Showing papers by "University of Alabama at Birmingham published in 2011"
TL;DR: In this article, the authors have developed recommendations for reliable evaluation of kinetic parameters (the activation energy, the preexponential factor, and the reaction model) from the data obtained by means of thermal analysis methods such as TGA, differential scanning calorimetry (DSC), and differential thermal analysis (DTA).
4,112 citations
Brigham and Women's Hospital1, Boston University2, University of California, Los Angeles3, Boston Children's Hospital4, University of Alabama at Birmingham5, Stanford University6, Northwestern University7, Aalborg University8, Cardiff University9, University of Pennsylvania10, Erasmus University Rotterdam11, Medical University of South Carolina12
TL;DR: The revised guidelines for the management of thyroid disease in pregnancy include recommendations regarding the interpretation of thyroid function tests in pregnancy, iodine nutrition, thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy and thyrotoxicosis in pregnancy.
Abstract: Background: Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2...
2,409 citations
Seattle Children's1, National Health Service2, Beaumont Hospital3, University of Toronto4, University of Queensland5, Charles University in Prague6, Ludwig Maximilian University of Munich7, University College Dublin8, Case Western Reserve University9, Stanford University10, University of Paris11, University of Alabama at Birmingham12, Vertex Pharmaceuticals13, Queen's University Belfast14
TL;DR: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks and substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride.
Abstract: Background Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. Methods We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV1). Results The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained...
1,835 citations
TL;DR: The Alzheimer Disease Genetics Consortium performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1), two replication stages (stages 2 and 3), and both joint analysis and meta-analysis approaches were used.
Abstract: The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.
1,743 citations
University of Miami1, University of Texas Southwestern Medical Center2, University of Alabama at Birmingham3, Harvard University4, University of Illinois at Chicago5, Veterans Health Administration6, Wake Forest University7, Tulane University8, University of California, San Francisco9, University of Pennsylvania10, University of Michigan11, Temple University12, University of Münster13, National Institutes of Health14
TL;DR: It is reported that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort and suggested that chronically elevated F GF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
Abstract: Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor–dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF–receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
1,709 citations
Medical University of South Carolina1, Emory University2, Washington University in St. Louis3, Stony Brook University4, National Institutes of Health5, Oregon Health & Science University6, University of Florida7, University at Buffalo8, University of Alabama at Birmingham9, Houston Methodist Hospital10, St. Joseph's Hospital and Medical Center11, University of Texas Southwestern Medical Center12, Medical College of Wisconsin13, Mayo Clinic14
TL;DR: In patients with intracranial arterial stenosis, aggressive medical management was superior to PTAS with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because therisk of stroke with aggressive medical therapy alone was lower than expected.
Abstract: Enrollment was stopped after 451 patients underwent randomization, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non–stroke-related death, 0.4%) (P = 0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Currently, the mean duration of followup, which is ongoing, is 11.9 months. The probability of the occurrence of a primary end-point event over time differed significantly between the two treatment groups (P = 0.009), with 1-year rates of the primary end point of 20.0% in the PTAS group and 12.2% in the medical-management group. Conclusions In patients with intracranial arterial stenosis, aggressive medical management was superior to PTAS with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected. (Funded by the National Institute of Neurological Disorders and Stroke and others; SAMMPRIS ClinicalTrials.gov number, NCT00576693.)
1,377 citations
TL;DR: Modest weight losses of 5 to <10% were associated with significant improvements in CVD risk factors at 1 year, but larger weight losses had greater benefits.
Abstract: OBJECTIVE Overweight and obese individuals are encouraged to lose 5–10% of their body weight to improve cardiovascular disease (CVD) risk, but data supporting this recommendation are limited, particularly for individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted an observational analysis of participants in the Look AHEAD (Action For Health in Diabetes) study ( n = 5,145, 40.5% male, 37% from ethnic/racial minorities) and examined the association between the magnitude of weight loss and changes in CVD risk factors at 1 year and the odds of meeting predefined criteria for clinically significant improvements in risk factors in individuals with type 2 diabetes. RESULTS The magnitude of weight loss at 1 year was strongly ( P P = 0.79). Compared with weight-stable participants, those who lost 5 to 1c (odds ratio 3.52 [95% CI 2.81–4.40]), a 5-mmHg decrease in diastolic blood pressure (1.48 [1.20–1.82]), a 5-mmHg decrease in systolic blood pressure (1.56 [1.27–1.91]), a 5 mg/dL increase in HDL cholesterol (1.69 [1.37–2.07]), and a 40 mg/dL decrease in triglycerides (2.20 [1.71–2.83]). The odds of clinically significant improvements in most risk factors were even greater in those who lost 10–15% of their body weight. CONCLUSIONS Modest weight losses of 5 to
1,369 citations
TL;DR: The results are consistent with, and extend, previous findings by definitively showing a significant and large reduction in hospitalisation for patients with NYHA class III heart failure who were managed with a wireless implantable haemodynamic monitoring system.
1,316 citations
North Shore-LIJ Health System1, Johns Hopkins University School of Medicine2, University of California, Los Angeles3, Charles University in Prague4, Oklahoma Medical Research Foundation5, University of Alabama at Birmingham6, University of Southern California7, SUNY Downstate Medical Center8, Human Genome Sciences9, Karolinska Institutet10
TL;DR: Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.
Abstract: Objective To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE) Methods In a phase III, multicenter, randomized, placebo-controlled trial, 819 antinuclear antibody-positive or anti-double-stranded DNA-positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4-point reduction in SELENA-SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline) Results Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (432% versus 335%; P = 0017) The rate with 1 mg/kg belimumab was 406% (P = 0089) Response rates at week 76 were 324%, 391%, and 385% with placebo, 1 mg/kg belimumab, and 10 mg/kg belimumab, respectively In post hoc sensitivity analyses evaluating higher SELENA-SLEDAI score thresholds, 10 mg/kg belimumab achieved better discrimination at weeks 52 and 76 Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg belimumab (34%) (P = 0023) and 10 mg/kg belimumab (23%) (P = 013) Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups Conclusion Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE
1,277 citations
TL;DR: The Society for Vascular Surgery and the American Venous Forum have developed clinical practice guidelines for the care of patients with varicose veins of the lower limbs and pelvis, including recommendations on the management of superficial and perforating vein incompetence in patients with associated, more advanced chronic venous diseases.
1,162 citations
TL;DR: It is shown that functional loss of GD-linked glucocerebrosidase in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies.
Constantine A. Gatsonis1, Denise R. Aberle2, Christine D. Berg, William C. Black3 +1333 more•Institutions (31)
TL;DR: The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer.
Abstract: The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5% It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest The NLST is such a trial The rationale for and design of the NLST are presented
TL;DR: Exosomes used to encapsulate curcumin or a signal transducer and activator of transcription 3 (Stat3) inhibitor were delivered noninvasively to microglia cells via an intranasal route and demonstrated that this strategy may provide a noninvasive and novel therapeutic approach for treating brain inflammatory-related diseases.
University of Colorado Denver1, Denver Health Medical Center2, University of Minnesota3, University of Alabama at Birmingham4, University of California, Los Angeles5, Veterans Health Administration6, Temple University7, University of Michigan8, University of California, San Francisco9, Regions Hospital10, Mayo Clinic11, University of Pittsburgh12, University of Maryland, Baltimore13, University of Manitoba14
TL;DR: Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects.
Abstract: A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exac erbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among par ticipants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerba tions per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P = 0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George’s Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithro mycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P = 0.004); the percentage of participants with more than the minimal clinically important difference of −4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P = 0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P = 0.04). Conclusions Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.)
TL;DR: The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.
Abstract: Purpose The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. Patients and Methods Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m 2 nab-paclitaxel followed by gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. Results A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m 2 , respectively. The MTD was 1,000 mg/m 2 of gemcitabine plus 125 mg/m 2 of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [ 18 F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone.
Emory University1, University of Texas Southwestern Medical Center2, University of Utah3, Indiana University4, Stanford University5, Yale University6, Duke University7, Tufts University8, Wayne State University9, University of Texas Health Science Center at Houston10, University of Alabama at Birmingham11, University of New Mexico12, University of Iowa13, Case Western Reserve University14, University of Cincinnati15, Brown University16, Centers for Disease Control and Prevention17, National Institutes of Health18
TL;DR: In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease, suggesting that Escherichia coli is an important EO pathogen.
Abstract: BACKGROUND: Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen. OBJECTIVE: To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers. METHODS: Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence. RESULTS: Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%). CONCLUSION: In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.
TL;DR: Studies that assessed possible shared etiological components between PD and other diseases show that REM sleep behavior disorder and mental illness increase PD risk and that PD patients have lower cancer risk, but methodological concerns exist.
Abstract: The etiology of Parkinson’s disease (PD) is not well understood but likely to involve both genetic and environmental factors. Incidence and prevalence estimates vary to a large extent—at least partly due to methodological differences between studies—but are consistently higher in men than in women. Several genes that cause familial as well as sporadic PD have been identified and familial aggregation studies support a genetic component. Despite a vast literature on lifestyle and environmental possible risk or protection factors, consistent findings are few. There is compelling evidence for protective effects of smoking and coffee, but the biologic mechanisms for these possibly causal relations are poorly understood. Uric acid also seems to be associated with lower PD risk. Evidence that one or several pesticides increase PD risk is suggestive but further research is needed to identify specific compounds that may play a causal role. Evidence is limited on the role of metals, other chemicals and magnetic fields. Important methodological limitations include crude classification of exposure, low frequency and intensity of exposure, inadequate sample size, potential for confounding, retrospective study designs and lack of consistent diagnostic criteria for PD. Studies that assessed possible shared etiological components between PD and other diseases show that REM sleep behavior disorder and mental illness increase PD risk and that PD patients have lower cancer risk, but methodological concerns exist. Future epidemiologic studies of PD should be large, include detailed quantifications of exposure, and collect information on environmental exposures as well as genetic polymorphisms.
TL;DR: The major diseases of bone remodeling are reviewed, emphasizing the current understanding of the underlying pathophysiological mechanisms.
Abstract: The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms.
Emory University1, University of Alabama at Birmingham2, University of Louisville3, St. Luke's Hospital4, Kaiser Permanente5, Mount Sinai St. Luke's and Mount Sinai Roosevelt6, Mayo Clinic7, Ohio State University8, Carolinas Medical Center9, University of Colorado Denver10, Northwestern University11, Advocate Lutheran General Hospital12, University of South Florida13, Rush University Medical Center14, National Institutes of Health15, University of Texas MD Anderson Cancer Center16
TL;DR: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine andInterleukin-2 than with interleuk in-2 alone.
Abstract: Background Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. Methods We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end p...
TL;DR: Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks, and the improvement persisted at 52 weeks, suggesting that bardoxlone methyl may have promise for the treatment of CKD.
Abstract: Results Patients receiving bardoxolone methyl had significant increases in the mean (±SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m 2 of 8.2±1.5 ml in the 25-mg group, 11.4±1.5 ml in the 75-mg group, and 10.4±1.5 ml in the 150-mg group; P<0.001). The increases were maintained through week 52, with significant differences per minute per 1.73 m 2 of 5.8±1.8 ml, 10.5±1.8 ml, and 9.3±1.9 ml, respectively. Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related. Hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were more common among patients receiving bardoxolone methyl. Conclusions Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD. (Funded by Reata Pharmaceuticals; BEAM ClinicalTrials.gov number, NCT00811889.)
TL;DR: The efficacy and safety of two doses of phentermine plus topiramate controlled-release combination as an adjunct to diet and lifestyle modification for weight loss and metabolic risk reduction in individuals who were overweight and obese, with two or more risk factors is assessed.
TL;DR: Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient.
Abstract: Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice
SUNY Downstate Medical Center1, University of Mississippi2, Johns Hopkins University3, Children's National Medical Center4, Howard University5, Duke University6, University of Texas at Dallas7, Medical University of South Carolina8, University of Miami9, Emory University10, Boston Children's Hospital11, University of Alabama at Birmingham12, Georgia Regents University13, National Institutes of Health14
TL;DR: Hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia, with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion.
TL;DR: The potential benefits of EHRs that include clinical outcomes, organizational outcomes, financial and operational benefits, and societal outcomes are described, which include improved ability to conduct research, improved population health, reduced costs.
Abstract: The Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009 that was signed into law as part of the “stimulus package” represents the largest US initiative to date that is designed to encourage widespread use of electronic health records (EHRs). In light of the changes anticipated from this policy initiative, the purpose of this paper is to review and summarize the literature on the benefits and drawbacks of EHR systems. Much of the literature has focused on key EHR functionalities, including clinical decision support systems, computerized order entry systems, and health information exchange. Our paper describes the potential benefits of EHRs that include clinical outcomes (eg, improved quality, reduced medical errors), organizational outcomes (eg, financial and operational benefits), and societal outcomes (eg, improved ability to conduct research, improved population health, reduced costs). Despite these benefits, studies in the literature highlight drawbacks associated with EHRs, which include the high upfront acquisition costs, ongoing maintenance costs, and disruptions to workflows that contribute to temporary losses in productivity that are the result of learning a new system. Moreover, EHRs are associated with potential perceived privacy concerns among patients, which are further addressed legislatively in the HITECH Act. Overall, experts and policymakers believe that significant benefits to patients and society can be realized when EHRs are widely adopted and used in a “meaningful” way.
TL;DR: This review addresses recent advances in the understanding of the transmission of HIV-1 and of acute HIV- 1 infection.
Abstract: More than 33 million people are living with HIV-1, and more than 2.5 million additional cases are detected each year. This review addresses recent advances in our understanding of the transmission of HIV-1 and of acute HIV-1 infection.
TL;DR: Some of the reasons why cell culture studies may not always reliably predict in vivo responses are presented, and potential applications that may benefit from the use of RGD peptides are highlighted.
TL;DR: Recent advances in understanding the biochemical, immunologic, and genetic pathogenesis of IgA nephropathy are discussed, and five distinct susceptibility loci are identified that potentially influence these processes and contain candidate mediators of disease.
Abstract: Here we discuss recent advances in understanding the biochemical, immunologic, and genetic pathogenesis of IgA nephropathy, the most common primary glomerulonephritis. Current data indicate that at least four processes contribute to development of IgA nephropathy. Patients with IgA nephropathy often have a genetically determined increase in circulating levels of IgA1 with galactose-deficient O-glycans in the hinge-region (Hit 1). This glycosylation aberrancy is, however, not sufficient to induce renal injury. Synthesis and binding of antibodies directed against galactose-deficient IgA1 are required for formation of immune complexes that accumulate in the glomerular mesangium (Hits 2 and 3). These immune complexes activate mesangial cells, inducing proliferation and secretion of extracellular matrix, cytokines, and chemokines, which result in renal injury (Hit 4). Recent genome-wide association studies identify five distinct susceptibility loci—in the MHC on chromosome 6p21, the complement factor H locus on chromosome 1q32, and in a cluster of genes on chromosome 22q22—that potentially influence these processes and contain candidate mediators of disease. The significant variation in prevalence of risk alleles among different populations may also explain some of the sizable geographic variation in disease prevalence. Elucidation of the pathogenesis of IgA nephropathy provides an opportunity to develop disease-specific therapies.
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TL;DR: In this article, the authors summarize salient developments in research on aging and vision over the past 25 years, focusing on spatial contrast sensitivity, vision under low luminance, temporal sensitivity and motion perception, and visual processing speed.
Columbia University1, Yale University2, Peking University3, Shanghai Jiao Tong University4, University of Alabama at Birmingham5, University of Tennessee6, Icahn School of Medicine at Mount Sinai7, Istituto Giannina Gaslini8, University of Calgary9, University of Parma10, University of Brescia11, University of Foggia12, University of Turin13
TL;DR: Three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance, explain 4–7% of the disease variance and up to a tenfold variation in interindividual risk.
Abstract: We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10⁻²⁶ and 4.84 × 10⁻⁹ and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.
University of Marburg1, University of Pittsburgh2, Mayo Clinic3, University of Pennsylvania4, University College London5, University of Louisville6, Case Western Reserve University7, Erasmus University Rotterdam8, VU University Amsterdam9, University of Tübingen10, University of Barcelona11, University of Brescia12, University of Navarra13, National Institutes of Health14, Scripps Research Institute15, University of British Columbia16, University of Washington17, Rutgers University18, University of Giessen19, University of Michigan20, University of Würzburg21, Autonomous University of Madrid22, German Center for Neurodegenerative Diseases23, Karolinska Institutet24, University of California, Los Angeles25, French Institute of Health and Medical Research26, Centre national de la recherche scientifique27, Medical University of Vienna28, Sapienza University of Rome29, University of Antwerp30, Mount Sinai Hospital31, Flinders University32, Harvard University33, University of California, San Diego34, Emory University35, Indiana University36, Rush University Medical Center37, University of Toronto38, Baylor College of Medicine39, University of California, San Francisco40, Ludwig Maximilian University of Munich41, University of Kansas42, Mental Health Research Institute43, University of Göttingen44, Cardiff University45, Newcastle University46, University of Manchester47, Innsbruck Medical University48, Carlos III Health Institute49, University of Saskatchewan50, University of Maryland, Baltimore51, University of Cambridge52, University of Alabama at Birmingham53, Veterans Health Administration54, King's College London55, Johns Hopkins University56, Columbia University57, University of Texas Southwestern Medical Center58, University of Southern California59
TL;DR: Two independent variants in MAPT affecting risk for PSP are confirmed, one of which influences MAPT brain expression and the genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface and for a myelin structural component.
Abstract: Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10−3. We found significant previously unidentified signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.