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Samir K. Ballas;
Muge R. Kesen;
Morton F. Goldberg;
Gerard A. Lutty;
Carlton Dampier;
Ifeyinwa Osunkwo;
Winfred C. Wang;
Carolyn Hoppe;
Ward Hagar;
Deepika S. Darbari;
Punam Malik
The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of the globin gene resulting in the substitution of glutamic acid by valine at position 6 of the globin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes.
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Susanna W. Chang;
Joseph F. McGuire;
John T. Walkup;
Douglas W. Woods;
Lawrence Scahill;
Sabine Wilhelm;
Alan L. Peterson;
James Dziura;
John Piacentini
This paper examined neurocognitive functioning and its relationship to behavior treatment response among youth with Tourette's Disorder (TD) in a large randomized controlled trial. Participants diagnosed with TD completed a brief neurocognitive battery assessing inhibitory functions, working memory, and habit learning pre- and post-treatment with behavior therapy (CBIT, Comprehensive Behavioral Intervention for Tics) or psychoeducation plus supportive therapy (PST). At baseline, youth with tics and Attention Deficit Hyperactivity Disorder (ADHD) exhibited some evidence of impaired working memory and simple motor inhibition relative to youth with tics without ADHD. Additionally, a small negative association was found between antipsychotic medications and youth's performance speed. Across treatment groups, greater baseline working memory and aspects of inhibitory functioning were associated with a positive treatment response; no between-group differences in neurocognitive functioning at post-treatment were identified. Within the behavior therapy group, pre-treatment neurocognitive status did not predict outcome, nor was behavior therapy associated significant change in neurocognitive functioning post-treatment. Findings suggest that co-occurring ADHD is associated with some impairments in neurocognitive functioning in youth with Tourette's Disorder. While neurocognitive predictors of behavior therapy were not found, participants who received behavior therapy exhibited significantly reduced tic severity without diminished cognitive functioning.
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Amy Gaskell;
Rebecca Pullon;
Darren Hight;
Jonathan Termaat;
Gay Mans;
Logan Voss;
Matthias Kreuzer;
Sebastian Schmid;
Stephan Kratzer;
Amy Rodriguez;
Gerhard Schneider;
Paul Garcia;
Jamie Sleigh
Background: Postoperative delirium may manifest in the immediate post-anaesthesia care period. Such episodes appear to be predictive of further episodes of inpatient delirium and associated adverse outcomes. Frontal electroencephalogram (EEG) findings of suppression patterns and low proprietary index values have been associated with postoperative delirium and poor outcomes. However, the efficacy of titrating anaesthesia to proprietary index targets for preventing delirium remains contentious. We aim to assess the efficacy of two strategies which we hypothesise could prevent post-anaesthesia care unit (PACU) delirium by maximising the alpha oscillation observed in frontal EEG channels during the maintenance and emergence phases of anaesthesia. Methods: This is a 2 × 2 factorial, double-blind, stratified, randomised control trial of 600 patients. Eligible patients are those aged 60 years or over who are undergoing non-cardiac, non-intracranial, volatile-based anaesthesia of expected duration of more than 2 h. Patients will be stratified by pre-operative cognitive status, surgery type and site. For the maintenance phase of anaesthesia, patients will be randomised (1:1) to an alpha power-maximisation anaesthesia titration strategy versus standard care avoiding suppression patterns in the EEG. For the emergence phase of anaesthesia, patients will be randomised (1:1) to early cessation of volatile anaesthesia and emergence from an intravenous infusion of propofol versus standard emergence from volatile anaesthesia only. The primary study outcomes are the power of the frontal alpha oscillation during the maintenance and emergence phases of anaesthesia. Our main clinical outcome of interest is PACU delirium. Discussion: This is a largely exploratory study; the extent to which EEG signatures can be modified by titration of pharmacological agents is not known. The underlying concept is maximisation of anaesthetic efficacy by individualised drug titration to a clearly defined EEG feature. The interventions are already clinically used strategies in anaesthetic practice, but have not been formally evaluated. The addition of propofol during the emergence phase of volatile-based general anaesthesia is known to reduce emergence delirium in children; however, the efficacy of this strategy in older patients is not known. Trial registration: Australian and New Zealand Clinical Trial Registry, ID: 12617001354370. Registered on 27/09/2017.
Background Major depressive disorder (MDD) is a heterogeneous condition and individual patients are likely to be differentially responsive to specific treatments. In an exploratory factor analysis of three rating scales, the Genome-based Therapeutic Drugs for Depression (GENDEP) trial identified three factors that were differentially associated with outcome to nortriptyline and escitalopram. However, this factor analysis has neither been replicated or applied to a psychotherapy treatment. Methods We replicated the GENDEP analytic method in the Emory Predictors of Remission to Individual and Combined Treatments (PReDICT) study. The 17-item Hamilton Depression Rating Scale, Montgomery Asberg Depression Rating Scale, and Beck Depression Inventory were administered to 306 MDD patients in the PReDICT study, which randomized previously untreated adults to 12 weeks of treatment with cognitive behavior therapy (CBT), escitalopram, or duloxetine. Utilizing Item Response Theory methodologies, factor scores were derived from the three scales and the efficacy of the three treatments was compared for the identified factor scores. Results Four factors were identified: “Despair,” “Mood and Interest,” “Sleep,” and “Appetite.” These factors closely aligned with the factors identified in GENDEP. Compared to CBT, escitalopram and duloxetine produced more rapid but ultimately similar improvement on the Despair and Mood and Interest factors; no significant differences between treatments emerged on the other factors. Limitations The scales contained differing numbers of items pertaining to specific depressive symptoms. Conclusion The heterogeneity of MDD can be parsed into a consistent factor structure, with the factors showing differential rapidity, but ultimately similar, improvement across treatments.
In practice, disease outcomes are often measured in a continuous scale, and classification of subjects into meaningful disease categories is of substantive interest. To address this problem, we propose a general analytic framework for determining cut-points of the continuous scale. We develop a unified approach to assessing optimal cut-points based on various criteria, including common agreement and association measures. We study the nonparametric estimation of optimal cut-points. Our investigation reveals that the proposed estimator, though it has been ad-hocly used in practice, pertains to nonstandard asymptotic theory and warrants modifications to traditional inferential procedures. The techniques developed in this work are generally adaptable to study other estimators that are maximizers of nonsmooth objective functions while not belonging to the paradigm of M-estimation. We conduct extensive simulations to evaluate the proposed method and confirm the derived theoretical results. The new method is illustrated by an application to a mental health study.
Introduction Recent studies report racial disparities among individuals in organized colorectal cancer (CRC) programs; however, there is a paucity of information on CRC screening utilization by race/ethnicity among newly age-eligible adults in such programs. Methods This was a retrospective cohort study among Kaiser Permanente Northern California enrollees who turned age 50 years between 2007 and 2012 (N=138,799) and were served by a systemwide outreach and facilitated in-reach screening program based primarily on mailed fecal immunochemical tests to screening-eligible people. Kaplan–Meier and Cox model analyses were used to estimate differences in receipt of CRC screening in 2015–2016. Results Cumulative probabilities of CRC screening within 1 and 2 years of subjects’ 50th birthday were 51% and 73%, respectively. Relative to non-Hispanic whites, the likelihood of completing any CRC screening was similar in blacks (hazard ratio, 0.98; 95% CI=0.96, 1.00); 5% lower in Hispanics (hazard ratio, 0.95; 95% CI=0.93, 0.96); and 13% higher in Asians (hazard ratio, 1.13; 95% CI=1.11, 1.15) in adjusted analyses. Fecal immunochemical testing was the most common screening modality, representing 86% of all screening initiations. Blacks and Hispanics had lower receipt of fecal immunochemical testing in adjusted analyses. Conclusions CRC screening uptake was high among newly screening-eligible adults in an organized CRC screening program, but Hispanics were less likely to initiate screening near age 50 years than non-Hispanic whites, suggesting that cultural and other individual-level barriers not addressed within the program likely contribute. Future studies examining the influences of culturally appropriate and targeted efforts for screening initiation are needed.
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Santhosh Girirajan;
Zoran Brkanac;
Bradley P. Coe;
Carl Baker;
Laura Vives;
Tiffany H. Vu;
Neil Shafer;
Raphael Bernier;
Giovanni B. Ferrero;
Margherita Silengo;
Stephen Warren;
Carlos S Moreno;
Marco Fichera;
Corrado Romano;
Wendy H. Raskind;
Evan E. Eichler
While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (<1 Mbp) is significantly greater for ID-associated phenotypes compared to autism (p = 9.58×10-11, odds ratio = 4.59), dyslexia (p = 3.81×10-18, odds ratio = 14.45), or controls (p = 2.75×10-17, odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (<50 kbp) in autism (10%, p = 2.4×10-6, odds ratio = 6) or ID (16%, p = 3.55×10-12, odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).
Background: Patients on dialysis are physically inactive, with most reporting activity levels below the fifth percentile of healthy age-matched groups. Several small studies have reported efficacy of diverse exercise interventions among persons with CKD and those on dialysis. However, no single intervention has been widely adopted in real-world practice, despite a clear need in this vulnerable population with high rates of mortality, frailty, and skilled nursing hospitalizations. Methods/design: We describe a pragmatic clinical trial for an exercise intervention among patients transitioning to dialysis. We will use an existing framework - Exercise is Medicine (EIM) - developed by the American College of Sports Medicine. After undertaking formative qualitative research to tailor the EIM framework to the advanced CKD population (eGFR < 30 ml/min/1.73m2), we will randomize 96 patients from two regions - Atlanta and Bay Area - in two intervention arms with incremental levels of clinical-community integration: physical activity assessment during Nephrology clinical visit, brief counseling at pre-dialysis education, and physical activity wearable (group 1) versus group 1 intervention components plus a referral to a free, EIM practitioner-led group exercise program over 16 weeks (group 2; 8 week core intervention; 8-week follow up). We will assess efficacy by comparing between group differences in minutes/week of objectively measured moderate intensity physical activity. To evaluate implementation, we will use questionnaires for assessing barriers to referral, participation and retention along the path of the intervention. Further we will have a plan for dissemination of the intervention by partnering with relevant stakeholders. Discussion: The overall goal is to inform the development of a practical, cost-conscious intervention "package" that addresses barriers and challenges to physical activity commonly faced by patients with advanced CKD and can be disseminated amongst interested practices. Trial registration: ClinicalTrials.gov identifier (Dated:10/17/2017): NCT03311763.
Objective: The purpose of this study is to compare the effectiveness of a combined 12-week home-based exercise (EX)/cognitive behavioral therapy (CBT) program (n=18) with CBT alone (n=19), EX alone (n=20), and with usual care (UC, n=17) in stable New York Heart Association Class II to III heart failure (HF) patients diagnosed with depression. Methods: Depressive symptom severity [Hamilton Rating Scale for Depression (HAM-D)] , physical function [6-min walk test (6MWT)], and health-related quality of life (HRQOL) (Minnesota Living with Heart Failure Questionnaire) were evaluated at baseline (T1), after the 12-week intervention/control (T2), and following a 3-month telephone follow-up (T3). A repeated measures analysis of variance was used to determine group differences. Depression severity was dichotomized as minor (HAM-D, 11-14) and moderate-to-major depression (HAM-D, ≥15), and group intervention and control responses were also evaluated on that basis. Results: The greatest reduction in HAM-D scores over time occurred in the EX/CBT group (-10.4) followed by CBT (-9.6), EX (-7.3), and UC (-6.2), but none were statistically significant. The combined group showed a significant increase in 6-min walk distance at 24 weeks (F=13.5, P < 001). Among all groups with moderate-to-major depression, only those in CBT/EX had sustained lower HAM-D scores at 12 and 24 weeks, 6MWT distances were significantly greater at 12 (P=018) and 24 (P=013) weeks, and the greatest improvement in HRQOL also occurred. Conclusions: Interventions designed to improve both physical and psychological symptoms may provide the best method for optimizing functioning and enhancing HRQOL in patients with HF.