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Phase 0 Feasibility and Design of Mobile Health Applications for Use in Rural Settings
Get PDFBackground. Mobile Health (mHealth) interventions, when meant to serve as decision support, require an in-depth investigation of current workflows and decisional needs to ensure future usability and acceptability. Rural groups were prioritized due to their limited healthcare access, and therefore, their increased need for interventions like mHealth apps that address health disparities.
Objective. To assess the decisional needs of parents/caregivers and/or Healthcare Providers (HCPs) in rural areas regarding emergencies with children with medical complexity (CMC, Project 1), COVID-19 vaccination (Project 2), and HPV and COVID-19 vaccination (Project 3).
Methods. Parents and HCPs were approached through various methods for participation, primarily by phone. Based on their background, they either participated in a focus group or key informant interview (KIIs). These interviews were de-identified, transcribed, analyzed for themes, and summarized into recommendations for future mHealth app changes.
Results. Our study of rural parents and emergency medical providers (Project 1) revealed that respondents found the Emergency Information Form (EIF) to be an easy way to engage parents and emergency personnel about the specifics of a CMC’s care before or during an emergency. They also identified areas for improvement regarding the organization, deployment, and optimal usage of the EIF in practice.
Our study of high-priority parents (Project 2) revealed that COVID-19 vaccine hesitancy encompasses multi-factorial concerns among parents/caregivers. These encompassed themes of vaccine newness, over-politicization, concerns about social pressure, and possible negative side effects.
Our study of rural parents and HCPs (Project 3) revealed that rural parents/caregivers and some HCPs were less familiar with the HPV vaccine, as compared to COVID-19 vaccines, and actively wanted more information on the vaccine. Parents/caregivers also reported that, beyond rapport with their HCP, they value external infographics, consistent vaccine discussions while they are not ready to vaccinate, and straightforward answers. From these results, a mHealth tool was constructed.
Conclusion. Phase 0 research to determine the information needs and workflows of parents/caregivers and healthcare providers can provide critical insights for mHealth intervention design and delivery, thus potentially increasing the effectiveness of these interventions in real-world settings
The Impact of Aging on Fibroblast Gene Expression in Post-Extraction Wound Healing: A Single-Cell RNA Sequencing Study
Get PDFWound healing is slower in aged patients. Immediately after tooth extraction, fibroblasts are activated to rebuild the ECM, which is later remodeled through the expression of MMPs. Gene expression may be altered in fibroblasts of aged patients leading to deficiencies in ECM deposition and the recruitment and proliferation of immune cells, resulting in a slow-healing fibrotic wound.
Using scRNA-seq, soft tissue was profiled from two healthy patients: one young and one aged at the time of tooth extraction. Two weeks post-extraction, a second soft tissue sample was harvested. Differentially expressed genes were used to identify enriched pathways for each patient. Six cell clusters were identified and assigned based on the gene profiles of each cluster. Three subclusters of fibroblasts were identified: pro-inflammatory fibroblasts (PIFs), anti-inflammatory fibroblasts (AIFs), and gingival mesenchymal stem cells (GMSC).
In the young patient, AIFs were enriched for pathways involved in maintaining the ECM. The expression profile in young PIFs exhibited pro-inflammatory pathways, while the aged PIFs were enriched for ECM pathways like AIFs. The GMSCs of both patients had a significant overlap in differentially expressed genes for cellular homeostasis. This may mean that GMSCs resist age-related changes and could be a source of therapy. At two weeks, the aged patient still expressed genes for ECM production and fibrosis, while the young patient expressed genes associated with proliferation. This indicates that the aged patient was in a prolonged state of inflammation and fibrosis. Differences in fibroblast gene expression suggest that fibroblasts in aged patients may contribute towards a slow-healing fibrotic wound
Targeting Transitioning Lung Monocytes/Macrophages as Treatment Strategies in Lung Disease Related to Environmental Exposures
Get PDFBackground: Environmental/occupational exposures cause significant lung diseases. Agricultural organic dust extracts (ODE) and bacterial component lipopolysaccharide (LPS) induce recruited,transitioning murine lung monocytes/macrophages, yet their cellular role remains unclear.
Methods: CCR2 RFP+ mice were intratracheally instilled with high concentration ODE (25%), LPS (10 μg), or gram-positive peptidoglycan (PGN, 100 μg) for monocyte/macrophage cell-trafficking studies. CCR2 knockout (KO) mice and administration of intravenous clodronate liposomes strategies were employed to reduce circulating monocytes available for lung recruitment following LPS exposure.Lung tissues and bronchoalveolar lavage fluid (BALF) were collected. Pro-inflammatory and/or pro-fibrotic cytokines, chemokines, and lung extracellular matrix mediators were quantitated by ELISA. Infiltrating lung cells including monocyte/macrophage subpopulations, neutrophils, and lymphocytes were characterized by flow cytometry.Lung histopathology, collagen content, vimentin, and post-translational protein citrullination and malondialdehyde acetaldehyde (MAA) modification were quantitated. Parametric statistical tests (one-way ANOVA, Tukey\u27s multiple comparison) and nonparametric statistical (Kruskal-Wallis, Dunn\u27s multiple comparison) tests were used following Shapiro-Wilk testing for normality.
Results: Intratracheal instillation of ODE, LPS, or PGN robustly induced the recruitment of inflammatory CCR2+ CD11cintCD11bhi monocytes/macrophages and both CCR2+ and CCR2- CD11c-CD11bhi monocytes at 48 h. There were also increases in CCR2+ CD4+ and CD8+ T cells and NK cells. Despite reductions in LPS-induced lung infiltrating CD11cintCD11bhi cells (54% reduction), CCR2 knockout (KO) mice were not protected against LPS-induced inflammatory and pro-fibrotic consequences. Instead, compensatory increases in lung neutrophils and CCL2 and CCL7 release occurred. In contrast, the depletion of circulating monocytes through the administration of intravenous clodronate (vs. vehicle) liposomes 24 h prior to LPS exposure reduced LPS-induced infiltrating CD11cintCD11bhi monocyte-macrophage subpopulation by 59% without compensatory changes in other cell populations. Clodronate liposome pre-treatment significantly reduced LPS-induced IL-6 (66% reduction), matrix metalloproteinases (MMP)-3 (36%), MMP-8 (57%), tissue inhibitor of metalloproteinases (61%), fibronectin (38%), collagen content (22%), and vimentin (40%). LPS-induced lung protein citrullination and MAA modification, post-translational modifications implicated in lung disease, were reduced (39% and 48%) with clodronate vs. vehicle liposome.
Conclusion: Highly concentrated environmental/occupational exposures induced the recruitment of CCR2+ and CCR2-transitioning monocyte-macrophage and monocyte subpopulations and targeting peripheralmonocytes may reduce the adverse lung consequences resulting from exposures to LPS-enriched inhalants
Addressing Equitable Access in a Safety-Net Hospital System: An Implementation Framework
Get PDFAcute care organizations face a significant challenge in effectively implementing health equity programs, particularly in rural areas where guidance is often lacking. Despite abundant literature focusing on health outcomes, there remains a noticeable dearth of published data on implementing health equity initiatives. In response to this gap, I present a comprehensive analysis that utilizes readily available, open-sourced data to address this critical issue.
A thorough assessment of the demographic characteristics of acute care facilities within the catchment regions was conducted based on data from reputable sources such as the US Census Bureau, the American Community Survey, and the County Health Rankings. While specific to a New York health system, this research offers a replicable framework that can be adapted with minimal resources to suit various institutional settings.
This approach emphasizes the importance of utilizing performance improvement models and techniques to initiate and sustainably evaluate health equity and access initiatives. By leveraging ubiquitous data sources and adopting a population-targeted approach, institutions can take proactive steps toward reducing health disparities and promoting equitable healthcare delivery, particularly in underserved rural communities.
This research fills a critical gap in the literature and provides actionable insights for acute care organizations seeking to enhance their commitment to health equity. Through strategic implementation and ongoing evaluation, institutions can be pivotal in advancing equitable healthcare practices and improving outcomes for all individuals within their catchment areas
Discovery of an Aldo-Keto Reductase 1C3 (AKR1C3) Degrader
Get PDFAldo-keto reductase 1C3 (AKR1C3) is a protein upregulated in prostate cancer, hematological malignancies, and other cancers where it contributes to proliferation and chemotherapeutic resistance. Androgen receptor splice variant 7 (ARv7) is the most common mutation of the AR receptor that confers resistance to clinical androgen receptor signalling inhibitors in castration-resistant prostate cancer. AKR1C3 interacts with ARv7 promoting stabilization. Herein we report the discovery of the first-in-class AKR1C3 Proteolysis-Targeting Chimera (PROTAC) degrader. This first-generation degrader potently reduced AKR1C3 expression in 22Rv1 prostate cancer cells with a half-maximal degradation concentration (DC50) of 52 nM. Gratifyingly, concomitant degradation of ARv7 was observed with a DC50 = 70 nM, along with degradation of the AKR1C3 isoforms AKR1C1 and AKR1C2 to a lesser extent. This compound represents a highly useful chemical tool and a promising strategy for prostate cancer intervention
Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Get PDFChronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacologic agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NFκB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its antileukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NFκB signaling and the UPR, culminating in profound antitumor properties independent of TME stimuli.
SIGNIFICANCE: SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NFκB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NFκB pathway and UPR) highlighting its use in drug-resistant CLL
Dual Gallium Drug Treatment Against Carbapenem-Resistant Klebsiella Pneumoniae: Efficacy and Potential Mechanism(s) of Action and Resistance
Get PDFKlebsiella pneumoniae (KLP) is a Gram-negative pathogen that can be highly antibiotic-resistant. Our group has worked with gallium-based compounds as a means of treating bacterial infections. Here the possible mechanism is investigated for dual therapy comprised of gallium nitrate (Ga(NO3)3) and gallium protoporphyrin (GaPP) on KLP. It is found that in vitro the combination of Ga(NO3)3 and GaPP is synergistic against KLP. The in vivo efficacy is of the dual therapy is additionally tested by treating pulmonary KLP infections in mice. Much greater effectiveness are observed in bacterial clearance and survival of mice receiving the dual therapy than that of singly treated or untreated mice. It is found that in in vitro the dual therapy increased reactive oxygen stress in treated bacteria. Combination therapy impacted KLP catalase, but not superoxide dismutase (SOD) activity. Finally, alterations in KLP genes encoding 6-phosphogluconate phosphatase or cytochrome C assembly protein are found to be associated with increased resistance to combination gallium therapy, raising the MIC to both Ga(NO3)3 and GaPP by 4-fold. These cumulative data lend validation to the potential for the use of Ga(NO3)3 and GaPP combination therapy against KLP and suggest that increased oxidative stress is involved in the mechanism of action
Resilience of Mental Health Services Amidst Ebola Disease Outbreaks in Africa
No full textINTRODUCTION: Health systems including mental health (MH) systems are resilient if they protect human life and produce better health outcomes for all during disease outbreaks or epidemics like Ebola disease and their aftermaths. We explored the resilience of MH services amidst Ebola disease outbreaks in Africa; specifically, to (i) describe the pre-, during-, and post-Ebola disease outbreak MH systems in African countries that have experienced Ebola disease outbreaks, (ii) determine the prevalence of three high burden MH disorders and how those prevalences interact with Ebola disease outbreaks, and, (iii) describe the resilience of MH systems in the context of these outbreaks.
METHODS: This was a scoping review employing an adapted PRISMA statement. We conducted a five-step Boolean strategy with both free text and Medical Subject Headings (MeSH) to search 9 electronic databases and also searched WHO MINDbank and MH Atlas.
RESULTS: The literature search yielded 1,230 publications. Twenty-five studies were included involving 13,449 participants. By 2023, 13 African nations had encountered a total of 35 Ebola outbreak events. None of these countries had a metric recorded in MH Atlas to assess the inclusion of MH in emergency plans. The three highest-burden outbreak-associated MH disorders under the MH and Psychosocial Support (MHPSS) framework were depression, post-traumatic stress disorder (PTSD), and anxiety with prevalence ranges of 1.4-7%, 2-90%, and 1.3-88%, respectively. Furthermore, our analysis revealed a concerning lack of resilience within the MH systems, as evidenced by the absence of pre-existing metrics to gauge MH preparedness in emergency plans. Additionally, none of the studies evaluated the resilience of MH services for individuals with pre-existing needs or examined potential post-outbreak degradation in core MH services.
DISCUSSION: Our findings revealed an insufficiency of resilience, with no evaluation of services for individuals with pre-existing needs or post-outbreak degradation in core MH services. Strengthening MH resilience guided by evidence-based frameworks must be a priority to mitigate the long-term impacts of epidemics on mental well-being
