Showing papers by "Columbia University published in 2010"

Atomically thin MoS2: a new direct-gap semiconductor

Abstract: The electronic properties of ultrathin crystals of molybdenum disulfide consisting of N=1,2,…,6 S-Mo-S monolayers have been investigated by optical spectroscopy Through characterization by absorption, photoluminescence, and photoconductivity spectroscopy, we trace the effect of quantum confinement on the material's electronic structure With decreasing thickness, the indirect band gap, which lies below the direct gap in the bulk material, shifts upwards in energy by more than 06 eV This leads to a crossover to a direct-gap material in the limit of the single monolayer Unlike the bulk material, the MoS₂ monolayer emits light strongly The freestanding monolayer exhibits an increase in luminescence quantum efficiency by more than a factor of 10⁴ compared with the bulk material

Boron nitride substrates for high-quality graphene electronics

Abstract: Graphene devices on standard SiO(2) substrates are highly disordered, exhibiting characteristics that are far inferior to the expected intrinsic properties of graphene. Although suspending the graphene above the substrate leads to a substantial improvement in device quality, this geometry imposes severe limitations on device architecture and functionality. There is a growing need, therefore, to identify dielectrics that allow a substrate-supported geometry while retaining the quality achieved with a suspended sample. Hexagonal boron nitride (h-BN) is an appealing substrate, because it has an atomically smooth surface that is relatively free of dangling bonds and charge traps. It also has a lattice constant similar to that of graphite, and has large optical phonon modes and a large electrical bandgap. Here we report the fabrication and characterization of high-quality exfoliated mono- and bilayer graphene devices on single-crystal h-BN substrates, by using a mechanical transfer process. Graphene devices on h-BN substrates have mobilities and carrier inhomogeneities that are almost an order of magnitude better than devices on SiO(2). These devices also show reduced roughness, intrinsic doping and chemical reactivity. The ability to assemble crystalline layered materials in a controlled way permits the fabrication of graphene devices on other promising dielectrics and allows for the realization of more complex graphene heterostructures.

Transcatheter Aortic-Valve Implantation for Aortic Stenosis in Patients Who Cannot Undergo Surgery

Abstract: Background Many patients with severe aortic stenosis and coexisting conditions are not candi dates for surgical replacement of the aortic valve. Recently, transcatheter aortic-valve implantation (TAVI) has been suggested as a less invasive treatment for high-risk patients with aortic stenosis. Methods We randomly assigned patients with severe aortic stenosis, whom surgeons considered not to be suitable candidates for surgery, to standard therapy (including balloon aortic valvuloplasty) or transfemoral transcatheter implantation of a balloon-expandable bovine pericardial valve. The primary end point was the rate of death from any cause. Results A total of 358 patients with aortic stenosis who were not considered to be suitable candidates for surgery underwent randomization at 21 centers (17 in the United States). At 1 year, the rate of death from any cause (Kaplan–Meier analysis) was 30.7% with TAVI, as compared with 50.7% with standard therapy (hazard ratio with TAVI, 0.55; 95% confidence interval [CI], 0.40 to 0.74; P<0.001). The rate of the composite end point of death from any cause or repeat hospitalization was 42.5% with TAVI as com pared with 71.6% with standard therapy (hazard ratio, 0.46; 95% CI, 0.35 to 0.59; P<0.001). Among survivors at 1 year, the rate of cardiac symptoms (New York Heart Association class III or IV) was lower among patients who had undergone TAVI than among those who had received standard therapy (25.2% vs. 58.0%, P<0.001). At 30 days, TAVI, as compared with standard therapy, was associated with a higher incidence of major strokes (5.0% vs. 1.1%, P = 0.06) and major vascular complications (16.2% vs. 1.1%, P<0.001). In the year after TAVI, there was no deterioration in the functioning of the bioprosthetic valve, as assessed by evidence of stenosis or regurgitation on an echocardiogram. Conclusions In patients with severe aortic stenosis who were not suitable candidates for surgery, TAVI, as compared with standard therapy, significantly reduced the rates of death from any cause, the composite end point of death from any cause or repeat hospitalization, and cardiac symptoms, despite the higher incidence of major strokes and major vascular events. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.)

Early Palliative Care for Patients with Metastatic Non–Small-Cell Lung Cancer

Abstract: Background Patients with metastatic non–small-cell lung cancer have a substantial symptom burden and may receive aggressive care at the end of life. We examined the effect of introducing palliative care early after diagnosis on patient-reported outcomes and end-of-life care among ambulatory patients with newly diagnosed disease. Methods We randomly assigned patients with newly diagnosed metastatic non–small-cell lung cancer to receive either early palliative care integrated with standard oncologic care or standard oncologic care alone. Quality of life and mood were assessed at baseline and at 12 weeks with the use of the Functional Assessment of Cancer Therapy–Lung (FACT-L) scale and the Hospital Anxiety and Depression Scale, respectively. The primary outcome was the change in the quality of life at 12 weeks. Data on end-of-life care were collected from electronic medical records. Results Of the 151 patients who underwent randomization, 27 died by 12 weeks and 107 (86% of the remaining patients) completed assessments. Patients assigned to early palliative care had a better quality of life than did patients assigned to standard care (mean score on the FACT-L scale [in which scores range from 0 to 136, with higher scores indicating better quality of life], 98.0 vs. 91.5; P = 0.03). In addition, fewer patients in the palliative care group than in the standard care group had depressive symptoms (16% vs. 38%, P = 0.01). Despite the fact that fewer patients in the early palliative care group than in the standard care group received aggressive end-of-life care (33% vs. 54%, P = 0.05), median survival was longer among patients receiving early palliative care (11.6 months vs. 8.9 months, P = 0.02). Conclusions Among patients with metastatic non–small-cell lung cancer, early palliative care led to significant improvements in both quality of life and mood. As compared with patients receiving standard care, patients receiving early palliative care had less aggressive care at the end of life but longer survival. (Funded by an American Society of Clinical Oncology Career Development Award and philanthropic gifts; ClinicalTrials.gov number, NCT01038271.)

Improved side‐chain torsion potentials for the Amber ff99SB protein force field

Abstract: Recent advances in hardware and software have enabled increasingly long molecular dynamics (MD) simulations of biomolecules, exposing certain limitations in the accuracy of the force fields used for such simulations and spurring efforts to refine these force fields. Recent modifications to the Amber and CHARMM protein force fields, for example, have improved the backbone torsion potentials, remedying deficiencies in earlier versions. Here, we further advance simulation accuracy by improving the amino acid side-chain torsion potentials of the Amber ff99SB force field. First, we used simulations of model alpha-helical systems to identify the four residue types whose rotamer distribution differed the most from expectations based on Protein Data Bank statistics. Second, we optimized the side-chain torsion potentials of these residues to match new, high-level quantum-mechanical calculations. Finally, we used microsecond-timescale MD simulations in explicit solvent to validate the resulting force field against a large set of experimental NMR measurements that directly probe side-chain conformations. The new force field, which we have termed Amber ff99SB-ILDN, exhibits considerably better agreement with the NMR data. Proteins 2010. © 2010 Wiley-Liss, Inc.

Anomalous lattice vibrations of single- and few-layer MoS2.

Abstract: Molybdenum disulfide (MoS2) of single- and few-layer thickness was exfoliated on SiO2/Si substrate and characterized by Raman spectroscopy. The number of S−Mo−S layers of the samples was independently determined by contact-mode atomic force microscopy. Two Raman modes, E12g and A1g, exhibited sensitive thickness dependence, with the frequency of the former decreasing and that of the latter increasing with thickness. The results provide a convenient and reliable means for determining layer thickness with atomic-level precision. The opposite direction of the frequency shifts, which cannot be explained solely by van der Waals interlayer coupling, is attributed to Coulombic interactions and possible stacking-induced changes of the intralayer bonding. This work exemplifies the evolution of structural parameters in layered materials in changing from the three-dimensional to the two-dimensional regime.

Biological, clinical and population relevance of 95 loci for blood lipids

Abstract: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Effects of intensive blood-pressure control in type 2 diabetes mellitus.

Abstract: After 1 year, the mean systolic blood pressure was 1193 mm Hg in the intensivetherapy group and 1335 mm Hg in the standard-therapy group The annual rate of the primary outcome was 187% in the intensive-therapy group and 209% in the standard-therapy group (hazard ratio with intensive therapy, 088; 95% confidence interval [CI], 073 to 106; P = 020) The annual rates of death from any cause were 128% and 119% in the two groups, respectively (hazard ratio, 107; 95% CI, 085 to 135; P = 055) The annual rates of stroke, a prespecified secondary outcome, were 032% and 053% in the two groups, respectively (hazard ratio, 059; 95% CI, 039 to 089; P = 001) Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (33%) and 30 of the 2371 participants in the standard-therapy group (13%) (P<0001) Conclusions In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events (ClinicalTrialsgov number, NCT00000620)

Review of Particle Physics

Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions, plus 2158 new measurements from 551 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on neutrino mass, mixing, and oscillations, QCD, top quark, CKM quark-mixing matrix, V-ud & V-us, V-cb & V-ub, fragmentation functions, particle detectors for accelerator and non-accelerator physics, magnetic monopoles, cosmological parameters, and big bang cosmology.

Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis

Abstract: For 2502 patients over a median follow-up period of 2.5 years, there was no significant difference in the estimated 4-year rates of the primary end point between the stenting group and the endarterectomy group (7.2% and 6.8%, respectively; hazard ratio with stenting, 1.11; 95% confidence interval, 0.81 to 1.51; P = 0.51). There was no differential treatment effect with regard to the primary end point according to symptomatic status (P = 0.84) or sex (P = 0.34). The 4-year rate of stroke or death was 6.4% with stenting and 4.7% with endarterectomy (hazard ratio, 1.50; P = 0.03); the rates among symptomatic patients were 8.0% and 6.4% (hazard ratio, 1.37; P = 0.14), and the rates among asymptomatic patients were 4.5% and 2.7% (hazard ratio, 1.86; P = 0.07), respectively. Periprocedural rates of individual components of the end points differed between the stenting group and the endarterectomy group: for death (0.7% vs. 0.3%, P = 0.18), for stroke (4.1% vs. 2.3%, P = 0.01), and for myocardial infarction (1.1% vs. 2.3%, P = 0.03). After this period, the incidences of ipsilateral stroke with stenting and with endarterectomy were similarly low (2.0% and 2.4%, respectively; P = 0.85). CONCLUSIONS Among patients with symptomatic or asymptomatic carotid stenosis, the risk of the composite primary outcome of stroke, myocardial infarction, or death did not differ significantly in the group undergoing carotid-artery stenting and the group undergoing carotid endarterectomy. During the periprocedural period, there was a higher risk of stroke with stenting and a higher risk of myocardial infarction with endarterectomy. (ClinicalTrials.gov number, NCT00004732.)

Global fire emissions and the contribution of deforestation, savanna, forest, agricultural, and peat fires (1997-2009)

Abstract: . New burned area datasets and top-down constraints from atmospheric concentration measurements of pyrogenic gases have decreased the large uncertainty in fire emissions estimates. However, significant gaps remain in our understanding of the contribution of deforestation, savanna, forest, agricultural waste, and peat fires to total global fire emissions. Here we used a revised version of the Carnegie-Ames-Stanford-Approach (CASA) biogeochemical model and improved satellite-derived estimates of area burned, fire activity, and plant productivity to calculate fire emissions for the 1997–2009 period on a 0.5° spatial resolution with a monthly time step. For November 2000 onwards, estimates were based on burned area, active fire detections, and plant productivity from the MODerate resolution Imaging Spectroradiometer (MODIS) sensor. For the partitioning we focused on the MODIS era. We used maps of burned area derived from the Tropical Rainfall Measuring Mission (TRMM) Visible and Infrared Scanner (VIRS) and Along-Track Scanning Radiometer (ATSR) active fire data prior to MODIS (1997–2000) and estimates of plant productivity derived from Advanced Very High Resolution Radiometer (AVHRR) observations during the same period. Average global fire carbon emissions according to this version 3 of the Global Fire Emissions Database (GFED3) were 2.0 Pg C year−1 with significant interannual variability during 1997–2001 (2.8 Pg C year−1 in 1998 and 1.6 Pg C year−1 in 2001). Globally, emissions during 2002–2007 were relatively constant (around 2.1 Pg C year−1) before declining in 2008 (1.7 Pg C year−1) and 2009 (1.5 Pg C year−1) partly due to lower deforestation fire emissions in South America and tropical Asia. On a regional basis, emissions were highly variable during 2002–2007 (e.g., boreal Asia, South America, and Indonesia), but these regional differences canceled out at a global level. During the MODIS era (2001–2009), most carbon emissions were from fires in grasslands and savannas (44%) with smaller contributions from tropical deforestation and degradation fires (20%), woodland fires (mostly confined to the tropics, 16%), forest fires (mostly in the extratropics, 15%), agricultural waste burning (3%), and tropical peat fires (3%). The contribution from agricultural waste fires was likely a lower bound because our approach for measuring burned area could not detect all of these relatively small fires. Total carbon emissions were on average 13% lower than in our previous (GFED2) work. For reduced trace gases such as CO and CH4, deforestation, degradation, and peat fires were more important contributors because of higher emissions of reduced trace gases per unit carbon combusted compared to savanna fires. Carbon emissions from tropical deforestation, degradation, and peatland fires were on average 0.5 Pg C year−1. The carbon emissions from these fires may not be balanced by regrowth following fire. Our results provide the first global assessment of the contribution of different sources to total global fire emissions for the past decade, and supply the community with an improved 13-year fire emissions time series.

Effects of combination lipid therapy in type 2 diabetes mellitus.

Abstract: Methods We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. Results The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P = 0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P = 0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P = 0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P = 0.057 for interaction). Conclusions The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women

Abstract: The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.

Social Conditions as Fundamental Causes of Health Inequalities Theory, Evidence, and Policy Implications

Abstract: Link and Phelan (1995) developed the theory of fundamental causes to explain why the association between socioeconomic status (SES) and mortality has persisted despite radical changes in the diseases and risk factors that are presumed to explain it. They proposed that the enduring association results because SES embodies an array of resources, such as money, knowledge, prestige, power, and beneficial social connections that protect health no matter what mechanisms are relevant at any given time. In this article, we explicate the theory, review key findings, discuss refinements and limits to the theory, and discuss implications for health policies that might reduce health inequalities. We advocate policies that encourage medical and other health-promoting advances while at the same time breaking or weakening the link between these advances and socioeconomic resources. This can be accomplished either by reducing disparities in socioeconomic resources themselves or by developing interventions that, by their nature, are more equally distributed across SES groups.

Atomic-Level Characterization of the Structural Dynamics of Proteins

Abstract: Molecular dynamics (MD) simulations are widely used to study protein motions at an atomic level of detail, but they have been limited to time scales shorter than those of many biologically critical conformational changes. We examined two fundamental processes in protein dynamics—protein folding and conformational change within the folded state—by means of extremely long all-atom MD simulations conducted on a special-purpose machine. Equilibrium simulations of a WW protein domain captured multiple folding and unfolding events that consistently follow a well-defined folding pathway; separate simulations of the protein’s constituent substructures shed light on possible determinants of this pathway. A 1-millisecond simulation of the folded protein BPTI reveals a small number of structurally distinct conformational states whose reversible interconversion is slower than local relaxations within those states by a factor of more than 1000.

The Cement of Society: A Survey of Social Order

Abstract: Preface and acknowledgements Introduction: the two problems of social order 1. Collective action 2. Bargaining 3. Social norms 4. Bargaining and collective action 5. Collective action and social norms 6. Bargaining and social norms Conclusion: the cement of society References Index.

Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites

Abstract: mirSVR is a new machine learning method for ranking microRNA target sites by a down-regulation score. The algorithm trains a regression model on sequence and contextual features extracted from miRanda-predicted target sites. In a large-scale evaluation, miRanda-mirSVR is competitive with other target prediction methods in identifying target genes and predicting the extent of their downregulation at the mRNA or protein levels. Importantly, the method identifies a significant number of experimentally determined non-canonical and non-conserved sites.

Frictional Characteristics of Atomically Thin Sheets

Abstract: Using friction force microscopy, we compared the nanoscale frictional characteristics of atomically thin sheets of graphene, molybdenum disulfide (MoS2), niobium diselenide, and hexagonal boron nitride exfoliated onto a weakly adherent substrate (silicon oxide) to those of their bulk counterparts. Measurements down to single atomic sheets revealed that friction monotonically increased as the number of layers decreased for all four materials. Suspended graphene membranes showed the same trend, but binding the graphene strongly to a mica surface suppressed the trend. Tip-sample adhesion forces were indistinguishable for all thicknesses and substrate arrangements. Both graphene and MoS2 exhibited atomic lattice stick-slip friction, with the thinnest sheets possessing a sliding-length-dependent increase in static friction. These observations, coupled with finite element modeling, suggest that the trend arises from the thinner sheets' increased susceptibility to out-of-plane elastic deformation. The generality of the results indicates that this may be a universal characteristic of nanoscale friction for atomically thin materials weakly bound to substrates.

Error Correction, Sensory Prediction, and Adaptation in Motor Control

Abstract: Motor control is the study of how organisms make accurate goal-directed movements. Here we consider two problems that the motor system must solve in order to achieve such control. The first problem is that sensory feedback is noisy and delayed, which can make movements inaccurate and unstable. The second problem is that the relationship between a motor command and the movement it produces is variable, as the body and the environment can both change. A solution is to build adaptive internal models of the body and the world. The predictions of these internal models, called forward models because they transform motor commands into sensory consequences, can be used to both produce a lifetime of calibrated movements, and to improve the ability of the sensory system to estimate the state of the body and the world around it. Forward models are only useful if they produce unbiased predictions. Evidence shows that forward models remain calibrated through motor adaptation: learning driven by sensory prediction errors.

Microaggressions in Everyday Life: Race, Gender, and Sexual Orientation

Abstract: Foreword Preface Acknowledgments About the Author SECTION ONE: PSYCHOLOGICAL MANIFESTATION AND DYNAMICS OFMICROAGGRESSIONS CHAPTER ONE: The Manifestation of Racial, Gender, andSexual-Orientation Microaggressions CHAPTER TWO: Taxonomy of Microaggressions CHAPTER THREE: The Psychological Dilemmas and Dynamics ofMicroaggressions SECTION TWO: MICROAGGRESSIVE IMPACT ON TARGETS ANDPERPETRATORS CHAPTER FOUR: The Microaggression Process Model: From Beginningto End CHAPTER FIVE: Microaggressive Stress: Impact on Physical andMental Health CHAPTER SIX: Microaggressive Perpetrators and Oppression: TheNature of the Beast SECTION THREE: GROUP-SPECIFIC MICROAGGRESSIONS: RACE, GENDER,AND SEXUAL ORIENTATION CHAPTER SEVEN: Racial/Ethnic Microaggressions and Racism CHAPTER EIGHT: Gender Microaggressions and Sexism CHAPTER NINE: Sexual-Orientation Microaggressions andHeterosexism SECTION FOUR: MICROAGGRESSIONS IN EMPLOYMENT, EDUCATION, ANDMENTAL HEALTH PRACTICE CHAPTER TEN: Microaggressive Impact in the Workplace andEmployment CHAPTER ELEVEN: Microaggressive Impact on Education andTeaching: Facilitating Diffi cult Dialogues on Race in theClassroom CHAPTER TWELVE: Microaggressive Impact on Mental HealthPractice References Index

Lipoprotein(a) as a cardiovascular risk factor: current status

Abstract: AIMS: The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies. METHODS AND RESULTS: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated Lp(a), recurrent CVD despite statin treatment, ≥3% 10-year risk of fatal CVD according to European guidelines, and/or ≥10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for Lp(a) <80th percentile (less than ∼50 mg/dL). Treatment should primarily be niacin 1-3 g/day, as a meta-analysis of randomized, controlled intervention trials demonstrates reduced CVD by niacin treatment. In extreme cases, LDL-apheresis is efficacious in removing Lp(a). CONCLUSION: We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level <50 mg/dL as a function of global cardiovascular risk, and use of niacin for Lp(a) and CVD/CHD risk reduction.

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy

Abstract: Summary Purpose: We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy Methods: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation Results: One hundred ten participants were randomized Baseline monthly median seizure frequency was 195 In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0002) Unadjusted median declines at the end of the blinded phase were 145% in the control group and 404% in the stimulated group Complex partial and “most severe” seizures were significantly reduced by stimulation By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months Five deaths occurred and none were from implantation or stimulation No participant had symptomatic hemorrhage or brain infection Two participants had acute, transient stimulation-associated seizures Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events Discussion: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures Benefit persisted for 2 years of study Complication rates were modest Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures

PINK1-dependent recruitment of Parkin to mitochondria in mitophagy

Abstract: Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARK2/Parkin mutations cause autosomal recessive forms of Parkinson's disease. Upon a loss of mitochondrial membrane potential (DeltaPsi(m)) in human cells, cytosolic Parkin has been reported to be recruited to mitochondria, which is followed by a stimulation of mitochondrial autophagy. Here, we show that the relocation of Parkin to mitochondria induced by a collapse of DeltaPsi(m) relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal DeltaPsi(m). We also show that once at the mitochondria, Parkin is in close proximity to PINK1, but we find no evidence that Parkin catalyzes PINK1 ubiquitination or that PINK1 phosphorylates Parkin. However, co-overexpression of Parkin and PINK1 collapses the normal tubular mitochondrial network into mitochondrial aggregates and/or large perinuclear clusters, many of which are surrounded by autophagic vacuoles. Our results suggest that Parkin, together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy. Thus by impairing this process, mutations in either Parkin or PINK1 may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson's disease.

Predicting Survival in Pulmonary Arterial Hypertension Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL)

Abstract: Background— Factors that determine survival in pulmonary arterial hypertension (PAH) drive clinical management. A quantitative survival prediction tool has not been established for research or clinical use. Methods and Results— Data from 2716 patients with PAH enrolled consecutively in the US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) were analyzed to assess predictors of 1-year survival. We identified independent prognosticators of survival and derived a multivariable, weighted risk formula for clinical use. One-year survival from the date of enrollment was 91.0% (95% confidence interval [CI], 89.9 to 92.1). In a multivariable analysis with Cox proportional hazards, variables independently associated with increased mortality included pulmonary vascular resistance >32 Wood units (hazard ratio [HR], 4.1; 95% CI, 2.0 to 8.3), PAH associated with portal hypertension (HR, 3.6; 95% CI, 2.4 to 5.4), modified New York Heart Association/World Health Organization functional class IV (HR, 3.1; 95% CI, 2.2 to 4.4), men >60 years of age (HR, 2.2; 95% CI, 1.6 to 3.0), and family history of PAH (HR, 2.2; 95% CI, 1.2 to 4.0). Renal insufficiency, PAH associated with connective tissue disease, functional class III, mean right atrial pressure, resting systolic blood pressure and heart rate, 6-minute walk distance, brain natriuretic peptide, percent predicted carbon monoxide diffusing capacity, and pericardial effusion on echocardiogram all predicted mortality. Based on these multivariable analyses, a prognostic equation was derived and validated by bootstrapping technique. Conclusions— We identified key predictors of survival based on the patient’s most recent evaluation and formulated a contemporary prognostic equation. Use of this tool may allow the individualization and optimization of therapeutic strategies. Serial follow-up and reassessment are warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214.

Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia

Abstract: Blood disorders caused by abnormal β-globin — β-thalassaemia and sickle cell disease — are the most prevalent inherited disorders worldwide, with patients often remaining dependent on blood transfusions throughout their lives So a report of the successful use of gene therapy in a case of severe β-thalassaemia — using a lentiviral vector expressing the β-globin gene — is an eagerly awaited event More than two years after gene transfer, the adult male patient has been transfusion-independent for 21 months The therapeutic benefit seems to result from a dominant, myeloid-biased cell clone that may remain benign, although it could yet develop into leukaemia — a reminder that gene therapy is still at an early stage Disorders caused by abnormal β-globin, such as β-thalassaemia, are the most prevalent inherited disorders worldwide For treatment, many patients are dependent on blood transfusions; thus far the only cure has involved matched transplantation of haematopoietic stem cells Here it is shown that lentiviral β-globin gene transfer can be an effective substitute for regular transfusions in a patient with severe β-thalassaemia The β-haemoglobinopathies are the most prevalent inherited disorders worldwide Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells Compound βE/β0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1,2 The βE-globin allele bears a point mutation that causes alternative splicing The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated βE-globin with partial instability1,2 When this is compounded with a non-functional β0 allele, a profound decrease in β-globin synthesis results, and approximately half of βE/β0-thalassaemia patients are transfusion-dependent1,2 The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months Blood haemoglobin is maintained between 9 and 10 g dl−1, of which one-third contains vector-encoded β-globin Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells

Does Algorithmic Trading Improve Liquidity

Abstract: Algorithmic trading has sharply increased over the past decade Does it improve market quality, and should it be encouraged? We provide the first analysis of this question The NYSE automated quote dissemination in 2003, and we use this change in market structure that increases algorithmic trading as an exogenous instrument to measure the causal effect of algorithmic trading on liquidity For large stocks in particular, algorithmic trading narrows spreads, reduces adverse selection, and reduces trade-related price discovery The findings indicate that algorithmic trading improves liquidity and enhances the informativeness of quotes

How Big is a Big Odds Ratio? Interpreting the Magnitudes of Odds Ratios in Epidemiological Studies

Abstract: The odds ratio (OR) is probably the most widely used index of effect size in epidemiological studies. The difficulty of interpreting the OR has troubled many clinical researchers and epidemiologists for a long time. We propose a new method for interpreting the size of the OR by relating it to differences in a normal standard deviate. Our calculations indicate that OR = 1.68, 3.47, and 6.71 are equivalent to Cohen's d = 0.2 (small), 0.5 (medium), and 0.8 (large), respectively, when disease rate is 1% in the nonexposed group; Cohen's d 0.8 when OR > 5.

Deforestation driven by urban population growth and agricultural trade in the twenty-first century

Abstract: Reducing tropical deforestation is at present considered a cost-effective option for mitigating climate change. Satellite-based estimates of forest loss suggest that urban population growth and urban and international demand for agricultural products are key drivers of deforestation in the tropics. Reducing atmospheric carbon emissions from tropical deforestation is at present considered a cost-effective option for mitigating climate change. However, the forces associated with tropical forest loss are uncertain1. Here we use satellite-based estimates of forest loss for 2000 to 2005 (ref. 2) to assess economic, agricultural and demographic correlates across 41 countries in the humid tropics. Two methods of analysis—linear regression and regression tree—show that forest loss is positively correlated with urban population growth and exports of agricultural products for this time period. Rural population growth is not associated with forest loss, indicating the importance of urban-based and international demands for agricultural products as drivers of deforestation. The strong trend in movement of people to cities in the tropics is, counter-intuitively, likely to be associated with greater pressures for clearing tropical forests. We therefore suggest that policies to reduce deforestation among local, rural populations will not address the main cause of deforestation in the future. Rather, efforts need to focus on reducing deforestation for industrial-scale, export-oriented agricultural production, concomitant with efforts to increase yields in non-forested lands to satisfy demands for agricultural products.