Subject Disease Research Articles

Impact of a Family-Based Educational Intervention on Knowledge, Attitudes, and Burden of Alzheimer's Caregivers

Background: Family caregivers always encounter high levels of psychological distress and physical strain when caring for a person with dementia. Family-based intervention is an important option for providing effective and practical support. The study aimed to examine the effects of a specific educational intervention on improving Alzheimer's caregivers' knowledge and attitudes and explore how it reduces their subjective burdens. Material and Methods: A quasi-experimental research design was used with a purposive sample of 80 Alzheimer caregivers recruited conveniently from the Geriatric Society Association located at Almontazahat District, Jeddah, Saudi Arabia. To achieve the objectives of the current study 4 tools were used including demographic and personal data, Alzheimer's Disease Knowledge Scale (ADKS), The Dementia Attitudes Scale, and the burden scale of caregivers. Validity and reliability of the tools were confirmed and Cronbach's alpha of the Dementia Attitudes Scale was 0.87 and Cronbach's alpha of the burden scale of caregivers 0.941. Results: the age of the studied subjects ranged from 20 to 60 years with a mean of 35.6±12.2 years. the studied subject's knowledge level and attitudes were improved post-intervention than before. These differences were statistically significant (t: 108.008, P:<0.001). While, the studied subject's disease burden level was decreased post-intervention than before These differences were statistically significant (t: 8.378, P:<0.001). There is a weak positive significant relation between the studied subject's knowledge level and attitude regarding dementia (r:0.286, P:0.010). Whereas there is no correlation noted between knowledge level and caregiver burden with no statistical significance (r: -.048, P: 0.674). Conclusion and recommendation: the findings concluded that the studied subject's knowledge, attitude, and burden level were improved post-intervention than before with statistically significant differences. Therefore, it is recommended to develop a well-planned and structured educational program should be undertaken to improve the level of awareness and contribute to a better understanding of AD and dementia. Keywords: Alzheimer's burden, caregivers' attitudes, families, intervention, knowledge.

Early Detection of Alzheimer's Disease Using Magnetic Resonance Imaging: A Novel Approach Combining Convolutional Neural Networks and Ensemble Learning.

Early detection is critical for effective management of Alzheimer’s disease (AD) and screening for mild cognitive impairment (MCI) is common practice. Among several deep-learning techniques that have been applied to assessing structural brain changes on magnetic resonance imaging (MRI), convolutional neural network (CNN) has gained popularity due to its superb efficiency in automated feature learning with the use of a variety of multilayer perceptrons. Meanwhile, ensemble learning (EL) has shown to be beneficial in the robustness of learning-system performance via integrating multiple models. Here, we proposed a classifier ensemble developed by combining CNN and EL, i.e., the CNN-EL approach, to identify subjects with MCI or AD using MRI: i.e., classification between (1) AD and healthy cognition (HC), (2) MCIc (MCI patients who will convert to AD) and HC, and (3) MCIc and MCInc (MCI patients who will not convert to AD). For each binary classification task, a large number of CNN models were trained applying a set of sagittal, coronal, or transverse MRI slices; these CNN models were then integrated into a single ensemble. Performance of the ensemble was evaluated using stratified fivefold cross-validation method for 10 times. The number of the intersection points determined by the most discriminable slices separating two classes in a binary classification task among the sagittal, coronal, and transverse slice sets, transformed into the standard Montreal Neurological Institute (MNI) space, acted as an indicator to assess the ability of a brain region in which the points were located to classify AD. Thus, the brain regions with most intersection points were considered as those mostly contributing to the early diagnosis of AD. The result revealed an accuracy rate of 0.84 ± 0.05, 0.79 ± 0.04, and 0.62 ± 0.06, respectively, for classifying AD vs. HC, MCIc vs. HC, and MCIc vs. MCInc, comparable to previous reports and a 3D deep learning approach (3D-SENet) based on a more state-of-the-art and popular Squeeze-and-Excitation Networks model using channel attention mechanism. Notably, the intersection points accurately located the medial temporal lobe and several other structures of the limbic system, i.e., brain regions known to be struck early in AD. More interestingly, the classifiers disclosed multiple patterned MRI changes in the brain in AD and MCIc, involving these key regions. These results suggest that as a data-driven method, the combined CNN and EL approach can locate the most discriminable brain regions indicated by the trained ensemble model while the generalization ability of the ensemble model was maximized to successfully capture AD-related brain variations early in the disease process; it can also provide new insights into understanding the complex heterogeneity of whole-brain MRI changes in AD. Further research is needed to examine the clinical implication of the finding, capability of the advocated CNN-EL approach to help understand and evaluate an individual subject’s disease status, symptom burden and progress, and the generalizability of the advocated CNN-EL approach to locate the most discriminable brain regions in the detection of other brain disorders such as schizophrenia, autism, and severe depression, in a data-driven way.

Combining biomarkers linearly and nonlinearly for classification using the area under the ROC curve.

In biomedical studies, it is often of interest to classify/predict a subject's disease status based on a variety of biomarker measurements. A commonly used classification criterion is based on area under the receiver operating characteristic curve (AUC). Many methods have been proposed to optimize approximated empirical AUC criteria, but there are two limitations to the existing methods. First, most methods are only designed to find the best linear combination of biomarkers, which may not perform well when there is strong nonlinearity in the data. Second, many existing linear combination methods use gradient-based algorithms to find the best marker combination, which often result in suboptimal local solutions. In this paper, we address these two problems by proposing a new kernel-based AUC optimization method called ramp AUC (RAUC). This method approximates the empirical AUC loss function with a ramp function and finds the best combination by a difference of convex functions algorithm. We show that as a linear combination method, RAUC leads to a consistent and asymptotically normal estimator of the linear marker combination when the data are generated from a semiparametric generalized linear model, just as the smoothed AUC method. Through simulation studies and real data examples, we demonstrate that RAUC outperforms smooth AUC in finding the best linear marker combinations, and can successfully capture nonlinear pattern in the data to achieve better classification performance. We illustrate our method with a dataset from a recent HIV vaccine trial. Copyright © 2016 John Wiley & Sons, Ltd.

Abstract 3099: Longitudinal genomic and transcriptomic analysis of mantle cell lymphoma in a targeted combination trial of a selective CDK4/6 inhibitor

Abstract We used whole exome (WES) and whole transcriptome sequencing (WTS) to study progression of Mantle Cell Lymphoma (MCL) in the context of a clinical trial of targeted combination therapy of a CDK4 inhibitor PD0332991 (palbociclib) and a proteasome inhibitor bortezomib. Our longitudinal study design coupled with an integrative analysis approach enabled detailed molecular characterization of each subject's disease. This includes multiple time points for three therapy Responders (Rs) and two Non-Responders (NRs); a primary goal was to understand genetic reasons for differential response. To that end, we identified copy number variants (CNVs) and single nucleotide variants (SNVs) specific to NRs that are supported by both WES and WTS data and implicate pathways relevant to mechanisms of drug action. CNVs were identified using multiple orthogonal methods that use read depth and genome-wide allele frequencies. These revealed a 29Mb chr9 hemizygous deletion unique to NRs. This region includes 15 interferon genes of the type 1 interferon signaling pathway (enrichment: p<10-9), which is involved in B cell differentiation and proliferation, and T cell and natural killer cell activation. Interferon signaling is implicated in bortezomib function and loss of interferon genes may contribute to resistance in non-responders. Additional key genes in deleted regions are JAK2, RPS6, and CDKN2A, a CDK2 inhibitor, loss of which may antagonize palbociclib-induced G1 arrest NRs also shared a 24Mb chr3 duplication resulting in gain of PIK3CA and PIK3CB. Amplification of these genes is common in cancers, including MCL (classical analysis) and DLBCL, and often associated with poor prognosis. But, this is the only longitudinal study of PI3K CNV in a targeted therapy. In context of PD+bortezomib treatment, higher levels of PI3K may affect sensitivity to proteasome inhibition activated autophagy since bortezomib's inhibitory activity involves suppression of the PI3K/AKT/mTOR pathway. PIK3CA is amplified in a responder as well, suggesting additional determinants for clinical response. Other CNVs differentiating Rs and NRs are a 24Mb chr8 deletion found only in Rs and a 4Mb chr17 deletion found only in NRs, which includes p53 in a subject who also has a p53 mutation, resulting in 100% expression of the mutant allele. The described CNVs result in detectable shifts in expression of a large proportion of affected genes. Coupled with SNV data, where we identified 21 SNVs shared by NRs and absent in Rs, these results offer molecular clues to mechanisms of resistance in NRs, which we are currently pursuing with functional studies. Overall, we performed a thorough genomic and transcriptomic analysis of a longitudinal investigation of MCL patients during a targeted combination therapy phase I clinical trial and identified potential biomarkers of response spanning CNVs, SNVs, and differentially expressed genes. Citation Format: Priyanka Vijay, Pedro Blecua, Maurizio Di Liberto, David Chiron, Xiangao Huang, Olivier Elemento, Peter Martin, John P. Leonard, Christopher E. Mason, Selina Chen-Kiang. Longitudinal genomic and transcriptomic analysis of mantle cell lymphoma in a targeted combination trial of a selective CDK4/6 inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3099. doi:10.1158/1538-7445.AM2015-3099

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Introduction: Measurement of CI is an integral component of contemporary goal-directed therapy in critically ill subjects. Despite the lack of definitive evidence in support of routine use of the PAC in this setting, it has contributed significantly to the existing literature of bedside CI determination. Recent technological advances have resulted in less invasive methods of measuring CI. Our observation based on use of these less invasive technologies (FloTrac Sensor/Vigileo Monitor, Edwards Lifesciences Corporation, Irvine, CA) is that the agreement with CI values obtained from the PAC varies depending on the subject's disease. Methods: Simultaneous, paired measurements of CI were recorded in consecutive, critically ill subjects with a PAC and FloTrac who met criteria for the consensus definitions of severe sepsis and septic shock. A cohort of subjects with CV collapse were similarly evaluated, as defined by SBP<90 mm Hg or <40 mm from known baseline after a 30 mL/kg bolus, requiring vasopressors, with a history of cardiac disease (MI, CHF, abnormal ejection fraction) or concurrent myocardial dysfunction, and elevated troponin I. Data limited to the first 3 days of resuscitation were analyzed using Bland and Altman statistics. Results: Twelve patients with severe sepsis contributed 28 data points. Demographics were (mean + SD): age 67 ± 15 yrs, 5 Male: 7 Female, APACHE II 25 ± 2, BSA 1.8 ± 0.4 m2. Mean CI was 3.6 ± 0.8 L/min/m2 (PAC) and 2.8 ± 0.7 L/min/m2 (FloTrac). Bias was 0.79; precision was 0.83. Limits of Agreement (LOA) were -0.87 to 2.45. Percentage error was 46%. Fifty-two patients with septic shock contributed 142 data points. Demographics were: age 64 ± 16 yrs, 29 Male: 23 Female, APACHE II 27 ± 3, BSA 1.9 ± 0.4 m2, Mean CI was 3.6 ± 0.9 L/min/m2 (PAC), and 3.1 ± 0.9 L/min/m2 (FloTrac). Bias was 0.49; precision was 0.95. LOA was -1.41 to 2.39. Percentage error was 53%. Fourteen patients with CV collapse contributed 32 data points. Demographics were: age 67 ± 12 yrs, 8 Male: 6 Female, APACHE II 29 ± 4, BSA 1.8 ± 0.2 m2. Mean CI was 3.4 ± 0.7 L/min/m2 (PAC), and 3.3 ± 0.8 L/min/m2 (FloTrac). Bias was 0.06; precision was 0.64. LOA were -1.22 to 1.34. Percentage error was 37%. Conclusions: Comparison of CI measurements between PAC and FloTrac demonstrated the least amount of divergence in subjects with CV collapse, as compared to subjects with severe sepsis or septic shock. This may be reflective of the algorithm used in the FloTrac system.

A Retrospective Evaluation Of Insurance Status As It Relates To Outcomes In Diffuse Large B-Cell Lymphoma

IntroductionDespite the advances in Diffuse Large B-Cell Lymphoma (DLBCL) treatment, there is a lack of uniformity regarding survival among the entire patient population. This study investigates several individual-level markers of socioeconomic and clinical status in relation to DLBCL survival. MethodsThis is a retrospective cohort study that utilizes a study population that was derived from the Moffitt Cancer Center Total Cancer Care protocol, a database that contains clinical, biological, and demographic information for over 73,000 patients as well as molecular and cytogenetic information on over 36,000 tumors.The database included 440 persons who were diagnosed with Diffuse Large B-Cell Lymphoma between 1998 and 2012. Of these persons, 274 met the eligibility criteria. A descriptive analysis was first conducted on all variables in the study and was then stratified by insurance status. A forward step-wise Cox proportional hazard regression was performed to calculate adjusted hazard ratios (HR) and their 95% confidence intervals for the association between insurance status and relapse, progression, or death utilizing SAS 9.3 (SAS Institute, Inc., Cary, NC). The Kaplan-Meier method was used to generate survival curves for each insurance group and compared according to the log-rank test. This was done in order to examine any differences in median survival time (in months) between the two groups. ResultsIn terms of both overall survival and event-free survival, race was a significant prognostic factor in this study with non-Caucasian subjects being more likely to experience mortality (HR 2.33; 95% CI, 1.39 - 3.88). Subjects who presented with b-symptoms (fevers, unintentional weight loss >10%, and night sweats) at the time of diagnosis were significantly more likely to experience mortality (HR 2.48; 95% CI, 1.67 - 3.67) than those who were without them. Both stage and nodal status of a subject's disease at the time of diagnosis were significantly associated with the outcome as subject's with advanced stage disease (HR 3.89; 95% CI, 2.25 - 6.76) and extra nodal disease (HR 1.58; 95% CI, 1.04 - 2.39) had a higher risk of death.For overall survival, subjects in the privately-insured group experienced a significant difference in overall survival time (Log-Rank p=0.04) compared to those subjects with government-subsidized insurance (Figure 1). There was also a statistically significant difference in event-free survival between the two insurance groups (Log-Rank p=0.05) (Figure 2). Notably, age was not a significant covariate for OS or EFS, suggesting that the government-subsidized group was not biased by an increased proportion of elderly Medicare enrolled patients. [Display omitted] [Display omitted] DiscussionIn this retrospective cohort study, we observed that event-free survival time among subjects with private insurance were significantly improved from those subjects with government-subsidized insurance and overall survival time among subjects with private insurance were significantly improved from those subjects with government-subsidized insurance. We determined that after adjustment for demographic and clinical covariates, the covariates race, presentation of b-symptoms at the time of diagnosis, stage at the time of diagnosis, and nodal status of a subject's disease were all significant prognostic factors in both overall and event-free survival. Disclosures:No relevant conflicts of interest to declare.

Occupational silica and solvent exposures and risk of systemic lupus erythematosus in urban women

To assess the risk of systemic lupus erythematosus (SLE) associated with occupational exposure to silica dust and organic solvents in an urban population. Women with SLE were identified through both community screening and hospital databases in 4 predominantly African American neighborhoods in Boston. Female control patients were volunteers from the same communities and were screened for the absence of connective tissue disease. Demographic factors, smoking history, and a detailed occupational history, including exposures to specific chemicals, were obtained by in-person interviews. The exposure assessment was based on independent evaluation of the occupational history by 2 reviewers who were blinded to each subject's disease status. The risks associated with exposure to silica and solvents were analyzed using multivariate conditional logistic regression models, adjusted for potential confounders. Ninety-five patients and 191 age- and race-matched controls were included in this analysis. Exposure to silica for longer than 1 year was associated with SLE (odds ratio [OR] 4.3, 95% confidence interval [95% CI] 1.7-11.2). An exposure-response effect was seen for longer duration of exposures to silica (P for trend = 0.01). The association between occupational exposure to organic solvents and SLE was not statistically significant (OR 1.04, 95% CI 0.34-3.2). Silica exposure from a variety of industrial occupations in urban areas is associated with an increased risk of SLE. A longer duration of exposure to silica dust is associated with greater risks. This study provides further impetus for additional research into the influence of modifiable exposures on the pathogenesis of SLE.

Robust Bayesian prediction of subject disease status and population prevalence using several similar diagnostic tests.

Sometimes several diagnostic tests are performed on the same population of subjects with the aim of assessing disease status of individuals and the prevalence of the disease in the population, but no test is a reference test. Although the diagnostic tests may have the same biological underpinnings, test results may disagree for some specific animals. In that case, it may be difficult to determine disease status for individual subjects, and consequently population prevalence estimation becomes difficult. In this paper, we propose a robust method of estimating disease status and prevalence that uses heavy-tailed sampling distributions in a hierarchical model to protect against the influence of conflicting observations on inferences. If a subject has a test outcome that is discordant with the other test results then it is downweighted in diagnosing a subject's disease status, and for estimating disease prevalence. The amount of downweighting depends on the degree of conflict among the test results for the subject.

A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease

Clinical experience suggests that 6-mercaptopurine (6-MP) is effective therapy for children with active steroid-dependent Crohn's disease (CD). We report the results of a prospective, placebo-controlled, multicenter trial evaluating the combination of 6-MP and prednisone as therapy for children with newly diagnosed moderate-to-severe CD. Fifty-five children (age, 13+/-2 years) were randomized to treatment with 6-MP (1.5 mg x kg(-1) x day(-1)) or placebo within 8 weeks of initial diagnosis. Both groups also received prednisone (40 mg/day). Prednisone dosage adjustments were based on a defined schedule determined by the change in a subject's disease activity score, and steroid administration was discontinued as remission was achieved. Study treatment with 6-MP or placebo continued for 18 months. Groups were comparable for age, sex, and site and activity of disease. In the 6-MP group, the duration of steroid use was shorter (P<0.001) and the cumulative steroid dose lower at 6, 12, and 18 months (P<0.01). Although remission was induced in 89% of both groups, only 9% of the remitters in the 6-MP group relapsed compared with 47% of controls (P = 0.007). Growth was comparable in both groups. No clinically significant adverse events occurred, although mild leukopenia and increases in aminotransferase activity were noted in the 6-MP group. Addition of 6-MP to a regimen of corticosteroids significantly lessens the need for prednisone and improves maintenance of remission. 6-MP should be part of the initial treatment regimen for children with newly diagnosed moderate-to-severe CD.

Health status of older male prisoners: a comprehensive survey.

Although prison populations remain predominantly young, the number of older inmates in state and federal correctional facilities has been increasing. This report describes the results of a health survey of 119 male inmates 50 years of age and older residing in Iowa state correctional facilities. Subject's disease history included hypertension (40%), myocardial infarction (19%), and emphysema (18%). Most participants (97%) had missing teeth, 42% had gross physical functional impairments, and 70% smoked cigarettes. These findings have implications for health care provision and release planning.