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The article presents a study on the mortality, cardiovascular and cerebrovascular risks associated with the long-term nonsteroidal anti-inflammatory drug (NSAID) use in patients with osteoarthritis. Results revealed that exposure to any NSAID is associated with the decreased risk of death and the increased risks of cardiovascular and cerebrovascular diseases. It is concluded that NSAIDs are associated with an increased risk of cardiovascular or cerebrovascular disease.

Purpose: Better understanding patient uptake of pharmacogenomic (PGx) testing may inform its implementation and maximize the benefits that such testing can confer. This study examined patient and provider factors associated with PGx test ordering in a national health care system in which panel-based testing was implemented as part of routine care., Methods: We used a retrospective matched cohort design and data from the Veterans Health Administration Corporate Data Warehouse. A conditional logistic model was used to identify factors associated with a PGx order receipt and estimate odds ratios and 95% confidence intervals., Results: The following patient factors predicted receipt of a PGx test order: younger age, married status, rural residence, non-Hispanic Black or Hispanic race/ethnicity, PGx educational mailer receipt, depression diagnosis, allergy to a drug on the panel, prescriptions for drugs on the panel, and specialty care visits (P < .05). Additionally, patients whose providers were female, younger, a nurse practitioner/physician assistant or pharmacist, or participated in an educational mailer program were more likely to receive an order (P < .05)., Conclusion: This study highlights factors that may facilitate or hinder the widespread and equitable implementation of PGx testing in a large national health care system. The information is being used to further refine the program., Competing Interests: Conflict of Interest Rebekah Ryanne Wu is an employee and equity holder of 23andMe. She is also a board member and shareholder of MeTree&You. Neither organization participated in or benefited from this work., (Published by Elsevier Inc.)

Purpose/objective: Individuals with spinal cord injuries and disorders (SCI/D) are at increased risk for experiencing loneliness and social isolation. The aim is to describe facilitators identified by individuals living with SCI/D to alleviate loneliness and perceived social isolation., Research Method/design: Descriptive qualitative design using in-depth interviews with veterans with SCI/D ( n = 23). Descriptive statistics was used to calculate demographic and injury characteristics. Audio-recorded and transcribed verbatim transcripts were coded and analyzed using Braun and Clarke's (2006) six thematic analysis phases., Results: Participants were male (70%), white (78%), and not currently married (35%), with an average age of 66 years (42-88). Participants had paraplegia (61%), with traumatic etiology (65%) and were injured 14 years (1-45) on average. Eight themes were identified by participants living with SCI/D that described facilitators to alleviate loneliness and perceived social isolation. (a) Engage in/pursue interests; (b) Interact with/spend time with others; (c) Embrace acceptance; (d) Take part in reciprocity; (e) Find a purpose/accomplish goals; (f) Get out of residence, get outside; (g) Connect with SCI/D community/SCI/D peers; and (h) Seek help from (mental) healthcare professionals., Conclusions/implications: Individuals with SCI/D identified facilitators to alleviate loneliness that encompasses changes in ways of thinking, actions to expand participation in life, and efforts focused on involving others. Findings can be used to guide healthcare delivery and develop interventions to target feelings of loneliness and social isolation in persons with SCI/D, which may be particularly impactful if they involve reciprocal interactions with peers with SCI/D. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Objective: To identify variables independently associated with moderate to high loneliness in individuals living with Spinal Cord Injuries or Disorders (SCI/D)., Design: A cross-sectional, national survey of a random sample of community-dwelling Veterans with SCI/D in the United States. Survey methodology was used to collect data on demographic and injury characteristics, general health, chronic and SCI-secondary conditions, and loneliness., Setting: The VHA SCI/D System of Care including 25 regional SCI/D Centers (or Hubs)., Participants: Among 2466 Veterans with SCI/D, 592 completed surveys (24%). Most participants were men (91%), white (81%), not currently married (42%), had tetraplegia (33%), and on average injured for 18 years at the time of data collection (N=562)., Interventions: Not applicable., Main Outcome Measure: The dependent variable, loneliness, was collected using the UCLA-3 instrument. Loneliness was dichotomized into never/low loneliness and moderate/high loneliness (UCLA score ≥ 4)., Results: Bivariate analyses assessed unadjusted associations in demographics, injury characteristics, chronic disease, and SCI-secondary conditions. Multivariable logistic regression was used to identify factors independently associated with moderate/high loneliness. Participants had a mean loneliness score of 5.04, SD=1.99. The point prevalence of moderate to high loneliness was 66%. Lower duration of injury, paraplegia, being unmarried, being in fair/poor general health, having dysfunctional sleep, and having a diagnosis of bowel dysfunction were each independently associated with greater odds of moderate/high loneliness., Conclusions: Findings suggest that interventions to reduce/manage loneliness in the Veteran SCI/D population should focus on those who are more newly injured, have paraplegia, currently unmarried, have bowel problems, and experience dysfunctional sleep., (Published by Elsevier Inc.)

Context/objective: Examine demographics, injury characteristics, objective measures of social isolation and health factors that are associated with perceived social isolation (PSI) among Veterans with spinal cord injury and disorders (SCI/D)., Design: Cross-sectional survey., Setting: The Veterans Health Administrations (VHA) SCI/D system of care., Participants: Veterans with SCI/D who have used the VHA health care system., Intervention: Not applicable., Outcomes Measures: We assessed unadjusted associations of high PSI (above population mean) vs low (normative/below population mean), and multivariable logistic regression for independent associations with PSI., Results: Out of 1942 Veterans with SCI/D, 421 completed the survey (22% response rate). Over half (56%) had PSI mean scores higher than the general population. Among the objective measures, having a smaller social network size was associated with increased odds of high PSI (OR 3.59, P < .0001); additionally, for health factors, having depression (OR 3.98, P < 0.0001), anxiety (OR 2.29, P = 0.009), and post-traumatic stress (OR 2.56, P = 0.003) in the previous 6 months, and having 4 or more chronically occurring secondary conditions (OR 1.78, P = 0.045) was associated with increased odds of high PSI. The most commonly identified contributors to feelings of PSI included mobility concerns (63%), having a SCI/D (61%), and concerns about being a burden on others (57%)., Conclusions: Factors such as social network size may be used to identify individuals with SCI/D at risk for PSI. Additionally, by identifying mental health problems, presence of multiple chronically occurring secondary conditions, and Veteran-identified contributors of PSI, we can target these factors in a patient-centered interventions to identify and reduce PSI.

Importance: Venous thromboembolism (VTE) represents a major source of preventable morbidity and mortality and is a leading cause of death in the US after cancer surgery. Previous research demonstrated variability in VTE chemoprophylaxis prescribing, although it is unknown how these rates compare with performance in the Veterans Health Administration (VHA)., Objective: To determine VTE rates after cancer surgery, as well as rates of inpatient and outpatient (posthospital discharge) chemoprophylaxis adherence within the VHA., Design, Setting, and Participants: This retrospective cohort study within 101 hospitals of the VHA health system included patients aged 41 years or older without preexisting bleeding disorders or anticoagulation usage who underwent surgical treatment for cancer with general surgery, thoracic surgery, or urology between January 1, 2015, and December 31, 2022. The VHA Corporate Data Warehouse, Pharmacy Benefits Management database, and the Veterans Affairs Surgical Quality Improvement Program database were used to identify eligible patients. Data analysis was conducted between January 2022 and July 2023., Exposures: Inpatient surgery for cancer with general surgery, thoracic surgery, or urology., Main Outcomes and Measures: Rates of postoperative VTE events within 30 days of surgery and VTE chemoprophylaxis adherence were determined. Multivariable Poisson regression was used to determine incidence-rate ratios of inpatient and postdischarge chemoprophylaxis adherence by surgical specialty., Results: Overall, 30 039 veterans (median [IQR] age, 67 [62-71] years; 29 386 men [97.8%]; 7771 African American or Black patients [25.9%]) who underwent surgery for cancer and were at highest risk for VTE were included. The overall postoperative VTE rate was 1.3% (385 patients) with 199 patients (0.7%) receiving a diagnosis during inpatient hospitalization and 186 patients (0.6%) receiving a diagnosis postdischarge. Inpatient chemoprophylaxis was ordered for 24 139 patients (80.4%). Inpatient chemoprophylaxis ordering rates were highest for patients who underwent procedures with general surgery (10 102 of 10 301 patients [98.1%]) and lowest for patients who underwent procedures with urology (11 471 of 17 089 patients [67.1%]). Overall, 3142 patients (10.5%) received postdischarge chemoprophylaxis, with notable variation by specialty., Conclusions and Relevance: These findings indicate the overall VTE rate after cancer surgery within the VHA is low, VHA inpatient chemoprophylaxis rates are high, and postdischarge VTE chemoprophylaxis prescribing is similar to that of non-VHA health systems. Specialty and procedure variation exists for chemoprophylaxis and may be justified given the low risks of overall and postdischarge VTE.

Background: Spinal cord injury (SCI) healthcare providers are aware of the harmful consequences of overweight/obesity in persons with SCI, but many are unaware of available information and lack training to guide weight management care in the SCI population., Objective: Describe the development and content of an educational curriculum for healthcare providers to help individuals with SCI prevent or manage overweight/obesity., Methods: The biopsychoecological framework guided curriculum planning, data collection, and product development. Thematic analysis of interviews conducted with individuals with SCI, informal caregivers, and SCI healthcare providers pinpointed central educational curriculum topics. SCI healthcare providers evaluated the curriculum., Results: Seven comprehensive topics were developed: 1. Scope and consequences of overweight/obesity in SCI; 2. Classifying and measuring overweight/obesity in SCI; 3. Guidelines related to weight management in SCI; 4. Identifying challenges (and solutions) to weight management in SCI; 5. Strategies for providers to facilitate weight management; 6. Understanding goals, motivators, and desired feedback for weight management; and 7. Knowing how informal caregivers are affected by weight and weight management of care recipients with SCI. High ratings (>80% strong agreement) were achieved on content, word choice, organization, relevance, and actionability. Modification needs were identified and subsequently made to layout, visual aids, and provision of tangible resources. Providers described the curriculum as a scientifically rigorous resource that addresses a knowledge gap, provides population-specific content, and is useful across interdisciplinary teams., Conclusion: We developed a self-directed learning educational curriculum addressing topics most salient to stakeholders involved in overweight/obesity management of persons with SCI., (Published by Elsevier Inc.)

Background: Carbapenem-resistant Enterobacteriaceae (CRE) cause approximately 13 100 infections, with an 8% mortality rate in the United States annually. Carbapenemase-producing CRE (CP-CRE) a subset of CRE infections infections have much higher mortality rates (40%-50%). There has been little research on characteristics unique to CP-CRE. The goal of the current study was to assess differences between US veterans with non-CP-CRE and those with CP-CRE cultures., Methods: A retrospective cohort of veterans with CRE cultures from 2013-2018 and their demographic, medical, and facility level covariates were collected. Clustered multiple logistic regression models were used to assess independent factors associated with CP-CRE., Results: The study included 3096 unique patients with cultures positive for either non-CP-CRE or CP-CRE. Being African American (odds ratio, 1.44 [95% confidence interval, 1.15-1.80]), diagnosis in 2017 (3.11 [2.13-4.54]) or 2018 (3.93 [2.64-5.84]), congestive heart failure (1.35 [1.11-1.64]), and gastroesophageal reflux disease (1.39 [1.03-1.87]) were associated with CP-CRE cultures. There was no known antibiotic exposure in the previous year for 752 patients (24.3% of the included patients). Those with no known antibiotic exposure had increased frequency of prolonged proton pump inhibitor use (17.3%) compared to those with known antibiotic exposure (5.6%)., Discussion: Among a cohort of patients with CRE, African Americans, patients with congestive heart failure, and those with gastroesophageal reflux disease had greater odds of having a CP-CRE culture. Roughly 1 in 4 patients with CP-CRE had no known antibiotic exposure in the year before their positive culture., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Objectives: To explore the personal meanings of healthy eating and physical activity among individuals living with spinal cord injury (SCI) and the information and resources they find beneficial. Methods: We conducted in-depth semistructured individual interviews to understand the personal meanings of healthy eating and physical activity among individuals with SCI. We completed a thematic analysis of qualitative data. Results: Participants were 11 Veterans and 14 civilians, predominantly male, non-Hispanic White, and with paraplegia. Data were described across two categories, including the personal meaning of healthy eating and the personal meaning of physical activity/exercise. Individuals with SCI described their meaning of healthy eating around four themes: types of food, amounts/portions of food, conscious/mindful eating, and eating to enhance health. Individuals wanted information on tailored diets for individuals with paraplegia and tetraplegia and healthy foods that are easy to prepare by people with SCI. Their personal meaning of physical activity/exercise focused on four themes: types of physical activity and exercise, staying active, moving/movement, and differences from non-SCI. Desired information around physical activity included cardiovascular workouts that are effective and possible to do in a wheelchair so that people with SCI can burn enough of the calories they consume to lose or maintain weight. Conclusion: Results provide a better understanding of what healthy eating and physical activity mean to people with SCI and information they desire toward these goals, which can be used to guide patient-provider discussions, develop health promotion programs, and tailor interventions to capitalize on meaningful concepts and beliefs that facilitate healthy behaviors., Competing Interests: Disclosures The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government., (© 2021 American Spinal Injury Association.)

Objective: To gain a fuller understanding, in the context of biopsychoecological factors, of drivers/motivators, goal setting, and feedback, individuals with spinal cord injury (SCI) find helpful to gauge their weight management progress. Research Method/Design: We conducted in-depth interviews around weight management in SCI. Participants included veterans and civilians with SCI. Thematic analysis methodology was used to categorize data into relevant recurrent and/or conceptually significant themes. Results: Twenty-five individuals identified three primary reasons they wanted to participate in weight management, including overall health and wellness, appearance, and functional mobility. Their self-identified weight management goals included reaching/maintaining a specific body weight and/or trimming a focused body part; engaging in any or more physical activity/exercise; gaining strength and endurance; participating in life and activities; and alleviating weight-related health symptoms (e.g., pain). Individuals identified progress assessments, recognition, regular check-ins, and encouragement as helpful feedback toward weight management achievement. Conclusions/Implications: Our work identified what drives weight management in individuals with SCI, what is important to them in terms of goal setting, and what feedback they would find helpful. These findings may be used in intervention planning and program development to facilitate participation and behavior modification. Weight management efforts and interventions are needed that 1) incorporate motivators for weight management that are important to individuals with SCI; 2) help them identify actionable process and performance goals to facilitate achievement of self-identified meaningful outcome goals; and 3) provide person-centered weight management progress feedback such as those identified in this study (progress assessments, recognition, regular check-ins, and encouragement). (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: The Veterans Choice Program (VCP), aimed at improving access to care, included expanded options for Veterans to receive primary care through community providers., Objectives: The objective of this study was to characterize and compare Veterans use of Veterans Health Administration (VA) primary care services at VA facilities and through a VA community care network (VA-CCN) provider., Research Design: This was a retrospective, observational over fiscal years (FY) 2015-2018., Subjects: Veterans receiving primary care services paid for by the VA., Measures: Veteran demographic, socioeconomic and clinical factors and use of VA primary care services under the VCP each year., Results: There were 6.3 million Veterans with >54 million VA primary care visits, predominantly (98.5% of visits) at VA facility. The proportion of VA-CCN visits increased in absolute terms from 0.7% in 2015 to 2.6% in 2018. Among Veterans with any VA-CCN primary care, the proportion of VA-CCN visits increased from 22.6% to 55.3%. Logistic regression indicated that Veterans who were female, lived in rural areas, had a driving distance >40 miles, had health insurance or had a psychiatric/depression condition were more likely to receive VA-CCN primary care. Veterans who were older, identified as Black race, required to pay VA copayments, or had a higher Nosos score, were less likely to receive VA-CCN primary care., Conclusion: As the VA transitions from the VCP to MISSION and VA facilities gain experience under the new contracts, attention to factors that impact Veterans' use of primary care services in different settings are important to monitor to identify access barriers and to ensure Veterans' health care needs are met., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: To address concerns about access to care, the Veterans Access, Choice, and Accountability Act of 2014 was enacted to make care available in the community when Veterans Health Administration (VA) care was unavailable or not timely. This paper examined VA referrals for diagnostic sleep studies from federal fiscal year (FY) 2015-2018., Design: Sleep studies completed between FY2015 and 2018 for Veterans tested within VA facilities (VAF) or referred to VA community care (VACC) providers were identified using VA administrative data files. Sleep studies were divided into laboratory and home studies., Key Results: The number of sleep studies conducted increased over time; the proportion of home studies increased in VAF (32 to 47%). Veterans were more likely to be referred for a sleep study to VACC if they lived in a rural or highly rural area (ORs = 1.47 and 1.55, respectively), and had public or public and private insurance (ORs = 2.01 and 1.35), and were less likely to be referred to VACC if they were age 65+ (OR = 0.72) and were in the highest utilization risk based on Nosos score (OR = 0.78). Regression analysis of sleep study type revealed that lab studies were much more likely for VACC referrals (OR = 3.16), for persons living in rural areas (OR = 1.21), with higher comorbidity scores (OR = 1.28) and for ages 44-54, 55 to 64, and 65+ (ORs = 1.12, 1.28, 1.45, respectively) compared to younger Veterans. Veterans with some or full VA copayments (ORs = 0.91 and 0.86, respectively), and overweight Veterans (OR = 0.94) were less likely to have lab studies., Conclusions: The number of sleep studies performed on Veterans increased from 2015 to 2018. Access to sleep studies improved through a combination of providing care through the Veteran Choice Program, predominantly used by rural Veterans, and increased use of home sleep studies by VA.

Importance: Evidence-based care plans can fail when they do not consider relevant patient life circumstances, termed contextual factors, such as a loss of social support or financial hardship. Preventing these contextual errors can reduce obstacles to effective care., Objective: To evaluate the effectiveness of a quality improvement program in which clinicians receive ongoing feedback on their attention to patient contextual factors., Design, Setting, and Participants: In this quality improvement study, patients at 6 Department of Veterans Affairs outpatient facilities audio recorded their primary care visits from May 2017 to May 2019. Encounters were analyzed using the Content Coding for Contextualization of Care (4C) method. A feedback intervention based on the 4C coded analysis was introduced using a stepped wedge design. In the 4C coding schema, clues that patients are struggling with contextual factors are termed contextual red flags (eg, sudden loss of control of a chronic condition), and a positive outcome is prospectively defined for each encounter as a quantifiable improvement of the contextual red flag. Data analysis was performed from May to October 2019., Interventions: Clinicians received feedback at 2 intensity levels on their attention to patient contextual factors and on predefined patient outcomes at 4 to 6 months., Main Outcomes and Measures: Contextual error rates, patient outcomes, and hospitalization rates and costs were measured., Results: The patients (mean age, 62.0 years; 92% male) recorded 4496 encounters with 666 clinicians. At baseline, clinicians addressed 413 of 618 contextual factors in their care plans (67%). After either standard or enhanced feedback, they addressed 1707 of 2367 contextual factors (72%), a significant difference (odds ratio, 1.3; 95% CI, 1.1-1.6; P = .01). In a mixed-effects logistic regression model, contextualized care planning was associated with a greater likelihood of improved outcomes (adjusted odds ratio, 2.5; 95% CI, 1.5-4.1; P < .001). In a budget analysis, estimated savings from avoided hospitalizations were $25.2 million (95% CI, $23.9-$26.6 million), at a cost of $337 242 for the intervention., Conclusions and Relevance: These findings suggest that patient-collected audio recordings of the medical encounter with feedback may enhance clinician attention to contextual factors, improve outcomes, and reduce hospitalizations. In addition, the intervention is associated with substantial cost savings.

Introduction: To develop and validate the first real-world data-based type 2 diabetes progression model (RAPIDS) employing econometric techniques that can study the comparative effects of complex dynamic patterns of glucose-lowering drug use., Methods: The US Department of Veterans Affairs (VA) electronic medical record and claims databases were used to identify over 500,000 diabetes patients in 2003 with up to 9-year follow-up. The RAPIDS model contains interdependent first-order Markov processes over quarters for each of the micro- and macrovascular events, hypoglycemia, and death, as well as predictive models for 8 biomarker levels. Model parameters varied by static demographic factors and dynamic factors, such as age, duration of diabetes, 13 possible glucose-lowering treatment combinations, any blood pressure and any cholesterol-lowering medications, and cardiovascular history. To illustrate model capabilities, a simple comparative study was set up to compare observed treatment use patterns to alternate patterns if perfect adherence is assumed following initiating the use of any of these medications., Results: Data were randomly split into 307,288, 105,195, and 105,081 patients to perform estimation, out-of-sample calibration, and validation, respectively. Model predictions in the validation sample closely aligned with the observed longitudinal trajectory of biomarkers and outcomes. Perfect adherence among initiators increased proportion of days covered by only 6 months. Most of this increase came from increased adherence to monotherapies and did not lead to meaningful changes in any of the outcomes over the 9-year period., Conclusion: Future value of increasing medication adherence among VA patients with diabetes may lie among those who never initiate treatment or are late in initiating treatment. The first-of-its-kind real-world data-based model has the potential to carry out many complex comparative-effectiveness research (CER) studies of dynamic glucose-lowering drug regimens.

The transcriptional regulation of phenylalanine metabolism is particularly important in conifers, long-lived species that use large amounts of carbon in wood. Here, we show that the Pinus pinaster transcription factor, PpNAC1, is a main regulator of phenylalanine biosynthesis and utilization. A phylogenetic analysis classified PpNAC1 in the NST proteins group and was selected for functional characterization. PpNAC1 is predominantly expressed in the secondary xylem and compression wood of adult trees. Silencing of PpNAC1 in P. pinaster results in the alteration of stem vascular radial patterning and the down-regulation of several genes associated with cell wall biogenesis and secondary metabolism. Furthermore, transactivation and EMSA analyses showed that PpNAC1 is able to activate its own expression and PpMyb4 promoter, while PpMyb4 is able to activate PpMyb8, a transcriptional regulator of phenylalanine and lignin biosynthesis in maritime pine. Together, these results suggest that PpNAC1 is a functional ortholog of the ArabidopsisSND1 and NST1 genes and support the idea that key regulators governing secondary cell wall formation could be conserved between gymnosperms and angiosperms. Understanding the molecular switches controlling wood formation is of paramount importance for fundamental tree biology and paves the way for applications in conifer biotechnology., (© 2017 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Aim: Diabetic foot ulcers are associated with an increased risk of death. We evaluated whether ulcer severity at presentation predicts mortality., Methods: Patients from a national, retrospective, cohort of veterans with type 2 diabetes who developed incident diabetic foot ulcers between January 1, 2006 and September 1, 2010, were followed until death or the end of the study period, January 1, 2012. Ulcers were characterized as early stage, osteomyelitis, or gangrene at presentation. Cox proportional hazard regression identified independent predictors of death, controlling for comorbidities, laboratory parameters, and healthcare utilization., Results: 66,323 veterans were included in the cohort and followed for a mean of 27.7months: 1-, 2-, and 5-year survival rates were 80.80%, 69.01% and 28.64%, respectively. Compared to early stage ulcers, gangrene was associated with an increased risk of mortality (HR 1.70, 95% CI 1.57-1.83, p<0.001). The magnitude of this effect was greater than diagnosed vascular disease, i.e., coronary artery disease, peripheral arterial disease, or stroke., Conclusion: Initial diabetic foot ulcer severity is a more significant predictor of subsequent mortality than coronary artery disease, peripheral arterial disease, or stroke. Unrecognized or under-estimated vascular disease and/or sepsis secondary to gangrene should be explored as possible causal explanations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Characterization of the expression and function of genes regulating embryo development in conifers is interesting from an evolutionary point of view. However, our knowledge about the regulation of embryo development in conifers is limited. During early embryo development in Pinus species the proembyo goes through a cleavage process, named cleavage polyembryony, giving rise to four embryos. One of these embryos develops to a dominant embryo, which will develop further into a mature, cotyledonary embryo, while the other embryos, the subordinate embryos, are degraded. The main goal of this study has been to identify processes that might be important for regulating the cleavage process and for the development of a dominant embryo., Results: RNA samples from embryos and megagametophytes at four early developmental stages during seed development in Pinus sylvestris were subjected to high-throughput sequencing. A total of 6.6 million raw reads was generated, resulting in 121,938 transcripts, out of which 36.106 contained ORFs. 18,638 transcripts were differentially expressed (DETs) in embryos and megagametophytes. GO enrichment analysis of transcripts up-regulated in embryos showed enrichment for different cellular processes, while those up-regulated in megagametophytes were enriched for accumulation of storage material and responses to stress. The highest number of DETs was detected during the initiation of the cleavage process. Transcripts related to embryogenic competence, cell wall modifications, cell division pattern, axis specification and response to hormones and stress were highly abundant and differentially expressed during early embryo development. The abundance of representative DETs was confirmed by qRT-PCR analyses., Conclusion: Based on the processes identified in the GO enrichment analyses and the expression of the selected transcripts we suggest that (i) processes related to embryogenic competence and cell wall loosening are involved in activating the cleavage process; (ii) apical-basal polarization is strictly regulated in dominant embryos but not in the subordinate embryos; (iii) the transition from the morphogenic phase to the maturation phase is not completed in subordinate embryos. This is the first genome-wide transcript expression profiling of the earliest stages during embryo development in a Pinus species. Our results can serve as a framework for future studies to reveal the functions of identified genes.

Objective: Many asthma patients suffer from chronic conditions other than asthma. We investigated the specific contribution of common comorbidities on mortality and morbidity in adult asthma., Methods: In an observational study of adults with incident asthma identified between 1999 and 2003 using National Veterans Affairs and Centers for Medicare and Medicaid Services encounter databases (n = 25 975, follow-up 3.0 ± 1.7 years), association between 13 most prevalent comorbidities (hypertension, ischemic heart disease (IHD), osteoarthritis, rheumatoid arthritis, diabetes, mental disorders, substance/drug abuse, enlarged prostate, depression, cancer, alcoholism, HIV and heart failure) and four conditions previously associated with asthma (sleep apnea, gastroesophageal reflux disease (GERD), rhinitis and sinusitis) and mortality, hospitalizations and asthma exacerbations were assessed using multivariate regression analyses adjusted for other clinically important covariates., Results: HIV followed by alcoholism and mental disorders among 18-45-years old, and heart failure, diabetes, IHD and cancer among those ≥ 65 years old were associated with an increased risk of all-cause mortality. Many conditions were associated with increased risk for all-cause hospitalizations, but the increased risk was consistent across all ages for mental disorders. For asthma exacerbations, mental disorder followed by substance abuse and IHD were associated with increased risk among those 18-45 years old, and chronic sinusitis, mental disorder and IHD among those ≥ 65-years old. GERD was associated with decreased risk for asthma exacerbation in all ages., Conclusions: Many comorbidities are associated with poor outcome in adult asthmatics and their effect differs by age. Mental disorders are associated with increased risk of mortality and morbidity across ages.

Background: The rate of guideline concordance with antidepressant treatment for persons with depression is low. The problem may be even more pronounced for patients with depression and other multiple chronic conditions (MCC)., Objectives: To study, for persons with new depressive episodes, the association between MCC and the likelihood of receiving guideline-concordant depression treatment., Research Design: Retrospective cohort study using Veterans Affairs administrative data., Subjects: A total of 43,189 Veterans Affairs patients who had a new depressive episode during 2007 were included., Measures: We assessed whether patients had an adequate supply of antidepressants during acute and continuation phases of depression treatment, which indicates guideline-concordant care. We determined the association between comorbid conditions and receipt of adequate antidepressant supplies after adjusting for potential confounders., Results: Compared with patients with depression alone, those with comorbid cardiovascular/cerebrovascular disease, peptic ulcer/gastroesophageal reflux disease (GERD), or arthritis were 8%-13% more likely to receive adequate antidepressant supplies during the acute phase. Patients with depression and substance/alcohol abuse were 15% less likely to receive adequate supplies in the acute treatment phase. Those with cardiovascular/cerebrovascular disease or peptic ulcer/GERD were 9%-10% more likely to receive continuation phase guideline-concordant depression treatment. Patients with comorbid substance/alcohol abuse were 19% less likely to receive continuation phase guideline-concordant depression treatment. Relatively few of the most prevalent MCC clusters were significantly associated with receipt of guideline-concordant depression treatment., Conclusions: There was no consistent association between specific clusters of chronic conditions and adequate antidepressant supplies. There continues to be need for practice-level and system-level interventions to increase quality of depression treatment, particularly among persons with certain comorbid conditions such as cardiovascular/cerebrovascular disease, peptic ulcer/GERD, and arthritis.

During the life cycles of conifer trees, such as maritime pine (Pinus pinaster Ait.), large quantities of carbon skeletons are irreversibly immobilized in the wood. In energetic terms this is an expensive process, in which carbon from photosynthesis is channelled through the shikimate pathway for the biosynthesis of phenylpropanoids. This crucial metabolic pathway is finely regulated, primarily through transcriptional control, and because phenylalanine is the precursor for phenylpropanoid biosynthesis, the precise regulation of phenylalanine synthesis and use should occur simultaneously. The promoters of three genes encoding the enzymes prephenate aminotransferase (PAT), phenylalanine ammonia lyase (PAL) and glutamine synthetase (GS1b) contain AC elements involved in the transcriptional activation mediated by R2R3-Myb factors. We have examined the capacity of the R2R3-Myb transcription factors Myb1, Myb4 and Myb8 to co-regulate the expression of PAT, PAL and GS1b. Only Myb8 was able to activate the transcription of the three genes. Moreover, the expression of this transcription factor is higher in lignified tissues, in which a high demand for phenylpropanoids exits. In a gain-of-function experiment, we have shown that Myb8 can specifically bind a well-conserved eight-nucleotide-long AC-II element in the promoter regions of PAT, PAL and GS1b, thereby activating their expression. Our results show that Myb8 regulates the expression of these genes involved in phenylalanine metabolism, which is required for channelling photosynthetic carbon to promote wood formation. The co-localization of PAT, PAL, GS1b and MYB8 transcripts in vascular cells further supports this conclusion., (© 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.)

Asparagine, a key amino acid for nitrogen storage and transport in plants, is synthesized via the ATP-dependent reaction catalyzed by the enzyme asparagine synthetase (AS; EC 6.3.5.4). In this work, we present the molecular analysis of two full-length cDNAs that encode asparagine synthetase in maritime pine (Pinus pinaster Ait.), PpAS1, and PpAS2. Phylogenetic analyses of the deduced amino acid sequences revealed that both genes are class II AS, suggesting an ancient origin of these genes in plants. A comparative study of PpAS1 and PpAS2 gene expression profiles showed that PpAS1 gene is highly regulated by developmental and environmental factors, while PpAS2 is expressed constitutively. To determine the molecular mechanisms underpinning the differential expression of PpAS1, the promoter region of the gene was isolated and putative binding sites for MYB transcription factors were identified. Gel mobility shift assays showed that a MYB protein from Pinus taeda (PtMYB1) was able to interact with the promoter region of PpAS1. Furthermore, transient expression analyses in pine cells revealed a negative effect of PtMYB1 on PpAS1 expression. The potential role of MYB factors in the transcriptional regulation of PpAS1 in vascular cells is discussed.

Study Objective: To evaluate outcomes associated with six treatment regimens with theophylline versus each regimen without theophylline in patients with chronic obstructive pulmonary disease (COPD)., Design: Retrospective cohort study., Setting: Veterans Affairs health care system., Patients: A total of 183,573 patients aged 45 years or older who had a diagnosis of COPD and were receiving respiratory drug therapy., Measurements and Main Results: Patients' treatment regimens were identified by using data from October 1, 2002-March 31, 2003, and patients were followed for events by using data from April 1, 2003-September 30, 2005. Data from October 1, 2001-September 30, 2002, were used to define the patients' baseline characteristics. Primary outcome measures were all-cause mortality, COPD exacerbations, and COPD-related hospitalizations. Two approaches were used: first, treatment assignment was based on drug therapy at baseline, and second, exposure was measured as a time-varying covariate. Treatment groups were stratified based on propensity to receive theophylline. Mortality was compared by using Cox proportional hazards models, and other outcomes were compared with use of negative binomial models. Comparisons were conducted within individual treatment regimens that were the same with the exception of theophylline. Patients treated with ipratropium plus theophylline (largest group) compared with those treated with ipratropium alone had a 1.11-fold increase in the risk of death (95% confidence interval [CI] 1.04-1.18). For each of the other regimens, the risk of mortality associated with theophylline was greater than that in the regimens without theophylline (hazard ratios [HRs] 1.17-1.31). In the time-varying exposure analysis, theophylline (HR 1.23, 95% CI 1.09-1.39) was associated with an increased mortality risk., Conclusion: Patients receiving regimens that included theophylline had slightly increased risks of mortality, COPD exacerbations, and COPD hospitalizations compared with patients receiving the same regimens without theophylline. However, the benefits of theophylline on other factors, including symptoms, quality of life, and activities of daily living, were not measured. Clinicians should consider all of the potential benefits and harms associated with theophylline when making treatment recommendations.

Objective: To examine medication adherence and persistence among COPD patients during their last year of life., Data Source: National VA databases were used to identify patients who had COPD and died between 1999 and 2003., Study Design: We examined use of inhaled corticosteroids (ICS), long acting beta(2) agonists (LABA), methylxanthines (MTX), and anticholinergics (AC), alone and in combination. Medication possession ratios (MPR) were compared between regimens by quarterly periods using General Estimating Equations (GEE). Medication persistence was examined in monotherapy users with Kaplan-Meier survival analysis and extended Cox proportional hazard models., Principal Findings: Only half of the identified patients in the COPD cohort (5913 of 11,376) used any medications. Among 5913 patients, overall mean (SD) MPR was 0.44 (0.32) during the last year of life. A positive linear trend in MPR was observed across quarterly periods in AC users (beta=0.014, p<0.0001), and was highest for MTX users (beta=0.11, p<0.0001). Of 3436 on monotherapy only, 40% discontinued medication within 30 days, and 70% discontinued within 90 days. MTX users were less likely to discontinue (HR=0.714, p=0.012) than reference (AC) group., Conclusion: COPD patients in their last year of life tended to use respiratory medications sporadically. Further research is needed to qualify whether minor differences in MPR between regimens reflect behavioral differences related to regimen or reflect refill policy and MPR calculation technique.

The aims of this study were to characterize causes of death among veterans with COPD using multiple cause of death coding, and to examine whether causes of death differed according to timing of COPD diagnosis. Veterans with COPD who died during a five-year follow-up period were identified from national VA databases linked to National Death Index files. Primary, secondary, underlying, and all-coded causes of death were compared between recent and preexistent COPD cohorts using proportional mortality ratios (PMRs), which compares proportion dying from specific causes as opposed to absolute risk of death. Of 26,357 decedents, 7,729 were categorized preexistent and 18,628 were recent COPD cases. Unspecified COPD was listed as underlying cause of death in a significantly greater proportion of preexistent COPD cases compared to recent cases, 20% vs 10%, PMR = 2.0 (95% CI: 1.9-2.1). A relatively higher proportion of recently diagnosed cases died from lung/bronchus, prostate, and site-unspecified cancers. Respiratory failure (J969) was rarely coded as an underlying or primary cause (< 1%), but was a second-code cause of death in 9% of recent and 12% of preexistent cases. Differences in coded causes of death between patients with a recent diagnosis of COPD compared to a preexistent diagnosis of COPD suggests that there is either coded cause-related bias or true differences in cause of death related to length of time with diagnosis. Thus, methods used to identify cohorts of COPD patients, i.e., incidence versus prevalence-based approaches, and coded cause of death can affect estimates of cause-specific mortality.

Background: Concerns exist regarding increased risk for mortality associated with some chronic obstructive pulmonary disease (COPD) medications., Objective: To examine the association between various respiratory medications and risk for death in veterans with newly diagnosed COPD., Design: Nested case-control study in a cohort identified between 1 October 1999 and 30 September 2003 and followed through 30 September 2004 by using National Veterans Affairs inpatient, outpatient, pharmacy, and mortality databases; Centers for Medicare & Medicaid Services databases; and National Death Index Plus data. Cause of death was ascertained for a random sample of 40% of those who died during follow-up. Case patients were categorized on the basis of all-cause, respiratory, or cardiovascular death. Mortality risk associated with medications was assessed by using conditional logistic regression adjusted for comorbid conditions, health care use, and markers of COPD severity., Setting: U.S. Veterans Health Administration health care system., Participants: 32 130 case patients and 320 501 control participants in the all-cause mortality analysis. Of 11 897 patients with cause-of-death data, 2405 case patients had respiratory deaths and 3159 case patients had cardiovascular deaths., Measurements: All-cause mortality; respiratory and cardiovascular deaths; and exposure to COPD medications, inhaled corticosteroids, ipratropium, long-acting beta-agonists, and theophylline in the 6 months preceding death., Results: Adjusted odds ratios (ORs) for all-cause mortality were 0.80 (95% CI, 0.78 to 0.83) for inhaled corticosteroids, 1.11 (CI, 1.08 to 1.15) for ipratropium, 0.92 (CI, 0.88 to 0.96) for long-acting beta-agonists, and 1.05 (CI, 0.99 to 1.10) for theophylline. Ipratropium was associated with increased cardiovascular deaths (OR, 1.34 [CI, 1.22 to 1.47]), whereas inhaled corticosteroids were associated with reduced risk for cardiovascular death (OR, 0.80 [CI, 0.72 to 0.88]). Results were consistent across sensitivity analyses., Limitations: Current smoking status and lung function were not measured. Misclassification of cause-specific mortality is unknown., Conclusion: The possible association between ipratropium and elevated risk for all-cause and cardiovascular death needs further study.

Global Initiative on Chronic Obstructive Lung Disease (GOLD) guidelines recently removed stage 0, a group with symptoms but without airways obstruction, from their severity staging. However, in practice this group may still be diagnosed and medically managed. The aim of this study was to characterize healthcare utilization patterns of chronic obstructive pulmonary disease (COPD) patients by disease severity, focusing on the possible unique attributes of patients who would have been classified as GOLD stage 0. This is a prospective cohort pilot study performed at the Hines Veterans Administration Hospital. One hundred twenty patients with a diagnosis of COPD were enrolled. The participants completed quality-of-life questionnaires and a pulmonary function test. Healthcare utilization data were obtained 1 year prior and 2 years after the enrollment date. Three disease severity groups were defined based on GOLD criteria for comparison [GOLD stage 1-2 (GS 1-2), GOLD stage 3-4 (GS 3-4), and formerly GOLD stage 0 ("at risk")]. The "at risk" group had an average of 14.4 (SD = 30.5) outpatient visits/year and 0.3 (SD = 0.8) hospitalizations/year, which were higher than the other groups, but this was not statistically significant. Respiratory medications were used by 6 (26%), 30 (59%), and 40 (91%) patients from "at risk" to GS 3-4, respectively. Patients in the "at risk" group had a decrement in health status, significant utilization of healthcare services, and were often receiving medications not consistent with guidelines.

Purpose: Diseases are often described and studied in isolation, yet there is increasing recognition of the complex interrelatedness of diseases and treatments in patients with multiple chronic diseases. Our objective was to describe the impact of selected diseases involving chronic inflammation (chronic obstructive pulmonary disease [COPD], osteoarthritis, and rheumatoid arthritis) on mortality., Methods: We identified a cohort aged 55 to 64 years with one or more chronic conditions. Clusters of mutually exclusive disease combinations were created. Five-year all-cause mortality was determined and the relative risk (RR) of mortality was estimated when COPD, osteoarthritis, and rheumatoid arthritis were added to clusters., Results: In 741,847 persons the 5-year mortality rates were lowest among persons with one condition and increased with more chronic conditions. The presence of osteoarthritis in a cluster was an exception where the risk was lower compared with that cluster without osteoarthritis: COPD (RR = 0.73 [95% confidence interval (CI), 0.65, 0.81]); ischemic heart disease (0.63 [0.52, 0.76]); hypertension (0.77 [0.71, 0.83]); dementia (0.63 [0.42, 0.93]); depression (0.65 [0.50, 0.84]); hypertension plus diabetes (0.85 [0.77, 0.93]); and ischemic heart disease plus hypertension (0.83 [0.73, 0.94])., Conclusions: The association between osteoarthritis and lower rates of mortality is notable and replicating these findings to explore causal relationships is important.

Background: Evidence indicates increased risk of cardiovascular events with certain nonsteroidal anti-inflammatory drug (NSAID) use; however, less is known about NSAID use and mortality. In addition, it is unclear whether risks observed with NSAIDs are modified by coronary artery disease (CAD). The association between NSAID exposure and mortality, cardiovascular, and cerebrovascular events was examined., Methods: A nested case-control study in a cohort of 565,451 US veterans with a diagnosis of osteoarthritis was conducted. The cohort was divided into those with preexisting CAD (16,869 cases) and those without (11,912 cases). Up to 20 controls were selected for each case., Results: The average age of participants was 69.8 years (non-CAD) and 71.8 years (CAD). Relative to no exposure, adjusted odds ratios for cardiovascular or cerebrovascular events for any NSAID were 1.14 (95% confidence interval [CI], 1.08-1.21) in the non-CAD group and 1.18 (95% CI, 1.11-1.27) in the CAD group. Exposure to NSAIDs was associated with a decreased risk of all-cause mortality in both the non-CAD (0.72, 95% CI, 0.68-0.77) and CAD (0.79, 95% CI, 0.73-0.86) groups., Conclusions: As in previous reports, there was an increased risk of cardiovascular and cerebrovascular events for NSAIDs. However, NSAID exposure was associated with a reduced risk of death. This study raises important questions about NSAIDs in patients with osteoarthritis given that they seem to increase the risk of cardiovascular events but decrease overall mortality.

Background: Little is known about current use of pulmonary function testing in clinical practice. This study evaluated spirometry use in persons with COPD receiving care from the Veterans Health Administration health-care system., Methods: Administrative data were used to identify a cohort of patients who were >/= 40 years of age with recently diagnosed COPD. Spirometry was identified using administrative data. Spirometry use was characterized over a 12-month period, and the use of spirometry around acute exacerbations and surgical procedures was examined., Results: A total of 197,878 patients met the inclusion criteria in 1999. The average age was 67.5 years (SD, 10.0), and 98.2% of patients were male. A total of 66,744 patients (33.7%) underwent spirometry. The use of spirometry for newly diagnosed COPD patients decreased with age and was 3.3 times higher for those visiting pulmonologists., Conclusions: This study suggests that spirometry is inconsistently used in the diagnosis of COPD or the care of patients with COPD. This inconsistent pattern of use is seen even with the endorsement of spirometry use for patients with COPD by two national guidelines; however, the data predate the most recent version of the guidelines. It is unclear whether it is lack of physician knowledge of, attitudes about, or belief in the utility of spirometry that underlie the current patterns of physician use of this clinical tool.

Digital pulley reconstruction with a synthetic material, PTFE membrane, was compared with suture repair of the native A3 pulley at the time of tenorrhaphy in the chicken model. The surgically treated foot was immobilized in flexion for either 28 or 35 days and then allowed full ambulation for periods of up to 42 days postoperatively. At sacrifice digits underwent range-of-motion testing, and the pulley and tenorrhaphy sites were explored. No disruptions were noted in the reconstructed PTFE pulleys. The number of tenorrhaphy disruptions was similar between the PTFE pulley group (11%) and the suture repair of the native pulley group (14%). No decrease in range of motion was demonstrated in the PTFE pulley digits, and no deleterious effect of increasing immobilization time (35 days versus 28 days) was noted. The results indicate that this synthetic pulley did not interfere with normal tendon healing processes. PTFE membrane may prove to be a promising reconstructive alternative when the native pulley is irreparably damaged.

Reconstruction or replacement of the damaged pulley is a difficult surgical problem because of the need to find suitable biological material, the bulkiness of the repair, and adhesion formation between the pulley and flexor tendons. Therefore, a method was developed to reconstruct the fibro-osseous pulleys with polytetrafluoroethylene (PTFE) membrane. Twenty White Leghorn chickens had the A3 pulley of the long digit excised; this was followed by a standard injury to the flexor profundus tendon. The A3 pulley was then reconstructed with PTFE membrane. In the opposite foot, the A3 pulley was transected laterally, the tendon injured in the same manner, and the native pulley sutured. Seven control chickens had a PTFE pulley reconstruction without tendon injury in one foot and the opposite foot did not undergo surgery. At postoperative days 0, 21, and 35, the animals were killed to evaluate the effectiveness of the PTFE pulleys. Flexor tendon function was assessed by determining the active range of motion of the digit. There was no significant difference between the PTFE pulleys and suture repair of the native pulleys at postoperative days 21 and 35. This indicates that the PTFE pulleys were capable of preventing tendon bow-stringing and did not significantly impair tendon gliding. The breaking strength of the PTFE pulley was less than that of the normal A3 pulleys, but it was sufficient to allow immediate mobilization of the digits postoperatively without fear of pulley rupture. The synthetic PTFE pulley appears to have the potential to function as an effective immediate replacement for the fibro-osseous pulleys.