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Background Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). Methods Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. Results Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5–62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%–94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. Conclusions Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.

BACKGROUND Blood pressure (BP) measured in the office setting increases from early through later adulthood. However, it is unknown to what extent out-of-office BP derived via ambulatory BP monitoring (ABPM) increases over time, and which participant characteristics and risk factors might contribute to these increases. METHODS We assessed 25-year change in office- and ABPM-derived BP across sex, race, diabetes mellitus (DM), and body mass index (BMI) subgroups in the Coronary Artery Risk Development in Young Adults study using multivariable-adjusted linear mixed effects models. RESULTS We included 288 participants who underwent ABPM at the Year 5 Exam (mean [SD] age, 25.1 [3.7]; 45.8% men) and 455 participants who underwent ABPM at the Year 30 Exam (mean [SD] age, 49.5 [3.7]; 42.0% men). Office, daytime, and nighttime systolic BP (SBP) increased 12.8 (95% confidence interval [CI], 7.6–17.9), 14.7 (95% CI, 9.7–19.8), and 16.6 (95% CI, 11.4–21.8) mm Hg, respectively, over 25 years. Office SBP increased 6.5 (95% CI, 2.3–10.6) mm Hg more among black compared with white participants. Daytime SBP increased 6.3 (95% CI, 0.2–12.4) mm Hg more among participants with a BMI ≥25 vs. CONCLUSIONS Office- and ABPM-derived BP increased more from early through middle adulthood among black adults and participants with DM and BMI ≥25 kg/m2.

Dystonia is an understudied motor feature of Parkinson's disease (PD). Although considerable efforts have focused on brain oscillations related to the cardinal symptoms of PD, whether dystonia is associated with specific electrophysiological features is unclear.The objective of this study was to investigate subcortical and cortical field potentials at rest and during contralateral hand and foot movements in patients with PD with and without dystonia.We examined the prevalence and distribution of dystonia in patients with PD undergoing deep brain stimulation surgery. During surgery, we recorded intracranial electrophysiology from the motor cortex and directional electrodes in the subthalamic nucleus (STN) both at rest and during self-paced repetitive contralateral hand and foot movements. Wavelet transforms and mixed models characterized changes in spectral content in patients with and without dystonia.Dystonia was highly prevalent at enrollment (61%) and occurred most commonly in the foot. Regardless of dystonia status, cortical recordings display beta (13-30 Hz) desynchronization during movements versus rest, while STN signals show increased power in low frequencies (6.0 ± 3.3 and 4.2 ± 2.9 Hz peak frequencies for hand and foot movements, respectively). Patients with PD with dystonia during deep brain stimulation surgery displayed greater M1 beta power at rest and STN low-frequency power during movements versus those without dystonia.Spectral power in motor cortex and STN field potentials differs markedly during repetitive limb movements, with cortical beta desynchronization and subcortical low-frequency synchronization, especially in patients with PD with dystonia. Greater knowledge on field potential dynamics in human motor circuits can inform dystonia pathophysiology in PD and guide novel approaches to therapy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

To establish criterion and construct validity of a novel, clinically feasible assessment of lower-extremity dexterity for PD patients.Thirty-three PD patients performed a unilateral lower-extremity dexterity task "off" and "on" dopaminergic medications with each leg. The task involves iteratively tapping targets with the foot in a specified pattern, and the measured outcome is the time to complete the movement sequence, with longer times indicating worse performance. We correlated leg movement time with standard, validated measures of gait (comfortable and maximal walk speeds), general mobility (timed up and go), upper-extremity dexterity (9-Hole Pegboard), and elements of the Unified Parkinson Disease Rating Scale (MDS-UPDRS).We found significant relationships between lower extremity dexterity and each of these tasks "off" and "on" medications. Task performance also captures known features of PD, including dopamine-mediated improvement in performance and asymmetrical symptom presentation.This task provides a simple assessment of lower extremity function that correlates with validated measures of dexterity, gait, and mobility. It provides objective, continuous data, is inexpensive, requires little technical expertise/equipment, has a small physical footprint, and can be administered quickly. These features increase the feasibility of implementing this assessment tool in clinical settings.Implications for rehabilitationWe introduce a novel task that captures lower extremity dexterity in individuals with Parkinson's disease (PD).The task is validated against gold standard measures of upper extremity dexterity, gait, and general mobility.Performance on the task is sensitive to known features of PD, including dopamine-mediated improvements and asymmetrical symptom presentation.The task is easy to implement and provides higher quality data compared to other common clinical assessments (e.g., MDS-UPDRS).

BackgroundDystonia is an under-studied motor feature of Parkinson disease (PD). Although considerable efforts have focused on brain oscillations related to the cardinal symptoms of PD, whether dystonia is associated with specific electrophysiological features is unclear.ObjectivesTo investigate subcortical and cortical field potentials at rest and during contralateral hand and foot movements in PD patients with and without dystonia.MethodsWe examined the prevalence and distribution of dystonia in PD patients undergoing deep brain stimulation surgery and recorded intracranial electrophysiology from motor cortex and directional electrodes in subthalamic nucleus (STN) both at rest and during self-paced repetitive contralateral hand and foot movements. Wavelet transforms and mixed models characterized changes in spectral content in patients with and without dystonia.ResultsDystonia was highly prevalent at enrollment (61%) and occurred most commonly in the foot. Regardless of dystonia status, cortical recordings display beta (13-30 Hz) desynchronization during movements versus rest, while STN signals show increased power in low frequencies (6.0±3.3 and 4.2±2.9 Hz peak frequencies for hand and foot movements respectively). PD patients with dystonia during DBS surgery displayed greater M1 beta power at rest and STN low frequency power during movements versus those without dystonia.ConclusionsSpectral power in motor cortex and STN field potentials differs markedly during repetitive limb movements, with cortical beta desynchronization and subcortical low frequency synchronization, especially in PD patients with dystonia. Greater knowledge on field potential dynamics in human motor circuits can inform dystonia pathophysiology in PD and guide novel approaches to therapy.

In this paper, we apply the nearly exact discretization schemes to propose a discrete model for the FitzHugh–Nagumo model. We show that the discrete model obtained preserves the dynamics and the known features of the continuous FitzHugh–Nagumo model. We do so by performing distance-based and probability-based similarity analysis. Additionally, a sensitivity analysis is also performed to analyze the most influential parameters of the discrete system.

PURPOSE Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis. METHODS Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m2/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses. RESULTS Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings. CONCLUSION To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. Mirdametinib given at 2 mg/m2/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.

An outcome measure of toileting skills, the Toileting Abilities Survey or TAS, with sensitivity to detect change in a neurodegenerative disorder such as MPS II, was developed. The TAS was used in a research study of patients (n = 86) with the neuronopathic form of MPS II to measure treatment benefit of intrathecal idursulfase. Treatment with idursulfase and intrathecal idursulfase is associated with significantly higher individual and overall toileting skills versus treatment with idursulfase alone., Highlights • The Toileting Abilities Survey was designed to detect change in MPS II. • The TAS was used to measure treatment benefit of intrathecal idursulfase. • Results indicated intrathecal idursulfase positively impacts toileting abilities.

Electroencephalogram (EEG) is a common tool used to understand brain activities. The data are typically obtained by placing electrodes at the surface of the scalp and recording the oscillations of currents passing through the electrodes. These oscillations can sometimes lead to various interpretations, depending on, for example, the subject's health condition, the experiment carried out, the sensitivity of the tools used, or human manipulations. The data obtained over time can be considered a time series. There is evidence in the literature that epilepsy EEG data may be chaotic. Either way, the Embedding Theory in dynamical systems suggests that time series from a complex system could be used to reconstruct its phase space under proper conditions. In this letter, we propose an analysis of epilepsy EEG time series data based on a novel approach dubbed complex geometric structurization. Complex geometric structurization stems from the construction of strange attractors using Embedding Theory from dynamical systems. The complex geometric structures are themselves obtained using a geometry tool, the α-shapes from shape analysis. Initial analyses show a proof of concept in that these complex structures capture the expected changes brain in lobes under consideration. Further, a deeper analysis suggests that these complex structures can be used as biomarkers for seizure changes.

Background: Perfusion weighted imaging on MRI (MRP) and computerized tomography perfusion (CTP) are increasingly required to manage large vessel disease. Computerized algorithms can quantify perfusion data, but the programs are expensive and not widely used outside acute stroke evaluation. We aimed to determine how well human observers can identify asymmetries in cerebral perfusion images compared with an automated computer algorithm. Methods: Ten clinicians experienced in treating carotid artery disease (4 vascular neurologists, 3 neuroradiologists, 1 vascular surgeon, 1 neurosurgeon, 1 interventional radiologist) were given 28 post-processed, color-coded, axial-slice MRP scans from patients in the Carotid Revascularization Endovascular versus Stenting Trial - Hemodynamics (CREST-H) study. All patients had >70%, unilateral, asymptomatic carotid artery stenosis and had varying degrees of time-to-peak (TTP) delay on the side of stenosis, ranging from 0 to 2 secs, quantified by a semi-automated system that computes quantitative perfusion maps, using deconvolution of tissue and arterial signals (Olea, Cambridge, MA). A minimum volume of 10cc was required for a given TTP delay. Clinicians were asked to determine asymmetry (y/n) and side of occlusion for each case. Number of correct responses that matched the computer output were tallied. Results: We averaged correct responses by the 10 clinicians for cases at each increment of TTP delay; (Figure). At TTP delays ≥1.5 seconds, accuracy was ≥80%. At 1.25 sec accuracy fell to 60%, and at ≤ 1 sec, accuracy was ≤50%. For TTP=0 (no asymmetry), accuracy was 71%. Conclusions: Visual impression of hemodynamic asymmetry among experienced clinicians was reasonably accurate for TTP delays ≥1.5 seconds, but declined with more subtle asymmetries. Depending on the clinical impact of TTP delays (for CREST-H: correlation with cognitive decline), experienced clinicians may perform as well as an automated algorithm.

Alzheimer’s disease (AD) is the leading cause of dementia and has received considerable research attention, including using neuroimaging biomarkers to classify patients and/or predict disease progression. Generalized linear models, e.g., logistic regression, can be used as classifiers, but since the spatial measurements are correlated and often outnumber subjects, penalized and/or Bayesian models will be identifiable, while classical models often will not. Many useful models, e.g., the elastic net and spike-and-slab lasso, perform automatic variable selection, which removes extraneous predictors and reduces model variance, but neither model exploits spatial information in selecting variables. Spatial information can be incorporated into variable selection by placing intrinsic autoregressive priors on the logit probabilities of inclusion within a spike-and-slab elastic net framework. We demonstrate the ability of this framework to improve classification performance by using cortical thickness and tau-PET images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to classify subjects as cognitively normal or having dementia, and by using a simulation study to examine model performance using finer resolution images.

The linear mixed model, sometimes referred to as the multi-level model, is one of the most widely used tools for analyses involving clustered data. Various definitions of R2 have been proposed for the linear mixed model, but several limitations prevail. Presently, there is no method to compute R2 for the linear mixed model that accommodates an interpretation based on variance partitioning, a method to quantify uncertainty and produce confidence limits for the R2 statistic, and a capacity to use the R2 statistic to conduct covariance model selection in a manner similar to information criteria. In this article, we introduce such an R2 statistic. The proposed R2 measures the proportion of generalized variance explained by fixed effects in the linear mixed model. Simulated and real longitudinal data are used to illustrate the statistical properties of the proposed R2 and its capacity to be applied to covariance model selection.

Background Nocturnal hypertension, defined by a mean asleep systolic blood pressure (SBP)/diastolic blood pressure (BP) ≥120/70 mm Hg, and nondipping SBP , defined by an awake‐to‐asleep decline in SBP Methods and Results We developed predictive equations to identify adults with a high probability of having nocturnal hypertension or nondipping SBP using data from the CARDIA (Coronary Artery Risk Development in Young Adults) study (n=787), JHS (Jackson Heart Study) (n=1063), IDH (Improving the Detection of Hypertension) study (n=395), and MHT (Masked Hypertension) study (n=772) who underwent 24‐hour ambulatory BP monitoring. Participants were randomized to derivation (n=2511) or validation (n=506) data sets. The prevalence rates of nocturnal hypertension and nondipping SBP were 39.7% and 44.9% in the derivation data set, respectively, and 36.6% and 44.5% in the validation data set, respectively. The predictive equation for nocturnal hypertension included age, race/ethnicity, smoking status, neck circumference, height, high‐density lipoprotein cholesterol, albumin/creatinine ratio, and clinic SBP and diastolic BP. The predictive equation for nondipping SBP included age, sex, race/ethnicity, waist circumference, height, alcohol use, high‐density lipoprotein cholesterol, and albumin/creatinine ratio. Concordance statistics (95% CI) for nocturnal hypertension and nondipping SBP predictive equations in the validation data set were 0.84 (0.80–0.87) and 0.73 (0.69–0.78), respectively. Compared with reference models including antihypertensive medication use and clinic SBP and diastolic BP as predictors, the continuous net reclassification improvement (95% CI) values for the nocturnal hypertension and nondipping SBP predictive equations were 0.52 (0.35–0.69) and 0.51 (0.34–0.69), respectively. Conclusions These predictive equations can direct ambulatory BP monitoring toward adults with high probability of having nocturnal hypertension and nondipping SBP .

The mechanisms by which cigarette smoking impairs airway mucus clearance are not well understood. We recently established a ferret model of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) exhibiting chronic bronchitis. We investigated the effects of cigarette smoke on mucociliary transport (MCT).Adult ferrets were exposed to cigarette smoke for 6 months, with in vivo mucociliary clearance measured by technetium-labelled DTPA retention. Excised tracheae were imaged with micro-optical coherence tomography. Mucus changes in primary human airway epithelial cells and ex vivo ferret airways were assessed by histology and particle tracking microrheology. Linear mixed models for repeated measures identified key determinants of MCT.Compared to air controls, cigarette smoke-exposed ferrets exhibited mucus hypersecretion, delayed mucociliary clearance (−89.0%, p−1, pin vivo or in vitro, and contributed to diminished MCT. Primary cells from smokers with and without COPD recapitulated these findings, which persisted despite the absence of continued smoke exposure.Cigarette smoke impairs MCT by inducing airway dehydration and increased mucus viscosity, and can be partially abrogated by cholinergic secretion of fluid secretion. These data elucidate the detrimental effects of cigarette smoke exposure on mucus clearance and suggest additional avenues for therapeutic intervention.

As researchers increasingly rely on linear mixed models to characterize longitudinal data, there is a need for improved techniques for selecting among this class of models which requires specification of both fixed and random effects via a mean model and variance-covariance structure. The process is further complicated when fixed and/or random effects are non nested between models. This paper explores the development of a hypothesis test to compare non nested linear mixed models based on extensions of the work begun by Sir David Cox. We assess the robustness of this approach for comparing models containing correlated measures of body fat for predicting longitudinal cardiometabolic risk.

Measuring the proportion of variance explained (R2) by a statistical model and the relative importance of specific predictors (semi-partial R2) can be essential considerations when building a parsimonious statistical model. The R2 statistic is a familiar summary of goodness-of-fit for normal linear models and has been extended in various ways to more general models. In particular, the generalized linear mixed model (GLMM) extends the normal linear model and is used to analyze correlated (hierarchical), non-normal data structures. Although various R2 statistics have been proposed, there is no consensus in statistical literature for the most sensible definition of R2 in this context. This research aims to build upon existing knowledge and definitions of R2 and to concisely define the statistic for the GLMM. Here, we derive a model and semi-partial R2 statistic for fixed (population) effects in the GLMM by utilizing the penalized quasi-likelihood estimation method based on linearization. We show that...

Background The Patient-Reported Outcomes Measurement Information System® (PROMIS®) created pediatric self-report scales measuring a variety of health attributes (domains), but their responsiveness to changes in health status has not yet been determined in children with sickle cell disease (SCD). Procedure A convenience cohort of symptomatic SCD children, aged 8–17 years, was asked to complete PROMIS pediatric scales at an initial clinic visit, at the end of a subsequent hospitalization for sickle pain, at a subsequent clinic visit or at home 2–3 weeks after hospitalization, and at a clinic visit 1–2 years after their initial assessment. Results A total of 121 participants (mean age 12.5 ± 3.1 years, 56.2% female) participated in the study. Pain interference and fatigue domain scores were elevated at baseline, increased substantially during hospitalization, and largely returned to baseline by the recovery period, whereas the depressive symptoms, anger, and anxiety domain scores displayed a less pronounced elevation during hospitalizations and a slower return to baseline levels. The two physical functioning scales showed a substantial decline in response to hospitalization, but only modest improvements at the recovery assessment, likely representing incomplete recovery. Conclusions Several PROMIS pediatric measures were responsive to changes in health status associated with occurrence and resolution of acute vaso-occlusive pain requiring hospitalization. The substantial differences in these domains during SCD-related pain exacerbations support their potential usefulness in clinical research or in clinical practice. Further studies to characterize variations in symptom patterns over time may provide insights into strategies for more effective management of sickle pain.

BACKGROUND Bevacizumab treatment at 2.5–5 mg/kg/week is associated with hearing improvement and tumor shrinkage in about 40% of patients with neurofibromatosis 2 (NF2) and progressive vestibular schwannomas (VS). Treatment-emergent hypertension and proteinuria are common with prolonged treatment, and data supporting strategies to maintain hearing and minimize toxicity are lacking. METHODS We conducted a multicenter, phase II, open-label study of bevacizumab for subjects (≥6 years old) with NF2, hearing loss, and progressive VS. After 6 months of induction therapy (10 mg/kg every 2 weeks), subjects received low dose bevacizumab at 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing decline was defined as a significant decrease in word recognition score below baseline. Progressive disease was defined as ≥20% increase in tumor volume from baseline. RESULTS Twenty of 22 subjects (median age=23 years) were treated with maintenance bevacizumab. The proportion of subjects free from hearing decline at 6, 12, and 18 months was 88%, 94%, and 85%, respectively; the proportion free from tumor progression at 6, 12, and 18 months from baseline was 88%, 94%, and 85%, respectively. Three subjects (15%) experienced hearing loss during maintenance and required dose escalation. Maintenance chemotherapy with bevacizumab was well tolerated: 1 subject discontinued due to perirectal abscess and 2 discontinued by choice. Grade 3 hypertension occurred in 2 subjects (10%). Adverse events of interest included hypertension (55%), proteinuria (20%), and irregular menstruation (6/13, 46%). CONCLUSIONS Maintenance chemotherapy with bevacizumab at 5 mg/kg every 3 weeks is associated with prolonged hearing and tumor stability that surpasses historical controls. A minority of subjects require dose escalation during low dose bevacizumab treatment.

Masked uncontrolled hypertension (MUCH) is defined as controlled automated office blood pressure (BP; AOBP

Objective.To evaluate the association between patient-reported outcome (PRO) and performance-based (PB) measures of physical functioning (PF) among individuals with self-identified arthritis to inform decisions of which to use when evaluating the effectiveness of a physical activity intervention.Methods.Secondary data analysis of a nonrandomized 2-arm pre-post community trial of 462 individuals who self-identified as having arthritis and participated in the Walk with Ease (WWE) intervention. Two PRO and 8 PB assessments were collected at baseline (preintervention) and at 6-week followup. We calculated correlations between PB and PRO measures, assessed how measures identified changes in PF from baseline to followup, and compared PRO and PB measures to arthritis symptoms of pain, stiffness, and fatigue.Results.Strength of correlations between PB and PRO measures varied depending on the PB measure, ranging from 0.21 to 0.54. PRO and PB measures identified PF improvements from baseline to followup, but none showed significant differences between the 2 WWE modalities (instructor-led or self-directed groups). Correlations with arthritis symptoms were stronger for PRO (0.30–0.46) than PB measures (0.03–0.31).Conclusion.PRO measures may provide us with insights into aspects of PF that are not identified by PB measures alone. Use of PRO measures allows patients to communicate their perceptions of PF, which may provide a more accurate representation of overall PF. Our study does not suggest abandoning the use of PB measures to characterize PF in patients with self-identified arthritis, but recommends that PRO measures may serve as complementary or surrogate endpoints for some studies.

Prospective evidence of associations of dietary patterns with cognitive decline is limited and inconsistent. We examined how cognitive changes among Chinese older adults relate to either an adapted Mediterranean diet score or factor analysis-derived dietary patterns.This prospective cohort study comprised 1,650 adults ≥55 years of age, who completed a cognitive screening test at two or more waves of the China Health and Nutrition Survey in 1997, 2000, or 2004. Outcomes were repeated measures of global cognitive scores, composite cognitive z scores (standardized units [SU]), and standardized verbal memory scores (SU). Baseline diet was measured by 24-hour recalls over 3 days. We used linear mixed effects models to evaluate how changes in cognitive scores were associated with adapted Mediterranean diet score and two dietary pattern scores derived from factor analysis.Among adults ≥65 years of age, compared with participants in the lowest tertile of adapted Mediterranean diet, those in the highest tertile had a slower rate of cognitive decline (difference in mean SU change/year β = 0.042; 95% confidence interval [CI]: 0.002, 0.081). A wheat-based diverse diet derived by factor analysis shared features of the adapted Mediterranean diet, with the top tertile associated with slower annual decline in global cognitive function (β = 0.069 SU/year; 95% CI: 0.023, 0.114). We observed no associations among adults65 years of age.Our findings suggest that an adapted Mediterranean diet or a wheat-based, diverse diet with similar components may reduce the rate of cognitive decline in later life in the Chinese population.

No study describes the use of extracorporeal membrane oxygenation (ECMO) in pediatric patients with abdominal sepsis (AS) requiring surgery. A description of outcomes in this patient population would assist clinical decision-making and provide a context for discussions with patients and families. The Extracorporeal Life Support Organization database was queried for pediatric patients (30 days to 18 years) with AS requiring surgery. Forty-five of 61 patients survived (73.8%). Reported bleeding complications (57.1 vs 48.8%), the number of pre-ECMO ventilator hours (208.1 vs 178.9), and the timing of surgery before (50 vs 66.7%) and on-ECMO (50 vs 26.7%) were similar in survivors and nonsurvivors. Decreased pre-ECMO mean pH (7.1 vs 7.3) was associated with increased mortality (odds ratio, 1.49; 95% confidence interval, 1.04 to 2.14). ECMO use for pediatric patients with AS requiring surgery is associated with increased mortality and an increased rate of bleeding complications compared with all pediatric patients receiving ECMO support. Acidemia predicts mortality and provides a potential target of examination for future studies.

Patients with early-stage lung cancer often have comorbid illnesses and fear debility and death when contemplating surgery. However, data that compare physical function of patients who receive surgery with similar patients who do not are sparse. The authors report 1-year outcome results for surgical and nonsurgical patients in a prospective lung cancer cohort to address this gap.The authors enrolled 386 patients with early-stage lung cancer. A 106-item survey was completed at the time of enrollment including the Short-Form 12 (SF-12) Health Survey to assess functional status. Patients were followed for a year. Chart abstractions were obtained to determine comorbid illnesses and surgical status. Death was ascertained through vital records. The SF-12 was repeated 1 year after the enrollment. Regression models were constructed to identify predictors of 1-year mortality and decline in physical function.Fifty-nine patients (15.3%) died before 1-year follow-up. Mortality in the surgical group was 10.8% compared with 22.8% in the nonsurgical group (P0.001). In regression analysis controlling for age and comorbidities, surgical treatment was associated with a reduction in 1-year mortality (odds ratio: 0.5 and 95% confidence interval: 0.3-1.0) but did not worsen physical function relative to the untreated group (average decrease in physical component score of SF-12 = 1.9 for surgery group and 2.5 for no surgery group, P = 0.66).Functional decline between surgically treated and untreated patients did not differ. This result casts doubt on its value as a treatment determinant. Cancer mortality seems to be a more essential issue in treatment decisions.

Objectives To identify changes in health-related quality of life (HRQoL) after diagnosis of bladder cancer in older adults in comparison with a group of adults without bladder cancer (controls). Patients and methods Data from the Surveillance, Epidemiology and End Results registries were linked with Medicare Health Outcomes Survey (MHOS) data. Medicare beneficiaries aged ≥65 years in the period 1998-2013, who were diagnosed with bladder cancer between baseline and follow-up through the MHOS, were matched with control subjects without cancer using propensity scores. Linear mixed models were used to estimate predictors of HRQoL changes. Results After matching, 535 patients with bladder cancer (458 non-muscle-invasive bladder cancer [NMIBC] and 77 with muscle-invasive bladder cancer [MIBC]) and 2 770 control subjects without cancer were identified. Both patients with NMIBC and those with MIBC reported significant declines in HRQoL scores over time vs controls: physical component summary -2 and -5.3 vs -0.4, respectively; bodily pain -1.9 and -3.6 vs -0.7; role physical -2.7 and -4.7 vs -0.7; general health -2.4 and -6.1 vs 0; vitality -1.2 and -3.5 vs -0.1; and social functioning -2.1 and -5.7 vs -0.8. All scores ranged from 0 to 100. When stratified by time since diagnosis, HRQoL improved over 1 year for some domains (role physical), but remained lower across most domains. Conclusions After diagnosis, patients with bladder cancer experienced significant declines in physical, mental and social HRQoL relative to controls. Decrements were most pronounced among individuals with MIBC. Methods to better understand and address HRQoL decrements among patients with bladder cancer are needed.

Previous studies provided evidence for the validity of the PROMIS Pediatric measures in cross-sectional studies. This study evaluated the ability of the PROMIS Pediatric measures to detect change over time in children and adolescents with cancer, nephrotic syndrome (NS), or sickle cell disease (SCD).Participants (8-17 years) completed measures of fatigue, pain interference, anger, anxiety, depressive symptoms, mobility, upper extremity, and peer relationships at three or four time points (T1-T4). Between T1 and T2, children with cancer received chemotherapy and children with SCD experienced a pain exacerbation. Children with NS were first assessed during active disease (T2), with T3 and T4 conducted at disease remission. For the primary analysis of responsiveness, we expected better scores at T3 (recovery) compared to T2 (event) for all diseases. T1 and T4 are also expected to have better scores than T2. Linear mixed models were used and adjusted for time, gender, age, race/ethnicity, education, comorbid conditions, and disease.Enrolled were 96 children with cancer, 121 children with SCD, and 127 children with NS. Fatigue, pain interference, mobility, and upper extremity scores worsened from T1 (baseline) to T2 (event) (p 0.01), and significantly improved from T2 to T3 and T4 (p 0.01). Similarly, anxiety and depressive symptoms significantly improved from T2 to T3 and T4 (p 0.01).This study provides evidence for the responsiveness of seven PROMIS Pediatric measures to clinical disease state in three chronic illnesses. The findings support use of PROMIS Pediatric measures in clinical research.

Early extubation is increasingly common in congenital heart surgery, but there are limited outcomes data across the spectrum of case complexity. We performed a retrospective review of 201 pediatric operations using cardiopulmonary bypass between 2012 and 2014. Patients extubated in the operating room or immediately on arrival to the ICU were compared to those extubated by traditional protocols. In-hospital mortality, major complications, need for re-intubation, hospital length of stay, and chest-tube days were compared between groups and by Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery Congenital Heart Surgery (STAT) mortality category. Outcome measures of hospital length of stay and chest tube days were analyzed using multivariable regression modeling. Early extubation subjects were older, weighed more, had shorter bypass and aortic cross-clamp time, more often received caudal anesthesia, and had shorter hospital length of stay and fewer chest tube days. Subjects not extubated early had more chromosomal abnormalities, more preoperative co-morbidities, and had more major complications. Inhospital death, major complications, and re-intubation were rare outcomes for both groups across all STAT categories. Multivariable regression analysis showed that cardiopulmonary bypass time was a significant predictor of hospital length of stay and chest tube days. Hospital LOS and chest tube days were significantly lower for the early extubation group in both the unadjusted and adjusted analyses. Early extubation can be performed safely in congenital heart surgery across a spectrum of case complexity. No increased early mortality or re-intubation was observed with early extubation although there were important differences between the groups that merits further study. The potential benefits of early extubation include decreased hospital length of stay and fewer chest tube days, particularly in young children and patients with long bypass times.

Background: Recent reports on the state of nutrition in U.S. medical schools suggest that these schools are challenged to incorporate nutrition into an already full curriculum. Objective: The aim of this study was to determine the current state of nutrition education in US medical schools based on information reported by individuals responsible for teaching nutrition to medical students. Design: Between July 1999 and May 2000, we surveyed 122 U.S. medical and osteopathic schools. The survey was mailed to the nutrition educator at each institution; recipients could return the survey via mail, fax, or the web. Results: The majority of the 98 medical schools responding to the survey provided nutrition education. In 90% of responding U.S. medical and osteopathic schools (representing 88 of 98 schools and over 65% of all institutions), all students were guaranteed exposure to nutrition. An average of 18 ± 12 hours of nutrition was required, including material integrated into other types of courses. Conclusions: Our findings indicate that nutrition education is an integral part of the curriculum of the majority of US medical schools surveyed. A number of medical schools have chosen to incorporate nutrition education into already established basic science and clinical courses. Key Words -Medical education, nutrition education, computer-assisted instruction, curriculum, medical students, nutrition teaching, nutrition in medicine.

Jared Weiss,1 Briana J Stephenson,2 Lloyd J Edwards,2 Maureen Rigney,3 Amy Copeland31Division of Hematology and Oncology, University of North Carolina, 2Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA; 3Lung Cancer Alliance, Washington, DC, USA Introduction: Lung cancer is the leading cause of cancer death, yet public engagement with efforts against lung cancer is low. Public engagement with a cancer is critical to efforts to combat it, yet the reasons for low support for efforts against lung cancer have not been systematically characterized. Methods: We conducted a telephone survey of 1,071 people to determine levels of engagement and attitudes that might potentially drive engagement. These were then analyzed by univariate and multivariate analysis. Results: Eight percent of participants were involved with a lung cancer organization and 12% chose it among cancers to receive more support. Most participants felt that lung cancer was principally caused by external factors, that it could be cured if caught early, and that lung cancer patients were at least partly to blame for their illness. In multivariate analysis, participants who were supportive in some way of efforts against lung cancer were more likely to be employed, live in suburbia, and to be unsure of the cause of lung cancer. Potential supporters were more likely to be employed, female, younger, have higher income, to believe that genetics is the primary cause of lung cancer, and to believe that lung cancer can be cured when caught early. Participants frequently noted that they supported a particular cancer because of knowing someone affected by that cancer. Conclusion: As the lung cancer movement attempts to grow and increase its impact, the most successful recruitment efforts will be targeted to these groups. Keywords: stigma, advocacy, lung cancer

Background The use of 24-h ambulatory blood pressure monitoring (ABPM) in clinical practice and observational epidemiological studies has grown considerably in the past 25 years. ABPM is a very effective technique for assessing biological, environmental, and drug effects on blood pressure. Objectives In order to enhance the effectiveness of ABPM for clinical and observational research studies using analytical and graphical results, developing alternative data analysis approaches using modern statistical techniques are important. Methods The linear mixed model for the analysis of longitudinal data is particularly well suited for the estimation of, inference about, and interpretation of both population (mean) and subject-specific trajectories for ABPM data. We propose using a linear mixed model with orthonormal polynomials across time in both the fixed and random effects to analyze ABPM data. Results We demonstrate the proposed analysis technique using data from the Dietary Approaches to Stop Hypertension (DASH) study, a multicenter, randomized, parallel arm feeding study that tested the effects of dietary patterns on blood pressure. Conclusion The linear mixed model is relatively easy to implement (given the complexity of the technique) using available software, allows for straightforward testing of multiple hypotheses, and the results can be presented to research clinicians using both graphical and tabular displays. Using orthonormal polynomials provides the ability to model the nonlinear trajectories of each subject with the same complexity as the mean model (fixed effects).

Objective:Resistant hypertension (RHTN) is defined as uncontrolled blood pressure (BP) (clinic BP > = 130/80 mmHg, 24-hr ambulatory BP [ABPM] >= 125/75 mmHg) on 3 or more medications including a diuretic. As previously described by us a novel 24hr circadian BP pattern with a large morning dip and ev

Resistant hypertension (RHTN) is defined as uncontrolled blood pressure (BP) (automated office BP [AOBP] ≥ 130/80 mmHg, 24-hr ambulatory BP [ABPM] ≥ 125/75 mmHg) on 3 or more medications including a diuretic; BP controlled on 4 or more medications is defined as controlled RHTN. Controlled non

Perceived quality of lung cancer communication is strongly associated with receiving potentially curative surgery for early-stage disease. The patient characteristics associated with poor quality communication in the setting of new lung cancer diagnosis are not known, although race may be a contributing factor. Using data from a prospective study of decision making in early-stage non-small cell lung cancer patients in five academic and community medical centers (N = 386), the authors used logistic regression techniques to identify patient-level characteristics correlated with scoring in the lowest quartile of a communication scale and a single-item communication variable describing shared communication. Income, lung cancer diagnostic status, and trust score were significantly associated with the overall communication scale. Lung cancer diagnostic status and trust score were also associated with patient perceptions of the single shared communication item, in addition to participation in a religious organization. Improving patient perceptions of communication with their provider is an important next step in ensuring that eligible patients receive optimal care for this deadly disease. This analysis identifies several modifiable factors that could improve patient perceptions of patient-provider communication. The fact that patient perception of communication is a predictor of the decision to undergo surgery independent of race highlights the need for broad communication interventions to ensure that as many eligible patients as possible are receiving surgery.

Background Though peanut oral immunotherapy (OIT) is a promising investigational therapy, its potential is limited by substantial adverse events (AEs), which are relatively understudied. Objective A retrospective analysis was conducted, pooling data from 3 pediatric peanut OIT trials, comprising the largest analysis of peanut OIT safety to date. Methods We pooled data from 104 children with peanut allergy from 3 peanut OIT studies. We catalogued AEs from parental reports, daily symptom diaries, and dose escalations. We included events that were considered likely related to OIT and identified potential baseline predictors of higher AE rates using generalized linear regression models. Results Eighty percent of subjects experienced likely related AEs during OIT (72% during buildup and 47% during maintenance). Of these AEs, over 90% occurred while at home. Approximately 42% of subjects experienced systemic reactions, and 49% experienced gastrointestinal symptoms. Twenty percent of subjects dropped out, with half (10% of the overall group) due to persistent gastrointestinal symptoms. Baseline allergic rhinitis (AR) and peanut SPT wheal size were significant predictors of higher overall AE rates. SPT wheal size predicted increased gastrointestinal AEs, and AR predicted increased systemic reactions. Over the course of OIT, 61% of subjects received treatment for likely related AEs, 59% with antihistamines and 12% with epinephrine. Conclusions Peanut OIT is associated with frequent AEs, with rates declining over time, and most graded mild. However, systemic reactions and intolerable gastrointestinal AEs do occur and are significantly associated with AR and peanut SPT wheal size, respectively. Further study is needed of predictive biomarkers and the overall risks and benefits of OIT.

Arthritis is the leading cause of disability in the United States (1) with osteoarthritis (OA) being the most common type. OA often results in pain, disability and poor psychological well-being. Arthritis interventions (e.g., coping, self-management, exercise) have been shown through randomized controlled trials to be effective ways to manage OA symptoms (2–5). Effective interventions include, but are not limited to the Arthritis Foundation Aquatics Program (6), the Arthritis Self-Management Program (ASMP), (7–9), Walk-with-Ease (4), and psychological interventions for symptom management (10). Such interventions have been shown to decrease pain, depression, medical visits, disability, discomfort, medical expenses, and to increase relaxation, quality of life, self-efficacy, functional ability, self-care behavior, and knowledge about arthritis (2,10). However, the positive effect is only true for the populations the interventions reach. Research consistently highlights the lack of inclusion and lack of participation of Blacks in health related research and clinical trials (11–13). Similar problems have been found with arthritis behavioral intervention programs and research. The majority of arthritis intervention studies have been conducted with predominantly White populations without any special attention to minorities (e.g., examining effectiveness, recruitment and retention, social or structural needs, preferences or expectations; 2,5,10). The paucity of studies focused on Blacks in arthritis interventions emphasizes the need to understand present challenges (e.g., preferences of the individual, social determinants, healthcare delivery system structure) that may serve as a barrier to the inclusion of Blacks in arthritis interventions particularly when considering the potential impact of the lack of inclusion on health outcomes. Culture related barriers are a factor that deserves some attention in this field. Race is a multi-dimensional social construct that provides an overarching category for individuals who may have shared norms, values, experiences, and histories that may uniquely contribute either proximally or distally to the lack of inclusion in healthcare options of this type (14,15). Exploring how race differences in preferences and barriers might contribute to the lack of inclusion of Blacks in arthritis interventions is an important topic. In addition, designing effective interventions that can be successfully implemented and disseminated among Blacks with arthritis is predicated on understanding the potential influence of the cultural aspect of race. Recent research has acknowledged that the lack of inclusion of minorities in arthritis intervention research is problematic. Researchers have begun to make an effort to address this gap in the literature by including Blacks in studies of the ASMP (16,17) and other community-based arthritis interventions (18), adapting the materials to become more culturally sensitive (16,18), including Black intervention leaders and coordinators, and by working with African-American community-based organizations (e.g., churches, sororities; 16–18). However, in these studies the process of modifying the materials and delivery of the program for cultural sensitivity were not described in detail (16,17), and the effectiveness, satisfaction, or acceptability of the strategies amongst Blacks were not reported (18). Moreover, 17% of the participants (N=458) in the study conducted by Goeppinger et al. (17) were Black, and Altpeter et al. (18) reported that 19% of a combined sample (N=1,517) from four community-based arthritis interventions were Black; however, analyses specific to Blacks were not presented. To our knowledge only one study to date has examined the acceptability or the effectiveness of an arthritis intervention (i.e., ASMP) among Blacks (16). Without randomized controlled trials for arthritis interventions including and reporting findings on minorities (e.g., Blacks) the question remains as to whether arthritis interventions are appealing, acceptable, feasible, or effective in racial/ethnic minority populations. Therefore the purpose of this research was to determine if there were racial differences or similarities in barriers to participating in arthritis interventions or in preferences of arthritis intervention content, structure, and delivery. Past research has examined the needs of patients with arthritis, however samples included predominately White participants, and analyses did not examine race differences (19,20). While limited work using needs assessments have been conducted in the area of arthritis and arthritis disparities, utilizing needs assessments to evaluate the care needs of a target population is not a novel concept (21,22). Researchers have used needs assessments to gather information on health service needs and cultural diversity in other contexts [e.g., health service needs for Latino youth (21) and end of life care needs for African Americans (22)], and to use this information to make interventions appropriate for diverse individuals. Our project addressed the following research questions: 1) Are there race differences in barriers to arthritis interventions between Blacks and Whites with OA, and 2) Are there race differences in intervention preferences (i.e., content, structure, and delivery) between Blacks and Whites with OA? Based on previous literature (12,13,23,24), it was hypothesized that there would be significant race differences in barriers to participation in arthritis interventions. Black participants were predicted to be more likely to report that lack of trust in the healthcare system, family responsibilities, cost, and transportation were barriers to participating in arthritis interventions. Due to the lack of an extensive previous literature on issues of preferences for arthritis interventions, racial differences in the other issues were explored without hypotheses.

The association between visit-to-visit variability of blood pressure (BP) and cognitive decline over time remains incompletely understood in a general population of older adults. We assessed the hypothesis that higher visit-to-visit variability in BP, but not mean BP, would be associated with faster decline in cognitive function among community-dwelling older adults. This prospective cohort study comprised 976 adults who had 3 or 4 visits with BP measurements as part of the China Health and Nutrition Survey from 1991, up to their first cognitive tests, and completed cognitive screening tests at ≥2 visits in 1997, 2000, or 2004. Visit-to-visit BP variability was expressed as the SD, coefficient of variation, or as the variation independent of mean BP across visits conducted at a mean interval of 3.2 years. Mean (SD) age at the first cognitive test was 64 (6) years. Using multivariable-adjusted linear mixed–effects models, we found higher visit-to-visit variability in systolic BP, but not mean systolic BP, was associated with a faster decline of cognitive function (adjusted mean difference [95% confidence interval] for high versus low tertile of SD variability: standardized composite scores −0.038 standard units (SU)/y [−0.066 to −0.009] and verbal memory −0.041 SU/y [−0.075 to −0.008]). Higher visit-to-visit variability in diastolic BP was associated with a faster decline of cognitive function, independent of mean diastolic BP, among adults aged 55 to 64 years but not those ≥65 years. Our results suggest that higher long-term BP visit-to-visit variability is associated with a faster rate of cognitive decline among older adults.

Background Stage IIIA(N2) non-small cell lung cancer is a heterogeneous spectrum ranging from microscopic lymph node metastases to bulky multistation nodal disease. While some favor surgical resection after neoadjuvant therapy, others favor definitive chemoradiation for treatment. Our aim was to determine practice patterns of thoracic surgeons. Methods We invited 2,539 active surgeons identified on the Cardiothoracic Surgery Network as expressing interest in general thoracic surgery to participate in an anonymous Web-based survey. The participants evaluated clinical vignettes of a patient with single station N2 disease. Results In all, 513 surgeons (20%) responded, with 222 (43%) in academic practice. For microscopic N2 disease, 84% (n = 430) preferred neoadjuvant therapy followed by surgery. For grossly involved N2 disease, 62% (n = 318) favored neoadjuvant therapy followed by surgery if N2 disease was downstaged. In patients with normal pulmonary function tests, requiring pneumonectomy, in the presence of bulky, single station N2 disease, there was less consensus: 32% (n = 163) favored neoadjuvant therapy followed by lobectomy (less radical surgery than initially predicted) if feasible and N2 disease had downstaged, 30% (n = 159) favored neoadjuvant therapy followed by pneumonectomy if N2 disease downstaged, 12% (n = 60) would favor surgery regardless of N2 disease downstaging, and 22% (n = 114) favored definitive chemoradiation. If the patient did not have adequate pulmonary function for pneumonectomy but could tolerate lobectomy, 50% favored neoadjuvant therapy followed by reassessment for lobectomy and 41% favored definitive chemoradiation. Conclusions There is no clear consensus on management of patients with stage IIIA lung cancer in the United States. Diversity of opinion is greatest in patients with more advanced lung cancer, and limited pulmonary function.

This study examines the timing of menarche in relation to infant-feeding methods, specifically addressing the potential effects of soy isoflavone exposure through soy-based infant feeding. Subjects were participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Mothers were enrolled during pregnancy and their children have been followed prospectively. Early-life feeding regimes, categorised as primarily breast, early formula, early soy and late soy, were defined using infant-feeding questionnaires administered during infancy. For this analysis, age at menarche was assessed using questionnaires administered approximately annually between ages 8 and 14.5. Eligible subjects were limited to term, singleton, White females. We used Kaplan-Meier survival curves and Cox proportional hazards models to assess age at menarche and risk of menarche over the study period. The present analysis included 2920 girls. Approximately 2% of mothers reported that soy products were introduced into the infant diet at or before 4 months of age (early soy). The median age at menarche [interquartile range (IQR)] in the study sample was 153 months [144-163], approximately 12.8 years. The median age at menarche among early soy-fed girls was 149 months (12.4 years) [IQR, 140-159]. Compared with girls fed non-soy-based infant formula or milk (early formula), early soy-fed girls were at 25% higher risk of menarche throughout the course of follow-up (hazard ratio 1.25 [95% confidence interval 0.92, 1.71]). Our results also suggest that girls fed soy products in early infancy may have an increased risk of menarche specifically in early adolescence. These findings may be the observable manifestation of mild endocrine-disrupting effects of soy isoflavone exposure. However, our study is limited by few soy-exposed subjects and is not designed to assess biological mechanisms. Because soy formula use is common in some populations, this subtle association with menarche warrants more in-depth evaluation in future studies.

Traditional linear regression at the level taught in most introductory statistics courses involves the use of ‘fixed effects’ as predictors of a particular outcome. This treatment of the independent variable is often sufficient. However, as research questions have become more sophisticated, coupled with the rapid advancement in computational abilities, the use of random effects in statistical modeling has become more commonplace. Treating predictors in a model as a random effect allows for more general conclusions—a great example being the treatment of the studies that comprise a meta-analysis as random rather than fixed. In addition, utilization of random effects allows for more accurate representation of data that arise from complicated study designs, such as multilevel and longitudinal studies, which in turn allows for more accurate inference on the fixed effects that tend to be of primary interest. It is important to note the distinctions between fixed and random effects in the most general of settings, while also knowing the benefits and risks to their simultaneous use in specific yet common situations. WIREs Comput Stat 2012, 4:181–190. doi: 10.1002/wics.201

The linear mixed model assumes normality of its two sources of randomness: the random effects and the residual error. Recent research demonstrated that a simple transformation of the response targets normality of both sources simultaneously. However, estimating the transformation can lead to biased estimates of the variance components. Here, we provide guidance regarding this potential bias and propose a correction for it when such bias is substantial. This correction allows for accurate estimation of the random effects when using a transformation to achieve normality. The utility of this approach is demonstrated in a study of sleep-wake behavior in preterm infants.