databases were searched. Randomized clinical trials (RCTs) of ≥16 weeks’ duration comparing GLP-1 RAs versus basal insulins in adults with type 2 diabetes inadequately controlled with oral antihyperglycemic drugs were included. Data were extracted on the change from baseline to 26 weeks (±10 weeks) of treatment in hemoglobin A1c (HbA1c) and weight, as well as the proportion of patients experiencing hypoglycemia. Fixed-effect pairwise meta-analyses were conducted where data were available from ≥ two studies. Results Fifteen RCTs were identified and 11 meta-analysed. The once-weekly GLP-1 RAs, exenatide long acting release (LAR) and dulaglutide, led to greater, statistically significant mean HbA1c reductions versus basal insulins (exenatide: -0.31% [95% confidence interval -0.42, -0.19], dulaglutide: -0.39% [-0.49, -0.29]) whilst once-daily liraglutide and twice-daily exenatide did not (liraglutide: 0.06% [-0.06, 0.18], exenatide: 0.01% [-0.11, 0.13]). Mean weight reduction was seen with all GLP-1 RAs while mean weight gain was seen with basal insulins Interpretation of the analysis of hypoglycemia was limited by inconsistent definitions and reporting. Due to the limited number of available studies sensitivity analyses to explore heterogeneity could not be conducted. Conclusions Although weight reduction is seen with all GLP-1RA’s, only the once weekly agents, exenatide LAR and dulaglutide, demonstrate significant HbA1c reductions when compared to basal insulins.

Aims To determine whether thiazolidinedione use is associated with a risk of bladder cancer.

Summary Background Selective serotonin reuptake inhibitors (SSRIs) have been associated with upper gastrointestinal haemorrhage (UGIH) but the magnitude and characteristics of this reaction and possible interaction with concurrent Non-Steroidal Anti-Inflammatory Drug (NSAID) therapy are unknown. Aim To evaluate systematically the risk of UGIH with SSRIs, including interaction with NSAIDs. Methods We searched PubMED, Science Citation Index, and trial registries for data on SSRIs, NSAIDs and UGIH. We evaluated spontaneous case reports from pharmacovigilance databases. Results Random effects meta-analysis of four observational studies involving 153 000 patients showed an odds ratio of 2.36 (95% CI: 1.44–3.85; P = 0.0006) for SSRI associated UGIH. The odds ratio increased to 6.33 (95% CI: 3.40–11.8; P

Fortilin, a 172-amino acid polypeptide with potent anti-apoptotic activity, is ubiquitously expressed in normal tissues. It had been validated through calcium-overlay assays that fortilin binds cal...

Gravin is an A-Kinase Anchoring Protein (AKAP) that scaffolds protein kinase A (PKA), protein kinase C (PKC), phosphatase 2B, β2-adrenergic receptors to specific subcellular compartments. Studies show that scaffolding of PKC by gravin decreases PKC activity due to sequestration. Also, PKC is involved in the translocation and distribution of gravin. Our goal is to study the role of gravin in PKC signaling in the heart. Basal PKC activity in the cytosolic fractions of the homogenized hearts was found to be greater in gravin truncated (t/t) mice as compared to wild type (WT). This correlation was preserved following stimulation of the samples with a PKC activator, PMA (Phorbol 12-myristate 13-acetate). However, no change was observed in the extent of PKC substrate phosphorylation between these groups. It supports previous studies that PKC scaffolding by gravin decreases PKC activity. The next step is to study the effect of PKC on gravin translocation in cardiomyocytes using PKC activator PMA and inhibitor ch...