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This study examined how social engagement (SE) and mild cognitive impairment (MCI) influence changes in mobility over three years of follow-up. We performed a secondary analysis of longitudinal data among primary care patients aged >64 years (N=430). Mobility outcomes include performance-based function via the Short Physical Performance Battery (SPPB) and patient reported function via the Late-Life Function Instrument (LLFI). Independent variables include: 1) MCI determined by a comprehensive cognitive battery and scores 1.5 SD < age-adjusted mean; 2) SE measured by standardized self-report of social activities. Multivariate linear mixed regression models demonstrate that MCI is associated with lower scores on SPPB and LLFI (β= -0.76, p

Background Physical activity is an important clinical marker of disease status in COPD. COPD is also characterized by low-grade systemic inflammation. However, the relationship between physical activity and systemic inflammation in COPD is unclear. Methods We monitored daily step count, a directly measured physical activity, using the StepWatch Activity Monitor, an ankle-worn accelerometer, in 171 people with stable COPD. Exercise capacity was assessed with the 6-min walk test (6MWT). We measured plasma C-reactive protein (CRP) and IL-6 levels. Linear regression models examined the cross-sectional associations of daily step count and 6MWT distance with CRP and IL-6 levels. Results Subjects had a mean age 72 ± 8 years and mean FEV 1 1.5 ± 0.57 L (54 ± 20% predicted). Median daily step count was 5,203 (interquartile range [IQR], 3,627-7,024], CRP level was 2.4 mg/L (IQR, 1.2-5.0), and IL-6 level was 2.9 pg/mL (IQR, 2.0-5.1). Each 1,000-step increase in daily step count was associated with a 0.94 mg/L and 0.96 pg/mL decrease in CRP ( P = .020) and IL-6 ( P = .044) levels, respectively, adjusting for age, FEV 1 % predicted, pack-years smoked, cardiac disease, current statin use, history of acute exacerbations, and season. There was a significant linear trend of increasing daily step count by quartiles and decreasing CRP ( P = .0007) and IL-6 ( P = .023) levels. Higher 6MWT distance was also significantly associated with lower CRP and IL-6 values. Conclusion People with COPD who walked the most had the lowest plasma CRP and IL-6 levels. These results provide the conceptual basis to study whether an intervention to promote walking will reduce systemic inflammation in people with COPD.

Adipose tissue is a major regulator of bone metabolism and in the general population obesity is associated with greater bone mineral density (BMD). However, bone-fat interactions are multifactorial, and may involve pathways that influence both bone formation and resorption with competing effects on the skeleton. One such pathway involves adipocyte production of adipokines that regulate bone metabolism. In this study we determined the association between BMD, walking status, and circulating adipokines (adiponectin and leptin) in 149 men with chronic spinal cord injury (SCI). Although adipokine levels did not vary significantly based on walking status, there was a significant inverse association between adiponectin and BMD in wheelchair users independent of body composition. We found no association between adiponectin and BMD in the walkers and no association between leptin and BMD in either group. These findings suggest that for subjects with chronic SCI, walking may mitigate the effect of adiponectin mediated bone loss. For wheelchair users, adipose-derived adiponectin may contribute to SCI-induced osteoporosis because the osteoprotective benefits of obesity appear to require mechanical loading during ambulation.

The proliferation of broadband mobile devices, which many students bring to school with them as mobile phones, makes the widespread adoption of AR pedagogies a possibility, but pedagogical, distribution, and training models are needed to make this innovation an integrated part of education, This paper employs Social Construction of Technology (SCOT) to argue for a participatory model of scaling by key stakeholders groups (students, teachers, researchers, administrators), and demonstrates through various cases how ARIS (arisgames.org) — a free, open-source tool for educators to create and disseminate mobile AR learning experiences — may be such a model.

SummaryLike other acidic transactivation domains (TAD), the minimal TAD from the erythroid-specific transcription factor EKLF (EKLFTAD) has been shown to contribute both to its transcriptional activity as well as to its ubiquitin(UBI)-mediated degradation. In this article, we examine the activation-degradation role of the acidic TAD of EKLF and demonstrate that the first 40 residues (EKLFTAD1) within this region form a noncovalent interaction with UBI. Nuclear magnetic resonance (NMR) structural studies of an EKLFTAD1-UBI complex show that EKLFTAD1 adopts a 14-residue α helix that forms the recognition interface with UBI in a similar manner as the UBI-interacting helix of Rabex5. We also identify a similar interaction between UBI and the activation-degradation region of SREBP1a, but not with the activation-degradation regions of p53, GAL4, and VP16. These results suggest that select activation-degradation regions like the ones found in EKLF and SREBP1a function in part through their ability to form noncovalent interactions with UBI.

SummaryPurpose To evaluate whether use of a bisphosphonate (risedronate) in addition to calcium and vitamin D in male veterans with epilepsy who were taking antiepileptic drugs (AEDs) long term can prevent the loss of bone mass (BMD, bone mineral density) associated with AED use compared to patients who were treated with a placebo plus calcium and vitamin D. As a secondary end point we studied the incidence of new morphometric vertebral and nonvertebral fractures. Methods Antiepileptic drug and osteoporosis prevention trial (ADOPT) was designed as a prospective 2-year double-blind, randomized placebo controlled study involving 80 male veterans with epilepsy who were being treated with AEDs such as phenytoin, phenobarbital, sodium valproate, or carbamazepine for a minimum of 2 years. All enrolled participants received calcium and vitamin D supplementation, and were randomized to risedronate or matching placebo. Total body, bilateral proximal femora, and anteroposterior (AP) lumbar spine BMDs in addition to morphometric lateral vertebral assessments (LVAs) were evaluated by a dual energy x-ray absorptiometry (DXA) instrument. Comparisons of BMDs were made between baseline, 1 year, and after 2 years of enrollment in the study. The incidence of new vertebral and nonvertebral fractures was secondary end point. Key Findings Of the 80 patients initially enrolled in the study, 53 patients completed the study. Baseline characteristics of the two groups were similar. At the end of the study, in the placebo plus calcium and vitamin D group, we observed a significant improvement in BMD at any of the evaluated sites when compared to their baseline scans in 69% (18/26) of the participants. In the risedronate plus calcium and vitamin D group, we observed significant improvement of BMDs in 70% (19/27) of the participants. At the end of the study, the risedronate group experienced a significant increase of BMD at the lumbar spine L1-4 (1.267–1.332 g/cm2), which was significantly larger than that seen in the placebo group) (1.229 g/cm2 vs. 1.245 g/cm2; p = 0.0066).There were nonsignificant differences between the two groups regarding changes of total body BMD or at the proximal bilateral femora. Five new vertebral fractures and one nonvertebral fracture were observed only in the placebo group. Significance Calcium and vitamin D supplementation or calcium and vitamin D supplementation in addition to risedronate improved BMD in more than 69% of male veterans with epilepsy who were taking AEDs. In the group receiving risedronate plus calcium and vitamin D there was a significant improvement of BMD at the lumbar spine as compared to the placebo group, which also received calcium and vitamin D. The use of risedronate plus calcium and vitamin D prevented the incidence of new vertebral fractures and one nonvertebral fracture in this cohort.

The bovine papillomavirus type 1 (BPV1) E2 protein binds as a dimer to the viral genome to promote its transcription, replication and maintenance in keratinocytes. Although BPV1 E2 dimerizes primarily through its DNA-binding domain, it was shown previously that its transactivation domain (TAD) can also dimerize in vitro through formation of a disulfide bond between cysteine 57 (C57) of adjacent monomers and of an ion pair between arginine 172 (R172) and aspartic acid 175 (D175). The function of this TAD dimerization interface in vivo remains unknown. Here, we report the effects of substituting C57, R172 and D175 by alanine on the transactivation activity of BPV E2 as well as on its ability to support viral DNA replication using a novel luciferase-based assay. Results for this mutational analysis suggest that the TAD dimerization interface is not essential for either process but may contribute to the DNA replication activity of BPV1 E2.

Background: Anemia is increasingly being identified as a poor prognostic factor in patients with heart failure with reduced ejection fraction. However, few studies, and with small sample sizes, have examined the role of anemia in patients with heart failure with preserved ejection fraction (HFpEF). Thus, the purpose of our study is to examine whether anemia is associated with mortality in a large national cohort of patients with HFpEF. Methods: We identified subjects with HFpEF using a validated algorithm in the national Veterans Affairs patient database from 2002 to 2012. The criteria for HFpEF included: all recorded ejection fractions > 50% and symptoms, signs and treatment for heart failure. Anemia was identified using the International Classification of Diseases (ICD-9) code at the index time of HFpEF diagnosis. All-cause mortality was confirmed from medical death records and Center for Medicare Services data. Using a multivariable Cox proportional hazards model, we examined the association of anemia at the time of HFpEF diagnosis with all-cause mortality. Results: In total, 29,022 HFpEF patients met criteria for HFpEF. Mean age of the participants was 71±12 years; 96% were men, 84% were white, 35% had anemia, 88% had hypertension, 65% had hyperlipidemia and 42% had coronary artery disease at baseline. After a median follow-up of 3.6 years (IQR: 1.7-6.4), 17,269 deaths occurred. After adjusting for age, sex, race, body mass index, coronary artery disease, hypertension, hyperlipidemia, atrial fibrillation, chronic obstructive pulmonary disease, diabetes mellitus, serum sodium, renal function, heart rate and ejection fraction, patients with anemia had higher mortality (HR 1.52, 95% CI 1.47-1.57, p < 0.0001) as compared to those without anemia. Conclusion: Our study suggests that prevalent anemia is associated with an increased risk of all-cause mortality among US veterans with HFpEF. Further studies may shed light on its role as a prognosticator and potential therapeutic target in this population.

Introduction: Increased levels of cardiac troponin at the time of myocardial infarction (MI) have been shown to predict mortality. However, troponin is renally cleared and kidney function itself impacts mortality. We tested the hypothesis that baseline kidney function modifies the relationship between peak cardiac troponin I ratio (cTnI-R) and 30 day mortality after MI. Methods: Data from the Veterans Health Administration was used to create a national sample of hospitalized Veterans with a discharge diagnosis of MI between 2002 and 2015. The peak cTnI-R, calculated as the highest cTnI during the hospitalization compared to the upper limit of normal for each assay, was used as a proxy for the date of the MI event. Veterans with a history of cancer or blood vessel surgery 5 days before peak cTnI were excluded. The closest estimated glomerular filtration rate (eGFR) measured within 2 years prior to hospital admission was used as a marker of baseline kidney function. We created quartiles of peak cTnI-R and clinically relevant levels of eGFR (2 ) and fitted Cox regression adjusting for calendar year, age, length of hospital stay, region, diabetes, major mental health conditions and baseline use of diuretics, anti-hypertensives and anti-lipemics. We used subjects in the first quartile of troponin with eGFR of 60+ as common reference. Results: Among 56,073 Veterans hospitalized for MI, mean age was 67 and 98% were men. During 28 days mean follow up, 4,533 deaths occurred. 30 day mortality steadily increased across quartiles of peak cTnI-R; however, the increase in mortality was higher in eGFR below 30, suggesting effect modification of troponin-mortality relation by eGFR (p for interaction between eGFR and troponin 0.03) (Figure). Conclusions: Our data show that the positive relation of troponin with 30 day mortality post MI is modified by kidney function. Veterans with impaired kidney function carry a higher risk of 30 day mortality after MI compared to those with normal eGFR for a given troponin quartile.

Background: More than one-third of US adults are obese and the prevalence has remained stable since 2003. In the largest cohort of 515,912 men and women participating in the Million Veteran Program (MVP), we analyzed trends in baseline weight/obesity across the years of enrollment. Objective: The goal of this study is to examine prevalence and trends in baseline characteristics among US Veterans enrolled in MVP between 2011 and 2016. We highlight the trends in BMI over the enrollment period. Methods: BMI was computed for 479,521 Veterans who enrolled in MVP between 2011 to September 2016. Participants reported weight and height on the baseline survey. Missing survey data was supplemented with patient EMR data taken closest to enrollment date and stratified by year of enrollment. Results: Mean age was 61.2 (SD=13.8), 91.6% (391,124/427,187) were men, 73.8% (353,720/479,520) White, 18.8% (90,020/479,520) Black, and 7.4% (35,593/479,520) Hispanic. Overall, mean BMI was 29.7 [range 11.3 to 78.5]. Prevalence of underweight, normal weight, and overweight was 0.7% (3,164/479,521), 19.4% (93,318/479,521), 38.4% (184,625/479,521), respectively, in this cohort. While the prevalence of obesity increased with consecutive years of enrollment in men and overall, we did not observe such trend for other categories of adiposity (Fig). When stratified by race we did not observe any difference in prevalence of underweight and normal weight among White and Black participants. Prevalence of obesity was higher in Blacks, but the rate of obesity among Whites appears to be growing at a faster rate than in Blacks. Compared to the general VHA (Veterans Health Administration) population, prevalence of obesity and the distributions of race, gender, and ethnicity were similar among participants in MVP. Conclusion: Our data show that the prevalence of overweight/obesity is high among US Veterans. Across consecutive years of enrollment, prevalence of obesity but not overweight appears to increase across each ethnic group.

Background: While some but not all trial data have suggested a slightly elevated risk of type 2 diabetes (T2D), limited data are available on the relation of statin use with glycemia among US veterans. Objective: To test the hypothesis that treatment with a statin is associated with elevated serum glucose and a higher risk of T2D among US veterans. Methods: We studied 549,143 US veterans with electronic health records from 1998 to 2016. We used the VA Corporate Data Warehouse to obtain information on glucose (fasting and non-fasting). Statin use was captured using the pharmacy database. T2D was defined as having at least one inpatient diagnosis or at least 2 outpatient diagnoses of T2D using ICD 9 codes 250.xx, or the use of hypoglycemic agents. We addressed confounding by indication using propensity score (included 444 variables/interactions) for receiving statin and inverse probability weighting in the Cox regression. Results: The mean age was 60±12.8 y; 94.3% were men; 77.1% were white; and 15.4% were black. In this cohort, simvastatin was the most prescribed statin (84%) followed by lovastatin (7%). During a median follow-up of 4.4 years, 130,819 new cases of T2D occurred. Among 418,847 veterans receiving statin, we observed a 2 mg/dl increase in serum glucose when comparing serum glucose measured at the time of statin initiation and short-term Conclusions: Our data show a positive association between statin use and increase in both serum glucose and incidence of T2D among US veterans. If confirmed by others, this suggests closer monitoring of patients at risk of T2D when statin therapy is initiated.

OBJECTIVE Rigorous evidence is lacking whether online games can improve patients’ longer-term health outcomes. We investigated whether an online team-based game delivering diabetes self-management education (DSME) to patients via e-mail or mobile application (app) can generate longer-term improvements in hemoglobin A1c (HbA1c). RESEARCH DESIGN AND METHODS Patients (n = 456) on oral diabetes medications with HbA1c ≥58 mmol/mol were randomly assigned between a DSME game (with a civics booklet) and a civics game (with a DSME booklet). The 6-month games sent two questions twice weekly via e-mail or mobile app. Participants accrued points based on performance, with scores posted on leaderboards. Winning teams and individuals received modest financial rewards. Our primary outcome measure was HbA1c change over 12 months. RESULTS DSME game patients had significantly greater HbA1c reductions over 12 months than civics game patients (−8 mmol/mol [95% CI −10 to −7] and −5 mmol/mol [95% CI −7 to −3], respectively; P = 0.048). HbA1c reductions were greater among patients with baseline HbA1c >75 mmol/mol: −16 mmol/mol [95% CI −21 to −12] and −9 mmol/mol [95% CI −14 to −5] for DSME and civics game patients, respectively; P = 0.031. CONCLUSIONS Patients with diabetes who were randomized to an online game delivering DSME demonstrated sustained and meaningful HbA1c improvements. Among patients with poorly controlled diabetes, the DSME game reduced HbA1c by a magnitude comparable to starting a new diabetes medication. Online games may be a scalable approach to improve outcomes among geographically dispersed patients with diabetes and other chronic diseases.

tudy Objective The free fraction of valproate (the pharmacologically active moiety, normally 5–10%) may vary significantly in critically ill patients, but this topic is understudied, with only four prior intensive care unit (ICU) case reports. The objective of this study was to evaluate the range of valproate plasma protein binding in ICU patients. Design Observational study of consecutive ICU patients. Setting Neurocritical and medical critical care services in a nonuniversity academic medical center. Patients Consecutive ICU patients treated with valproate with serum albumin less than 4 g/dl. Measurements and Main Results Simultaneous total and free trough serum valproate concentrations were measured as were serum creatinine, blood urea nitrogen, albumin, platelets, and transaminase values. The reference concentration range was 50–125 mg/L (total) and 5–17 mg/L (free). Valproate concentrations were categorized as within reference range, low, or high, and as concordant if both concentrations were in the same category. Data are reported as median (interquartile range). Fifteen patients (nine men) were evaluated. The median age was 63 (34–70) years. The valproate dose was 3 g/day (35 mg/kg/day). No patient had a valproate free fraction of 5–10%; the median was 48%, and the range was 15–89%. Total and free concentrations showed poor correlation (0.43) and were concordant in only two patients (both in the reference range). Free valproate concentration was poorly predicted by an equation correcting for albumin (r = 0.45). Suspected adverse drug events occurred in 10 patients: hyperammonemia in 7 of 12 tested (58%), elevated transaminases in 2 of 15 (13%), and thrombocytopenia in 5 of 15 (33%). Conclusions Protein binding of valproate was highly inconsistent in this cohort of ICU patients, and total valproate concentrations did not predict free concentrations, even when correcting for albumin. Additional research to define best practice for dosing and monitoring valproate and the relationship between free valproate concentrations and clinical or adverse effects in ICU patients is needed.

Introduction To examine the risk of Alzheimer's disease (AD) among cancer survivors in a national database. Methods Retrospective cohort of 3,499,378 mostly male US veterans aged ≥65 years were followed between 1996 and 2011. We used Cox models to estimate risk of AD and alternative outcomes (non-AD dementia, osteoarthritis, stroke, and macular degeneration) in veterans with and without a history of cancer. Results Survivors of a wide variety of cancers had modestly lower AD risk, but increased risk of the alternative outcomes. Survivors of screened cancers, including prostate cancer, had a slightly increased AD risk. Cancer treatment was independently associated with decreased AD risk; those who received chemotherapy had a lower risk than those who did not. Discussion Survivors of some cancers have a lower risk of AD but not other age-related conditions, arguing that lower AD diagnosis is not simply due to bias. Cancer treatment may be associated with decreased risk of AD.

We identified a protective bone effect at the knee with lipophilic statin use in individuals with chronic spinal cord injury. Lipophilic statin users gained bone at the knee compared to non-users and wheelchair users lost bone compared to walkers. Ambulation and or statins may be effective osteogenic interventions in chronic spinal cord injury (SCI). SCI increases the risk of osteoporosis and low-impact fractures, particularly at the knee. However, during the chronic phase of SCI, the natural history and factors associated with longitudinal change in bone density remain poorly characterized. In this study, we prospectively assessed factors associated with change in bone density over a mean of 21 months in 152 men and women with chronic SCI. A mixed model procedure with repeated measures was used to assess predictors of change in bone mineral density (PROC MIXED) at the distal femur and proximal tibia. Factors with a p value of

The purpose was to describe the use of valproate therapy for agitation in critically ill patients, examine its safety, and describe its relationship with agitation and delirium.This retrospective cohort study evaluated critically ill adults treated with valproate for agitation from December 2012 through February 2015. Information on valproate prescribing practices and safety was collected. Incidence of agitation, delirium, and concomitant psychoactive medication use was compared between valproate day 1 and valproate day 3. Concomitant psychoactive medication use was analyzed using mixed models.Fifty-three patients were evaluated. The median day of valproate therapy initiation was ICU day 7, and it was continued for a median of 7 days. The median maintenance dose was 1500 mg/d (23 mg/kg/d). The incidence of agitation (96% vs 61%, P.0001) and delirium (68% vs 49%, P = .012) significantly decreased by valproate day 3. Treatment with opioids (77% vs 65%, P = .02) and dexmedetomidine (47% vs 24%, P = .004) also decreased. In mixed models analyses, valproate therapy was associated with reduced fentanyl equivalents (-185 μg/d, P = .0003) and lorazepam equivalents (-2.1 mg/d, P = .0004). Hyperammonemia (19%) and thrombocytopenia (13%) were the most commonly observed adverse effects.Valproate therapy was associated with a reduction in agitation, delirium, and concomitant psychoactive medication use within 48 hours of initiation.

This article presents a simple linear damage accumulation model that may have applicability for predicting damage from sustained winds in double-sided acrylic foam tape used to attach curtain wall glazing panels to buildings. The purpose of this model is to investigate the possible cumulative effects of years of wind-induced stresses that are less than the peak stress expected during a 3-s gust, as specified in current design guidelines established by the structural glazing industry and adopted by the manufacturer of these structural glazing tapes. Several representative wind histories are selected to provide input data for the model. These wind histories provide multiple years of average wind speeds over either 10-min or 1-h recording intervals, depending on the source. Each entry in a wind speed history is converted to stress on the glazing adhesive tape on assumed window dimensions using the standard wind loading design equations of ASCE 7-05. A creep rupture prediction equation, developed from...

Spinal cord injury (SCI) results in profound bone loss due to muscle paralysis and the inability to ambulate. Sclerostin, a Wnt signaling pathway antagonist produced by osteocytes, is a potent inhibitor of bone formation. Short-term studies in rodent models have shown increased sclerostin in response to mechanical unloading that is reversed with reloading. These studies suggest that complete spinal cord injury, a condition resulting in mechanical unloading of the paralyzed lower extremities, will be associated with high sclerostin levels. We assessed the relationship between circulating sclerostin and bone density in 39 subjects with chronic SCI and 10 without SCI. We found that greater total limb bone mineral content was significantly associated with greater circulating levels of sclerostin. Sclerostin levels were reduced, not elevated, in subjects with SCI who use a wheelchair compared with those with SCI who walk regularly. Similarly, sclerostin levels were lower in subjects with SCI who use a wheelchair compared with persons without SCI who walk regularly. These findings suggest that circulating sclerostin is a biomarker of osteoporosis severity, not a mediator of ongoing bone loss, in long-term, chronic paraplegia. This is in contrast to the acute sclerostin-mediated bone loss shown in animal models of mechanical unloading in which high sclerostin levels suppress bone formation. Because these data indicate important differences in the relationship between mechanical unloading, sclerostin, and bone in chronic SCI compared with short-term rodent models, it is likely that sclerostin is not a good therapeutic target to treat chronic SCI-induced osteoporosis. © 2012 American Society for Bone and Mineral Research

This is a second part of a paper on measurements of mechanical characteristics of high-performance acrylic pressure sensitive adhesive (PSA) tapes, an alternate fastening method for structural glazing. The acrylic PSA used in the study was 3M™ VHB™ G23F Tape. For comparison, parallel creep tests were also conducted on 3 silicones: two one-part and one two-part compositions. Mechanical characteristics determined for the acrylic foam PSA include the viscoelastic properties over a range of temperatures and test rates. Creep rupture results are summarized here as the Part II paper while ramp-to-fail strength and DMA (dynamic mechanical analysis) results were summarized in an accompanying paper (Part I paper). Using the time–temperature superposition principle, master curves of VHB™ Tape storage and loss moduli in shear and tension were developed with data from a dynamic mechanical analyzer. The thermal shift factors obtained from these constitutive tests were successfully applied to the creep rupture and ramp-to-fail data collected at 23, 40, and 60 °C, resulting in master curves of ramp-to-fail strength (Part I paper) and creep rupture durability (in Part II) measured in both shear and tension. The creep results revealed some of the design tradeoffs inherent in the application of VHB™ Structural Glazing Tapes versus structural silicones. VHB™ Tape has more time and temperature dependence than the silicones. VHB™ Tape has lower strength than most structural silicones over the time ranges studied, a fact that is addressed by lower design stresses for VHB™ Structural Glazing Tape and larger tape widths for equivalent creep performance to structural silicone sealants. On the other hand, the short-term strength of VHB™ Tape approaches and even exceed that of structural silicones, a feature that may be advantageous in applications like wind loading and protective glazing. While both bonded VHB™ Tape and structural silicone specimens exhibited some voids, there was less sensitivity of time to failure to the voids and defects seen in the VHB™ Tape specimens tested and significantly less scatter in the time to failure data than specimens made with the structural silicones.

The objective of this study was to determine relevant, primary mechanical characteristics of high-performance acrylic foam pressure sensitive adhesive (PSA) tapes, an alternate fastening method for structural glazing applications. Traditional fastening methods for structural glazing typically employ structural silicones and, consequently, relevant ASTM test standards and specifications appear to be more appropriate for silicones and similar products that exhibit limited time dependence. This study was aimed at characterizing and evaluating acrylic foam PSA tapes for structural glazing applications, and because of their time dependence, viscoelastic characterization was included. Since there may be significant differences in the viscoelastic responses of acrylic foam PSA tapes and silicones, the study may account for important differences between acrylics and silicones in structural glazing applications. The acrylic foam PSA used in the study was 3M™ VHB™ Tape G23F. For comparison, parallel ramp-to-fail tests were also conducted on 3 silicones: two one-part and one two-part compositions. Mechanical characteristics determined for the VHB™ Tape included the viscoelastic properties over a range of temperatures and test rates. Mechanical characteristics available in the literature were assumed for the silicones and confirm their limited time dependence. Ramp-to-fail strength data (Part I paper) and creep rupture (accompanying paper, Part II paper) data was collected for the VHB™ Tape and the silicones. Using the time–temperature superposition principle, master curves of VHB™ Tape storage and loss moduli in shear and tension were developed with data from a dynamic mechanical analyzer (DMA). The thermal shift factors obtained from these constitutive tests were successfully applied to the VHB™ Tape creep rupture and ramp-to-fail data collected at 23, 40, and 60 °C, resulting in master curves of ramp-to-fail strength (in Part I of paper) and creep rupture durability (Part II paper) in shear and tension.

Objectives Heritability in the risk for developing posttraumatic stress disorder (PTSD) has been established, but most genome-wide association studies (GWASs) of PTSD involve relatively small sample sizes and limited identification of associated genetic loci. This report describes the methodology of a Veterans Affairs (VA) Cooperative Studies Program GWAS of PTSD among combat-exposed U.S. veterans. Methods Probable cases (with PTSD) and probable controls (without PTSD) were identified from among veterans enrolled in the VA Million Veteran Program (MVP) with an algorithm developed using questionnaire responses and electronic health record information. This algorithm, based on a statistical model, relied on medical chart reviews as a reference standard and was refined using telephone interviews. Subsequently, to evaluate the impact of probabilistic phenotyping on statistical power, the threshold probability for case-control selection was varied in simulations. Results As of September 2018, >695,000 veterans have enrolled in MVP. For current analyses, genotyping data were available for >353,000 participants, including >83,000 combat-exposed veterans. A threshold probability of 0.7 for case and control designation yielded an interim >16,000 cases and >33,000 controls. Conclusions A formal methodological approach was used to identify cases and controls for subsequent GWAS analyses to identify genetic risk loci for PTSD.

Context Prostate cancer screening with prostate-specific antigen (PSA) is frequently performed, counter to clinical practice guidelines. Background It was hypothesized that an e-mail–based intervention termed "spaced education" could reduce clinicians' inappropriate screening for prostate cancer. Design The study was conducted as an RCT. Setting/participants The study involved 95 primary care clinicians in eight Veterans Affairs medical centers from January 2007 to February 2009. Intervention Participants were randomized into two cohorts: spaced education clinicians received four isomorphic cycles of nine e-mails over 36 weeks (zero to two e-mails per week), whereas control clinicians received no intervention. Each e-mail presented a clinical scenario and asked whether it was appropriate to obtain a PSA test. Participants received immediate feedback after submitting their answers. Main outcome measures The primary outcome was the number and percentage of inappropriate PSA screening tests ordered. Inappropriate testing was defined as use of PSA for prostate cancer screening in patients aged >76 or Results During the intervention period (Weeks 1–36), clinicians receiving spaced education e-mails ordered significantly fewer inappropriate PSA screening tests than control clinicians (10.5% vs 14.2%, p =0.041). Over the 72-week period following the intervention (Weeks 37–108), spaced education clinicians continued to order fewer inappropriate tests compared to controls (7.8% vs 13.1%, respectively, p =0.011), representing a 40% relative reduction in inappropriate screening. Conclusions Spaced education durably improves the prostate cancer screening behaviors of clinicians and represents a promising new methodology to improve patient care across healthcare systems.

Background Exposure to gadolinium in patients with kidney disease has been linked to risk of developing nephrogenic systemic fibrosis. The US Food and Drug Administration (FDA) has issued warnings against the use of gadolinium in this population. We studied the impact of these warnings on the use of gadolinium-enhanced magnetic resonance (GE-MR) studies in patients with decreased estimated glomerular filtration rate (eGFR) and the practice of measuring serum creatinine before gadolinium exposure. Study Design Cross-sectional study of patients who had undergone MR studies from October 2002 to September 2008. Setting & Participants Patients receiving medical care in the US Department of Veterans Affairs Health Care System. Predictor Date of MR imaging, serum creatinine level, and eGFR using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. Outcomes & Measurements The rate of MR studies performed with and without gadolinium from July 2005 to September 2008 in patients with different stages of kidney disease, defined using eGFR. The proportion of GE-MR studies with a screening serum creatinine level. Results There was a 71% decrease in the rate of GE-MR use in patients with GFR 2 2 years after the release of the first public health advisory, although studies continued to be performed in patients with stages 4 and 5 chronic kidney disease. The proportion of GE-MR studies with serum creatinine measured within 1 month before the study increased by 99%. Limitations Data available up to September 30, 2008. Indications for the GE-MR studies were not assessed. The accuracy of Current Procedural Terminology and International Classification of Diseases, Ninth Revision coding was not assessed. Conclusion There was a large decrease in the use of GE-MR studies in patients with GFR 30 mL/min/1.73 m 2 and a large but not universal increase in the practice of measuring serum creatinine before GE-MR after the release of the FDA warnings.

Although well-described for patients who require dialysis, information on transfusion burden related to anemia in the nondialysis patient population with chronic kidney disease (CKD) is lacking.A retrospective study was conducted of patients with CKD and chronic anemia from 2002 through 2007 in the Veterans Administration Healthcare System. Included patients had stage 3 CKD or higher and anemia (one or more hemoglobin [Hb] levels11 g/dl or received anemia therapy [erythropoiesis-stimulating agents [ESAs], iron, or both]). The outcome of interest was transfusion events, which was evaluated in relation to the absolute Hb level and changes in Hb levels overall and according to the type of treatment received (no treatment, iron therapy, ESA therapy, or ESA and iron therapy) concurrent with each Hb measurement.Among 97,636 patients with CKD and anemia, we observed 68,556 transfusion events (61 events per 100 person-years), 86.6% of which occurred in inpatient settings. At all Hb levels, transfusion events were highest during periods of no treatment and increased with declining Hb levels. Between an Hb of 10.0 and 10.9 g/dl, the transfusion rate was 2.0% for those who received an ESA, iron, or both and 22% for those who received no treatment; at an Hb level of 7.0 to 7.9 g/dl, the transfusion rate was 10 to 12% for treated and 58% for untreated patients. Low absolute Hb levels but not Hb changes was most predictive of a transfusion even after adjustment for patient case mix.Transfusions are still used to treat anemia in patients who have CKD and do not require dialysis, although they occur considerably less frequently in patients who receive other available anemia therapies.

New technology introduced over time results in changes in densitometers during longitudinal studies of bone mineral density (BMD). This requires that a cross-calibration process be completed to translate measurements from the old densitometer to the new one. Previously described cross-calibration methods for research settings have collected single measures on each densitometer and used linear regression to estimate cross-calibration corrections. Thus, these methods may produce corrections that have limited precision and underestimate the variability in converted BMD values. Furthermore, most of the previous studies have included small samples recruited from specialized populations. Increasing the sample size, obtaining multiple measures on each machine, and using linear mixed models to account for between- and within-subject variability may improve cross-calibration estimates. The purpose of this study was to conduct an in vivo cross-calibration of a Lunar DPX-L (Lunar Corporation, Madison, WI) with a Lunar Prodigy densitometer (GE Medical Systems Lunar, Madison, WI) using a sample of 249 healthy volunteers who were scanned twice on each densitometer, without repositioning, at both the femur and spine. Scans were analyzed using both automated and manual placement of regions of interest. Wilcoxon rank-sum tests and Bland-Altman plots were used to examine possible differences between repeat scans within and across densitometers. We used linear mixed models to determine the cross-calibration equations for the femoral neck, trochanter, total hip, and lumbar spine (L2-L4) regions. Results using automated and manual placement of the regions of interest did not differ significantly. The DPX-L densitometer exhibited larger median absolute differences in the BMD values by repeat scans of femoral neck (0.016 vs 0.012, p=0.1) and trochanter (0.011 vs. 0.009, p=0.06) compared with the Prodigy densitometer. The Bland-Altman plots revealed no statistically significant linear relationship between the differences in paired measures between machines and mean BMD. In our large sample of healthy volunteers, we did detect systematic differences between the DPX-L and Prodigy densitometers. Our proposed cross-calibration method, which includes acquiring multiple measures and using linear mixed models, provides researchers with a more realistic estimate of the variance of cross-calibrated BMD measures, potentially reducing the chance of making a type I error in longitudinal studies of changes in BMD.

Many podiatric clinicians note that foot problems are common in older persons 1, 2, yet very little epidemiologic information exists on foot pain, especially in relation to shoewear, in older persons. National data reveal that foot and toe symptoms are among the top twenty reasons for physician office visits among those aged 65–74 years3. Prior research indicates that not enough attention has been given to foot pain and other foot disorders since historically these factors have not been regarded as important health risks1. Women are more likely to have foot pain than men4, 5, but it is unknown whether this is due to a higher prevalence of foot deformities, underlying disease, shoewear or other lifestyle choices. Foot pain and foot disorders are serious burdens for many older individuals, especially those with rheumatic diseases6–8. While foot pain is considered to be a very common musculoskeletal complaint in the U.S. adult population, relatively little is known of the prevalence or cause of foot pain in older Americans in a population-based sample. Examining the association between shoewear and foot pain may lead to a greater understanding of this relationship, which is important when considering strategies to prevent sequelae due to foot pain in older adults. Previous studies have examined the influence of footwear on foot problems and other diseases in older adults but have focused on small numbers of older adults or diseased patients. A 1993 study by Frey et al9 presented descriptive information on shoe trends and their effect on the development of foot deformities and pain in 356 women, aged 20–60. They observed that the majority of women wore shoes that were too small for their feet and had foot pain. However, no statistical analysis was presented in this paper. In a 2005 study by Menz and Morris, the relationship between footwear characteristics (length, width and area) and the prevalence of common forefoot problems were examined in 176 older adults residing in a retirement community10. Similar to the study by Frey, it was found that incorrectly fitting footwear is common and associated with forefoot disease and foot pain. Menz et al have also examined the relationship between footwear characteristics and the risk of indoor and outdoor falls in the same cohort of older adults. They found that there was no association between the type of shoe and the risk of falling either inside or outside the home11. Harrison et al reported an assessment of the fit of footwear in 100 patients with diabetes in 2007 and found that many diabetics wear shoes that are too narrow for their feet12. Garrow et al conducted a population-based foot pain and disability survey in 3417 adults, which examined age- and sex-differences in a variety of foot symptoms, but did not have any information on shoewear13. In addition, the preventative effects of footwear, like plantar pressure relief, have been shown to be important in previous studies. Lobman et al studied the effect of preventative footwear on foot pressure in 81 older diabetic patients14. This type of footwear was shown to be successful in reducing plantar pressure. Also, Burnfield et al found that, in 20 healthy, older adults, faster walking speed and walking barefoot result in higher foot pressures15. To evaluate the relationship between foot pain and shoewear in a large, population-based cross-sectional study, we collected information on major type of shoe worn currently and in the past, along with self-report of foot pain, by men and women of the Framingham Study. In addition to the aforementioned information, the Framingham Study has extensive data collected on many clinical and other factors, notably medical conditions, comorbidities and other potential confounders. The purpose of this study was to evaluate the relationship between type of shoe worn and foot pain, accounting for other possible risk factors, in men and women of the Framingham cohort.

Morse LR, Lazzari AA, Battaglino R, Stolzmann KL, Matthess KR, Gagnon DR, Davis SA, Garshick E. Dual energy x-ray absorptiometry of the distal femur may be more reliable than the proximal tibia in spinal cord injury. Objective To evaluate the precision of dual energy x-ray absorptiometry scanning at 2 skeletal sites at the knee (proximal femur and distal tibia) in people with SCI. Design Cross-sectional. Setting Veterans Affairs Medical Center. Participants Subjects (N=20) with chronic SCI. Interventions Not applicable. Main Outcome Measures Precision as determined by root mean square coefficient of variation (RMS-CV) and root mean square standard deviation (RMS-SD). Results At the distal femur the root RMS-CV was 3.01% and the RMS-SD was 0.025g/cm 2 . At the proximal tibia the RMS-CV was 5.91% and the RMS-SD was 0.030g/cm 2 . Conclusions Precision at the distal femur is greater than at the proximal tibia and we recommend it as the preferred site for the longitudinal assessment of bone mineral density at the knee in chronic SCI.

Waddimba AC, Jain NB, Stolzmann K, Gagnon DR, Burgess JF, Kazis LE, Garshick E. Predictors of cardiopulmonary hospitalization in chronic spinal cord injury. Objective To investigate longitudinal risk factors of hospitalization for circulatory and pulmonary diseases among veterans with chronic spinal cord injury (SCI). Circulatory and respiratory system illnesses are leading causes of death in patients with chronic SCI, yet risk factors for related hospitalizations have not been characterized. Design Prospective cohort study. Setting Veterans Affairs (VA) Boston Healthcare System, Boston, Massachusetts. Participants/Data Sources Veterans (N=309) greater than or equal to 1 year post-SCI from the VA Boston Chronic SCI cohort who completed a health questionnaire and underwent spirometry at study entry. Baseline data were linked to 1996 through 2003 hospitalization records from the VA National Patient Care Database. Interventions Not applicable. Main Outcome Measures Cardiopulmonary hospital admissions, the predictors of which were assessed by multivariate Cox regression. Results Of 1478 admissions observed, 143 were a result of cardiopulmonary (77 circulatory and 66 respiratory) illnesses. Independent predictors were greater age (3% increase/y), hypertension, and the lowest body mass index quintile ( 2 ). A greater percentage-predicted forced expiratory volume in 1 second was associated with reduced risk. SCI level and completeness of injury were not statistically significant after adjusting for these risk factors. Conclusions Cardiopulmonary hospitalization risk in persons with chronic SCI is related to greater age and medical factors that, if recognized, may result in strategies for reducing future hospitalizations.

Background Hybrid procedures combine endovascular and open surgical techniques. We examined utilization rates and ways of performing them more efficiently. Methods Hybrids were selected using codes for femoral endarterectomy, infrainguinal, or aorto-iliac-femoral bypass and angioplasty from Nationwide Inpatient Sample (NIS) data, then categorized as staged, or performed on the same day. Outcomes included utilization rates, total hospital charges, and length of stay (LOS). Confounders of charges and LOS were identified and excluded from final comparisons. Results Utilization increased 7% from 2000 to 2004. Univariate associations linked staging to variables included in linear regressions for hospital charges and LOS. Excluding identified confounders from the final subgroup analysis still showed large differences in charges (same-day = $34,206, staged=$60,087) and LOS (same-day = 3 days, staged=7 days). Conclusions Utilization of hybrids is increasing. Performing hybrids on the same day, if possible, greatly reduces hospital charges and LOS, emphasizing preadmission planning and simultaneous coordination of both portions.

Vitamin C is essential for collagen formation and normal bone development. We evaluated associations of total, supplemental, and dietary vitamin C intake with bone mineral density (BMD) at the hip [femoral neck, trochanter], spine, and radial shaft and 4-y BMD change in elderly participants from the Framingham Osteoporosis Study. Energy-adjusted vitamin C intakes were estimated from the Willett FFQ in 1988-89. Mean BMD and 4-y BMD change was estimated, for men and women, by tertile/category of vitamin C intake, adjusting for covariates. We tested for interaction with smoking, calcium, and vitamin E intake. Among 334 men and 540 women, the mean age was 75 y and mean vitamin D intake was 8.25 mug/d (women) and 8.05 mug/d (men). We observed negative associations between total and supplemental vitamin C intake and trochanter-BMD among current male smokers (P-trend = 0.01). Among male nonsmokers, total vitamin C intake was positively associated with femoral neck BMD (P-trend = 0.04). Higher total vitamin C intake was associated with less femoral neck and trochanter-BMD loss in men with low calcium (all P-trend

Clinicians commonly use nonindicated (or "off-label") medications for the treatment of alcoholism, although there is no clear evidence to support this practice. Quetiapine and trazodone are 2 medications frequently used in this manner, especially to treat sleep disturbance associated with alcohol withdrawal. Using national administrative data from the Department of Veterans Affairs, we compared the differences among these medications in time to rehospitalization after discharge from an index hospitalization for alcohol dependence. Our outcome measure was the difference in time (weeks) to rehospitalization for patients given medications in 1 of 4 groups: quetiapine alone (median, 6.1 weeks); trazodone alone (median, 10.1 weeks); quetiapine combined (median, 7.1 weeks); and trazodone combined (median, 10.3 weeks) with other frequently used psychotropic drugs. Differences between groups were examined with Cox's proportional hazards regression using trazodone in combination with other medications as the reference category. Crude hazard ratios were determined first and then adjusted for covariates. There was no difference in the risk of rehospitalization when patients using quetiapine in combination were compared with the reference category (hazard ratio [HR] = 1.08; confidence interval [CI], 0.99-1.17; P < 0.0936). In contrast, when quetiapine was used alone there was a significantly higher risk of rehospitalization (HR = 1.22; CI = 1.06-1.41; P < 0.005). When trazodone was used alone there was no difference in risk in the unadjusted analysis (HR = 1.05; CI = 0.96-1.14; P < 0.3076); however, the HR increased to a significant level after adjusting for covariates (HR, 1.14; CI = 1.05-1.24; P < 0.0029) and for those with 2+ previous discharges (HR = 1.25; CI = 1.14-1.37; P < 0.0001). These findings suggest the need for additional studies to better understand what symptoms of alcoholism benefit from the use of these medications, at what dose levels, and with what other medication combinations.

Health care quality improvement interventions are often evaluated in randomized trials in which individual physicians serve as the unit of randomization. These cluster randomized trials present a unique data structure that consists of many clusters of highly variable size. The appropriate method of analysis for these trials is unknown. We conducted a simulation study to compare several methods for analyzing data which were generated to replicate the structure of our motivating example. We varied the treatment effect size and the distributional assumptions about the random effect. Simulation was used to estimate power, coverage, bias, and mean squared error of full maximum likelihood estimation (MLE), approximate MLE using penalized quasi-likelihood (PQL), generalized estimating equations (GEE), group-bootstrapped logistic regression, and a clustered permutation test. Across all conditions tested, GEE and full MLE performed comparably. Bootstrapped methods were less powerful and had higher mean squared error under conditions of variable cluster size. PQL yielded biased results. The permutation test preserved Type I error rates, but had less power than the other methods considered.

We determined age-stratified associations of elevated alanine aminotransferase (ALAT), as a likely indicator of non-alcoholic steatonecrosis (NASH), with body mass index (BMI) and diabetes among older male, veteran outpatients.Administrative files at three, urban Veteran Administration Healthcare Systems were surveyed. 47.916 male outpatients, mean age 69.2 years, without ICD-9CM documented liver diseases or alcohol- or drug-abuse, had the highest of one or more ALAT results analyzed. Logistic regression determined age-stratified predictors of elevated ALAT among groups50 ("younger-aged"), 50-70 ("middle-aged") and70 ("older-aged"). BMI, diabetes and "statin" use were predictors.1272 (2.7%) patients had their highest ALAT greater than the upper limit of normal (mean=98.4U/L). 4.9% of all diabetics and 15.2, 6.1 and 3.4% of the "younger-aged", middle-aged" and "older-aged" diabetics, respectively, had elevated ALATs. BMI values from 25 to30 and 30 to 45, compared with those from20 to25, predicted elevated ALAT in the two younger groups. In contrast, among "older-aged" patients, diabetes independently predicted elevated ALAT, whereas BMI did not.The cross-sectional findings support previous epidemiologic data associating ALAT elevations with obesity and diabetes, and provide new evidence that in elderly male patients, ALAT elevations, absent other known liver diseases, may selectively associate with diabetes.

Background Typical survival studies follow individuals to an event and measure explanatory variables for that event, sometimes repeatedly over the course of follow up. The Cox regression model has been used widely in the analyses of time to diagnosis or death from disease. The associations between the survival outcome and time dependent measures may be biased unless they are modeled appropriately. Methods In this paper we explore the Time Dependent Cox Regression Model (TDCM), which quantifies the effect of repeated measures of covariates in the analysis of time to event data. This model is commonly used in biomedical research but sometimes does not explicitly adjust for the times at which time dependent explanatory variables are measured. This approach can yield different estimates of association compared to a model that adjusts for these times. In order to address the question of how different these estimates are from a statistical perspective, we compare the TDCM to Pooled Logistic Regression (PLR) and Cross Sectional Pooling (CSP), considering models that adjust and do not adjust for time in PLR and CSP. Results In a series of simulations we found that time adjusted CSP provided identical results to the TDCM while the PLR showed larger parameter estimates compared to the time adjusted CSP and the TDCM in scenarios with high event rates. We also observed upwardly biased estimates in the unadjusted CSP and unadjusted PLR methods. The time adjusted PLR had a positive bias in the time dependent Age effect with reduced bias when the event rate is low. The PLR methods showed a negative bias in the Sex effect, a subject level covariate, when compared to the other methods. The Cox models yielded reliable estimates for the Sex effect in all scenarios considered. Conclusions We conclude that survival analyses that explicitly account in the statistical model for the times at which time dependent covariates are measured provide more reliable estimates compared to unadjusted analyses. We present results from the Framingham Heart Study in which lipid measurements and myocardial infarction data events were collected over a period of 26 years. Electronic supplementary material The online version of this article (doi:10.1186/s12874-016-0248-6) contains supplementary material, which is available to authorized users.

Erectile dysfunction (ED) is a prevalent condition and a predictor of future cardiovascular events. Screening and treatment of ED may improve management of cardiovascular risk factors. We evaluated the potential beneficial effect of newly treating ED on the management of hypertension in men in the New England Veteran Affairs Healthcare System. We conducted a retrospective cohort study using medical record data to identify patients diagnosed with and treated at any time for hypertension who received a prescription for a phosphodiesterase type 5 inhibitor (PDE5i) before February 1, 2003. Fifty percent of 6,768 men (mean +/- SD 61.6 +/- 9.9 years of age) had a systolic blood pressure (BP) > or =140 mm Hg before PDE5i administration. Overall, there was a decrease in systolic BP by 1.43 mm Hg (95% confidence interval -1.69 to -1.18) after initiation of PDE5i. The decrease in systolic BP was most pronounced in men with a systolic BP > or =160 mm Hg at baseline (-17.8 mm Hg, 95% confidence interval -18.8 to -16.8). After initiating therapy with PDE5i, patients were more likely to start an antihypertensive medication (17.3%) versus stop therapy (2.3%) and add additional antihypertensive medication to their existing therapy (42.2%) versus decrease the number of medications (17.3%). Surveillance also increased with total number of systolic BP measurements increasing by 42%. In conclusion, men with high systolic BP who initiated ED therapy had improvements in systolic BP control that may be related to clinically relevant behaviors, such as more aggressive monitoring and treatment with antihypertensive medications.

The papillomavirus (PV) E1 helicase contains a conserved C-terminal domain (CTD), located next to its ATP-binding site, whose function in vivo is still poorly understood. The CTD is comprised of an alpha helix followed by an acidic region (AR) and a C-terminal extension termed the C-tail. Recent biochemical studies on bovine papillomavirus 1 (BPV1) E1 showed that the AR and C-tail regulate the oligomerization of the protein into a double hexamer at the origin. In this study, we assessed the importance of the CTD of human papillomavirus 11 (HPV11) E1 in vivo , using a cell-based DNA replication assay. Our results indicate that combined deletion of the AR and C-tail drastically reduces DNA replication, by 85%, and that further truncation into the alpha-helical region compromises the structural integrity of the E1 helicase domain and its interaction with E2. Surprisingly, removal of the C-tail alone or mutation of highly conserved residues within the domain still allows significant levels of DNA replication (55%). This is in contrast to the absolute requirement for the C-tail reported for BPV1 E1 in vitro and confirmed here in vivo . Characterization of chimeric proteins in which the AR and C-tail from HPV11 E1 were replaced by those of BPV1 indicated that while the function of the AR is transferable, that of the C-tail is not. Collectively, these findings define the contribution of the three CTD subdomains to the DNA replication activity of E1 in vivo and suggest that the function of the C-tail has evolved in a PV type-specific manner. IMPORTANCE While much is known about hexameric DNA helicases from superfamily 3, the papillomavirus E1 helicase contains a unique C-terminal domain (CTD) adjacent to its ATP-binding site. We show here that this CTD is important for the DNA replication activity of HPV11 E1 in vivo and that it can be divided into three functional subdomains that roughly correspond to the three conserved regions of the CTD: an alpha helix, needed for the structural integrity of the helicase domain, followed by an acidic region (AR) and a C-terminal tail (C-tail) that have been shown to regulate the oligomerization of BPV1 E1 in vitro . Characterization of E1 chimeras revealed that, while the function of the AR could be transferred from BPV1 E1 to HPV11 E1, that of the C-tail could not. These results suggest that the E1 CTD performs multiple functions in DNA replication, some of them in a virus type-specific manner.

Introduction: Clinicians are hesitant to prescribe oral anticoagulants to older adults with atrial fibrillation (AF) due to concerns over bleeding risk. Hypothesis: As many data on bleeding events are from trials of rigorously selected patients, we hypothesized that major bleeding events (requiring hospitalization) would be more common than previously reported. Methods: We created a retrospective cohort of 31,951 Veterans with AF aged ≥75 years who were new referrals to VA anticoagulation clinics (warfarin) from 1/1/02 - 12/31/12. Patients with comorbid conditions requiring warfarin (e.g. pulmonary embolus) were excluded. Data were extracted from the VA electronic medical record and linked with Medicare claims data for subsequent hospitalizations. The primary outcome was any hospitalization for bleeding. We identified bleeding subtypes by source, and compared characteristics of patients with and without bleeding hospitalizations. Results: Mean population age was 81.1 years, 98.1% were male, and 8.4% were nonwhite. Over a median follow-up period of 2.62 years, 7288 patients (22.8%) were hospitalized for bleeding. There were 12,004 total bleeding events; overall, 980 (13.4%) patients experienced multiple events. The most common bleeding sources (first event) were gastrointestinal (50.8%), genitourinary (21.6%), and intracranial (9.4%) (Figure). The median time to first bleeding event was 1.59 years. Patients hospitalized for bleeding were more likely to have coronary disease (48.4% vs. 40.9%, P Conclusions: After initiating warfarin, over one in five older Veterans are hospitalized for bleeding, most commonly from a gastrointestinal source. Comorbidity burden and labile INR place these patients at increased risk.

The replication of human polyomavirus JCV, which causes Progressive Multifocal Leukoencephalopathy, is initiated by the virally encoded T-antigen (T-ag). The structure of the JC virus T-ag origin-binding domain (OBD) was recently solved by X-ray crystallography. This structure revealed that the OBD contains a C-terminal pocket, and that residues from the multifunctional A1 and B2 motifs situated on a neighboring OBD molecule dock into the pocket. Related studies established that a mutation in a pocket residue (F258L) rendered JCV T-ag unable to support JCV DNA replication. To establish why this mutation inactivated JCV T-ag, we have solved the structure of the F258L JCV T-ag OBD mutant. Based on this structure, it is concluded that the structural consequences of the F258L mutation are limited to the pocket region. Further analyses, utilizing the available polyomavirus OBD structures, indicate that the F258 region is highly dynamic and that the relative positions of F258 are governed by DNA binding. The possible functional consequences of the DNA dependent rearrangements, including promotion of OBD cycling at the replication fork, are discussed., Author Summary A conserved feature of Polyomavirus T-antigens is a phenylalanine situated at the C-termini of their origin-binding domains (OBDs). Using the T-antigen encoded by JC virus, we have investigated why this residue is critical for viral DNA replication. The studies presented herein establish that the consequences of this mutation are limited to the interface formed by the docking of the phenylalanine containing C-terminal pocket region of the OBD with the multifunctional A1/B2 region. Related studies indicate that the conformation of the C-terminal region of the OBD is altered by DNA binding. These observations suggest a model whereby cycling of the OBDs within the hexameric spiral structure at the replication fork is promoted by DNA binding.

The approach to sedation, analgesia, and neuromuscular blockade during targeted temperature management (TTM) remains largely unstudied, forcing clinicians to adapt previous research from other patient environments. During TTM, very little data guide drug selection, doses, and specific therapeutic goals. Sedation should be deep enough to prevent awareness during neuromuscular blockade, but titration is complex as metabolism and clearance are delayed for almost all drugs during hypothermia. Deeper sedation is associated with prolonged intensive care unit (ICU) and ventilator therapy, increased delirium and infection, and delayed wakening which can confound early critical neurological assessments, potentially resulting in erroneous prognostication and inappropriate withdrawal of life support. We review the potential therapeutic goals for sedation, analgesia, and neuromuscular blockade during TTM; the adverse events associated with that treatment; data suggesting that TTM and organ dysfunction impair drug metabolism; and controversies and potential benefits of specific monitoring. We also highlight the areas needing better research to guide our therapy.

Patients with chronic kidney disease (CKD) are at high risk of death or myocardial infarction (MI) after percutaneous coronary interventions (PCI). We assessed whether prolonged dual antiplatelet therapy beyond the recommended 12 months may prevent adverse outcomes in patients with CKD receiving drug-eluting stents (DES) or bare-metal stents (BMS).We studied all Veterans receiving PCI with BMS or first-generation DES in the Veterans Affairs (VA) Healthcare System between 2002 and 2006, classified by CKD (estimated glomerular filtration rate60 mL/min) or normal renal function. We used landmark analyses from 12 months after PCI with Cox proportional hazards multivariable and propensity-adjusted models to assess the effect of prolonged clopidogrel (more than 12 months) versus 12 months or less after PCI on clinical outcomes from 1 year to 4 years after PCI.Of 23 042 eligible subjects receiving PCI, 4880 (21%) had CKD. Compared with normal renal function, patients with CKD had higher risks of death or MI 1-4 years after DES (21% vs 12%, HR=1.75; 95% CI 1.51 to 2.04) or BMS (28% vs 15%, HR=2.10; 95% CI 1.90 to 2.32). In patients with CKD receiving DES, clopidogrel use of more than 12 months after PCI was associated with lower risks of death or MI (18% vs 24%, HR=0.74; 95% CI 0.58 to 0.95), and death (15% vs 23%, HR=0.61; 95% CI 0.47 to 0.80), but had no effect on repeat revascularisation 1-4 years after PCI.In patients with CKD, prolonging clopidogrel beyond 12 months after PCI may decrease the risk of death or MI only in patients receiving first-generation DES. These results support a patient-tailored approach to prolonging clopidogrel after PCI.

Background Recent large clinical trials show lower rates of late cardiovascular events by extending clopidogrel >12 months after percutaneous coronary revascularization (PCI). However, concerns of increased bleeding have elicited support for limiting prolonged treatment to high-risk patients. Objectives The aim of this analysis was to determine the effect of prolonging clopidogrel therapy >12 months versus ≤12 months after PCI on very late outcomes in patients with diabetes mellitus (DM). Methods Using the Veterans Health Administration, 28,849 patients undergoing PCI between 2002 and 2006 were categorized into 3 groups: 1) 16,332 without DM; 2) 9,905 with DM treated with oral medications or diet; and 3) 2,612 with DM treated with insulin. Clinical outcomes, stratified by stent type, ≤4 years after PCI were determined from the Veterans Health Administration and Medicare databases and risk was assessed by multivariable and propensity score analyses using a landmark analysis starting 1 year after the index PCI. The primary endpoint of the study was the risk of all-cause death or myocardial infarction (MI). Results In patients with DM treated with insulin who received drug-eluting stents (DES), prolonged clopidogrel treatment was associated with a decreased risk of death (hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.42 to 0.82) and death or MI (HR: 0.67; 95% CI: 0.49 to 0.92). Similarly, in patients with noninsulin-treated DM receiving DES, prolonged clopidogrel treatment was associated with less death (HR: 0.61; 95% CI: 0.48 to 0.77) and death or MI (HR: 0.61; 95% CI: 0.5 to 0.75). Prolonged clopidogrel treatment was not associated with a lower risk in patients without DM or in any group receiving bare-metal stents. Conclusions Extending the duration of clopidogrel treatment >12 months may decrease very late death or MI only in patients with DM receiving first-generation DES. Future studies should address this question in patients receiving second-generation DES.

Objectives— Atherosclerotic coronary artery calcification (CAC) is associated with increased coronary heart disease (CHD) risk. Matrix Gla protein (MGP) is an inhibitor of calcification in vivo. However, little is known regarding the distribution of circulating MGP and its associations with CHD risk factors or with CAC in humans. Methods and Results— Serum MGP concentrations were determined in 2 independent populations of men and women free of clinically apparent cardiovascular disease: study A, n=316, mean age 58 years, and study B, n=452, mean age 68 years. CAC was determined by computed tomography. Mean MGP concentrations were 98.4 and 198 ng/mL in men, and 97.4 and 201 ng/mL in women, in study A and study B, respectively. In both cohorts, MGP levels were higher with increasing age. In age-adjusted analyses, there was an association of circulating MGP with increasing Framingham CHD risk score (in study A, P =0.003 in men and P =0.016 in women, respectively; in study B, a nonsignificant increase in men and P =0.05 in women, respectively). Significant associations of circulating MGP with high-density lipoprotein and other individual CHD risk factors were also noted in both cohorts. There were no consistent associations between MGP and CAC after adjustment for CHD risk score in the 2 cohorts. Conclusions— MGP is associated with individual CHD risk factors and the Framingham CHD risk score in men and women free of clinically apparent CHD. The relation of MGP with CAC deserves further study in larger populations.

Jain NB, Brown R, Tun CG, Gagnon D, Garshick E. Determinants of forced expiratory volume in 1second (FEV1), forced vital capacity (FVC), and FEV1/FVC in chronic spinal cord injury. Objective To assess factors that influence pulmonary function, because respiratory system dysfunction is common in chronic spinal cord injury (SCI). Design Cross-sectional cohort study. Setting Veterans Affairs Boston SCI service and the community. Participants Between 1994 and 2003, 339 white men with chronic SCI completed a respiratory questionnaire and underwent spirometry. Interventions Not applicable. Main Outcome Measures Forced expiratory volume in 1second (FEV1), forced vital capacity (FVC), and FEV1/FVC. Results Adjusting for SCI level and completeness, FEV1 (–21.0mL/y; 95% confidence interval [CI], –26.3 to –15.7mL/y) and FVC (–17.2mL/y; 95% CI, –23.7 to –10.8mL/y) declined with age. Lifetime cigarette use was also associated with a decrease in FEV1 (–3.8mL/pack-year; 95% CI, –6.5 to –1.1mL/pack-year), and persistent wheeze and elevated body mass index were associated with a lower FEV1/FVC. A greater maximal inspiratory pressure (MIP) was associated with a greater FEV1 and FVC. FEV1 significantly decreased with injury duration (–6.1mL/y; 95% CI, –11.7 to –0.6mL/y), with the greatest decrement in the most neurologically impaired. The most neurologically impaired also had a greater FEV1/FVC, and their FEV1 and FVC were less affected by age and smoking. Conclusions Smoking, persistent wheeze, obesity, and MIP, in addition to SCI level and completeness, were significant determinants of pulmonary function. In SCI, FEV1, FVC, and FEV1/FVC may be less sensitive to factors associated with change in airway size and not reliably detect the severity of airflow obstruction.

Purpose To develop and compare three operational definitions of polypharmacy using a large prescription database. Methods We defined Cumulative polypharmacy as all prescriptions filled during a 178 day window—which captured 95% of eventual refills as calculated from Kaplan–Meier and cumulative incidence curves. Continuous polypharmacy was all prescriptions filled in two such windows 6 months apart. Simultaneous polypharmacy was the number of prescriptions active on a particular day, as determined by fill dates and amount of medication given. We applied these definitions to the outpatient prescription files of New England veterans and compared the resulting estimates of polypharmacy using descriptive statistics. Results 118 013 patients received at least one prescription between January 1998 and July 1999. Cumulative polypharmacy averaged 3.54 (SD = 4.95) medications and continuous polypharmacy averaged 1.96 (SD = 3.23). Examination of simultaneous polypharmacy over 40 2-week intervals revealed an average of 2.63 (CI 2.61–2.65), a minimum of 1.09 (CI 1.08–1.10) and maximum of 4.94 (CI 4.92–4.96). One arbitrarily selected observation point had an average of 3.87 (SD = 3.17). Conclusions Our definitions of cumulative and continuous polypharmacy serve to set upper and lower bounds for the estimate of polypharmacy. Our method for simultaneous polypharmacy gives numbers that diverge in some respects, but it is better at showing transient changes in medications. The methods are complementary and allow exploration of various aspects of medication use, such as cumulative medication exposure over time, the influence of chronic medical problems, and the causes of rapid changes in medications. Published in 2004 by John Wiley & Sons, Ltd.