Search results for: community empowerment ethnic group

Authors: Gertraud Koch, Teresa Stumpf, Alejandra Tijerina García

Abstract:

Discourse analysis research approaches belong to the central research strategies applied throughout the humanities; they focus on the countless forms and ways digital texts and images shape present-day notions of the world. Despite the constantly growing number of relevant digital, multimodal discourse resources, digital humanities (DH) methods are thus far not systematically developed and accessible for discourse analysis approaches. Specifically, the significance of multimodality and meaning plurality modelling are yet to be sufficiently addressed. In order to address this research gap, the D-WISE project aims to develop a prototypical working environment as digital support for the sociology of knowledge approach to discourse analysis and new IT-analysis approaches for the use of context-oriented embedding representations. Playing an essential role throughout our research endeavor is the constant optimization of hermeneutical methodology in the use of (semi)automated processes and their corresponding epistemological reflection. Among the discourse analyses, the sociology of knowledge approach to discourse analysis is characterised by the reconstructive and accompanying research into the formation of knowledge systems in social negotiation processes. The approach analyses how dominant understandings of a phenomenon develop, i.e., the way they are expressed and consolidated by various actors in specific arenas of discourse until a specific understanding of the phenomenon and its socially accepted structure are established. This article presents insights and initial findings from D-WISE, a joint research project running since 2021 between the Institute of Anthropological Studies in Culture and History and the Language Technology Group of the Department of Informatics at the University of Hamburg. As an interdisciplinary team, we develop central innovations with regard to the availability of relevant DH applications by building up a uniform working environment, which supports the procedure of the sociology of knowledge approach to discourse analysis within open corpora and heterogeneous, multimodal data sources for researchers in the humanities. We are hereby expanding the existing range of DH methods by developing contextualized embeddings for improved modelling of the plurality of meaning and the integrated processing of multimodal data. The alignment of this methodological and technical innovation is based on the epistemological working methods according to grounded theory as a hermeneutic methodology. In order to systematically relate, compare, and reflect the approaches of structural-IT and hermeneutic-interpretative analysis, the discourse analysis is carried out both manually and digitally. Using the example of current discourses on digitization in the healthcare sector and the associated issues regarding data protection, we have manually built an initial data corpus of which the relevant actors and discourse positions are analysed in conventional qualitative discourse analysis. At the same time, we are building an extensive digital corpus on the same topic based on the use and further development of entity-centered research tools such as topic crawlers and automated newsreaders. In addition to the text material, this consists of multimodal sources such as images, video sequences, and apps. In a blended reading process, the data material is filtered, annotated, and finally coded with the help of NLP tools such as dependency parsing, named entity recognition, co-reference resolution, entity linking, sentiment analysis, and other project-specific tools that are being adapted and developed. The coding process is carried out (semi-)automated by programs that propose coding paradigms based on the calculated entities and their relationships. Simultaneously, these can be specifically trained by manual coding in a closed reading process and specified according to the content issues. Overall, this approach enables purely qualitative, fully automated, and semi-automated analyses to be compared and reflected upon.

Keywords: entanglement of structural IT and hermeneutic-interpretative analysis, multimodality, plurality of meaning, sociology of knowledge approach to discourse analysis

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Authors: Claire Harrison, Raajit K. Rampal, Vikas Gupta, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew Kuykendall, Alessandro Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J. Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Sanjay Akhani, Rafael Muñoz-Carerras, Yury Sheykin, Gozde Colak, Morgan Harris, John Mascarenhas

Abstract:

Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively. MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment. The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 10^9/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 10^9/L vs 100–200 × 10^9/L) and spleen volume (≥1800 cm^3 vs <1800 cm^3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7 day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks. Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020. MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keywords: CPI-0610, JAKi treatment-naïve, MANIFEST-2, myelofibrosis, pelabresib

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Authors: Rebeca V. Tholen, Elaine Bundy

Abstract:

Background: Liver transplantation (LT) is considered the only curative treatment for end-stage liver disease Background: Liver transplantation (LT) is considered the only curative treatment for end-stage liver disease (ESLD). The effects of alcoholism can cause irreversible liver damage, cirrhosis and subsequent liver failure. Alcohol relapse after transplant occurs in 20-50% of patients and increases the risk for recurrent cirrhosis, organ rejection, and graft failure. Alcohol relapse after transplant has been identified as a problem among liver transplant recipients at a large urban academic transplant center in the United States. Transplantation will reverse the complications of ESLD, but it does not treat underlying alcoholism or reduce the risk of relapse after transplant. The purpose of this quality improvement project is to implement and evaluate the effectiveness of a High-Risk Alcoholism Relapse (HRAR) Scale to screen and identify patients at high-risk for alcohol relapse after receiving an LT. Methods: The HRAR Scale is a predictive tool designed to determine the severity of alcoholism and risk of relapse after transplant. The scale consists of three variables identified as having the highest predictive power for early relapse including, daily number of drinks, history of previous inpatient treatment for alcoholism, and the number of years of heavy drinking. All adult liver transplant recipients at a large urban transplant center were screened with the HRAR Scale prior to hospital discharge. A zero to two ordinal score is ranked for each variable, and the total score ranges from zero to six. High-risk scores are between three to six. Results: Descriptive statistics revealed 25 patients were newly transplanted and discharged from the hospital during an 8-week period. 40% of patients (n=10) were identified as being high-risk for relapse and 60% low-risk (n=15). The daily number of drinks were determined by alcohol content (1 drink = 15g of ethanol) and number of drinks per day. 60% of patients reported drinking 9-17 drinks per day, and 40% reported ≤ 9 drinks. 50% of high-risk patients reported drinking ≥ 25 years, 40% for 11-25 years, and 10% ≤ 11 years. For number of inpatient treatments for alcoholism, 50% received inpatient treatment one time, 20% ≥ 1, and 30% reported never receiving inpatient treatment. Findings reveal the importance and value of a validated screening tool as a more efficient method than other screening methods alone. Integration of a structured clinical tool will help guide the drinking history portion of the psychosocial assessment. Targeted interventions can be implemented for all high-risk patients. Conclusions: Our findings validate the effectiveness of utilizing the HRAR scale to screen and identify patients who are a high-risk for alcohol relapse post-LT. Recommendations to help maintain post-transplant sobriety include starting a transplant support group within the organization for all high-risk patients. (ESLD). The effects of alcoholism can cause irreversible liver damage, cirrhosis and subsequent liver failure. Alcohol relapse after transplant occurs in 20-50% of patients, and increases the risk for recurrent cirrhosis, organ rejection, and graft failure. Alcohol relapse after transplant has been identified as a problem among liver transplant recipients at a large urban academic transplant center in the United States. Transplantation will reverse the complications of ESLD, but it does not treat underlying alcoholism or reduce the risk of relapse after transplant. The purpose of this quality improvement project is to implement and evaluate the effectiveness of a High-Risk Alcoholism Relapse (HRAR) Scale to screen and identify patients at high-risk for alcohol relapse after receiving a LT. Methods: The HRAR Scale is a predictive tool designed to determine severity of alcoholism and risk of relapse after transplant. The scale consists of three variables identified as having the highest predictive power for early relapse including, daily number of drinks, history of previous inpatient treatment for alcoholism, and the number of years of heavy drinking. All adult liver transplant recipients at a large urban transplant center were screened with the HRAR Scale prior to hospital discharge. A zero to two ordinal score is ranked for each variable, and the total score ranges from zero to six. High-risk scores are between three to six. Results: Descriptive statistics revealed 25 patients were newly transplanted and discharged from the hospital during an 8-week period. 40% of patients (n=10) were identified as being high-risk for relapse and 60% low-risk (n=15). The daily number of drinks were determined by alcohol content (1 drink = 15g of ethanol) and number of drinks per day. 60% of patients reported drinking 9-17 drinks per day, and 40% reported ≤ 9 drinks. 50% of high-risk patients reported drinking ≥ 25 years, 40% for 11-25 years, and 10% ≤ 11 years. For number of inpatient treatments for alcoholism, 50% received inpatient treatment one time, 20% ≥ 1, and 30% reported never receiving inpatient treatment. Findings reveal the importance and value of a validated screening tool as a more efficient method than other screening methods alone. Integration of a structured clinical tool will help guide the drinking history portion of the psychosocial assessment. Targeted interventions can be implemented for all high-risk patients. Conclusions: Our findings validate the effectiveness of utilizing the HRAR scale to screen and identify patients who are a high-risk for alcohol relapse post-LT. Recommendations to help maintain post-transplant sobriety include starting a transplant support group within the organization for all high-risk patients.

Keywords: alcoholism, liver transplant, quality improvement, substance abuse

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral, dental, and general health and well-being; where it normally bathes the oral cavity acting as a clearing agent. This becomes more apparent when the amount and quality of saliva are significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the 5th most common malignancy worldwide, during which the salivary glands are included within the radiation field/zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely as they become malnourished and experience a significant decrease in their QoL. Accordingly, the formulation of a radio-protection/-prevention modality and development of an alternative Rx to restore damaged salivary gland tissue is eagerly awaited and highly desirable. Objectives: Assess the pre-clinical radio-protective effect and reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs, followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: cancer, head and neck, oncology, drug development, drug delivery systems, nanotechnology, nanoncology

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral and dental health (consequently, general health and well-being). Where it normally bathes the oral cavity and acts as a clearing agent. This becomes more apparent when the amount and quality of salivare significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the fifth most common malignancy worldwide, during which the salivary glands are included within the radiation field or zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely because they become malnourished and experience a significant decrease in their quality of life. Accordingly, the development of an alternative treatment to restore or regenerate damaged salivary gland tissue is eagerly awaited. Likewise, the formulation of a radioprotection modality and early damage prevention strategy is also highly desirable. Objectives: To assess the pre-clinical radio-protective effect as well as the reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned in this experimental work for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs (in solution and powder formats), followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy (revised from our previous 15Gy model) was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: saliva, head and neck cancer, nanotechnology, controlled drug delivery, xerostomia, mucositis, biopolymers, innovation

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