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4 minutes | Jun 17, 2021
Nutrition Interventions to Support Mitochondrial Health During Aging
Host: Eric Verdin, MD Here to talk about some of the cellular changes associated with aging, how these changes manifest clinically as we age, and emerging nutritional interventions to target these changes is Dr. Eric Verdin, the President and Chief Executive Officer of the Buck Institute for Research on Aging.
5 minutes | Jul 30, 2020
A Specific Mutation in Muc2 Determines Early Dysbiosis in Colitis-Prone Winnie Mice
Host: Ivy Ka Man Law, PhD A Specific Mutation in Muc2 Determines Early Dysbiosis in Colitis-Prone Winnie Mice Marina Liso, Stefania De Santis, Giulio Verna, Manuela Dicarlo, Maria Calasso, Angelo Santino, Isabella Gigante, Rajaraman Eri, Sathuwarman Raveenthiraraj, Anastasia Sobolewski, Valeria Palmitessa, Antonio Lippolis, Mauro Mastronardi, Raffaele Armentano, Grazia Serino, Maria De Angelis, Marcello Chieppa Background: Inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), is a multifactorial disorder characterized by chronic inflammation and altered gut barrier function. Dysbiosis, a condition defined by dysregulation of the gut microbiome, has been reported in patients with IBD and in experimental models of colitis. Although several factors have been implicated in directly affecting gut microbial composition, the genetic determinants impacting intestinal dysbiosis in IBD remain relatively unknown. Methods: We compared the microbiome of normal, uninflamed wild-type (WT) mice with that of a murine model of UC (ie, Winnie strain). Winnie mice possess a missense mutation in Muc2 that manifests in altered mucus production as early as 4 weeks of age, with ensuing colonic inflammation. To better address the potential role of mutant Muc2 in promoting dysbiosis in Winnie mice, we evaluated homozygous mutant mice (Winnie-/-) with their WT littermates that, after weaning from common mothers, were caged ...
4 minutes | Jul 22, 2020
Proactive vs. Reactive Therapeutic Drug Monitoring of Infliximab in Crohn’s Disease
Host: Abdullah Abdussalam, MD Proactive Vs Reactive Therapeutic Drug Monitoring of Infliximab in Crohn’s Diana M Negoescu, Eva A Enns, PhD, Brooke Swanhorst, Bonnie Baumgartner, James P Campbell, Mark T Osterman, MD, Konstantinos Papamichael, PhD, Adam S Cheifetz, MD, Byron P Vaughn, MD Background: Therapeutic drug monitoring (TDM) is increasingly performed for Infliximab (IFX) in patients with Crohn's disease (CD). Reactive TDM is a cost-effective strategy to empiric IFX dose escalation. The cost-effectiveness of proactive TDM is unknown. The aim of this study is to assess the cost-effectiveness of proactive vs reactive TDM in a simulated population of CD patients on IFX. Methods: We developed a stochastic simulation model of CD patients on IFX and evaluated the expected health costs and outcomes of a proactive TDM strategy compared with a reactive strategy. The proactive strategy measured IFX concentration and antibody status every 6 months, or at the time of a flare, and dosed IFX to a therapeutic window. The reactive strategy only did so at the time of a flare. Results: The proactive strategy led to fewer flares than the reactive strategy. More patients stayed on IFX in the proactive vs reactive strategy (63.4% vs 58.8% at year 5). From a health sector perspective, ...
4 minutes | Mar 18, 2020
Real-World Pattern of Biologic Use in Patients with Inflammatory Bowel Disease
Guest: Anish Patel, DO, FACG Real-world Pattern of Biologic Use in Patients With Inflammatory Bowel Disease: Treatment Persistence, Switching, and Importance of Concurrent Immunosuppressive Therapy Chao Chen, PhD, Abraham G Hartzema, PhD, Hong Xiao, PhD, Yu-Jung Wei, PhD, Naueen Chaudhry, MD, Ofor Ewelukwa, MD, Sarah C Glover, DO, Ellen M Zimmermann, MD BACKGROUND AND AIMS:Medication persistence, defined as the time from drug initiation to discontinuation of therapy, has been suggested as a proxy for real-world therapeutic benefit and safety. This study seeks to compare the persistence of biologic drugs among patients with inflammatory bowel disease (IBD). METHODS:Patients with newly diagnosed IBD were included in a retrospective study using Truven MarketScan database. Treatment persistence and switching was compared among biologic medications including infliximab, adalimumab, certolizumab, golimumab, and vedolizumab. Predictors for discontinuation and switching were evaluated using time-dependent proportional hazard regression. RESULTS:In total, 5612 patients with Crohn's disease (CD) and 3533 patients with ulcerative colitis (UC) were included in this analysis. Less than half of the patients continued using their initial biologic treatment after 1 year (48.48% in CD cohort; 44.78% in UC cohort). In the first year, adalimumab had the highest persistence and lowest switching rates for both CD (median survival time: 1.04 years) and UC ...
5 minutes | Mar 6, 2020
Improving the Quality of Inpatient Ulcerative Colitis Management
Guest: Robin Dalal, MD Improving the Quality of Inpatient Ulcerative Colitis Management: Promoting Evidence-Based Practice and Reducing Care Variation With an Inpatient Protocol Sara M Lewin, MD, Ryan A McConnell, MD, Roshan Patel, MD, Suzanne R Sharpton, MD, MAS, Fernando Velayos, MD, MPH, Uma Mahadevan, MD BACKGROUND:Hospitalization for ulcerative colitis is a high-risk period associated with increased risk of Clostridium difficile infection, thromboembolism, and opiate use. The study aim was to develop and implement a quality-improvement intervention for inpatient ulcerative colitis management that standardizes gastroenterology consultant recommendations and improves delivery of evidence-based care. METHODS:All adult patients hospitalized for ulcerative colitis between July 1, 2014, and December 31, 2017, who received intravenous corticosteroids were included. On July 1, 2016, the UCSF Inpatient Ulcerative Colitis Protocol was implemented, featuring standardized core recommendations and a daily checklist for gastroenterology consultant notes, a bundled IBD electronic order set, and an opiate awareness campaign. The composite primary outcome was adherence to all 3 evidence-based care metrics: C. difficile testing performed, pharmacologic venous thromboembolism (VTE) prophylaxis ordered, and opiates avoided. RESULTS:Ninety-three ulcerative colitis hospitalizations occurred, including 36 preintervention and 57 postintervention. Age, gender, disease duration, disease extent, and medication use were similar preintervention and postintervention. C. difficile testing was performed ...
4 minutes | Aug 29, 2019
Measuring the Effectiveness of the BD MAX™ Enteric Viral Panel in the Diagnosis of Enteric Disease
Multicenter Clinical Validation of the Molecular-Based BD MAX™ Enteric Viral Panel for the Detection of Enteric Pathogens. William Stokes, MD, Patricia J. Simner, MSc, PhD, Joel Mortensen, PhD, Margret Oethinger, MD, PhD, Kathleen Stellrecht, PhD, Elizabeth Lockamy, PhD, Tricia Lay, MS, Peggy Bouchy, PhD, Dylan Pillai, MD, PhD Background: Conventional methodology for gastrointestinal pathogens remains time-consuming, expensive, and of limited sensitivity. Objective: Performance evaluation of the BD MAX™ Enteric Viral Panel (MAX EVP) assay for identification of viral pathogens in stool specimens from individuals with symptoms of acute gastroenteritis, enteritis, or colitis. Study Design: Prospective and archival stool specimens were collected in Cary-Blair medium or unpreserved containers from adult and pediatric patients with diarrhea. Specimens tested via the MAX EVP (on the BD MAX™ System) were compared to reference method (alternate PCR assays, followed by bi-directional sequencing). Positive percent agreement (PPA) and negative percent agreement (NPA) were calculated. Results: A total of 2,239 specimens were collected, with 2,148 included for analysis. In this population, 39.6% of specimens were from outpatients, 42.1% were from patients < 21 years, and 49.7% were from females. Prevalence rates for prospective specimens were 7.3%, 4.5%, 3.5%, 2.4%, and 1.2% for norovirus, sapovirus, astrovirus, rotavirus, and ...
7 minutes | Jun 19, 2019
Assessing the Correlation Between Perianal Fistula Healing & Trough Levels of Infliximab in Children with IBD
Host: Alka Goyal, MD Higher Postinduction Infliximab Serum Trough Levels Are Associated With Healing of Fistulizing Perianal Crohn’s Disease in Children. Wael El-Matary, MD, MSc Thomas D Walters, MD Hien Q Huynh, MDJennifer deBruyn, MD David R Mack, MD Kevan Jacobson, MD Mary E Sherlock, MDPeter Church, MD Eytan Wine, MD, PhD Matthew W Carroll, MD, Eric I Benchimol, MD, PhD Sally Lawrence, MD Anne M Griffiths, MD Background: There is some evidence in adults that higher serum infliximab (IFX) levels are needed to adequately treat fistulizing perianal Crohn's disease (CD). However, data in children are lacking. We aimed to determine postinduction serum trough IFX levels that are associated with healing of fistulizing perianal CD (PCD) at week 24. Methods: In a multicenter inception cohort study, consecutive children younger than age 17 years with fistulizing perianal CD treated with IFX between April 2014 and June 2017 who had serum trough IFX titers measured before the fourth infusion were included. Area under the receiver operating characteristic curve (AUROC) was calculated to determine the best cutoff to predict fistula healing. Results: A total of 667 children with Crohn's disease were recruited, with 85 (12.7%) patients diagnosed with fistulizing PCD. There were 27 of 52 (52%) children ...
4 minutes | Jun 19, 2019
Does Obesity Play a Role in the History of Inflammatory Bowel Diseases?
Host: Louis J Cohen, MD Impact of Obesity on Short- and Intermediate-Term Outcomes in Inflammatory Bowel Disease: Pooled Analysis of Placebo Arms of Infliximab Clinical Trials. Siddharth Singh, MD, MS James Proudfoot, MS Ronghui Xu, PhDWilliam J Sandborn, MD Background: To assess whether obesity may affect natural history of inflammatory bowel diseases (IBD), we conducted an individual participant data (IPD) pooled analysis of placebo arms, using data from clinical trials of infliximab in IBD and using the Yale Open Data Access (YODA) Project. Methods: We obtained IPD from 4 placebo-controlled trials of infliximab in adults with IBD (ACCENT-I and ACCENT-II; ACT-1 and ACT-2). Patients were categorized into quartiles based on body mass index (BMI) or weight at time of trial entry. Primary outcome was clinical remission (Crohn’s disease activity index [CDAI]<150, Mayo Clinic Score <3); secondary outcomes were clinical response and mucosal healing. Using multivariable logistic regression analysis, we compared association between quartiles of BMI (or weight) and achieving remission, after adjusting for sex, smoking, disease activity, and concomitant prednisone or immunomodulators. Results: We included 575 placebo-treated patients (mean age 38 years, 51.6% males, 16% obese). Obesity was not associated with odds of achieving clinical remission (Q4 vs Q1: adjusted OR, 1.36; 95% CI, 0.65–2.89; ...
6 minutes | Mar 29, 2019
Iron Sequestration in Microbiota Biofilms in Treatment for IBD
Host: Damian Maseda, D.M.Sc., PhD Iron Sequestration in Microbiota Biofilms As A Novel Strategy for Treating Inflammatory Bowel Disease. Jean-Paul Motta, PhD Thibault Allain, PhD Luke E Green-Harrison, BScRyan A Groves, MSc Troy Feener, MSc Hena Ramay, PhD Paul L Beck, MD/PhDIan A Lewis, PhD John L Wallace, PhD Andre G Buret, PhD ABSTRACT: Significant alterations of intestinal microbiota and anemia are hallmarks of inflammatory bowel disease (IBD). It is widely accepted that iron is a key nutrient for pathogenic bacteria, but little is known about its impact on microbiota associated with IBD. We used a model device to grow human mucosa-associated microbiota in its physiological anaerobic biofilm phenotype. Compared to microbiota from healthy donors, microbiota from IBD patients generate biofilms ex vivo that were larger in size and cell numbers, contained higher intracellular iron concentrations, and exhibited heightened virulence in a model of human intestinal epithelia in vitro and in the nematode Caenorhabditis elegans. We also describe an unexpected iron-scavenging property for an experimental hydrogen sulfide-releasing derivative of mesalamine. The findings demonstrate that this new drug reduces the virulence of IBD microbiota biofilms through a direct reduction of microbial iron intake and without affecting bacteria survival or species composition within the microbiota. Metabolomic analyses ...
5 minutes | Jan 29, 2019
Reliability of Measuring Ileo-Colonic Disease Activity in Crohn's Disease by MR Enterography
Guest: Yash Mittal, MD Reliability of Measuring Ileo-Colonic Disease Activity in Crohn's Disease by Magnetic Resonance Enterography. Vipul Jairath, MD, PhD, Ingrid Ordas, MD, PhD, Guangyong Zou, PhD, Julian Panes, MD, Jaap Stoker, MD, PhD, Stuart A Taylor, MD, Cynthia Santillan, MD, Karin Horsthuis, MD, Mark A Samaan, MD, Lisa M Shackelton, PhD, Larry W Stitt, MSc, Pieter Hindryckx, MD, PhD, Reena Khanna, MD, William J Sandborn, MD ,Geert D'Haens, MD, PhD, Brian G Feagan, MD, Barrett G Levesque, MD, and Jordi Rimola, MD, PhD BACKGROUND: Magnetic resonance enterography is increasingly utilized for assessment of luminal Crohn's disease activity. The Magnetic Resonance Index of Activity and the London Index are the most commonly used outcome measures in clinical trials. We assessed the reliability of these indices and several additional items. METHODS: A consensus process clarified scoring conventions and identified additional items based on face validity. Four experienced radiologists evaluated 50 images in triplicate, in random order, at least 1 month apart, using a central image management system. Intra- and interrater reliability were assessed by calculating and comparing intraclass correlation coefficients. RESULTS: Intrarater intraclass correlation coefficients (95% confidence intervals) for the Magnetic Resonance Index of Activity, London, and London "extended" indices and a visual analogue ...
4 minutes | Jan 29, 2019
Success of Adalimumab Dose Escalation & De-Escalation in Ulcerative Colitis
Guest: Shail Govani, MD, MSc Incidence and Predictors of Success of Adalimumab Dose Escalation and De-escalation in Ulcerative Colitis: a Real-World Belgian Cohort Study. Saartje Van de Vondel, MD, Filip Baert, MD, PhD, Christine Reenaers, MD, PhD, Stijn Vanden Branden, MD, Leila Amininejad, MD, Pieter Dewint, MD, PhD, Wouter Van Moerkercke, MD, Jean-François Rahier, MD, PhD, Pieter Hindryckx, MD, PhD, Peter Bossuyt, MD, Marc Ferrante, MD, PhD, and Belgian IBD Research and Development (BIRD) BACKGROUND: Adalimumab (ADM) has been shown efficacious in ulcerative colitis (UC). In randomized controlled trials, dose escalation from 40 mg ADM every other week to 40 mg every week was required in 20%–25% of patients within 1 year. Real-life data suggest higher escalation rates. Attempts for dose de-escalation have not been studied yet. We assessed the need for, outcome of, and predictors of dose escalation and de-escalation in a large retrospective cohort of UC patients treated with ADM. METHODS: We included 231 consecutive patients from 10 Belgian centers initiating ADM treatment for active UC before September 1, 2015 (follow-up ≥1 year in each patient). We performed detailed chart review to identify variables associated with short-term clinical benefit (based on physician global assessment and absence of rectal bleeding at week 10), success ...
5 minutes | Jan 2, 2018
Infliximab Trough Levels at Induction to Predict Treatment Failure During Maintenance
Infliximab Trough Levels at Induction to Predict Treatment Failure During Maintenance. Liefferinckx C1, Minsart C, Toubeau JF, Cremer A, Amininejad L, Quertinmont E, Devière J, Gils A, van Gossum A, Franchimont D. BACKGROUND: Infliximab (IFX) is indicated for the treatment of inflammatory bowel diseases (IBD). Nevertheless, loss of response (LOR) to IFX is reported in up to 10% to 30% of patients within the first year of treatment. Our objective was to evaluate the impact of the pharmacokinetics of IFX at induction on treatment failure. METHODS: This is a longitudinal cohort study on 269 patients with IBD treated with IFX in a single center. A total of 2331 blood samples were prospectively collected from 2007 until March 2015 with a retrospective analysis of clinical data. IFX trough levels (TLs) were measured by enzyme-linked immunosorbent assay. Antibodies to IFX were measured by drug-sensitive bridging assay. RESULTS: During follow-up, patients were defined according to treatment outcome. At week 6, median IFX TL in patients requiring a switch to another treatment due to LOR (LOR switched group) (2.32 μg/mL [0.12-19.93 μg/mL]) was lower than in patients with long-term response (long-term responders) (8.66 μg/mL [0.12-12.09 μg/mL], P = 0.007) and in patients responding to ...
7 minutes | Oct 30, 2017
Anti-TNF Treatment for Extraintestinal Manifestations of Inflammatory Bowel Disease in the Swiss IBD Cohort Study
Anti-TNF Treatment for Extraintestinal Manifestations of Inflammatory Bowel Disease in the Swiss IBD Cohort Study. Vavricka SR1, Gubler M, Gantenbein C, Spoerri M, Froehlich F, Seibold F, Protic M, Michetti P, Straumann A, Fournier N, Juillerat P, Biedermann L, Zeitz J, Misselwitz B, Scharl M, Heinrich H, Manser CN, Safroneeva E, Raja Ali RA, Rogler G, Schoepfer AM, Greuter T; Swiss IBD Cohort Study Group. BACKGROUND: Extraintestinal manifestations (EIMs) in patients with inflammatory bowel disease (IBD) are frequently observed. Little is known about the efficacy of anti-tumor necrosis factor (TNF) in EIM management. We assessed the effect of 3 anti-TNF agents (infliximab, adalimumab, and certolizumab pegol) on EIM evolution. METHODS: Data on 1249 patients from the Swiss IBD Cohort Study (SIBDCS) were analyzed. All EIMs were diagnosed by relevant specialists. Response was classified into improvement, stable disease, and clinical worsening based on the physician's interpretation. RESULTS: Of the 366 patients with at least 1 EIM, 213 (58.2%) were ever treated with an anti-TNF. A total of 299 treatments were started for 355 EIMs. Patients with EIM were significantly more often treated with anti-TNF compared with those without EIM (58.2% versus 21.0%, P < 0.001). Infliximab was the most frequently used ...
6 minutes | Jul 28, 2017
Anti-TNFα Treatment After Surgical Resection for Crohn's Disease Is Effective Despite Previous Pharmacodynamic Failure
Anti-TNFα Treatment After Surgical Resection for Crohn's Disease Is Effective Despite Previous Pharmacodynamic Failure Assa A1, Bronsky J, Kolho KL, Zarubova K, de Meij T, Ledder O, Sladek M, van Biervliet S, Strisciuglio C, Shamir R. BACKGROUND: The outcome of patients with Crohn's disease who failed anti-tumor necrosis factor alpha (anti-TNFα) therapy despite adequate serum drug levels (pharmacodynamic failure) is unclear. We aimed to assess such pediatric patients who underwent intestinal resection and were re-treated with the same anti-TNFα agent postoperatively. METHODS: Pediatric patients with Crohn's disease who underwent intestinal resection and were treated with anti-TNFα agents postoperatively were assessed retrospectively. Patients were stratified to those with preoperative anti-TNFα pharmacodynamic failure and those with no preoperative anti-TNFα treatment. RESULTS: A total of 53 children were included, 18 with pharmacodynamic failure and 35 controls. Median age at intestinal resection was 14.8 years with 23 (43%) girls. The median time from intestinal resection to anti-TNFα initiation was 8 months (interquartile range 4-14 months). At the time of postoperative anti-TNFα initiation, there were no differences in clinical, laboratory, and anthropometric measures between groups. Similar proportions of patients from both groups were in clinical remission on anti-TNFα treatment after 12 months and at the ...
5 minutes | May 4, 2017
Vedolizumab as Induction and Maintenance Therapy for Crohn’s Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy
Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Sands BE1, Sandborn WJ, Van Assche G, Lukas M, Xu J, James A, Abhyankar B, Lasch K. BACKGROUND: Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). METHODS: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. RESULTS: Among patients who responded to vedolizumab induction at week 6, 48.9% ...
5 minutes | Feb 27, 2017
Predictors of Emergency Department Use by Persons with Inflammatory Bowel Diseases: A Population-Based Study
Predictors of Emergency Department Use by Persons with Inflammatory Bowel Diseases: A Population-based Study Nugent, Zoann PhD; Singh, Harminder MD, MPH; Targownik, Laura E. MD; Strome, Trevor MS; Snider, Carolyn MD, MPH; Bernstein, Charles N. MD Background: To describe the patterns and predictors of emergency department (ED) attendance and post-ED hospitalization by persons with inflammatory bowel disease (IBD). Methods: We linked the University of Manitoba IBD Epidemiology Database with the Emergency Department Information System of the Winnipeg Regional Health Authority to determine the rates of presentation to the ED by persons with IBD from January 01, 2009 to March 31, 2012. Incident cases were diagnosed during the study period and all others were considered prevalent cases. Multivariate logistic regression was used to determine predictors of attendance in the ED and for hospitalization within 2 days of ED attendance. Results: The study population included 300 incident and 3394 prevalent IBD cases, of whom 76% and 49%, respectively, attended the ED at least once during the study period. Incident cases with Crohn's disease or with a history of opioid use were more likely to attend the ED. Those who had seen a gastroenterologist within the year before diagnosis were less likely to ...
4 minutes | Oct 31, 2016
Impact of Specialized Inpatient IBD Care on Outcomes of IBD Hospitalizations
Impact of Specialized Inpatient IBD Care on Outcomes of IBD Hospitalizations: A Cohort Study Law, Cindy C. Y. MD; Sasidharan, Saranya MD; Rodrigues, Rodrigo MD; Nguyen, Deanna D. MD; Sauk, Jenny MD; Garber, John MD; Giallourakis, Cosmas MD; Xavier, Ramnik MD, PhD; Khalili, Hamed MD, MPH; Yajnik, Vijay MD, PhD; Ananthakrishnan, Ashwin N. MD, MPH Host: Dr. Manish Singla, Gastroenterology Division, Department of Internal Medicine, Walter Reed National Military Medical Center, Bethesda, MD Background: The management of inflammatory bowel diseases (IBDs; Crohn's disease, ulcerative colitis) is increasingly complex. Specialized care has been associated with improved ambulatory IBD outcomes. Aims: To examine if the implementation of specialized inpatient IBD care modified short-term and long-term clinical outcomes in IBD-related hospitalizations. Methods: This retrospective cohort study included IBD patients hospitalized between July 2013 and April 2015 at a single tertiary referral center where a specialized inpatient IBD care model was implemented in July 2014. In-hospital medical and surgical outcomes as well as postdischarge outcomes at 30 and 90 days were analyzed along with measures of quality of in-hospital care. Effect of specialist IBD care was examined on multivariate analysis. Results: A total of 408 IBD-related admissions were included. With implementation of specialized IBD ...
3 minutes | Oct 25, 2016
Tissue-Specific Protein Clusters May Help Predict Risk of Alzheimer’s Disease
A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease Rosie Freer, Pietro Sormanni, Giulia Vecchi, Prajwal Ciryam, Christopher M. Dobson, and Michele Vendruscolo Science Advances 10 Aug 2016: Vol. 2, no. 8, e1600947 DOI: 10.1126/sciadv.1600947 Abstract: In Alzheimer’s disease, aggregates of Aβ and tau in amyloid plaques and neurofibrillary tangles spread progressively across brain tissues following a characteristic pattern, implying a tissue-specific vulnerability to the disease. We report a transcriptional analysis of healthy brains and identify an expression signature that predicts—at ages well before the typical onset—the tissue-specific progression of the disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the expression patterns of the proteins that coaggregate in amyloid plaques and neurofibrillary tangles, together with those of the protein homeostasis components that regulate Aβ and tau. Because this expression signature is evident in healthy brains, our analysis provides an explanatory link between a tissue-specific environmental risk of protein aggregation and a corresponding vulnerability to Alzheimer’s disease.
4 minutes | Aug 1, 2016
Journal of Cystic Fibrosis: Efficacy and Safety of Levofloxacin Inhalation Solution (APT-1026) in Stable Cystic Fibrosis Patients
A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients. Flume PA, VanDevanter DR, Morgan EE, Dudley MN, Loutit JS, Bell SC, Kerem E, Fischer R, Smyth AR, Aaron SD, Conrad D, Geller DE,Elborn JS. J Cyst Fibros. 2016 Jul;15(4):495-502. doi: 10.1016/j.jcf.2015.12.004. Epub 2016 Feb 4. Abstract RATIONALE: For patients with cystic fibrosis (CF), the use of inhaled antibiotics has become standard of care to suppress chronic Pseudomonas airways infection. There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time, making additional inhaled antibiotic classes desirable. APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF. OBJECTIVES: To compare the safety and efficacy of a 28-day course of treatment with LIS 240mg or placebo BID in persons ≥12years old with CF and chronic P. aeruginosa infection. METHODS: A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28days in CF patients ≥12years with chronic P. aeruginosa infection. Time to exacerbation was the primary endpoint. FEV1 (% predicted) and patient-reported quality oflife were among secondary endpoints. ...
3 minutes | Aug 1, 2016
Journal of Cystic Fibrosis: Microbial Colonization and Lung Function in Adolescents With Cystic Fibrosis
Microbial colonization and lung function in adolescents with cystic fibrosis. Hector A, Kirn T, Ralhan A, Graepler-Mainka U, Berenbrinker S, Riethmueller J, Hogardt M, Wagner M, Pfleger A, Autenrieth I, Kappler M, Griese M, Eber E, Martus P, Hartl D. J Cyst Fibros. 2016 May;15(3):340-9. doi: 10.1016/j.jcf.2016.01.004. Epub 2016 Feb 5. Abstract With intensified antibiotic therapy and longer survival, patients with cystic fibrosis (CF) are colonized with a more complex pattern ofbacteria and fungi. However, the clinical relevance of these emerging pathogens for lung function remains poorly defined. The aim ofthis study was to assess the association of bacterial and fungal colonization patterns with lung function in adolescent patients with CF. Microbial colonization patterns and lung function parameters were assessed in 770 adolescent European (German/Austrian) CF patients in a retrospective study (median follow-up time: 10years). Colonization with Pseudomonas aeruginosa and MRSA were most strongly associated with loss of lung function, while mainly colonization with Haemophilus influenzae was associated with preservedlung function. Aspergillus fumigatus was the only species that was associated with an increased risk for infection with P. aeruginosa.Microbial interaction analysis revealed three distinct microbial clusters within the longitudinal course of CF lung disease. Collectively, this study identified potentially protective ...
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