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Introduction Alveolar macrophages (AMs) are lung-resident immune cells that phagocytose inhaled particles and pathogens, and help coordinate the lung’s immune response to infection. Little is known about the impact of chronic e-cigarette use (ie, vaping) on this important pulmonary cell type. Thus, we determined the effect of vaping on AM phenotype and gene expression. Aims and Methods We recruited never-smokers, smokers, and e-cigarette users (vapers) and performed research bronchoscopies to isolate AMs from bronchoalveolar lavage fluid samples and epithelial cells from bronchial brushings. We then performed morphological analyses and used the Nanostring platform to look for changes in gene expression. Results AMs obtained from smokers and vapers were phenotypically distinct from those obtained from nonsmokers, and from each other. Immunocytochemistry revealed that vapers AMs had significantly elevated inducible nitric oxide synthase (M1) expression and significantly reduced CD301a (M2) expression compared with nonsmokers or smokers. Vapers’ AMs and bronchial epithelia exhibited unique changes in gene expression compared with nonsmokers or smokers. Moreover, vapers’ AMs were the most affected of all groups and had 124 genes uniquely downregulated. Gene ontology analysis revealed that vapers and smokers had opposing changes in biological processes. Conclusions These data indicate that vaping causes unique changes to AMs and bronchial epithelia compared with nonsmokers and smokers which may impact pulmonary host defense. Implications These data indicate that normal “healthy” vapers have altered AMs and may be at risk of developing abnormal immune responses to inflammatory stimuli.

The sum of target lesions is routinely used to evaluate patient objective responses to treatment in the RECIST criteria, but it fails to address response heterogeneity across metastases. This study argues that spatiotemporal heterogeneity across metastases and organ-specific response is informative for drug efficacy and patient survival. We analyzed the longitudinal data of 11,404 metastatic lesions in 2,802 colorectal cancer patients from five phase III clinical trials. Initially, a metric Gower distance was applied to quantify response heterogeneity across metastases. Next, the spatiotemporal response heterogeneity across anatomic sites, therapies, and KRAS mutation status was assessed and examined for its association with drug efficacy and long-term patient survival. The response of metastatic lesions broadly differed across anatomic sites and therapies. About 60% of patients had at least one lesion respond contrarily from total tumor size. High interlesion heterogeneity was associated with shorter progression-free survival and overall survival. Targeted therapies (bevacizumab or panitumumab) combined with standard chemotherapy reduced interlesion heterogeneity and elicited more favorable effects from liver lesions (P < 0.001) than chemotherapy alone. Moreover, the favorable responses in liver metastases (> 30% shrinkage) were associated with extended patient overall survival (P < 0.001), in contrast to lesions in the lungs and lymph nodes. Altogether, the spatiotemporal response heterogeneity across metastases informed drug efficacy and patient survival, which could improve the current methods for treatment evaluation and patient prognosis. Significance: These findings support the modification of RECIST criteria to include individual lesion response to improve assessments of drug efficacy.

Background: We compared women's acceptability of urine and cervico-vaginal sample self-collection for high-risk (oncogenic) human papillomavirus (hrHPV) testing and assessed whether acceptability v...

Background Hereditary Hemorrhagic Telangiectasia (HHT) is a rare inherited disorder characterized by development of mucocutaneous telangiectases and visceral organ arteriovenous malformations, which can lead to recurrent, spontaneous bleeding and development of iron deficiency anemia. The primary objective of this study was to ascertain the relationship between epistaxis severity scores (ESS), laboratory values, genotype, and phenotype in HHT. Our secondary objective was to assess efficacy of systemic antifibrinolytic therapy in reducing ESS in HHT. Methodology We conducted a retrospective review of patients seen at the UNC HHT Center from January 1, 2009 to February 28, 2015. ESS, demographics, and results of genetic testing were abstracted from the medical record. Response to antifibrinolytic therapy was evaluated by comparing pre-post ESS. Results One hundred and forty nine patients were eligible with 116 having genetic testing and 33 without. Age, hemoglobin and ferritin levels were predictive of ESS. Of the 116 patients that underwent genetic testing: 63 had an ACVRL1 mutation, 40 had an ENG mutation, 2 had a SMAD4 mutation, and 11 patients had no pathologic HHT genetic variation detected. Compared to patients without a detectable HHT-associated genetic variation, patients with a HHT-associated genetic variation had higher ESS scores (p 4 were started on antifibrinolytic therapy (tranexamic acid or aminocaproic acid) and had a post-treatment ESS recorded. All patients had a decrease in ESS of > 0.71 (minimal meaningful difference), but patients taking antifibrinolytics displayed larger decreases. No patients on antifibrinolytics experienced a VTE with median follow up of 13 months. Conclusions We demonstrate that the ESS correlates with age, hemoglobin and ferritin. Additionally, we demonstrate that HHT patients with genetic mutations have higher ESS scores. Our data demonstrate that antifibrinolytics are effective in decreasing epistaxis severity and safe with long-term use in HHT patients.

In patients with Plasmodium vivax malaria treated with effective blood-stage therapy, the recurrent illness may occur due to relapse from latent liver-stage infection or reinfection from a new mosquito bite. Classification of the recurrent infection as either relapse or reinfection is critical when evaluating the efficacy of an anti-relapse treatment. Although one can use whether a shared genetic variant exists between baseline and recurrence genotypes to classify the outcome, little has been suggested to use both sharing and nonsharing variants to improve the classification accuracy. In this paper, we develop a novel classification criterion that utilizes transition likelihoods to distinguish relapse from reinfection. When tested in extensive simulation experiments with known outcomes, our classifier has superior operating characteristics. A real data set from 78 Cambodian P. vivax malaria patients was analyzed to demonstrate the practical use of our proposed method.

Over 50% of colorectal cancer patients develop resistance after a transient response to therapy. Understanding tumor resistance from an evolutionary perspective leads to better predictions of treatment outcomes. The objectives of this study were to develop a computational framework to analyze tumor longitudinal measurements and recapitulate the individual evolutionary dynamics in metastatic colorectal cancer (mCRC) patients. A stochastic modeling framework was developed to depict the whole spectrum of tumor evolution prior to diagnosis and during and after therapy. The evolutionary model was optimized using a nonlinear mixed effect (NLME) method based on the longitudinal measurements of liver metastatic lesions from 599 mCRC patients. The deterministic limits in the NLME model were applied to optimize the stochastic model for each patient. Cox proportional hazards models coupled with the least absolute shrinkage and selection operator (LASSO) algorithm were applied to predict patients' progression-free survival (PFS) and overall survival (OS). The stochastic evolutionary model well described the longitudinal profiles of tumor sizes. The evolutionary parameters optimized for each patient indicated substantial interpatient variability. The number of resistant subclones at diagnosis was found to be a significant predictor to survival, and the hazard ratios with 95% CI were 1.09 (0.79–1.49) and 1.54 (1.01–2.34) for patients with three or more resistant subclones. Coupled with several patient characteristics, evolutionary parameters strongly predict patients' PFS and OS. A stochastic computational framework was successfully developed to recapitulate individual patient evolutionary dynamics, which could predict clinical survival outcomes in mCRC patients. Significance: A data analysis framework depicts the individual evolutionary dynamics of mCRC patients and can be generalized to project patient survival outcomes.

In modern scientific research, data are often collected from multiple modalities. Since different modalities could provide complementary information, statistical prediction methods using multi-modality data could deliver better prediction performance than using single modality data. However, one special challenge for using multi-modality data is related to block-missing data. In practice, due to dropouts or the high cost of measures, the observations of a certain modality can be missing completely for some subjects. In this paper, we propose a new DIrect Sparse regression procedure using COvariance from Multi-modality data (DISCOM). Our proposed DISCOM method includes two steps to find the optimal linear prediction of a continuous response variable using block-missing multi-modality predictors. In the first step, rather than deleting or imputing missing data, we make use of all available information to estimate the covariance matrix of the predictors and the cross-covariance vector between the predictors and the response variable. The proposed new estimate of the covariance matrix is a linear combination of the identity matrix, the estimates of the intra-modality covariance matrix and the cross-modality covariance matrix. Flexible estimates for both the sub-Gaussian and heavy-tailed cases are considered. In the second step, based on the estimated covariance matrix and the estimated cross-covariance vector, an extended Lasso-type estimator is used to deliver a sparse estimate of the coefficients in the optimal linear prediction. The number of samples that are effectively used by DISCOM is the minimum number of samples with available observations from two modalities, which can be much larger than the number of samples with complete observations from all modalities. The effectiveness of the proposed method is demonstrated by theoretical studies, simulated examples, and a real application from the Alzheimer’s Disease Neuroimaging Initiative. The comparison between DISCOM and some existing methods also indicates the advantages of our proposed method.

Background Anger and extreme stress can trigger potentially fatal cardiovascular events in susceptible people. Political elections, such as the 2016 US presidential election, are significant stressors. Whether they can trigger cardiac arrhythmias is unknown. Methods and Results In this retrospective case‐crossover study, we linked cardiac device data, electronic health records, and historic voter registration records from 2436 patients with implanted cardiac devices. The incidence of arrhythmias during the election was compared with a control period with Poisson regression. We also tested for effect modification by demographics, comorbidities, political affiliation, and whether an individual's political affiliation was concordant with county‐level election results. Overall, 2592 arrhythmic events occurred in 655 patients during the hazard period compared with 1533 events in 472 patients during the control period. There was a significant increase in the incidence of composite outcomes for any arrhythmia (incidence rate ratio [IRR], 1.77 [95% CI, 1.42–2.21]), supraventricular arrhythmia (IRR, 1.82 [95% CI, 1.36–2.43]), and ventricular arrhythmia (IRR, 1.60 [95% CI, 1.22–2.10]) during the election relative to the control period. There was also an increase in specific types of arrhythmia, including atrial fibrillation (IRR, 1.50 [95% CI, 1.06–2.11]), supraventricular tachycardia (IRR, 3.7 [95% CI, 2.2–6.2]), nonsustained ventricular tachycardia (IRR, 1.7 [95% CI, 1.3–2.2]), and daily atrial fibrillation burden ( P Conclusions There was a significant increase in cardiac arrhythmias during the 2016 US presidential election. These findings suggest that exposure to stressful sociopolitical events may trigger arrhythmogenesis in susceptible people.

Aim: Determine if incentive spirometry (IS) values correlate with postoperative pain control. Design: Prospective observational study. Setting & participants: A total of 100 patients undergoing major abdominal procedures at the University of North Carolina Medical Center. Interventions: Patients studied as a single cohort. All patients received thoracic epidural analgesia preoperatively. Outcome: Preoperative and daily postoperative numeric pain scores, subjective pain description and IS values were collected for all patients. Results: There was a strong correlation with IS values relative to baseline for both the numeric pain scores (p

HIV-infected individuals have a known increased risk of sudden cardiac death (SCD) compared to uninfected individuals. Implantable cardioverter defibrillators (ICDs) are standard therapy for preventing sudden arrhythmic death; however, there is limited data on the use and outcomes of ICDs in HIV-infected individuals. This is a retrospective cohort study of 35 consecutive HIV- Infected patients and 36 uninfected controls matched by age, race, and gender who were treated at University of North Carolina, Chapel Hill Medical Center in the outpatient or inpatient setting from 2014 to the present and had undergone primary or secondary prevention ICD implantation. For HIV-positive subjects, multivariate Poisson regression analysis was performed to evaluate the association between covariates and ICD therapies. Among HIV-infected subjects, mean CD4 count was 582.5 cells/mm3 and 69 % had an undetectable viral load. The median followup was 6.4 years. There was a trend towards longer corrected QT interval at the time of ICD implantation in HIV-infected subjects compared to uninfected controls (469.7 +/- 35.8 vs. 454.7 +/- 35.7 msec, p=0.089). HIV-infected subjects had both a higher number of appropriate ICD shocks or anti-tachycardia pacing (ATP) therapy per person-year as well as a higher number of inappropriate ICD shocks per person-year than uninfected controls (1.512 vs. 0.590 and 0.122 vs. 0.0166 respectively, p

Multimodal data, where different types of data are collected from the same subjects, are fast emerging in a large variety of scientific applications. Factor analysis is commonly used in integrative analysis of multimodal data, and is particularly useful to overcome the curse of high dimensionality and high correlations. However, there is little work on statistical inference for factor analysis based supervised modeling of multimodal data. In this article, we consider an integrative linear regression model that is built upon the latent factors extracted from multimodal data. We address three important questions: how to infer the significance of one data modality given the other modalities in the model; how to infer the significance of a combination of variables from one modality or across different modalities; and how to quantify the contribution, measured by the goodness-of-fit, of one data modality given the others. When answering each question, we explicitly characterize both the benefit and the extra cost of factor analysis. Those questions, to our knowledge, have not yet been addressed despite wide use of factor analysis in integrative multimodal analysis, and our proposal bridges an important gap. We study the empirical performance of our methods through simulations, and further illustrate with a multimodal neuroimaging analysis.

Introduction: Hospital length of stay with transcatheter aortic valve replacements (TAVRs) has decreased, though the rate of heart block requiring permanent pacemaker (PPM) implantation after TAVR has remained steady. It is unknown whether more patients are being readmitted for PPM after discharge from TAVR. Objective: To explore frequency, timing, and risk factors for PPM implant after TAVR in a nationally representative database. Methods: Patients who underwent TAVR from January 2012 through December 2017 were identified in the Nationwide Readmissions Database (NRD). Smoothing splines and logistic regression were used to analyze trends in length of stay and timing of PPM implantation after TAVR respectively. Multivariable logistic regression analysis was performed to identify risk factors for overall, early (during index hospitalization), and late (during subsequent hospitalization) PPM after TAVR. Results: Of the 62,083 included, 6,817 (11.0%) underwent PPM implantation [6,137 (9.9%) early and 680 (1.1%) late]. Rates of PPM remained stable between 8% and 12.5% with an increasing proportion occurring late (7% in 2012 increasing to 13% in 2017, p < 0.0001 for trend) (Figure 1). Late PPM was associated with atrial fibrillation (p < 0.01), diabetes mellitus (p < 0.001), chronic kidney disease (p < 0.05), second degree AVB (p < 0.001), left bundle branch block (p < 0.001), right bundle branch block (p < 0.001), and bifascicular block (p < 0.001). Conclusions: There has been a significant increase in the proportion of patients requiring readmission for PPM implantation after TAVR. As this high-risk population grows, algorithms for extended in-hospital observation or ambulatory cardiac monitoring post-TAVR are needed to reduce the risk for adverse events.

The sum of target lesions is routinely used to evaluate patient objective responses to treatment in the RECIST criteria, but it neglects the response heterogeneity across metastases. This study argues that the spatiotemporal response heterogeneity across metastases informs drug efficacy and patient survival. We analyzed the longitudinal data of 11,404 metastatic lesions in 2,802 colorectal cancer patients and examined their response heterogeneity. The response dynamics of metastatic lesions varied broadly across anatomical locations and therapies. High inter-lesion heterogeneity is associated with worse survival (p < 0.001), while targeted therapies (bevacizumab or panitumumab) reduced the inter-lesion heterogeneity (p < 0.05) and elicited more favorable effects on liver lesions (p < 0.001) than chemotherapy alone. The responses of liver lesions predicted patient survival more significantly than the lesions in the lungs and lymph nodes. Altogether, the high spatiotemporal heterogeneity across metastases should be integrated into current methods for treatment evaluation and patient prognosis.SignificanceThe spatiotemporal heterogeneity across metastases in response to first-line therapies in colorectal cancer is informative for drug efficacy and patient survival, particularly in targeted therapy. Our findings provide evidence to support the inclusion of individual lesion response in the RECIST to improve the assessment of drug efficacy and patient survival.

BACKGROUND: More rapid fluid removal during hemodialysis is associated with adverse cardiovascular outcomes and longer dialysis recovery times. The effect of ultrafiltration (UF) profiling, independent of concomitant sodium profiling, on markers of intradialytic hemodynamics and other outcomes has been inadequately studied. METHODS: Four-phase, blinded crossover trial. Participants (UF rates >10 mL/h/kg) were assigned in random order to receive hemodialysis with UF profiling (constantly declining UF rate, intervention) vs. hemodialysis with conventional UF (control). Each 3-week 9-treatment period was followed by a 1-week 3-treatment washout period. Participants crossed into each study arm twice (2 phases/arm); 18 treatments per treatment type. The primary outcomes were intradialytic hypotension, pre- to post-dialysis troponin T change, and change from baseline in left ventricular global longitudinal strain. Other outcomes included intradialytic symptoms and blood volume measured-plasma refill (post-dialysis volume status measure), among others. Each participant served as their own control. RESULTS: On average, the 34 randomized patients (mean age 56 years, 24% female, mean dialysis vintage 6.3 years) had UF rates >10 mL/h/kg in 56% of treatments during the screening period. All but 2 patients completed the 15-week study (prolonged hospitalization, kidney transplant). There was no significant difference in intradialytic hypotension, troponin T change, or left ventricular strain between hemodialysis with UF profiling and conventional UF. With UF profiling, participants had significantly lower odds of light-headedness and plasma refill compared to hemodialysis with conventional UF. CONCLUSIONS: UF profiling did not reduce the odds of treatment-related cardiac stress but did reduce the odds of light-headedness and post-dialysis hypervolemia. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03301740 (registered October 4, 2017)

To identify associations with either early or late permanent pacemaker (PPM) implantation after transcatheter aortic valve replacement (TAVR) in order to develop an easily interpretable management algorithm.Injury to the conduction system after TAVR occasionally requires PPM. There is limited data on how to identify which patients will require PPM, particularly after discharge from index hospitalization after TAVR.All patients having undergone TAVR at the University of North Carolina through August 2019 were identified and records were manually reviewed. Multivariable analyses were performed to identify associations with post-TAVR PPM due to high-degree atrioventricular block (HAVB). Comparisons were made between patients with no PPM (n = 304) and PPM required, stratified into early (during index hospitalization, n = 32) and late (during subsequent hospitalization, n = 11) PPM cohorts.Of the 347 patents included for analysis, 43 (12.4%) underwent post-TAVR PPM. In multivariable regression models, early PPM was associated with baseline bifascicular block (OR: 42.16; p .001), requiring any pacing on first post-TAVR electrocardiogram (ECG) (OR: 31.55; p .001), and valve oversizing15% (OR: 3.61; p .05). Late PPM was associated with baseline right bundle branch block (RBBB) (OR 12.62; p .001) and history of atrial fibrillation/flutter (OR 4.83; p .05).Bifascicular block, any pacing on first post-TAVR ECG, and15% valve oversizing are associated with early PPM, while RBBB and history of atrial fibrillation/flutter are associated with late PPM. We suggest a management strategy for post-TAVR surveillance and management of HAVB.

Study objective Our study sought to determine whether or not nitrous oxide analgesia decreases pain compared to oxygen placebo during external cephalic version for breech presentation. Procedural success may be limited by pain and anxiety. Although neuraxial anesthesia has been studied extensively for these procedures, many centers lack resources for routine use. Nitrous oxide is noninvasive, has minimal side effects and requires limited facilities. We hypothesized that its analgesic properties would decrease pain compared to oxygen placebo during external cephalic version. Design Double-blinded randomized placebo-controlled trial. Setting Labor and delivery triage room. Patients Forty-eight patients, ≥18 years of age, 37-weeks' gestation or beyond, singleton pregnancy, breech presentation, and American Society of Anesthesiology physical status I-III, having an external cephalic version. Interventions Patients undergoing external cephalic version were randomized to receive self-administered 50% nitrous oxide/50% oxygen versus 100% oxygen placebo. Measurements The primary outcome measured was intra-procedural pain. Secondary outcomes were intra-procedural anxiety, patient satisfaction, and procedure difficulty. Main results Forty-eight patients were enrolled; 23 received nitrous oxide and 25 received oxygen. No difference was noted in mean pain scores (nitrous oxide 5.5 ± 2.3, placebo 5.4 ± 2.7, [CI95% = −1.40, 1.51]; P = 0.943) or anxiety scores (nitrous oxide 1.6 ± 2.0, placebo 1.2 ± 1.8, [CI95% = −0.74, 1.45]; P = 0.515). Procedural difficulty (1–10 scale, 1 = very easy, 10 = extremely difficult) was not different between groups (nitrous oxide 6.1 ± 2.2, placebo 6.1 ± 3.2, [CI95% = −1.54, 1.66]; P = 0.944). There was a significant increase in the number of version attempts in the nitrous oxide group (nitrous oxide 3.9 ± 1.9, placebo 2.8 ± 1.4, [CI95% = 0.05, 2]; P = 0.046). Patient satisfaction was significantly lower in the nitrous oxide group (nitrous oxide 4.3 ± 4.0, placebo 6.9 ± 3.6, [CI95% = −4.93, −0.34]; P = 0.025). Conclusion Despite the desirable properties of nitrous oxide, there was no analgesic benefit over oxygen for external cephalic version. Its routine use for these procedures was not supported.

Multiple types of data measured on a common set of subjects arise in many areas. Numerous empirical studies have found that integrative analysis of such data can result in better statistical performance in terms of prediction and feature selection. However, the advantages of integrative analysis have mostly been demonstrated empirically. In the context of two-class classification, we propose an integrative linear discriminant analysis method and establish a theoretical guarantee that it achieves a smaller classification error than running linear discriminant analysis on each data type individually. We address the issues of outliers and missing values, frequently encountered in integrative analysis, and illustrate our method through simulations and a neuroimaging study of Alzheimer's disease.

PURPOSE: The use of traditional, complementary, and alternative medicine (TCAM) for cancer may influence the delivery or effectiveness of conventional cancer treatment. In this systematic review, we aimed to 1.) summarize the available prevalence data on traditional medicine use by cancer patients in less developed countries (LDCs), and 2.) stratify the prevalence data by world region and country income level. METHODS: A literature search for cancer, TCAM, and low income (LI) and lower-middle income (LMI) countries was conducted across 5 databases. A total of 2,365 publications were reviewed for eligibility, of which 25 studies met inclusion criteria. RESULTS: The combined sample size was 6,878 cancer patients, with a median of 54.5% reporting the use of TCAM for cancer care. Of the studies providing data on the concomitant use of TCAM and conventional cancer treatment (n = 4,872 cancer patients), a median of 26.7% of participants reported combining the two systems of medicine. CONCLUSION: From the data available, it is apparent that TCAM use among cancer patients in less developed countries is common; however, additional studies are needed to support the safe and effective management of cancer for patients in LI and LMI countries.

Background Mechanisms underlying oral immunotherapy (OIT) are unclear and the effects on immune cells at varying maintenance doses are unknown. Objective We aimed to determine the immunologic changes caused by peanut OIT in preschool aged children and determine the effect on these immune responses in groups ingesting low or high-dose peanut OIT (300 mg or 3000 mg, respectively) as maintenance therapy. Methods Blood was drawn at several time-points throughout the OIT protocol and PBMCs isolated and cultured with peanut antigens. Secreted cytokines were quantified via multiplex assay, whereas Treg and peanut-responsive CD4 T cells were studied with flow cytometry. Basophil activation assays were also conducted. Results Th2-, Th1-, Th9- and Tr1-type cytokines decreased over the course of OIT in groups on high- and low-dose OIT. There were no significant differences detected in cytokine changes between the high- and low-dose groups. The initial increase in both the number of peanut-responsive CD4 T cells and the number of Tregs was transient and no significant differences were found between groups. Basophil activation following peanut stimulation was decreased over the course of OIT and associated with increased peanut-IgG4/IgE ratios. No differences were found between high- and low-dose groups in basophil activation at the time of desensitization or sustained unresponsiveness oral food challenges. Conclusions and clinical relevance Peanut OIT leads to decreases in pro-allergic cytokines, including IL-5, IL-13, and IL-9 and decreased basophil activation. No differences in T cell or basophil responses were found between subjects on low or high-dose maintenance OIT, which has implications for clinical dosing strategies.

Background Virtual Reality (VR) is used as an effective tool for distraction and as an adjunct for pain management. This study was conducted to compare VR to standard iPad use after surgery and examine its effect on pain score and opioid consumption. Methods This was a randomized controlled study, with stratification by surgery type, age group (7-12yo, 13-18yo) and gender. Pain and anxiety were assessed with validated scales (STAI, FACES, VAS, FLACC) and outcomes were compared between each group. Results 50 of the 106 enrolled patients used the VR device. After adjusting for age, gender, and STAI, patients had a decreased FLACC score while using the VR device compared to the iPad group (odds ratio 2.95, P = .021). The younger patients were found to have lower FLACC scores while using the VR device (odds ratio 1.15, p=0.044); this finding was most significant when patients used the VR device for 20-30 minutes (odds ratio 1.67, P = .0003). Additionally, after adjusting for treatment group, gender, and STAI, the younger patients had higher odds of withdrawal or exclusion from the study (odds ratio 1.18, P = .021). No significant difference in opioid consumption between the groups was found. Discussion Virtual reality was well tolerated and more effective in decreasing pain during the immediate postoperative period than iPad use. Despite a slightly higher withdrawal rate, younger patients benefited more from the intervention.

In the era of big data, integrative analyses that pool data from different sources are now extensively conducted in order to improve performance. Among many interesting applications, genomics research is an area where integrative methods become popular tools to identify prognostic biomarkers for various diseases. In this paper, we propose such a framework for pathway and gene identification. Our method employs a hierarchical decomposition on genes’ effects followed by a proper regularization to identify important pathways and genes across multiple studies. Asymptotic theories are provided to show that our method is both pathway and gene selection consistent. More importantly, we explicitly show that pathway selection consistency needs milder statistical conditions than gene selection consistency, as it would allow false positives and negatives at the gene selection level. Finite-sample performance of our method is shown to be superior than other ad hoc methods in various simulation studies. We further apply our method to analyze five cardiovascular disease studies. Our method is intrinsically a general method on group-wise and element-wise selections from integrative analysis, which can have other applications beyond genomic research.

Background Peanut sublingual immunotherapy (SLIT) for 1 year has been shown to induce modest clinical desensitization in allergic children. Studies of oral immunotherapy, epicutaneous immunotherapy, and SLIT have suggested additional benefit with extended treatment. Objective We sought to investigate the safety, clinical effectiveness, and immunologic changes with long-term SLIT in children with peanut allergy. Methods Children with peanut allergy aged 1 to 11 years underwent extended maintenance SLIT with 2 mg/d peanut protein for up to 5 years. Subjects with peanut skin test wheals of less than 5 mm and peanut-specific IgE levels of less than 15 kU/L were allowed to discontinue therapy early. Desensitization was assessed through a double-blind, placebo-controlled food challenge (DBPCFC) with up to 5000 mg of peanut protein after completion of SLIT dosing. Sustained unresponsiveness was further assessed by using identical DBPCFCs after 2 to 4 weeks without peanut exposure. Results Thirty-seven of 48 subjects completed 3 to 5 years of peanut SLIT, with 67% (32/48) successfully consuming 750 mg or more during DBPCFCs. Furthermore, 25% (12/48) passed the 5000-mg DBPCFC without clinical symptoms, with 10 of these 12 demonstrating sustained unresponsiveness after 2 to 4 weeks. Side effects were reported with 4.8% of doses, with transient oropharyngeal itching reported most commonly. Side effects requiring antihistamine treatment were uncommon (0.21%), and no epinephrine was administered. Peanut skin test wheals, peanut-specific IgE levels, and basophil activation decreased significantly, and peanut-specific IgG4 levels increased significantly after peanut SLIT. Conclusion Extended-therapy peanut SLIT provided clinically meaningful desensitization in the majority of children with peanut allergy that was balanced with ease of administration and a favorable safety profile.

Low adherence to anti-hypertensive medications contributes to worse outcomes. The authors conducted a secondary data analysis to examine the effects of a health-coaching intervention on medication adherence and blood pressure (BP), and to explore whether changes in medication adherence over time were associated with changes in BP longitudinally in 477 patients with hypertension. Data regarding medication adherence and BP were collected at baseline, 6, 12, 18, and 24 months. The intervention resulted in increases in medication adherence (5.75→5.94, P = .04) and decreases in diastolic BP (81.6→76.1 mm Hg, P < .001) over time. The changes in medication adherence were associated with reductions in diastolic BP longitudinally (P = .047). Patients with low medication adherence at baseline had significantly greater improvement in medication adherence and BP over time than those with high medication adherence. The intervention demonstrated improvements in medication adherence and diastolic BP and offers promise as a clinically applicable intervention in rural primary care.

We prospectively evaluated adolescent organized physical activity (PA) as a factor in adult female bone traits. Annual DXA scans accompanied semiannual records of anthropometry, maturity, and PA for 42 participants in this preliminary analysis (criteria: appropriately timed DXA scans at ~1 year premenarche [predictor] and ~5 years postmenarche [dependent variable]). Regression analysis evaluated total adolescent interscan PA and PA over 3 maturity subphases as predictors of young adult bone outcomes: 1) bone mineral content (BMC), geometry, and strength indices at nondominant distal radius and femoral neck; 2) subhead BMC; 3) lumbar spine BMC. Analyses accounted for baseline gynecological age (years pre- or postmenarche), baseline bone status, adult body size and interscan body size change. Gymnastics training was evaluated as a potentially independent predictor, but did not improve models for any outcomes (p < .07). Premenarcheal bone traits were strong predictors of most adult outcomes (semipartial r2 = .21-0.59, p < .001). Adult 1/3 radius and subhead BMC were predicted by both total PA and PA 1-3 years postmenarche (p < .03). PA 3-5 years postmenarche predicted femoral narrow neck width, endosteal diameter, and buckling ratio (p < .05). Thus, participation in organized physical activity programs throughout middle and high school may reduce lifetime fracture risk in females.

Objective Lower health literacy is associated with poorer health outcomes. Few interventions poised to mitigate the impact of health literacy in hypertensive patients have been published. We tested if a multi-level quality improvement intervention could differentially improve Systolic Blood Pressure (SBP) more so in patients with low vs. higher health literacy. Methods We conducted a non-randomized prospective cohort trial of 525 patients referred with uncontrolled hypertension. Stakeholder informed and health literacy sensitive strategies were implemented at the practice and patient level. Outcomes were assessed at 0, 6, 12, 18 and 24 months. Results At 12 months, the low and higher health literacy groups had statistically significant decreases in mean SBP (6.6 and 5.3 mmHg, respectively), but the between group difference was not significant (Δ 1.3 mmHg, P = 0.067). At 24 months, the low and higher health literacy groups reductions were 8.1 and 4.6 mmHg, respectively, again the between group difference was not significant (Δ 3.5 mmHg, p = 0.25). Conclusions/practice implications A health literacy sensitive multi-level intervention may equally lower SBP in patients with low and higher health literacy. Practical health literacy appropriate tools and methods can be implemented in primary care settings using a quality improvement approach.

Background To test whether the vitamin D status of anesthesia department caregivers practicing at high Northern latitudes is compatible with current recommendations, the 25-hydroxyvitamin D (25(OH)D) levels of caregivers at hospitals in Iceland (64°08′ N) and in Wisconsin (43°07′ N) were compared at the end of winter. Methods Anesthesia department faculty and resident physicians, non-physician anesthetists, and critical care nurses completed a questionnaire, and provided blood samples for analysis of 25(OH)D by reverse-phase high performance liquid chromatography. Results One hundred and six participants in Iceland and 124 participants in Wisconsin were enrolled. No difference in mean serum 25(OH)D levels between Iceland [70.53 nmol/l, standard deviation (SD) 30.87 nmol/l] and Wisconsin (70.0 nmol/l, SD 30.0 nmol/l) was observed. In Iceland and Wisconsin, 25(OH)D levels below 25 nmol/l were observed in 4.7% and 4.0%, below 50 nmol/l in 34.9% and 25.0%, and below 75 nmol/l in 56.6% and 61.3% of caregivers, respectively. Conclusions 25(OH)D levels below the 50 nmol/l (20 ng/ml) threshold recommended by the Institute of Medicine and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and below the 75 nmol/l (30 ng/ml) threshold recommended by The Endocrine Society, are highly prevalent among anesthesia caregivers working at two Northern hospitals at the end of winter who may otherwise not meet criteria to be tested. Anesthesia and critical care providers may wish to determine their 25(OH)D levels and use effective, safe, and low cost supplementation to target a 25(OH)D level compatible with optimal health.

Rapid fluid removal (ultrafiltration, UF) is associated with higher cardiovascular morbidity and mortality among individuals receiving maintenance hemodialysis (HD). Fluid removal rates that exceed vascular refill rates can result in hemodynamic instability, end-organ damage to the heart, kidneys, gut and brain, among other organs, and patient symptoms. There are no known evidence-based HD treatment strategies to reduce harm from higher UF rates. Ultrafiltration profiling, the practice of varying UF rates to maximize fluid removal during periods of greatest hydration and plasma oncotic pressure, has been proposed as an HD treatment intervention that may reduce UF rate-related complications. This study is a randomized 4-phase cross-over trial in which participants are successively alternated between study arms with intervening washout periods, and treatment order is randomized. After 4-week screening and 6-week baseline periods, participants are randomized to HD with conventional UF or HD with UF profiling for a period of 3 weeks followed by a 1-week washout period before crossing over. Participants cross into conventional UF and UF profiling phases twice (2 phases per arm). The primary outcomes of interest are intradialytic hypotension (nadir intradialytic systolic blood pressure

Background: Lower adherence to anti-hypertensive medications contributes to sub-optimal patient outcomes, yet there are few successful interventions in rural primary care that target improved adherence. The purpose of this study was to determine whether a multi-component quality improvement intervention that included literacy-sensitive health coaching with motivational interviewing was associated with improved medication adherence and reductions in blood pressure (BP) in patients with a history of uncontrolled hypertension (HTN). Methods: Adult patients in six rural primary care settings with one or more visits in the last year with a systolic BP > 150 mmHg were recruited. Project faculty facilitated systematic changes in care delivery in local practices. Patients also received monthly phone-based literacy-sensitive health coaching including a focus on medication adherence, and a BP cuff for home monitoring. Data regarding medication adherence (Morisky Medication Adherence Scale-8) and BP were collected at baseline, 6, 12, 18, and 24 months. Linear mixed effects modeling was used to determine the effects of the multi-component intervention on medication adherence and whether changes in medication adherence were associated with changes in systolic and diastolic BP. Results: There were 477 patients enrolled; the majority were female, black, and reported an annual household income of < $40,000. At baseline, 39% of the patients had low medication adherence (MMAS-8 score < 6). In linear mixed effects models, the intervention resulted in modest increases in medication adherence [5.75 ± 1.37 at baseline to 5.94 ± 1.33 at 24 months (p = .04)]. Corresponding changes in BP were: from 138.6 ± 21.8/81.6 ± 12.9 mmHg at baseline to 132.7 ± 19.5/76.1 ± 14.5 mmHg at 24 months follow-up [mean 0.22-0.25/0.24-0.26 mmHg per month before and after adjustment for covariates (p < .001)]. Changes in medication adherence were significantly associated with reductions in diastolic BP longitudinally (p = .047). Conclusion: A practice-based quality improvement intervention that includes health coaching is associated with improvements in medication adherence and BP, and offers promise as a clinically applicable intervention in rural primary care.

We examined site-specific bone development in relation to childhood and adolescent artistic gymnastics exposure, comparing up to 10years of prospectively acquired longitudinal data in 44 subjects, including 31 non-gymnasts (NON) and 13 gymnasts (GYM) who participated in gymnastics from pre-menarche to ≥1.9years post-menarche. Subjects underwent annual regional and whole-body DXA scans; indices of bone geometry and strength were calculated. Anthropometrics, physical activity, and maturity were assessed annually, coincident with DXA scans. Non-linear mixed effect models centered growth in bone outcomes at menarche and adjusted for menarcheal age, height, and non-bone fat-free mass to evaluate GYM-NON differences. A POST-QUIT variable assessed the withdrawal effect of quitting gymnastics. Curves for bone area, mass (BMC), and strength indices were higher in GYM than NON at both distal radius metaphysis and diaphysis (p

Many contemporary studies involve the classification of a subject into two classes based on n observations of the p variables associated with the subject. Under the assumption that the variables are normally distributed, the well-known linear discriminant analysis (LDA) assumes a common covariance matrix over the two classes while the quadratic discriminant analysis (QDA) allows different covariance matrices. When p is much smaller than n, even if they both diverge, the LDA and QDA have the smallest asymptotic misclassification rates for the cases of equal and unequal covariance matrices, respectively. However, modern statistical studies often face classification problems with the number of variables much larger than the sample size n, and the classical LDA and QDA can perform poorly. In fact, we give an example in which the QDA performs as poorly as random guessing even if we know the true covariances. Under some sparsity conditions on the unknown means and covariance matrices of the two classes, we propose a sparse QDA based on thresholding that has the smallest asymptotic misclassification rate conditional on the training data. We discuss an example of classifying normal and tumor colon tissues based on a set of p = 2; 000 genes and a sample of size n = 62, and another example of a cardiovascular study for n = 222 subjects with p = 2; 434 genes. A simulation is also conducted to check the performance of the proposed method.

Twenty-two sixth-grade girls who participated in a 7-month school-based resistance-training program were compared to 22 controls. In a subanalysis of Tanner breast II (T2) and III (T3) subjects (n = 21 controls subjects (CON), n = 17 subjects in the high-intervention (INT)-dose group (HI)), T2 HI had greater narrow neck (NN) width gains than T2 CON (p 0.05) and T3 HI had greater L3 bone mineral density (BMD) gains than T3 CON (p 0.05).Physical activity modulates bone growth during adolescence, but an effective activity has not been identified for general use. The purpose of this study was to examine the effect of a school-based resistance-training program on skeletal growth in pre-menarcheal females.Sixth-grade girls participated in a 7-month, resistance-training program (INT) embedded in physical education (PE) classes. Age- and maturity-matched CON from a neighboring school participated in the standard PE classes. INT dose defined high (HI) and low (LO) groups. At baseline (BL) and follow-up (FU), non-INT organized physical activity (PA, hours per week) and maturity status were recorded; DXA scans assessed total body, distal radius, proximal femur, and lumbar spine. Regression models analyzed growth in bone outcomes for HI versus CON, accounting for age, Tanner stage, height, and PA.Forty-four girls (22 HI, 22 CON) were 11.7 ± 0.3 years of age at BL; all were ≤6 months postmenarche and did not differ in bone growth over the course of the intervention (p 0.05). However, in a subanalysis limited to subjects who were T2 or T3 at BL (n = 21 CON, n = 17 HI), T2 HI had greater gains in NN width (p = 0.01) compared to T2 CON, while T3 HI had greater gains in L3 BMD (p = 0.03) compared to T3 CON.In a group of T2 and T3 sixth-grade girls, a school-based resistance-training intervention produced maturity-specific differential gains for HI versus CON at the hip and spine.

Background: Racial disparities in blood pressure (BP) control persist, but whether differences by race in antihypertensive medication intensification (AMI) contribute is unknown. Objective: To compare AMI by race for patients with elevated home BP readings. Methods: This prospective cohort study followed adult patients from 6 rural primary care practices who used home BP monitoring (HBPM) and recorded/reported values. For providers, AMI was encouraged when mean HBPM systolic blood pressure (SBP) values were ⩾135 mm Hg; patients received phone-based coaching on HBPM technique and sharing HBPM findings. AMI was assessed between baseline and 12 months using defined daily dose (DDD) and summed to create a total antihypertensive DDD value. Results: A total of 217 patients (mean age = 61.4 ± 10.2 years; 66% female; 57% black) provided usable HBPM data. Among 90 (41%) intensification-eligible hypertensive patients (ie, mean HBPM SBP values for 6-months ⩾135 mm Hg), mean total antihypertensive DDD was increased in 61% at 12 months. Blacks had significantly higher mean DDD at baseline and 12 months, but intensification (+0.72 vs +0.65; P = 0.83) was similar by race. However, intensification was greater in males than females (+1.1 vs +0.39; P = 0.031). Reduction in mean SBP following intensification was greater in white versus black patients (−8.2 vs −3.9 mm Hg; P = 0.14). Conclusion/Relevance: Treatment intensification in HBPM users was similar by race, differed significantly by gender, and may produce a greater response in white patients. Differential AMI in HBPM users does not appear to contribute to persistent racial disparities in BP control.