Showing papers by "Veterans Health Administration published in 2011"
TL;DR: In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions.
Abstract: A b s t r ac t Background Atherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis. Lesion-related risk factors for such events are poorly understood. Methods In a prospective study, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicated to be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The median follow-up period was 3.4 years. Results The 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline (mean [±SD] diameter stenosis, 32.3±20.6%). However, on multivariate analysis, nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm 2 or less (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P = 0.001) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI, 1.77 to 6.36; P<0.001). Conclusions In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics, as determined by gray-scale and radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano; ClinicalTrials.gov number, NCT00180466.)
2,649 citations
TL;DR: A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function, and these findings suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
1,829 citations
University of Miami1, University of Texas Southwestern Medical Center2, University of Alabama at Birmingham3, Harvard University4, University of Illinois at Chicago5, Veterans Health Administration6, Wake Forest University7, Tulane University8, University of California, San Francisco9, University of Pennsylvania10, University of Michigan11, Temple University12, University of Münster13, National Institutes of Health14
TL;DR: It is reported that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort and suggested that chronically elevated F GF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
Abstract: Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor–dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF–receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
1,709 citations
Stephan Ripke1, Alan R. Sanders2, Kenneth S. Kendler3, Douglas F. Levinson4 +207 more•Institutions (71)
TL;DR: The authors examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects.
Abstract: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).
1,671 citations
TL;DR: Most current readmission risk prediction models that were designed for either comparative or clinical purposes perform poorly and although in certain settings such models may prove useful, efforts to improve their performance are needed as use becomes more widespread.
Abstract: Context Predicting hospital readmission risk is of great interest to identify which patients would benefit most from care transition interventions, as well as to risk-adjust readmission rates for the purposes of hospital comparison. Objective To summarize validated readmission risk prediction models, describe their performance, and assess suitability for clinical or administrative use. Data Sources and Study Selection The databases of MEDLINE, CINAHL, and the Cochrane Library were searched from inception through March 2011, the EMBASE database was searched through August 2011, and hand searches were performed of the retrieved reference lists. Dual review was conducted to identify studies published in the English language of prediction models tested with medical patients in both derivation and validation cohorts. Data Extraction Data were extracted on the population, setting, sample size, follow-up interval, readmission rate, model discrimination and calibration, type of data used, and timing of data collection. Data Synthesis Of 7843 citations reviewed, 30 studies of 26 unique models met the inclusion criteria. The most common outcome used was 30-day readmission; only 1 model specifically addressed preventable readmissions. Fourteen models that relied on retrospective administrative data could be potentially used to risk-adjust readmission rates for hospital comparison; of these, 9 were tested in large US populations and had poor discriminative ability (c statistic range: 0.55-0.65). Seven models could potentially be used to identify high-risk patients for intervention early during a hospitalization (c statistic range: 0.56-0.72), and 5 could be used at hospital discharge (c statistic range: 0.68-0.83). Six studies compared different models in the same population and 2 of these found that functional and social variables improved model discrimination. Although most models incorporated variables for medical comorbidity and use of prior medical services, few examined variables associated with overall health and function, illness severity, or social determinants of health. Conclusions Most current readmission risk prediction models that were designed for either comparative or clinical purposes perform poorly. Although in certain settings such models may prove useful, efforts to improve their performance are needed as use becomes more widespread.
1,593 citations
TL;DR: The roles and limitations of pilot studies are described here using a clinical trial as an example to evaluate the feasibility of recruitment, randomization, retention, assessment procedures, new methods, and implementation of the novel intervention.
1,366 citations
TL;DR: Heterochronic parabiosis shows that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice, and identifies chemokines—including CCL11 (also known as eotaxin)—the plasma levels of which correlate with reduced neuroGenesis in heterochronics parabionts and aged mice and which are increased in the plasma and cerebrospinal fluid of healthy ageing humans.
Abstract: In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.
1,341 citations
TL;DR: An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4, and a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals was identified.
Abstract: We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10−7). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.
1,312 citations
TL;DR: It is revealed that a distinct process exists in which tissue macrophages undergo rapid in situ proliferation in order to increase population density, and expansion of innate cells necessary for pathogen control or wound repair can occur without recruitment of potentially tissue-destructive inflammatory cells.
Abstract: A defining feature of inflammation is the accumulation of innate immune cells in the tissue that are thought to be recruited from the blood. We reveal that a distinct process exists in which tissue macrophages undergo rapid in situ proliferation in order to increase population density. This inflammatory mechanism occurred during T helper 2 (T(H)2)-related pathologies under the control of the archetypal T(H)2 cytokine interleukin-4 (IL-4) and was a fundamental component of T(H)2 inflammation because exogenous IL-4 was sufficient to drive accumulation of tissue macrophages through self-renewal. Thus, expansion of innate cells necessary for pathogen control or wound repair can occur without recruitment of potentially tissue-destructive inflammatory cells.
1,270 citations
Wellcome Trust Sanger Institute1, University of Oxford2, St James's University Hospital3, Karolinska Institutet4, University of Milan5, University of Cambridge6, University of Southampton7, University of Pavia8, University of Dundee9, Harvard University10, Veterans Health Administration11, University of Texas MD Anderson Cancer Center12, University of Cologne13
TL;DR: Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes and were associated with down-regulation of key gene networks, including core mitochondrial pathways.
Abstract: BACKGROUND Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. METHODS We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. RESULTS We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. CONCLUSIONS Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.).
1,090 citations
Duke University1, Cleveland Clinic2, University of Alberta3, Stavanger University Hospital4, Pierre-and-Marie-Curie University5, University of California, San Francisco6, Veterans Health Administration7, University of Glasgow8, Université de Montréal9, University of Gothenburg10, University of North Carolina at Chapel Hill11, Charité12, University of Oslo13, Rabin Medical Center14, Johnson & Johnson15, Emory University16, Universidade Federal do Rio Grande do Sul17, Pontifical Catholic University of Chile18, Linköping University19, MetroHealth20, University of California, Los Angeles21, Janssen Pharmaceutica22, University of Maryland, Baltimore23, University of Florida24, University of Pennsylvania25, Dalhousie University26, Ford Motor Company27, Monash University28, Vilnius University29, University of Washington30, Mexican Social Security Institute31, University of Brescia32, Seoul National University33, Mayo Clinic34, Wrocław Medical University35, Mahidol University36, University of Otago37, University of Groningen38, Thomas Jefferson University39
TL;DR: In this article, Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies.
Abstract: A b s t r ac t Background Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. Methods We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. Results Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P = 0.03) and 24 hours (68.2% vs. 66.1%, P = 0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, −0.7 percentage points; 95% confidence interval [CI], −2.1 to 0.7; P = 0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, −0.4 percentage points; 95% CI, −1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P = 0.11). Conclusions Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.)
University of Colorado Denver1, Denver Health Medical Center2, University of Minnesota3, University of Alabama at Birmingham4, University of California, Los Angeles5, Veterans Health Administration6, Temple University7, University of Michigan8, University of California, San Francisco9, Regions Hospital10, Mayo Clinic11, University of Pittsburgh12, University of Maryland, Baltimore13, University of Manitoba14
TL;DR: Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects.
Abstract: A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exac erbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among par ticipants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerba tions per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P = 0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George’s Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithro mycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P = 0.004); the percentage of participants with more than the minimal clinically important difference of −4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P = 0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P = 0.04). Conclusions Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.)
TL;DR: A significant association between self-monitoring and weight loss was consistently found; however, the level of evidence was weak and the most significant limitations of the reviewed studies were the homogenous samples and reliance on self-report.
Abstract: Self-monitoring is the centerpiece of behavioral weight loss intervention programs This article presents a systematic review of the literature on three components of self-monitoring in behavioral weight loss studies: diet, exercise, and self-weighing This review included articles that were published between 1993 and 2009 that reported on the relationship between weight loss and these self-monitoring strategies Of the 22 studies identified, 15 focused on dietary self-monitoring, one on self-monitoring exercise, and six on self-weighing A wide array of methods was used to perform self-monitoring; the paper diary was used most often Adherence to self-monitoring was reported most frequently as the number of diaries completed or the frequency of log-ins or reported weights The use of technology, which included the Internet, personal digital assistants, and electronic digital scales were reported in five studies Descriptive designs were used in the earlier studies whereas more recent reports involved prospective studies and randomized trials that examined the effect of self-monitoring on weight loss A significant association between self-monitoring and weight loss was consistently found; however, the level of evidence was weak because of methodologic limitations The most significant limitations of the reviewed studies were the homogenous samples and reliance on self-report In all but two studies, the samples were predominantly white and women This review highlights the need for studies in more diverse populations, for objective measures of adherence to self-monitoring, and for studies that establish the required dose of self-monitoring for successful outcomes
TL;DR: The value of history and physical examination for predicting airflow obstruction; the value of spirometry for screening or diagnosis of COPD; and COPD management strategies, specifically evaluation of various inhaled therapies, pulmonary rehabilitation programs, and supplemental oxygen therapy are addressed.
Abstract: This guideline from 4 medical societies updates the 2007 American College of Physicians clinical practice guideline on diagnosis and management of stable chronic obstructive pulmonary disease (COPD...
TL;DR: The use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5- year mortality, and such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes.
Abstract: A b s t r ac t Background Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events. Methods We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial. Results Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P = 0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups. Conclusions As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.)
TL;DR: The inflammatory mediators and their relationship to early and late DR are reviewed, and the potential of anti-inflammatory approaches to inhibit development of different stages of the retinopathy is discussed.
TL;DR: Among older women, those with sleep-disordered breathing compared with those without sleep- disordered breathing had an increased risk of developing cognitive impairment, and measures of hypoxia, sleep fragmentation, and sleep duration were investigated as underlying mechanisms for this relationship.
Abstract: Context Sleep-disordered breathing (characterized by recurrent arousals from sleep and intermittent hypoxemia) is common among older adults. Cross-sectional studies have linked sleep-disordered breathing to poor cognition; however, it remains unclear whether sleep-disordered breathing precedes cognitive impairment in older adults. Objectives To determine the prospective relationship between sleep-disordered breathing and cognitive impairment and to investigate potential mechanisms of this association. Design, Setting, and Participants Prospective sleep and cognition study of 298 women without dementia (mean [SD] age: 82.3 [3.2] years) who had overnight polysomnography measured between January 2002 and April 2004 in a substudy of the Study of Osteoporotic Fractures. Sleep-disordered breathing was defined as an apnea-hypopnea index of 15 or more events per hour of sleep. Multivariate logistic regression was used to determine the independent association of sleep-disordered breathing with risk of mild cognitive impairment or dementia, adjusting for age, race, body mass index, education level, smoking status, presence of diabetes, presence of hypertension, medication use (antidepressants, benzodiazepines, or nonbenzodiazepine anxiolytics), and baseline cognitive scores. Measures of hypoxia, sleep fragmentation, and sleep duration were investigated as underlying mechanisms for this relationship. Main Outcome Measures Adjudicated cognitive status (normal, dementia, or mild cognitive impairment) based on data collected between November 2006 and September 2008. Results Compared with the 193 women without sleep-disordered breathing, the 105 women (35.2%) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (31.1% [n = 60] vs 44.8% [n = 47]; adjusted odds ratio [AOR], 1.85; 95% confidence interval [CI], 1.11-3.08). Elevated oxygen desaturation index (≥15 events/hour) and high percentage of sleep time (>7%) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR, 1.71 [95% CI, 1.04-2.83] and AOR, 2.04 [95% CI, 1.10-3.78], respectively). Measures of sleep fragmentation (arousal index and wake after sleep onset) or sleep duration (total sleep time) were not associated with risk of cognitive impairment. Conclusion Among older women, those with sleep-disordered breathing compared with those without sleep-disordered breathing had an increased risk of developing cognitive impairment.
TL;DR: The data suggests the existence of a core pulmonary bacterial microbiome that includes Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonas within the same lung of subjects with advanced COPD.
Abstract: Although culture-independent techniques have shown that the lungs are not sterile, little is known about the lung microbiome in chronic obstructive pulmonary disease (COPD). We used pyrosequencing of 16S amplicons to analyze the lung microbiome in two ways: first, using bronchoalveolar lavage (BAL) to sample the distal bronchi and air-spaces; and second, by examining multiple discrete tissue sites in the lungs of six subjects removed at the time of transplantation. We performed BAL on three never-smokers (NS) with normal spirometry, seven smokers with normal spirometry (“heathy smokers”, HS), and four subjects with COPD (CS). Bacterial 16 s sequences were found in all subjects, without significant quantitative differences between groups. Both taxonomy-based and taxonomy-independent approaches disclosed heterogeneity in the bacterial communities between HS subjects that was similar to that seen in healthy NS and two mild COPD patients. The moderate and severe COPD patients had very limited community diversity, which was also noted in 28% of the healthy subjects. Both approaches revealed extensive membership overlap between the bacterial communities of the three study groups. No genera were common within a group but unique across groups. Our data suggests the existence of a core pulmonary bacterial microbiome that includes Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonas. Most strikingly, there were significant micro-anatomic differences in bacterial communities within the same lung of subjects with advanced COPD. These studies are further demonstration of the pulmonary microbiome and highlight global and micro-anatomic changes in these bacterial communities in severe COPD patients.
TL;DR: Evaluation of rapamycin's effects on mice is likely to help delineate the role of the mammalian target ofRapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging.
Abstract: Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice. Resveratrol (at 300 and 1200 ppm food) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice. Further evaluation of rapamycin's effects on mice is likely to help delineate the role of the mammalian target of rapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging.
TL;DR: The current understanding and future directions in BDNF-related research in the central nervous system are reviewed, with an emphasis on the possible therapeutic application of BDNF in modifying fundamental processes underlying neural disease.
Abstract: The growth factor brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase receptor type B (TRKB) are actively produced and trafficked in multiple regions in the adult brain, where they influence neuronal activity, function and survival throughout life. The diverse presence and activity of BDNF suggests a potential role for this molecule in the pathogenesis and treatment of both neurological and psychiatric disorders. This article reviews the current understanding and future directions in BDNF-related research in the central nervous system, with an emphasis on the possible therapeutic application of BDNF in modifying fundamental processes underlying neural disease.
TL;DR: Data suggest that perturbations in the PACAP–PAC1 pathway are involved in abnormal stress responses underlying PTSD, and sex-specific effects may occur via oestrogen regulation of ADCYAP1R1.
Abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.
TL;DR: A systematic review of the research literature and summarized twenty-one randomized clinical trials of transitional care interventions targeting chronically ill adults identified nine interventions that demonstrated positive effects on measures related to hospital readmissions-a key focus of health reform.
Abstract: Under the Affordable Care Act of 2010, a variety of transitional care programs and services have been established to improve quality and reduce costs. These programs help hospitalized patients with complex chronic conditions—often the most vulnerable—transfer in a safe and timely manner from one level of care to another or from one type of care setting to another. We conducted a systematic review of the research literature and summarized twenty-one randomized clinical trials of transitional care interventions targeting chronically ill adults. We identified nine interventions that demonstrated positive effects on measures related to hospital readmissions—a key focus of health reform. Most of the interventions led to reductions in readmissions through at least thirty days after discharge. Many of the successful interventions shared similar features, such as assigning a nurse as the clinical manager or leader of care and including in-person home visits to discharged patients. Based on these findings, we reco...
TL;DR: The rate of serious adverse events, serious infections, lymphoma, and congestive heart failure were not statistically significantly different between biologics and control treatment, and direct comparisons revealed that abatacept and anakinra were associated with a significantly lower risk ofserious adverse events compared to most other biologicics.
Abstract: Background Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates. Objectives To compare the adverse effects of tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS). Methods Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open-label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre-specified adverse outcomes were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network meta-analysis, we performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework. Main results We included 163 RCTs with 50,010 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for tuberculosis (TB) reactivation, lymphoma, and congestive heart failure. Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events (odds ratio (OR) 1.19, 95% CI 1.09 to 1.30; number needed to treat to harm (NNTH) = 30, 95% CI 21 to 60) and withdrawals due to adverse events (OR 1.32, 95% CI 1.06 to 1.64; NNTH = 37, 95% CI 19 to 190) and an increased risk of TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706) compared to control.The rate of serious adverse events, serious infections, lymphoma, and congestive heart failure were not statistically significantly different between biologics and control treatment. Certolizumab pegol was associated with significantly higher risk of serious infections compared to control treatment (OR 3.51, 95% CI 1.59 to 7.79; NNTH = 17, 95% CI 7 to 68). Infliximab was associated with significantly higher risk of withdrawals due to adverse events compared to control (OR 2.04, 95% CI 1.43 to 2.91; NNTH = 12, 95% CI 8 to 28). Indirect comparisons revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events compared to most other biologics. Although the overall numbers are relatively small, certolizumab pegol was associated with significantly higher odds of serious infections compared to etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab; abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections. Abatacept, adalimumab, etanercept and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. Authors' conclusions Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results.There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics. National and international registries and other types of large databases are relevant sources for providing complementary evidence regarding the short- and longer-term safety of biologics.
TL;DR: Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery.
Abstract: Acute kidney injury (AKI) occurs commonly after pediatric cardiac surgery and associates with poor outcomes. Biomarkers may help the prediction or early identification of AKI, potentially increasing opportunities for therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 311 children undergoing surgery for congenital cardiac lesions to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. Severe AKI, defined by dialysis or doubling in serum creatinine during hospital stay, occurred in 53 participants at a median of 2 days after surgery. The first postoperative urine IL-18 and urine NGAL levels strongly associated with severe AKI. After multivariable adjustment, the highest quintiles of urine IL-18 and urine NGAL associated with 6.9- and 4.1-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation. The accuracy of urine IL-18 and urine NGAL for diagnosis of severe AKI was moderate, with areas under the curve of 0.72 and 0.71, respectively. The addition of these urine biomarkers improved risk prediction over clinical models alone as measured by net reclassification improvement and integrated discrimination improvement. In conclusion, urine IL-18 and urine NGAL, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery.
University of Texas Health Science Center at San Antonio1, Arizona State University2, Veterans Health Administration3, SUNY Downstate Medical Center4, Louisiana State University5, University of Southern California6, Georgetown University7, University of California, San Diego8, University of Tennessee Health Science Center9, Memorial Hospital of South Bend10
TL;DR: As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema.
Abstract: RESULTS Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA1c (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P = 0.03), a reduced rate of carotid intima–media thickening (31.5%, P = 0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P = 0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P = 0.007). CONCLUSIONS As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.)
University of Michigan1, Baylor College of Medicine2, University of Texas Southwestern Medical Center3, University of North Carolina at Chapel Hill4, Veterans Health Administration5, University of Texas Health Science Center at Houston6, University of Mississippi7, University of Minnesota8, Johns Hopkins University9
TL;DR: In this paper, the authors evaluated whether cardiac troponin T (cTnT) measured with a new highly sensitive assay was associated with incident coronary heart disease (CHD), mortality, and hospitalization for heart failure (HF) in a general population of participants in the ARIC Study.
Abstract: Background—We evaluated whether cardiac troponin T (cTnT) measured with a new highly sensitive assay was associated with incident coronary heart disease (CHD), mortality, and hospitalization for heart failure (HF) in a general population of participants in the Atherosclerosis Risk in Communities (ARIC) Study. Methods and Results—Associations between increasing cTnT levels and CHD, mortality, and HF hospitalization were evaluated with Cox proportional hazards models adjusted for traditional CHD risk factors, kidney function, high-sensitivity C-reactive protein, and N-terminal pro–B-type natriuretic peptide in 9698 participants aged 54 to 74 years who at baseline were free from CHD and stroke (and HF in the HF analysis). Measurable cTnT levels (≥0.003 μg/L) were detected in 66.5% of individuals. In fully adjusted models, compared with participants with undetectable levels, those with cTnT levels in the highest category (≥0.014 μg/L; 7.4% of the ARIC population) had significantly increased risk for CHD (haza...
TL;DR: A power analysis revealed that FDG-ROI values have greater statistical power than ADAS-cog to detect attenuation of cognitive decline in AD and MCI patients.
TL;DR: The factors that affect concussion rate are identified and improved techniques and rule changes can be improved to minimize the rate and severity of concussions in sports.
TL;DR: Focus is placed on the neuroanatomy of medial temporal lobe and diencephalic structures important for memory, multiple memory systems, visual perception, immediate memory, memory consolidation, the locus of long-term memory storage, the concepts of recollection and familiarity, and the question of how different medialporal lobe structures may contribute differently to memory functions.
Abstract: Work with patient H.M., beginning in the 1950s, established key principles about the organization of memory that inspired decades of experimental work. Since H.M., the study of human memory and its disorders has continued to yield new insights and to improve understanding of the structure and organization of memory. Here we review this work with emphasis on the neuroanatomy of medial temporal lobe and diencephalic structures important for memory, multiple memory systems, visual perception, immediate memory, memory consolidation, the locus of long-term memory storage, the concepts of recollection and familiarity, and the question of how different medial temporal lobe structures may contribute differently to memory functions.
TL;DR: The Brief Negative Symptom Scale (BNSS) is a 13-item instrument designed for clinical trials and other studies that measures these 5 domains and the interrater, test-retest, and internal consistency of the instrument were strong.
Abstract: The participants in the NIMH-MATRICS Consensus Development Conference on Negative Symptoms recommended that an instrument be developed that measured blunted affect, alogia, asociality, anhedonia, and avolition. The Brief Negative Symptom Scale (BNSS) is a 13-item instrument designed for clinical trials and other studies that measures these 5 domains. The interrater, test-retest, and internal consistency of the instrument were strong, with respective intraclass correlation coefficients of 0.93 for the BNSS total score and values of 0.89-0.95 for individual subscales. Comparisons with positive symptoms and other negative symptom instruments supported the discriminant and concurrent validity of the instrument.