Perceived stress and telomere length: A systematic review, meta-analysis, and methodologic considerations for advancing the field.

IMPORTANCE: Psychological stress contributes to numerous diseases and may do so in part through damage to telomeres, protective non-coding segments on the ends of chromosomes. OBJECTIVE: We conducted a systematic review and meta-analysis to determine the association between self-reported, perceived psychological stress (PS) and telomere length (TL). DATA SOURCES: We searched 3 databases (PubMed, PsycInfo, and Scopus), completed manual searches of published and unpublished studies, and contacted all study authors to obtain potentially relevant data. STUDY SELECTION: Two independent reviewers assessed studies for original research measuring (but not necessarily reporting the correlation between) PS and TL in human subjects. 23 studies met inclusion criteria; 22 (totaling 8948 subjects) could be meta-analyzed. DATA EXTRACTION AND SYNTHESIS: We assessed study quality using modified MINORS criteria. Since not all included studies reported PS-TL correlations, we obtained them via direct calculation from author-provided data (7 studies), contact with authors (14 studies), or extraction from the published article (1 study). MAIN OUTCOMES AND MEASURES: We conducted random-effects meta-analysis on our primary outcome, the age-adjusted PS-TL correlation. We investigated potential confounders and moderators (sex, life stress exposure, and PS measure validation) via post hoc subset analyses and meta-regression. RESULTS: Increased PS was associated with a very small decrease in TL (n=8724 total; r=-0.06; 95% CI: -0.10, -0.008; p=0.01; α=0.025), adjusting for age. This relationship was similar between sexes and within studies using validated measures of PS, and marginally (nonsignificantly) stronger among samples recruited for stress exposure (r=-0.13; vs. general samples: b=-0.11; 95% CI: -0.27, 0.01; p=0.05; α=0.013). Publication bias may exist; correcting for its effects attenuated the relationship. CONCLUSIONS AND RELEVANCE: Our analysis finds a very small, statistically significant relationship between increased PS (as measured over the past month) and decreased TL that may reflect publication bias, although fully parsing the effects of publication bias from other sample-size correlates is challenging, as discussed. The association may be stronger with known major stressors and is similar in magnitude to that noted between obesity and TL. All included studies used single measures of short-term stress; the literature suggests long-term chronic stress may have a larger cumulative effect. Future research should assess for potential confounders and use longitudinal, multidimensional models of stress.

Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension.

RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by progressive loss of pulmonary microvessels. Although mutations in the bone morphogenetic receptor 2 (BMPR2) are found in 80% of heritable and ∼15% of patients with IPAH, their low penetrance (∼20%) suggests that other unidentified genetic modifiers are required for manifestation of the disease phenotype. Use of whole-exome sequencing (WES) has recently led to the discovery of novel susceptibility genes in heritable PAH, but whether WES can also accelerate gene discovery in IPAH remains unknown. OBJECTIVES: To determine whether WES can help identify novel gene modifiers in patients with IPAH. METHODS: Exome capture and sequencing was performed on genomic DNA isolated from 12 unrelated patients with IPAH lacking BMPR2 mutations. Observed genetic variants were prioritized according to their pathogenic potential using ANNOVAR. MEASUREMENTS AND MAIN RESULTS: A total of nine genes were identified as high-priority candidates. Our top hit was topoisomerase DNA binding II binding protein 1 (TopBP1), a gene involved in the response to DNA damage and replication stress. We found that TopBP1 expression was reduced in vascular lesions and pulmonary endothelial cells isolated from patients with IPAH. Although TopBP1 deficiency made endothelial cells susceptible to DNA damage and apoptosis in response to hydroxyurea, its restoration resulted in less DNA damage and improved cell survival. CONCLUSIONS: WES led to the discovery of TopBP1, a gene whose deficiency may increase susceptibility to small vessel loss in IPAH. We predict that use of WES will help identify gene modifiers that influence an individual's risk of developing IPAH.

Health and economic benefits of early vaccination and nonpharmaceutical interventions for a human influenza A (H7N9) pandemic: a modeling study.

BACKGROUND: Vaccination for the 2009 pandemic did not occur until late in the outbreak, which limited its benefits. Influenza A (H7N9) is causing increasing morbidity and mortality in China, and researchers have modified the A (H5N1) virus to transmit via aerosol, which again heightens concerns about pandemic influenza preparedness. OBJECTIVE: To determine how quickly vaccination should be completed to reduce infections, deaths, and health care costs in a pandemic with characteristics similar to influenza A (H7N9) and A (H5N1). DESIGN: Dynamic transmission model to estimate health and economic consequences of a severe influenza pandemic in a large metropolitan city. DATA SOURCES: Literature and expert opinion. TARGET POPULATION: Residents of a U.S. metropolitan city with characteristics similar to New York City. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Vaccination of 30% of the population at 4 or 6 months. OUTCOME MEASURES: Infections and deaths averted and cost-effectiveness. RESULTS OF BASE-CASE ANALYSIS: In 12 months, 48 254 persons would die. Vaccinating at 9 months would avert 2365 of these deaths. Vaccinating at 6 months would save 5775 additional lives and $51 million at a city level. Accelerating delivery to 4 months would save an additional 5633 lives and $50 million. RESULTS OF SENSITIVITY ANALYSIS: If vaccination were delayed for 9 months, reducing contacts by 8% through nonpharmaceutical interventions would yield a similar reduction in infections and deaths as vaccination at 4 months. LIMITATION: The model is not designed to evaluate programs targeting specific populations, such as children or persons with comorbid conditions. CONCLUSION: Vaccination in an influenza A (H7N9) pandemic would need to be completed much faster than in 2009 to substantially reduce morbidity, mortality, and health care costs. Maximizing non-pharmaceutical interventions can substantially mitigate the pandemic until a matched vaccine becomes available. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality, National Institutes of Health, and Department of Veterans Affairs.

Centralized monitoring and virtual consultant models of tele-ICU care: a side-by-side review.

BACKGROUND: Telemedicine-based "tele-intensive care unit" ("tele-ICU") solutions represent an increasingly popular hospital platform to provide ICU specialist expertise while remaining sensitive to healthcare costs. This side-by-side review directly compares the Centralized Monitoring and Virtual Consultant tele-ICU Models. MATERIALS AND METHODS: We identified all publications in any language addressing the use and efficacy of centralized monitoring and virtual consultant tele-ICU systems through reviews of the PubMed, CINAHL, and Web of Science Web sites, corporate documents, corporate Internet sites, and discussions with corporate representatives. Of the 1,468 documents identified, 1,371 documents were excluded, with the 91 included documents addressing the following: clinical outcomes, 46 documents (enhanced guideline compliance, 5; mortality and length of stay, 28; and feasibility, 13); financial sustainability, 9 documents; and ICU staff workflow and acceptance, 36 documents. We performed qualitative comparative reviews of documents addressing technology, financial sustainability, clinical outcomes, and ICU staff workflow and acceptance. RESULTS: The Centralized Monitoring tele-ICU Model showed improved mortality and/or length of stay and staff acceptance, particularly in rural or specific patient populations, likely because of the presence of integrated clinical information systems and analytics. However, there are high costs and unclear savings. The Virtual Consultant Model could not be adequately evaluated for effects on clinical outcomes or staff acceptance given minimal data. This model can be both portable and implemented at a lower cost profile but cannot integrate different data streams. Improved compliance with clinical practice guidelines was seen in both models. CONCLUSIONS: Further study is required to adequately compare these tele-ICU models with regard to clinical outcomes and financial sustainability. With respect to tele-ICU effects on mortality and length of stay improvements and on-site staff acceptance, existing evidence favors the Centralized Monitoring Model. Studies addressing the Virtual Consultant Model are growing in number and are necessary before proper comparisons can be made.

Centralized monitoring and virtual consultant models of tele-ICU care: a systematic review.

BACKGROUND: Increasing intensivist shortages and demand coupled with the escalating cost of care have created enthusiasm for intensive care unit (ICU)-based telemedicine ("tele-ICU"). This systematic literature review compares the Centralized Monitoring and Virtual Consultant tele-ICU Models. MATERIALS AND METHODS: With an experienced medical reference librarian, we identified all language publications addressing the employment and efficacy of the centralized monitoring and virtual consultant tele-ICU systems through PubMed, CINAHL, and Web of Science. We performed quantitative and qualitative reviews of documents regarding financial sustainability, clinical outcomes, and ICU staff workflow and acceptance. RESULTS: Of 1,468 documents identified, 1,371 documents were excluded, with the remaining 91 documents addressing clinical outcomes (46 documents [enhanced guideline compliance, 5; mortality and length of stay, 28; and feasibility, 13]), financial sustainability (9 documents), and ICU staff workflow and acceptance (36 documents). Quantitative review showed that studies evaluating the Centralized Monitoring Model were twice as frequent, with a mean of 4,891 patients in an average of six ICUs; Virtual Consultant Model studies enrolled a mean of 372 patients in an average of one ICU. Ninety-two percent of feasibility studies evaluated the Virtual Consultant Model, of which 50% were in the last 3 years. Qualitative review largely confirmed findings in previous studies of centralized monitoring systems. Both the Centralized Monitoring and Virtual Consultant Models showed clinical practice adherence improvement. Although definitive evaluation was not possible given lack of data, the Virtual Consultant Model generally indicated lean absolute cost profile in contrast to centralized monitoring systems. CONCLUSIONS: Compared with the Virtual Consultant tele-ICU Model, studies addressing the Centralized Monitoring Model of tele-ICU care were greater in quantity and sample size, with qualitative conclusions of clinical outcomes, staff satisfaction and workload, and financial sustainability largely consistent with past systematic reviews. Attention should be focused on performing more high-quality studies to allow for equitable comparisons between both models.

Effectiveness and cost-effectiveness of vaccination against pandemic influenza (H1N1) 2009.

BACKGROUND: Decisions on the timing and extent of vaccination against pandemic (H1N1) 2009 virus are complex. OBJECTIVE: To estimate the effectiveness and cost-effectiveness of pandemic influenza (H1N1) vaccination under different scenarios in October or November 2009. DESIGN: Compartmental epidemic model in conjunction with a Markov model of disease progression. DATA SOURCES: Literature and expert opinion. TARGET POPULATION: Residents of a major U.S. metropolitan city with a population of 8.3 million. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: Vaccination in mid-October or mid-November 2009. OUTCOME MEASURES: Infections and deaths averted, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness. RESULTS OF BASE-CASE ANALYSIS: Assuming each primary infection causes 1.5 secondary infections, vaccinating 40% of the population in October or November would be cost-saving. Vaccination in October would avert 2051 deaths, gain 69 679 QALYs, and save $469 million compared with no vaccination; vaccination in November would avert 1468 deaths, gain 49 422 QALYs, and save $302 million. RESULTS OF SENSITIVITY ANALYSIS: Vaccination is even more cost-saving if longer incubation periods, lower rates of infectiousness, or increased implementation of nonpharmaceutical interventions delay time to the peak of the pandemic. Vaccination saves fewer lives and is less cost-effective if the epidemic peaks earlier than mid-October. LIMITATIONS: The model assumed homogenous mixing of case-patients and contacts; heterogeneous mixing would result in faster initial spread, followed by slower spread. Additional costs and savings not included in the model would make vaccination more cost-saving. CONCLUSION: Earlier vaccination against pandemic (H1N1) 2009 prevents more deaths and is more cost-saving. Complete population coverage is not necessary to reduce the viral reproductive rate sufficiently to help shorten the pandemic. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and National Institute on Drug Abuse.

Effectiveness and cost-effectiveness of expanded antiviral prophylaxis and adjuvanted vaccination strategies for an influenza A (H5N1) pandemic.

BACKGROUND: The pandemic potential of influenza A (H5N1) virus is a prominent public health concern of the 21st century. OBJECTIVE: To estimate the effectiveness and cost-effectiveness of alternative pandemic (H5N1) mitigation and response strategies. DESIGN: Compartmental epidemic model in conjunction with a Markov model of disease progression. DATA SOURCES: Literature and expert opinion. TARGET POPULATION: Residents of a U.S. metropolitan city with a population of 8.3 million. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: 3 scenarios: 1) vaccination and antiviral pharmacotherapy in quantities similar to those currently available in the U.S. stockpile (stockpiled strategy), 2) stockpiled strategy but with expanded distribution of antiviral agents (expanded prophylaxis strategy), and 3) stockpiled strategy but with adjuvanted vaccine (expanded vaccination strategy). All scenarios assumed standard nonpharmaceutical interventions. OUTCOME MEASURES: Infections and deaths averted, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness. RESULTS OF BASE-CASE ANALYSIS: Expanded vaccination was the most effective and cost-effective of the 3 strategies, averting 68% of infections and deaths and gaining 404 030 QALYs at $10 844 per QALY gained relative to the stockpiled strategy. RESULTS OF SENSITIVITY ANALYSIS: Expanded vaccination remained incrementally cost-effective over a wide range of assumptions. LIMITATIONS: The model assumed homogenous mixing of cases and contacts; heterogeneous mixing would result in faster initial spread, followed by slower spread. We did not model interventions for children or older adults; the model is not designed to target interventions to specific groups. CONCLUSION: Expanded adjuvanted vaccination is an effective and cost-effective mitigation strategy for an influenza A (H5N1) pandemic. Expanded antiviral prophylaxis can help delay the pandemic while additional strategies are implemented. PRIMARY FUNDING SOURCE: National Institutes of Health and Agency for Healthcare Research and Quality.

Systematic review: safety and efficacy of extended-duration antiviral chemoprophylaxis against pandemic and seasonal influenza.

BACKGROUND: Neuraminidase inhibitors (NAIs) are stockpiled internationally for extended use in an influenza pandemic. PURPOSE: To evaluate the safety and efficacy of extended-duration (>4 weeks) NAI chemoprophylaxis against influenza. DATA SOURCES: Studies published in any language through 11 June 2009 identified by searching 10 electronic databases and 3 trial registries. STUDY SELECTION: Randomized, placebo-controlled, double-blind human trials of extended-duration NAI chemoprophylaxis that reported outcomes of laboratory-confirmed influenza or adverse events. DATA EXTRACTION: 2 reviewers independently assessed study quality and abstracted information from eligible studies. DATA SYNTHESIS: Of 1876 potentially relevant citations, 7 trials involving 7021 unique participants met inclusion criteria. Data were pooled by using random-effects models. Chemoprophylaxis with NAIs decreased the frequency of symptomatic influenza (relative risk [RR], 0.26 [95% CI, 0.18 to 0.37]; risk difference [RD], -3.9 percentage points [CI, -5.8 to -1.9 percentage points]) but not asymptomatic influenza (RR, 1.03 [CI, 0.81 to 1.30]; RD, -0.4 percentage point [CI, -1.6 to 0.9 percentage point]). Adverse effects were not increased overall among NAI recipients (RR, 1.01 [CI, 0.94 to 1.08]; RD, 0.1 percentage point [CI, -0.2 to 0.4 percentage point]), but nausea and vomiting were more common among those who took oseltamivir (RR, 1.48 [CI, 1.86 to 2.33]; RD, 1.7 percentage points [CI, 0.6 to 2.9 percentage points]). Prevention of influenza did not statistically significantly differ between zanamivir and oseltamivir. LIMITATIONS: All trials were industry-sponsored. No study was powered to detect rare adverse events, and none included diverse racial groups, children, immunocompromised patients, or individuals who received live attenuated influenza virus vaccine. CONCLUSION: Extended-duration zanamivir and oseltamivir chemoprophylaxis seems to be highly efficacious for preventing symptomatic influenza among immunocompetent white and Japanese adults. Extended-duration oseltamivir is associated with increased nausea and vomiting. Safety and efficacy in several subpopulations that might receive extended-duration influenza chemoprophylaxis are unknown.

Direct-to-Consumer Drug Advertisements Can Paradoxically Increase Intentions to Adopt Lifestyle Changes.

Background: Direct-to-consumer (DTC) prescription drug advertisements are thought to induce "boomerang effects," meaning they reduce the perceived effectiveness of a potential alternative option: non-pharmaceutical treatment via lifestyle change. Past research has observed such effects using artificially created, text-only advertisements that may not adequate capture the complex, conflicting portrayal of lifestyle change in real television advertisements. In other risk domains, individual "problem status" often moderates boomerang effects, such that subjects who currently engage in the risky behavior exhibit the strongest boomerang effects. Objectives: We aimed to assess whether priming with real DTC television advertisements elicited boomerang effects on perceptions of lifestyle change and whether these effects, if present, were moderated by individual problem status. Methods: We assembled a sample of real, previously aired DTC television advertisements in order to naturalistically capture the portrayal of lifestyle change in real advertisements. We randomized 819 adults in the United States recruited via Amazon Mechanical Turk to view or not view an advertisement for a prescription drug. We further randomized subjects to judge either lifestyle change or drugs on three measures: general effectiveness, disease severity for a hypothetical patient, and personal intention to use the intervention if diagnosed with the target health condition. Results: Advertisement exposure induced a statistically significant, but weak, boomerang effect on general effectiveness (p = 0.01, partial R2 = 0.007) and did not affect disease severity score (p = 0.32, partial R2 = 0.0009). Advertisement exposure elicited a reverse boomerang effect of similar effect size on personal intentions, such that advertisement-exposed subjects reported comparatively higher intentions to use lifestyle change relative to drugs (p = 0.006, partial R2 = 0.008). Individual problem status did not significantly moderate these effects. Conclusion: In contrast to previous literature finding large boomerang effects using artificial advertisement stimuli, real television advertisements elicited only a weak boomerang effect on perceived effectiveness and elicited an unexpected reverse boomerang effect on personal intentions to use lifestyle change versus drugs. These findings may reflect real advertisements' induction of descriptive norms and self-efficacy; future research could address such possibilities by systematically manipulating advertisement content.

Impact of insulin resistance on ventricular function in pulmonary arterial hypertension.

BACKGROUND: Insulin resistance (IR) is an independent prognostic marker in pulmonary arterial hypertension (PAH), although the mechanism by which it engenders risk is unknown. We prospectively investigated the clinical, laboratory, hemodynamic, and echocardiographic characteristics of insulin-sensitive (IS) and IR patients with PAH. METHODS: This was a prospective cohort study including well-phenotyped patients with PAH proven at cardiac catheterization. Patients were classified as IS or IR on the basis of the well-validated triglyceride/high-density lipoprotein-cholesterol ratio. Clinical, laboratory, and hemodynamic characteristics were compared between cohorts. Distance walked on the 6-minute walk test (6MWT) and echocardiograms were compared between IS and IR for the sub-set of patients that had these tests within 1 month of cardiac catheterization. RESULTS: Of the 111 PAH patients enrolled, 59 were IS, 25 were IR, and 27 were classified as indeterminate. Mean age was 45.8 ± 15.0 years. IR was associated with worse New York Heart Association class (p = 0.02). There were no differences in hemodynamics, biomarkers, 6MWT distance, or parameters of right ventricular function (i.e., tricuspid annular plane systolic excursion, myocardial performance index, and fractional area change) between groups. Despite similar systemic vascular resistance, parameters of left ventricular diastolic function were more favorable for IS vs IR, including mitral inflow E wave velocity (82 ± 17 vs. 64 ± 19 msec, p = 0.02), E/A ratio (1.2 ± 0.4 vs. 0.8 ± 0.2, p = 0.01), and lateral mitral valve E' velocity (13.9 ± 3.5 vs. 10.4 ± 2.2 msec, p = 0.01). CONCLUSIONS: IR is associated with worse functional class and diastology compared with IS in PAH, although other prognostic parameters are similar.

Demographic and clinical predictors of mortality from highly pathogenic avian influenza A (H5N1) virus infection: CART analysis of international cases.

BACKGROUND: Human infections with highly pathogenic avian influenza (HPAI) A (H5N1) viruses have occurred in 15 countries, with high mortality to date. Determining risk factors for morbidity and mortality from HPAI H5N1 can inform preventive and therapeutic interventions. METHODS: We included all cases of human HPAI H5N1 reported in World Health Organization Global Alert and Response updates and those identified through a systematic search of multiple databases (PubMed, Scopus, and Google Scholar), including articles in all languages. We abstracted predefined clinical and demographic predictors and mortality and used bivariate logistic regression analyses to examine the relationship of each candidate predictor with mortality. We developed and pruned a decision tree using nonparametric Classification and Regression Tree methods to create risk strata for mortality. FINDINGS: We identified 617 human cases of HPAI H5N1 occurring between December 1997 and April 2013. The median age of subjects was 18 years (interquartile range 6-29 years) and 54% were female. HPAI H5N1 case-fatality proportion was 59%. The final decision tree for mortality included age, country, per capita government health expenditure, and delay from symptom onset to hospitalization, with an area under the receiver operator characteristic (ROC) curve of 0.81 (95% CI: 0.76-0.86). INTERPRETATION: A model defined by four clinical and demographic predictors successfully estimated the probability of mortality from HPAI H5N1 illness. These parameters highlight the importance of early diagnosis and treatment and may enable early, targeted pharmaceutical therapy and supportive care for symptomatic patients with HPAI H5N1 virus infection.

Seasonal patterns in human A (H5N1) virus infection: analysis of global cases.

BACKGROUND: Human cases of highly pathogenic avian influenza (HPAI) A (H5N1) have high mortality. Despite abundant data on seasonal patterns in influenza epidemics, it is unknown whether similar patterns exist for human HPAI H5N1 cases worldwide. Such knowledge could help decrease avian-to-human transmission through increased prevention and control activities during peak periods. METHODS: We performed a systematic search of published human HPAI H5N1 cases to date, collecting month, year, country, season, hemisphere, and climate data. We used negative binomial regression to predict changes in case incidence as a function of season. To investigate hemisphere as a potential moderator, we used AIC and the likelihood-ratio test to compare the season-only model to nested models including a main effect or interaction with hemisphere. Finally, we visually assessed replication of seasonal patterns across climate groups based on the Köppen-Geiger climate classification. FINDINGS: We identified 617 human cases (611 with complete seasonal data) occurring in 15 countries in Southeast Asia, Africa, and the Middle East. Case occurrence was much higher in winter (n = 285, p = 0.03) than summer (n = 64), and the winter peak occurred across diverse climate groups. There was no significant interaction between hemisphere and season. INTERPRETATION: Across diverse climates, HPAI H5N1 virus infection in humans increases significantly in winter. This is consistent with increased poultry outbreaks and HPAI H5N1 virus transmission during cold and dry conditions. Prioritizing prevention and control activities among poultry and focusing public health messaging to reduce poultry exposures during winter months may help to reduce zoonotic transmission of HPAI H5N1 virus in resource-limited settings.

Quality improvement strategies for children with asthma: a systematic review.

OBJECTIVE: To evaluate the evidence that quality improvement (QI) strategies can improve the processes and outcomes of outpatient pediatric asthma care. DATA SOURCES: Cochrane Effective Practice and Organisation of Care Group database (January 1966 to April 2006), MEDLINE (January 1966 to April 2006), Cochrane Consumers and Communication Group database (January 1966 to May 2006), and bibliographies of retrieved articles. STUDY SELECTION: Randomized controlled trials, controlled before-after trials, or interrupted time series trials of English-language QI evaluations. INTERVENTIONS: Must have included 1 or more QI strategies for the outpatient management of children with asthma. MAIN OUTCOME MEASURES: Clinical status (eg, spirometric measures); functional status (eg, days lost from school); and health services use (eg, hospital admissions). RESULTS: Seventy-nine studies met inclusion criteria: 69 included at least some component of patient education, self-monitoring, or self-management; 13 included some component of organizational change; and 7 included provider education. Self-management interventions increased symptom-free days by approximately 10 days/y (P = .02) and reduced school absenteeism by about 0.1 day/mo (P = .03). Interventions of provider education and those that incorporated organizational changes were likely to report improvements in medication use. Quality improvement interventions that provided multiple educational sessions, had longer durations, and used combinations of instructional modalities were more likely to result in improvements for patients than interventions lacking these characteristics. CONCLUSIONS: A variety of QI interventions improve the outcomes and processes of care for children with asthma. Use of similar outcome measures and thorough descriptions of interventions would advance the study of QI for pediatric asthma care.