VA Cooperative Study Research Articles

APPLICATION OF A NEW TOOL FOR PLANNING IMPLEMENTATION EVALUATIONS IN CLINICAL TRIALS

Abstract The VA Cooperative Studies Program (CSP) study “Geriatric OUt-of-hospital Randomized MEal Trial in heart failure – Veterans Affairs” (GOURMET-VA) is a randomized, single-blind, multi-center, clinical trial investigating the effects of home-delivered meals in Veterans discharged from hospitalization for heart failure. GOURMET-VA is one of the first CSP studies to integrate implementation scientists during protocol planning. We describe how the three phases of the new Implementation Planning Assessment (IPA) Tool was used proactively to guide planning of the implementation evaluation for the trial, oriented towards future adoption and sustainment of the intervention. Phase 1 (“Planning, Framing, & Aligning Interested Parties”): During early protocol development, the implementation team helped identify and facilitated meetings with relevant VA national leadership. These meetings resulted in plans for engagement throughout the trial and input on trial design. Phase 2 (“Implementation Process Data Collection”): Guided by IPA, the implementation evaluation uses mixed methods to understand the context into which the intervention is being implemented, experiences of Veterans and clinicians with the intervention, and barriers and facilitators to implementation at the patient, healthcare provider, and leadership levels. Phase 3 (“Planning for Sustainment of Effective Trials”): A preliminary dissemination and sustainability plan was drafted, including how the implementation evaluation data may be used to inform adaptations of the GOURMET-VA intervention to improve effectiveness and uptake. We found that the structured guides that comprise the IPA were valuable in helping the implementation scientists and the trial team to find common ground in terms of rationale, methods, and language.

Editorial introductions.

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Matthew A. CiorbaMatthew A. CiorbaDr Matthew Ciorba is a gastroenterologist and biomedical researcher dedicated to advancing care in the Inflammatory Bowel Diseases (IBD) and Colon Cancer. His clinical expertise is in caring for patients with Crohn's and ulcerative colitis and preventing colon cancer. He is Director of the IBD Center at Washington University, USA, and leads one of the largest clinical teams in the USA dedicated to providing comprehensive and cutting-edge clinical care to more than 8000 patients affected by IBD. His basic-translational research program is dedicated to defining pathways and mechanisms of intestinal inflammation and the transition to colon cancer. His lab has developed methods to study intestinal organoids and tumoroids to facilitate studies of the epithelial response to inflammation, injury and repair. His lab investigations have spawned four ground-breaking Bench-to-Bedside clinical trials addressing unmet patient needs in colitis, enteritis and rectal cancer using probiotics, novel immunotherapies and manipulating bile acids. In addition to his own lab, Dr Ciorba is also Director of IBD Research at Washington University and use this platform to foster collaborative discovery between the world-class scientific investigators and the robust IBD clinical program. Finally, he is deeply committed to training the next generation of medical investigators who will advance discovery and treatment of digestive diseases. Supporting this mission, he serves as Associate Director of the GI Fellowship's T32 Research Training grant and serves on several training grant review committees for several organizations including the CCF, AGA and NIH. Stuart J. SpechlerStuart J. SpechlerStuart Jon Spechler, MD is Chief of the Division of Gastroenterology and Co-Director of the Center for Esophageal Diseases at Baylor University Medical Center at Dallas, as well as the Co-Director of the Center for Esophageal Research at the Baylor Scott and White Research Institute. Prior to joining Baylor University Medical Center in January 2017, Dr Spechler was the Chief of the Division of Gastroenterology for the VA North Texas Healthcare System, Professor of Medicine, and holder of the Berta M. and Cecil O. Patterson Chair in Gastroenterology at the University of Texas Southwestern Medical Center, and he had been the Director of the Center for Swallowing Disorders at the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts. Dr Spechler's research has focused primarily on disorders of the esophagus, especially GERD and its complications, and eosinophilic esophagitis. He has chaired three VA Cooperative Studies on medical and surgical treatments for gastroesophageal reflux disease. He described the condition known as “short-segment Barrett's esophagus” in 1994. Dr. Spechler has published more than 300 scientific reports, editorials, review articles, and book chapters on esophageal disorders. He is best known for his work in the areas of GERD, Barrett's esophagus, and eosinophilic esophagitis. Dr Spechler has served on the editorial boards of numerous journals including Gastroenterology, Gut, Alimentary Pharmacology and Therapeutics, Digestive Diseases and Sciences and Diseases of the Esophagus, and he has served as Chair of the Gastroenterology Teaching Project and the Esophago-Gastro-Duodenal Section of the American Gastroenterological Association.

Telephone informed consent in a pragmatic point-of-care clinical trial embedded in primary care

BackgroundOne benefit of pragmatic clinical trials is reduction of the burden on patients and clinical staff while facilitating a learning healthcare system. One way to decrease the work of clinical staff is through decentralized telephone consent. MethodsThe Diuretic Comparison Project (DCP) was a nationwide Point of Care pragmatic clinical trial conducted by the VA Cooperative Studies Program. The purpose of the trial was to compare the clinical effectiveness on major CV outcomes of two commonly used diuretics, hydrochlorothiazide and chlorthalidone, in an elderly patient population. Telephone consent was allowed for this study because of its minimal risk designation. Telephone consent was more difficult than initially anticipated and the study team constantly adjusted methods to find timely solutions. ResultsThe major challenges can be categorized as call center-related, telecommunications, operational, and study population based. In particular, the possible technical and operational pitfalls are rarely discussed. By presenting hurdles here, future studies may avoid these challenges and start studies with a more effective system in place. ConclusionsDCP is a novel study designed to answer an important clinical question. The lessons learned from implementing a centralized call center for the Diuretic Comparison Project helped the study reach enrollment goals and develop a centralized telephone consent system that can be utilized for future pragmatic and explanatory clinical trials. Clinical trial registrationThe study is registered on ClinicalTrials.gov; NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Association of Gulf War Illness with Characteristics in Deployed vs. Non-Deployed Gulf War Era Veterans in the Cooperative Studies Program 2006/Million Veteran Program 029 Cohort: A Cross-Sectional Analysis.

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990-1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA's Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990-1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018-2019 survey, 35,902 respondents met study inclusion criteria, 13,107 deployed to the GW theater. GWI phenotypes were derived from Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions: (a) KS Symptoms (KS Sym+), (b) KS GWI (met symptom criteria and without exclusionary health conditions) [KS GWI: Sym+/Dx-], (c) CDC GWI and (d) CDC GWI Severe. The prevalence of each phenotype was 67.1% KS Sym+, 21.5% KS Sym+/Dx-, 81.1% CDC GWI, and 18.6% CDC GWI severe. These findings affirm the persistent presence of GWI among GW veterans providing a foundation for further exploration of biological and environmental underpinnings of this condition.

The Story of the Silent Killer

Hypertension is the leading risk factor for death and disability-adjusted life-years lost globally. Despite this tremendous impact on health, blood pressure measurement and treatment are relatively new to medical practice, with widespread measurement beginning just over 100years ago. How, in such a short time, did blood pressure become such an integral measurement in medical practice that it is now considered one of the vital signs? Key revelations through Stephen Hales and his horse experiment, Riva-Rocci's modern blood pressure cuff, Korotkoff sounds, and President Roosevelt's death set the stage for discovery. Landmark trials such as the VA Cooperative studies of the 1960s through the recent Systolic Blood Pressure Intervention Trial and Prevention with Mediterranean Diet trials provide the foundation for modern clinical practice. An understanding of the history of hypertension can directly affect current clinical practice and offers unique insights into how the medical community has approached the management of one of the deadliest medical conditions in history.

Editorial introductions

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Miguel RegueiroMiguel RegueiroMiguel Regueiro earned his bachelor's degree at the University of Pennsylvania, USA, his medical degree at Drexel (Hahnemann) University, USA, and completed his internal medicine internship, residency, and clinical and research fellowship training in gastroenterology at Harvard Medical School's Beth Israel Hospital, USA. Dr Regueiro was Professor of Medicine and Clinical and Translational Science at the University of Pittsburgh School of Medicine, USA, from 2000 to 2018. There he served as the IBD Clinical Medical Director, Senior Medical Lead of Specialty Medical Homes, was Professor with Tenure, and honored as the UPMC Endowed Chair for Patient Centered Care in Inflammatory Bowel Diseases. Dr Regueiro is currently the Chair of the Department of Gastroenterology, Hepatology, and Nutrition, and Vice Chair of the Digestive Disease and Surgery Institute at Cleveland Clinic in Ohio. He serves as Medical Co-Chair of Digestive Disease and Surgical Institute Research Governance committee and is Professor of Medicine at the Lerner College of Medicine, Cleveland Clinic, USA. He also holds the Pier C. and Renee A. Borra Family Endowed Chair in Gastroenterology and Hepatology, Digestive Disease and Surgery Institute. Dr Regueiro's main clinical and research interest is Inflammatory Bowel Diseases (IBD) with a focus on the natural course of these diseases and postoperative prevention of Crohn's disease. Recently, he has been involved in transformative medicine initiatives and developing new models of healthcare, including the first-of-its kind specialty medical home and neighborhood for IBD. Dr Regueiro is investigating alternative models of care in population-based health that integrates patients, payers, providers, pharmaceutical industry, and other facets of healthcare delivery around these novel programs. Stuart J. SpechlerStuart J. SpechlerStuart J. Spechler, MD is Chief of the Division of Gastroenterology and Co-Director of the Center for Esophageal Diseases at Baylor University Medical Center at Dallas, as well as the Co-Director of the Center for Esophageal Research at the Baylor Scott and White Research Institute. Prior to joining Baylor University Medical Center in January 2017, Dr Spechler was the Chief of the Division of Gastroenterology for the VA North Texas Healthcare System, Professor of Medicine, and holder of the Berta M. and Cecil O. Patterson Chair in Gastroenterology at the University of Texas Southwestern Medical Center, and he had been the Director of the Center for Swallowing Disorders at the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts. Dr Spechler's research has focused primarily on disorders of the esophagus, especially GERD and its complications, and eosinophilic esophagitis. He has chaired three VA Cooperative Studies on medical and surgical treatments for gastroesophageal reflux disease. He described the condition known as “short-segment Barrett's esophagus” in 1994. Dr Spechler has published more than 300 scientific reports, editorials, review articles, and book chapters on esophageal disorders. He is best known for his work in the areas of GERD, Barrett's esophagus, and eosinophilic esophagitis. Dr Spechler has served on the editorial boards of numerous journals including Gastroenterology, Gut, Alimentary Pharmacology and Therapeutics, Digestive Diseases and Sciences and Diseases of the Esophagus, and he has served as Chair of the Gastroenterology Teaching Project and the Esophago-Gastro-Duodenal Section of the American Gastroenterological Association.

Long-term negative emotional outcomes of warzone TBI

Objective Many veterans of the Iraq and Afghanistan Wars have experienced traumatic brain injury (TBI). Although prior work has examined associations between TBI and development of psychiatric syndromes, less is known about associations between TBI and component emotions constituting these syndromes, especially in the long term. The purpose of this study was to examine the long-term emotional consequences of deployment-related TBI. Methods As part of VA Cooperative Studies Program #566, we assessed a sample of n = 456 US Army soldiers prior to an index deployment to Iraq, and again an average of 8.3 years (SD = 2.4 years) after their deployment for a long-term follow-up assessment. In this report, we used adjusted regression analyses to examine the relationship of deployment TBI to depression, anxiety, and stress symptom severity measured at the long-term follow-up assessment. A structured interview was used to determine TBI history; the Depression, Anxiety, and Stress Scale, 21-item version (DASS-21) was used to determine emotional status at the follow-up evaluation. Results Warzone TBI events, particularly when greater than mild in severity, were independently associated with depression, anxiety, and stress severity at long-term follow-up, even after taking into account variance attributable to pre-deployment emotional distress and war-zone stress. Post-hoc analyses did not detect independent associations of either number of events or injury mechanism with outcomes. Conclusions These findings highlight the potentially enduring and multi-faceted emotional effects of deployment TBI, underscoring the need for early assessment of negative affectivity in warzone veterans reporting TBI.

Epiaortic Ultrasound for Assessment of Intraluminal Atheroma; Insights from the REGROUP Trial

To assess the use of epiaortic ultrasound in contemporary cardiac surgery, as well as its impact on surgical cannulation strategy and cerebrovascular events. Epiaortic ultrasound data was prospectively collected in the Randomized Endovein Graft Prospective (REGROUP) trial (VA Cooperative Studies Program #588, ClinicalTrials.gov, NCT01850082), which randomized 1,150 coronary artery bypass graft patients between 2014 and 2017 to endoscopic or open-vein graft harvest. Sixteen cardiac surgery programs within the Veterans Affairs Healthcare System with expertise at performing endoscopic vein-graft harvesting. Veterans Affairs patients, greater than 18 years of age, undergoing elective or urgent coronary artery bypass grafting with cardiopulmonary bypass and cardioplegic arrest with at least one planned saphenous vein graft were eligible for enrollment. Epiaortic ultrasound was performed by the surgeon using a high frequency (>7 MHz) ultrasound transducer. Two-dimensional images of the ascending aorta in multiple planes were acquired before aortic cannulation and cross-clamping. Epiaortic ultrasound was performed in 34.1% (269 of 790) of patients in REGROUP. Among these patients, simple intraluminal atheroma was observed in 21.9% (59 269), and complex intraluminal atheroma comprised 2.2% (6 of 269). The aortic cannulation or cross-clamp strategy was modified based on these findings in 7.1% of cases (19 of 269). There was no difference in stroke between patients who underwent epiaortic ultrasound and those who did not (1.9% v 1.2% p = 0.523). Despite current guidelines recommending routine use of epiaortic ultrasound (IIa/B) to reduce the risk of stroke in cardiac surgery, in this contemporary trial, use remains infrequent, with significant site-to-site variability.

Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-up

BackgroundWe previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.MethodsWe observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome.ResultsThere were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P=0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).ConclusionsParticipants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.)

444 - Characterization of Conditions Underlying Heartburn Refractory to Proton Pump Inhibitors (PPIS) in a VA Cooperative Study of Medical and Surgical Treatments for PPI-Refractory Heartburn

444 - Characterization of Conditions Underlying Heartburn Refractory to Proton Pump Inhibitors (PPIS) in a VA Cooperative Study of Medical and Surgical Treatments for PPI-Refractory Heartburn

Research site mentoring: A novel approach to improving study recruitment.

Background/AimsThe VA Cooperative Studies Program's (CSP) Network of Dedicated Enrollment Sites (NODES) is a consortium of nine VA medical centers (VAMCs) with teams (nodes) dedicated to enhance performance, compliance, and management of CSP multi-site clinical trials. The West Haven CSP Coordinating Center (WH-CSPCC), study coordinating center for CSP #577, Colonoscopy Versus Fecal Immunochemical Test (FIT) in Reducing Mortality from Colorectal Cancer (CONFIRM) trial, and NODES piloted a “site mentoring” (hub-and-spoke) model. In this model, a node site would work one-on-one with a low enrolling CONFIRM site to identify and overcome barriers to recruitment. The aim was to determine the impact of a research site mentoring model on study recruitment and examine site-level characteristics that facilitate or impede it.ResultsSites in the mentorship pilot had an average improvement of 5 ± 4 participants randomized per month (min −2.6; max 11.6; SD 4.3). Four of ten sites (40%) demonstrated continuous improvement in the average number of randomized participants per month after the pilot intervention and at three-month follow-up (post-intervention), as compared to the five-month period preceding the intervention. An additional two sites (20%) demonstrated improvement in the average number of randomized participants per month after the pilot intervention, and sustained that level of improvement at three-month follow-up (post-intervention). Additionally, six of ten sites (60%) demonstrated an increased number of participants screened for eligibility immediately following the intervention and at three-month follow-up (post-intervention). Only one site showed a decreased monthly average of randomized participants shortly after the intervention and through the three-month follow-up period.ConclusionsThe site mentoring model was successful in improving recruitment at low enrolling CONFIRM sites. An additional feasibility assessment is needed to determine if this mentoring model will be effective with other CSP trials.

Associations of Stress Exposures and Social Support With Long-Term Mental Health Outcomes Among U.S. Iraq War Veterans

The long-term mental health effects of war-zone deployment in the Iraq and Afghanistan wars on military personnel are a significant public health concern. Using data collected prospectively at three distinct assessments during 2003–2014 as part of the Neurocognition Deployment Health Study and VA Cooperative Studies Program Study #566, we explored how stress exposures prior, during, and after return from deployment influence the long-term mental health outcomes of posttraumatic stress disorder (PTSD), depression, anxiety disorders, and problem drinking. Longer-term mental health outcomes were assessed in 375 service members and military veterans an average of 7.5 years (standard deviation = 1.0 year) after the initial (i.e., “index”) Iraq deployment following their predeployment assessment. Anxiety disorder was the most commonly observed long-term mental health outcome (36.0%), followed by depression (24.5%), PTSD (24.3%), and problem drinking (21.0%). Multivariable regression models showed that greater postdeployment stressors, as measured by the Post-Deployment Life Events scale, were associated with greater risk of depression, anxiety disorders, and problem drinking. Anxiety disorder was the only outcome affected by predeployment stress concerns. In addition, greater postdeployment social support was associated with lower risk of all outcomes except problem drinking. These findings highlight the importance of assessing postdeployment stress exposures, such as stressful or traumatic life events, given the potential impact of these stressors on long-term mental health outcomes. This study also highlights the importance of postdeployment social support as a modifiable protective factor that can be used to help mitigate risk of long-term adverse mental health outcomes following war-zone exposure.

Design and conduct of a provider survey to determine a clinically persuasive effect size in planning VA Cooperative Study #590 (Li+).

BackgroundThe estimation of an effect size is an important step in designing an adequately powered, feasible clinical trial intended to change clinical practice. During the planning phase of VA Cooperative Study #590, “Double-Blind Placebo-Controlled Study of Lithium for Preventing Repeated Suicidal Self-Directed Violence in Patients with Depression or Bipolar Disorder (Li+),” it was not clear what effect size would be considered large enough to influence prescribing behavior among practicing clinicians.MethodsWe conducted an online survey of VA psychiatrists to assess their interest in the study question, their clinical experience with lithium, and their opinion about what suicide reduction rate would change their prescribing habits. The 9-item survey was hosted on SurveyMonkey© and VA psychiatrists were individually emailed an invitation to complete an anonymous online survey. Three email waves were sent over three weeks.ResultsOverall, 862 of 2713 VA psychiatrists (response rate = 31.8%) responded to the anonymous survey. 74% of the respondents would refer a patient to the proposed trial, 9% would not, and 17% were unsure. Presented with suicide reduction rates in 10% increments ranging from 10 to 100%, 61% of respondents indicated that they would use lithium if suicide attempts were reduced by at least 40%; 83% would use lithium if it reduced attempts by at least 50%.ConclusionsEven with the limitations of response bias and the reliability of responses on future prescribing behavior, a survey of potential users of a clinical trial's results offers a convenient, empirical method for determining and justifying clinically relevant effect sizes.

Editorial introductions

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce one of the Section Editors for this issue. SECTION EDITORS Claudio FiocchiClaudio FiocchiDr Fiocchi is originally from Rome, Italy. He graduated from the Santa Casa de Misericordia School of Medicine in São Paulo, Brazil, and moved to the Cleveland Clinic Foundation, in Cleveland, Ohio, USA, where he received additional training in internal medicine, gastroenterology and basic immunology. Dr Fiocchi is currently Professor of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio and Professor of Pathology and Pediatrics at Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. In addition, he is a Staff Member in the Departments of Pathobiology, Lerner Research Institute, and Gastroenterology & Hepatology, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation. Dr Fiocchi has published numerous papers and has served or serves on the editorial boards of several journals, including Gastroenterology, American Journal of Physiology, Inflammatory Bowel Diseases, Journal of Crohn's & Colitis, Current Opinion in Gastroenterology, and Digestive and Liver Disease. He has been or is a member of numerous study sections of the National Institutes of Health and the Crohn's & Colitis Foundation of America. He received the prestigious MERIT Award from the National Institutes of Health, and the Clifford and Jane Anthony Chair in Digestive Disease Research and Education. In addition, he is the recipient of the Premier Physician Award and the Henry Janowitz Lifetime Achievement Award in Inflammatory Bowel Disease from the Crohn's & Colitis Foundation of America, and the International Herbert Falk Award, Germany. He is also Honorary Foreign Member of the Brazilian Academy of Medicine. Dr Fiocchi's research is focused on the pathogenesis of inflammatory bowel disease. Studies include the identification of mechanisms of mucosal T-cell death and survival in gut inflammation, investigation of tolerance of mucosal T-cells for the autologous enteric flora and its possible loss in IBD, characterization of the interactions between mucosal T-cells and endothelial and stromal cells, and the study of immune-driven angiogenesis and fibrogenesis in intestinal inflammation. Stuart J. SpechlerStuart J. SpechlerStuart J. Spechler, MD is Chief of the Division of Gastroenterology at the Dallas VA Medical Center, Professor of Medicine, and holder of the Berta M. and Cecil O. Patterson Chair in Gastroenterology at The University of Texas Southwestern Medical Center at Dallas, USA. He is a graduate of Boston University School of Medicine, USA, and he spent many years working in Boston, both at Boston University and at the Beth Israel Deaconess Medical Center, USA, and Harvard Medical School, USA, where he was the Director of the Center for Swallowing Disorders from 1990 to 1997. He has been in Dallas on the faculty of UT Southwestern Medical Center since 1997. Dr Spechler's research has focused primarily on disorders of the esophagus, especially gastroesophageal reflux disease and its complications. He chaired the VA Cooperative Study on gastroesophageal reflux disease that was conducted in the 1980 s, and he now chairs a new VA Cooperative Study on the treatment of GERD that is refractory to treatment with proton pump inhibitors. Dr Spechler has published more than 300 scientific reports, editorials, review articles, and book chapters on esophageal disorders. He is perhaps best known for his work in the areas of GERD, Barrett's esophagus and, most recently on eosinophilic esophagitis. Dr Spechler has served on the editorial boards of numerous journals including Gastroenterology, Gut, Alimentary Pharmacology and Therapeutics, and Diseases of the Esophagus, and he has served as Chair of the Gastroenterology Teaching Project and the Esophago-gastro-duodenal Section of the American Gastroenterological Association.

Timeline of History of Hypertension Treatment.

It is surprising that only about 50 years ago hypertension was considered an essential malady and not a treatable condition. Introduction of thiazide diuretics in late 50s made some headway in successful treatment of hypertension and ambitious multicenter VA co-operative study (phase 1 and 2) started in 1964 for diastolic hypertension ranging between 90 and 129 mmHg and completed by 1971 established for the first time that treating diastolic hypertension reduced CV events such as stroke and heart failure and improved mortality. In the following decade, these results were confirmed for the wider US and non-US population, including women and goal-oriented BP treatment to diastolic 90 became the standard therapy recommendation. But isolated systolic hypertension (accounting for two-thirds of the 70 million hypertensive population in USA alone) was not considered treatable until 1991 when SHEP study (systolic hypertension in elderly program) was completed and showed tremendous benefits of treating systolic BP over 160 mmHg using only a simple regimen using small dose chlorthalidone with addition of atenolol if needed. In the next two decades, ALLHAT and other studies examined the comparability of outcomes with use of different classes and combinations of antihypertensive drugs. Although diastolic BP goal was established as 90 in the late 70s and later confirmed by HOT study, the goal BP for systolic hypertension was not settled until very recently with completion of SPRINT study. ACCORD study showed no significant difference in outcome with sys 140 vs. 120 in diabetics. But recently completed SPRINT study with somewhat similar protocol as in ACCORD but in non-diabetic showed almost one-quarter reduction in all-cause mortality and one-third reduction of CV events with systolic BP goal 120.

Follow-up of Glycemic Control and Cardiovascular Outcomes in Type 2 Diabetes

BackgroundThe Veterans Affairs Diabetes Trial previously showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1791 military veterans (median follow-up, 5.6 years). We report the extended follow-up of the study participants.MethodsAfter the conclusion of the clinical trial, we followed participants, using central databases to identify procedures, hospitalizations, and deaths (complete cohort, with follow-up data for 92.4% of participants). Most participants agreed to additional data collection by means of annual surveys and periodic chart reviews (survey cohort, with 77.7% follow-up). The primary outcome was the time to the first major cardiovascular event (heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death). Secondary outcomes were cardiovascular mortality and all-cause mortality.ResultsThe difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome than did the standard-therapy group (hazard ratio, 0.83; 95% confidence interval [CI], 0.70 to 0.99; P=0.04), with an absolute reduction in risk of 8.6 major cardiovascular events per 1000 person-years, but did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; P=0.42). No reduction in total mortality was evident (hazard ratio in the intensive-therapy group, 1.05; 95% CI, 0.89 to 1.25; P=0.54; median follow-up, 11.8 years).ConclusionsAfter nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival. (Funded by the VA Cooperative Studies Program and others; VADT ClinicalTrials.gov number, NCT00032487.)

Design of VA Cooperative Study #591: CERV-PTSD, Comparative Effectiveness Research in Veterans with PTSD

CERV-PTSD is a randomized controlled trial of two of the most effective treatments for PTSD, Prolonged Exposure (PE) and Cognitive Processing Therapy (CPT). Despite solid evidence that both treatments are effective, there is limited evidence about their effectiveness relative to one another. The primary objective is to compare the effectiveness of PE and CPT for reducing PTSD symptom severity in a healthcare system that offers both treatments. The secondary objective is to compare the effectiveness of PE and CPT for reducing the severity of comorbid mental health problems and service utilization as well as improving functioning and quality of life. The tertiary objective is to examine whether discrepancy between patient preferences and treatment assignment reduces the effectiveness of each treatment. Exploratory analyses will examine whether demographic and clinical characteristics predict differential response to PE and CPT. The study is designed to randomize 900 male and female veterans with PTSD due to any traumatic military event to receive PE or CPT. The standard dose of treatment is 12 weekly sessions but veterans who improve more rapidly may finish in fewer sessions and veterans who improve more slowly may have additional sessions. The primary outcome is improvement in PTSD symptoms, measured during and after treatment and then 3 and 6 months later. As a large multi-site trial with men and women, CERV-PTSD is designed to advance the delivery of care for PTSD by providing conclusive information about whether one treatment is better than the other, overall, and for different types of patients.

Elucidating the transdiagnostic dimensional structure of trauma-related psychopathology: Findings from VA cooperative study 504 – risperidone treatment for military service related chronic post traumatic stress disorder

BackgroundThree of the most common trauma-related mental disorders—posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD)—are highly comorbid and share common transdiagnostic symptom dimensions of threat (i.e., fear) and loss (i.e., dysphoria) symptomatology. However, empirical evaluation of the dimensional structure of component aspects of these disorders is lacking. MethodsUsing structured clinical interview data from U.S. military veterans with chronic military-related PTSD, we evaluated the transdiagnostic dimensional structure of PTSD, MDD, and GAD symptoms. We then examined the relationship between the best-fitting transdiagnostic model of these symptoms, and measures of physical and mental functioning, and life satisfaction and well-being. ResultsExploratory factor analysis revealed that a 3-factor transdiagnostic model comprised of loss (i.e., dysphoria), threat (i.e., anxious arousal, re-experiencing, and avoidance symptoms), and somatic anxiety (i.e., physiological manifestations of anxiety) symptoms provided the best representation of trauma-related PTSD, MDD, and GAD symptoms. Somatic anxiety symptoms were independently associated with physical functioning, while loss symptoms were independently associated with mental functioning and life satisfaction and well-being. LimitationsEvaluation of study aims in a relatively homogeneous sample of veterans with chronic, military-related PTSD. ConclusionsResults of this study suggest that a 3-factor transdiagnostic model best characterizes the dimensional structure of PTSD, MDD, and GAD symptoms in military veterans with chronic military-related PTSD. This model evidenced external validity in demonstrating differential associations with measures of physical and mental functioning, and life satisfaction and well-being. Results provide support for emerging contemporary models of psychopathology, which emphasize transdiagnostic and dimensional conceptualizations of mental disorders. Such models may have utility in understanding the functional status of trauma survivors.

The impact of frequency of patient self-testing of prothrombin time on time in target range within VA Cooperative Study #481: The Home INR Study (THINRS), a randomized, controlled trial.

Anticoagulation (AC) is effective in reducing thromboembolic events for individuals with atrial fibrillation (AF) or mechanical heart valve (MHV), but maintaining patients in target range for international normalized ratio (INR) can be difficult. Evidence suggests increasing INR testing frequency can improve time in target range (TTR), but this can be impractical with in-clinic testing. The objective of this study was to test the hypothesis that more frequent patient-self testing (PST) via home monitoring increases TTR. This planned substudy was conducted as part of The Home INR Study, a randomized controlled trial of in-clinic INR testing every 4 weeks versus PST at three different intervals. The setting for this study was 6 VA centers across the United States. 1,029 candidates with AF or MHV were trained and tested for competency using ProTime INR meters; 787 patients were deemed competent and, after second consent, randomized across four arms: high quality AC management (HQACM) in a dedicated clinic, with venous INR testing once every 4 weeks; and telephone monitored PST once every 4 weeks; weekly; and twice weekly. The primary endpoint was TTR at 1-year follow-up. The secondary endpoints were: major bleed, stroke and death, and quality of life. Results showed that TTR increased as testing frequency increased (59.9 ± 16.7 %, 63.3 ± 14.3 %, and 66.8 ± 13.2 % [mean ± SD] for the groups that underwent PST every 4 weeks, weekly and twice weekly, respectively). The proportion of poorly managed patients (i.e., TTR <50 %) was significantly lower for groups that underwent PST versus HQACM, and the proportion decreased as testing frequency increased. Patients and their care providers were unblinded given the nature of PST and HQACM. In conclusion, more frequent PST improved TTR and reduced the proportion of poorly managed patients.

The association of PTSD with physical and mental health functioning and disability (VA Cooperative Study #569: the course and consequences of posttraumatic stress disorder in Vietnam-era Veteran twins)

To assess the relationship of posttraumatic stress disorder (PTSD) with health functioning and disability in Vietnam-era Veterans. A cross-sectional study of functioning and disability in male Vietnam-era Veteran twins. PTSD was measured by theComposite International Diagnostic Interview; health functioning and disability were assessed using the Veterans RAND 36-Item Health Survey (VR-36) and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). All data collection took place between 2010 and 2012. Average age of the 5,574 participating Veterans (2,102 Vietnam theater and 3,472 non-theater) was 61.0years. Veterans with PTSD had poorer health functioning across all domains of VR-36 and increased disability for all subscales of WHODAS 2.0 (all p<.001) compared with Veterans without PTSD. Veterans with PTSD were in poorer overall health on the VR-36 physical composite summary (PCS) (effect size=0.31 in theater and 0.47 in non-theater Veterans; p<.001 for both) and mental composite summary (MCS) (effect size=0.99 in theater and 0.78 in non-theater Veterans; p<.001 for both) and had increased disability on the WHODAS 2.0 summary score (effect size=1.02 in theater and 0.96 in non-theater Veterans; p<.001 for both). Combat exposure, independent of PTSD status, was associated with lower PCS and MCS scores and increased disability (all p<.05, for trend). Within-pair analyses in twins discordant for PTSD produced consistent findings. Vietnam-era Veterans with PTSD have diminished functioning and increased disability. The poor functional status of aging combat-exposed Veterans is of particular concern.