Showing papers by "Brown University published in 2013"

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012

Abstract: To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008. A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7–9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a Pao 2/Fio 2 ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a Pao 2/Fi o 2 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5–10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven “absolute”’ adrenal insufficiency (2C). Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

Nine-year Wilkinson Microwave Anisotropy Probe (WMAP) Observations: Cosmological Parameter Results

Abstract: We present cosmological parameter constraints based on the final nine-year WMAP data, in conjunction with a number of additional cosmological data sets. The WMAP data alone, and in combination, continue to be remarkably well fit by a six-parameter CDM model. When WMAP data are combined with measurements of the high-l cosmic microwave background (CMB) anisotropy, the baryon acoustic oscillation (BAO) scale, and the Hubble constant, the matter and energy densities, bh 2 , ch 2 , and , are each determined to a precision of 1.5%. The amplitude of the primordial spectrum is measured to within 3%, and there is now evidence for a tilt in the primordial spectrum at the 5 level, confirming the first detection of tilt based on the five-year WMAP data. At the end of the WMAP mission, the nine-year data decrease the allowable volume of the six-dimensional CDM parameter space by a factor of 68,000 relative to pre-WMAP measurements. We investigate a number of data combinations and show that their CDM parameter fits are consistent. New limits on deviations from the six-parameter model are presented, for example: the fractional contribution of tensor modes is limited to r < 0.13 (95% CL); the spatial curvature parameter is limited to k = 0.0027 +0.0039 0.0038 ; the summed mass of neutrinos is limited to P m < 0.44 eV (95% CL); and the number of relativistic species is found to lie within Ne = 3.84±0.40, when the full data are analyzed. The joint constraint on Ne and the primordial helium abundance, YHe, agrees with the prediction of standard Big Bang nucleosynthesis. We compare recent Planck measurements of the Sunyaev‐Zel’dovich eect with our seven-year measurements, and show their mutual agreement. Our analysis of the polarization pattern around temperature extrema is updated. This confirms a fundamental prediction of the standard cosmological model and provides a striking illustration of acoustic oscillations and adiabatic initial conditions in the early universe. Subject headings: cosmic microwave background, cosmology: observations, early universe, dark matter, space vehicles, space vehicles: instruments, instrumentation: detectors, telescopes

The cancer genome atlas pan-cancer analysis project

Abstract: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

Abstract: BACKGROUND—Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined The relationships between patterns of mutations and epigenetic phenotypes are not yet clear METHODS—We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis RESULTS—AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes Of these, an average of 5 are in genes that are recurrently mutated in AML A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcriptionfactor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumorsuppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%) Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories CONCLUSIONS—We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification (Funded by the National Institutes of Health) The molecular pathogenesis of acute myeloid leukemia (AML) has been studied with the use of cytogenetic analysis for more than three decades Recurrent chromosomal structural variations are well established as diagnostic and prognostic markers, suggesting that acquired genetic abnormalities (ie, somatic mutations) have an essential role in pathogenesis 1,2 However, nearly 50% of AML samples have a normal karyotype, and many of these genomes lack structural abnormalities, even when assessed with high-density comparative genomic hybridization or single-nucleotide polymorphism (SNP) arrays 3-5 (see Glossary) Targeted sequencing has identified recurrent mutations in FLT3, NPM1, KIT, CEBPA, and TET2 6-8 Massively parallel sequencing enabled the discovery of recurrent mutations in DNMT3A 9,10 and IDH1 11 Recent studies have shown that many patients with

Mutational landscape and significance across 12 major cancer types

Abstract: The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.

Nine-Year Wilkinson Microwave Anisotropy Probe (WMAP) Observations: Final Maps and Results

Abstract: We present the final nine-year maps and basic results from the Wilkinson Microwave Anisotropy Probe (WMAP) mission. The full nine-year analysis of the time-ordered data provides updated characterizations and calibrations of the experiment. We also provide new nine-year full sky temperature maps that were processed to reduce the asymmetry of the effective beams. Temperature and polarization sky maps are examined to separate cosmic microwave background (CMB) anisotropy from foreground emission, and both types of signals are analyzed in detail.We provide new point source catalogs as well as new diffuse and point source foreground masks. An updated template-removal process is used for cosmological analysis; new foreground fits are performed, and new foreground reduced are presented.We nowimplement an optimal C(exp -1)1 weighting to compute the temperature angular power spectrum. The WMAP mission has resulted in a highly constrained Lambda-CDM cosmological model with precise and accurate parameters in agreement with a host of other cosmological measurements. When WMAP data are combined with finer scale CMB, baryon acoustic oscillation, and Hubble constant measurements, we find that big bang nucleosynthesis is well supported and there is no compelling evidence for a non-standard number of neutrino species (N(sub eff) = 3.84 +/- 0.40). The model fit also implies that the age of the universe is (sub 0) = 13.772 +/- 0.059 Gyr, and the fit Hubble constant is H(sub 0) = 69.32 +/- 0.80 km/s/ Mpc. Inflation is also supported: the fluctuations are adiabatic, with Gaussian random phases; the detection of a deviation of the scalar spectral index from unity, reported earlier by the WMAP team, now has high statistical significance (n(sub s) = 0.9608+/-0.0080); and the universe is close to flat/Euclidean (Omega = −0.0027+0.0039/−0.0038). Overall, the WMAP mission has resulted in a reduction of the cosmological parameter volume by a factor of 68,000 for the standard six-parameter Lambda-CDM model, based on CMB data alone. For a model including tensors, the allowed seven-parameter volume has been reduced by a factor 117,000. Other cosmological observations are in accord with the CMB predictions, and the combined data reduces the cosmological parameter volume even further.With no significant anomalies and an adequate goodness of fit, the inflationary flat Lambda-CDM model and its precise and accurate parameters rooted in WMAP data stands as the standard model of cosmology.

Comprehensivemolecular characterization of clear cell renal cell carcinoma

Abstract: Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.

The State of US Health, 1990-2010: Burden of Diseases, Injuries, and Risk Factors

Abstract: Importance Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. Objectives To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. Design We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. Results US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. Conclusions and Relevance From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.

Abstract: In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle interven tion that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascu lar causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. Results The trial was stopped early on the basis of a futility analysis when the median fol low-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in gly cated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P = 0.51). Conclusions An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.)

Gestational Diabetes Mellitus

Abstract: Background: Gestational diabetes mellitus, defined as diabetes diagnosed during pregnancy that is not clearly overt diabetes, is becoming more common as the epidemic of obesity and type 2 diabetes continues. Newly proposed diagnostic criteria will, if adopted universally, further increase the prevalence of this condition. Much controversy surrounds the diagnosis and management of gestational diabetes. Content: This review provides information regarding various approaches to the diagnosis of gestational diabetes and the recommendations of a number of professional organizations. The implications of gestational diabetes for both the mother and the offspring are described. Approaches to self-monitoring of blood glucose concentrations and treatment with diet, oral medications, and insulin injections are covered. Management of glucose metabolism during labor and the postpartum period are discussed, and an approach to determining the timing of delivery and the mode of delivery is outlined. Summary: This review provides an overview of current controversies as well as current recommendations for gestational diabetes care.

Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials

Abstract: RESULTS During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.781.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.

Monodisperse Au nanoparticles for selective electrocatalytic reduction of CO2 to CO.

Abstract: We report selective electrocatalytic reduction of carbon dioxide to carbon monoxide on gold nanoparticles (NPs) in 0.5 M KHCO3 at 25 °C. Among monodisperse 4, 6, 8, and 10 nm NPs tested, the 8 nm Au NPs show the maximum Faradaic efficiency (FE) (up to 90% at −0.67 V vs reversible hydrogen electrode, RHE). Density functional theory calculations suggest that more edge sites (active for CO evolution) than corner sites (active for the competitive H2 evolution reaction) on the Au NP surface facilitates the stabilization of the reduction intermediates, such as COOH*, and the formation of CO. This mechanism is further supported by the fact that Au NPs embedded in a matrix of butyl-3-methylimidazolium hexafluorophosphate for more efficient COOH* stabilization exhibit even higher reaction activity (3 A/g mass activity) and selectivity (97% FE) at −0.52 V (vs RHE). The work demonstrates the great potentials of using monodisperse Au NPs to optimize the available reaction intermediate binding sites for efficient and ...

Towards Understanding Action Recognition

Abstract: Although action recognition in videos is widely studied, current methods often fail on real-world datasets. Many recent approaches improve accuracy and robustness to cope with challenging video sequences, but it is often unclear what affects the results most. This paper attempts to provide insights based on a systematic performance evaluation using thoroughly-annotated data of human actions. We annotate human Joints for the HMDB dataset (J-HMDB). This annotation can be used to derive ground truth optical flow and segmentation. We evaluate current methods using this dataset and systematically replace the output of various algorithms with ground truth. This enables us to discover what is important - for example, should we work on improving flow algorithms, estimating human bounding boxes, or enabling pose estimation? In summary, we find that high-level pose features greatly outperform low/mid level features, in particular, pose over time is critical, but current pose estimation algorithms are not yet reliable enough to provide this information. We also find that the accuracy of a top-performing action recognition framework can be greatly increased by refining the underlying low/mid level features, this suggests it is important to improve optical flow and human detection algorithms. Our analysis and J-HMDB dataset should facilitate a deeper understanding of action recognition algorithms.

Efficient stochastic generation of special quasirandom structures

Abstract: We present a new algorithm to generate Special Quasirandom Structures (SQS), i.e., best periodic supercell approximations to the true disordered state for a given number of atoms per supercell. The method is based on a Monte Carlo simulated annealing loop with an objective function that seeks to perfectly match the maximum number of correlation functions (as opposed to merely minimizing the distance between the SQS correlation and the disordered state correlations for a pre-specified set of correlations). The proposed method optimizes the shape of the supercell jointly with the occupation of the atomic sites, thus ensuring that the configurational space searched is exhaustive and not biased by a pre-specified supercell shape. The method has been implemented in the “mcsqs” code of the Alloy Theoretic Automated Toolkit (ATAT) in the most general framework of multicomponent multisublattice systems and in a way that minimizes the amount of input information the user needs to specify and that allows for efficient parallelization.

Change in End-of-Life Care for Medicare Beneficiaries: Site of Death, Place of Care, and Health Care Transitions in 2000, 2005, and 2009

Abstract: In 2009, 28.4% (95% CI, 27.9%-28.5%) of hospice use at the time of death was for 3 days or less. Of these late hospice referrals, 40.3% (95% CI, 39.7%-40.8%) were preceded by hospitalization with an ICU stay. Conclusion and Relevance Among Medicare beneficiaries who died in 2009 and 2005 compared with 2000, a lower proportion died in an acute care hospital, although both ICU use and the rate of health care transitions increased in the last month of life.

Tuning Nanoparticle Catalysis for the Oxygen Reduction Reaction

Abstract: Advances in chemical syntheses have led to the formation of various kinds of nanoparticles (NPs) with more rational control of size, shape, composition, structure and catalysis. This review highlights recent efforts in the development of Pt and non-Pt based NPs into advanced nanocatalysts for efficient oxygen reduction reaction (ORR) under fuel-cell reaction conditions. It first outlines the shape controlled synthesis of Pt NPs and their shape-dependent ORR. Then it summarizes the studies of alloy and core-shell NPs with controlled electronic (alloying) and strain (geometric) effects for tuning ORR catalysis. It further provides a brief overview of ORR catalytic enhancement with Pt-based NPs supported on graphene and coated with an ionic liquid. The review finally introduces some non-Pt NPs as a new generation of catalysts for ORR. The reported new syntheses with NP parameter-tuning capability should pave the way for future development of highly efficient catalysts for applications in fuel cells, metal-air batteries, and even in other important chemical reactions.

The 'Out of Africa' Hypothesis, Human Genetic Diversity, and Comparative Economic Development

Abstract: This research advances and empirically establishes the hypothesis that, in the course of the prehistoric exodus of Homo sapiens out of Africa, variation in migratory distance to various settlements across the globe affected genetic diversity and has had a persistent humpshaped effect on comparative economic development, reflecting the trade-off between the beneficial and the detrimental effects of diversity on productivity. While the low diversity of Native American populations and the high diversity of African populations have been detrimental for the development of these regions, the intermediate levels of diversity associated with European and Asian populations have been conducive for development. (JEL N10, N30, N50, O10, O50, Z10) Prevailing hypotheses of comparative economic development highlight various determinants of the remarkable inequality in income per capita across the globe. The significance of geographical, institutional, and cultural factors, human capital, ethnolinguistic fractionalization, colonialism, and globalization has been at the heart of a debate concerning the genesis of the astounding transformation in the pattern of comparative development over the past few centuries. While early research focused on the proximate forces that contributed to the divergence in living

Results of Initial Low-Dose Computed Tomographic Screening for Lung Cancer

Abstract: Background Lung cancer is the largest contributor to mortality from cancer. The National Lung Screening Trial (NLST) showed that screening with low-dose helical computed tomography (CT) rather than with chest radiography reduced mortality from lung cancer. We describe the screening, diagnosis, and limited treatment results from the initial round of screening in the NLST to inform and improve lung-cancer-screening programs. Methods At 33 U.S. centers, from August 2002 through April 2004, we enrolled asymptomatic participants, 55 to 74 years of age, with a history of at least 30 pack-years of smoking. The participants were randomly assigned to undergo annual screening, with the use of either low-dose CT or chest radiography, for 3 years. Nodules or other suspicious findings were classified as positive results. This article reports findings from the initial screening examination. Results A total of 53,439 eligible participants were randomly assigned to a study group (26,715 to low-dose CT and 26,724 to chest radiography); 26,309 participants (98.5%) and 26,035 (97.4%), respectively, underwent screening. A total of 7191 participants (27.3%) in the low-dose CT group and 2387 (9.2%) in the radiography group had a positive screening result; in the respective groups, 6369 participants (90.4%) and 2176 (92.7%) had at least one follow-up diagnostic procedure, including imaging in 5717 (81.1%) and 2010 (85.6%) and surgery in 297 (4.2%) and 121 (5.2%). Lung cancer was diagnosed in 292 participants (1.1%) in the low-dose CT group versus 190 (0.7%) in the radiography group (stage 1 in 158 vs. 70 participants and stage IIB to IV in 120 vs. 112). Sensitivity and specificity were 93.8% and 73.4% for low-dose CT and 73.5% and 91.3% for chest radiography, respectively. Conclusions The NLST initial screening results are consistent with the existing literature on screening by means of low-dose CT and chest radiography, suggesting that a reduction in mortality from lung cancer is achievable at U.S. screening centers that have staff experienced in chest CT. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).

Pre-colonial Ethnic Institutions and Contemporary African Development

Abstract: We investigate the role of deeply rooted pre-colonial ethnic institutions in shaping comparative regional development within African countries. We combine information on the spatial distribution of ethnicities before colonization with regional variation in contemporary economic performance, as proxied by satellite images of light density at night. We document a strong association between pre-colonial ethnic political centralization and regional development. This pattern is not driven by differences in local geographic features or by other observable ethnic-specific cultural and economic variables. The strong positive association between pre-colonial political complexity and contemporary development also holds within pairs of adjacent ethnic homelands with different legacies of pre-colonial political institutions.

Case Definitions, Diagnostic Algorithms, and Priorities in Encephalitis: Consensus Statement of the International Encephalitis Consortium

Abstract: Background Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research. Methods In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study. Results We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed. Conclusions We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.

Global shifts towards positive species interactions with increasing environmental stress

Abstract: The study of positive species interactions is a rapidly evolving field in ecology. Despite decades of research, controversy has emerged as to whether positive and negative interactions predictably shift with increasing environmental stress as hypothesised by the stress-gradient hypothesis (SGH). Here, we provide a synthesis of 727 tests of the SGH in plant communities across the globe to examine its generality across a variety of ecological factors. Our results show that plant interactions change with stress through an outright shift to facilitation (survival) or a reduction in competition (growth and reproduction). In a limited number of cases, plant interactions do not respond to stress, but they never shift towards competition with stress. These findings are consistent across stress types, plant growth forms, life histories, origins (invasive vs. native), climates, ecosystems and methodologies, though the magnitude of the shifts towards facilitation with stress is dependent on these factors. We suggest that future studies should employ standardised definitions and protocols to test the SGH, take a multi-factorial approach that considers variables such as plant traits in addition to stress, and apply the SGH to better understand how species and communities will respond to environmental change.

Observation of a new boson with mass near 125 GeV in pp collisions at $ \sqrt{s}=7 $ and 8 TeV

Abstract: A detailed description is reported of the analysis used by the CMS Collaboration in the search for the standard model Higgs boson in pp collisions at the LHC, which led to the observation of a new boson. The data sample corresponds to integrated luminosities up to 5.1 inverse femtobarns at sqrt(s) = 7 TeV, and up to 5.3 inverse femtobarns at sqrt(s) = 8 TeV. The results for five Higgs boson decay modes gamma gamma, ZZ, WW, tau tau, and bb, which show a combined local significance of 5 standard deviations near 125 GeV, are reviewed. A fit to the invariant mass of the two high resolution channels, gamma gamma and ZZ to 4 ell, gives a mass estimate of 125.3 +/- 0.4 (stat) +/- 0.5 (syst) GeV. The measurements are interpreted in the context of the standard model Lagrangian for the scalar Higgs field interacting with fermions and vector bosons. The measured values of the corresponding couplings are compared to the standard model predictions. The hypothesis of custodial symmetry is tested through the measurement of the ratio of the couplings to the W and Z bosons. All the results are consistent, within their uncertainties, with the expectations for a standard model Higgs boson.

The Genome of the Ctenophore Mnemiopsis leidyi and Its Implications for Cell Type Evolution

Abstract: An understanding of ctenophore biology is critical for reconstructing events that occurred early in animal evolution. Toward this goal, we have sequenced, assembled, and annotated the genome of the ctenophore Mnemiopsis leidyi. Our phylogenomic analyses of both amino acid positions and gene content suggest that ctenophores rather than sponges are the sister lineage to all other animals. Mnemiopsis lacks many of the genes found in bilaterian mesodermal cell types, suggesting that these cell types evolved independently. The set of neural genes in Mnemiopsis is similar to that of sponges, indicating that sponges may have lost a nervous system. These results present a newly supported view of early animal evolution that accounts for major losses and/or gains of sophisticated cell types, including nerve and muscle cells.

Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.

Abstract: Importance Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. Objective To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. Design, Setting, and Participants We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. Interventions Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. Main Outcome Measures The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. Results Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, −1.1; 95% CI, −5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. Conclusions and Relevance Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. Trial Registration clinicaltrials.gov Identifier: NCT00334828

Graphene microsheets enter cells through spontaneous membrane penetration at edge asperities and corner sites

Abstract: Understanding and controlling the interaction of graphene-based materials with cell membranes is key to the development of graphene-enabled biomedical technologies and to the management of graphene health and safety issues. Very little is known about the fundamental behavior of cell membranes exposed to ultrathin 2D synthetic materials. Here we investigate the interactions of graphene and few-layer graphene (FLG) microsheets with three cell types and with model lipid bilayers by combining coarse-grained molecular dynamics (MD), all-atom MD, analytical modeling, confocal fluorescence imaging, and electron microscopic imaging. The imaging experiments show edge-first uptake and complete internalization for a range of FLG samples of 0.5- to 10-μm lateral dimension. In contrast, the simulations show large energy barriers relative to kBT for membrane penetration by model graphene or FLG microsheets of similar size. More detailed simulations resolve this paradox by showing that entry is initiated at corners or asperities that are abundant along the irregular edges of fabricated graphene materials. Local piercing by these sharp protrusions initiates membrane propagation along the extended graphene edge and thus avoids the high energy barrier calculated in simple idealized MD simulations. We propose that this mechanism allows cellular uptake of even large multilayer sheets of micrometer-scale lateral dimension, which is consistent with our multimodal bioimaging results for primary human keratinocytes, human lung epithelial cells, and murine macrophages.

HDDM: Hierarchical Bayesian estimation of the Drift-Diffusion Model in Python.

Abstract: The diffusion model is a commonly used tool to infer latent psychological processes underlying decision making, and to link them to neural mechanisms based on reaction times. Although efficient open source software has been made available to quantitatively fit the model to data, current estimation methods require an abundance of reaction time measurements to recover meaningful parameters, and only provide point estimates of each parameter. In contrast, hierarchical Bayesian parameter estimation methods are useful for enhancing statistical power, allowing for simultaneous estimation of individual subject parameters and the group distribution that they are drawn from, while also providing measures of uncertainty in these parameters in the posterior distribution. Here, we present a novel Python-based toolbox called HDDM (hierarchical drift diffusion model), which allows fast and flexible estimation of the the drift-diffusion model and the related linear ballistic accumulator model. HDDM requires fewer data per subject / condition than non-hierarchical method, allows for full Bayesian data analysis, and can handle outliers in the data. Finally, HDDM supports the estimation of how trial-by-trial measurements (e.g. fMRI) influence decision making parameters. This paper will first describe the theoretical background of drift-diffusion model and Bayesian inference. We then illustrate usage of the toolbox on a real-world data set from our lab. Finally, parameter recovery studies show that HDDM beats alternative fitting methods like the chi-quantile method as well as maximum likelihood estimation. The software and documentation can be downloaded at: http://ski.clps.brown.edu/hddm_docs

SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs)

Abstract: New technologies enabling genome-wide interrogation have led to a large and rapidly growing number of autism spectrum disorder (ASD) candidate genes. Although encouraging, the volume and complexity of these data make it challenging for scientists, particularly non-geneticists, to comprehensively evaluate available evidence for individual genes. Described here is the Gene Scoring module within SFARI Gene 2.0 (https://gene.sfari.org/autdb/GS_Home.do), a platform developed to enable systematic community driven assessment of genetic evidence for individual genes with regard to ASD.

Do healthier foods and diet patterns cost more than less healthy options? A systematic review and meta-analysis.

Abstract: Objective To conduct a systematic review and meta-analysis of prices of healthier versus less healthy foods/diet patterns while accounting for key sources of heterogeneity. Data sources MEDLINE (2000–2011), supplemented with expert consultations and hand reviews of reference lists and related citations. Design Studies reviewed independently and in duplicate were included if reporting mean retail price of foods or diet patterns stratified by healthfulness. We extracted, in duplicate, mean prices and their uncertainties of healthier and less healthy foods/diet patterns and rated the intensity of health differences for each comparison (range 1–10). Prices were adjusted for inflation and the World Bank purchasing power parity, and standardised to the international dollar (defined as US$1) in 2011. Using random effects models, we quantified price differences of healthier versus less healthy options for specific food types, diet patterns and units of price (serving, day and calorie). Statistical heterogeneity was quantified using I 2 statistics. Results 27 studies from 10 countries met the inclusion criteria. Among food groups, meats/protein had largest price differences: healthier options cost $0.29/serving (95% CI $0.19 to $0.40) and $0.47/200 kcal ($0.42 to $0.53) more than less healthy options. Price differences per serving for healthier versus less healthy foods were smaller among grains ($0.03), dairy (−$0.004), snacks/sweets ($0.12) and fats/oils ($0.02; p Conclusions This meta-analysis provides the best evidence until today of price differences of healthier vs less healthy foods/diet patterns, highlighting the challenges and opportunities for reducing financial barriers to healthy eating.