Showing papers by "University of Alabama at Birmingham published in 2013"
Radboud University Nijmegen Medical Centre1, University of Michigan2, Radboud University Nijmegen3, University of Toronto4, McGill University5, University of Basel6, University of Florence7, Auckland City Hospital8, University of Pittsburgh9, Charité10, University of California, Los Angeles11, University College London12, University of Zurich13, University of Paris14, Marche Polytechnic University15, University of Texas Health Science Center at Houston16, Newcastle University17, University of Pécs18, Georgetown University19, Istanbul University20, Medical University of Białystok21, University of Giessen22, Seconda Università degli Studi di Napoli23, University College Dublin24, Stanford University25, University of Colorado Denver26, National Health Service27, Medical College of Wisconsin28, University of Alabama at Birmingham29, University of Manchester30, Rutgers University31, Thomas Jefferson University32, University of Toledo33, Amgen34, Boston University35, Medical University of South Carolina36, University of Pennsylvania37, Northwestern University38
TL;DR: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria and should allow for more patients to be classified correctly as having the disease.
Abstract: OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
2,743 citations
Brigham and Women's Hospital1, Partners HealthCare2, University of North Carolina at Chapel Hill3, University of California, Los Angeles4, University of Alabama at Birmingham5, Geisinger Health System6, Baylor College of Medicine7, University of California, San Francisco8, Stanford University9, American College of Medical Genetics10, National Institutes of Health11
TL;DR: It is recommended that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here and encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.
2,215 citations
Institute for Health Metrics and Evaluation1, University of Texas Health Science Center at San Antonio2, Emory University3, Mayo Clinic4, Harvard University5, Boston University6, Michigan State University7, National Institutes of Health8, Cedars-Sinai Medical Center9, Health Effects Institute10, Loyola University Chicago11, University of Washington12, University of California, San Diego13, University of Pennsylvania14, Veterans Health Administration15, Beth Israel Medical Center16, Johns Hopkins University17, Imperial College London18, Carnegie Mellon University19, Howard University20, University of California, San Francisco21, Columbia University22, New York University23, Karolinska Institutet24, George Mason University25, Nova Southeastern University26, University of Miami27, Northwestern University28, Thomas Jefferson University29, China Medical Board30, Pacific Institute31, Duke University32, Brigham and Women's Hospital33, California Environmental Protection Agency34, Centers for Medicare and Medicaid Services35, Brigham Young University36, University of Missouri37, University of California, Los Angeles38, Vanderbilt University39, University of Maryland, College Park40, University of Alabama at Birmingham41, Brandeis University42, University of Tokyo43, The Queen's Medical Center44, Drexel University45, Cincinnati Children's Hospital Medical Center46, National Institute for Occupational Safety and Health47, Brown University48, University of Melbourne49
TL;DR: 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), systematic analysis of descriptive epidemiology was used.
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.
2,159 citations
Brown University1, National Institutes of Health2, Johns Hopkins University3, Pennington Biomedical Research Center4, University of Tennessee Health Science Center5, University of Minnesota6, Wake Forest University7, Baylor College of Medicine8, Centers for Disease Control and Prevention9, University of Texas Health Science Center at San Antonio10, University of Colorado Denver11, Harvard University12, University of Pittsburgh13, University of Washington14, University of Alabama at Birmingham15, University of Pennsylvania16, Mount Sinai St. Luke's and Mount Sinai Roosevelt17, University of Arkansas for Medical Sciences18
TL;DR: 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.
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.)
2,048 citations
Radboud University Nijmegen1, University of Michigan2, University of Toronto3, McGill University4, University of Basel5, University of Florence6, Auckland City Hospital7, University of Pittsburgh8, Complutense University of Madrid9, Charité10, University of California, Los Angeles11, University College London12, University of Zurich13, University of Paris14, Marche Polytechnic University15, University of Texas Health Science Center at Houston16, Newcastle University17, University of Pécs18, Georgetown University19, Istanbul University20, Medical University of Białystok21, University of Giessen22, Seconda Università degli Studi di Napoli23, University College Dublin24, Stanford University25, University of Colorado Denver26, Amgen27, Medical College of Wisconsin28, University of Alabama at Birmingham29, National Health Service30, University of Manchester31, Rutgers University32, Thomas Jefferson University33, University of Toledo34, Boston University35, University of Pennsylvania36, Medical University of South Carolina37, Northwestern University38, University of Western Ontario39
TL;DR: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria and should allow for more patients to be classified correctly as having the disease.
Abstract: Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud9s phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusions The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
1,899 citations
Icahn School of Medicine at Mount Sinai1, Cedars-Sinai Medical Center2, Beth Israel Deaconess Medical Center3, University of Alabama at Birmingham4, Mayo Clinic5, Cleveland Clinic Lerner College of Medicine6, Northwestern University7, University of Utah8, Brigham and Women's Hospital9, Baker IDI Heart and Diabetes Institute10
TL;DR: These updated guidelines reflect recent additions to the evidence base and include Examples of expanded topics in this update include: the roles of sleeve gastrectomy, bariatric surgery in patients with type‐2 diabetes,bariatric surgery for patients with mild obesity, copper deficiency, informed consent, and behavioral issues.
Abstract: The development of these updated guidelines was commissioned by the AACE, TOS, and ASMBS Board of Directors and adheres to the AACE 2010 protocol for standardized production of clinical practice guidelines (CPG). Each recommendation was re-evaluated and updated based on the evidence and subjective factors per protocol. Examples of expanded topics in this update include: the roles of sleeve gastrectomy, bariatric surgery in patients with type-2 diabetes, bariatric surgery for patients with mild obesity, copper deficiency, informed consent, and behavioral issues. There are 74 recommendations (of which 56 are revised and 2 are new) in this 2013 update, compared with 164 original recommendations in 2008. There are 403 citations, of which 33 (8.2%) are EL 1, 131 (32.5%) are EL 2, 170 (42.2%) are EL 3, and 69 (17.1%) are EL 4. There is a relatively high proportion (40.4%) of strong (EL 1 and 2) studies, compared with only 16.5% in the 2008 AACE-TOS-ASMBS CPG. These updated guidelines reflect recent additions to the evidence base. Bariatric surgery remains a safe and effective intervention for select patients with obesity. A team approach to perioperative care is mandatory with special attention to nutritional and metabolic issues.
1,565 citations
French Institute of Health and Medical Research1, University of Paris-Sud2, Institut Gustave Roussy3, Harvard University4, Agency for Science, Technology and Research5, Pasteur Institute6, Institut national de la recherche agronomique7, University of Orléans8, University of Alabama at Birmingham9, Agro ParisTech10, University of Burgundy11
TL;DR: It is demonstrated that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs, which suggests that the gut microbiota help shape the anticancer immune response.
Abstract: Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.
1,487 citations
TL;DR: The neurocognitive changes observed in normal aging are described, followed by a description of the structural and functional alterations seen in aging brains.
1,253 citations
Harvard University1, University of California, Los Angeles2, Stanford University3, Fred Hutchinson Cancer Research Center4, National Institutes of Health5, Georgetown University6, University of Arizona7, University at Buffalo8, Ohio State University9, University of Florida10, Regions Hospital11, Yeshiva University12, University of Pittsburgh13, Brown University14, Case Western Reserve University15, AstraZeneca16, University of Tennessee Health Science Center17, University of Alabama at Birmingham18, George Washington University19, University of Massachusetts Medical School20, University of Miami21, Rush University Medical Center22, Wayne State University23, Northwestern University24, Wake Forest University25, University of Iowa26
TL;DR: Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up and the 2 WHI hormone therapy trials do not support use of this therapy.
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.
1,181 citations
TL;DR: A critical review of the recent prospective and experimental research on the association of sleep and pain tries to identify trends suggestive of directionality and potential mechanisms to guide future clinical efforts to develop and augment treatments for chronic sleep disturbance and chronic pain.
956 citations
TL;DR: The group’s goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screenings guidelines incorporating longer screening intervals and co-testing.
TL;DR: An overview of available methods for implementing parametric WGR models is provided, selected topics that emerge in applications are discussed, and a general discussion of lessons learned from simulation and empirical data analysis in the last decade are presented.
Abstract: Genomic-enabled prediction is becoming increasingly important in animal and plant breeding and is also receiving attention in human genetics. Deriving accurate predictions of complex traits requires implementing whole-genome regression (WGR) models where phenotypes are regressed on thousands of markers concurrently. Methods exist that allow implementing these large-p with small-n regressions, and genome-enabled selection (GS) is being implemented in several plant and animal breeding programs. The list of available methods is long, and the relationships between them have not been fully addressed. In this article we provide an overview of available methods for implementing parametric WGR models, discuss selected topics that emerge in applications, and present a general discussion of lessons learned from simulation and empirical data analysis in the last decade.
TL;DR: The 5th annual report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) summarizes and analyzes the first 6 years of patient and data collection.
Abstract: The 5th annual report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) summarizes and analyzes the first 6 years of patient and data collection. The current analysis includes more than 6000 patients and updated risk factors for continuous flow pumps. Among continuous flow pumps, actuarial survival is 80% at 1 year and 70% at 2 years. Quality of life indicators are generally favorable and adverse event burden will likely influence patient selections of advanced heart failure therapies.
University of Pennsylvania1, University of Florida2, Primary Children's Hospital3, Washington University in St. Louis4, National Institutes of Health5, Mayo Clinic6, University of Texas Medical Branch7, Marshfield Clinic8, University of California, San Francisco9, Henry Ford Health System10, University of Maryland, Baltimore11, University of Alabama at Birmingham12, Vanderbilt University13, Tulane University14, Icahn School of Medicine at Mount Sinai15, Duke University16, Yeshiva University17, University of Utah18, Harvard University19
TL;DR: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy and there was a significant interaction between dosing strategy and race.
Abstract: Background The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. Methods We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. Results At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There ...
TL;DR: A group of US experts in adult and pediatric AKI and critical care nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns concluded that there is insufficient evidence to support their widespread application to clinical care in the United States.
TL;DR: New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Abstract: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
TL;DR: It is identified that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4+ T cells that limit pathological adaptive immune cell responses to commensal bacteria.
Abstract: Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4(+) T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt(+)) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORγt(+) ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4(+) T-cell responses. Consistent with this, selective deletion of MHCII in murine RORγt(+) ILCs resulted in dysregulated commensal bacteria-dependent CD4(+) T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4(+) T cells that limit pathological adaptive immune cell responses to commensal bacteria.
TL;DR: Future directions for Behavioral InfoSec research, which is a newer, growing area of research, are highlighted, including separating insider deviant behavior from insider misbehavior, approaches to understanding hackers, improving information security compliance, cross-cultural Behavioral Info Sec research, and data collection and measurement issues.
TL;DR: What is known about the mechanisms of cholesterol uptake, esterification and release in macrophages is described to help develop novel therapeutic interventions for atherosclerosis.
TL;DR: The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer.
Abstract: Purpose: Patients with hormone receptor–negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer. Experimental Design: Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer. Results: Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%–39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11–22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed. Conclusion: AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer. Clin Cancer Res; 19(19); 5505–12. ©2013 AACR.
TL;DR: In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months.
Abstract: A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide– azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the com parison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P = 0.01) and at 12 months (P = 0.009) but not at 18 months (P = 0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. Conclusions In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the Na tional Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)
Icahn School of Medicine at Mount Sinai1, Cedars-Sinai Medical Center2, Beth Israel Deaconess Medical Center3, University of Alabama at Birmingham4, Mayo Clinic5, Cleveland Clinic Lerner College of Medicine6, Northwestern University7, University of Utah8, Brigham and Women's Hospital9, Baker IDI Heart and Diabetes Institute10
TL;DR: These updated guidelines reflect recent additions to the evidence base and include Examples of expanded topics in this update include: the roles of sleeve gastrectomy, bariatric surgery in patients with type-2 diabetes,bariatric surgery for patients with mild obesity, copper deficiency, informed consent, and behavioral issues.
University of California, San Francisco1, Washington University in St. Louis2, Lund University3, University Health Network4, Princess Alexandra Hospital5, Royal Melbourne Hospital6, University of Chicago7, Deutsche Sammlung von Mikroorganismen und Zellkulturen8, University of Florida9, University of Alabama at Birmingham10, Ohio State University11, Boston Children's Hospital12, Johns Hopkins University13, Nationwide Children's Hospital14, University of Colorado Denver15
TL;DR: Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
Abstract: The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
TL;DR: It is suggested that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia and the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain is supported.
TL;DR: The origins, modes of activation, and fate of myofibroblasts in various important fibrotic diseases are discussed and how manipulation of macrophage activation could help ameliorate fibrosis is described.
Abstract: Myofibroblasts accumulate in the spaces between organ structures and produce extracellular matrix (ECM) proteins, including collagen I. They are the primary “effector” cells in tissue remodeling and fibrosis. Previously, leukocyte progenitors termed fibrocytes and myofibroblasts generated from epithelial cells through epithelial-to-mesenchymal transition (EMT) were considered the primary sources of ECM-producing myofibroblasts in injured tissues. However, genetic fate mapping experiments suggest that mesenchyme-derived cells, known as resident fibroblasts, and pericytes are the primary precursors of scar-forming myofibroblasts, whereas epithelial cells, endothelial cells, and myeloid leukocytes contribute to fibrogenesis predominantly by producing key fibrogenic cytokines and by promoting cell-to-cell communication. Numerous cytokines derived from T cells, macrophages, and other myeloid cell populations are important drivers of myofibroblast differentiation. Monocyte-derived cell populations are key regul...
University of Pennsylvania1, Columbia University2, University of Michigan3, University of Chicago4, University of Pittsburgh5, University of Alabama at Birmingham6, Johns Hopkins University7, Stanford University8, Indiana University – Purdue University Indianapolis9, Vanderbilt University10, Duke University11
TL;DR: In this paper, a 10-center prospective cohort study was performed to identify donor, recipient, and perioperative risk factors for primary graft dysfunction (PGD) in lung transplant patients.
Abstract: Rationale: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors.Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD.Methods: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression.Measurements and Main Results: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2–2.6; P = 0.002); FiO2 during allograft reperfusion (OR, 1.1 per 10% ...
Harvard University1, University College London2, Vrije Universiteit Brussel3, University of Alabama at Birmingham4, Princess Margaret Cancer Centre5, Henry Ford Health System6, Cedars-Sinai Medical Center7, St. Joseph's Hospital and Medical Center8, University of Texas MD Anderson Cancer Center9, University of Melbourne10, Royal Melbourne Hospital11, Medical University of Graz12, AstraZeneca13, Erasmus University Rotterdam14
TL;DR: This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomUSTine in patients with recurrent glioblastoma, although cedIRanib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects.
Abstract: Purpose A randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recentin in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan–vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. Patients and Methods Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m2); (3) lomustine (110 mg/m2) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans. Results The primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone...
TL;DR: A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines as discussed by the authors.
Abstract: A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines. The group's goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screening guidelines incorporating longer screening intervals and co-testing. In addition to literature review, data from almost 1.4 million women in the Kaiser Permanente Northern California Medical Care Plan provided evidence on risk after abnormal tests. Where data were available, guidelines prescribed similar management for women with similar risks for CIN 3, AIS, and cancer. Most prior guidelines were reaffirmed. Examples of updates include: Human papillomavirus-negative atypical squamous cells of undetermined significance results are followed with co-testing at 3 years before return to routine screening and are not sufficient for exiting women from screening at age 65 years; women aged 21-24 years need less invasive management, especially for minor abnormalities; postcolposcopy management strategies incorporate co-testing; endocervical sampling reported as CIN 1 should be managed as CIN 1; unsatisfactory cytology should be repeated in most circumstances, even when HPV results from co-testing are known, while most cases of negative cytology with absent or insufficient endocervical cells or transformation zone component can be managed without intensive follow-up.
National Institutes of Health1, Northwestern University2, Vanderbilt University3, Geisinger Medical Center4, Washington University in St. Louis5, Medical College of Wisconsin6, Icahn School of Medicine at Mount Sinai7, Marshfield Clinic8, Cleveland Clinic9, University of California, San Diego10, University of Alabama at Birmingham11, Baylor College of Medicine12, Ohio State University13, Mayo Clinic14, Harvard University15, University of Chicago16, University of Pennsylvania17, University of Maryland, Baltimore18, Johns Hopkins University19, Duke University20
TL;DR: The National Human Genome Research Institute brought together a number of institutions to describe their ongoing projects and challenges, identify common infrastructure and research needs, and outline an implementation framework for investigating and introducing similar programs elsewhere.
TL;DR: This review synthesizes the state of engagement in HIV care in the United States, focusing on research, practice, and policy considerations, and includes a look to the future in addressing the greatest challenge and opportunity facing the authors' domestic HIV epidemic.
Abstract: The National HIV/AIDS Strategy and the promise of treatment as prevention have garnered considerable attention from the policy, practice, and scientific communities, with the treatment cascade becoming the sentinel image illustrating the domestic human immunodeficiency virus (HIV) epidemic. The cascade depicts prevalence estimates for sequential steps from HIV diagnosis through viral suppression, the most striking of which is that >50% of persons diagnosed with HIV are not in medical care. This heterogeneous group includes individuals not linked to medical care following HIV diagnosis and those entering care who are not retained, requiring reengagement from a range of community settings. This review synthesizes the state of engagement in HIV care in the United States, focusing on research, practice, and policy considerations. Included are conceptual frameworks, a review of health implications, measurement, monitoring, and evidence-based intervention approaches, and a look to the future in addressing the greatest challenge and opportunity facing our domestic HIV epidemic.