Tonya S. King

Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.

IMPORTANCE In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency. OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels. DESIGN, SETTING, AND PARTICIPANTS The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institutes AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized. INTERVENTIONS Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained. MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care). RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]). CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01248065.

Cluster Analysis of Obesity and Asthma Phenotypes

Background Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype. Methodology and Principal Findings In a cohort of clinical trial participants (n = 250), minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCRα) and induction of MAP kinase phosphatase-1 (MKP-1) expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m2) and severity of asthma symptoms (AEQ score) the most significant determinants of cluster membership (F = 57.1, p<0.0001 and F = 44.8, p<0.0001, respectively). Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ) and control (ACQ), exhaled nitric oxide concentration (FENO) and airway hyperresponsiveness (methacholine PC20) but were similar with regard to measures of lung function (FEV1 (%) and FEV1/FVC), airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP). Members of obese clusters demonstrated evidence of reduced expression of GCRα, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasone Conclusions and Significance Obesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals. Reduced expression of the dominant functional isoform of the GCR may mediate GC insensitivity in obese asthmatics.

Comparison of Physician-, Biomarker-, and Symptom-Based Strategies for Adjustment of Inhaled Corticosteroid Therapy in Adults With Asthma: The BASALT Randomized Controlled Trial

CONTEXT No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms. OBJECTIVE To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma. DESIGN, SETTING, AND PARTICIPANTS A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. INTERVENTIONS For physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use. MAIN OUTCOME MEASURE The primary outcome was time to treatment failure. RESULTS There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3). CONCLUSION Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00495157.

Outcomes of states' scholarship, loan repayment, and related programs for physicians.

Context:Many states attempt to entice young generalist physicians into rural and medically underserved areas with financial support-for-service programs—scholarships, service-option loans, loan repayment, direct financial incentives, and resident support programs—with little documentation of their effectiveness. Objective:The objective of this study was to assess outcomes of states’ support-for-service programs as a group and to compare outcomes of the 5 program types. Design:We conducted a cross-sectional, primarily descriptive study. Participants:We studied all 69 state programs operating in 1996 that provided financial support to medical students, residents, and practicing physicians in exchange for a period of service in underserved areas; federally funded initiatives were excluded. We also surveyed 434 generalist physicians who served in 29 of these state programs and a matched comparison group of 723 nonobligated young generalist physicians. Data Collection:Information on eligible programs was collected by telephone, mail questionnaires, and from secondary sources. Obligated and nonobligated physicians were surveyed, with 80.3% and 72.8% response rates, respectively. Main Outcome Measures:Levels of socioeconomic need of communities and patients served by physicians, programs’ participant service completion and retention rates, and physicians’ satisfaction levels. Results:Compared with young nonobligated generalists, physicians serving obligations to state programs practiced in demonstrably needier areas and cared for more patients insured under Medicaid and uninsured (48.5% vs. 28.5%, P <0.001). Service completion rates were uniformly high for loan repayment, direct incentive, and resident-support programs (93% combined) but lower for student-targeting service-option loan (mean, 44.7%) and scholarship (mean, 66.5%) programs. State-obligated physicians were more satisfied than nonobligated physicians, and 9 of 10 indicated that they would enroll in their programs again. Obligated physicians also remained longer in their practices than nonobligated physicians (P = 0.03), with respective group retention rates of 71% versus 61% at 4 years and 55% versus 52% at 8 years. Retention rates were highest for loan repayment, direct incentive, and loan programs. Conclusions:States’ support-for-service programs bring physicians to needy communities where a strong majority work happily and with at-risk patient populations; half stay over 8 years. Loan repayment and direct financial incentive programs demonstrate the broadest successes.

The influence of a family program on adolescent tobacco and alcohol use.

OBJECTIVES This study examined a family-directed programs effectiveness in preventing adolescent tobacco and alcohol use in a general population. METHODS Adolescents aged 12 to 14 years and their families were identified by random-digit dialing throughout the contiguous United States. After providing baseline data by telephone interviews, they were randomly allocated to receive or not receive a family-directed program featuring mailed booklets and telephone contacts by health educators. Follow-up telephone interviews were conducted 3 and 12 months after program completion. RESULTS The findings suggested that smoking onset was reduced by 16.4% at 1 year, with a 25.0% reduction for non-Hispanic Whites but no statistically significant program effect for other races/ethnicities. There were no statistically significant program effects for smokeless tobacco or alcohol use onset. CONCLUSIONS The family-directed program was associated with reduced smoking onset for non-Hispanic Whites, suggesting that it is worthy of further application, development, and evaluation.

Melatonin secretion after surgery

Sleep disturbance is common postoperatively. We examined whether melatonin concentrations were related to this disturbance in seven postoperative patients. Nocturnal concentrations of melatonin were significantly (p=0.005) lower on the first than on the second or third nights after surgery. This finding raises the possibility that melatonin suppression and associated sleep disturbance might be prevented by melatonin replacement.

Influence of a family program on adolescent smoking and drinking prevalence

Reducing the prevalence of adolescent cigarette smoking and alcohol drinking are public health goals of the United States. Although families have strong influence on their children, few randomized studies have examined whether family-directed programs influence those behaviors in general universal populations. This paper reports findings from an evaluation of a family program that features the mailing of four booklets to adult family members with follow-up telephone calls by health educators. A national sample of adolescent–parent pairs and a randomized experimental design were used to evaluate the program. Baseline users and nonusers of those substances were considered simultaneously in analyses so that program influences on smoking and drinking prevalence could be examined. The findings suggest that the program significantly reduced the prevalence of smoking cigarettes and drinking alcohol among adolescents. These findings are discussed in the context of earlier reports of research on the family program and implications for public health.

Sphingosine kinase 1 protein and mRNA are overexpressed in non-Hodgkin lymphomas and are attractive targets for novel pharmacological interventions.

Sphingosine kinase 1 (SphK1) is an oncoprotein capable of directly transforming cells and is associated with resistance to chemotherapy and radiotherapy. SphK1 is increased in various human cancers; whereas, blockade restores sensitivity to therapeutic killing in chemotherapy resistant cancer cell lines. We investigated SphK1 expression in clinical tissue samples from patients with non-Hodgkin lymphomas (NHL). Tissues from 69 patients with either NHL (n = 44) or reactive lymphoid hyperplasias (RH) (n = 25) were examined for expression of SphK1 protein by Western blot and immunohistochemistry (IHC), and SphK1 and SphK2 mRNA by quantitative real-time reverse transcriptase polymerase chain reaction. SphK1 protein (p = 0.008) and mRNA (p = 0.035) levels were higher in NHL than RH, with a clear trend toward increasing levels with increasing clinical grade (p = 0.005 for SphK1 protein, p = 0.035 for IHC score and p = 0.002 for SphK1 mRNA). IHC generally confirmed protein signal in neoplastic cells, but some lymphomas exhibited staining in non-neoplastic cells. SphK1 is overexpressed in NHL and increases with increasing clinical grade. These results, combined with prior mechanistic studies suggest that SphK1 is an attractive novel target for pharmacological interventions for NHL.

Vapor Rub, Petrolatum, and No Treatment for Children With Nocturnal Cough and Cold Symptoms

OBJECTIVE: To determine if a single application of a vapor rub (VR) or petrolatum is superior to no treatment for nocturnal cough, congestion, and sleep difficulty caused by upper respiratory tract infection. METHODS: Surveys were administered to parents on 2 consecutive days—on the day of presentation when no medication had been given the previous evening, and the next day when VR ointment, petrolatum ointment, or no treatment had been applied to their childs chest and neck before bedtime according to a partially double-blinded randomization scheme. RESULTS: There were 138 children aged 2 to 11 years who completed the trial. Within each study group, symptoms were improved on the second night. Between treatment groups, significant differences in improvement were detected for outcomes related to cough, congestion, and sleep difficulty; VR consistently scored the best, and no treatment scored the worst. Pairwise comparisons demonstrated the superiority of VR over no treatment for all outcomes except rhinorrhea and over petrolatum for cough severity, child and parent sleep difficulty, and combined symptom score. Petrolatum was not significantly better than no treatment for any outcome. Irritant adverse effects were more common among VR-treated participants. CONCLUSIONS: In a comparison of VR, petrolatum, and no treatment, parents rated VR most favorably for symptomatic relief of their childs nocturnal cough, congestion, and sleep difficulty caused by upper respiratory tract infection. Despite mild irritant adverse effects, VR provided symptomatic relief for children and allowed them and their parents to have a more restful night than those in the other study groups.

ROBUST ESTIMATORS OF THE CONCORDANCE CORRELATION COEFFICIENT

This paper proposes a generalized version of Lins (1989, Biometrics 45, 255–268) concordance correlation coefficient for the agreement assessment of continuous data. Lins coefficient evaluates the accuracy and precision between two measures, and is based on the expected value of the squared distance function. We generalize Lins coefficient, apply alternative distance functions, and produce more robust versions of the concordance correlation coefficient. In this paper, we develop the asymptotic theory for this class of estimators, investigate small-sample properties via computer simulation, and demonstrate their use with two real data examples.