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Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately in patients without diabetes.We did a systematic review and meta-analysis of SGLT2 inhibitor trials. We searched the MEDLINE and Embase databases for trials published from database inception to Sept 5, 2022. SGLT2 inhibitor trials that were double-blind, placebo-controlled, performed in adults (age ≥18 years), large (≥500 participants per group), and at least 6 months in duration were included. Summary-level data used for analysis were extracted from published reports or provided by trial investigators, and inverse-variance-weighted meta-analyses were conducted to estimate treatment effects. The main efficacy outcomes were kidney disease progression (standardised to a definition of a sustained ≥50% decrease in estimated glomerular filtration rate [eGFR] from randomisation, a sustained low eGFR, end-stage kidney disease, or death from kidney failure), acute kidney injury, and a composite of cardiovascular death or hospitalisation for heart failure. Other outcomes were death from cardiovascular and non-cardiovascular disease considered separately, and the main safety outcomes were ketoacidosis and lower limb amputation. This study is registered with PROSPERO, CRD42022351618.We identified 13 trials involving 90 413 participants. After exclusion of four participants with uncertain diabetes status, we analysed 90 409 participants (74 804 [82·7%] participants with diabetes [99% with type 2 diabetes] and 15 605 [17·3%] without diabetes; trial-level mean baseline eGFR range 37-85 mL/min per 1·73 mIn addition to the established cardiovascular benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function.UK Medical Research Council and Kidney Research UK.

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 m(2) 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.

This analysis assessed the incidence and total events of hypoglycemia in VERTIS CV (NCT01986881) , the cardiovascular (CV) outcome trial for ertugliflozin (ERTU) in patients (pts) with type 2 diabetes and atherosclerotic CV disease. Hypoglycemia was categorized as level 1, a documented symptomatic event with plasma glucose (PG) ≤70 mg/dL (prespecified) ; level 2, a documented event with PG Overall, 8246 pts were randomized, mean follow-up was 3.5 yrs. The incidence rate (ERTU vs PBO) of first HYPO-broad was 14.3 vs. 16.2/100 pt-yrs; adjusted hazard ratio [aHR], 95% CI: 0.93 [0.85, 1.00] and HYPO-strict was 9.5 vs. 11.1/100 pt-yrs; aHR: 0.89 [0.81, 0.97] [Figure A]. Exposure-adjusted event rates were lower in ERTU vs PBO [Figure B]. The increase in percentage of insulin users (end of study vs. baseline) was less with ERTU (3.5% 5 + 15 mg) compared with PBO (6.2%) . In VERTIS CV, pts randomized to ERTU had a lower risk of hypoglycemia, including first and recurrent events, than PBO-treated pts. This may in part be due to the lesser increase in insulin users with ERTU vs. PBO. Disclosure S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. C.P.Cannon: Advisory Panel; Alnylam Pharmaceuticals, Inc., Amarin Corporation, Amgen Inc., Amryt Pharma Plc, Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Rhoshan, Sanofi, Research Support; Amgen Inc., Better Therapeutics, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. F.Cosentino: Advisory Panel; Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Merck Sharp & Dohme Corp., Novo Nordisk. D.K.Mcguire: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, ESPERION Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. J.Liu: Employee; Merck & Co., Inc. C.Liu: Employee; Merck & Co., Inc., Stock/Shareholder; Merck & Co., Inc. R.Frederich: Employee; Pfizer Inc., Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc. J.P.Mancuso: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. Funding This study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

The effect of ertugliflozin (ERTU) on serum uric acid (SUA) and gout-related outcomes in VERTIS CV (NCT01986881) was investigated. Patients with T2D and ASCVD were randomized to ERTU 5 mg (n=2752) , 15 mg (n=2747) (doses pooled for analyses) , placebo (PBO; n=2747) . Changes in SUA and composite of gout onset or initiation of anti-gout medication were assessed. LSM changes from baseline in SUA (mg/dL [95% CI]) at week 260 were −0. (−0.25, −0.13) and 0. (−0.02, 0.15) in the ERTU and PBO groups, respectively, nominal P Disclosure V.S.Sridhar: None. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. F.Cosentino: Advisory Panel; Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Merck Sharp & Dohme Corp., Novo Nordisk. S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. R.Frederich: Employee; Pfizer Inc., Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc. M.N.Essex: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. M.Maldonado: Employee; Merck & Co., Inc. C.Liu: Employee; Merck & Co., Inc., Stock/Shareholder; Merck & Co., Inc. J.P.Mancuso: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. Funding The VERTIS CV study and this analysis were sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

Among patients with type 2 diabetes (T2D) treated with statins, residual cardiovascular (CV) risk remains. Because icosapent ethyl (IPE) has been shown to decrease CV risk in patients on statin therapy, we explored potential eligibility for IPE therapy in VERTIS CV (NCT01986881) , the CV outcomes trial of ertugliflozin in which all patients had T2D and atherosclerotic CV disease (ASCVD) . We analyzed eligibility for IPE based on REDUCE-IT trial inclusion criteria (on statin, fasting triglyceride of 135 to 499 mg/dL and low-density lipoprotein cholesterol of 41 to 100 mg/dL) . Among 8246 patients randomized, the mean age was 64 years and 30% were female. At baseline, 6747 (81.8%) patients used statins, while 293 (3.6%) used ezetimibe, 389 (4.7%) used fish oil, and 8 (0.1%) used IPE. The REDUCE-IT trial inclusion criteria were met by 2444 (29.6%) patients at baseline and an additional 2500 (30.3%) did not fully meet the criteria but had baseline triglyceride level >135 mg/dL (Figure) . In conclusion, this analysis of the VERTIS CV trial population identified important opportunities to reduce residual CV risk: consideration of adding statin therapy in 18% of patients and of adding IPE based on the REDUCE-IT trial inclusion criteria or triglyceride level threshold in 60% of patients. These findings highlight the need to optimize lipid therapies in patients with T2D and ASCVD. Disclosure J.M.Kim: Other Relationship; Pfizer Inc. R.Frederich: Employee; Pfizer Inc., Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc. J.P.Mancuso: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. C.P.Cannon: Advisory Panel; Alnylam Pharmaceuticals, Inc., Amarin Corporation, Amgen Inc., Amryt Pharma Plc, Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Rhoshan, Sanofi, Research Support; Amgen Inc., Better Therapeutics, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. D.L.Bhatt: Research Support; Afimmune Limited, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Chiesi USA, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Novartis AG, Sanofi. S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. F.Cosentino: Advisory Panel; Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Merck Sharp & Dohme Corp., Novo Nordisk. D.K.Mcguire: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, ESPERION Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. C.Liu: Employee; Merck & Co., Inc., Stock/Shareholder; Merck & Co., Inc. N.B.Cater: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. Funding Merck Sharp & Dohme Corp.

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.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.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.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.NCT01986881.

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.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).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 value0.001), 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 were0.0001 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.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.

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.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.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 (PIn 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.

Introduction Sodium–glucose cotransporter 2 (SGLT2) inhibitors have been shown to slow the decline of kidney function in outcome trials, but the biological mediator(s) underlying the therapeutic benefit are not well established. Purpose We performed a post-hoc analysis exploring potential mediators of the effects of the SGLT2 inhibitor ertugliflozin on the VERTIS CV exploratory kidney composite outcome (sustained 40% decrease from baseline in estimated glomerular filtration rate [eGFR], chronic kidney replacement therapy or kidney death). Methods In VERTIS CV, 8246 participants with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease were randomised to placebo, ertugliflozin 5 mg or 15 mg (pooled for analyses, as prospectively planned), and were followed for a mean of 3.5 years. The hazard ratio (HR; 95% confidence interval) for the pre-specified exploratory kidney composite outcome was 0.66 (0.50, 0.88). Cox regression models were used to evaluate covariates that were significantly differentially changed from baseline with ertugliflozin treatment as candidate mediators, with a mediator identified as a covariate when added to an unadjusted model of randomised treatment assignment a) yielded a larger hazard ratio; and b) the mediator retained P100%. Results Of 22 covariates significantly changed by ertugliflozin, nine were identified as potential mediators (Table). The covariates with a high percentage of mediation were those related to changes in blood erythrocytes (haemoglobin, haematocrit and red blood cell mass), with average changes in haemoglobin having the highest percentage of mediation (61.8%). Serum uric acid was associated with a mediation of 29.4% and 50.0% for the early and average post-randomisation effect periods, respectively. Early changes in glycated haemoglobin had a large mediation (50%), but the average change during the trial was not significant. Average change in serum albumin had a large mediation (29.4%). Average changes in body weight and systolic blood pressure had percentages of mediation of 41.2% and 14.7%, respectively. Conclusion Multiple factors may be involved in the reduction of the kidney composite outcome observed with ertugliflozin. In the short-term, changes in glycaemia had a high mediation effect. Over the long-term, changes suggestive of haemoconcentration and/or haematopoiesis (natriuresis-related effects), showed the highest percentage of mediation, followed by changes in serum uric acid and body weight (glucosuria-related effects). Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA in collaboration with Pfizer Inc., New York, NY, USA

As the elderly population of Taiwan continues to rise, appearing the shortage of care measures and human resource. Emotional sounds can reflect physical and mental states of children, which are very important in child care. In this paper, we use emotional voice recognition technology to assist caregivers to understand the demands of the elderly and children, so that they can give appropriate care in time. Empirical mode decomposition (EMD) is applied to improve the detection and recognition of emotional sounds. Moreover, ensemble deep learning is further applied to alleviate the problem of overfitting. The experiments show that the classification accuracy of the proposed approach is 91.6%, which is much higher than that without EMD. We hope this technology will bring the benefit to the care of elderly and children.

519 Background: Pembro is a 1L treatment for cisplatin-ineligible pts with UC. This post hoc landmark analysis evaluated clinical outcomes by response at 9 wk to 1L pembro monotherapy in pts with advanced/unresectable or metastatic UC from the single-arm phase 2 KEYNOTE-052 (NCT02335424) and the randomized phase 3 KEYNOTE-361 (NCT02853305) trials. Methods: Cisplatin-ineligible pts with advanced UC were enrolled in KEYNOTE-052 and received pembro (200 mg Q3W for ≤2 y). Platinum-eligible pts with advanced UC who had not previously received systemic chemotherapy (chemo) were enrolled in KEYNOTE-361 and randomly assigned 1:1:1 to receive pembro (200 mg Q3W for ≤2 y), pembro + chemo (1000 mg/m2 gemcitabine on d1 and d8 + cisplatin [70 mg/m2] or carboplatin [AUC 5] on d1 of each 3-wk cycle), or chemo. The primary analysis group included pembro monotherapy–treated pts; the sensitivity analysis group included pembro monotherapy–treated pts from KEYNOTE-052 and the choice of carboplatin subpopulation of pembro monotherapy–treated pts from KEYNOTE-361. Landmark analyses of OS by pts with CR, PR, SD, or PD per RECIST v1.1 by BICR at first imaging assessment (wk 9) were pooled for the ITT populations. Duration of CR/PR/SD and OS were estimated using the Kaplan-Meier method. Data cutoffs were Sep 26, 2020 (KEYNOTE-052) and Apr 29, 2020 (KEYNOTE-361). Results: The primary analysis group included 681 pembro-treated pts (KEYNOTE-052, N = 374; KEYNOTE-361, N = 307); the sensitivity analysis group included 544 pembro-treated pts (KEYNOTE-052, N = 374; KEYNOTE-361, N = 170). Median time from randomization to cutoff was 51.9 mo (range, 22.0-65.3) and 53.7 mo (range, 22.0-65.3) for the primary and sensitivity analysis groups, respectively. Twenty-five pts (4.6%) had CR and 135 (24.6%) had PR (primary group); 17 pts (3.9%) had CR and 105 (24.1%) had PR (sensitivity group). Median DOR was 25.9 mo for pts with CR/PR at wk 9; pts with CR/PR or SD at wk 9 had longer OS than pts with PD at wk 9 (Table). Conclusions: In this post hoc analysis, pts with advanced UC in KEYNOTE-052 and KEYNOTE-361 with CR/PR at wk 9 had better clinical outcomes with pembro monotherapy than pts with SD or PD; 1L pembro monotherapy continues to show efficacy in advanced UC. Clinical trial information: NCT02335424 and NCT02853305. [Table: see text]

ObjectiveSwitching 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).MethodsThis 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.ResultsIn 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.ConclusionSwitching from an oral antipsychotic to AL was feasible in an outpatient setting for patients with schizophrenia, and the 12-week retention rate was favorable.

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, multicenter 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 in the registry. Measurements Monthly visits were evaluated for the full population and for patient subgroups 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 outpatient care. On average, patients received 5 injections (median 3; range 1-25). The median number of injections administered within 6 months was higher in patients who at baseline were employed (3 vs 2 unemployed, P=0.02) or had private insurance (5 vs 2 self-payment, P=0.005; vs 2 state-funded, P

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​​​​.

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.

Background Nearly 50% of people living with HIV in the US are ≥50 years old. Older people are more likely to have late-stage HIV infection at diagnosis, greater risk for cardiovascular disease and certain cancers, and concurrent medications for common age-related conditions. Doravirine (DOR) is a next-generation NNRTI with activity against first-generation NNRTI-associated mutations, a neutral impact on lipids, and few drug-drug interactions with commonly used medications. Methods We compared Week 96 results from DOR Phase 2 and Phase 3 trials (P007, P018, and P021) in treatment-naïve adults ≥50 vs < 50 years old. 855 participants received DOR 100mg +2 NRTIs in P007 & P018 or fixed combination DOR/3TC/TDF in P021; 383 participants received ritonavir-boosted darunavir (DRV) +2 NRTIs in P018; and 472 received efavirenz (EFV) 600mg +FTC/TDF in P007 or fixed combination EFV/FTC/TDF in P021. Participants who took ≥1 dose of study drug were included; the Observed Failure approach was used for missing efficacy data. All analyses were done by descriptive statistics. Results Of 1710 participants, 187 (11%) were 50-70 (median 54) years old at study entry. Baseline characteristics and treatment outcomes are summarized below for participants < 50 vs ≥50 years old. The older cohort had more women, more participants with AIDS, and lower median CD4+ T-cell counts than the younger cohort, whereas baseline HIV-1 RNA was similar between age cohorts. Hypertension and use of analgesics were more common in older participants. In each treatment group, the older cohort had a higher proportion of participants with HIV-1 RNA< 50 copies/mL at week 96 and fewer discontinuations due to lack of efficacy than the younger cohort. Mean change in CD4+ T-cell count was similar between age cohorts in the DOR and DRV groups and was lower for older participants in the EFV group. Rates of drug-related AEs and serious drug-related AEs were similar between age cohorts across all treatment groups. Discontinuations due to drug-related AEs were similar between age cohorts in the DOR group and were slightly higher for older participants in the DRV and EFV groups. Conclusion DOR is a beneficial option for adults ≥50 years old, given its similar efficacy and favorable safety profile compared to younger adults. Doravirine Phase 2 and Phase 3 Trials in Treatment-Naïve Adults Disclosures Anthony Mills, MD, Gilead (Grant/Research Support, Advisor or Review Panel member)Janssen Pharmaceutica (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Shionogi (Grant/Research Support)ViiV Healthcare (Grant/Research Support, Advisor or Review Panel member) Elizabeth A. Martin, DO, MPH, MBA, Merck & Co., Inc. (Employee) Chih-Chin Liu, PhD, Merck & Co., Inc. (Employee) Martine Drolet, BPharm, LPH, MBA, Merck & Co., Inc. (Employee) Peter Sklar, MD, MPH, Merck & Co., Inc. (Employee)

e16122 Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE-224 (NCT02702414) evaluated pembrolizumab (pembro; anti–PD-1) in sorafenib (sora)-treated pts with aHCC and showed an ORR of 17% that was durable in responders receiving pembro, ultimately leading to FDA approval. In KEYNOTE-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KEYNOTE-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KEYNOTE-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KEYNOTE-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to evaluate the association between survival after the landmark with response achieved before the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HR and 95% CI for survival after the landmark were calculated from the Cox proportional hazards model using Efron method of tie handling, with responder status as a single covariate. Analysis was performed on the ITT population. Results: As of Jan 2, 2019, median time from randomization to data cutoff was 21.2 mo (range 13.4-30.4) for pembro. In the pembro arm, 51 pts (18.3%) had a best OR of CR or PR and 6 pts (4.4%) in the pbo arm had a best OR of PR (no CR) (excluded from landmark analyses). OS after landmark time was longer for responders than nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders vs nonresponders was 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis showed that pts with sora-treated aHCC who achieved OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KEYNOTE-224. Clinical trial information: NCT02702401. [Table: see text]

435 Background: The phase III KEYNOTE-361 study compared efficacy and safety of 1L pembro + chemo or pembro vs chemo in pts with advanced UC. The trial did not meet its primary endpoints of PFS or OS superiority for pembro + chemo vs chemo; formal testing for OS for pembro vs chemo was not performed. We present a post hoc landmark analysis to examine the durability of CR/PR/SD and long-term survival in pts with CR, PR, or SD to pembro vs chemo at week 9 in KEYNOTE-361 (NCT02853305). Methods: Landmark analyses of OS by CR/PR/SD at 9 weeks after randomization in the ITT population were performed. Pts were included if they had a best response of CR/PR/SD per RECIST v1.1 by blinded independent central review at the landmark date of week 9 (first imaging assessment per study protocol). Duration of CR/PR/SD and OS were estimated by the Kaplan-Meier method. No formal comparisons were performed. Results: 307 pts were randomized to receive pembro and 352 pts to receive chemo in the KEYNOTE-361 study. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 32.5 (22.0-42.4) mo for the pembo arm and 31.4 (22.1-41.6) mo for the chemo arm. In the landmark analysis, fewer pts had CR/PR/SD at week 9 with pembro (n=137 [45%]) than with chemo (n=253 [72%]). Median (range) duration of response for pembro vs chemo was 18.7 (4.4+-35.4+) vs 12.3 (0.0+-29.7+) mo for pts with CR, and 35.0 (1.1-36.1+) vs 6.1 (0.0+-36.3+) mo for pts with PR. Median (range) duration of SD was 4.8 mo (0.0-38.2+) with pembro and 4.6 mo (0.0-16.1+) with chemo. Median OS (95% CI) for pembro vs chemo was not reached (NR) (25.5-NR) vs NR (19.1-NR) for pts with CR; NR (NR-NR) vs 14.8 mo (12.1-21.0) for pts with PR; and 18.5 mo (13.8-28.8) vs 11.1 mo (8.1-14.6) for pts with SD, respectively. Long-term OS rates were higher with pembro vs chemo across all groups (CR/PR/SD) at week 9 (Table). Conclusions: In this post hoc landmark analysis, chemo was associated with more initial responses than pembro, whereas pembro was associated with longer median duration of CR and PR, and generally longer median OS than chemo. Among pts who achieved CR/PR/SD at week 9, the relative OS benefit for pembro vs chemo increased over time. Clinical trial information: NCT02853305. [Table: see text]

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.

318 Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE (KN)-224 (NCT02702414) evaluated pembrolizumab (pembro; anti-PD-1) in sorafenib (sora)-treated pts with aHCC and demonstrated an OR rate of 17% that was durable in responders receiving pembro, ultimately leading to its FDA approval. In KN-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KN-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KN-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KN-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to examine the association between survival after the landmark with response achieved prior to the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HRs and 95% CIs for survival after the landmark were calculated from the Cox proportional model with Efron’s method of tie handling with responder status as a single covariate. Analyses were performed in the ITT population. Results: As of Jan 2, 2019, the median time from randomization to data cutoff was 21.2 months (range 13.4-30.4) for pembro. There were 51 pts (18.3%) with a BOR of CR or PR in the pembro arm and 6 pts (4.4%) with a BOR of PR (no CR) in the pbo arm (excluded from landmark analyses). OS after landmark time was longer for responders compared with nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders versus nonresponders were 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis demonstrates that pts with sora-treated aHCC who achieve OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KN-224. Clinical trial information: NCT02702401. [Table: see text]

4020 Background: Patients (pts) with anal squamous cell carcinoma (ASCC) have poor outcomes and few treatment options. We report a pooled analysis of pembrolizumab (pembro) antitumor activity and safety in the ASCC cohorts of the multicohort studies KEYNOTE-028 (NCT02054806; phase 1b) and KEYNOTE-158 (NCT02628067; phase 2), providing a robust sample size and longer follow-up. Methods: Eligible pts were aged ≥18 y with histologically/cytologically confirmed metastatic/unresectable ASCC, had prior failure of/intolerance to standard therapy or no standard therapy options, measurable disease (RECIST v1.1), ECOG PS 0/1, and a tissue sample evaluable for PD-L1/biomarkers (KEYNOTE-028 required PD-L1 positivity). Baseline PD-L1 expression was assessed using a prototype IHC assay (QualTek) in KEYNOTE-028 and the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies) in KEYNOTE-158. Pts received pembro 10 mg/kg Q2W (KEYNOTE-028) or 200 mg Q3W (KEYNOTE-158) for 2 y or until PD/unacceptable AEs. The primary endpoint in both studies was ORR (per RECIST v1.1). Secondary endpoints were duration of response (DOR), PFS, OS, and safety. Results: 137 pts with ASCC were treated in KEYNOTE-028 (n = 25) or KEYNOTE-158 (n = 112) and were included in this analysis (median age, 61 y; 83.2% women; 73.0% had PD-L1–positive tumors). Median follow-up was 11.7 mo; 124 pts (90.5%) had discontinued treatment. ORR (95% CI) was 10.9% (6.3%–17.4%). 8 pts had CR and 7 had PR. ORR (95% CI) by PD-L1 status was 14.0% (7.9%–22.4%) in the PD-L1 positive group and 3.3% (0.1%–17.2%) in the PD-L1 negative group. Among all treated pts, median DOR was not reached (range, 6.0+ to 57.5+ mo). By Kaplan-Meier estimation, 84.6% of responders had a DOR ≥24 mo. Median PFS was 2.1 mo (95% CI, 2.0–2.1) and median OS was 11.7 mo (95% CI, 8.8–14.5). The 12-mo PFS and OS rates were 14.5% and 47.4%. 85 pts (62.0%) had +1 treatment-related AE, 24 pts (17.5%) with grade 3–4 events (no grade 5 events). 32 pts (23.4%) had immune-mediated AEs; 2 pts (1.5%) had infusion related reactions. Conclusions: In pts with previously treated advanced ASCC, pembro showed durable antitumor activity, particularly in pts with PD-L1–positive tumors, and manageable toxicity. Clinical trial information: NCT02054806 (KEYNOTE-028), NCT02628067 (KEYNOTE-158) .

4587 Background: The effect of PD-1 inhibition on HBV infection is unclear, and pts with HBV are often excluded from trials. This analysis evaluated HBV viral load and liver function (ALT levels) in pts with HBV infection in 2 trials of pembro: KEYNOTE-224 and KEYNOTE-240. Methods: Eligible pts with aHCC post first-line sorafenib and controlled HBV received pembro 200 mg IV Q3W until progression. Pts with active HBV (HBsAg positive and/or HBV DNA detectable) and inactive HBV (anti-HBc positive, HBsAg negative, and HBV DNA not detectable) at baseline (BL) were included. Results: Of 104 pts in KEYNOTE-224 and 413 pts in KEYNOTE-240, 8 (7.7%) and 101 (24.5%) had active HBV and 13 (12.5%) and 102 (24.7%) had inactive HBV, respectively. All pts with HBV received nucleos(t)ide analogs. In KEYNOTE-240, 2 (2.8%) pts with active HBV in the pembro arm and 1 (3.4%) in placebo (pbo) had a > 1 log increase (incr) of HBV DNA and 1000 IU/mL over BL; none in the pembro arm were associated with ALT elevation. No pts with inactive HBV in KEYNOTE-240 and no pts in KEYNOTE-224 had a > 1 log incr and 1000 IU/mL over BL. No pts in KEYNOTE-224 and 28 (38.9%) with active HBV and 1 (1.4%) with inactive HBV in the pembro arm, and 8 (27.6%) with active HBV and 0 with inactive HBV in the pbo arm in KEYNOTE-240 had a > 1 log decrease (decr) in HBV DNA. Conclusions: Few pts with aHCC and HBV had viral load incr with pembro. In KEYNOTE-240 no clinically meaningful differences between pembro and pbo were observed. ALT elevation was not associated with viral load incr with pembro. These data suggest that pembro is unlikely to significantly affect underlying HBV infection in pts with aHCC receiving HBV antiviral therapy. Clinical trial information: KEYNOTE-224, NCT02702414; KEYNOTE-240, NCT02702401 . [Table: see text]

Objective.Clinical trials have shown that serotonin norepinephrine reuptake inhibitors, such as milnacipran, decrease pain in noninflammatory pain conditions such as fibromyalgia and osteoarthritis. We examined the effect of milnacipran on self-reported pain intensity and experimental pain sensitivity among patients with rheumatoid arthritis (RA) with widespread pain and stable RA disease activity.Methods.In this double-blind, crossover study, patients with RA with widespread pain, receiving a stable treatment regimen, were randomized (by a random number generator) to receive milnacipran 50 mg twice daily or placebo for 6 weeks, followed by a 3-week washout and crossed over to the other arm for the remaining 6 weeks. The primary outcome was change in average pain intensity, assessed by the Brief Pain Inventory short form. The sample size was calculated to detect a 30% improvement in pain with power = 0.80 and α = 0.05.Results.Of the 43 randomized subjects, 41 received the study drug, and 32 completed the 15-week study per protocol. On a 0–10 scale, average pain intensity decreased by 0.39 (95% CI −1.27 to 0.49, p = 0.37) more points during 6 weeks of milnacipran treatment compared with placebo. In the subgroup of subjects with swollen joint count ≤ 1, average pain intensity decreased by 1.14 more points during 6 weeks of milnacipran compared with placebo (95% CI −2.26 to −0.01, p = 0.04). Common adverse events included nausea (26.8%) and loss of appetite (9.7%).Conclusion.Compared with placebo, milnacipran did not improve overall, self-reported pain intensity among subjects with widespread pain receiving stable RA medications. Trial registration:ClinicalTrials.govNCT01207453.

BackgroundColchicine 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.MethodsThe 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.ResultsWe 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).ConclusionsColchicine use was associated with a reduced risk of a CV event among patients with gout.

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.