Maggie Hong Chen

A prospective molecular surveillance study evaluating the clinical impact of community-acquired respiratory viruses in lung transplant recipients.

Background. Community-acquired respiratory viral infections (RVIs) are common in lung transplant patients and may be associated with acute rejection and bronchiolitis obliterans syndrome (BOS). The use of sensitive molecular methods that can simultaneously detect a large panel of respiratory viruses may help better define their effects. Methods. Lung transplant recipients undergoing serial surveillance and diagnostic bronchoalveolar lavages (BALs) during a period of 3 years were enrolled. BAL samples underwent multiplex testing for a panel of 19 respiratory viral types/subtypes using the Luminex xTAG respiratory virus panel assay. Results. Demographics, symptoms, and forced expiratory volume in 1 sec were prospectively collected for 93 lung transplant recipients enrolled. Mean number of BAL samples was 6.2±3.1 per patient. A respiratory virus was isolated in 48 of 93 (51.6%) patients on at least one BAL sample. Of 81 positive samples, the viruses isolated included rhinovirus (n=46), parainfluenza 1 to 4 (n=17), coronavirus (n=11), influenza (n=4), metapneumovirus (n=4), and respiratory syncytial virus (n=2). Biopsy-proven acute rejection (≥grade 2) or decline in forced expiratory volume in 1 sec ≥20% occurred in 16 of 48 (33.3%) patients within 3 months of RVI when compared with 3 of 45 (6.7%) RVI-negative patients within a comparable time frame (P=0.001). No significant difference was seen in incidence of acute rejection between symptomatic and asymptomatic patients. Biopsy-proven obliterative bronchiolitis or BOS was diagnosed in 10 of 16 (62.5%) patients within 1 year of infection. Conclusion. Community-acquired RVIs are frequently detected in BAL samples from lung transplant patients. In a significant percentage of patients, symptomatic or asymptomatic viral infection is a trigger for acute rejection and obliterative bronchiolitis/BOS.

Harassment and discrimination in medical training: a systematic review and meta-analysis.

Purpose Harassment and discrimination include a wide range of behaviors that medical trainees perceive as being humiliating, hostile, or abusive. To understand the significance of such mistreatment and to explore potential preventive strategies, the authors conducted a systematic review and meta-analysis to examine the prevalence, risk factors, and sources of harassment and discrimination among medical trainees. Method In 2011, the authors identified relevant studies by searching MEDLINE and EMBASE, scanning reference lists of relevant studies, and contacting experts. They included studies that reported the prevalence, risk factors, and sources of harassment and discrimination among medical trainees. Two reviewers independently screened all articles and abstracted study and participant characteristics and study results. The authors assessed the methodological quality in individual studies using the Newcastle–Ottawa Scale. They also conducted a meta-analysis. Results The authors included 57 cross-sectional and 2 cohort studies in their review. The meta-analysis of 51 studies demonstrated that 59.4% of medical trainees had experienced at least one form of harassment or discrimination during their training (95% confidence interval [CI]: 52.0%–66.7%). Verbal harassment was the most commonly cited form of harassment (prevalence: 63.0%; 95% CI: 54.8%–71.2%). Consultants were the most commonly cited source of harassment and discrimination, followed by patients or patients’ families (34.4% and 21.9%, respectively). Conclusions This review demonstrates the surprisingly high prevalence of harassment and discrimination among medical trainees that has not declined over time. The authors recommend both drafting policies and promoting cultural change within academic institutions to prevent future abuse.

Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis

Background: Cognitive enhancers, including cholinesterase inhibitors and memantine, are used to treat dementia, but their effectiveness for mild cognitive impairment is unclear. We conducted a systematic review to examine the efficacy and safety of cognitive enhancers for mild cognitive impairment. Methods: Our eligibility criteria were studies of the effects of donepezil, rivastigmine, galantamine or memantine on mild cognitive impairment reporting cognition, function, behaviour, global status, and mortality or harms. We identified relevant material by searching electronic databases (e.g., MEDLINE, Embase), the references of included studies, trial registries and conference proceedings, and by contacting experts. Two reviewers independently screened the results of the literature search, abstracted data and appraised risk of bias using the Cochrane risk-of-bias tool. Results: We screened 15 554 titles and abstracts and 1384 full-text articles. Eight randomized clinical trials and 3 companion reports met our inclusion criteria. We found no significant effects of cognitive enhancers on cognition (Mini–Mental State Examination: 3 randomized clinical trials [RCTs], mean difference [MD] 0.14, 95% confidence interval [CI] −0.22 to 0.50; Alzheimer’s Disease Assessment Scale — cognition subscale: 3 RCTs, standardized MD −0.07, 95% CI−0.16 to 0.01]) or function (Alzheimer’s Disease Cooperative Study activities of daily living inventory: 2 RCTs, MD 0.30, 95% CI −0.26 to 0.86). Cognitive enhancers were associated with higher risks of nausea, diarrhea and vomiting than placebo. Interpretation: Cognitive enhancers did not improve cognition or function among patients with mild cognitive impairment and were associated with a greater risk of gastrointestinal harms. Our findings do not support the use of cognitive enhancers for mild cognitive impairment.

Immunogenicity and Safety of an Intradermal Boosting Strategy for Vaccination Against Influenza in Lung Transplant Recipients

The immunogenicity of influenza vaccine is suboptimal in lung transplant recipients. Use of a booster dose and vaccine delivery by the intradermal rather than intramuscular route may improve response. We prospectively evaluated the immunogenicity and safety of a 2‐dose boosting strategy of influenza vaccine. Sixty lung transplant recipients received a standard intramuscular injection of the 2006–2007 inactivated influenza vaccine, followed 4 weeks later by an intradermal booster of the same vaccine. Immunogenicity was assessed by measurement of geometric mean titer of antibodies after both the intramuscular injection and the intradermal booster. Vaccine response was defined as 4‐fold or higher increase of antibody titers to at least one vaccine antigen. Thirty‐eight out of 60 patients (63%) had a response after intramuscular vaccination. Geometric mean titers increased for all three vaccine antigens following the first dose (p < 0.001). However, no significant increases in titer were observed after the booster dose for all three antigens. Among nonresponders, 3/22 (13.6%) additional patients responded after the intradermal booster (p = 0.14). The use of basiliximab was associated with a positive response (p = 0.024). After a single standard dose of influenza vaccine, a booster dose given by intradermal injection did not significantly improve vaccine immunogenicity in lung transplant recipients.

Effectiveness of quality improvement strategies for coordination of care to reduce use of health care services: a systematic review and meta-analysis

Background: Frequent users of health care services are a relatively small group of patients who account for a disproportionately large amount of health care utilization. We conducted a meta-analysis of the effectiveness of interventions to improve the coordination of care to reduce health care utilization in this patient group. Methods: We searched MEDLINE, Embase and the Cochrane Library from inception until May 2014 for randomized clinical trials (RCTs) assessing quality improvement strategies for the coordination of care of frequent users of the health care system. Articles were screened, and data abstracted and appraised for quality by 2 reviewers, independently. Random effects meta-analyses were conducted. Results: We identified 36 RCTs and 14 companion reports (total 7494 patients). Significantly fewer patients in the intervention group than in the control group were admitted to hospital (relative risk [RR] 0.81, 95% confidence interval [CI] 0.72–0.91). In subgroup analyses, a similar effect was observed among patients with chronic medical conditions other than mental illness, but not among patients with mental illness. In addition, significantly fewer patients 65 years and older in the intervention group than in the control group visited emergency departments (RR 0.69, 95% CI 0.54–0.89). Interpretation: We found that quality improvement strategies for coordination of care reduced hospital admissions among patients with chronic conditions other than mental illness and reduced emergency department visits among older patients. Our results may help clinicians and policy-makers reduce utilization through the use of strategies that target the system (team changes, case management) and the patient (promotion of self-management).

Lack of Association Between ß-herpesvirus Infection and Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients in the Era of Antiviral Prophylaxis

Background. Cytomegalovirus (CMV), human herpesvirus-6 and -7 (HHV-6 and -7) are &bgr;-herpesviruses that commonly reactivate and have been proposed to trigger acute rejection and chronic allograft injury. We assessed the contribution of these viruses in the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. Methods. Quantitative real-time polymerase chain reaction of bronchoalveolar lavage samples were performed for CMV, HHV-6 and -7 in a prospective cohort of lung transplant recipients. A time-dependent Cox regression analysis was used to correlate the risk of BOS and acute rejection in patients with and without &bgr;-herpesviruses infection. Results. Ninety-three patients were included in the study over a period of 3 years. A total of 581 samples from bronchoalveolar lavage were obtained. Sixty-one patients (65.6%) had at least one positive result for one of the &bgr;-herpesviruses: 48 patients (51.6%) for CMV and 19 patients (20.4%) for both HHV-6 and -7. Median peak viral load was 3419 copies/mL for CMV, 258 copies/mL for HHV-6, and 665 copies/mL for HHV-7. Acute rejection (≥grade 2) occurred in 46.2% and BOS (≥stage 1) in 19.4% of the patients. In the Cox regression model the relative risk of acute rejection or BOS was not increased in patients with any &bgr;-herpesviruses reactivation. Acute rejection was the only independently associated risk factor for BOS. Conclusions. In lung transplant recipients receiving prolonged antiviral prophylaxis, reactivation of &bgr;-herpesviruses within the allograft was common. However, despite high viral loads in many patients, virus replication was not associated with the development of rejection or BOS.

Determining optimal sample sizes for multistage adaptive randomized clinical trials from an industry perspective using value of information methods.

Background  Most often, sample size determinations for randomized clinical trials are based on frequentist approaches that depend on somewhat arbitrarily chosen factors, such as type I and II error probabilities and the smallest clinically important difference. As an alternative, many authors have proposed decision-theoretic (full Bayesian) approaches, often referred to as value of information methods that attempt to determine the sample size that maximizes the difference between the trial’s expected utility and its expected cost, referred to as the expected net gain. Taking an industry perspective, Willan proposes a solution in which the trial’s utility is the increase in expected profit. Furthermore, Willan and Kowgier, taking a societal perspective, show that multistage designs can increase expected net gain. Purpose  The purpose of this article is to determine the optimal sample size using value of information methods for industry-based, multistage adaptive randomized clinical trials, and to demonstrate the increase in expected net gain realized. At the end of each stage, the trial’s sponsor must decide between three actions: continue to the next stage, stop the trial and seek regulatory approval, or stop the trial and abandon the drug. Methods  A model for expected total profit is proposed that includes consideration of per-patient profit, disease incidence, time horizon, trial duration, market share, and the relationship between trial results and probability of regulatory approval. The proposed method is extended to include multistage designs with a solution provided for a two-stage design. An example is given. Results  Significant increases in the expected net gain are realized by using multistage designs. Limitations  The complexity of the solutions increases with the number of stages, although far simpler near-optimal solutions exist. The method relies on the central limit theorem, assuming that the sample size is sufficiently large so that the relevant statistics are normally distributed. Conclusion  From a value of information perspective, the use of multistage designs in industry trials leads to significant gains in the expected net gain.

Following 411 Cochrane Protocols to Completion: A Retrospective Cohort Study

Background Cochrane reviews are regarded as being scientifically rigorous and are increasingly used by a variety of stakeholders. However, factors predicting the publication of Cochrane reviews have never been reported. This is important because if a higher proportion of Cochrane protocols with certain characteristics (e.g., funding) are being published, this may lead to inaccurate decisions. We examined the frequency of published and unpublished Cochrane reviews and protocol factors that predict the publication of Cochrane reviews. Methodology/Principal Findings Retrospective cohort study of Cochrane protocols published in 2000 (Issues 2 to 4) and 2001 (Issue 1). The publication status of these reviews was followed up to Issue 1, 2008 in The Cochrane Library. Survival analysis of the time from protocol publication to the first review publication and protocol factors predicting the time to publication was conducted. There were 411 new Cochrane protocols in the cohort. After excluding 39; 71/372 (19.1%) were unpublished and 301/372 (80.9%) were published as full Cochrane reviews at the time of study analysis (January 2008). The median time to publication was 2.4 years (range: 0.15 to 8.96). Multivariate analyses revealed that shorter time to publication was associated with the review subsequently being updated (hazard ratio, HR: 1.80 [95% confidence interval, CI: 1.39 to 2.33 years]) and longer time to publication was associated with the review having two published protocols, indicating changes to the review plan (HR: 0.33 [95% CI: 0.12 to 0.90 years]). Conclusions/Significance Only about 80% Cochrane protocols were published as full reviews after over 8 years of follow-up. The median time to publication was 2.4 years and some reviews took much longer. Strategies to decrease time to publication should be considered, such as streamlining the review process, increased support for authors when protocol amendments occur, and better infrastructure for updating Cochrane reviews.

Cost-effectiveness of compression technologies for evidence-informed leg ulcer care: results from the Canadian Bandaging Trial

BackgroundVenous leg ulcers, affecting approximately 1% of the population, are costly to manage due to poor healing and high recurrence rates. We evaluated an evidence-informed leg ulcer care protocol with two frequently used high compression systems: ‘four-layer bandage’ (4LB) and ‘short-stretch bandage’ (SSB).MethodsWe conducted a cost-effectiveness analysis using individual patient data from the Canadian Bandaging Trial, a publicly funded, pragmatic, randomized trial evaluating high compression therapy with 4LB (n = 215) and SSB (n = 209) for community care of venous leg ulcers. We estimated costs (in 2009–2010 Canadian dollars) from the societal perspective and used a time horizon corresponding to each trial participant’s first year.ResultsRelative to SSB, 4LB was associated with an average 15 ulcer-free days gained, although the 95% confidence interval [−32, 21 days] crossed zero, indicating no treatment difference; an average health benefit of 0.009 QALYs gained [−0.019, 0.037] and overall, an average cost increase of

Use of a catalytic model to estimate hepatitis A incidence in a low-endemicity country: implications for modeling immunization policies.

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