Showing papers by "University of Texas Southwestern Medical Center published in 2014"

Angiotensin-neprilysin inhibition versus enalapril in heart failure.

Abstract: Background We compared the angiotensin receptor–neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. Methods In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. Results The trial was stopped early, according to prespecified rules, after a median followup of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P = 0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. Conclusions LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.)

Comprehensive molecular characterization of urothelial bladder carcinoma

Abstract: Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsThis paper is distributed under the terms of the Creative Commons. Attribution-Non-Commercial-Share Alike license, and the online version of the paper is freely available to all readers.

Defining the clinical course of multiple sclerosis: The 2013 revisions

Abstract: Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

The bone marrow niche for haematopoietic stem cells

Abstract: Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.

Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs

Abstract: Importance Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials. Objectives To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival. Design, Setting, and Participants From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival. Interventions Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies. Main Outcomes and Measures Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival. Results From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR , 122 (17%); ALK rearrangements, 57 (8%); other EGFR , 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2 ), 19 (3%); BRAF , 16 (2%); PIK3CA , 6 ( MET amplification, 5 ( NRAS , 5 ( MEK1 , 1 ( AKT1 , 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score–adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006). Conclusions and Relevance Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival. Trial Registration clinicaltrials.gov Identifier:NCT01014286.

Management of Sickle Cell Disease: Summary of the 2014 Evidence-Based Report by Expert Panel Members

Abstract: Importance Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100 000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused. Objective To support and expand the number of health professionals able and willing to provide care for persons with SCD. Evidence Review Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists. Findings Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (≥200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated. Conclusions and Relevance Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD.

HDL Cholesterol Efflux Capacity and Incident Cardiovascular Events

Abstract: Background It is unclear whether high-density lipoprotein (HDL) cholesterol concentration plays a causal role in atherosclerosis. A more important factor may be HDL cholesterol efflux capacity, the ability of HDL to accept cholesterol from macrophages, which is a key step in reverse cholesterol transport. We investigated the epidemiology of cholesterol efflux capacity and its association with incident atherosclerotic cardiovascular disease outcomes in a large, multiethnic population cohort. Methods We measured HDL cholesterol level, HDL particle concentration, and cholesterol efflux capacity at baseline in 2924 adults free from cardiovascular disease who were participants in the Dallas Heart Study, a probability-based population sample. The primary end point was atherosclerotic cardiovascular disease, defined as a first nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization or death from cardiovascular causes. The median follow-up period was 9.4 years. Results In contrast to HDL ch...

Transcriptional landscape of the prenatal human brain

Abstract: The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.

Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia

Abstract: BACKGROUND Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR–ABL1–positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6–NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.)

Primary age-related tauopathy (PART): a common pathology associated with human aging

Abstract: We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.

Abstract: Helen Hobbs, Jonathan Cohen and colleagues identify a nonsynonymous variant in TM6SF2 associated with susceptibility to nonalcoholic fatty acid liver disease. They further show that knockdown of Tm6sf2 in mice results in increased liver triglyceride content and reduced very-low-density lipoprotein (VLDL) secretion, suggesting that impaired TM6SF2 function contributes causally to disease risk.

Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children.

Abstract: The pseudotumor cerebri syndrome (PTCS) may be primary (idiopathic intracranial hypertension) or arise from an identifiable secondary cause. Characterization of typical neuroimaging abnormalities, clarification of normal opening pressure in children, and features distinguishing the syndrome of intracranial hypertension without papilledema from intracranial hypertension with papilledema have furthered our understanding of this disorder. We propose updated diagnostic criteria for PTCS to incorporate advances and insights into the disorder realized over the past 10 years.

A comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium

Abstract: We present primary results from the Sequencing Quality Control (SEQC) project, coordinated by the US Food and Drug Administration. Examining Illumina HiSeq, Life Technologies SOLiD and Roche 454 platforms at multiple laboratory sites using reference RNA samples with built-in controls, we assess RNA sequencing (RNA-seq) performance for junction discovery and differential expression profiling and compare it to microarray and quantitative PCR (qPCR) data using complementary metrics. At all sequencing depths, we discover unannotated exon-exon junctions, with >80% validated by qPCR. We find that measurements of relative expression are accurate and reproducible across sites and platforms if specific filters are used. In contrast, RNA-seq and microarrays do not provide accurate absolute measurements, and gene-specific biases are observed for all examined platforms, including qPCR. Measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling. The complete SEQC data sets, comprising >100 billion reads (10Tb), provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings.

Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis

Abstract: Liver cirrhosis is a major yet largely preventable and underappreciated cause of global health loss. Variations in cirrhosis mortality at the country level reflect differences in prevalence of risk factors such as alcohol use and hepatitis B and C infection. We estimated annual age-specific mortality from liver cirrhosis in 187 countries between 1980 and 2010. We systematically collected vital registration and verbal autopsy data on liver cirrhosis mortality for the period 1980 to 2010. We corrected for misclassification of deaths, which included deaths attributed to improbable or nonfatal causes. We used ensemble models to estimate liver cirrhosis mortality with uncertainty by age, sex, country and year. We used out-of-sample predictive validity to select the optimal model. Global liver cirrhosis deaths increased from around 676,000 (95% uncertainty interval: 452,863 to 1,004,530) in 1980 to over 1 million (1,029,042; 670,216 to 1,554,530) in 2010 (about 2% of the global total). Over the same period, the age-standardized cirrhosis mortality rate decreased by 22%. This was largely driven by decreasing cirrhosis mortality rates in China, the US and countries in Western Europe. In 2010, Egypt, followed by Moldova, had the highest age-standardized cirrhosis mortality rates, 72.7 and 71.2 deaths per 100,000, respectively, while Iceland had the lowest. In Egypt, almost one-fifth (18.1%) of all deaths in males 45- to 54-years old were due to liver cirrhosis. Liver cirrhosis mortality in Mexico is the highest in Latin America. In France and Italy, liver cirrhosis mortality fell by 50% to 60%; conversely, in the United Kingdom, mortality increased by about one-third. Mortality from liver cirrhosis was also comparatively high in Central Asia countries, particularly Mongolia, Uzbekistan and Kyrgyzstan, and in parts of sub-Saharan Africa, notably Gabon. Liver cirrhosis is a significant cause of global health burden, with more than one million deaths in 2010. Our study identifies areas with high and/or rapidly increasing mortality where preventive measures to control and reduce liver cirrhosis risk factors should be urgently strengthened. Please see related commentary: http://www.biomedcentral.com/1741-7015/12/159/abstract .

Enhancement of oxidative and drought tolerance in Arabidopsis by overaccumulation of antioxidant flavonoids

Abstract: The notion that plants use specialized metabolism to protect against environmental stresses needs to be experimentally proven by addressing the question of whether stress tolerance by specialized metabolism is directly due to metabolites such as flavonoids. We report that flavonoids with radical scavenging activity mitigate against oxidative and drought stress in Arabidopsis thaliana. Metabolome and transcriptome profiling and experiments with oxidative and drought stress in wild-type, single overexpressors of MYB12/PFG1 (PRODUCTION OF FLAVONOL GLYCOSIDES1) or MYB75/PAP1 (PRODUCTION OF ANTHOCYANIN PIGMENT1), double overexpressors of MYB12 and PAP1, transparent testa4 (tt4) as a flavonoid-deficient mutant, and flavonoid-deficient MYB12 or PAP1 overexpressing lines (obtained by crossing tt4 and the individual MYB overexpressor) demonstrated that flavonoid overaccumulation was key to enhanced tolerance to such stresses. Antioxidative activity assays using 2,2-diphenyl-1-picrylhydrazyl, methyl viologen, and 3,3'-diaminobenzidine clearly showed that anthocyanin overaccumulation with strong in vitro antioxidative activity mitigated the accumulation of reactive oxygen species in vivo under oxidative and drought stress. These data confirm the usefulness of flavonoids for enhancing both biotic and abiotic stress tolerance in crops.

Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity

Abstract: The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.

International Consensus on drug allergy.

Abstract: When drug reactions resembling allergy occur, they are called drug hypersensitivity reactions (DHRs) before showing the evidence of either drug-specific antibodies or T cells. DHRs may be allergic or nonallergic in nature, with drug allergies being immunologically mediated DHRs. These reactions are typically unpredictable. They can be life-threatening, may require or prolong hospitalization, and may necessitate changes in subsequent therapy. Both underdiagnosis (due to under-reporting) and overdiagnosis (due to an overuse of the term ‘allergy’) are common. A definitive diagnosis of such reactions is required in order to institute adequate treatment options and proper preventive measures. Misclassification based solely on the DHR history without further testing may affect treatment options, result in adverse consequences, and lead to the use of more-expensive or less-effective drugs, in contrast to patients who had undergone a complete drug allergy workup. Several guidelines and/or consensus documents on general or specific drug class-induced DHRs are available to support the medical decision process. The use of standardized systematic approaches for the diagnosis and management of DHRs carries the potential to improve outcomes and should thus be disseminated and implemented. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), formed by the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), and the World Allergy Organization (WAO), has decided to issue an International CONsensus (ICON) on drug allergy. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences and deficiencies of evidence, thus providing a comprehensive reference document for the diagnosis and management of DHRs.

Long-term follow-up after bariatric surgery: A systematic review

Abstract: Importance Bariatric surgery is an accepted treatment for obesity. Despite extensive literature, few studies report long-term follow-up in cohorts with adequate retention rates. Objective To assess the quality of evidence and treatment effectiveness 2 years after bariatric procedures for weight loss, type 2 diabetes, hypertension, and hyperlipidemia in severely obese adults. Evidence Review MEDLINE and Cochrane databases were searched from 1946 through May 15, 2014. Search terms included bariatric surgery, individual bariatric procedures, and obesity. Studies were included if they described outcomes for gastric bypass, gastric band, or sleeve gastrectomy performed on patients with a body mass index of 35 or greater, had more than 2 years of outcome information, and had follow-up measures for at least 80% of the initial cohort. Two investigators reviewed each study and a third resolved study inclusion disagreements. Findings Of 7371 clinical studies reviewed, 29 studies (0.4%, 7971 patients) met inclusion criteria. All gastric bypass studies (6 prospective cohorts, 5 retrospective cohorts) and sleeve gastrectomy studies (2 retrospective cohorts) had 95% confidence intervals for the reported mean, median, or both exceeding 50% excess weight loss. This amount of excess weight loss occurred in 31% of gastric band studies (9 prospective cohorts, 5 retrospective cohorts). The mean sample-size–weighted percentage of excess weight loss for gastric bypass was 65.7% (n = 3544) vs 45.0% (n = 4109) for gastric band. Nine studies measured comorbidity improvement. For type 2 diabetes (glycated hemoglobin 40 mg/dL, low-density lipoprotein Conclusions and Relevance Very few bariatric surgery studies report long-term results with sufficient patient follow-up to minimize biased results. Gastric bypass has better outcomes than gastric band procedures for long-term weight loss, type 2 diabetes control and remission, hypertension, and hyperlipidemia. Insufficient evidence exists regarding long-term outcomes for gastric sleeve resections.

Decreased segregation of brain systems across the healthy adult lifespan

Abstract: Healthy aging has been associated with decreased specialization in brain function. This characterization has focused largely on describing age-accompanied differences in specialization at the level of neurons and brain areas. We expand this work to describe systems-level differences in specialization in a healthy adult lifespan sample (n = 210; 20–89 y). A graph-theoretic framework is used to guide analysis of functional MRI resting-state data and describe systems-level differences in connectivity of individual brain networks. Young adults’ brain systems exhibit a balance of within- and between-system correlations that is characteristic of segregated and specialized organization. Increasing age is accompanied by decreasing segregation of brain systems. Compared with systems involved in the processing of sensory input and motor output, systems mediating “associative” operations exhibit a distinct pattern of reductions in segregation across the adult lifespan. Of particular importance, the magnitude of association system segregation is predictive of long-term memory function, independent of an individual’s age.