Differential nuclear localization does not determine the silencing status of Saccharomyces cerevisiae telomeres.

In Saccharomyces cerevisiae, genes near telomeres are transcriptionally repressed, a phenomenon termed telomere position effect (TPE). Yeast telomeres cluster near the nuclear periphery, as do foci of proteins essential for TPE: Rap1p, Sir2-4p, and yKu70p/yKu80p. However, it is not clear if localization of telomeres to the periphery actually contributes to TPE. We examined the localization patterns of two telomeres with different levels of TPE: truncated VII-L and native VI-R. For both telomeres, localization to the nuclear periphery or to the silencing foci was neither necessary nor sufficient for TPE. Moreover, there was no correlation between TPE levels and the extent of localization. Tethering the truncated VII-L telomere to the nuclear periphery resulted in a modest increase in TPE. However, tethering did not bypass the roles of yKu70p, Sir4p, or Esc1p in TPE. Using mutations in RIF genes that bypass the role of Ku in TPE, a correlation between the level of silencing and the number of Rap1p foci present in the nucleus was observed, suggesting that Sir protein levels at telomeres determine both the level of TPE and the number of foci.

A patient-reported, non-interventional, cross-sectional discrete choice experiment to determine treatment attribute preferences in treatment-naïve overactive bladder patients in the US.

PURPOSE: Many pharmacotherapeutic treatment options are available for the symptoms of overactive bladder (OAB), each offering varying efficacy, safety, and tolerability profiles that must be carefully considered when selecting treatment. The objective of the present study was to characterize pharmacotherapy treatment preferences of individuals with symptoms of OAB and to examine how preferences differ by both patient characteristics and disease burden metrics. PATIENTS AND METHODS: Patient preferences for OAB treatment attributes were examined using a discrete choice experiment (DCE). Attributes were identified through literature review, clinical relevance, and input from patients. Eligible respondents were required to be ≥18 years of age, have a self-reported physician OAB diagnosis or have self-reported symptoms of OAB, and be naïve to pharmacotherapy or invasive OAB treatments. A hierarchical Bayesian random-effects-only model was used to estimate the mean relative preference weights and mean relative importance scores of treatment attributes. Multivariable linear regression models with backward selection were used to analyze the differences in relative importance scores by demographic characteristics and disease burden-related metrics. RESULTS: In total, 514 individuals participated in the study. Most respondents were <65 years of age (66.0%), female (68.5%), and reported moderate/severe OAB symptoms (64.2%). Overall, respondents placed the greatest importance on drug delivery method, with a preference for oral and patches over injectables, followed by efficacy defined as reduced daytime micturition and out-of-pocket cost. Multivariable linear regression analyses revealed that females were less likely to select injectables, that symptom control of incontinence was the most important to respondents who reported greater work productivity loss, and that out-of-pocket cost was the most important to respondents with moderate/severe OAB. CONCLUSION: OAB treatment preferences vary depending on individual patient characteristics and disease severity. Overall, drug delivery method, reduced daytime micturition, and out-of-pocket costs were the most important treatment attributes among treatment-naïve individuals with symptoms of OAB. Preferences for OAB treatment were also found to vary depending on patient demographics and disease comorbidities, which has previously not been examined.

Variation in hospital resource use and cost among surgical procedures using topical absorbable hemostats.

BACKGROUND: Adjunctive hemostats are used to assist with the control of intraoperative bleeding. The most common types are flowables, gelatins, thrombins, and oxidized regenerated celluloses (ORCs). In the US, Surgicel(®) products are the only US Food and Drug Administration-approved ORCs. OBJECTIVE: To compare the outcomes of health care resource utilization (HRU) and costs associated with using ORCs compared to other adjunctive hemostats (OAHs are defined as flowables, gelatins, and topical thrombins) for surgical procedures in the US inpatient setting. PATIENTS AND METHODS: A retrospective, US-based cohort study was conducted using hospital inpatient discharges from the 2011-2012 calendar years in the Premier Healthcare Database. Patients with either an ORC or an OAH who underwent a cardiovascular procedure (valve surgery and/or coronary artery bypass graft surgery), carotid endarterectomy, cholecystectomy, or hysterectomy were included. Propensity score matching was used to create comparable groups of ORC and OAH patients. Clinical, economic, and HRU outcomes were compared. RESULTS: The propensity score matching created balanced patient cohorts for cardiovascular procedure (22,718 patients), carotid endarterectomy (10,890 patients), cholecystectomy (6,090 patients), and hysterectomy (9,348 patients). In all procedures, hemostatic agent costs were 28%-56% lower for ORCs, and mean hemostat units per discharge were 16%-41% lower for ORCs compared to OAHs. Length of stay and total procedure costs for patients treated with ORCs were lower for carotid endarterectomy patients (0.3 days and US$700) and for cholecystectomy patients (1 day and US$3,350) (all P<0.001). CONCLUSION: Costs and HRU for patients treated with ORCs were lower than or similar to patients treated with OAHs. Proper selection of the appropriate hemostatic agents has the potential to influence clinical outcomes and treatment costs.

Reduction in hospital costs and resource consumption associated with the use of advanced topical hemostats during inpatient procedures.

OBJECTIVE: The use of hemostatic agents has increased over time for all surgical procedures. The purpose of this study was to evaluate the newer topical absorbable hemostat products Surgicel * Fibrillar † and Surgicel SNoW ‡ (Surgicel advanced products, abbreviated as SAPs) compared to the older product Surgicel Original (SO) with respect to healthcare resource use and costs in procedures where these hemostats are most commonly used. RESEARCH DESIGN AND METHODS: A retrospective analysis of the Premier hospital database was used to identify adults who underwent brain/cerebral (BC), cardiovascular (CV: valve surgery and coronary artery bypass graft) and carotid endarterectomy (CEA) between January 2011-December 2012. Among these patients, those treated with SAPs were compared to those treated with SO. Propensity score matching (PSM) was used to create comparable groups to evaluate differences between SAPs and SO. MAIN OUTCOME MEASURES: The primary end-points for this study were length of stay (LOS), all-cause total cost, number of intensive care unit (ICU) days, ICU cost, transfusion costs and units, and SO/SAP product units per discharge. RESULTS: Matched PSM created patient cohorts for SO and SAPs were created for BC (n = 758 for both groups), CV (n = 3388 for both groups), and CEA (n = 2041 for both groups) procedures. Patients that received SAPs had a 14-16% lower mean LOS for each procedure compared to SO, as well as 12-18% lower total mean cost per discharge for each procedure (p < 0.02 for all results). Mean ICU costs for SAPs were also lower, with a reduction of 20% for BC and 19% for CV compared to SO (p < 0.01). However, for CEA, there was no statistically significant difference in ICU costs for SAPs compared to SO. CONCLUSIONS: In a retrospective hospital database analysis, the use of SAPs were associated with lower healthcare resource utilization and costs compared to SO.