Publications by authors named "Wenqiong Xue"

18 Publications

  • Page 1 of 1

Tiotropium/Olodaterol Delays Clinically Important Deterioration Compared with Tiotropium Monotherapy in Patients with Early COPD: a Post Hoc Analysis of the TONADO Trials.

Adv Ther 2021 01 11;38(1):579-593. Epub 2020 Nov 11.

Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UK.

Introduction: Since chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, a composite endpoint of clinically important deterioration (CID) may provide a more holistic assessment of treatment efficacy. We compared long-acting muscarinic antagonist/long-acting β-agonist combination therapy with tiotropium/olodaterol versus tiotropium alone using a composite endpoint for CID. CID was evaluated overall and in patients with low exacerbation history (at most one moderate exacerbation in the past year [not leading to hospitalisation]), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 patients and maintenance-naïve patients with COPD. We assessed whether early treatment optimisation is more effective with tiotropium/olodaterol versus tiotropium in delaying and reducing the risk of CID.

Methods: Data were analysed from 2055 patients treated with either tiotropium/olodaterol 5/5 μg or tiotropium 5 μg (delivered via Respimat) in two replicate, 52-week, parallel-group, double-blind studies (TONADO 1/2). CID was defined as a decline of at least 0.1 L from baseline in trough forced expiratory volume in 1 s, increase from baseline of at least 4 units in St. George's Respiratory Questionnaire score, or moderate/severe exacerbation. Time to first occurrence of one of these events was recorded as time to first CID.

Results: Overall, treatment with tiotropium/olodaterol significantly increased the time to, and reduced the risk of, CID versus tiotropium (median time to CID 226 versus 169 days; hazard ratio [HR] 0.76 [95% confidence interval 0.68, 0.85]; P < 0.0001). Significant reductions were also observed in patients with low exacerbation history (241 versus 170; HR 0.73 [0.64, 0.83]; P < 0.0001), GOLD 2 patients (241 versus 169; 0.72 [0.61, 0.84]; P < 0.0001) and maintenance-naïve patients (233 versus 171; 0.75 [0.62, 0.91]; P = 0.0030).

Conclusion: In patients with COPD, including patients with low exacerbation history, GOLD 2 patients and maintenance-naïve patients, tiotropium/olodaterol reduced the risk of CID versus tiotropium. These results demonstrate the advantages of treatment optimisation with tiotropium/olodaterol over tiotropium monotherapy.

Trial Registration: ClinicalTrials.gov identifier: TONADO 1 and 2 (NCT01431274 and NCT01431287, registered 8 September 2011).
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http://dx.doi.org/10.1007/s12325-020-01528-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854451PMC
January 2021

Blood eosinophils as a biomarker of future COPD exacerbation risk: pooled data from 11 clinical trials.

Respir Res 2020 Sep 17;21(1):240. Epub 2020 Sep 17.

Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

Background: Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation and chronic inflammation. Predicting exacerbations of COPD, which contribute to disease progression, is important to guide preventative treatment and improve outcomes. Blood eosinophils are a biomarker for patient responsiveness to inhaled corticosteroids (ICS); however, their effectiveness as a predictive biomarker for COPD exacerbations is unclear.

Methods: This post hoc analysis pooled data from 11 Boehringer Ingelheim-sponsored Phase III and IV randomised COPD studies with similar methodologies. Exacerbation data were collected from these studies, excluding patients from the ICS withdrawal arm of the WISDOM® study. Patients were grouped according to their baseline blood eosinophil count, baseline ICS use and number of exacerbations in the year prior to each study.

Results: Exacerbation rate data and baseline eosinophil count were available for 22,125 patients; 45.6% presented with a baseline blood eosinophil count of ≤ 150 cells/μL, 34.3% with 150-300 cells/μL and 20.1% with > 300 cells/μL. The lowest exacerbation rates were observed in patients with ≤ 150 cells/μL, with small increases in exacerbation rate observed with increasing eosinophil count. When stratified by exacerbation history, the annual rate of exacerbations for patients with 0 exacerbations in the previous year increased in line with increasing eosinophil counts (0.38 for ≤ 150 cells/μL, 0.39 for 150-300 cells/μL and 0.44 for > 300 cells/μL respectively). A similar trend was identified for patients with one exacerbation in the previous year, 0.62, 0.66 and 0.67 respectively. For patients with ≥ 2 exacerbations, exacerbation rates fluctuated between 1.02 (≤ 150 cells/μL) to 1.10 (150-300 cells/μL) and 1.07 (> 300 cells/μL). Higher exacerbation rates were noted in patients treated with ICS at baseline (range 0.75 to 0.82 with increasing eosinophil count) compared with patients not on ICS (range 0.45 to 0.49).

Conclusion: We found no clinically important relationship between baseline blood eosinophil count and exacerbation rate. Hence, the current analysis does not support the use of blood eosinophils to predict exacerbation risk; however, previous exacerbation history was found to be a more reliable predictor of future exacerbations.

Trial Registration: ClinicalTrials.gov Identifiers: NCT00168844 , NCT00168831 , NCT00387088 , NCT00782210 , NCT00782509 , NCT00793624 , NCT00796653 , NCT01431274 , NCT01431287 , NCT02296138 and NCT00975195 .
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http://dx.doi.org/10.1186/s12931-020-01482-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499955PMC
September 2020

COPD Maintenance Therapy with Tiotropium/Olodaterol Compared with Tiotropium: An Analysis in the Absence of Additional ICS Therapy.

COPD 2020 Oct 15;17(5):477-484. Epub 2020 Sep 15.

Pneumology Department, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.

The American Thoracic Society guidelines recommend long-acting β-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilation over LAMA or LABA monotherapy as maintenance therapy for patients with chronic obstructive pulmonary disease suffering from dyspnea or exercise intolerance. Previous studies, which included patients receiving background inhaled corticosteroids (ICS), have shown the benefits of dual bronchodilation over monotherapy. This analysis aimed to confirm the benefits of LAMA/LABA over LAMA alone, without any confounding effects from ICS use. This pooled analysis compared the efficacy of tiotropium/olodaterol with tiotropium alone in patients from the TONADO and OTEMTO clinical trials who were not receiving ICS at study entry or during the studies. We analyzed change from baseline in trough forced expiratory volume in 1 s (FEV), St. George's Respiratory Questionnaire (SGRQ) score and Transition Dyspnea Index (TDI) score in all patients, by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage, baseline SGRQ score, and Baseline Dyspnea Index score. In this analysis of 1596 patients, tiotropium/olodaterol improved trough FEV, SGRQ and TDI compared with tiotropium alone. The observed mean differences were: trough FEV, 0.054 L (95% confidence interval [CI] 0.036, 0.073;  < 0.001); SGRQ, -1.918 (95% CI -2.994, -0.843;  < 0.001); and TDI, 0.575 (95% CI 0.301, 0.848;  < 0.001). Similar improvements were seen in each of the subgroup analyses. Tiotropium/olodaterol therapy significantly improved lung function, symptoms and health status compared with tiotropium alone. In a population free from ICS treatment, these data confirm the benefits of dual bronchodilation versus monotherapy.
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http://dx.doi.org/10.1080/15412555.2020.1813269DOI Listing
October 2020

Tiotropium/Olodaterol Decreases Exacerbation Rates Compared with Tiotropium in a Range of Patients with COPD: Pooled Analysis of the TONADO/DYNAGITO Trials.

Adv Ther 2020 10 10;37(10):4266-4279. Epub 2020 Aug 10.

Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

Introduction: Previous studies demonstrated that tiotropium/olodaterol reduced rates of exacerbations in patients with chronic obstructive pulmonary disease (COPD). However, this should be examined in a wider population.

Methods: This post hoc analysis pooled data from TONADO 1 + 2 and DYNAGITO, three 52-week, parallel-group, randomised, double-blind, phase III trials investigating patients with moderate-to-very severe COPD, with and without previous exacerbations, who received tiotropium/olodaterol 5/5 µg or tiotropium 5 µg. Subgroup analyses were conducted on patients stratified by exacerbation history, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2-4 disease severity and baseline inhaled corticosteroid (ICS) use.

Results: In 9942 patients, tiotropium/olodaterol was associated with lower rates of moderate/severe exacerbations (0.68 vs. 0.77 per patient-year; rate ratio (RR) vs. tiotropium 0.89, 95% confidence interval (CI) 0.84, 0.95; P = 0.0003) and exacerbations requiring hospitalisation (0.11 vs. 0.13 per patient-year; RR 0.86, 95% CI 0.75, 0.99; P = 0.0380) versus tiotropium. Lower rates of moderate/severe exacerbations with tiotropium/olodaterol versus tiotropium were evident in patients with 0-1 moderate exacerbation in the previous year (0.54 vs. 0.60 per patient-year; RR 0.90, 95% CI 0.82, 0.98; P = 0.0187) and at least two moderate or at least one severe exacerbation(s) in the previous year (0.97 vs. 1.09 per patient-year; RR 0.89, 95% CI 0.82, 0.97; P = 0.0096). In patients with GOLD 2 and GOLD 3 COPD, moderate/severe exacerbation rates were lower with tiotropium/olodaterol versus tiotropium; GOLD 4 patients showed negligible difference between treatments. When evaluating patients by baseline ICS use, there was a significantly lower rate of moderate/severe exacerbations with tiotropium/olodaterol versus tiotropium in patients receiving ICS.

Conclusions: Tiotropium/olodaterol decreased the rate of moderate/severe exacerbations and exacerbations leading to hospitalisation versus tiotropium. Results from this large, pooled, post hoc analysis support the use of dual bronchodilation with tiotropium/olodaterol in a broad range of patients, reflective of patients with COPD in clinical practice.

Trial Registration: TONADO 1 (ClinicalTrials.gov: NCT01431274); TONADO 2 (ClinicalTrials.gov: NCT01431287); DYNAGITO (ClinicalTrials.gov: NCT02296138). People with chronic obstructive pulmonary disease (COPD) may have times when their symptoms worsen, known as exacerbations. This may mean that they need to take additional medications, such as antibiotics or oral steroids. Studies have shown that a combination of two types of inhaled medicine-tiotropium and olodaterol-can help to reduce exacerbations in some people. To see if this is also the case across a larger and more diverse range of people, we combined the results from three studies (TONADO 1 + 2 and DYNAGITO) that looked at people who were taking tiotropium and olodaterol together and people who were taking tiotropium alone. We showed that, across a wide range of people, treatment with tiotropium/olodaterol was generally better at reducing exacerbations than tiotropium. Tiotropium/olodaterol also decreased the number of exacerbations that led to hospitalisation compared with tiotropium. Overall, our results support the use of combined tiotropium/olodaterol in people at different stages of COPD.
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http://dx.doi.org/10.1007/s12325-020-01438-3DOI Listing
October 2020

Efficacy of Tiotropium/Olodaterol Compared with Tiotropium as a First-Line Maintenance Treatment in Patients with COPD Who Are Naïve to LAMA, LABA and ICS: Pooled Analysis of Four Clinical Trials.

Adv Ther 2020 10 15;37(10):4175-4189. Epub 2020 Jul 15.

Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA.

Introduction: The efficacy of tiotropium/olodaterol compared with tiotropium in patients with chronic obstructive pulmonary disease (COPD) has been demonstrated in a large clinical programme. Currently, randomised controlled trial (RCT) data on dual bronchodilation as first-line maintenance therapy are limited. In this post hoc analysis of pooled data from four RCTs, we compared the efficacy of tiotropium/olodaterol versus tiotropium as maintenance therapy in patients with COPD who were not receiving maintenance treatment with long-acting muscarinic antagonists (LAMAs), long-acting β-agonists (LABAs) or inhaled corticosteroids (ICS) ("maintenance naïve") at study entry.

Methods: TONADO 1/2 (52 weeks) and OTEMTO 1/2 (12 weeks) were phase III RCTs in patients with COPD. TONADO 1/2 and OTEMTO 1/2 enrolled patients with post-bronchodilator forced expiratory volume in 1 s (FEV) < 80% predicted (lower limit FEV ≥ 30% in OTEMTO 1/2 only). We examined the effect of tiotropium/olodaterol 5/5 µg versus tiotropium 5 µg on trough FEV response, St. George's Respiratory Questionnaire (SGRQ) total score and Transition Dyspnoea Index (TDI) focal score at 12 weeks in four pooled studies.

Results: The pooled analysis included 1078 maintenance-naïve patients. There were significant improvements with tiotropium/olodaterol versus tiotropium in trough FEV [0.056 L; 95% confidence interval (CI) 0.033, 0.079; P < 0.0001], SGRQ score (- 1.780; 95% CI - 3.126 to - 0.434; P = 0.0096) and TDI score (0.409; 95% CI 0.077, 0.741; P = 0.0158) at week 12. For patients receiving tiotropium/olodaterol, the odds of achieving a minimal clinically important difference from baseline in any of the analysed outcomes (FEV ≥ 0.1 L, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) were higher versus tiotropium.

Conclusions: In patients who were maintenance naïve at baseline, treatment initiation with tiotropium/olodaterol resulted in greater improvements in lung function, health status and dyspnoea severity compared with tiotropium alone, without compromising patient safety. These results support the use of dual bronchodilation with tiotropium/olodaterol as first-line maintenance treatment in patients with COPD.

Trial Registration: ClinicalTrials.gov: TONADO 1 and 2 (NCT01431274 and NCT01431287, registered 8 September 2011) and OTEMTO 1 and 2 (NCT01964352 and NCT02006732, registered 14 October 2013).
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http://dx.doi.org/10.1007/s12325-020-01411-0DOI Listing
October 2020

Benefits of Tiotropium/Olodaterol Compared with Tiotropium in Patients with COPD Receiving only LAMA at Baseline: Pooled Analysis of the TONADO and OTEMTO Studies.

Adv Ther 2020 08 27;37(8):3485-3499. Epub 2020 May 27.

Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA.

Introduction: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting β-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted.

Methods: TONADO 1&2 and OTEMTO 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with LAMA monotherapy at baseline who were randomised to receive either 5 µg tiotropium (LAMA) or 5/5 µg tiotropium/olodaterol (LAMA/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV), St. George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI).

Results: Overall, 151 patients received tiotropium; 148 received tiotropium/olodaterol. Mean differences from baseline with tiotropium/olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV, - 2.675 (95% CI - 5.060, - 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/olodaterol versus tiotropium for trough FEV (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P < 0.0001), SGRQ (OR 1.49, 95% CI 0.93, 2.40; P = 0.0980) and TDI (OR 2.81, 95% CI 1.71, 4.60; P < 0.0001). Minimum clinically important difference from baseline in any of the analysed outcomes (FEV ≥ 0.1 l, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) was more likely in patients treated with tiotropium/olodaterol versus tiotropium (OR 2.43, 95% CI 1.32, 4.51; P = 0.0046).

Conclusion: In patients with COPD receiving only LAMA monotherapy, treatment escalation to tiotropium/olodaterol resulted in statistically significant and clinically relevant improvements in lung function, health status and breathlessness. These results support early therapy optimisation to dual bronchodilation with tiotropium/olodaterol in patients receiving tiotropium alone.

Trial Registration: TONADO 1 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431274). TONADO 2 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431287). OTEMTO 1 was registered in the US National Library of Medicine on 17 October 2013 (Clinicaltrials.gov: NCT01964352). OTEMTO 2 was registered in the US National Library of Medicine on 10 December 2013 (Clinicaltrials.gov: NCT02006732).
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http://dx.doi.org/10.1007/s12325-020-01373-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370969PMC
August 2020

A Bayesian Spatial Model to Predict Disease Status Using Imaging Data From Various Modalities.

Front Neurosci 2018 26;12:184. Epub 2018 Mar 26.

Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, United States.

Relating disease status to imaging data stands to increase the clinical significance of neuroimaging studies. Many neurological and psychiatric disorders involve complex, systems-level alterations that manifest in functional and structural properties of the brain and possibly other clinical and biologic measures. We propose a Bayesian hierarchical model to predict disease status, which is able to incorporate information from both functional and structural brain imaging scans. We consider a two-stage whole brain parcellation, partitioning the brain into 282 subregions, and our model accounts for correlations between voxels from different brain regions defined by the parcellations. Our approach models the imaging data and uses posterior predictive probabilities to perform prediction. The estimates of our model parameters are based on samples drawn from the joint posterior distribution using Markov Chain Monte Carlo (MCMC) methods. We evaluate our method by examining the prediction accuracy rates based on leave-one-out cross validation, and we employ an importance sampling strategy to reduce the computation time. We conduct both whole-brain and voxel-level prediction and identify the brain regions that are highly associated with the disease based on the voxel-level prediction results. We apply our model to multimodal brain imaging data from a study of Parkinson's disease. We achieve extremely high accuracy, in general, and our model identifies key regions contributing to accurate prediction including caudate, putamen, and fusiform gyrus as well as several sensory system regions.
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http://dx.doi.org/10.3389/fnins.2018.00184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879954PMC
March 2018

Inpatient Glucose Values: Determining the Nondiabetic Range and Use in Identifying Patients at High Risk for Diabetes.

Am J Med 2018 04 6;131(4):443.e11-443.e24. Epub 2017 Oct 6.

Medical Subspecialty/Endocrinology, Atlanta VA Medical Center, Decatur, Ga; Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Ga.

Background: Many individuals with diabetes remain undiagnosed, leading to delays in treatment and higher risk for subsequent diabetes complications. Despite recommendations for diabetes screening in high-risk groups, the optimal approach is not known. We evaluated the utility of inpatient glucose levels as an opportunistic screening tool for identifying patients at high risk for diabetes.

Methods: We retrospectively examined 462,421 patients in the US Department of Veterans Affairs healthcare system, hospitalized on medical/surgical services in 2000-2010, for ≥3 days, with ≥2 inpatient random plasma glucose (RPG) measurements. All had continuity of care: ≥1 primary care visit and ≥1 glucose measurement within 2 years before hospitalization and yearly for ≥3 years after discharge. Glucose levels during hospitalization and incidence of diabetes within 3 years after discharge in patients without diabetes were evaluated.

Results: Patients had a mean age of 65.0 years, body mass index of 29.9 kg/m, and were 96% male, 71% white, and 18% black. Pre-existing diabetes was present in 39.4%, 1.3% were diagnosed during hospitalization, 8.1% were diagnosed 5 years after discharge, and 51.3% were never diagnosed (NonDM). The NonDM group had the lowest mean hospital RPG value (112 mg/dL [6.2 mmol/L]). Having at least 2 RPG values >140 mg/dL (>7.8 mmol/L), the 95th percentile of NonDM hospital glucose, provided 81% specificity for identifying incident diabetes within 3 years after discharge.

Conclusions: Screening for diabetes could be considered in patients with at least 2 hospital glucose values at/above the 95th percentile of the nondiabetic range (141 mg/dL [7.8 mmol/L]).
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http://dx.doi.org/10.1016/j.amjmed.2017.09.021DOI Listing
April 2018

Plasma microRNA-based signatures to predict 3-year postoperative recurrence risk for stage II and III gastric cancer.

Int J Cancer 2017 11 28;141(10):2093-2102. Epub 2017 Jul 28.

Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.

Our aim was to identify plasma microRNA (miRNA)-based signatures to predict 3-year postoperative recurrence risk for patients with stage II and III gastric cancer (GC), so as to provide insights for individualized adjuvant therapy. Plasma miRNA expression was investigated in three phases, involving 407 patients recruited from three centers. ABI miRNA microarray and TaqMan Low Density Array were adopted in the discovery phase to identify potential miRNAs. Quantitative reverse-transcriptase polymerase chain reaction was used to assess the expression of selected miRNAs. Logistic regression models were constructed in the training set (n = 170) and validated in the validation set (n = 169). Receiver operating characteristic analyses, survival analyses and subgroup analyses were further used to assess the accuracy of the models. We identified a 7 miRNA classifier and 7miR + pathological factors index that provided high predictive accuracy of GC recurrence (area under the curve = 0.725 and 0.841 in the training set; and 0.627 and 0.771 in the validation set). High-risk patients defined by the signatures had significantly shorter disease-free survival and overall survival than low-risk patients. The 7 miRNA classifier is an independent prognostic factor, and could add predictive value to traditional prognostic factors. Subgroup analyses revealed the satisfactory performance persisted regardless of stage, and the two models both displayed high accuracy in stage IIA patients. In conclusion, identified microRNA signature may potentially provide some additional benefit for prediction of disease recurrence in patients with stage II and III GC.
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http://dx.doi.org/10.1002/ijc.30895DOI Listing
November 2017

Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD.

Eur Respir J 2017 04 19;49(4). Epub 2017 Apr 19.

Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC, Canada.

Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all the Respimat inhaler. Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose).295 and 291 patients were treated in MORACTO 1 and 2, respectively. Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity placebo and monotherapies (p<0.0001), and significant improvements in exercise endurance time placebo (p<0.0001). Intensity of breathing discomfort was reduced following both doses of tiotropium/olodaterol placebo (p<0.0001).Once-daily tiotropium/olodaterol yielded improvements in lung hyperinflation placebo and statistically significant improvements monotherapies. Tiotropium/olodaterol also showed improvements in dyspnoea and exercise tolerance placebo but not consistently monotherapies.
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http://dx.doi.org/10.1183/13993003.01348-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898947PMC
April 2017

Prognostic efficacy of combining tumor volume with Epstein-Barr virus DNA in patients treated with intensity-modulated radiotherapy for nasopharyngeal carcinoma.

Oral Oncol 2016 09 30;60:18-24. Epub 2016 Jun 30.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Electronic address:

Objectives: To evaluate the prognostic effect of combining tumor volume with pre-treatment plasma Epstein-Barr virus DNA (EBV DNA) in patients treated with intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC).

Materials And Methods: A total of 180 consecutive NPC patients enrolled in this observational, prospective study and underwent IMRT. Tumor volume was delineated with IMRT planning system and plasma EBV DNA level was quantified by polymerized chain-reaction assay. The effects of tumor volume and EBV DNA level, either alone or in combination, on 5-year overall survival (OS) were cross-compared.

Results: The 5-year OS in patients with gross tumor volume of nasopharynx (GTVnx)⩽20cc and >20cc was significantly different (P=0.001). The 5-year OS in patients with EBV DNA <6800copies/mL and ⩾6800copies/mL was also significantly different (P<0.001). Based on the combination of GTVnx with EBV DNA, the 5-year OS in different subgroups was: low-risk (100%), intermediate-risk (87.8%, 95% CI: 70.6-95.2%) and high-risk (61.3%, 95% CI: 47.9-72.2%). Patients with small tumor volume and high EBV DNA level had a worse prognosis than those with large tumor and low EBV DNA level. Patients with low EBV DNA levels, and either small or large tumor volumes, had favorable prognosis. According to small or large tumor volume, patients with high EBV DNA level were divided into intermediaterisk and high-risk subgroups.

Conclusion: Combining tumor volume with pre-treatment plasma EBV DNA level altered survival-risk definition for subgroups of NPC patients and this combination, more than individual factors alone, improved the accuracy of prognostic evaluation.
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http://dx.doi.org/10.1016/j.oraloncology.2016.06.013DOI Listing
September 2016

Risk factors for kidney injury during vancomycin and piperacillin/tazobactam administration, including increased odds of injury with combination therapy.

BMC Res Notes 2015 Oct 17;8:579. Epub 2015 Oct 17.

Grady Health System Infectious Diseases Program, Atlanta, GA, USA.

Background: Acute kidney injury (AKI) occurs frequently in hospitalized patients and has been associated with the administration of certain medications. Concerns have been raised in recent reports that the antibiotic combination of vancomycin and piperacillin/tazobactam (combV/P) may be more associated with AKI than monotherapy with either drug.

Methods: To compare the incidence of and risk factors for AKI in patients receiving combV/P versus monotherapy with either drug, a retrospective study was conducted in non-critically ill inpatients at a large urban teaching hospital. AKI was defined as either: (1) Increase in serum creatinine ≥0.5 mg/dl OR (2) ≥1.5-fold creatinine increase from admission baseline. In addition to standard multivariable regression adjustment, propensity score weighting was used as a robust approach to reduce the effects of covariate confounding when estimating the adjusted odds of AKI.

Results: A total of 228 patients were evaluated. The overall incidence of AKI was 11.8 % (27 of 228 patients). AKI occurred in 4 of 101 patients in the vanc group (4.0 %), 4 of 26 patients in the piptazo group (15.4 %), and 19 of 101 patients in the combV/P group (18.8 %). The univariable odds of AKI was significantly lower in the vanc group compared to both the combV/P group (OR 0.178, 95 % CI 0.058-0.544, p = 0.003) and piptazo (OR 0.227, 95 % CI 0.053-0.978, p = 0.047) group. A multivariable model accounting for baseline characteristics again showed that vanc monotherapy was associated with lower odds of AKI than combV/P (OR 0.14, 95 % CI 0.04-0.52, p = 0.004). Male sex was also associated with lower odds of AKI (OR 0.28, 95 % CI 0.10-0.79, p = 0.02) in the multivariable model. In the propensity score analysis using inverse probability of treatment weighting (IPTW), vanc monotherapy and male sex were again associated with lower odds of AKI (OR 0.17; 95 % CI 0.04-0.62, p = 0.008 and OR 0.28, 95 % CI 0.09-0.89, p = 0.03, respectively).

Conclusion: This study substantiates recent reports that combV/P may be more associated with AKI than vanc monotherapy in hospital inpatients. AKI also appears to be more likely in females during therapy with these antimicrobials. While severity of illness is difficult to account for, these findings are further justification for narrowing antibiotic coverage when possible after this combination has been initiated in hospitalized patients.
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http://dx.doi.org/10.1186/s13104-015-1518-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609063PMC
October 2015

A multimodal approach for determining brain networks by jointly modeling functional and structural connectivity.

Front Comput Neurosci 2015 20;9:22. Epub 2015 Feb 20.

The Mind Research Network/Lovelace Biomedical and Environmental Research Institute Albuquerque, NM, USA ; Neurology Department, University of New Mexico School of Medicine Albuquerque, NM, USA.

Recent innovations in neuroimaging technology have provided opportunities for researchers to investigate connectivity in the human brain by examining the anatomical circuitry as well as functional relationships between brain regions. Existing statistical approaches for connectivity generally examine resting-state or task-related functional connectivity (FC) between brain regions or separately examine structural linkages. As a means to determine brain networks, we present a unified Bayesian framework for analyzing FC utilizing the knowledge of associated structural connections, which extends an approach by Patel et al. (2006a) that considers only functional data. We introduce an FC measure that rests upon assessments of functional coherence between regional brain activity identified from functional magnetic resonance imaging (fMRI) data. Our structural connectivity (SC) information is drawn from diffusion tensor imaging (DTI) data, which is used to quantify probabilities of SC between brain regions. We formulate a prior distribution for FC that depends upon the probability of SC between brain regions, with this dependence adhering to structural-functional links revealed by our fMRI and DTI data. We further characterize the functional hierarchy of functionally connected brain regions by defining an ascendancy measure that compares the marginal probabilities of elevated activity between regions. In addition, we describe topological properties of the network, which is composed of connected region pairs, by performing graph theoretic analyses. We demonstrate the use of our Bayesian model using fMRI and DTI data from a study of auditory processing. We further illustrate the advantages of our method by comparisons to methods that only incorporate functional information.
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http://dx.doi.org/10.3389/fncom.2015.00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335182PMC
March 2015

Identifying functional co-activation patterns in neuroimaging studies via poisson graphical models.

Biometrics 2014 Dec 21;70(4):812-22. Epub 2014 Aug 21.

Department of Biostatistics and Bioinformatics, Center for Biomedical Imaging Statistics, Rollins School of Public Health, Emory University, Atlanta, Georgia, U.S.A.; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, U.S.A.

Studying the interactions between different brain regions is essential to achieve a more complete understanding of brain function. In this article, we focus on identifying functional co-activation patterns and undirected functional networks in neuroimaging studies. We build a functional brain network, using a sparse covariance matrix, with elements representing associations between region-level peak activations. We adopt a penalized likelihood approach to impose sparsity on the covariance matrix based on an extended multivariate Poisson model. We obtain penalized maximum likelihood estimates via the expectation-maximization (EM) algorithm and optimize an associated tuning parameter by maximizing the predictive log-likelihood. Permutation tests on the brain co-activation patterns provide region pair and network-level inference. Simulations suggest that the proposed approach has minimal biases and provides a coverage rate close to 95% of covariance estimations. Conducting a meta-analysis of 162 functional neuroimaging studies on emotions, our model identifies a functional network that consists of connected regions within the basal ganglia, limbic system, and other emotion-related brain regions. We characterize this network through statistical inference on region-pair connections as well as by graph measures.
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http://dx.doi.org/10.1111/biom.12216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276452PMC
December 2014

Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women.

Nat Commun 2014 Aug 19;5:4682. Epub 2014 Aug 19.

1] Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China [2] Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.

Ovarian cancer is the leading cause of death from gynaecological malignancies worldwide. Here we perform a three-stage genome-wide association study (GWAS) in Han Chinese women to identify risk genetic variants for epithelial ovarian cancer (EOC). We scan 900,015 single-nucleotide polymorphisms (SNPs) in 1,057 EOC cases and 1,191 controls in stage I, and replicate 41 SNPs (P(meta)<10(-4)) in 960 EOC cases and 1,799 controls (stage II), and an additional 492 EOC cases and 1,004 controls (stage III). Finally, we identify two EOC susceptibility loci at 9q22.33 (rs1413299 in COL15A1, P(meta) = 1.88 × 10(-8)) and 10p11.21 (rs1192691 near ANKRD30A, P(meta) = 2.62 × 10(-8)), and two consistently replicated loci at 12q14.2 (rs11175194 in SRGAP1, P(meta) = 1.14 × 10(-7)) and 9q34.2 (rs633862 near ABO and SURF6, P(meta) = 8.57 × 10(-7)) (P<0.05 in all three stages). These results may advance our understanding of genetic susceptibility to EOC.
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http://dx.doi.org/10.1038/ncomms5682DOI Listing
August 2014

Warfarin therapy in the HIV medical home model: low rates of therapeutic anticoagulation despite adherence and differences in dosing based on specific antiretrovirals.

AIDS Patient Care STDS 2012 Aug 28;26(8):454-62. Epub 2012 Jun 28.

Emory University Department of Medicine, Division of Infectious Diseases, Atlanta, GA, USA.

To determine the indications for, rates of therapeutic anticoagulation during, and complications of warfarin therapy in HIV-infected individuals, in whom long-term anticoagulation is frequently indicated. To identify risk factors for nonoptimal anticoagulation and to determine if warfarin dosing is differentially affected by specific antiretroviral agents. Retrospective study of a dedicated anticoagulation program at one of the largest clinics for HIV-infected individuals in the United States. Seventy-three HIV-infected individuals on warfarin were followed for a total of 911 visits. The rate of therapeutic internation normalized ratio (INR) levels was 34.5% when including only visits at which patients were assessed to be adherent with warfarin. In multivariable analysis, injection drug use at baseline was an independent risk factor for subtherapeutic INR (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.3-4.7, p=0.01). Additionally, warfarin adherence was protective of both subtherapeutic (OR 0.4, 95% CI 0.2-0.6, p<0.0001) and supratherapeutic (OR 0.5, 95% CI 0.3-0.9, p=0.02) INR status. Efavirenz-based antiretroviral regimens were associated with lower weekly warfarin doses (46 mg) to maintain therapeutic INR compared to lopinavir/ritonavir-based regimens (68 mg; p=0.01) and atazanavir/ritonavir-based regimens (71 mg; p=0.007). Consistently therapeutic warfarin therapy is difficult to achieve in HIV-infected individuals, even with a dedicated anticoagulation program. Adherence to warfarin therapy is important but rates of therapeutic INR levels are nonetheless low. Lower warfarin dosing was required for efavirenz compared to two commonly used protease inhibitor-based regimens. Because of these factors, the emergence of new oral anticoagulants is an important development for HIV-infected individuals who require long term anticoagulation therapy.
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http://dx.doi.org/10.1089/apc.2012.0068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462408PMC
August 2012

Irrigating drains for severe odontogenic infections do not improve outcome.

J Oral Maxillofac Surg 2013 Jan 21;71(1):42-6. Epub 2012 Jun 21.

Rollins School of Public Health, Department of Biostatistics and Bioinformatics, Emory University School of Medicine, Atlanta, GA 30322, USA.

Purpose: The need to irrigate surgical drains in the postoperative period in patients with odontogenic infections is controversial. The purpose of this study was to evaluate the efficacy of irrigating surgical drains postoperatively in patients with severe odontogenic infections.

Materials And Methods: Consecutive patients presenting with severe odontogenic infections who required incision and drainage were randomized to irrigating drains (red rubber catheters) or nonirrigating drains (Penrose drains). The primary predictor variable was the type of drain and the use of postoperative irrigation. The primary outcome variable was length of stay. Secondary outcomes included postoperative temperature, need for additional procedures, and complications. The t test was used for the primary outcome, and a P value lower than .05 was considered statistically significant.

Results: Forty-six patients completed the study. There was no statistically significant difference in overall length of stay, length of stay after surgery, temperature, or need for additional procedures between the 2 treatment groups.

Conclusions: The use of nonirrigating drains appears to be equally efficacious as irrigating drains in the management of severe odontogenic infection.
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http://dx.doi.org/10.1016/j.joms.2012.04.043DOI Listing
January 2013

Temporary central venous catheter utilization patterns in a large tertiary care center: tracking the "idle central venous catheter".

Infect Control Hosp Epidemiol 2012 Jan 1;33(1):50-7. Epub 2011 Dec 1.

Division of Hospital Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Objectives: Although central venous catheter (CVC) dwell time is a major risk factor for catheter-related bloodstream infections (CR-BSIs), few studies reveal how often CVCs are retained when not needed ("idle"). We describe use patterns for temporary CVCs, including peripherally inserted central catheters (PICCs), on non-ICU wards.

Design: A retrospective observational study.

Setting: A 579-bed acute care, academic tertiary care facility.

Methods: A retrospective observational study of a random sample of patients on hospital wards who have a temporary, nonimplanted CVC, with a focus on on daily ward CVC justification. A uniform definition of idle CVC-days was used.

Results: We analyzed 89 patients with 146 CVCs (56% of which were PICCs); of 1,433 ward CVC-days, 361 (25.2%) were idle. At least 1 idle day was observed for 63% of patients. Patients had a mean of 4.1 idle days and a mean of 3.4 days with both a CVC and a peripheral intravenous catheter (PIV). After adjusting for ward length of stay, mean CVC dwell time was 14.4 days for patients with PICCs versus 9.0 days for patients with non-PICC temporary CVCs (other CVCs; P<.001). Patients with a PICC had 5.4 days in which they also had a PIV, compared with 10 days in other CVC patients (P<.001). Patients with PICCs had more days in which the only justification for the CVC was intravenous administration of antimicrobial agents (8.5 vs 1.6 days; P=.0013).

Conclusions: Significant proportions of ward CVC-days were unjustified. Reducing "idle CVC-days" and facilitating the appropriate use of PIVs may reduce CVC-days and CR-BSI risk.
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http://dx.doi.org/10.1086/663645DOI Listing
January 2012