Understanding Factors Associated With Intention To Go To Your Doctor To Ask For Sickle Cell Trait Screening Among African Americans Within Middle Reproductive Age

Thesis (Ph.D.) - Indiana University, Public Health, 2015Background: Current guidelines recommend that African Americans (AA) know their sickle cell trait status to inform their reproductive decisions. Two studies based on the Reasoned Action Approach (RAA) and the Extended Parallel Process Model were conducted with AA between 18 and 35 to understand their intention to get screened to determine their status. The aim of the main study was to identify factors underlying intention to go to their doctor to ask for sickle cell screening in the next 12 months. The aim of the secondary study was to identify how exposure to a brochure with information about sickle cell trait screening might influence knowledge and beliefs. Methods: Data were collected during March through May 2015 from community sites and via referral to Qualtrics from 300 AA residing in three cities in Indiana. After participants answered eligibility and knowledge questions, they were randomly exposed to one of two brochures. The control brochure had two boxes of information on sickle cell trait susceptibility, severity, and screening; the intervention brochure was identical to the control brochure with the recommended response (e.g., “Go to your doctor to ask for sickle cell trait screening.”) inserted between the two boxes. Then the participants completed a 45-item questionnaire. Results: In the main study sequential regression was used to predict intention. Adding the three RAA constructs of perceived behavioral control (β = .579, p<.001), attitude (β = .354, p<.001), and perceived norm (β = .177, p<.001) significantly increased the adjusted R2 from .173 to .639 (F=34.136, df, 16, 283 p<.001) over the model with four demographic variables and three knowledge and belief variables. In the secondary study, the multivariate t-test comparing those exposed to the control brochure to those exposed to the intervention brochure with the recommended response revealed no significant multivariate effects. However, a paired sample t-test comparing knowledge and beliefs before and after the brochures revealed that exposure to the brochure improved knowledge and beliefs about sickle cell trait screening. Conclusion: RAA was demonstrated to be a useful behavioral theory to understand factors underlying this genetic screening decision. Implications for interventions and research were discussed

Impact of germline DNA repair gene variants on prognosis and treatment of men with advanced prostate cancer.

The clinical importance of germline variants in DNA repair genes (DRGs) is becoming increasingly recognized, but their impact on advanced prostate cancer prognosis remains unclear. A cohort of 221 newly diagnosed metastatic castration-resistant prostate cancer (mCRPC) patients were screened for pathogenic germline variants in 114 DRGs. The primary endpoint was progression-free survival (PFS) on first-line androgen signaling inhibitor (ARSI) treatment for mCRPC. Secondary endpoints were time to mCRPC progression on initial androgen deprivation therapy (ADT) and overall survival (OS). Twenty-seven patients (12.2%) carried a germline DRG variant. DRG carrier status was independently associated with shorter PFS on first-line ARSI [HR 1.72 (1.06-2.81), P = 0.029]. At initiation of ADT, DRG carrier status was independently associated with shorter progression time to mCRPC [HR 1.56, (1.02-2.39), P = 0.04] and shorter OS [HR 1.99, (1.12-3.52), P = 0.02]. Investigating the contributions of individual germline DRG variants on PFS and OS revealed CHEK2 variants to have little effect. Furthermore, prior taxane treatment was associated with worse PFS on first-line ARSI for DRG carriers excluding CHEK2 (P = 0.0001), but not for noncarriers. In conclusion, germline DRG carrier status holds independent prognostic value for predicting advanced prostate cancer patient outcomes and may potentially inform on optimal treatment sequencing already at the hormone-sensitive stage

Combining TCAD and Monte Carlo methods to simulate CMOS pixel sensors with a small collection electrode using the Allpix2^{2} framework

Combining electrostatic field simulations with Monte Carlo methods enables realistic modeling of the detector response for novel monolithic silicon detectors with strongly non-linear electric fields. Both the precise field description and the inclusion of Landau fluctuations and production of secondary particles in the sensor are crucial ingredients for the understanding and reproduction of detector characteristics. In this paper, a CMOS pixel sensor with small collection electrode design, implemented in a high-resistivity epitaxial layer, is simulated by integrating a detailed electric field model from finite element TCAD into a Monte Carlo based simulation with the framework. The simulation results are compared to data recorded in test-beam measurements and very good agreement is found for various quantities such as cluster size, spatial resolution and efficiency. Furthermore, the observables are studied as a function of the intra-pixel incidence position to enable a detailed comparison with the detector behavior observed in data. The validation of such simulations is fundamental for modeling the detector response and for predicting the performance of future prototype designs. Moreover, visualization plots extracted from the charge carrier drift model of the framework can aid in understanding the charge propagation behavior in different regions of the sensor

MTSS1 and SCAMP1 cooperate to prevent invasion in breast cancer

Cell–cell adhesions constitute the structural “glue” that retains cells together and contributes to tissue organisation and physiological function. The integrity of these structures is regulated by extracellular and intracellular signals and pathways that act on the functional units of cell adhesion such as the cell adhesion molecules/adhesion receptors, the extracellular matrix (ECM) proteins and the cytoplasmic plaque/peripheral membrane proteins. In advanced cancer, these regulatory pathways are dysregulated and lead to cell–cell adhesion disassembly, increased invasion and metastasis. The Metastasis suppressor protein 1 (MTSS1) plays a key role in the maintenance of cell–cell adhesions and its loss correlates with tumour progression in a variety of cancers. However, the mechanisms that regulate its function are not well-known. Using a system biology approach, we unravelled potential interacting partners of MTSS1. We found that the secretory carrier-associated membrane protein 1 (SCAMP1), a molecule involved in post-Golgi recycling pathways and in endosome cell membrane recycling, enhances Mtss1 anti-invasive function in HER2+/ER−/PR− breast cancer, by promoting its protein trafficking leading to elevated levels of RAC1-GTP and increased cell–cell adhesions. This was clinically tested in HER2 breast cancer tissue and shown that loss of MTSS1 and SCAMP1 correlates with reduced disease-specific survival. In summary, we provide evidence of the cooperative roles of MTSS1 and SCAMP1 in preventing HER2+/ER−/PR− breast cancer invasion and we show that the loss of Mtss1 and Scamp1 results in a more aggressive cancer cell phenotype

Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains

TAR DNA-binding protein 43 (TDP-43) inclusions are pathological hallmarks of patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Loss of TDP-43 in zebrafish engenders a severe muscle and vascular phenotype with a concomitant elevation of filamin C (FLNC) levels, an observation confirmed in the frontal cortex of FTLD-TDP patients. Here, we aimed to further assess the contribution of FLNC to frontotemporal dementia (FTD) etiology. We conducted a mutational screening of FLNC in a cohort of 529 unrelated Belgian FTD and FTD-ALS patients, and a control cohort of 920 unrelated and age-matched individuals. Additionally we performed an in-depth characterization of FLNC expression levels in FTD patients and a murine FTD model. In total 68 missense variants were identified of which 19 (MAF C) loss-of-function mutation. Increased FLNC levels were, to a lesser extent, also identified in a FLNC p.V831I variant carrier and in FTD patients with the p.R159H mutation in valosin-containing protein (VCP). The GRN-associated increase of FLNC was confirmed in the frontal cortex of aged Grn knockout mice starting at 16-18 months of age. Combined quantitative proteomic and bioinformatic analyses of the frontal cortex of FTD patients possessing elevated FLNC levels, identified multiple altered protein factors involved in accelerated aging, neurodegeneration and synaptogenesis. Our findings further support the involvement of aberrant FLNC expression levels in FTD pathogenesis. Identification of increased FLNC levels in aged Grn mice and impaired pathways related to aging and neurodegeneration, implies a potential role for FLNC in mediating or accelerating the aging process

Combining TCAD and Monte Carlo Methods to Simulate CMOS Pixel Sensors with a Small Collection Electrode using the Allpix Squared Framework

Combining electrostatic field simulations with Monte Carlo methods enables realistic modeling of the detector response for novel monolithic silicon detectors with strongly non-linear electric fields. Both the precise field description and the inclusion of Landau fluctuations and production of secondary particles in the sensor are crucial ingredients for the understanding and reproduction of detector characteristics. In this paper, a CMOS pixel sensor with small collection electrode design, implemented in a high-resistivity epitaxial layer, is simulated by integrating a detailed electric field model from finite element TCAD into a Monte Carlo based simulation with the Allpix$^2$ framework. The simulation results are compared to data recorded in test-beam measurements and very good agreement is found for various quantities such as cluster size, spatial resolution and efficiency. Furthermore, the observables are studied as a function of the intra-pixel incidence position to enable a detailed comparison with the detector behavior observed in data. The validation of such simulations is fundamental for modeling the detector response and for predicting the performance of future prototype designs. Moreover, visualization plots extracted from the charge carrier drift model of the framework can aid in understanding the charge propagation behavior in different regions of the sensor.Comment: 15 pages, 18 figure

Defining the critical material attributes of lactose monohydrate in carrier based dry powder inhaler formulations using artificial neural networks

The study aimed to establish a function-based relationship between the physical and bulk properties of pre-blended mixtures of fine and coarse lactose grades with the in vitro performance of an adhesive active pharmaceutical ingredient (API). Different grades of micronised and milled lactose (Lactohale (LH) LH300, LH230, LH210 and Sorbolac 400) were pre-blended with coarse grades of lactose (LH100, LH206 and Respitose SV010) at concentrations of 2.5, 5, 10 and 20 wt.%. The bulk and rheological properties and particle size distributions were characterised. The pre-blends were formulated with micronised budesonide and in vitro performance in a Cyclohaler device tested using a next-generation impactor (NGI) at 90 l/min. Correlations between the lactose properties and in vitro performance were established using linear regression and artificial neural network (ANN) analyses. The addition of milled and micronised lactose fines with the coarse lactose had a significant influence on physical and rheological properties of the bulk lactose. Formulations of the different pre-blends with budesonide directly influenced in vitro performance attributes including fine particle fraction, mass median aerodynamic diameter and pre-separator deposition. While linear regression suggested a number of physical and bulk properties may influence in vitro performance, ANN analysis suggested the critical parameters in describing in vitro deposition patterns were the relative concentrations of lactose fines % < 4.5 μm and % < 15 μm. These data suggest that, for an adhesive API, the proportion of fine particles below % < 4.5 μm and % < 15 μm could be used in rational dry powder inhaler formulation design

Behavioural and neural characteristics of navigation impairments in preclinical Alzheimer’s disease

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk preclinical individuals. This thesis focuses on spatial navigation deficits, which are increasingly shown to be present in atrisk individuals, because the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Experimental chapters 2 and 3, show that a novel test battery captures navigation deficits that precede the onset of verbal and non-verbal episodic memory deficits in preclinical disease and that resting-state functional connectivity between the EC and the PCC underpins such deficits. Evidence for moderate test re-test reliability in the same non-clinical sample is presented in chapter 4. Moving beyond detection of preclinical disease, and towards prevention, in chapter 5 we examined whether marine fish oils help preserve the volume of AD vulnerable brain regions and found that low circulating DHA blood concentration predicts preservation of hippocampal and entorhinal volume in preclinical AD. This is potentially due to increased DHA uptake from the blood to the brain due to preclinical disease. Taken together, the research advances our conceptual understanding of the pathological and compensatory changes that characterise preclinical AD and offers important information toward generating more accurate risk profiles for AD vulnerable adults