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Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapy
Get PDFRheumatoid arthritis (RA) primarily affects the joints but can also affect multiple organs and profoundly impacts patients’ ability to carry out daily activities, mental health, and life expectancy. Current treatments for RA are limited in terms of duration, efficacy, and adverse effects. PD-L1 is a checkpoint protein that plays important roles in immune regulation and has been implicated in the initiation and progression of multiple autoimmune diseases. In a previous study, we demonstrated that intra-articular injection with adeno-associated virus (AAV) vectors encoding wild type PD-L1 improved local inflammation in the joint in the collagen-induced arthritis (CIA) mouse model of RA. To further improve efficacy, we explored AAV-mediated delivery of the soluble PD-L1 (sPD-L1) to CIA mice. After intra-articular injection of AAV6 vectors expressing the optimal isoform of sPD-L1 (shPD-L1), more potency was observed when compared to wild type PD-L1, with a lower dose of AAV6/shPD-L1 needed for arthritis improvement. To study the therapeutic effect of systemic expression of sPD-L1, we administered AAV8/shPD-L1 gene therapy in CIA mice via retro-orbital injection and found significant improvements in joint inflammation and paw swelling, exhibiting similar phenotypes to that in naïve mice. The levels of total immunoglobulin and anti-collagen specific antibodies were lower in AAV8/shPD-L1 treated CIA mice than those in controls. The levels of pro-inflammatory cytokines in blood were also significantly decreased in shPD-L1 treated mice. Additionally, T cell apoptosis rates in the spleen showed a 2-fold increase in treated mice. Finally, we investigated the therapeutic effect of AAV/shPD-L1 via intramuscular injection. After injection of AAV6/shPD-L1, decreased paw swelling, reduced joint inflammation, and lower levels of pro-inflammatory cytokines in blood were achieved. The therapeutic effect of shPD-L1 was dose dependent via intramuscular treatment with AAV vectors. In conclusion, the findings in this study suggest that intra-articular injection of AAV vectors encoding sPD-L1 results in greater therapeutic benefit on arthritis, and systemic AAV/sPD-L1 is able to block the development of inflammatory arthritis with inhibition of the systemic immune response, underlining the potential of gene therapy with systemic delivery of shPD-L1 via AAV vectors in RA
Identifying engagement strategies for Hispanic youth with anxiety: A youth-centered, Design-Thinking approach
Get PDFAnxiety is the most common and widespread mental health disorder impacting youth between the ages of 10-19. Youth of color including Hispanic youth are disproportionately impacted. Fewer than 20% of youth of color who need mental health services are receiving them. However, we know relatively little about how to best engage Hispanic youth to increase their use of mental health services. The aims of this study were to better understand the personal, environmental, and behavioral factors that impact Hispanic adolescents help-seeking behaviors and to identify the important criteria needed to develop an appealing intervention that would increase engagement with mental health services. This study used a Design Thinking process-a participatory research approach that included qualitative and engaged methods. In-depth interviews (n = 8) and a Design Thinking workshop (n = 11 participants) were conducted with Hispanic youth with anxiety residing in the San Francisco Bay Area. In-depth interviews were coded using Social Cognitive Theory to identify key themes that impact an adolescent's decision to seek help. The 90-minute workshop included ideation and Design Thinking activities including personas, mind-mapping, and analytical problem-solving to identify the most important tools and strategies that could be used to manage anxiety. The study identified several themes that directly impact program design, including barriers to seeking help for anxiety, coping strategies, sources of support, and specific program ideas. The findings revealed that Hispanic youth want a culturally relevant technology-based program that provides easily accessible educational information and coping strategies delivered in an engaging format that also facilitates mental health support with a trusted adult. The results reinforce the need to develop culturally inclusive and innovative programs designed specifically for priority populations to increase youth engagement with mental health services
A randomized, double-blind, Phase 1, single- and multiple-dose placebo-controlled study of the safety and pharmacokinetics of IN-006, an inhaled antibody treatment for COVID-19 in healthy volunteers
Get PDFBACKGROUND: Although COVID-19 is predominantly a respiratory tract infection, current antibody treatments are administered by systemic dosing. We hypothesize that inhaled delivery of a monoclonal antibody may be a more effective and convenient route. We investigated the safety, tolerability, and pharmacokinetics of IN-006, a reformulation of regdanvimab for nebulized delivery by a handheld nebulizer. METHODS: A Phase 1 study was conducted in healthy volunteers aged 18-55 a Phase 1 unit in Melbourne, Australia (ACTRN12621001235897). Study staff and participants were blinded to treatment assignment, except for pharmacy staff preparing the study drug. The ratio of active:placebo randomization to each cohort was set at 3:1. The primary outcomes were safety and tolerability. Exploratory outcomes were pharmacokinetics of IN-006 in nasal fluid and serum. FINDINGS: Twenty-three participants were enrolled and randomized across two single dose and one multiple dose cohorts (30 mg or 90 mg single nebulized dose, or seven daily 90 mg doses). There were no serious adverse events. All enrolled participants completed the study without treatment interruption or discontinuation. All treatment-emergent adverse events were transient, non-dose dependent, and graded mild to moderate in severity. Nebulization was well-tolerated and completed in an average of 6 min. Geometric mean nasal fluid concentrations of IN-006 in the multiple dose cohort were 739.8 μg/mL at 30 min after dosing and 1.2 μg/mL at 22 h. Geometric mean serum levels in the multiple dose cohort peaked at 0.51 μg/mL 3 days after the final dose. INTERPRETATION: IN-006 was well-tolerated and achieved concentrations in the respiratory tract orders of magnitude above the IC50 range typical of antiviral mAbs. These data support further development of nebulized delivery of antiviral mAbs for respiratory infectious disease. FUNDING: This work was funded by the U.S. Army Medical Research and Development Command (W81XWH-15-9-0001) and regdanvimab was provided by Celltrion, Inc
Two new positive psychosocial measures for persons living with dementia
Get PDFINTRODUCTION: Differences in adaptive strategies used by individuals and families living with dementia have the potential to impact day-to-day well-being. The Living Well Inventory for Dementia (LWI-D) is a new measure to capture these strategies and to illuminate new options to support families living with dementia. The Quality of Day Scale (QODS) is a new measure to capture global well-being in persons based on a shorter temporal frame than traditional quality of life measures. This article summarizes the initial evaluation of the LWI-D and the QODS for face validity, content validity, and user acceptability. METHODS: Initial acceptability and feasibility testing were conducted with a sample of 17 community-dwelling individuals with early-stage dementia (Montreal Cognitive Assessment [MoCA] scores of 12-30).After revision and optimization of the two measures, a second pilot test was conducted with a sample of 30 dyads (persons living with dementia and family caregivers) in nursing home, assisted living, and community settings. RESULTS: Data from both pilot studies are reported including item analysis and quantitative and qualitative results. Outcomes related to convergent validity between the LWI-D and the QODS with measures of positive affect-balance, quality of life, and well-being are presented. Within-dyad differences in ratings on both measures are discussed. DISCUSSION: The LWI-D and the QODS are developing measures that warrant further testing and may enhance the ability to (1) identify strengths in living well with dementia, and (2) identify and test new interventions to bolster care and support. Highlights: This article describes the process used to develop and test two new measures for research and clinical practice related to positive psychosocial approaches to dementia.The measures were developed with a team that included persons living with Alzheimer's disease as co-researchers in the process.A novel method of human-centered design was used to cultivate deep empathy, generate options, and conduct small, iterative tests of prototype measures
Development and assessment of a sustainable PhD internship program supporting diverse biomedical career outcomes
Get PDFA doctoral-level internship program was developed at the University of North Carolina at Chapel Hill with the intent to create customizable experiential learning opportunities for biomedical trainees to support career exploration, preparation, and transition into their postgraduate professional roles. We report the outcomes of this program over a 5-year period. During that 5-year period, 123 internships took place at over 70 partner sites, representing at least 20 academic, for-profit, and non-profit career paths in the life sciences. A major goal of the program was to enhance trainees’ skill development and expertise in careers of interest. The benefits of the internship program for interns, host/employer, and supervisor/principal investigator were assessed using a mixed-methods approach, including surveys with closed- and open-ended responses as well as focus group interviews. Balancing stakeholder interests is key to creating a sustainable program with widespread support; hence, the level of support from internship hosts and faculty members were the key metrics analyzed throughout. We hypothesized that once a successful internship program was implemented, faculty culture might shift to be more accepting of internships; indeed, the data quantifying faculty attitudes support this. Furthermore, host motivation and performance expectations of interns were compared with results achieved, and this data revealed both expected and surprising benefits to hosts. Data suggests a myriad of benefits for each stakeholder group, and themes are cataloged and discussed. Program outcomes, evaluation data, policies, resources, and best practices developed through the implementation of this program are shared to provide resources that facilitate the creation of similar internship programs at other institutions. Program development was initially spurred by National Institutes of Health pilot funding, thereafter, successfully transitioning from a grant-supported model, to an institutionally supported funding model to achieve long-term programmatic sustainability
Health care experiences of individuals accessing or undergoing in vitro fertilization (IVF) in the U.S.: a narrative review of qualitative studies
Get PDFBackground: In vitro fertilization (IVF) is an increasingly common method of assisted reproduction given the high rates of infertility in the United States (U.S.). However, despite growing utilization of IVF technologies, there is little known about the experiences of those accessing or undergoing IVF, particularly among adults in the U.S. The aims of this review are to (1) explore how economic, emotional and physical health, and interpersonal relationships impact and are impacted by accessing or undergoing IVF, and (2) understand the role of healthcare providers and the healthcare system. Methods: A narrative review was conducted to summarize the current literature and provide insight into potential channels for care improvement. Eligible studies were published in English from 2013 to 2024 which qualitatively evaluated experiences of individuals and couples accessing or undergoing IVF. Peer-reviewed publications were identified from three electronic bibliographic databases. Methodologic rigor was assessed by two reviewers who also abstracted data on the study’s characteristics as they pertained to four domains: health systems, economic, interpersonal, and physical and emotional health. Among the 32 papers retrieved for review, 22 met inclusion criteria and were retained for analysis. Results: The available literature suggests accessing and undergoing IVF can be positively and negatively influenced by health systems, economic, interpersonal, and physical and emotional health factors. Often an individual or couple experiences multiple factors that compound to create a complex situation. Health systems-related factors included physician interaction and challenges with information volume and processing. Economic challenges primarily pertained to financing IVF and navigating insurance coverage. Interpersonal factors related to changes in relationships with partners, family members, and friends due to IVF. Physical health concerns (e.g., pain) and emotional health concerns (e.g., sadness, stress) were also noted by all included papers. Conclusions: Efforts to improve care experiences of adults accessing or undergoing IVF are urgently needed. The evidence base points to a need for provider sensitivity trainings, clinic-based intervention, and community education in both physical and virtual spaces
Impact of the COVID-19 pandemic on hospitalizations for endocarditis, myocarditis, and pericarditis using an interrupted time series analysis of the United States National Inpatient Sample 2018 to 2020
Get PDFBackground The mitigation measures implemented in March 2020 in response to the COVID-19 pandemic resulted in an overall abrupt decline in hospitalizations. Endocarditis, myocarditis, and pericarditis are acute conditions that can lead to substantial morbidity and mortality when treatment is delayed. The effect of the COVID-19 pandemic on hospitalizations for those conditions has not been fully explored.ObjectiveTo compare national trends of endocarditis, myocarditis, and pericarditis hospitalizations in the US before and during the COVID-19 pandemic. Methods The ICD-10-CM codes from the National Inpatient Sample (NIS) data were used to identify hospitalizations for endocarditis, myocarditis, and pericarditis occurring from 2018 through 2020 among individuals 18 years of age or older. Using an interrupted time series analysis design, we compared the number of hospitalizations for those conditions during the pandemic period (March 2020 to December 2020) to the period before the COVID-19 pandemic (January 2018 to February 2020). All reported numbers are weighted and represent national estimates. Results Among 76,762,573 all-cause hospitalizations occurring nationally from January 2018 to February 2020, 193,930 were for endocarditis, 21,685 for myocarditis, and 49,650 for pericarditis. During the pandemic period (March 2020 to December 2020), of the total 26,422,315 hospitalizations, 72,030 were for endocarditis, 13,480 for myocarditis, and 17,110 for pericarditis. Hospital length of stay significantly increased for all three conditions during the pandemic compared to the pre-pandemic period: 13.4 versus 12.8 days for endocarditis (p ≤ 0.01), 8.7 days versus 6 days for myocarditis (p ≤ 0.01), and 6.7 versus 6.1 days for pericarditis (p ≤ 0.01). In-hospital mortality during the pandemic period for endocarditis was 11.1% versus 9.1% pre-pandemic (p ≤ 0.01), 16.8% versus 3.9% pre-pandemic (p ≤ 0.01) for myocarditis, and 4% versus 2.8% pre-pandemic for pericarditis (p ≤ 0.01). Interrupted time series analysis showed an immediate decrease in monthly admissions for endocarditis and pericarditis soon after the states’ COVID-19 shutdowns. However, myocarditis hospitalizations almost doubled from 880 in February 2020 to 1605 and 1740 in March and April 2020, respectively. Conclusions We observed an immediate increase in monthly hospitalizations for myocarditis and an immediate decrease in hospitalizations for endocarditis and pericarditis following the national COVID-19 lockdown compared to the pre-pandemic period. Length of stay and in-hospital mortality significantly increased during the pandemic period for all three health conditions
[DPA] Understanding the Current Drug Supply
No full textNew Drugs and Markets: Meeting the Challenge of a Changing Drug Policy Landscap
