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.

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.

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.

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.

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.

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.

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.

Prevalence and mapping of a plasmid encoding a type IV secretion system in Acinetobacter baumannii.

We investigated the prevalence of a type IV secretion system (T4SS)-bearing plasmid among clinical isolates of carbapenem-resistant Acinetobacter baumannii (CRAB) using plasmid replicon typing. The complete sequence of a T4SS-bearing plasmid, pAB_CC, isolated from A. baumannii TYTH-1 was determined, and a comparative analysis of the T4SS gene modules was performed. Of the 129 isolates studied, GR6 (repAci6) was the most common (45 of 96 isolates) and was strongly linked with the T4SS. A comparative analysis of the T4SS locus in seven plasmid genomes, including pAB_CC, pACICU2, pABKp1, pABTJ1, p1BJAB0714, p2BJAB0868, and p2ABTCDC0715, indicated that fourteen genes on these plasmids were highly conserved compared to those of the F plasmid. Additionally, the chromosomes in the seven representative isolates may be evolutionarily distinct from their intrinsic T4SS-bearing plasmids, suggesting that the two T4SS lineages emerged long before the appearance of EC II. These two lineages are now widespread in A. baumannii strains.

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.

Transcriptome profiling in imipenem-selected Acinetobacter baumannii.

BACKGROUND: Carbapenem-resistance in Acinetobacter baumannii has gradually become a global challenge. To identify the genes involved in carbapenem resistance in A. baumannii, the transcriptomic responses of the completely sequenced strain ATCC 17978 selected with 0.5 mg/L (IPM-2 m) and 2 mg/L (IPM-8 m) imipenem were investigated using RNA-sequencing to identify differences in the gene expression patterns. RESULTS: A total of 88 and 68 genes were differentially expressed in response to IPM-2 m and IPM-8 m selection, respectively. Among the expressed genes, 50 genes were highly expressed in IPM-2 m, 30 genes were highly expressed in IPM-8 m, and 38 genes were expressed common in both strains. Six groups of genes were simultaneously expressed in IPM-2 m and IPM-8 m mutants. The three gene groups involved in DNA recombination were up-regulated, including recombinase, transposase and DNA repair, and beta-lactamase OXA-95 and homologous recombination. The remaining gene groups involved in biofilm formation were down-regulated, including quorum sensing, secretion systems, and the csu operon. The antibiotic resistance determinants, including RND efflux transporters and multidrug resistance pumps, were over-expressed in response to IPM-2 m selection, followed by a decrease in response to IPM-8 m selection. Among the genes over-expressed in both strains, blaOXA-95, previously clustered with the blaOXA-51-like family, showed 14-fold (IPM-2 m) to 330-fold (IPM-8 m) over-expression. The expression of blaOXA-95 in IPM-2 m and IPM-8 m cells was positively correlated with the rate of imipenem hydrolysis, as demonstrated through Liquid Chromatography-Mass Spectrometry/Mass Spectrometry, suggesting that blaOXA-95 plays a critical role in conferring carbapenem resistance. In addition, A. baumannii shows an inverse relationship between carbapenem resistance and biofilm production. CONCLUSION: Gene recombination and blaOXA-95 play critical roles in carbapenem resistance in A. baumannii. Taken together, the results of the present study provide a foundation for future studies of the network systems associated with carbapenem resistance.

Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials.

BACKGROUND: SGLT2 inhibitors and GLP-1 receptor agonists both improve cardiovascular and kidney outcomes in patients with type 2 diabetes. We sought to evaluate whether the benefits of SGLT2 inhibitors are consistent in patients receiving and not receiving GLP-1 receptor agonists. METHODS: We conducted a collaborative meta-analysis of trials included in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium, restricted to participants with diabetes. Treatment effects from individual trials were obtained from Cox regression models and pooled using inverse variance weighted meta-analysis. The two main cardiovascular outcomes assessed included major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), and hospitalisation for heart failure or cardiovascular death. The main kidney outcomes assessed were chronic kidney disease progression (≥40% decline in estimated glomerular filtration rate [eGFR], kidney failure [eGFR <15 mL/min/1·73 m2, chronic dialysis, or kidney transplantation], or death due to kidney failure), and the rate of change in eGFR over time. Safety outcomes were also assessed. FINDINGS: Across 12 randomised, double-blind, placebo-controlled trials, 3065 (4·2%) of 73 238 participants with diabetes were using GLP-1 receptor agonists at baseline. SGLT2 inhibitors reduced the risk of major adverse cardiovascular events in participants both receiving and not receiving GLP-1 receptor agonists (hazard ratio [HR] 0·81, 95% CI 0·63-1·03 vs 0·90, 0·86-0·94; p-heterogeneity=0·31). Effects on hospitalisation for heart failure or cardiovascular death (0·76, 0·57-1·01 vs 0·78, 0·74-0·82; p-heterogeneity=0·90) and chronic kidney disease progression (0·65, 0·46-0·94 vs 0·67, 0·62-0·72; p-heterogeneity=0·81) were also consistent regardless of GLP-1 receptor agonist use, as was the effect on the chronic rate of change in eGFR over time (heterogeneity=0·92). Fewer serious adverse events occurred with SGLT2 inhibitors compared with placebo, irrespective of GLP-1 receptor agonist use (relative risk 0·87, 95% CI 0·79-0·96 vs 0·91, 0·89-0·93; p-heterogeneity=0·41). INTERPRETATION: The effects of SGLT2 inhibitors on cardiovascular and kidney outcomes are consistent regardless of the background use of GLP-1 receptor agonists. These findings suggest independent effects of these evidence-based therapies and support clinical practice guidelines recommending the use of these agents in combination to improve cardiovascular and kidney metabolic outcomes. FUNDING: National Health and Medical Research Council of Australia and the Ramaciotti Foundation.

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.

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.

Genome sequence of Acinetobacter baumannii TYTH-1.

Acinetobacter baumannii has emerged recently as a major cause of health care-associated infections due to the extent of its antimicrobial resistance and its propensity to cause large nosocomial outbreaks. Here we report the genome sequence of Acinetobacter baumannii TYTH-1 isolated in Taiwan during 2008.

Racial disparities in length of stay in hospice care by tumor stage in a large elderly cohort with non-small cell lung cancer.

This study examined whether there are racial disparities for length of stay in hospice for patients with non-small cell lung cancer (NSCLC).We studied 53,626 deceased patients aged ≥66 years diagnosed with American Joint Committee on Cancer stages I-IV NSCLC identified from the Surveillance, Epidemiology, and End Results-Medicare linked data who used hospice services in the last six months before death, and died between 1 January 1991 and 31 December 2005. Median time (days) and percent length of stay in hospice, and multivariate incidence rate ratios (IRRs) with 95% confidence intervals (CIs) using zero-truncated negative binomial regression described relationships. In 2000-2005, most patients (64.1%) had <30 days, including those (30.2%) with <7 days length of stay in hospice care. After adjusting for confounders, the IRR for length of stay in hospice compared to whites was 38% increased for blacks (IRR = 1.38; 95% CI: 1.01-1.89), and almost three-fold increased for Hispanics (IRR = 2.91;95% CI: 1.15-7.37) at stages I-II. However, blacks at stages III-IV had slightly decreased use of hospice services (IRR = 0.91; 95% CI: 0.85-0.97). Length of stay decreased slightly among blacks diagnosed with late stage (III-IV) NSCLC in 2000-2005.The gap in disparity for length of stay in hospice has narrowed for ethnic minorities compared to whites, while some ethnic minorities had greater length of stay at early disease stage.

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.

Risk of xerostomia in association with the receipt of radiation therapy in older patients with head and neck cancer.

The purpose of this study was to assess the incidence rate and risk of developing xerostomia in association with the receipt of radiation therapy (RT) among a large population-based cohort of elderly patients diagnosed with head and neck cancer (HNC). The study consisted of 10,387 men and women diagnosed with incident HNC cancer at age 65 years or older from 1991 through 2002, identified from the 16 registries of the Surveillance, Epidemiology and End Results-Medicare linked data. Patients were defined as having xerostomia if there were at least 2 claims (for diagnosis code 527.7) at 30 days apart after the date of HNC diagnosis. Patients receiving RT either with or without chemotherapy had a higher cumulative incidence of developing xerostomia compared with those with neither radiotherapy nor chemotherapy (5.6% and 3.8%, respectively vs. 0.5%) at a median follow-up of 2.4 years. Patients who received RT with concurrent chemotherapy were 9 times more likely to develop xerostomia (hazard ratio = 9.13, 95% confidence interval = 6.68-12.48) compared with patients who received neither RT nor chemotherapy, whereas those who received RT without chemotherapy were over 6 times more likely to develop xerostomia (6.29, 4.72-8.37). The strength of this association was similar when patients were stratified by tumor stage and anatomic tumor site. There was no significant association between the risk of developing xerostomia and ethnicity, marital, and socioeconomic status. Radiation therapy for the treatment of HNC is associated with a significant risk of developing xerostomia regardless of type of surgical treatment rendered, tumor stage, or anatomic tumor site.

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.