John A. Hermos

Proton pump inhibitors and risk for recurrent Clostridium difficile infection.

BACKGROUND Proton pump inhibitors (PPIs) are widely used gastric acid suppressants, but they are often prescribed without clear indications and may increase risk of Clostridium difficile infection (CDI). We sought to determine the association between PPI use and the risk of recurrent CDI. METHODS Retrospective, cohort study using administrative databases of the New England Veterans Healthcare System from October 1, 2003, through September 30, 2008. We identified 1166 inpatients and outpatients with metronidazole- or vancomycin hydrochloride-treated incident CDI, of whom 527 (45.2%) received oral PPIs within 14 days of diagnosis and 639 (54.8%) did not. We determined the hazard ratio (HR) for recurrent CDI, defined by a positive toxin finding in the 15 to 90 days after incident CDI. RESULTS Recurrent CDI was more common in those exposed to PPIs than in those not exposed (25.2% vs 18.5%). Using Cox proportional survival methods, we determined that the adjusted HR of recurrent CDI was greater in those exposed to PPIs during treatment (1.42; 95% confidence interval [CI], 1.11-1.82). Risks among exposed patients were highest among those older than 80 years (HR, 1.86; 95% CI, 1.15-3.01) and those receiving antibiotics not targeted to C difficile during follow-up (HR, 1.71; 95% CI, 1.11-2.64). [corrected] CONCLUSIONS Proton pump inhibitor use during incident CDI treatment was associated with a 42% increased risk of recurrence. Our findings warrant further studies to examine this association and careful consideration of the indications for prescribing PPIs during treatment of CDI.

A randomized placebo-controlled trial of d-cycloserine and exposure therapy for posttraumatic stress disorder

D-Cycloserine (DCS) is a partial NMDA receptor agonist that has been shown to enhance therapeutic response to exposure-based treatments for anxiety disorders, but has not been tested in the treatment of combat-related posttraumatic stress disorder (PTSD). The aim of this randomized, double-blind, placebo-controlled trial was to determine whether DCS augments exposure therapy for PTSD in veterans returning from Iraq and Afghanistan and to test whether a brief six-session course of exposure therapy could effectively reduce PTSD symptoms in returning veterans. In contrast to previous trials using DCS to enhance exposure therapy, results indicated that veterans in the exposure therapy plus DCS condition experienced significantly less symptom reduction than those in the exposure therapy plus placebo condition over the course of the treatment. Possible reasons for why DCS was associated with poorer outcome are discussed. Clinicaltrials.gov Registry #: NCT00371176; A Placebo-Controlled Trail of D-Cycloserine and Exposure Therapy for Combat-PTSD; www.clinicaltrials.gov/ct2/results?term=NCT00371176.

Mucosa of the Small Intestine in Folate-Deficient Alcoholics

Abstract Peroral mucosal biopsy specimens from the duodenojejunal junction were obtained from alcoholics with marrow megaloblastosis caused by folate deficiency. Three patients with severe megalobl...

Prescription Opioid Duration of Action and the Risk of Unintentional Overdose Among Patients Receiving Opioid Therapy

IMPORTANCE The unprecedented increase in unintentional overdose events that has occurred in tandem with escalating sales of prescription opioids over the past 2 decades has raised concerns about whether the therapeutic use of opioids has contributed to increases in overdose injury. Few controlled studies have examined the extent to which ecologic measures of increases in opioid prescribing and overdose injuries reflect risk among patients prescribed opioids, let alone whether some opioid regimens are safer than others. OBJECTIVE To examine whether the risk of unintentional overdose injury is associated with the duration of opioid action (ie, long-acting vs short-acting formulations). DESIGN, SETTING, AND PARTICIPANTS A propensity score-adjusted cohort study was conducted using population-based health care utilization data from the Veterans Administration Healthcare System. The patients were veterans with chronic painful conditions who began therapy with opioid analgesics between January 1, 2000, and December 31, 2009. MAIN OUTCOMES AND MEASURES Unintentional overdoses that are explicitly coded using International Classification of Disease, Ninth Revision codes as drug or medication poisonings of accidental intent (E850.x-860.x) or undetermined intent (E980.x or drug poisoning [960.x-980.x] without an accompanying external cause of injury code). RESULTS A total of 319 unintentional overdose events were observed. Patients initiating therapy with long-acting opioids were more than twice as likely to overdose compared with persons initiating therapy with short-acting opioids. After adjustment for age, sex, opioid dose, and other clinical characteristics, patients receiving long-acting opioids had a significantly higher rate of overdose injury than did those receiving short-acting opioids (hazard ratio [HR], 2.33; 95% CI, 1.26-4.32). The risk associated with long-acting agents was particularly marked during the first 2 weeks after initiation of treatment (HR, 5.25; 1.88-14.72). CONCLUSIONS AND RELEVANCE To our knowledge, the findings of the present study provide the first evidence that the risk of unintentional overdose injury is related to the prescribed opioids duration of action. If replicated in other cohorts, our findings suggest that clinicians weighing the benefits and risks of initiating different opioid regimens should consider not only the daily dose prescribed but also the duration of opioid action, favoring short-acting agents whenever possible, especially during the first 2 weeks of therapy.

A point-of-care clinical trial comparing insulin administered using a sliding scale versus a weight-based regimen

Background Clinical trials are widely considered the gold standard in comparative effectiveness research (CER) but the high cost and complexity of traditional trials and concerns about generalizability to broad patient populations and general clinical practice limit their appeal. Unsuccessful implementation of CER results limits the value of even the highest quality trials. Planning for a trial comparing two standard strategies of insulin administration for hospitalized patients led us to develop a new method for a clinical trial designed to be embedded directly into the clinical care setting thereby lowering the cost, increasing the pragmatic nature of the overall trial, strengthening implementation, and creating an integrated environment of research-based care. Purpose We describe a novel randomized clinical trial that uses the informatics and statistics infrastructure of the Veterans Affairs Healthcare System (VA) to illustrate one key component (called the point-of-care clinical trial – POC-CT) of a ‘learning healthcare system,’ and settles a clinical question of interest to the VA. Methods This study is an open-label, randomized trial comparing sliding scale regular insulin to a weight-based regimen for control of hyperglycemia, using the primary outcome length of stay, in non-ICU inpatients within the northeast region of the VA. All non-ICU patients who require in-hospital insulin therapy are eligible for the trial, and the VA’s automated systems will be used to assess eligibility and present the possibility of randomization to the clinician at the point of care. Clinicians will indicate their approval for informed consent to be obtained by study staff. Adaptive randomization will assign up to 3000 patients, preferentially to the currently ‘winning’ strategy, and all care will proceed according to usual practices. Based on a Bayesian stopping rule, the study has acceptable frequentist operating characteristics (Type I error 6%, power 86%) against a 12% reduction of median length of stay from 5 to 4.4 days. The adaptive stopping rule promotes implementation of a successful treatment strategy. Limitations Despite clinical equipoise, individual healthcare providers may have strong treatment preferences that jeopardize the success and implementation of the trial design, leading to low rates of randomization. Unblinded treatment assignment may bias results. In addition, generalization of clinical results to other healthcare systems may be limited by differences in patient population. Generalizability of the POC-CT method depends on the level of informatics and statistics infrastructure available to a healthcare system. Conclusions The methods proposed will demonstrate outcome-based evaluation of control of hyperglycemia in hospitalized veterans. By institutionalizing a process of statistically sound and efficient learning, and by integrating that learning with automatic implementation of best practice, the participating VA Healthcare Systems will accelerate improvements in the effectiveness of care.

Cell proliferation in three types of Barrett's epithelium

Barretts epithelium is a columnar, possibly premalignant, metaplasia of the oesophagus. To study the pattern of epithelial renewal in this disorder, we localised the lower oesophageal sphincter by manometry in 12 patients with known Barretts epithelium, obtained multiple suction biopsies above the sphincter, and organ cultured the biopsies over 3H-TdR-containing medium to label proliferating cells. Of 23 biopsies from the 12 patients, 13 were specialised columnar type, three were junctional type, and seven were fundic type. None of the patients showed clinical evidence of oesophageal carcinoma, and oesophageal cytological examinations were uniformly negative for neoplastic cells. When compared with control gastric fundic biopsies from normal volunteers, mean values for the labelling index and the proportion of the pit which was occupied by the proliferative zone in Barretts biopsies were not significantly different. However, four individual Barretts biopsies (three specialised columnar type and one junctional type) did have a proliferative zone which occupied a greater proportion of the pit than did the widest control zone. We propose that the pattern of epithelial proliferation in Barretts epithelium in general is similar to that found in other gastrointestinal columnar epithelia. However, a minority of patients with Barretts epithelium may have an expanded proliferative zone. The clinical implications of an expanded proliferative zone with regard to the subsequent development of oesophageal carcinoma require further investigation.

Web intervention for OEF/OIF veterans with problem drinking and PTSD symptoms: A randomized clinical trial

OBJECTIVE Veterans who served in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) commonly experience alcohol misuse and symptoms of posttraumatic stress disorder (PTSD) following their return from deployment to a war zone. We conducted a randomized clinical trial to evaluate the efficacy of a newly developed, 8-module, self-management web intervention (VetChange) based on motivational and cognitive-behavioral principles to reduce alcohol consumption, alcohol-related problems, and PTSD symptoms in returning combat veterans. METHOD Six hundred participants, recruited through targeted Facebook ads, were randomized to either an Initial Intervention Group (IIG; n = 404) or a Delayed Intervention Group (DIG; n = 196) that waited 8 weeks for access to VetChange. Primary outcome measures were Drinks per Drinking Day, Average Weekly Drinks, Percent Heavy Drinking Days, and PTSD symptoms. Intent-to-treat analyses compared changes in outcome measures over time between IIG and DIG as well as within-group changes. RESULTS IIG participants demonstrated greater reductions in drinking (p < .001 for each measure) and PTSD symptoms (p = .009) between baseline and end-of-intervention than did DIG participants between baseline and the end of the waiting period. DIG participants showed similar improvements to those in IIG following participation in VetChange. Alcohol problems were also reduced within each group between baseline and 3-month follow-up. CONCLUSIONS Results indicate that VetChange is effective in reducing drinking and PTSD symptoms in OIF/OEF veterans. Further studies of VetChange are needed to assess web-based recruitment and retention methods and to determine VetChanges effectiveness in demographic and clinical sub-populations of returning veterans.

The columnar-lined esophagus--analysis of 26 cases.

A review of 26 cases of columnar-lined (Barretts) esophagus suggests that this lesion is more common than generally appreciated, usually arising consequent to reflux esophagitis. The radiologically detectable lesions frequently do not support the idea that Barretts esophagus presents only with high esophageal ulcer and/or stricture. Hiatal hernia, gastroesophageal reflux, stricture, ulcers, and even minor mucosal abnormalities may be present alone or in combination, and may be variably located.

Risk of Community-Acquired Pneumonia in Veteran Patients to Whom Proton Pump Inhibitors Were Dispensed

BACKGROUND Observational studies linking proton pump inhibitor (PPI) exposure with community-acquired pneumonia (CAP) have reported either modest or no associations. Accordingly, we studied PPI exposure and CAP in veteran patients, using a retrospective, nested case-control design. METHODS From linked pharmacy and administrative databases of the New England Veterans Healthcare System, we identified 71985 outpatients newly prescribed PPIs between 1998 and 2007; 1544 patients met criteria for CAP subsequent to PPI initiation; 15440 controls were matched through risk-set sampling by age and time under observation. Crude and adjusted odds ratios comparing current with past PPI exposures, as well as tests for interactions, were conducted for the entire and stratified samples. RESULTS Current PPI use associated with CAP (adjusted odds ratio [OR], 1.29 [95% confidence interval {CI}, 1.15-1.45]). Risks were not substantially altered by age or year of diagnosis. Dementia (n = 85; P = .062 for interaction) and sedative/tranquilizer use (n = 224; P = .049 for interaction) were likely effect modifiers increasing a PPI-CAP association; conversely, for some chronic medical conditions, PPI-associated CAP risks were reversed. PPI exposures between 1 and 15 days increased CAP risks, compared with longer exposures, but PPI initiation also frequently occurred shortly after CAP diagnoses. Prescribed PPI doses >1 dose/day also increased PPI-associated CAP risks. CONCLUSIONS Among the veterans studied, current compared with past PPI exposures associated modestly with increased risks of CAP. However, our observations that recent treatment initiation and higher PPI doses were associated with greater risks, and the inconsistent PPI-CAP associations between patient subgroups, indicate that further inquiries are needed to separate out coincidental patterns of associations.

The Incidence and Severity of Hangover the Morning after Moderate Alcohol Intoxication

AIMS To determine the incidence and covariates of hangover following a night of moderate alcohol consumption at a targeted breath alcohol level. DESIGN Data were combined from three randomized cross-over trials investigating the effects of heavy drinking on next-day performance. A total of 172 participants received either alcoholic beverage (mean=0.115 g% breath alcohol concentration) or placebo on one night and the other beverage a week later. The next day, participants completed a hangover scale. PARTICIPANTS Participants were 54 professional merchant mariners attending a recertification course at Kalmar Maritime Academy (Kalmar, Sweden) and 118 university students or recent graduates recruited from greater Boston. SETTING One trial was conducted at Kalmar Maritime Academy (Sweden); the other two were conducted at the General Clinical Research Center at Boston Medical Center. MEASUREMENTS A nine-item scale assessed hangover. FINDINGS Hangover was reported by 76% of participants. Neither alcoholic beverage type nor participant characteristics was associated with incidence of hangover. CONCLUSIONS Our findings on the propensity of hangover suggest that 25-30% of drinkers may be resistant to hangover.