Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial.

Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7-48.8) months for pembrolizumab and 39.8 (31.7-47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4-22.5%) for pembrolizumab and 11.7% (6.8-17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3-13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0-23.4%) for pembrolizumab and 4.4% (1.6-9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC.

Effects of Ertugliflozin on Kidney Outcomes in Patients With Heart Failure at Baseline in the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS CV) Trial.

Introduction: In the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881), patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) were randomized (1:1:1) to placebo, ertugliflozin 5 mg or 15 mg (doses pooled for analyses as prospectively planned). In this post hoc analysis, the effects of ertugliflozin on kidney outcomes were assessed in analyses stratified by baseline heart failure (HF). Methods: Baseline HF was defined as a history of HF or prerandomization left ventricular ejection fraction ≤45%. Outcomes included estimated glomerular filtration rate (eGFR) over time, total 5-year eGFR slopes and time to first event of a prespecified exploratory kidney composite outcome of sustained ≥40% decrease from baseline eGFR, chronic kidney replacement therapy, or kidney death. All analyses were stratified by baseline HF status. Results: Compared with no-HF at baseline (n = 5807; 70.4%), patients with HF (n = 2439; 29.6%) had a notably faster rate of eGFR decline, which is unlikely to be explained by the slightly lower baseline eGFR in that group. Ertugliflozin treatment resulted in a slower rate of eGFR decline in both subgroups; total placebo-adjusted 5-year eGFR slopes (ml/min per 1.73 m2 per year [95% confidence intervals; CI]) were 0.96 (0.67-1.24) and 0.95 (0.76-1.14) for HF and no-HF subgroups, respectively. The placebo HF (vs. placebo no-HF) subgroup had a higher incidence of the composite kidney outcome (35/834 [4.20%] vs. 50/1913 [2.61%]). Hazard ratios (95% CI) for the effect of ertugliflozin on the composite kidney outcome did not differ significantly between HF and no-HF subgroups: 0.53 (0.33-0.84) and 0.76 (0.53-1.08), respectively (P interaction  = 0.22). Conclusion: Although patients with HF at baseline had a faster rate of eGFR decline in VERTIS CV, the beneficial effects of ertugliflozin on kidney outcomes did not differ when stratified by baseline HF.

Heart and Kidney Outcomes With Ertugliflozin in People with Non-albuminuric Diabetic Kidney Disease: A post hoc Analysis from the Randomized VERTIS CV Trial.

Introduction: Using data from the VERTIS CV trial (NCT01986881), the impact of ertugliflozin in patients with nonalbuminuric diabetic kidney disease (DKD-non-Alb) was assessed. Methods: Patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) were randomized to ertugliflozin or placebo. Subgroups were defined by estimated glomerular filtration rate (eGFR) (ml/min per 1.73 m2) and urinary albumin-to-creatinine ratios (UACRs) (mg/g): DKD-Non-Alb (eGFR < 60 + UACR < 30, n = 867); Alb DKD stage 3 (DKD stage 3 Alb, eGFR < 60 + UACR ≥ 30, n = 891); Alb DKD stages 1 + 2 (DKD stages 1-2 Alb, eGFR ≥ 60 + UACR ≥ 30, n = 2356); and no DKD (non-DKD, eGFR ≥ 60 + UACR < 30, n = 3916). eGFR slopes, eGFR and UACR over time, time to first event of a prespecified exploratory kidney composite outcome, albuminuria progression, and hospitalization for heart failure (HHF) were assessed. Results: Total eGFR slopes (ml/min per 1.73 m2 per year; weeks 0-260) with placebo were -0.23, -1.27, -2.29, and -1.19 for the DKD-Non-Alb, DKD stage 3 Alb, DKD stages 1 to 2 Alb, and non-DKD subgroups, respectively (P < 0.0001). Similar trends were found with ertugliflozin but with reduced rates of decline. Ertugliflozin treatment resulted in a significant reduction in the risk for albuminuria progression across subgroups, with Alb subgroups having the largest relative risk reduction (Pinteraction = 0.04). The hazard ratios (HRs) for ertugliflozin revealing reduction in the risk of the exploratory kidney composite outcome versus placebo was consistent across subgroups (Pinteraction = 0.34). Alb and the DKD-non-Alb subgroups had a larger relative risk reduction in the HHF outcome compared with other subgroups (Pinteraction = 0.046). Conclusion: Among the subgroups, participants with DKD-non-Alb had the slowest rate of eGFR decline. Ertugliflozin treatment resulted in reductions in albuminuria and slower decline in eGFR across subgroups. The effect of ertugliflozin on the HHF outcome was larger in those with more advanced kidney disease.

Initial eGFR Changes with Ertugliflozin and Associations with Clinical Parameters: Analyses from the VERTIS CV Trial.

INTRODUCTION: Using data from the ertugliflozin cardiovascular outcomes trial in patients with type 2 diabetes mellitus (VERTIS CV; NCT01986881), associations between the initial estimated glomerular filtration rate (eGFR) "dip" with eGFR slope, glucosuria/natriuresis-related measures, and safety were investigated. METHODS: Patients were categorized into tertiles based on change in eGFR at week 6: >+1.00 mL/min/1.73 m2 (tertile 1), >-5.99 and ≤+1.00 (tertile 2), and ≤-6.00 (tertile 3). eGFR slope after week 6 and week 18 was assessed by tertile. Glucosuria/natriuresis-related measures were also determined. Adverse events (AEs) were analyzed in the acute (baseline-week 6) and chronic periods (week 6-30 days after last dose of trial medication). RESULTS: In the ertugliflozin group, chronic eGFR slopes (95% CI, mL/min/1.73 m2/year; weeks 6-156) were -0.76 (-1.03, -0.50), -0.29 (-0.51, -0.07), and -0.05 (-0.26, 0.17) in tertiles 1, 2, and 3, respectively (p value <0.001), and approximately -1.5 mL/min/1.73 m2/year across tertiles in the placebo group (p value = 0.79). At week 18, least squares mean (LSM) changes from baseline in glycated hemoglobin (%) were -0.77, -0.71, and -0.67 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; a similar tertile-associated trend was observed for uric acid. At week 18, LSM changes from baseline in hematocrit (%) were 2.07, 2.33, and 2.55 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; similar tertile-associated trends were observed for blood pressure. All pinteraction values were <0.0001 for glucosuria- and natriuresis-related measures. Kidney-related AEs were reported more frequently in tertiles 3 and 2 in the chronic period for both placebo- and ertugliflozin-treated groups. In both periods and in all tertiles, incidences of AEs did not differ between placebo- and ertugliflozin-treated groups. CONCLUSION: With ertugliflozin, the tertile with the largest initial dip in eGFR had a slower rate of chronic eGFR decline. Initial eGFR changes were associated with changes in both glucosuria- and natriuresis-related measures.

Mediators of ertugliflozin effects on heart failure and kidney outcomes among patients with type 2 diabetes mellitus.

AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of hospitalization for heart failure (HHF) and composite kidney outcomes, but the mediators underlying these benefits are unknown. MATERIALS AND METHODS: Among participants from VERTIS CV, a trial of patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease randomized to ertugliflozin versus placebo, Cox proportional hazards regression models were used to evaluate the percentage mediation of ertugliflozin efficacy on the first HHF and kidney composite outcome in 26 potential mediators. Time-dependent approaches were used to evaluate associations between early (change from baseline to the first post-baseline measurement) and average (weighted average of change from baseline using all post-baseline measurements) changes in covariates with clinical outcomes. RESULTS: For the HHF analyses, early changes in four biomarkers (haemoglobin, haematocrit, serum albumin and urate) and average changes in seven biomarkers (early biomarkers + weight, chloride and serum protein) were identified as fulfilling the criteria as mediators of ertugliflozin effects on the risk of HHF. Similar results were observed for the composite kidney outcome, with early changes in four biomarkers (glycated haemoglobin, haemoglobin, haematocrit and urate), and average changes in five biomarkers [early biomarkers (not glycated haemoglobin) + weight, serum albumin] mediating the effects of ertugliflozin on the kidney outcome. CONCLUSIONS: In these analyses from the VERTIS CV trial, markers of volume status and haemoconcentration and/or haematopoiesis were the strongest mediators of the effect of ertugliflozin on reducing risk of HHF and composite kidney outcomes in the early and average change periods. GOV IDENTIFIER: NCT01986881.

The differential effects of ertugliflozin on glucosuria and natriuresis biomarkers: Prespecified analyses from VERTIS CV.

AIMS: This prespecified exploratory analyses from VERTIS CV (NCT01986881) aimed to assess the effects of the sodium-glucose cotransporter-2 (SGLT2) inhibitor ertugliflozin on glucosuria-related (glycated haemoglobin [HbA1c], uric acid, body weight) and natriuresis-related (blood pressure, haemoglobin, haematocrit, serum albumin) biomarkers according to kidney function risk category. MATERIALS AND METHODS: Patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg (1:1:1). Analyses compared placebo (n = 2747) versus ertugliflozin (pooled; n = 5499) on glucosuria- and natriuresis-related biomarkers according to baseline estimated glomerular filtration rate (eGFR) subgroup and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) risk category. RESULTS: Patients were classified according to KDIGO CKD low- (49%), moderate- (32%) and high-/very-high-risk categories (19%), and eGFR groups 1 (25%), 2 (53%) and 3 (19%). At Week 18, the high-/very-high-risk category had a smaller placebo-subtracted least squares mean (LSM) change from baseline (95% confidence interval) in HbA1c (-0.34 [-0.43, -0.25]) compared with the low- and moderate-risk categories (-0.54 [-0.60, -0.49] and - 0.47 [-0.54, -0.40], respectively). This pattern was maintained throughout the study (Pinteraction  = 0.0001). Similar patterns based on baseline eGFR G stage were observed. Placebo-subtracted LSM changes from baseline in uric acid were lowest in the high-/very-high-risk category at Weeks 6 and 18, but the pattern was not maintained after Week 156 (Pinteraction  = 0.15). Effects of ertugliflozin on body weight and natriuresis-related biomarkers did not differ across KDIGO CKD categories. CONCLUSIONS: In VERTIS CV, ertugliflozin was associated with physiologically favourable changes in glucosuria- and natriuresis-related biomarkers. Glycaemic efficacy of ertugliflozin was attenuated in patients with higher chronic kidney disease (CKD) risk. Effects on other biomarkers were consistent, regardless of CKD risk stage.

Ertugliflozin and Slope of Chronic eGFR: Prespecified Analyses from the Randomized VERTIS CV Trial.

BACKGROUND AND OBJECTIVES: A reduction in the rate of eGFR decline, with preservation of ≥0.75 ml/min per 1.73 m2 per year, has been proposed as a surrogate for kidney disease progression. We report results from prespecified analyses assessing effects of ertugliflozin versus placebo on eGFR slope from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease were randomized to placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg (1:1:1). The analyses compared the effect of ertugliflozin (pooled doses, n=5499) versus placebo (n=2747) on eGFR slope per week and per year by random coefficient models. Study periods (weeks 0-6 and weeks 6-52) and total and chronic slopes (week 0 or week 6 to weeks 104, 156, 208, and 260) were modeled separately and by baseline kidney status. RESULTS: In the overall population, for weeks 0-6, the least squares mean eGFR slopes (ml/min per 1.73 m2 per week [95% confidence interval (95% CI)]) were -0.07 (-0.16 to 0.03) and -0.54 (-0.61 to -0.48) for the placebo and ertugliflozin groups, respectively; the difference was -0.47 (-0.59 to -0.36). During weeks 6-52, least squares mean eGFR slopes (ml/min per 1.73 m2 per year [95% CI]) were -0.12 (-0.70 to 0.46) and 1.62 (1.21 to 2.02) for the placebo and ertugliflozin groups, respectively; the difference was 1.74 (1.03 to 2.45). For weeks 6-156, least squares mean eGFR slopes (ml/min per 1.73 m2 per year [95% CI]) were -1.51 (-1.70 to -1.32) and -0.32 (-0.45 to -0.19) for the placebo and ertugliflozin groups, respectively; the difference was 1.19 (0.95 to 1.42). During weeks 0-156, the placebo-adjusted difference in least squares mean slope was 1.06 (0.85 to 1.27). These findings were consistent by baseline kidney status. CONCLUSIONS: Ertugliflozin has a favorable placebo-adjusted eGFR slope >0.75 ml/min per 1.73 m2 per year, documenting the kidney function preservation underlying the clinical benefits of ertugliflozin on kidney disease progression in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: US National Library of Medicine, ClinicalTrials.gov NCT01986881. Date of trial registration: November 13, 2013.

Switching stable patients with schizophrenia from their oral antipsychotics to aripiprazole lauroxil: a post hoc safety analysis of the initial 12-week crossover period.

OBJECTIVE: Switching antipsychotic medications is common in patients with schizophrenia who are experiencing persistent symptoms or tolerability issues associated with their current drug regimen. This analysis assessed the safety of switching from an oral antipsychotic to the long-acting injectable antipsychotic aripiprazole lauroxil (AL). METHODS: This was a post hoc analysis of outpatients with schizophrenia who were prescribed an oral antipsychotic and who enrolled in an international, open-label, long-term (52-week) safety study of AL. The analysis focused on the first 3 injections of AL 882 mg over 12 weeks, divided into the immediate 4-week crossover period between the first and second AL injections (initiation phase) and the subsequent 8 weeks (stabilization phase). Patients were grouped by preswitch oral antipsychotic medication, and safety and clinical symptoms were assessed. RESULTS: In total, 190 patients had switched from one of the following oral antipsychotic medications: aripiprazole, conventional antipsychotics, risperidone/paliperidone, olanzapine, or quetiapine. The 12-week completion rate was high (92.1%) and similar across the different preswitch oral antipsychotic groups. Overall, adverse event (AE) rates experienced over 12 weeks were modest; no AEs were considered serious. The most common AEs in the initiation phase were injection site pain (5.8%), insomnia (5.8%), and akathisia (3.2%). No apparent relationship was observed between preswitch medication and early-onset AEs. Mean Positive and Negative Syndrome Scale total scores remained stable during this period across preswitch antipsychotic groups. CONCLUSION: Switching from an oral antipsychotic to AL was feasible in an outpatient setting for patients with schizophrenia, and the 12-week retention rate was favorable.

Extended-release naltrexone (XR-NTX) for opioid use disorder in clinical practice: Vivitrol's Cost and Treatment Outcomes Registry.

BACKGROUND AND AIMS: Extended-release naltrexone (XR-NTX), a µ-opioid receptor antagonist for prevention of relapse to opioid dependence, has demonstrated efficacy compared with placebo and comparative effectiveness with buprenorphine-naloxone. We report outcomes for XR-NTX in Vivitrol's Cost and Treatment Outcomes Registry. DESIGN: Observational, open-label, single-arm, multi-center registry assessing baseline characteristics and clinical and health-related quality-of-life outcomes associated with XR-NTX treatment in clinical practice. SETTING: 32 US treatment centers from 2011 to 2013. PARTICIPANTS: Patients with opioid dependence who were prescribed XR-NTX treatment and then enrolled into the registry. MEASUREMENTS: Monthly visits were evaluated for the full population and for patient ubgroups retrospectively, defined by injection number, focusing on the period between baseline and month 6 (1-, 2/3- or 6-XR-NTX). FINDINGS: Of 403 enrolled patients, 395 were analyzed. Most patients (n = 349) received out-patient care. On average, patients received five injections (median = 3; range = 1-25). The median number of injections administered within 6 months was higher in patients who at baseline were employed (three versus two unemployed, P = 0.02) or had private insurance (five versus two self-payment, P = 0.005; versus two state-funded, P < 0.001). The 1-, 2/3- and 6-XR-NTX groups had 132, 152 and 111 patients, respectively. At baseline, the 6-XR-NTX patients were more likely to meet normal/minimal mental illness criteria and attend school and less likely to report recent drug use. Within 6 months, the 6-XR-NTX group demonstrated improvements in employment, mental health and psychosocial functioning, and decreases in opioid craving, drug use and drug-related behavior. CONCLUSIONS: Among opioid-dependent people receiving XR-NTX treatment, better mental health, higher education and lower recent drug use at baseline are associated with greater treatment duration; in turn, longer treatment duration is associated with lower relapse rates and improved outcomes generally.

Prevalence and comparative analysis of the type IV secretion system in Aggregatibacter actinomycetemcomitan.

BACKGROUD/PURPOSE: Aggregatibacter actinomycetemcomitans has emerged as one of the aetiological agents in periodontal disease. Although Type IV secretion systems (T4SSs) are widely distributed in many bacteria, the genetic features and distribution of T4SSs in A. actinomycetemcomitans remain unclear. In this study, we investigated the prevalence of A. actinomycetemcomitans serotypes and their T4SSs in a Taiwanese population. METHODS: A comparative analysis of 20 A. actinomycetemcomitans genomes and their T4SSs deposited in GenBank was performed. One hundred subjects, including 20 periodontitis and 80 normal subjects, were enrolled and PCR identification of A. actinomycetemcomitans serotypes and T4SS genes were performed. RESULTS: Of 100 subjects, serotypes C (22%) and E (11%) were most common. In addition, T4SSs were distributed in all of the serotypes. The prevalence of T4SSs and their location in plasmids in periodontitis subjects were 1.28-2 fold higher but not significantly different compared to normal subjects. Of 20 A. actinomycetemcomitans genomes, only ten with complete T4SS modules could be detected, which was highly correlated with localized aggressive periodontitis (p < 0.1). Nine of ten T4SS modules were from periodontitis subjects. Phylogenetic analysis of 10 T4SSs in A. actinomycetemcomitans showed that they were clustered into two groups, T4SSAaI and T4SSAaII, with only T4SSAaI appearing in the Taiwanese subjects. CONCLUSION: A. actinomycetemcomitans strains with different serotypes carrying T4SSAaI are widely distributed in a Taiwanese population. This is the first report to show the distribution and detailed comparative genomics of T4SSs in A. actinomycetemcomitans.

Durability of Therapeutic Response With Long-Term Aripiprazole Lauroxil Treatment Following Successful Resolution of an Acute Episode of Schizophrenia.

OBJECTIVE: To evaluate durability of therapeutic effect of long-term treatment with aripiprazole lauroxil in patients with schizophrenia following successful treatment of an acute psychotic episode. METHODS: This post hoc analysis assessed long-term outcomes for a subgroup of patients who entered a 52-week extension study after being successfully stabilized with one of 2 doses of aripiprazole lauroxil (441 or 882 mg) in a pivotal 12-week, placebo-controlled, randomized clinical trial. Durability of therapeutic effect was measured by the proportion of patients completing the 1-year course of aripiprazole lauroxil, the trajectories of the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity (CGI-S) item scores beyond the first 12 weeks, and the likelihood of remission at any follow-up point. RESULTS: In total, 181 patients treated with aripiprazole lauroxil entered the extension study; 73% and 66% of patients from the 441 mg and 882 mg groups, respectively, completed all 13 aripiprazole lauroxil treatments scheduled every 4 weeks over 52 weeks. Both groups continued on a positive trajectory of symptom improvements (P < .0001 for reductions in PANSS total and CGI-S scores from week 12 to end of follow-up). Most patients (74% and 68% in the aripiprazole lauroxil 441 mg and 882 mg groups, respectively) achieved remission during follow-up. CONCLUSIONS: These post hoc analyses of a subgroup of patients demonstrate the continued therapeutic efficacy of aripiprazole lauroxil after successful treatment of an acute episode of schizophrenia. Both the 441 mg and 882 mg groups had similar retention rates, degree of symptom improvement, and likelihood of remission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039; European Clinical Trials Database (EudraCT) numbers: 2012-003445-15 and 2012-003996-20​​​​.

Pain Severity in Relation to the Final Menstrual Period in a Prospective Multiethnic Observational Cohort: Results From the Study of Women's Health Across the Nation.

The development of pain is common in midlife, resulting in increased health care utilization and costs. The aim of this study was to determine the longitudinal trajectory of overall bodily pain among women during the transition between the reproductive years and menopause. We conducted analyses on a community-based, longitudinal cohort of women enrolled in the Study of Women's Health Across the Nation. One thousand four hundred ninety-five women met inclusion criteria, including: 1) defined date of the final menstrual period (FMP), and 2) complete data on Short Form-36 bodily pain. The primary exposure was time to/from the FMP. The primary outcome was the rate of change in Short Form-36 bodily pain, measured on a scale of 0 to 100 with 100 being the most severe pain. We performed within-person trajectory analyses using piecewise regression following nonparametric modeling of functional forms. Mean bodily pain score at the time of the FMP was 29. Mean bodily pain increased at a rate of .26 per year during the transmenopause (the interval spanning 4.5 years before the FMP through .5 years after the FMP), and decreased at a rate of .23 per year after that. Depression and sleep problems were associated with greater increases in pain during the late reproductive years, whereas abdominal cramps at baseline predicted greater decreases in pain during the late reproductive years. PERSPECTIVE: This article shows that bodily pain increases during the transmenopause and then diminishes during postmenopause. These differences may reflect differences in underlying mechanisms of pain in the 2 periods. Although mean changes were small and unlikely to be clinically meaningful, the magnitude of change varied across subgroups of women.

Validation of claims-based algorithms for gout flares.

PURPOSE: Gout is a common inflammatory arthritis characterized by repeated acute flares. The ability to accurately identify gout flares is critical for comparative effectiveness studies of gout treatments. We developed and examined the accuracy of a claims-based algorithm to identify gout flares. METHODS: Patients receiving care at an academic medical center between 2006 and 2010 with a diagnosis of gout or hyperuricemia were selected using an electronic medical record-Medicare claims linked dataset. Gout flares were identified by several claims-based algorithms using a diagnosis of gout combined with gout-related medication claims and/or procedure codes for arthrocentesis or joint injection. We calculated positive predictive value of these algorithms based on physician documentation of gout flare in medical record as the gold standard. Negative predictive value of the gout flare algorithm was calculated in a randomly selected subgroup of 200 patients with gout. RESULTS: Among 3952 subjects with gout or hyperuricemia, 503 flares were identified using the medication-based algorithm, and 290 were identified using the procedure-based algorithm. The positive predictive value for gout flares ranged from 50-54% for the medication-based algorithms and 59-68% for the procedure-based algorithms. The negative predictive value of the algorithm combining both medication and procedure claims was high (85.2%). CONCLUSION: Use of gout diagnosis codes in combination with medication dispensing or procedure codes did not appear to accurately capture gout flares in patients with gout in a claims database. However, the claims-based flare algorithm could be useful in identifying a cohort of gout patients with no flares. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of colchicine on risk of cardiovascular events and mortality among patients with gout: a cohort study using electronic medical records linked with Medicare claims.

BACKGROUND: Colchicine may have beneficial effects on cardiovascular (CV) disease, but there are sparse data on its CV effect among patients with gout. We examined the potential association between colchicine and CV risk and all-cause mortality in gout. METHODS: The analyses used data from an electronic medical record (EMR) database linked with Medicare claims (2006-2011). To be eligible for the study cohort, subjects must have had a diagnosis of gout in the EMR and Medicare claims. New users of colchicine were identified and followed up from the first colchicine dispensing date. Non-users had no evidence of colchicine prescriptions during the study period and were matched to users on the start of follow-up, age and gender. Both groups were followed for the primary outcome, a composite of myocardial infarction, stroke or transient ischaemic attack. We calculated HRs in Cox regression, adjusting for potential confounders. RESULTS: We matched 501 users with an equal number of non-users with a median follow-up of 16.5 months. During follow-up, 28 primary CV events were observed among users and 82 among non-users. Incidence rates per 1000 person-years were 35.6 for users and 81.8 for non-users. After full adjustment, colchicine use was associated with a 49% lower risk (HR 0.51, 95% CI 0.30 to 0.88) in the primary CV outcome as well as a 73% reduction in all-cause mortality (HR 0.55, 95% CI 0.35 to 0.85, p=0.007). CONCLUSIONS: Colchicine use was associated with a reduced risk of a CV event among patients with gout.

Antimycobacterial Activities of Endolysins Derived From a Mycobacteriophage, BTCU-1.

The high incidence of Mycobacterium infection, notably multidrug-resistant M. tuberculosis infection, has become a significant public health concern worldwide. In this study, we isolate and analyze a mycobacteriophage, BTCU-1, and a foundational study was performed to evaluate the antimycobacterial activity of BTCU-1 and its cloned lytic endolysins. Using Mycobacterium smegmatis as host, a mycobacteriophage, BTCU-1, was isolated from soil in eastern Taiwan. The electron microscopy images revealed that BTCU-1 displayed morphology resembling the Siphoviridae family. In the genome of BTCU-1, two putative lytic genes, BTCU-1_ORF7 and BTCU-1_ORF8 (termed lysA and lysB, respectively), were identified, and further subcloned and expressed in Escherichia coli. When applied exogenously, both LysA and LysB were active against M. smegmatis tested. Scanning electron microscopy revealed that LysA and LysB caused a remarkable modification of the cell shape of M. smegmatis. Intracellular bactericidal activity assay showed that treatment of M. smegmatis-infected RAW 264.7 macrophages with LysA or LysB resulted in a significant reduction in the number of viable intracellular bacilli. These results indicate that the endolysins derived from BTCU-1 have antimycobacterial activity, and suggest that they are good candidates for therapeutic/disinfectant agents to control mycobacterial infections.

The effect of initiating pharmacologic insulin on serum uric acid levels in patients with diabetes: a matched cohort analysis.

OBJECTIVES: Gout is a common inflammatory arthropathy associated with hyperuricemia. Substantial evidence links hyperuricemia to the metabolic syndrome and diabetes. Rising serum insulin levels correlate with an increase in serum uric acid (UA). The current study evaluated the effect of pharmacologic insulin on serum UA levels in patients with diabetes. METHODS: We conducted a retrospective analysis of previously collected data. The study cohort consisted of patients with both gout and diabetes who had initiated insulin therapy and a matched set of non-insulin users. The change in UA levels was calculated in both groups and compared. Potential confounders were assessed and adjusted for in a matched linear regression model. RESULTS: In total, 23 patients met criteria for insulin initiators and were matched to 23 non-insulin users. In unadjusted analyses, patients started on insulin had a larger increase in UA (mean change = 1.25mg/dl, interquartile range, IQR: -0.7-2.3) in comparison to those not starting insulin (mean change = 0.06mg/dl, IQR: -1.1-0.9). After controlling for baseline UA and time between UA measurements, regression modeling showed that insulin use was significantly associated with an increase in UA (ß = 1.25mg/dl, p = 0.02). CONCLUSIONS: Initiation of insulin among patients with diabetes was associated with a statistically significant increase in serum UA levels. This may affect the risk of gout flares and might suggest the potential for prophylactic therapy.

Bone mineral density changes among women initiating proton pump inhibitors or H2 receptor antagonists: a SWAN cohort study.

Proton pump inhibitors (PPIs) have been associated with diminished bone mineral density (BMD) and an increased risk of fracture; however, prior studies have not yielded consistent results, and many have suboptimal ascertainment of both PPI use and BMD. We used data from the Study of Women's Health Across the Nation (SWAN), a multicenter, multi-ethnic, community-based longitudinal cohort study of women across the menopause transition to examine the association between annualized BMD changes and new use of PPIs. We compared changes in BMD in new PPI users with changes in BMD in new users of histamine 2 receptor antagonists (H2RAs) and with changes in BMD in subjects who did not use either class of medications. Mixed linear regression models included recognized risk factors for osteoporosis, including demographics, menopausal transition stage, body mass index (BMI), lifestyle factors, as well as comorbidities and concomitant medications. To provide further evidence for the validity of our analytic approach, we also examined the effects of hormone-replacement therapy (HT), a class of medications that should reduce bone loss, on changes in BMD as an internal positive control group. We identified 207 new users of PPIs, 185 new users of H2RAs, and 1,676 non-users. Study subjects had a mean age of 50 years and were followed for a median of 9.9 years. Adjusted models found no difference in the annualized BMD change at the lumbar spine, femoral neck, or total hip in PPI users compared with H2RA users or non-users. These results were robust to sensitivity analyses. BMD increased as expected in HT users, supporting the validity of our study design. These longitudinal analyses plus similar prior studies argue against an association between PPI use and BMD loss.

Application of 16S rRNA metagenomics to analyze bacterial communities at a respiratory care centre in Taiwan.

In this study, we applied a 16S ribosomal RNA (rRNA) metagenomics approach to survey inanimate hospital environments (IHEs) in a respiratory care center (RCC). A total of 16 samples, including 9 from medical devices and 7 from workstations, were analyzed. Besides, clinical isolates were retrospectively analyzed during the sampling period in the RCC. A high amount of microbial diversity was detected, with an average of 1,836 phylotypes per sample. In addition to Acinetobacter, more than 60 % of the bacterial communities present among the top 25 abundant genera were dominated by skin-associated bacteria. Differences in bacterial profiles were restricted to individual samples. Furthermore, compliance with hand hygiene guidelines may be unsatisfactory among hospital staff according to a principal coordinate analysis that indicated clustering of bacterial communities between devices and workstations for most of the sampling sites. Compared to the high incidence of clinical isolates in the RCC, only Staphylococcus and Acinetobacter were highly abundant in the IHEs. Despite Acinetobacter was the most abundant genus present in IHEs of the RCC, potential pathogens, e.g., Acinetobacter baumannii, might remain susceptible to carbapenem. This study is the first in Taiwan to demonstrate a high diversity of human-associated bacteria in the RCC via 16S rRNA metagenomics, which allows for new assessment of potential health risks in RCCs, aids in the evaluation of existing sanitation protocols, and furthers our understanding of the development of healthcare-associated infections.