Search results for: group charter

Authors: Lauren B. Birney

Abstract:

The envisioned long-term outcome of this three-year research, and implementation plan is for 1) teachers and students to design and build their own computational models of real-world environmental-human health phenomena occurring within the context of the “Human Harbor” and 2) project researchers to evaluate the degree to which these integrated Computer Science (CS) education experiences in New York City (NYC) public school classrooms (PreK-12) impact students’ computational-technical skill development, job readiness, career motivations, and measurable abilities to understand, articulate, and solve the underlying phenomena at the center of their models. This effort builds on the partnership’s successes over the past eight years in developing a benchmark Model of restoration-based Science, Technology, Engineering, and Math (STEM) education for urban public schools and achieving relatively broad-based implementation in the nation’s largest public school system. The Billion Oyster Project Curriculum and Community Enterprise for Restoration Science (BOP-CCERS STEM + Computing) curriculum, teacher professional developments, and community engagement programs have reached more than 200 educators and 11,000 students at 124 schools, with 84 waterfront locations and Out of School of Time (OST) programs. The BOP-CCERS Partnership is poised to develop a more refined focus on integrating computer science across the STEM domains; teaching industry-aligned computational methods and tools; and explicitly preparing students from the city’s most under-resourced and underrepresented communities for upwardly mobile careers in NYC’s ever-expanding “digital economy,” in which jobs require computational thinking and an increasing percentage require discreet computer science technical skills. Project Objectives include the following: 1. Computational Thinking (CT) Integration: Integrate computational thinking core practices across existing middle/high school BOP-CCERS STEM curriculum as a means of scaffolding toward long term computer science and computational modeling outcomes. 2. Data Science and Data Analytics: Enabling Researchers to perform interviews with Teachers, students, community members, partners, stakeholders, and Science, Technology, Engineering, and Mathematics (STEM) industry Professionals. Collaborative analysis and data collection were also performed. As a centerpiece, the BOP-CCERS partnership will expand to include a dedicated computer science education partner. New York City Department of Education (NYCDOE), Computer Science for All (CS4ALL) NYC will serve as the dedicated Computer Science (CS) lead, advising the consortium on integration and curriculum development, working in tandem. The BOP-CCERS Model™ also validates that with appropriate application of technical infrastructure, intensive teacher professional developments, and curricular scaffolding, socially connected science learning can be mainstreamed in the nation’s largest urban public school system. This is evidenced and substantiated in the initial phases of BOP-CCERS™. The BOP-CCERS™ student curriculum and teacher professional development have been implemented in approximately 24% of NYC public middle schools, reaching more than 250 educators and 11,000 students directly. BOP-CCERS™ is a fully scalable and transferable educational model, adaptable to all American school districts. In all settings of the proposed Phase IV initiative, the primary beneficiary group will be underrepresented NYC public school students who live in high-poverty neighborhoods and are traditionally underrepresented in the STEM fields, including African Americans, Latinos, English language learners, and children from economically disadvantaged households. In particular, BOP-CCERS Phase IV will explicitly prepare underrepresented students for skilled positions within New York City’s expanding digital economy, computer science, computational information systems, and innovative technology sectors.

Keywords: computer science, data science, equity, diversity and inclusion, STEM education

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Authors: Nahashon Mwirigi

Abstract:

The management of HIV/AIDS is a global challenge, demanding precise tools to predict disease progression and guide tailored treatment. CD4 cell count dynamics, a crucial immune function indicator, play an essential role in understanding HIV/AIDS progression and enhancing patient care through effective modeling. While several models assess disease progression, existing methods often fall short in capturing the complex, non-linear nature of HIV/AIDS, especially across diverse demographics. A need exists for models that balance predictive accuracy with clinical applicability, enabling individualized care strategies based on patient-specific progression rates. This study utilizes patient data from Kenyatta National Hospital (2003–2014) to model HIV/AIDS progression across six CD4-defined states. The Exponential, 2-Parameter Weibull, and 3-Parameter Weibull models are employed to analyze failure rates and explore progression patterns by age and gender. Model selection is based on Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC) to identify models best representing disease progression variability across demographic groups. The 3-Parameter Weibull model emerges as the most effective, accurately capturing HIV/AIDS progression dynamics, particularly by incorporating delayed progression effects. This model reflects age and gender-specific variations, offering refined insights into patient trajectories and facilitating targeted interventions. One key finding is that older patients progress more slowly through CD4-defined stages, with a delayed onset of advanced stages. This suggests that older patients may benefit from extended monitoring intervals, allowing providers to optimize resources while maintaining consistent care. Recognizing slower progression in this demographic helps clinicians reduce unnecessary interventions, prioritizing care for faster-progressing groups. Gender-based analysis reveals that female patients exhibit more consistent progression, while male patients show greater variability. This highlights the need for gender-specific treatment approaches, as men may require more frequent assessments and adaptive treatment plans to address their variable progression. Tailoring treatment by gender can improve outcomes by addressing distinct risk patterns in each group. The model’s ability to account for both accelerated and delayed progression equips clinicians with a robust tool for estimating the duration of each disease stage. This supports individualized treatment planning, allowing clinicians to optimize antiretroviral therapy (ART) regimens based on demographic factors and expected disease trajectories. Aligning ART timing with specific progression patterns can enhance treatment efficacy and adherence. The model also has significant implications for healthcare systems, as its predictive accuracy enables proactive patient management, reducing the frequency of advanced-stage complications. For resource limited providers, this capability facilitates strategic intervention timing, ensuring that high-risk patients receive timely care while resources are allocated efficiently. Anticipating progression stages enhances both patient care and resource management, reinforcing the model’s value in supporting sustainable HIV/AIDS healthcare strategies. This study underscores the importance of models that capture the complexities of HIV/AIDS progression, offering insights to guide personalized, data-informed care. The 3-Parameter Weibull model’s ability to accurately reflect delayed progression and demographic risk variations presents a valuable tool for clinicians, supporting the development of targeted interventions and resource optimization in HIV/AIDS management.

Keywords: HIV/AIDS progression, 3-parameter Weibull model, CD4 cell count stages, antiretroviral therapy, demographic-specific modeling

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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: Oluwaseun Adeleke, Samuel O. Ikani, Fidelis Edet, Anthony Nwala, Mopelola Raji, Simeon Christian Chukwu

Abstract:

Background The Delivering Innovations in Selfcare (DISC) project promotes universal access to quality selfcare services beginning with subcutaneous depot medroxy progesterone acetate (DMPA-SC) contraceptive self-injection (SI) option. Self-inject (SI) offers women a highly effective and convenient option that saves them frequent trips to providers. Its increased use has the potential to improve the efficiency of an overstretched healthcare system by reducing provider workloads. State Social and Behavioral Change Communications (SBCC) Officers lead project demand creation and service delivery innovations that have resulted in significant increases in SI uptake among women who opt for injectables. Strategies Service Delivery Innovations The implementation of the "Moment of Truth (MoT)" innovation helped providers overcome biases and address client fear and reluctance to self-inject. Bi-annual program audits and supportive mentoring visits helped providers retain their competence and motivation. Proper documentation, tracking, and replenishment of commodities were ensured through effective engagement with State Logistics Units. The project supported existing state monitoring and evaluation structures to effectively record and report subcutaneous depot medroxy progesterone acetate (DMPA-SC) service utilization. Demand creation Innovations SBCC Officers provide oversight, routinely evaluate performance, trains, and provides feedback for the demand creation activities implemented by community mobilizers (CMs). The scope and intensity of training given to CMs affect the outcome of their work. The project operates a demand creation model that uses a schedule to inform the conduct of interpersonal and group events. Health education sessions are specifically designed to counter misinformation, address questions and concerns, and educate target audience in an informed choice context. The project mapped facilities and their catchment areas and enlisted the support of identified influencers and gatekeepers to enlist their buy-in prior to entry. Each mobilization event began with pre-mobilization sensitization activities, particularly targeting male groups. Context-specific interventions were informed by the religious, traditional, and cultural peculiarities of target communities. Mobilizers also support clients to engage with and navigate online digital Family Planning (FP) online portals such as DiscoverYourPower website, Facebook page, digital companion (chat bot), interactive voice response (IVR), radio and television (TV) messaging. This improves compliance and provides linkages to nearby facilities. Results The project recorded 136,950 self-injection (SI) visits and a self-injection (SI) proportion rate that increased from 13 percent before the implementation of interventions in 2021 to 62 percent currently. The project cost-effectively demonstrated catalytic impact by leveraging state and partner resources, institutional platforms, and geographic scope to scale up interventions. The project also cost effectively demonstrated catalytic impact by leveraging on the state and partner resources, institutional platforms, and geographic scope to sustainably scale-up these strategies. Conclusion Using evidence-informed iterations of service delivery and demand creation models have been useful to significantly drive self-injection (SI) uptake. It will be useful to consider this implementation model during program design. Contemplation should also be given to systematic and strategic execution of strategies to optimize impact.

Keywords: family planning, contraception, DMPA-SC, self-care, self-injection, innovation, service delivery, demand creation.

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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: Julie M. Novak, Simone K. Brennan, Lacey Brim

Abstract:

Undergraduate medical education (UME) curriculum notably addresses micro-level communications (e.g., patient-provider, intercultural, inter-professional), yet frequently under-examines the role and impact of organizational communication, a more macro-level. Organizational communication, however, functions as foundation and through systemic structures of an organization and thereby serves as hidden curriculum and influences learning experiences and outcomes. Yet, little available research exists fully examining how students experience organizational communication while in medical school. Extant literature and best practices provide insufficient guidance for UME programs, in particular. The purpose of this study was to map and examine current organizational communication systems and processes in a UME program. Employing a phenomenology-grounded and participatory approach, this study sought to understand the organizational communication system from medical students' perspective. The research team consisted of a core team and 13 medical student co-investigators. This research employed multiple methods, including focus groups, individual interviews, and two surveys (one reflective of focus group questions, the other requesting students to submit ‘examples’ of communications). To provide context for student responses, nonstudent participants (faculty, administrators, and staff) were sampled, as they too express concerns about communication. Over 400 students across all cohorts and 17 nonstudents participated. Data were iteratively analyzed and checked for triangulation. Findings reveal the complex nature of organizational communication and student-oriented communications. They reveal program-impactful strengths, weaknesses, gaps, and tensions and speak to the role of organizational communication practices influencing both climate and culture. With regard to communications, students receive multiple, simultaneous communications from multiple sources/channels, both formal (e.g., official email) and informal (e.g., social media). Students identified organizational strengths including the desire to improve student voice, and message frequency. They also identified weaknesses related to over-reliance on emails, numerous platforms with inconsistent utilization, incorrect information, insufficient transparency, assessment/input fatigue, tacit expectations, scheduling/deadlines, responsiveness, and mental health confidentiality concerns. Moreover, they noted gaps related to lack of coordination/organization, ambiguous point-persons, student ‘voice-only’, open communication loops, lack of core centralization and consistency, and mental health bridges. Findings also revealed organizational identity and cultural characteristics as impactful on the medical school experience. Cultural characteristics included program size, diversity, urban setting, student organizations, community-engagement, crisis framing, learning for exams, inefficient bureaucracy, and professionalism. Moreover, they identified system structures that do not always leverage cultural strengths or reduce cultural problematics. Based on the results, opportunities for productive change are identified. These include leadership visibly supporting and enacting overall organizational narratives, making greater efforts in consistently ‘closing the loop’, regularly sharing how student input effects change, employing strategies of crisis communication more often, strengthening communication infrastructure, ensuring structures facilitate effective operations and change efforts, and highlighting change efforts in informational communication. Organizational communication and communications are not soft-skills, or of secondary concern within organizations, rather they are foundational in nature and serve to educate/inform all stakeholders. As primary stakeholders, students and their success directly affect the accomplishment of organizational goals. This study demonstrates how inquiries about how students navigate their educational experience extends research-based knowledge and provides actionable knowledge for the improvement of organizational operations in UME.

Keywords: medical education programs, organizational communication, participatory research, qualitative mixed methods

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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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