Inter-organ steroid hormone signaling promotes myoblast fusion via direct transcriptional regulation of a single key effector gene.

Steroid hormones regulate tissue development and physiology by modulating the transcription of a broad spectrum of genes. In insects, the principal steroid hormones, ecdysteroids, trigger the expression of thousands of genes through a cascade of transcription factors (TFs) to coordinate developmental transitions such as larval molting and metamorphosis. However, whether ecdysteroid signaling can bypass transcriptional hierarchies to exert its function in individual developmental processes is unclear. Here, we report that a single non-TF effector gene mediates the transcriptional output of ecdysteroid signaling in Drosophila myoblast fusion, a critical step in muscle development and differentiation. Specifically, we show that the 20-hydroxyecdysone (commonly referred to as "ecdysone") secreted from an extraembryonic tissue, amnioserosa, acts on embryonic muscle cells to directly activate the expression of antisocial (ants), which encodes an essential scaffold protein enriched at the fusogenic synapse. Not only is ants transcription directly regulated by the heterodimeric ecdysone receptor complex composed of ecdysone receptor (EcR) and ultraspiracle (USP) via ecdysone-response elements but also more strikingly, expression of ants alone is sufficient to rescue the myoblast fusion defect in ecdysone signaling-deficient mutants. We further show that EcR/USP and a muscle-specific TF Twist synergistically activate ants expression in vitro and in vivo. Taken together, our study provides the first example of a steroid hormone directly activating the expression of a single key non-TF effector gene to regulate a developmental process via inter-organ signaling and provides a new paradigm for understanding steroid hormone signaling in other developmental and physiological processes.

Projective light-sheet microscopy with flexible parameter selection.

Projection imaging accelerates volumetric interrogation in fluorescence microscopy, but for multi-cellular samples, the resulting images may lack contrast, as many structures and haze are summed up. Here, we demonstrate rapid projective light-sheet imaging with parameter selection (props) of imaging depth, position and viewing angle. This allows us to selectively image different sub-volumes of a sample, rapidly switch between them and exclude background fluorescence. Here we demonstrate the power of props by functional imaging within distinct regions of the zebrafish brain, monitoring calcium firing inside muscle cells of moving Drosophila larvae, super-resolution imaging of selected cell layers, and by optically unwrapping the curved surface of a Drosophila embryo. We anticipate that props will accelerate volumetric interrogation, ranging from subcellular to mesoscopic scales.

Social innovation in health training to engage researchers in resource-limited settings: process description and evaluation.

Research on social innovations in health has increased in recent years. However, little training is geared toward enhancing social innovation research capacity. Most health training for low- and middle-income countries (LMICs) is developed by individuals in high-income countries, disregarding LMIC researchers' wisdom and insights and the communities' needs. Our team organized a multi-phase investigation involving a series of surveys and co-creation group discussions to assess individuals' training needs that directly informed a subsequent co-created training workshop series. We conducted a Hennessy-Hicks Training Needs Assessment among the Social Innovation in Health Initiative (SIHI) network and formed a co-creation group comprising SIHI fellows to design related training workshops. We ran a final evaluation survey and analyzed the workshop series' strengths, weaknesses and threats. Descriptive and thematic analysis were employed to analyze survey data and open-ended responses. The final evaluation survey captured data from 165 learners in 35 countries, including 26 LMICs. Most participants (67.3%, 111/165) rated the training workshop series as excellent, and 30.3% (50/165) rated it as good on a five-point scale. The need for writing research grants and manuscripts was rated the highest priority. Learners were interested in community-engaged research and diversity, equity and inclusion. This workshop illustrated how co-creation could be an effective tool for developing training materials tailored for LMIC researchers. We also offer a template for conducting a needs assessment and subsequent training workshops for LMICs. The ground-up, locally developed courses may be more effective than externally developed training programs intended for LMICs.

Strengths and challenges among Black and Latinx people living with HIV during COVID-19: A mixed-methods investigation of the translation of self-management across syndemic health crises.

Black and Latinx people are disproportionately impacted by HIV, COVID-19, and other syndemic health crises with similar underlying social determinants of health. Lessons learned from the HIV pandemic and COVID-19 response have been invoked to improve health equity at the systemic level in the face of other emergent health crises. However, few have examined the potential translation of strategies between syndemics at the individual level. The current mixed-methods study examined strategies used to manage HIV during the COVID-19 pandemic and the extent to which they were helpful in managing COVID-19 vulnerability among Black and Latinx people living with HIV. Participants (n = 30) were interviewed by telephone and completed demographic, mental health, alcohol and substance use, health literacy, and clinical measures in October and November 2020 in Los Angeles County. Rapid qualitative analysis, descriptive statistics, and mixed-methods merging were used to analyze the data. Qualitative results demonstrated that participants found HIV self-management strategies translated to aspects of the COVID-19 pandemic including hygiene and social distancing and coping with a health-related stressor. Although telemedicine provided continuity of HIV care for most participants, technology access and literacy posed a potential barrier, particularly to those facing other sociodemographic marginalization (i.e., low education, disability). Findings suggest providers can encourage leveraging individual HIV self-management strategies in response to other public health crises. However, these interventions must be culturally responsive and address intersecting social determinants of health. Future research should examine mechanisms that predict individual translation of HIV management strategies to other health concerns. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Designathons in health research: a global systematic review.

INTRODUCTION: A designathon is a three-stage participatory activity informed by design thinking. There is a growing literature on designathons in health. This study synthesised designathons' effectiveness and implementation-related factors to address health challenges. METHODS: We searched Cochrane Library, Embase, PubMed, Scopus and the ClinicalTrials.gov registry for articles containing primary data on designathons for health from their dates of inception to 29 November 2022. We retrieved additional studies from citation searching and a complementary open call. We synthesised data on designathons' effectiveness (ie, engagement, outputs and implementation), required resources and implementation-related factors (ie, resources, facilitators, barriers, strengths and limitations). We assessed the risk of bias using a checklist adapted from Joanna Briggs Institute Critical Appraisal tools. RESULTS: In total, 4973 citations were identified, and 42 studies were included. In total, 26 studies (62%) were from high-income countries. The median number of total participants was 49, divided into a median of 8 teams. The duration of the intensive collaboration phase ranged from 3 hours to 7 days. Common evaluation criteria were feasibility, innovation and impact. Idea and prototype outputs included mobile phone applications, educational programmes and medical devices. Interventions developed from a designathon was estimated to be highly cost-effective. The most common facilitators were interdisciplinary participants and high-quality mentorship. The most common barriers were suboptimal execution of the events, difficulties in balancing interdisciplinary participants across teams and limited support for participants along the process. There were limited data on required resources and further implementation of solutions after designathons. CONCLUSION: Given designathons' adaptability in terms of budget, mode of delivery, type of output and involvement of diverse participants, including end users, designathons can be implemented in a wide range of contexts to address various health issues. PROSPERO REGISTRATION NUMBER: CRD42023389685.

Changes in Expression of Key Genes in Alzheimer's Disease: A Specific Brain Tissue Change.

Alzheimer's disease (AD) is an irreversible and neurodegenerative disorder. Its etiology is not clear, but the involvement of genetic components plays a central role in the onset of the disease. In the present study, the expression of 10 genes (APP, PS1 and PS2, APOE, APBA2, LRP1, GRIN2B, INSR, GJB1, and IDE) involved in the main pathways related to AD were analyzed in auditory cortices and cerebellum from 29 AD patients and 29 healthy older adults. Raw analysis revealed tissue-specific changes in genes LRP1, INSR, and APP. A correlation analysis showed a significant effect also tissue-specific AD in APP, GRIN2B, INSR, and LRP1. Furthermore, the E4 allele of the APOE gene revealed a significant correlation with change expression tissue-specific in ABPA2, APP, GRIN2B, LRP1, and INSR genes. To assess the existence of a correction between changes in target gene expression and a probability of AD in each tissue (auditory cortices and cerebellum) an analysis of the effect of expressions was realized and showed that the reduction in the expression of the APP in auditory cortex and GRIN2B cerebellum had a significant effect in increasing the probability of AD, in the same logic, our result also suggesting that increased expression of the LRP1 and INSR genes had a significant effect on increasing the probability of AD. Our results showed tissue-specific gene expression alterations associated with AD and certainly opened new perspectives to characterize factors involved in gene regulation and to obtain possible biomarkers for AD.

Wilms Tumor in Child With Trisomy 18 and Horseshoe Kidney.

Trisomy 18 is associated with several congenital malformations, including horseshoe kidney. It can be full, partial, or mosaic, and mosaicism is often associated with lesser severity and longer life expectancy, placing patients at greater risk of developing neoplasms or malignancies. One common tumor among children with Trisomy 18 is Wilms tumor, which is also associated with renal congenital abnormalities such as horseshoe kidney. We present a case describing the occurrence of these three characteristics: development of Wilms tumor in a patient with Trisomy 18 and a horseshoe kidney and discuss treatment with regards to these conditions.

Pharmacogenetics of angiotensin modulators according to APOE-ϵ4 alleles and the ACE insertion/deletion polymorphism in Alzheimer's disease.

OBJECTIVE: In Alzheimer's disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-ß by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-ß-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E (APOE)-ϵ4 carrier status and blood pressure response to angiotensin modulators. METHODS: Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking APOE-ϵ4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs. RESULTS: For 193 patients (67.4% women, 53.4% APOE-ϵ4 carriers), the ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p = 0.281), while arterial hypertension was prevalent in 80.3% (n = 124 used an ACEi, n = 21 used an ARB). ARBs benefitted mostly APOE-ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations. CONCLUSION: Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

Novel surgical technique to manage iStent inject over-implantation.

PURPOSE: To describe a novel surgical technique to manage over-implantation of the iStent inject intra-operatively, utilizing only the iStent inject delivery system itself to perform both device extraction and reimplantation, without the need for additional instrumentation. METHODS: A demonstration of managing over-implantation of the iStent inject, with two case examples. RESULTS: Over-implantation of the iStent inject can be successfully managed intra-operatively to ensure ideal positioning to optimise post-operative outcomes, with the use of only the iStent inject delivery system itself for both device extraction and reimplantation. CONCLUSION: This novel technique provides a cost-effective and feasible means to intra-operatively manage over-implantation of the iStent inject.

Characterizing suicidal ideation, suicidal behaviors, and service utilization among unhoused individuals using a health information exchange.

INTRODUCTION: Unhoused individuals have high rates of suicidal ideation (SI) and suicidal behaviors (SB), but few have studied the relative timing of homelessness and SI/SB. Our study examines the potential to use state-wide electronic health record data from Rhode Island's health information exchange (HIE) to identify temporal relationships, service utilization, and associations of SI/SB among unhoused individuals. METHODS: We use timestamped HIE data for 5368 unhoused patients to analyze service utilization and the relative timing of homelessness versus SI/SB onset. Multivariable models identified associations of SI/SB, hospitalization, and repeat acute care utilization within 30 days from clinical features representing 10,000+ diagnoses captured within the HIE. RESULTS: The onset of SI typically precedes homelessness onset, while the onset of SB typically follows. Weekly rates of suicide-related service utilization increased over 25 times the baseline rate during the week before and after homelessness onset. Over 50% of encounters involving SI/SB result in hospitalization. Of those engaging in acute care for suicide-related reasons, we found high rates of repeat acute care encounters. CONCLUSION: HIEs are a particularly valuable resource for understudied populations. Our study demonstrates how longitudinal, multi-institutional data from an HIE can be used to characterize temporal associations, service utilization, and clinical associations of SI and behaviors among a vulnerable population at scale. Increasing access to services that address co-occurring SI/SB, mental health, and substance use is needed.

Matching medical staff to long term care facilities to respond to COVID-19 outbreak.

BACKGROUND: Staff shortage is a long-standing issue in long term care facilities (LTCFs) that worsened with the COVID-19 outbreak. Different states in the US have employed various tools to alleviate this issue in LTCFs. We describe the actions taken by the Commonwealth of Massachusetts to assist LTCFs in addressing the staff shortage issue and their outcomes. Therefore, the main question of this study is how to create a central mechanism to allocate severely limited medical staff to healthcare centers during emergencies. METHODS: For the Commonwealth of Massachusetts, we developed a mathematical programming model to match severely limited available staff with LTCF demand requests submitted through a designed portal. To find feasible matches and prioritize facility needs, we incorporated restrictions and preferences for both sides. For staff, we considered maximum mileage they are willing to travel, available by date, and short- or long-term work preferences. For LTCFs, we considered their demand quantities for different positions and the level of urgency for their demand. As a secondary goal of this study, by using the feedback entries data received from the LTCFs on their matches, we developed statistical models to determine the most salient features that induced the LTCFs to submit feedback. RESULTS: We used the developed portal to complete about 150 matching sessions in 14 months to match staff to LTCFs in Massachusetts. LTCFs provided feedback for 2,542 matches including 2,064 intentions to hire the matched staff during this time. Further analysis indicated that nursing homes and facilities that entered higher levels of demand to the portal were more likely to provide feedback on the matches and facilities that were prioritized in the matching process due to whole facility testing or low staffing levels were less likely to do so. On the staffing side, matches that involved more experienced staff and staff who can work afternoons, evenings, and overnight were more likely to generate feedback from the facility that they were matched to. CONCLUSION: Developing a central matching framework to match medical staff to LTCFs at the time of a public health emergency could be an efficient tool for responding to staffing shortages. Such central approaches that help allocate a severely limited resource efficiently during a public emergency can be developed and used for different resource types, as well as provide crucial demand and supply information in different regions and/or demographics.

Using Human-Centered Design Strategies to Identify Unmet Adolescent Sexual Health Wants and Needs.

This paper describes a human-centered design approach to investigate unmet adolescent sexual health wants and needs among youth of color in low-income and rural communities in Texas, North Carolina, and Connecticut (n = 149). The approach involved gathering qualitative data through in-depth interviews and other human-centered design activities between April 2016 and August 2016. Data were analyzed using thematic content analysis after each round of data collection. Themes were triangulated across multiple data sources to identify key insights. Results highlighted several important unmet wants and needs. Participants shared that schools were not the preferred place to learn about sexual health and healthy relationships, due to uncomfortable and sometimes even hostile environments. When discussing the potential to use internet- and technology-based sexual health resources, participants expressed concerns over privacy, safety, and credibility of information available. Similarly, participants preferred mobile apps over websites due to the privacy of the experience. Most importantly, key emotions impacting adolescents' access to and use of sexual health resources were identified. Results indicated a preference for consuming story-based information in a text message format that described diverse experiences related to sexual health topics. Together, these findings led to the development of an innovative, mobile health intervention for adolescents, the Real Talk mobile app. This human-centered approach can support researchers and practitioners in strengthening intervention development efforts to improve the reach, adoption, and implementation of sexual health interventions.

MPH Capstone experiences: promising practices and lessons learned.

To ensure workforce readiness, graduate-level public health training programs must prepare students to collaborate with communities on improving public health practice and tools. The Council on Education for Public Health (CEPH) requires Master of Public Health (MPH) students to complete an Integrative Learning Experience (ILE) at the end of their program of study that yields a high-quality written product demonstrating synthesis of competencies. CEPH suggests written products ideally be "developed and delivered in a manner that is useful to external stakeholders, such as non-profit or governmental organizations." However, there are limited examples of the ILE pedagogies and practices most likely to yield mutual benefit for students and community partners. To address this gap, we describe a community-led, year-long, group-based ILE for MPH students, called Capstone. This service-learning course aims to (1) increase capacity of students and partner organizations to address public health issues and promote health equity; (2) create new or improved public health resources, programs, services, and policies that promote health equity; (3) enhance student preparedness and marketability for careers in public health; and (4) strengthen campus-community partnerships. Since 2009, 127 Capstone teams affiliated with the Department of Health Behavior at the Gillings School of Global Public Health at The University of North Carolina at Chapel Hill have worked with seventy-nine partner organizations to provide over 103,000 h of in-kind service and produce 635 unique products or "deliverables." This paper describes key promising practices of Capstone, specifically its staffing model; approach to project recruitment, selection, and matching; course format; and assignments. Using course evaluation data, we summarize student and community partner outcomes. Next, we share lessons learned from 13 years of program implementation and future directions for continuing to maximize student and community partner benefits. Finally, we provide recommendations for other programs interested in replicating the Capstone model.

Integrating Human-Centered Design Methods Into a Health Promotion Project: Supplemental Nutrition Assistance Program Education Case Study for Intervention Design.

BACKGROUND: Human-centered design, or design thinking, offers an extensive toolkit of methods and strategies for user-centered engagement that lends itself well to intervention development and implementation. These methods can be applied to the fields of public health and medicine to design interventions that may be more feasible and viable in real-world contexts than those developed with different methods. OBJECTIVE: The design team aimed to develop approaches to building food skills among caregivers of children aged 0-5 years who are eligible for a federal food assistance program while they were in the grocery store. METHODS: They applied 3 specific human-centered design methods-Extremes and Mainstreams, Journey Mapping, and Co-Creation Sessions-to collaboratively develop intervention approaches to enhance Supplemental Nutrition Assistance Program Education (SNAP-Ed) reach and impact across food retail settings. Extremes and Mainstreams is a specific kind of purposive sampling that selects individuals based on characteristics beyond demographics. Journey Mapping is a visual tool that asks individuals to identify key moments and decision points during an experience. Co-Creation Sessions are choreographed opportunities for individuals to explicitly contribute to the design of a solution alongside research or design team members. RESULTS: Ten caregivers with diverse lived experiences were selected to participate in remote design thinking workshops and create individual journey maps to depict their grocery store experiences. Common happy points and pain points were identified. Nine stakeholders, including caregivers, SNAP-Ed staff, and grocery store dieticians, cocreated 2 potential intervention approaches informed by caregivers' experiences and needs: a rewards program and a meal box option. CONCLUSIONS: These 3 human-centered design methods led to a meaningful co-design process where proposed interventions aligned with caregivers' wants and needs. This case study provides other public health practitioners with specific examples of how to use these methods in program development and stakeholder engagement as well as lessons learned when adapting these methods to remote settings.

CDK10, CDK11, FOXO1, and FOXO3 Gene Expression in Alzheimer's Disease Encephalic Samples.

Alzheimer's disease (AD) is a progressive neuroinflammatory and neurodegenerative disorder that affects different regions of the brain. Its pathophysiology includes the accumulation of ß-amyloid protein, formation of neurofibrillary tangles, and inflammatory processes. Genetic factors are involved in the onset of AD, but they are not fully elucidated. Identification of gene expression in encephalic tissues of patients with AD may help elucidate its development. Our objectives were to characterize and compare the gene expression of CDK10, CDK11, FOXO1, and FOXO3 in encephalic tissue samples from AD patients and elderly controls, from the auditory cortex and cerebellum. RT-qPCR was used on samples from 82 individuals (45 with AD and 37 controls). We observed a statistically significant increase in CDK10 (p = 0.029*) and CDK11 (p = 0.048*) gene expression in the AD group compared to the control, which was most evident in the cerebellum. Furthermore, the Spearman test demonstrated the presence of a positive correlation of gene expression both in the auditory cortex in the AD group (r = 0.046/p = 0.004) and control group (r = 0.454/p = 0.005); and in the cerebellum in the AD group (r = 0.654 /p < 0.001). There was no statistically significant difference and correlation in the gene expression of FOXO1 and FOXO3 in the AD group and the control. In conclusion, CDK10 and CDK11 have high expression in AD patients compared to control, and they present a positive correlation of gene expression in the analyzed groups and tissues, which suggests that they play an important role in the pathogenesis of AD.

RNA Sensing and Innate Immunity Constitutes a Barrier for Interspecies Chimerism.

Interspecies chimera formation with human pluripotent stem cells (PSCs) holds great promise to generate humanized animal models and provide donor organs for transplant. However, the approach is currently limited by low levels of human cells ultimately represented in chimeric embryos. Different strategies have been developed to improve chimerism by genetically editing donor human PSCs. To date, however, it remains unexplored if human chimerism can be enhanced in animals through modifying the host embryos. Leveraging the interspecies PSC competition model, here we discovered retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling, an RNA sensor, in "winner" cells plays an important role in the competitive interactions between co-cultured mouse and human PSCs. We found that genetic inactivation of Ddx58/Ifih1-Mavs-Irf7 axis compromised the "winner" status of mouse PSCs and their ability to outcompete PSCs from evolutionarily distant species during co-culture. Furthermore, by using Mavs-deficient mouse embryos we substantially improved unmodified donor human cell survival. Comparative transcriptome analyses based on species-specific sequences suggest contact-dependent human-to-mouse transfer of RNAs likely plays a part in mediating the cross-species interactions. Taken together, these findings establish a previously unrecognized role of RNA sensing and innate immunity in "winner" cells during cell competition and provides a proof-of-concept for modifying host embryos, rather than donor PSCs, to enhance interspecies chimerism.

Organoid generation from mouse mammary tumors captures the genetic heterogeneity of clinically relevant copy number alterations.

Breast cancer metastases exhibit many different genetic alterations, including copy number amplifications. Using publicly available datasets, we identify copy number amplifications in metastatic breast tumor samples and using our organoid-based metastasis assays, and we validate FGFR1 is amplified in collectively migrating organoids. Because the heterogeneity of breast tumors is increasingly becoming relevant to clinical practice, we demonstrate our organoid method captures genetic heterogeneity of individual tumors.

Histone Modifications in Alzheimer's Disease.

Since Late-onset Alzheimer's disease (LOAD) derives from a combination of genetic variants and environmental factors, epigenetic modifications have been predicted to play a role in the etiopathology of LOAD. Along with DNA methylation, histone modifications have been proposed as the main epigenetic modifications that contribute to the pathologic mechanisms of LOAD; however, little is known about how these mechanisms contribute to the disease's onset or progression. In this review, we highlighted the main histone modifications and their functional role, including histone acetylation, histone methylation, and histone phosphorylation, as well as changes in such histone modifications that occur in the aging process and mainly in Alzheimer's disease (AD). Furthermore, we pointed out the main epigenetic drugs tested for AD treatment, such as those based on histone deacetylase (HDAC) inhibitors. Finally, we remarked on the perspectives around the use of such epigenetics drugs for treating AD.

Examining the White Supremacist Practices of Funding Organizations for Public Health Research and Practice: A Composite Narrative From Female, BIPOC Junior Researchers in Public Health.

Background. It is challenging for junior public health investigators who identify as Black, Indigenous, or People of Color (BIPOC) to secure funding for projects and research. We used a narrative inquiry approach to understand and present the funding cascade from the perspectives of female, junior BIPOC researchers and provide funders with actionable recommendations to advance their antiracist goals. Approach. We applied a Critical Race Theory (CRT) framework to guide our narrative inquiry approach. The participants were the four co-authors and we each drafted individual narratives around our experience with the funding cascade and subsequently the five stages of narrative analysis. Results. We created a visual representation of key activities for funders and applicants organized by our perceived magnitude of inequities in a journey map, an interpreter table that describes common phrases and barriers encountered, and a composite counternarrative presented as a group text message conversation, elevating common themes including feeling pressured to have our research agendas conform to funders' interests and receiving limited key information and support in the funding process. Discussion. We discussed how our findings represented manifestations of White supremacy characteristics like power hoarding and paternalism. Implications for practice. We offered specific antidotes for funding organizations to make their processes more antiracist and invited leaders of public health funding organizations to join us to further identify antidotes and share lessons learned in Fall 2023.