tbuckley/cabot-search huggingface dataset:
Combination Therapy With Infliximab and Azathioprine Improves Infliximab Pharmacokinetic Features and Efficacy: A Post Hoc Analysis
Authors: Jean-Frédéric Colombel, Omoniyi J. Adedokun, Christopher Gasink, Long-Long Gao, Freddy J. Cornillie, Geert R. D'Haens, Paul J. Rutgeerts, Walter Reinisch, William J. Sandborn, Stephen B. Hanauer
Journal: Clinical Gastroenterology and Hepatology (2018)

Background & AimsAmong immunosuppressive- and biologic-naïve patients with moderately-to-severely active Crohn's disease (CD), a higher proportion of those treated with the combination of infliximab and azathioprine achieved corticosteroid-free remission at week 26 (CSFR26) than those given infliximab monotherapy; patients given the combination therapy also had higher serum concentrations of infliximab. Enhanced benefit of combination therapy may occur through synergistic modes of action or the influence of azathioprine on infliximab pharmacokinetics.MethodsWe analyzed data from 206 patients from whom week 30 serum samples were available: 97 received infliximab monotherapy (5 mg/kg, n = 97) and 109 received combination therapy (2.5 mg/kg/day; n = 109). Proportions of patients achieving CSFR26 and mucosal healing (absence of ulcers) at week 26 were calculated for each quartile of serum concentrations of infliximab, and exposure–response relationships were compared.ResultsWithin quartiles of serum concentrations of infliximab, CSFR26 did not differ significantly between patients who received combination therapy vs monotherapy. However, among patients in the lowest quartile of serum concentration of infliximab, twice as many patients who received infliximab monotherapy achieved CSFR26 vs combination therapy. Anti-drug antibodies were detected only in the lowest quartile of serum concentrations of infliximab—in 35.9% of patients given monotherapy and 8.3% of patients given combination therapy.ConclusionAmong patients with CD and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. Combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. ClinicalTrials.gov, NCT00094458.
Abstract 10997: Catheter Ablation of Non-paroxysmal Atrial Fibrillation Using Sinus Rhythm Defragmentation Plus Low Voltage Zone Homogenization After Pulmonary Vein Isolation: 30 Months’ Outcome From Nonrandomized Comparison With Stepwise Approach
Authors: Gang Yang, Bing Yang, Youquan Wei, Fengxiang Zhang, Weizhu Ju, Hongwu Chen, Mingfang Li, Kai Gu, Yazhou Lin, Benqi Wang, Kejiang Cao, Pipin Kojodjojo, Minglong Chen
Journal: Circulation (2015)

Introduction: The high prevalence of postprocedural atrial tachycardia (AT) reduces the absolute arrhythmia-free success rate of extensive ablation strategies to treat non-paraxysmal atrial fibrillation (NPAF). We hypothesized that a strategy of targeting low voltage zones (LVZ) and sites with abnormal electrograms during sinus rhythm (SR-AEs) in the left atrium (LA) after circumferential pulmonary vein isolation (CPVI) and cavotricuspid isthmus (CTI) ablation in NPAF patients is superior to the widely practiced step-wise approach for NPAF ablation. Methods and Results: 86 consecutive patients with NPAF (persistent or longstanding) were enrolled in study group. Following CPVI, CTI ablation and cardioversion to SR, high density mapping of LA was performed. Areas with LVZ and SR-AE were targeted for further homogenization and elimination respectively. 78 consecutive sex- and age- matched NPAF patients who were treated with the stepwise approach served as the historical control group. AF recurrence was assessed with Holters and regular clinic visits. In the study group, 92% (79/86) were successfully cardioverted after CPVI and CTI ablation. The remaining 8% (7/86) underwent further ablation in a stepwise approach to restore SR. Among the patients converted to SR, 70% (55/79) had LVZ and SR-AE and received additional ablation whereas in 30% (24/79) without SR-AE or LVZ, no further ablation was performed. Over the similar follow-up period (30 ± 8 vs. 33 ± 10 months), 66% (57/86) were free from recurrence and 3.5% (3/86) developed postprocedural AT after a single procedure in study group, compared to 37% (29/78) overall success rate and 30% (24/78) AT incidence in control group. (P=0.011 and P=0.0003, respectively). Conclusions: A strategy of selective electrophysiological substrate modification in sinus rhythm after CPVI and CTI ablation is clinically more effective than the stepwise approach for NPAF ablation.
Docetaxel, cisplatin, and 5-fluorouracil-based induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin in locally advanced stage III and IV nasopharyngeal cancer.
Authors: Faysal Dane, Beste Melek Atasoy, Zuleyha Akgun, Fulden Yumuk, Devrim Cabuk, Mehmet Teomete, Gul Basaran, Serdar Turhal, Ufuk Abacioglu
Journal: Journal of Clinical Oncology (2012)

e16015 Background: Concomitant chemoradiatiotherapy (CRT) is the standard treatment in locally advanced nasopharyngeal cancer (LANPC). We studied the activity and tolerability of docetaxel, cisplatin and 5-fluorouracil-based induction chemotherapy (IC) followed by concurrent CRT with cisplatin in LANPC. Methods: Between 2004 and 2010 a total of 33 (15 stage III, 18 non-metastatic stage IV) patients were included into this retrospective analysis. Median age was 51 (range, 19 to 75) years. Twenty-five patients were male. IC was planned for three courses in all patients. IC was consisted of docetaxel and cisplatin (DC) in 11 patients and fluoropyrimidine, dosetaxel and cisplatin (DCF) in 22 patients. G-CSF and ciprofloxacin were given prophylactically to all patients received DCF. 3D conformal radiotherapy (RT) was administered in conventional fractionation (2Gy/fr, 5 fraction per week) using 6-18MV photon energy and appropriate electron energies. Therefore, nasopharynx, level I-V and supraclavicular lymph nodes received 46 Gy (phase I) whereas, nasopharynx and clinically positive or initially bulky lymph nodes received 70 Gy (phase II). Cisplatin (75 mg/m 2 /21days) was administered during RT concomitantly. Results: Median follow up for surviving patients was 48 months. There was no progression after IC. Complete (CR) and partial responses (PR) were achieved in 6 and 23 patients in nasopharynx, respectively. We observed CR and PR in 19 and 13 patients in neck, respectively. All patients were given 3 cycles of IC. The dose of chemotherapy was reduced in 8 patients during IC. Sixty-six percent of the planned cisplatin dose could be given in the concomitant setting. In 11 patients, cisplatin was either reduced or permanently stopped. Thirty-one patients completed RT as planned. Five years PFS and OS rates were 65.5% and 72.2% respectively. Conclusions: In our LANPC patients, induction DC(F) chemotherapy followed by concomitant CRT was promising. This strategy should be evaluated in prospective studies.
Assessment of health care resource utilization (HRU) in patients with castration-resistant prostate cancer (CRPC).
Authors: Sophia Li, Zhijie Ding, Jennifer H Lin, Chris Pericone, Ajay S. Behl, Neal D. Shore
Journal: Journal of Clinical Oncology (2018)

89 Background: Although patients with CRPC frequently develop metastasis within 3 years following castration resistance, the impact of metastasis on HRU in these patients is not well understood. Methods: The Optum de-identified electronic health record database (1/1/2007 – 4/30/2016) was used in this single cohort observational study comparing HRU after metastasis with HRU before metastasis. The cohort included only non-metastatic CRPC (nmCRPC) patients who later developed metastasis. The pre-metastasis period spanned from nmCRPC identification to development of metastasis; the post-metastasis period spanned from metastasis until death or end of data availability. Per-patient per-month (PPPM) HRU was estimated during both pre- and post-metastasis periods by a generalized linear mixed model adjusted for log-transformed baseline PSA, age, testosterone levels, and Charlson Comorbidity Index. Results: With a mean time of 11 and 17 months of pre- and post-metastasis periods, respectively, 540 CRPC men were included, with a mean age at nmCRPC identification of 75 years. Higher HRU was seen across all service types during the post-metastasis period. There was a 2.5-fold increase in inpatient admissions and a 6.4-fold increase in inpatient length-of-stay in the post-metastasis period compared to the pre-metastasis period (p &lt; 0.01). For emergency department (ED) visits, there was a 2.0-fold increase from the pre- to post-metastasis periods (p &lt; 0.01). For observation unit visits, a 2.7-fold increase was seen in the post-metastasis period (p &lt; 0.01). Finally, patients were 40% more likely to have an office visit after developing metastasis (p &lt; 0.01). The PPPM use of intensive care unit, hospice or skilled nursing facility were too low for meaningful comparison between the pre- and post-metastasis periods. Conclusions: Shorter time to metastasis was observed in this cohort vs. other nmCRPC studies, likely due to delayed disease identification. CRPC patients incurred substantially higher HRU after developing metastasis, attributable to inpatient, ED, observation unit as well as office visits, suggesting that delaying metastasis may reduce or delay the increased HRU in patients with nmCRPC.
Motility and biofilm formation of the emerging gastrointestinal pathogen<i>Campylobacter concisus</i>differs under microaerophilic and anaerobic environments
Authors: Sandra Ovesen, Juliana Durack, Karina Frahm Kirk, Hans Linde Nielsen, Henrik Nielsen, Susan V. Lynch
Journal: Gut Microbes (2018)

Campylobacter concisus has been isolated from patients with gastroenteritis and inflammatory bowel disease (IBD), as well as healthy subjects. While strain differences may plausibly explain virulence differentials, an alternative hypothesis posits that the pathogenic potential of this species may depend on altered ecosystem conditions in the inflamed gut. One potential difference is oxygen availability, which is frequently increased under conditions of inflammation and is known to regulate bacterial virulence. Hence, we hypothesized that oxygen influences C. concisus physiology. We therefore characterized the effect of microaerophilic or anaerobic environments on C. concisus motility and biofilm formation, two important determinants of host colonization and dissemination. C. concisus isolates (n = 46) sourced from saliva, gut mucosal biopsies and feces of patients with IBD (n = 23), gastroenteritis (n = 8) and healthy subjects (n = 13), were used for this study. Capacity to form biofilms was determined using crystal violet assay, while assessment of dispersion through soft agar permitted motility to be assessed. No association existed between GI disease and either motility or biofilm forming capacity. Oral isolates exhibited significantly greater capacity for biofilm formation compared to fecal isolates (p<0.03), and showed a strong negative correlation between motility and biofilm formation (r = -0.7; p = 0.01). Motility significantly increased when strains were cultured under microaerophilic compared to anaerobic conditions (p<0.001). Increased biofilm formation under microaerophillic conditions was also observed for a subset of isolates. Hence, differences in oxygen availability appear to influence key physiological aspects of the opportunistic gastrointestinal pathogen C. concisus.
Employing electronic health record data to predict risk of emergency department visits for new patients.
Authors: Robert Michael Daly, Dmitriy Gorenshteyn, Lior Gazit, Stefania Sokolowski, Kevin Nicholas, Claire Perry, Lynn Adams, Abigail Baldwin, Lauren L. Katzen, Yeneat O. Chiu, Diane Lauren Reidy, Brett A Simon, Wendy Perchick, Isaac Wagner
Journal: Journal of Clinical Oncology (2018)

314 Background: Acute care accounts for half of cancer expenditures and is a measure of poor quality care. Identifying patients at high risk for ED visits enables institutions to target symptom management resources to those most likely to benefit. Risk stratification models developed to date have not been meaningfully employed in oncology, and there is a need for clinically relevant models to improve patient care. Methods: We established a predictive analytics framework for clinical use with attention to the modeling technique, clinician feedback, and application metrics. The model employs EHR data from initial visit to first antineoplastic administration for new patients at our institution from January 2014 to June 2017. The binary dependent variable is occurrence of an ED visit within the first 6 months of treatment. From over 1,400 data features, the model was refined to include 400 clinically relevant ones spanning demographics, pathology, clinician notes, labs, medications, and psychosocial information. Clinician review was performed to confirm EHR data input validity. The final regularized multivariate logistic regression model was chosen based on clinical and statistical significance. Parameter selection and model evaluation utilized the positive predictive value for the top 25% of observations ranked by model-determined risk. The final model was evaluated using a test set containing 20% of randomly held out data. The model was calibrated based on a 5-fold cross-validation scheme over the training set. Results: There are 5,752 antineoplastic starts in our training set, and 1,457 in our test set. The positive predictive value of this model for the top 25% riskiest new start antineoplastic patients is 0.53. The 400 clinically relevant features draw from multiple areas in the EHR. For example, those features found to increase risk include: combination chemotherapy, low albumin, social work needs, and opioid use, whereas those found to decrease risk include stage 1 disease, never smoker status, and oral antineoplastic therapy. Conclusions: We have constructed a framework to build a clinically relevant model. We are now piloting it to identify those likely to benefit from a home-based, digital symptom management intervention.
Abstract 17862: Benefit and Safety of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes in 4416 Women in the IMPROVE-IT Trial
Authors: Eri Toda Kato, Robert P Giugliano, Michael A Blazing, Erin Bohula May, Sema Guneri, Jennifer A White, Jeong-Gun Park, Andrew Tershakovec, Thomas Musliner, Eugene Braunwald, Christopher P Cannon
Journal: Circulation (2015)

Background: Statin therapy is established in primary and secondary prevention guidelines both for men and women, although some people have questioned the benefits in women, where data are more limited. Adding the non-statin ezetimibe to statin therapy further reduced future CV events post ACS in IMPROVE-IT, but detailed analyses by sex have not been reported. Methods: In the IMPROVE-IT trial, patients hospitalized with ACS and LDL-C ≤125 mg/dL were randomized to ezetimibe/simvastatin 40mg (E/S) or placebo/simvastatin 40mg (P/S) and were followed up for a median of 6 yrs. The primary composite endpoint was CVD, MI, hospitalization for UA, coronary revascularization &gt;30 days, and stroke. Efficacy and safety outcomes in women vs men were compared, one of 23 pre-specified subgroups. Results: Among 18144 patients from IMPROVE-IT, 4416 (24%) were women. Compared with men, women were more likely to be older, diabetic, and hypertensive, but less likely to have prior revascularization or multiple vessel disease. At 12 months, the median difference in LDL-C in both women and men was 16 mg/dl between E/S and P/S. Women receiving E/S had a 12% RRR of the primary endpoint (HR vs P/S, 0.88; 95% CI, 0.79 to 0.99), compared with a 5% reduction for men (HR vs P/S; 0.95, 95% CI, 0.90 to 1.01; p interaction p=0.26). There were no differences between E/S and P/S in this or safety events (E/S vs. P/S; AST and/or ALT&gt;3ULN, 2.5% vs. 2.6%, 2.5% vs. 2.2%, cholecystectomy, 1.8% vs. 1.6%, 1.4% vs. 1.4%, myopathy, 0.2% vs. 0.2%, 0.1% vs. 0.1%, gallbladder-related AEs, 3.9% vs. 4.3%, 2.9% vs. 3.3%, in women and in men, respectively, p=all NS). Conclusion: IMPROVE-IT demonstrated that adding ezetimibe to statin reduces LDL-C and CV events in both women and men. A safety profile of ezetimibe supports the use of intensive, combination lipid lowering therapy to optimize CV outcomes in women as well as men.
Abstract 19023: Aerobic Exercise Training-induced Increase in Circulating Irisin Level is Associated With Reduced Arterial Stiffness in Obesity
Authors: Kenichiro Inoue, Shumpei Fujie, Natsuki Hasegawa, Naoki Horii, Kiyoshi Sanada, Takafumi Hamaoka, Motoyuki Iemitsu
Journal: Circulation (2017)

Introduction: Aerobic exercise training reduces arterial stiffness mediated by nitric oxide (NO)-derived vasodilation in obese patients. Irisin is mainly expressed in myocytes and promotes NO relea...
Abstract 17830: Statin Use is Associated With a Reduced Risk of Intracerebral Hemorrhage Recurrence: A Population-based Cohort Study
Authors: Mei-Chuan Chou, Kai-Hung Cheng, Chih-Sheng Chu, Yu-Han Chang, Liang-Yin Ke, Wen-Ter Lai, Ching-Kuan Liu, Yi-Hsin Yang, Chu-Huang Chen
Journal: Circulation (2015)

Background: The safety of statin use in patients with intracerebral hemorrhage (ICH) is an unsettled issue of critical importance during stroke management. To assess the benefits and risks of statin use in ICH patients, we analyzed the big data from the Taiwan National Health Insurance Research Database (NHIRD) collected from a population known to have a higher ICH incidence than the Westerners. Methods and Results: A random sample of 1,000,000 subjects representative of the 23-million population registered in the NHIRD from 1997 to 2010 was used for this retrospective cohort study. The cumulative risks of ICH, ischemic stroke, and transient ischemic attack (TIA) were analyzed among three ICH cohorts: non-statin (NS; no statin use before or after ICH), statin (S; continued or initiated statin use after ICH), and statin-withdrawal (SW; statin use discontinued after ICH). A total of 2408 ICH patients (age 63.4±14.2 years, 62.5% male) were identified between 2000 and 2005 and followed for an average of 7.0 years. A Cox proportional hazard regression model was applied to estimate the hazard ratios (HRs) with adjustment for potential confounders. Compared to NS, S had a 71% (HR 0.29, CI 0.19-0.43; P&lt;0.001) reduction in ICH recurrence (Figure). The risk of ICH recurrence decreased as a function of the increment of cumulative defined daily doses (P trend &lt;0.0001). In contrast, SW had a 1.5-fold increase in ICH recurrence (HR 1.55, CI 1.09-2.22; P=0.016) and a 2-fold increase in ischemic stroke or TIA development (HR 2.01,CI 1.30-3.11; P=0.002). Conclusions: Based on this large database, continuation or initiation of stain use in ICH patients is associated with a reduced risk of ICH recurrence in a dose-dependent manner; discontinuation of statin use confers significant risks for both ICH recurrence and ischemic stroke/TIA development. Mechanistic studies are warranted to further validate the significance of this observation.
Distinct “Immunoallertypes” of Disease and High Frequencies of Sensitization in Non–Cystic Fibrosis Bronchiectasis
Authors: Micheál Mac Aogáin, Pei Yee Tiew, Albert Yick Hou Lim, Teck Boon Low, Gan Liang Tan, Tidi Hassan, Thun How Ong, Sze Lei Pang, Zi Yang Lee, Xiao Wei Gwee, Christopher Martinus, Yang Yie Sio, Sri Anusha Matta, Tan Ching Ong, Yuen Seng Tiong, Kang Ning Wong, Sriram Narayanan, Veonice Bijin Au, Damien Marlier, Holly R. Keir, Augustine Tee, John Arputhan Abisheganaden, Mariko Siyue Koh, De Yun Wang, John E. Connolly, Fook Tim Chew, James D. Chalmers, Sanjay H. Chotirmall
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Allergic sensitization is associated with poor clinical outcomes in asthma, chronic obstructive pulmonary disease, and cystic fibrosis; however, its presence, frequency, and clinical significance in non-cystic fibrosis bronchiectasis remain unclear.To determine the frequency and geographic variability that exists in a sensitization pattern to common and specific allergens, including house dust mite and fungi, and to correlate such patterns to airway immune-inflammatory status and clinical outcomes in bronchiectasis.Patients with bronchiectasis were recruited in Asia (Singapore and Malaysia) and the United Kingdom (Scotland) (n = 238), forming the Cohort of Asian and Matched European Bronchiectasis, which matched recruited patients on age, sex, and bronchiectasis severity. Specific IgE response against a range of common allergens was determined, combined with airway immune-inflammatory status and correlated to clinical outcomes. Clinically relevant patient clusters, based on sensitization pattern and airway immune profiles ("immunoallertypes"), were determined.A high frequency of sensitization to multiple allergens was detected in bronchiectasis, exceeding that in a comparator cohort with allergic rhinitis (n = 149). Sensitization was associated with poor clinical outcomes, including decreased pulmonary function and more severe disease. "Sensitized bronchiectasis" was classified into two immunoallertypes: one fungal driven and proinflammatory, the other house dust mite driven and chemokine dominant, with the former demonstrating poorer clinical outcome.Allergic sensitization occurs at high frequency in patients with bronchiectasis recruited from different global centers. Improving endophenotyping of sensitized bronchiectasis, a clinically significant state, and a "treatable trait" permits therapeutic intervention in appropriate patients, and may allow improved stratification in future bronchiectasis research and clinical trials.
Massive false-positive gene–gene interactions by Rothman’s additive model
Authors: Kwangwoo Kim
Journal: Annals of the Rheumatic Diseases (2018)

Rothman’s additive interaction model based on additivity of the relative risks of two disease-risk factors has frequently been used to investigate gene–gene interactions for various traits, especially for rheumatic diseases compared with other diseases (online supplementary text). For example, a recent paper by Diaz-Gallo et al 1 reported significant additive interactions between the HLA-DRB1 shared-epitope allele and numerous non-HLA rheumatoid arthritis (RA) risk variants (eg, PTPN22 variants) in anti-citrullinated protein antibody–positive (ACPA-positive) RA.### Supplementary data

[annrheumdis-2018-214297-supp1.pdf] 

This study investigated the validity of the additive interaction model in assessing gene–gene interactions. Genome-wide association study (GWAS) datasets including 1000 cases and 1000 controls were simulated 100 times based on an actual GWAS dataset from 2849 WTCCC2 controls (1958\_British\_Birth) to have European genomic features and a single variant with OR≈5, 3, 2, 1.5, 1.2 or 1 in a dominant genetic model (used in a typical additive interaction analysis). The simulated dataset is expected to have no true disease-risk effects of variants (except for an OR-simulated variant) and no true biological interaction effects between any variants on risk of a fake disease. Using the simulated datasets, all possible interactions between an OR-simulated variant and other variants in different chromosomes …