VA Palo Alto Healthcare System

About: VA Palo Alto Healthcare System is a healthcare organization based out in Palo Alto, California, United States. It is known for research contribution in the topics: Population & Health care. The organization has 2548 authors who have published 4605 publications receiving 209938 citations.

Exome-wide association study of plasma lipids in > 300,000 individuals

Abstract: We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

Effect of Citalopram on Agitation in Alzheimer Disease: The CitAD Randomized Clinical Trial

Abstract: Importance Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory. Objective The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. Design, Setting, and Participants The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013. Interventions Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability. Main Outcomes and Measures Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events. Results Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was −0.93 (95% CI, −1.80 to −0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (−1.05 points; 95% CI, −1.97 to −0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group. Conclusions and Relevance Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day. Trial Registration clinicaltrials.gov Identifier:NCT00898807

p63 regulates proliferation and differentiation of developmentally mature keratinocytes

Abstract: p63 is a multi-isoform p53 family member required for epidermal development Contrasting roles for p63 in either the initial commitment to the stratified epithelial cell fate or in stem cell-based self-renewal have been proposed To investigate p63 function in a post-developmental context, we used siRNAs directed against p63 to down-regulate p63 expression in regenerating human epidermis Loss of p63 resulted in severe tissue hypoplasia and inhibited both stratification and differentiation in a cell-autonomous manner Although p63-deficient cells exhibited hypoproliferation, differentiation defects were not due to tissue hypoplasia Simultaneous p63 and p53 knockdown rescued the cell proliferation defect of p63 knockdown alone but failed to restore differentiation, suggesting that defects in epidermal proliferation and differentiation are mediated via p53-dependent and -independent mechanisms, respectively Furthermore, ΔNp63 isoforms are the main mediators of p63 effects, although TAp63 isoforms may contribute to late differentiation These data indicate that p63 is required for both the proliferative and differentiation potential of developmentally mature keratinocytes

Notch signaling is necessary to maintain quiescence in adult muscle stem cells.

Abstract: Satellite cells (SCs) are myogenic stem cells found in skeletal muscle that function to repair tissue damaged by injury or disease. SCs are quiescent at rest, although the signaling pathways required to maintain quiescence are unknown. Using a transgenic Notch reporter mouse and quantitative reverse-transcription polymerase chain reaction analysis of Notch target genes, we determined that Notch signaling is active in quiescent SCs. SC-specific deletion of recombining binding protein-Jκ (RBP-Jκ), a nuclear factor required for Notch signaling, resulted in the depletion of the SC pool and muscles that lacked any ability to regenerate in response to injury. SC depletion was not due to apoptosis. Rather, RBP-Jκ-deficient SCs spontaneously activate, fail to self-renew, and undergo terminal differentiation. Intriguingly, most of the cells differentiate without first dividing. They then fuse with adjacent myofibers, leading to the gradual disappearance of SCs from the muscle. These results demonstrate the requirement of Notch signaling for the maintenance of the quiescent state and for muscle stem cell homeostasis by the regulation of self-renewal and differentiation, processes that are all critical for normal postnatal myogenesis.

Relationship of safety climate and safety performance in hospitals.

Abstract: Despite substantial efforts by many health care organizations, medical errors remain too common and continue to generate significant personal and financial burdens (Institute of Medicine 2006). Researchers who study organizations that face hazardous and turbulent task conditions, yet demonstrate sustained superior safety performance, attribute their achievement in large part to their culture of safety (Roberts 1990; Weick and Sutcliffe 2001). These organizations, often termed high-reliability organizations (HROs), are “systems operating in hazardous conditions that have fewer than their share of adverse events” (Reason 2000) and include aircraft carriers, air traffic control systems, and nuclear power plants. The main distinguishing feature of HROs is their ability to perform demanding activities with low incident rates and an almost complete absence of catastrophic failures over several years. Based on evidence from HROs, policy makers interested in improving health care delivery have called upon health care organizations to strengthen their safety culture to reduce adverse events (Institute of Medicine 2001). In this study, the safety culture of an organization is viewed as the values shared among organization members about what is important, their beliefs about how things operate in the organization, and the interaction of these with work unit and organizational structures and systems, which together produce behavioral norms in the organization that promote safety. Although this definition is similar to definitions of organizational culture more generally (Schein 1992), it is specific to the safety culture of an organization and highlights the role of interpersonal, work unit, and organizational contributions in forming shared basic assumptions that individuals working in organizations develop over time. Like others, we adopt the view that culture is difficult to measure, and that it is more feasible to track a related construct called safety climate (Zohar 1980; Griffin and Neal 2000), the perceptions and attitudes of the organization's workforce about surface features of the culture of safety in hospitals at a given point in time (Flin 2007). While most presume that better safety climate in hospitals will be associated with fewer errors and better outcomes, quantitative evidence establishing this link is limited. Anticipated benefits would stem from the ability of organizations with strong safety climates to cultivate behaviors that enhance collective learning by addressing unproductive beliefs and attitudes about errors, their cause and cure. Obtaining better information about the relationship between hospital safety climate and safety performance would be beneficial. By highlighting the importance of safety climate, such information would facilitate the development of benchmarks and initiatives to improve it. Further recognition of safety climate's importance would promote collaboration within and among organizations to compare the measures of safety climate and share useful approaches. Such information would also help hospital managers and clinicians target approaches to safety improvement of greatest potential value. In this study, we examined the relationship between hospital safety climate and measures of hospital performance on selected indicators of patient safety. We combined data from a survey that measured safety climate among personnel in a national sample of hospitals, with indicators of potential safety events from the Agency for Healthcare Research and Quality's Patient Safety Indicators (AHRQ PSIs).