Showing papers by "University of Maryland, Baltimore published in 2014"

A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma

Abstract: Background Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known. Methods In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary ...

A draft map of the human proteome

Abstract: The availability of human genome sequence has transformed biomedical research over the past decade. However, an equivalent map for the human proteome with direct measurements of proteins and peptides does not exist yet. Here we present a draft map of the human proteome using high-resolution Fourier-transform mass spectrometry. In-depth proteomic profiling of 30 histologically normal human samples, including 17 adult tissues, 7 fetal tissues and 6 purified primary haematopoietic cells, resulted in identification of proteins encoded by 17,294 genes accounting for approximately 84% of the total annotated protein-coding genes in humans. A unique and comprehensive strategy for proteogenomic analysis enabled us to discover a number of novel protein-coding regions, which includes translated pseudogenes, non-coding RNAs and upstream open reading frames. This large human proteome catalogue (available as an interactive web-based resource at http://www.humanproteomemap.org) will complement available human genome and transcriptome data to accelerate biomedical research in health and disease.

Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

The FNIH Sarcopenia Project: Rationale, Study Description, Conference Recommendations, and Final Estimates

Abstract: Background. Low muscle mass and weakness are common and potentially disabling in older adults, but in order to become recognized as a clinical condition, criteria for diagnosis should be based on clinically relevant thresholds and independently validated. The Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project used an evidence-based approach to develop these criteria. Initial findings were presented at a conference in May 2012, which generated recommendations that guided additional analyses to determine final recommended criteria. Details of the Project and its findings are presented in four accompanying manuscripts.

An improved dual-indexing approach for multiplexed 16S rRNA gene sequencing on the Illumina MiSeq platform

Abstract: To take advantage of affordable high-throughput next-generation sequencing technologies to characterize microbial community composition often requires the development of improved methods to overcome technical limitations inherent to the sequencing platforms. Sequencing low sequence diversity libraries such as 16S rRNA amplicons has been problematic on the Illumina MiSeq platform and often generates sequences of suboptimal quality. Here we present an improved dual-indexing amplification and sequencing approach to assess the composition of microbial communities from clinical samples using the V3-V4 region of the 16S rRNA gene on the Illumina MiSeq platform. We introduced a 0 to 7 bp “heterogeneity spacer” to the index sequence that allows an equal proportion of samples to be sequenced out of phase. Our approach yields high quality sequence data from 16S rRNA gene amplicons using both 250 bp and 300 bp paired-end MiSeq protocols and provides a flexible and cost-effective sequencing option.

PATRIC, the bacterial bioinformatics database and analysis resource

Abstract: The Pathosystems Resource Integration Center (PATRIC) is the all-bacterial Bioinformatics Resource Center (BRC) (http://www.patricbrc.org). A joint effort by two of the original National Institute of Allergy and Infectious Diseases-funded BRCs, PATRIC provides researchers with an online resource that stores and integrates a variety of data types [e.g. genomics, transcriptomics, protein–protein interactions (PPIs), three-dimensional protein structures and sequence typing data] and associated metadata. Datatypes are summarized for individual genomes and across taxonomic levels. All genomes in PATRIC, currently more than 10 000, are consistently annotated using RAST, the Rapid Annotations using Subsystems Technology. Summaries of different data types are also provided for individual genes, where comparisons of different annotations are available, and also include available transcriptomic data. PATRIC provides a variety of ways for researchers to find data of interest and a private workspace where they can store both genomic and gene associations, and their own private data. Both private and public data can be analyzed together using a suite of tools to perform comparative genomic or transcriptomic analysis. PATRIC also includes integrated information related to disease and PPIs. All the data and integrated analysis and visualization tools are freely available. This manuscript describes updates to the PATRIC since its initial report in the 2007 NAR Database Issue.

Effect of Structured Physical Activity on Prevention of Major Mobility Disability in Older Adults: The LIFE Study Randomized Clinical Trial

Abstract: Importance In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining whether physical activity prevents or delays mobility disability. Objective To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability. Design, Setting, and Participants The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban, and rural communities at 8 centers throughout the United States. We randomized a volunteer sample of 1635 sedentary men and women aged 70 to 89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m. Interventions Participants were randomized to a structured, moderate-intensity physical activity program (n = 818) conducted in a center (twice/wk) and at home (3-4 times/wk) that included aerobic, resistance, and flexibility training activities or to a health education program (n = 817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises. Main Outcomes and Measures The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m. Results Incident major mobility disability occurred in 30.1% (246 participants) of the physical activity group and 35.5% (290 participants) of the health education group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98], P = .03). Persistent mobility disability was experienced by 120 participants (14.7%) in the physical activity group and 162 participants (19.8%) in the health education group (HR, 0.72 [95% CI, 0.57-0.91]; P = .006). Serious adverse events were reported by 404 participants (49.4%) in the physical activity group and 373 participants (45.7%) in the health education group (risk ratio, 1.08 [95% CI, 0.98-1.20]). Conclusions and Relevance A structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability. These findings suggest mobility benefit from such a program in vulnerable older adults. Trial Registration clinicaltrials.gov Identifier:NCT01072500

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

Abstract: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

Preservation of Memory With Conformal Avoidance of the Hippocampal Neural Stem-Cell Compartment During Whole-Brain Radiotherapy for Brain Metastases (RTOG 0933): A Phase II Multi-Institutional Trial

Abstract: Purpose Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance.

Understanding Pharmaceutical Quality by Design

Abstract: This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.

Mitral-Valve Repair versus Replacement for Severe Ischemic Mitral Regurgitation

Abstract: Background Ischemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited. Methods We randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank. Results At 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, −6.6 and −6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement g...

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data

Abstract: The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women

Abstract: Background: This study was undertaken to characterize the vaginal microbiota throughout normal human pregnancy using sequence-based techniques. We compared the vaginal microbial composition of non-pregnant patients with a group of pregnant women who delivered at term. Results: A retrospective case–control longitudinal study was designed and included non-pregnant women (n = 32) and pregnant women who delivered at term (38 to 42 weeks) without complications (n = 22). Serial samples of vaginal fluid were collected from both non-pregnant and pregnant patients. A 16S rRNA gene sequence-based survey was conducted using pyrosequencing to characterize the structure and stability of the vaginal microbiota. Linear mixed effects models and generalized estimating equations were used to identify the phylotypes whose relative abundance was different between the two study groups. The vaginal microbiota of normal pregnant women was different from that of non-pregnant women (higher abundance of Lactobacillus vaginalis, L. crispatus, L. gasseri and L. jensenii and lower abundance of 22 other phylotypes in pregnant women). Bacterial community state type (CST) IV-B or CST IV-A characterized by high relative abundance of species of genus Atopobium as well as the presence of Prevotella, Sneathia, Gardnerella, Ruminococcaceae, Parvimonas, Mobiluncus and other taxa previously shown to be associated with bacterial vaginosis were less frequent in normal pregnancy. The stability of the vaginal microbiota of pregnant women was higher than that of non-pregnant women; however, during normal pregnancy, bacterial communities shift almost exclusively from one CST dominated by Lactobacillus spp. to another CST dominated by Lactobacillus spp. Conclusion: We report the first longitudinal study of the vaginal microbiota in normal pregnancy. Differences in the composition and stability of the microbial community between pregnant and non-pregnant women were observed. Lactobacillus spp. were the predominant members of the microbial community in normal pregnancy. These results can serve as the basis to study the relationship between the vaginal microbiome and adverse pregnancy outcomes.

Light as a central modulator of circadian rhythms, sleep and affect

Abstract: Light has profoundly influenced the evolution of life on earth. As widely appreciated, light enables us to generate images of our environment. However, light - through intrinsically photosensitive retinal ganglion cells (ipRGCs) - also influences behaviours that are essential for our health and quality of life but are independent of image formation. These include the synchronization of the circadian clock to the solar day, tracking of seasonal changes and the regulation of sleep. Irregular light environments lead to problems in circadian rhythms and sleep, which eventually cause mood and learning deficits. Recently, it was found that irregular light can also directly affect mood and learning without producing major disruptions in circadian rhythms and sleep. In this Review, we discuss the indirect and direct influence of light on mood and learning, and provide a model for how light, the circadian clock and sleep interact to influence mood and cognitive functions.

Elephant shark genome provides unique insights into gnathostome evolution

Abstract: The emergence of jawed vertebrates (gnathostomes) from jawless vertebrates was accompanied by major morphological and physiological innovations, such as hinged jaws, paired fins and immunoglobulin-based adaptive immunity. Gnathostomes subsequently diverged into two groups, the cartilaginous fishes and the bony vertebrates. Here we report the whole-genome analysis of a cartilaginous fish, the elephant shark (Callorhinchus milii). We find that the C. milii genome is the slowest evolving of all known vertebrates, including the ‘living fossil’ coelacanth, and features extensive synteny conservation with tetrapod genomes, making it a good model for comparative analyses of gnathostome genomes. Our functional studies suggest that the lack of genes encoding secreted calcium-binding phosphoproteins in cartilaginous fishes explains the absence of bone in their endoskeleton. Furthermore, the adaptive immune system of cartilaginous fishes is unusual: it lacks the canonical CD4 co-receptor and most transcription factors, cytokines and cytokine receptors related to the CD4 lineage, despite the presence of polymorphic major histocompatibility complex class II molecules. It thus presents a new model for understanding the origin of adaptive immunity. Whole-genome analysis of the elephant shark, a cartilaginous fish, shows that it is the slowest evolving of all known vertebrates, lacks critical bone formation genes and has an unusual adaptive immune system. The elephant shark (Callorhinchus milii) is a cartilaginous fish native to the temperate waters off southern Australia and New Zealand, living at depths of 200 to 500 metres and migrating into shallow waters during spring for breeding. The genome sequence is published in this issue of Nature. Comparison with other vertebrate genomes shows that it is the slowest evolving genome of all known vertebrates — coelacanth included. Genome analysis points to an unusual adaptive immune system lacking the CD4 receptor and some associated cytokines, indicating that cartilaginous fishes possess a primordial gnathostome adaptive immune system. Also absent are genes encoding secreted calcium-binding phosphoproteins, in line with the absence of bone in cartilaginous fish.

New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate.

Abstract: Green tea is rich in polyphenol flavonoids including catechins. Epigallocatechin 3-gallate (EGCG) is the most abundant and potent green tea catechin. EGCG has been extensively studied for its beneficial health effects as a nutriceutical agent. Based upon its chemical structure, EGCG is often classified as an antioxidant. However, treatment of cells with EGCG results in production of hydrogen peroxide and hydroxyl radicals in the presence of Fe (III). Thus, EGCG functions as a pro-oxidant in some cellular contexts. Recent investigations have revealed many other direct actions of EGCG that are independent from anti-oxidative mechanisms. In this review, we discuss these novel molecular mechanisms of action for EGCG. In particular, EGCG directly interacts with proteins and phospholipids in the plasma membrane and regulates signal transduction pathways, transcription factors, DNA methylation, mitochondrial function, and autophagy to exert many of its beneficial biological actions.

Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection

Abstract: Outbreaks of emerging infections present health professionals with the unique challenge of trying to select appropriate pharmacologic treatments in the clinic with little time available for drug testing and development. Typically, clinicians are left with general supportive care and often untested convalescent-phase plasma as available treatment options. Repurposing of approved pharmaceutical drugs for new indications presents an attractive alternative to clinicians, researchers, public health agencies, drug developers, and funding agencies. Given the development times and manufacturing requirements for new products, repurposing of existing drugs is likely the only solution for outbreaks due to emerging viruses. In the studies described here, a library of 290 compounds was screened for antiviral activity against Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Selection of compounds for inclusion in the library was dependent on current or previous FDA approval or advanced clinical development. Some drugs that had a well-defined cellular pathway as target were included. In total, 27 compounds with activity against both MERS-CoV and SARS-CoV were identified. The compounds belong to 13 different classes of pharmaceuticals, including inhibitors of estrogen receptors used for cancer treatment and inhibitors of dopamine receptor used as antipsychotics. The drugs identified in these screens provide new targets for in vivo studies as well as incorporation into ongoing clinical studies.

Concordance between administrative claims and registry data for identifying metastasis to the bone: an exploratory analysis in prostate cancer

Abstract: To assess concordance between Medicare claims and Surveillance, Epidemiology, and End Results (SEER) reports of incident BM among prostate cancer (PCa) patients. The prevalence and consequences of bone metastases (BM) have been examined across tumor sites using healthcare claims data however the reliability of these claims-based BM measures has not been investigated. This retrospective cohort study utilized linked registry and claims (SEER-Medicare) data on men diagnosed with incident stage IV M1 PCa between 2005 and 2007. The SEER-based measure of incident BM was cross-tabulated with three separate Medicare claims approaches to assess concordance. Sensitivity, specificity and positive predictive value (PPV) were calculated to assess the concordance between registry- and claims-based measures. Based on 2,708 PCa patients in SEER-Medicare, there is low to moderate concordance between the SEER- and claims-based measures of incident BM. Across the three approaches, sensitivity ranged from 0.48 (0.456 – 0.504) to 0.598 (0.574 - 0.621), specificity ranged from 0.538 (0.507 - 0.569) to 0.620 (0.590 - 0.650) and PPV ranged from 0.679 (0.651 - 0.705) to 0.690 (0.665 - 0.715). A comparison of utilization patterns between SEER-based and claims-based measures suggested avenues for improving sensitivity. Claims-based measures using BM ICD 9 coding may be insufficient to identify patients with incident BM diagnosis and should be validated against chart data to maximize their potential for population-based analyses.

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Abstract: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Mechanisms of Acupuncture-Electroacupuncture on Persistent Pain

Abstract: In the last decade, preclinical investigations of electroacupuncture mechanisms on persistent tissue injury (inflammatory), nerve injury (neuropathic), cancer, and visceral pain have increased. These studies show that electroacupuncture activates the nervous system differently in health than in pain conditions, alleviates both sensory and affective inflammatory pain, and inhibits inflammatory and neuropathic pain more effectively at 2 to 10 Hz than at 100 Hz. Electroacupuncture blocks pain by activating a variety of bioactive chemicals through peripheral, spinal, and supraspinal mechanisms. These include opioids, which desensitize peripheral nociceptors and reduce proinflammatory cytokines peripherally and in the spinal cord, and serotonin and norepinephrine, which decrease spinal N-methyl-D-aspartate receptor subunit GluN1 phosphorylation. Additional studies suggest that electroacupuncture, when combined with low dosages of conventional analgesics, provides effective pain management which can forestall the side effects of often-debilitating pharmaceuticals.

Physical complications in acute lung injury survivors: a two-year longitudinal prospective study.

Abstract: Objective Survivors of severe critical illness frequently develop substantial and persistent physical complications, including muscle weakness, impaired physical function, and decreased health-related quality of life (HRQOL). Our objective was to determine the longitudinal epidemiology of muscle weakness, physical function, and HRQOL, and their associations with critical illness and intensive care unit exposures.

Intermuscular fat: a review of the consequences and causes.

Abstract: Muscle's structural composition is an important factor underlying muscle strength and physical function in older adults. There is an increasing amount of research to support the clear disassociation between the loss of muscle lean tissue mass and strength with aging. This disassociation implies that factors in addition to lean muscle mass are responsible for the decreases in strength and function seen with aging. Intermuscular adipose tissue (IMAT) is a significant predictor of both muscle function and mobility function in older adults and across a wide variety of comorbid conditions such as stroke, spinal cord injury, diabetes, and COPD. IMAT is also implicated in metabolic dysfunction such as insulin resistance. The purpose of this narrative review is to provide a review of the implications of increased IMAT levels in metabolic, muscle, and mobility function. Potential treatment options to mitigate increasing levels of IMAT will also be discussed.

Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease The TEAM-AD VA Cooperative Randomized Trial

Abstract: Importance Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. Objective To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. Design, Setting, and Participants Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. Interventions Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). Main Outcomes and Measures Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. Results Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, −0.24 to 4.20; adjusted P = .40) than the placebo group’s decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of “infections or infestations,” with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). Conclusions and Relevance Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. Trial Registration clinicaltrials.gov Identifier:NCT00235716

Ventilator-associated pneumonia in the ICU

Abstract: Ventilator-associated pneumonia (VAP) is defined as pneumonia that occurs 48–72 hours or thereafter following endotracheal intubation, characterized by the presence of a new or progressive infiltrate, signs of systemic infection (fever, altered white blood cell count), changes in sputum characteristics, and detection of a causative agent [1]. VAP contributes to approximately half of all cases of hospital-acquired pneumonia [1, 2]. VAP is estimated to occur in 9–27 % of all mechanically ventilated patients, with the highest risk being early in the course of hospitalization [1, 3]. It is the second most common nosocomial infection in the intensive care unit (ICU) and the most common in mechanically ventilated patients [4, 5]. VAP rates range from 1.2 to 8.5 per 1,000 ventilator days and are reliant on the definition used for diagnosis [6]. Risk for VAP is greatest during the first 5 days of mechanical ventilation (3 %) with the mean duration between intubation and development of VAP being 3.3 days [1, 7]. This risk declines to 2 %/day between days 5 to 10 of ventilation, and 1 %/day thereafter [1, 8]. Earlier studies placed the attributable mortality for VAP at between 33–50 %, but this rate is variable and relies heavily on the underlying medical illness [1]. Over the years, the attributable risk of death has decreased and is more recently estimated at 9–13 % [9, 10], largely because of implementation of preventive strategies. Approximately 50 % of all antibiotics administered in ICUs are for treatment of VAP [2, 4]. Early onset VAP is defined as pneumonia that occurs within 4 days and this is usually attributed to antibiotic sensitive pathogens whereas late onset VAP is more likely caused by multidrug resistant (MDR) bacteria and emerges after 4 days of intubation [1, 4]. Thus, VAP poses grave implications in endotracheally intubated adult patients in ICUs worldwide and leads to increased adverse outcomes and healthcare costs. Independent risk factors for development of VAP are male sex, admission for trauma and intermediate underlying disease severity, with odds ratios (OR) of 1.58, 1.75 and 1.47–1.70, respectively [7].