Nayer Khazeni

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.

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 individuals risk of developing IPAH.

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

Proper planning for an influenza A (H5N1) pandemic is a public health priority. Khazeni and colleagues modeled 3 alternative pandemic mitigation strategies: a strategy with vaccination and extended...

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.

Health and Economic Benefits of Early Vaccination and Nonpharmaceutical Interventions for a Human Influenza A (H7N9) Pandemic: A Modeling Study

Context Determining how best to prepare for future influenza pandemics is urgent. Contribution In a model, widespread delivery of vaccine by 4 and 6 months decreased infections and deaths while saving health care costs compared with vaccine delivery at 9 months. Nonpharmaceutical strategies, such as the use of facemasks, hand washing, and social distancing, if fully utilized, were similar to delivering vaccine by 4 months. Caution The model was developed for a major U.S. city. Implication Accelerated vaccination and maximization of nonpharmacologic measures are strategies that should be considered in planning a response to future influenza pandemics. The Editors Two events have raised concerns about our preparedness for a severe influenza pandemic: Separate scientific groups recently published methods for genetically engineering an influenza A (H5N1) virus that may be capable of aerosol transmission between humans (1, 2); and a novel influenza virus, A (H7N9), is causing alarming morbidity and mortality in human infections throughout China (3). In addition, a new influenza virus, A (H10N8), was recently reported and associated with a human fatality (4). These developments offer an invaluable opportunity to evaluate our response to the 2009 influenza A (H1N1) pandemic and technologic advances since then to prepare for a severe influenza pandemic. In our previous work assessing efficacy of vaccination in the 2009 pandemic, we found that timing was crucial, with as little as a 4-week delay resulting in a substantial increase in infections, deaths, and costs. However, large-scale vaccination against 2009 influenza A (H1N1) occurred 9 months after the beginning of the pandemic, which is substantially later than the timing we found would have maximized health and economic benefits (5). The mortality rates of influenza A (H5N1) and A (H7N9) are remarkably high (59% and 19%, respectively) compared with a rate of less than 0.3% from A (H1N1) in 2009 (3, 6, 7). These data may be overestimated because of incomplete ascertainment of cases; nonetheless, the observed mortality rate remains a critical concern. If these viruses were lethal and transmissible between humans, a resulting pandemic would have more devastating health and economic consequences than in 2009. Advances in cell-based and recombinant vaccine (8) technologies could allow faster mass vaccination than current egg-based methods (9). To evaluate our progress and preparedness for a more severe outbreak than the mild 2009 pandemic, we modeled a severe pandemic caused by a virus with characteristics similar to those of influenza A (H7N9) and A (H5N1). We wanted to assess the value of accelerating vaccine production with new technologies. We evaluated effectiveness and cost-effectiveness of no vaccination or vaccination at 4 or 6 months versus 9 months. Methods Overview We created a dynamic transmission model of progression of a severe pandemic caused by a virus with characteristics similar to those of influenza A (H7N9) and A (H5N1) in a susceptible population (Table 1 and Appendix Figure 1). We evaluated vaccine interventions coupled with nonpharmaceutical interventions (NPIs). In accord with recommendations from the Panel on Cost-Effectiveness in Health and Medicine (10), we conducted the analysis using a societal perspective and discounted costs and benefits at 3% annually. We analyzed health and economic outcomes over the remaining lifetimes of the population. We measured outcomes in infections and deaths averted, costs, and cost savings. We constructed the model and did analyses in Microsoft Excel, version 2010 (Microsoft, Redmond, Washington) (11). We provide an annotated version of the model (Supplement 1) so that readers can test model output for different assumptions and circumstances. Table 1. Variables and Sources Appendix Figure 1. SEIR model. Dynamic infectious disease transmission model of progression of a severe pandemic with characteristics similar to influenza A (H7N9) and A (H5N1) in a susceptible population. We used a basic deterministic SEIR model with modifications to allow for various population groups (who receive pharmaceutical and nonpharmaceutical interventions). SEIR = susceptible, exposed, infected, and recovered. Supplement 1. Model of the Spread of a Pandemic Influenza Study Population and Disease Variables Susceptible Population We modeled a population of 8.3 million persons in a large metropolitan U.S. city with demographic characteristics similar to those of New York City (12). We assumed 1000 persons were infected at the start of the pandemic. In the absence of documented influenza A (H7N9) human infection in the United States (6), we assumed no preexisting population immunity. Infected Population We assumed a severe pandemic, similar to the 1918 Spanish influenza pandemic, with an R0 (the reproductive number; secondary infections caused by each infected person in a susceptible population), of 2.0 (13). We varied R0 between 1.8 and 2.2 in sensitivity analysis. On the basis of previous studies (1416), we assumed that 67% of infected persons were symptomatic and 50% of them were socially isolated, either voluntarily because of symptoms or involuntarily because of hospital admission. We assumed that the nonisolated 50% continued to infect others. On the basis of observations of the 2009 influenza A (H1N1) outbreak (17), we assumed that the mean incubation period was 3 days. On the basis of Centers for Disease Control and Prevention (CDC) estimates (18, 19), we assumed persons to be symptomatic for 10 days and infectious for 4 days. In sensitivity analysis, we varied infectivity between 3 and 7 days. We extrapolated from previous influenza A studies (19, 20) that symptomatic persons transmitted the disease 3 times faster than asymptomatic persons. Using CDC data, we estimated that 10% of persons with symptomatic infection would require 5 days of hospitalization, and 10% of that population would be admitted to the intensive care unit for 10 days (21). Recovered Population Studies find a 2% to 25% (22, 23) risk for reinfection with influenza A viruses. Reinfected persons tend to be asymptomatic or have moderate symptoms, a shorter duration of illness, and less viral shedding (23). We assumed that 5 months after recovery, 5% of the recovered population would become susceptible to reinfection. In sensitivity analysis, we analyzed reinfection rates ranging from 2% to 25%. Death From Influenza The mortality rates from influenza A (H7N9) and A (H5N1) infections (6) may be overestimated because asymptomatic and mildly symptomatic infections were undercounted (24, 25). However, mortality rates may be greater in resource-limited health care settings (7). We therefore assumed a 2.5% mortality rate for our model, which is much lower than the observed naturally occurring rate. In sensitivity analysis, we examined mortality rates ranging from 0.5% to 10%. We allowed age-specific mortality to vary, with increased rates in newborns and persons older than age 65 years, which is consistent with the 1957 and 1968 pandemics and seasonal influenza epidemics (18). In sensitivity analysis, we examined additional increases in mortality rates in young adults, which occurred in the 1918 and 2009 pandemics (26). On the basis of previous pandemics (27), we assumed that healthy persons would limit social interactions as mortality rates in the city increased. Interventions Vaccination Consistent with information on pandemic vaccine effectiveness in 2009 (28), we assumed an effectiveness of 56% and varied effectiveness from 30% to 80% in sensitivity analysis. On the basis of U.S. vaccination coverage in the 2009 influenza A (H1N1) pandemic and the 1947 smallpox vaccination campaign in New York City (29), we estimated that a mass vaccination exercise in a U.S. city of 8.3 million people could inoculate 30% of the population in 10 days. We anticipated that 45% of vaccinated persons would experience mild to moderate adverse effects, such as pain, redness, swelling, fatigue, headache, arthralgia, myalgia, shivering, sweating, and low-grade fevers, on the basis of 2009 influenza A (H1N1) vaccine studies (30, 31). Although we assumed a nonadjuvanted vaccine, we drew from adjuvanted vaccination data in Europe in 2009 and vaccination campaigns in 1976 and assumed that 0.001% of vaccinated persons would have severe adverse effects, such as angioedema, anaphylaxis, narcolepsy, or the GuillainBarr syndrome (32). We varied this number to 0.01% in sensitivity analysis, which yielded a rate of narcolepsy more than twice that seen with European adjuvanted 2009 influenza A (H1N1) vaccines (33, 34). NPIs The World Health Organization and CDC recommend concurrent use of nonpharmaceutical and pharmaceutical interventions to mitigate influenza pandemics (35). Nonpharmaceutical interventions include closures of school and child care facilities; home isolation; cough etiquette; hand washing; use of alcohol-based hand gels; and protective personal equipment, such as facemasks. Randomized trials of facemasks, hand hygiene, and social distancing have shown a reduction of transmission rates from 66% to 75% (36, 37). On the basis of available data (38, 39), our model assumes NPIs reduce contacts by 25%. We also examined effects of a 50% to 90% reduction in contacts in sensitivity analysis. Cost and Utilities We expressed all costs in 2012 U.S. dollars using the gross domestic product deflator (40). Our model incorporates costs associated with vaccination (including vaccine, administration, persons time, and treatment of adverse effects) and normal lifetime health expenditures for all persons who survive the pandemic (Table 1). Treatment costs are based on an average hospitalization for symptomatic influenza infection (41) or admission to the intensive care unit (42). We used 1 hour of average wages to estimate the opportunity cost of receiving the vaccine (43). We used EuroQol-5D (44) and

Effectiveness and Cost-Effectiveness of Vaccination against Pandemic (H1N1) 2009

Background A matched vaccine for the Pandemic (H1N1) 2009 virus will not be ready until autumn, 2009; decisions regarding timing of vaccination and percentage of population to vaccinate are complex.

Massive cavitary pulmonary rheumatoid nodules in a patient with HIV

The case of a 52-yr-old female with rheumatoid arthritis and HIV who developed massive, progressive, cavitary pulmonary nodules is described. Multiple diagnostic bronchoscopies and lung biopsies failed to demonstrate the presence of any microorganisms. Pathological analysis showed palisading histiocytes with necrobiosis consistent with rheumatoid nodules. The effect of co-existing HIV infection on the course and prognosis of rheumatoid arthritis is discussed, and it is concluded that the complex relationship between these two disease processes warrants further investigation.

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.