Diguanylate Cyclases AdrA and STM1987 Regulate Salmonella enterica Exopolysaccharide Production during Plant Colonization in an Environment-Dependent Manner.

Increasing evidence indicates that despite exposure to harsh environmental stresses, Salmonella enterica successfully persists on plants, utilizing fresh produce as a vector to animal hosts. Among the important S. enterica plant colonization factors are those involved in biofilm formation. S. enterica biofilm formation is controlled by the signaling molecule cyclic di-GMP and represents a sessile lifestyle on surfaces that protects the bacterium from environmental factors. Thus, the transition from a motile, planktonic lifestyle to a sessile lifestyle may represent a vital step in bacterial success. This study examined the mechanisms of S. enterica plant colonization, including the role of diguanylate cyclases (DGCs) and phosphodiesterases (PDEs), the enzymes involved in cyclic di-GMP metabolism. We found that two biofilm components, cellulose and curli, are differentially required at distinct stages in root colonization and that the DGC STM1987 regulates cellulose production in this environment independent of AdrA, the DGC that controls the majority of in vitro cellulose production. In addition, we identified a new function for AdrA in the transcriptional regulation of colanic acid and demonstrated that adrA and colanic acid biosynthesis are associated with S. enterica desiccation tolerance on the leaf surface. Finally, two PDEs with known roles in motility, STM1344 and STM1697, had competitive defects in the phyllosphere, suggesting that regulation of motility is crucial for S. enterica survival in this niche. Our results indicate that specific conditions influence the contribution of individual DGCs and PDEs to bacterial success, perhaps reflective of differential responses to environmental stimuli.

Cost Differences Between Open and Minimally Invasive Surgery.

PURPOSE: To analyze the cost difference between minimally invasive surgery (MIS) and open surgery from a commercial payer perspective for colectomy, ventral hernia repair, thoracic resection (resection of the lung), and hysterectomy. DESIGN: A retrospective claims data analysis was conducted using the 2011 and 2012 Truven Health Analytics MarketScan Commercial Claims and Encounter Database. Study eligibility criteria included age 18-64 years, pharmacy coverage, ≥ 1 month of eligibility in 2012, and a claim coded with 1 of the 4 surgical procedures of interest; the index year was 2012. METHODOLOGY: Average allowed facility and professional costs were calculated during inpatient stay (or day of surgery for outpatient hysterectomy) and the 30 days after discharge for MIS vs open surgery. Cost difference was compared after adjusting for presence of cancer, geographic region, and risk profile (age, gender, and comorbidities). RESULTS: In total, 46,386 cases in the 2012 MarketScan database represented one of the surgeries of interest. The difference in average allowed surgical procedure cost (facility and professional) between open surgery vs adjusted MIS was $10,204 for colectomy; $3,721, ventral hernia repair; $12,989, thoracic resection; and $1,174, noncancer hysterectomy (P < .001 for all comparisons).The difference in average allowed cost in the 30 days after surgery between open surgery vs adjusted MIS was $1,494 for colectomy, $1,320 for ventral hernia repair, negative $711 for thoracic resection, and negative $425 for noncancer hysterectomy (P < .001 for all comparisons, except P = .487 for thoracic resection). CONCLUSION: MIS was associated with statistically significantly lower costs than open surgery for all 4 analyzed surgeries.

Prevalence and Economic Burden of Epilepsy in the Institutionalized Medicare Fee-for-Service Population.

BACKGROUND: Based on data from 2003 to 2007, the prevalence of epilepsy was significantly higher in the institutionalized elderly population than in the noninstitutionalized population, but the recent prevalence and economic impact of epilepsy specifically in the institutionalized Medicare population have not been reported. OBJECTIVES: To estimate the prevalence and economic burden of epilepsy and inpatient utilization rates among institutionalized Medicare beneficiaries and to provide a 10-year projection of their population size and the associated costs. METHODS: We performed a cross-sectional analysis of the institutionalized Medicare population with and without epilepsy using Medicare 5% sample claims data from 2013 and 2014. The identification of epilepsy required ≥1 qualifying claims with an epilepsy diagnosis, or ≥2 qualifying claims ≥30 days apart with a diagnosis of convulsion, in 2014. Institutionalized status was identified by having ≥6 consecutive months of nursing facility claims in 2013 or 2014. Inpatient admissions and 30-day readmissions, average allowed costs, and risk-adjusted incremental costs of epilepsy were calculated and compared between the institutionalized population of Medicare beneficiaries with and without epilepsy. The 2015 Medicare 100% and 5% sample data and inputs from other external sources were used to project the 10-year trends in the size and cost of the institutionalized Medicare population with epilepsy. RESULTS: The prevalence of epilepsy in 2014 was 11.1% in the institutionalized Medicare population. The institutionalized population with epilepsy had significantly higher per-patient per-month (PPPM) costs ($3479 vs $2381, respectively; P <.001), inpatient admissions per 1000 beneficiaries (1105 vs 697, respectively; P <.001), and 30-day readmissions per 1000 beneficiaries (287 vs 145, respectively; P <.001) versus the institutionalized population without epilepsy. The risk-adjusted incremental cost of epilepsy for the institutionalized population was $507.33 PPPM. Based on our model, between 2017 and 2027 an 18% increase in size and a 72% increase in cost are projected for the institutionalized Medicare beneficiaries with epilepsy. CONCLUSION: The high cost and inpatient resource utilization, as well as the projected growth of the institutionalized Medicare population with epilepsy highlight the need for further investigation of care management opportunities to reduce the cost burden associated with this condition.

The cost impact to Medicare of shifting treatment of worsening heart failure from inpatient to outpatient management settings.

PURPOSE: The aim of this study was to quantify the potential cost savings to Medicare of shifting the site of treatment for worsening heart failure (HF) from inpatient to outpatient (OP) settings for a subset of worsening HF episodes among the Medicare fee-for-service (FFS) population. MATERIALS AND METHODS: A cross-sectional analysis of a random 5% sample of 2014 FFS Medicare beneficiaries was conducted. Incidence and cost of worsening HF episodes in both inpatient and OP settings were identified. These results were used to calculate cost savings associated with shifting a proportion of worsening HF episodes from the inpatient to OP settings. RESULTS: A total of 151,908 HF beneficiaries were identified. The estimated annual cost for the treatment of worsening HF across both inpatient and OP settings ranged from US$9.3 billion to US$17.0 billion or 2.4%-4.3% of total Medicare FFS spend. The cost saving associated with shifting worsening HF treatment from inpatient hospital setting to OP settings was US$667.5 million or 0.17% of total Medicare spend when 10% of HF admissions were targeted and 60% of targeted HF admissions were successfully shifted. The cost savings increased to US$2.098 billion or 0.53% of total Medicare spend when 20% of HF admissions were targeted and 90% of targeted HF admissions were successfully shifted. CONCLUSION: Treatment options that can shift costly hospital admissions for worsening HF treatment to less expensive OP settings potentially lead to significant cost savings to Medicare. Pursuit of OP therapy options for treating worsening HF might be considered a viable alternative.

The Clinical and Economic Burden of Hyperkalemia on Medicare and Commercial Payers.

BACKGROUND: Hyperkalemia (serum potassium >5.0 mEq/L) may be caused by reduced kidney function and drugs affecting the renin-angiotensin-aldosterone system and is often present in patients with chronic kidney disease (CKD). OBJECTIVE: To quantify the burden of hyperkalemia in US Medicare fee-for-service and commercially insured populations using real-world claims data, focusing on prevalence, comorbidities, mortality, medical utilization, and cost. METHODS: A descriptive, retrospective claims data analysis was performed on patients with hyperkalemia using the 2014 Medicare 5% sample and the 2014 Truven Health Analytics MarketScan Commercial Claims and Encounter databases. The starting study samples required patient insurance eligibility during ≥1 months in 2014. The identification of hyperkalemia and other comorbidities required having ≥1 qualifying claims in 2014 with an appropriate International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code in any position. To address the differences between patients with and without hyperkalemia, CKD subsamples were analyzed separately. Mortality rates were calculated in the Medicare sample population only. The claims were grouped into major service categories; the allowed costs reflected all costs incurred by each cohort divided by the total number of member months for that cohort. RESULTS: The prevalence of hyperkalemia in the Medicare and commercially insured samples was 2.3% and 0.09%, respectively. Hyperkalemia was associated with multiple comorbidities, most notably CKD. The prevalence of CKD in the Medicare and the commercially insured members with hyperkalemia was 64.8% and 31.8%, respectively. After adjusting for CKD severity, the annual mortality rate for Medicare patients with CKD and hyperkalemia was 24.9% versus 10.4% in patients with CKD without hyperkalemia. The allowed costs in patients with CKD and hyperkalemia in the Medicare and commercially insured cohorts were more than twice those in patients with CKD without hyperkalemia. Inpatient care accounted for >50% of costs in patients with CKD and hyperkalemia. CONCLUSION: Hyperkalemia is associated with substantial clinical and economic burden among US commercially insured and Medicare populations.

Computational modeling for cardiac safety pharmacology analysis: Contribution of fibroblasts.

INTRODUCTION: Drug-induced proarrhythmic potential is an important regulatory criterion in safety pharmacology. The application of in silico approaches to predict proarrhythmic potential of new compounds is under consideration as part of future guidelines. Current approaches simulate the electrophysiology of a single human adult ventricular cardiomyocyte. However, drug-induced proarrhythmic potential can be different when cardiomyocytes are surrounded by non-muscle cells. Incorporating fibroblasts in models of myocardium is important particularly for predicting a drugs cardiac liability in the aging population - a growing population who take more medications and exhibit increased cardiac fibrosis. In this study, we used computational models to investigate the effects of fibroblast coupling on the electrophysiology and response to drugs of cardiomyocytes. METHODS: A computational model of cardiomyocyte electrophysiology and ion handling (O'Hara, Virag, Varro, & Rudy, 2011) is coupled to a passive model of fibroblast electrophysiology to test the effects of three compounds that block cardiomyocyte ion channels. Results are compared to model results without fibroblast coupling to see how fibroblasts affect cardiomyocyte action potential duration at 90% repolarization (APD90) and propensity for early after depolarization (EAD). RESULTS: Simulation results show changes in cardiomyocyte APD90 with increasing concentration of three drugs that affect cardiac function (dofetilide, vardenafil and nebivolol) when no fibroblasts are coupled to the cardiomyocyte. Coupling fibroblasts to cardiomyocytes markedly shortens APD90. Moreover, increasing the number of fibroblasts can augment the shortening effect. DISCUSSION: Coupling cardiomyocytes and fibroblasts are predicted to decrease proarrhythmic susceptibility under dofetilide, vardenafil and nebivolol block. However, this result is sensitive to parameters which define the electrophysiological function of the fibroblast. Fibroblast membrane capacitance and conductance (CFB and GFB) have less of an effect on APD90 than the fibroblast resting membrane potential (EFB). This study suggests that in both theoretical models and experimental tissue constructs that represent cardiac tissue, both cardiomyocytes and non-muscle cells should be considered when testing cardiac pharmacological agents.

Cardiovascular event incidence and cost in type 2 diabetes mellitus: a Medicare claims-based actuarial analysis.

OBJECTIVE: To assess the economic burden of cardiovascular events in Medicare beneficiaries with type 2 diabetes mellitus (T2DM). METHODS: This claims-based actuarial analysis queried 2013 and 2014 Medicare 5% samples, defining a denominator of fee-for-service beneficiaries. Average per patient per month allowed cost ($PPPM) was calculated for T2DM, demographically adjusted non-T2DM, and denominator. Per member per month allowed cost ($PMPM) was calculated by dividing total population cost by member months in the denominator. Costs of five pre-specified cardiovascular events were calculated as a contribution to denominator $PMPM, as contribution to $PPPM in T2DM, and as incremental cost. RESULTS: During the study period, 22.1% of Medicare fee-for-service beneficiaries had T2DM; of these, 9.68% experienced a cardiovascular event or cardiovascular-related death. T2DM cost represented 37.9% of total allowed $PMPM for the denominator. Average total allowed $PPPM for a T2DM beneficiary was $1,834, compared with $850 for a non-T2DM beneficiary (2.2-times higher). Annual rates of myocardial infarction, stroke, unstable angina admission, heart failure admission, and coronary revascularization in T2DM were 3.3-, 2.4-, 3.2-, 4.0-, and 2.8-times higher than in non-T2DM, and utilization of health services was also greater in T2DM. Cardiovascular events in T2DM accounted for 50% of denominator cardiovascular event cost; 3.6% of denominator population $PMPM was attributable to cardiovascular events in T2DM. Risk-adjusted incremental cardiovascular event cost represented 18.1% of $PPPM in T2DM or 6.9% of $PMPM in the denominator population. CONCLUSIONS: Cardiovascular events in Medicare fee-for-service beneficiaries with T2DM contribute substantially to Medicare cardiovascular events, resource utilization, and cost.

Longitudinal Commercial Claims-Based Cost Analysis of Diabetic Retinopathy Screening Patterns.

BACKGROUND: Diabetic retinopathy is one of the most common complications of diabetes. The screening of patients with diabetes to detect retinopathy is recommended by several professional guidelines but is an underutilized service. OBJECTIVE: To analyze the relationship between the frequency of retinopathy screening and the cost of care in adult patients with diabetes. METHODS: Truven Health MarketScan commercial databases (2000-2013) were used to identify the diabetic population aged 18 to 64 years for the performance of a 2001-2013 annual trend analysis of patients with type 1 and type 2 diabetes and a 10-year longitudinal analysis of patients with newly diagnosed type 2 diabetes. In the trend analysis, the prevalence of diabetes, screening rate, and allowed cost per member per month (PMPM) were calculated. In the longitudinal analysis, data from 4 index years (2001-2004) of patients newly diagnosed with type 2 diabetes were combined, and the costs were adjusted to be comparable to the 2004 index year cohort, using the annual diabetes population cost trends calculated in the trend analysis. The longitudinal population was segmented into the number of years of diabetic retinopathy screening (ie, 0, 1-4, 5-7, and 8-10), and the relationship between the years of screening and the PMPM allowed costs was analyzed. The difference in mean incremental cost between years 1 and 10 in each of the 4 cohorts was compared after adjusting for explanatory variables. RESULTS: In the trend analysis, between 2001 and 2013, the prevalence of diabetes increased from 3.93% to 5.08%, retinal screening increased from 26.27% to 29.58%, and the average total unadjusted allowed cost of care for each patient with diabetes increased from $822 to $1395 PMPM. In the longitudinal analysis, the difference between the screening cohorts' mean incremental cost increase was $185 between the 0- and 1-4-year cohorts (P <.003) and $202 between the 0- and 5-7-year cohorts (P <.023). The cost differences between the other cohorts, including $217 between the 0- and 8-10-year cohorts (P <.066), were not statistically significant. CONCLUSIONS: Based on our analysis, the annual retinopathy screening rate for patients with diabetes has remained low since 2001, and has been well below the guideline-recommended screening levels. For patients with type 2 diabetes, the mean increase in healthcare expenditures over a 10-year period after diagnosis is not statistically different among those with various retinopathy screening rates, although the increase in healthcare spending is lower for patients with diabetes who were not screened for retinopathy compared with patients who did get screened.