Single-cell atlas of ABCA7 loss-of-function reveals impaired neuronal respiration via choline-dependent lipid imbalances.

Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase the risk of Alzheimer's disease (odds ratio ∼2), yet the pathogenic mechanisms and the neural cell types affected by these variants remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 human post-mortem samples from the prefrontal cortex of 12 ABCA7 LoF carriers and 24 matched non-carrier control individuals. ABCA7 LoF was associated with gene expression changes in all major cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed transcriptional changes related to lipid metabolism, mitochondrial function, cell cycle-related pathways, and synaptic signaling. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers), indicating that findings from our study may extend to large portions of the at-risk population. Consistent with ABCA7's function as a lipid exporter, lipidomic analysis of isogenic iPSC-derived neurons (iNs) revealed profound intracellular triglyceride accumulation in ABCA7 LoF, which was accompanied by a relative decrease in phosphatidylcholine abundance. Metabolomic and biochemical analyses of iNs further indicated that ABCA7 LoF was associated with disrupted mitochondrial bioenergetics that suggested impaired lipid breakdown by uncoupled respiration. Treatment of ABCA7 LoF iNs with CDP-choline (a rate-limiting precursor of phosphatidylcholine synthesis) reduced triglyceride accumulation and restored mitochondrial function, indicating that ABCA7 LoF-induced phosphatidylcholine dyshomeostasis may directly disrupt mitochondrial metabolism of lipids. Treatment with CDP-choline also rescued intracellular amyloid ß -42 levels in ABCA7 LoF iNs, further suggesting a link between ABCA7 LoF metabolic disruptions in neurons and AD pathology. This study provides a detailed transcriptomic atlas of ABCA7 LoF in the human brain and mechanistically links ABCA7 LoF-induced lipid perturbations to neuronal energy dyshomeostasis. In line with a growing body of evidence, our study highlights the central role of lipid metabolism in the etiology of Alzheimer's disease.

"The Hotel of 10,000 Stars": The Impact of Social-Structural Determinants of Health Among Im/migrant Shrimpers in the Gulf of Mexico.

Objectives. To identify appropriate interventions to prevent injury, we conducted a qualitative study among commercial shrimp fishermen in the Gulf of Mexico. Methods. Using qualitative and participatory research methods, including interviews, photovoice, and workplace observations in southeast Texas and the Rio Grande Valley in Texas, we examined the social‒structural dimensions that contribute to physical and psychological injury. Results. We found that multiple layers of vulnerability and danger exist among shrimpers with interacting themes: (1) recognizing risk, (2) precarious employment, and (3) psychological distress. Conclusions. Our results add to the growing body of knowledge that emphasizes the negative health impacts of underregulated, high-risk, and physically demanding work performed primarily by im/migrants. Public Health Implications. Our findings highlight the larger social‒structural conditions and context of hardships endemic to migrant labor and suggest implications for practice and policy interventions. (Am J Public Health. 2024;114(8):824-832. https://doi.org/10.2105/AJPH.2024.307696).

Family Medicine Team Perspectives on Screening for Health-Related Social Needs.

INTRODUCTION: Social drivers of health (SDH) strongly influence health outcomes and disparities. Although systemic level change is vital to address the disparities driven by SDH, it is also crucial that health care organizations develop the ability to care for patients in a manner that accounts for social factors and their influence on patient health. Although primary care is a natural fit for health-related social needs (HRSN) screening and intervention, significant barriers can impede primary care's effectiveness in this area. METHODS: We conducted 3 focus groups with family medicine clinicians, clinical staff, and social care workers in an academic medical center using a semistructured discussion guide to explore current practices, perceived benefits, barriers, and potential opportunities and approaches for integrating routine HRSN screening in primary care. RESULTS: 3 primary themes emerged from the focus groups. They included 1) the barriers to routine screening in primary care, including time, workload, emotional burden, patient factors, and team members' fear of inadequacy of resources or their own ability; 2) the importance and benefit of HRSN screening, including the opportunity to improve patient care through increased care team awareness of the patient's context, interventions to address HRSN, and improved relationships between the care team and the patient; and 3) recommendations for implementing routine screening in primary care, including opportunities to optimize workflow and technology, the importance of an electronic medical record (EMR)-integrated resource database, and the centrality of teamwork. DISCUSSION: Family medicine health care teams embrace the importance of HRSN screening and the potential for positive impact. However, there are vital barriers and considerations to address for HRSN screening to be effectively integrated into primary care visits.

Racial Discrimination and Interpersonal Violence in Asian American Adolescents During the COVID-19 Pandemic.

PURPOSE: Racial discrimination targeting Asians in the United States has increased sharply since the COVID-19 pandemic. Despite a well-established link with mental/physical health outcomes, little is known about how racial discrimination relates to interpersonal violence, particularly in adolescents. To address this gap in knowledge, we examined cross-sectional and longitudinal (1-year follow-up) associations between racial discrimination and interpersonal violence perpetration and victimization in Asian American adolescents in a large US city. METHODS: Data from Waves 3 (2020) and 4 (2021) of a randomized clinical trial of a school-based violence prevention program were examined. We limited our sample to participants who identified as Asian American (n = 344; 48.3% female; Meanage = 14.6 years at Wave 3). RESULTS: At Wave 3, 26.5% of the adolescents reported experiencing some form of racial discrimination, including 18.3% experiencing verbal harassment due to race and 16.0% reporting inequitable treatment due to race. Relative to their nonvictimized counterparts, adolescents who experienced racial discrimination were more likely to report being a victim of bullying and teen dating violence cross-sectionally and being a bullying victim longitudinally. Moreover, those who experienced racial discrimination reported more bullying and teen dating violence perpetration concurrently, as well as more dating violence perpetration 1 year later. DISCUSSION: In the understudied population of Asian American adolescents, we found that experiencing racial discrimination contributes to both interpersonal violence victimization and perpetration. Youth violence prevention could include strategies addressing racial discrimination.

Auditory rhythm complexity affects cardiac dynamics in perception and synchronization.

Accurate perception and production of auditory rhythms are key for human behaviors such as speech and music. Auditory rhythms in music range in their complexity: complex rhythms (based on non-integer ratios between successive tone durations) are more difficult to perceive and produce than simple rhythms (based on integer ratios). The physiological activity supporting this behavioral difference is not well understood. In a within-subjects design, we addressed how rhythm complexity affects cardiac dynamics during auditory perception and production. Musically trained adults listened to and synchronized with simple and complex auditory rhythms while their cardiac activity was recorded. Participants identified missing tones in the rhythms during the Perception condition and tapped on a keyboard to synchronize with the rhythms in the Synchronization condition. Participants were equally accurate at identifying missing tones in simple and complex rhythms during the Perception condition. Tapping synchronization was less accurate and less precise with complex rhythms than with simple rhythms. Linear cardiac analyses showed a slower mean heart rate and greater heart rate variability during perception than synchronization for both simple and complex rhythms; only nonlinear recurrence quantification analyses reflected cardiac differences between simple and complex auditory rhythms. Nonlinear cardiac dynamics were also more deterministic (predictable) during rhythm perception than synchronization. Individual differences during tapping showed that greater heart rate variability was correlated with poorer synchronization. Overall, these findings suggest that linear measures of musicians' cardiac activity reflect global task variability while nonlinear measures additionally reflect stimulus rhythm complexity.

Addressing Training Gaps: A Competency-Based, Telehealth Training Initiative for Community Health Workers.

Background: To overcome vast variations in Community Health Worker (CHW) training, investigators for the CHW Core Consensus Project (CCCP) derived three types of CHW (Category 1, 2, 3) and established competencies for each category. However, studies are needed that implement these competencies in real-world settings. Objective: Using the six competency domains of the CCCP as a theoretical backbone, we developed and evaluated a training for Category 1 CHWs, individuals whose focus is on community outreach and advocacy. Methods: We developed five telehealth-based, bilingual (Spanish/English) training sessions and implemented them among Category 1 Latino(a) CHWs. We measured the number of CHWs who achieved ≥70% correct on a domain-based posttest, attendance, and qualitative feedback. Results: All (18/18) CHWs achieved at least 70% on the posttest (mean: 93.7%; range 73.3-100%). Training attendance was 98.9%. Using a six-point scale, CHWs reported high levels of satisfaction overall (5.72 ± 0.57/6.0), with telehealth (5.72 ± 0.58/6.0), effectiveness of teaching strategies/methods (5.89 ± 0.32/6.0), achieving training objectives (5.96 ± 0.15/6.0), knowledge improvement (5.72 ± 0.57/6.0), and interest (5.78 ± 0.43/6.0). Conclusion: We successfully developed and evaluated a bilingual training program for Category 1 CHWs to address core competency gaps. High CHW attendance reinforces the value of telehealth modalities and their potential to increase the reach for CHW training. To overcome gaps in chronic disease training, investigations are needed to address additional CHW trainings. Trial Registration: NCT04835493.

Dissemination and Implementation of a Text Messaging Campaign to Improve Health Disparities among Im/Migrant Workers.

The use of short message service (SMS) text messaging technology has grown in popularity over the last twenty years, but there is limited data on the design and feasibility of campaigns to reduce work-related injury, particularly among rural workers, non-native English speakers, and illiterate or low-literacy populations. Although there is a critical need for tech equity or 'TechQuity' interventions that reduce injury and enhance the wellbeing of under-reached communities, the barriers and benefits to implementation must be empirically and systematically examined. Thus, our team used D&I science to design and implement an 18-week texting campaign for under-reached workers with a higher-than-average risk of fatal and non-fatal injury. The experimental project was conducted with English-, Spanish-, and Vietnamese-speaking commercial fishermen in the Gulf of Mexico to test the design and feasibility, and messaging focused on preventing injury from slips, trips, and falls, as well as hurricane preparedness. The ubiquity of mobile devices and the previous success of texting campaigns made this a promising approach for enhancing health and preventing injury among an under-reached population. However, the perceived benefits were not without their barriers. The lessons learned included the difficulty of navigating federal regulations regarding limits for special characters, enrolling migratory participants, and navigating areas with limited cellular service or populations with limited accessibility to technology. We conclude with short- and long-term suggestions for future technology interventions for under-reached worker populations, including ethical and policy regulations.

From the national to the local: Issues of trust and a model for community-academic-engagement.

Inequities in health and health care in the United States have persisted for decades, and the impacts on equity from the COVID-19 pandemic were no exception. In addition to the disproportionate burden of the disease across various populations, the pandemic posed several challenges, which exacerbated these existing inequities. This has undoubtedly contributed to deeply rooted public mistrust in medical research and healthcare delivery, particularly among historically and structurally oppressed populations. In the summer of 2020, given the series of social injustices posed by the pandemic and highly publicized incidents of police brutality, notably the murder of George Floyd, the Association of American Medical Colleges (AAMC) enlisted the help of a national collaborative, the AAMC Collaborative for Health Equity: Act, Research, Generate Evidence (CHARGE) to establish a three-way partnership that would gather and prioritize community perspectives and lived experiences from multiple regions across the US on the role of academic medicals centers (AMCs) in advancing health and social justice. Given physical gathering constraints posed by the pandemic, virtual interviews were conducted with 30 racially and ethnically diverse community members across the country who expressed their views on how medical education, clinical care, and research could or did impact their health experiences. These interviews were framed within the context of the relationship between historically oppressed groups and the COVID-19 vaccine clinical trials underway. From the three-way partnership formed with the AAMC, AAMC CHARGE participants, and 30 community members from racially and ethnically diverse groups, qualitative methods provided lived experiences supporting other literature on the lack of trust between oppressed communities and AMCs. This led to the development of the Principles of Trustworthiness (PoT) Toolkit, which features ten principles inspired by community members' insights into how AMCs can demonstrate they are worthy of their community's trust. In the end, the three-way partnership serves as a successful model for other national medical and health organizations to establish community engaged processes that elicit and prioritize lived experiences describing relationships between AMCs and oppressed communities.

Native functions of short tandem repeats.

Over a third of the human genome is comprised of repetitive sequences, including more than a million short tandem repeats (STRs). While studies of the pathologic consequences of repeat expansions that cause syndromic human diseases are extensive, the potential native functions of STRs are often ignored. Here, we summarize a growing body of research into the normal biological functions for repetitive elements across the genome, with a particular focus on the roles of STRs in regulating gene expression. We propose reconceptualizing the pathogenic consequences of repeat expansions as aberrancies in normal gene regulation. From this altered viewpoint, we predict that future work will reveal broader roles for STRs in neuronal function and as risk alleles for more common human neurological diseases.

Improving Initial Sepsis Management Through a Nurse-Driven Rapid Response Team Protocol.

BACKGROUND: Rapid identification and timely management of sepsis improve survival. Therefore, a bundled approach to care is recommended. LOCAL PROBLEM: In an acute care area of the study institution, a 2016 internal evaluation of 27 patients with sepsis showed a median time to first-dose antibiotic administration of 269 minutes, with no patients receiving antibiotics within the 60-minute target time. Additionally, only one-third of patients received appropriate fluid resuscitation (30-mL/kg bolus of intravenous crystalloids). Given poor bundle compliance, a nurse-driven rapid response team protocol for suspected sepsis was implemented. The purpose of this project was to assess the protocol's impact on the timeliness of treatment for sepsis. METHODS: This retrospective quality improvement evaluation involved patients aged 18 years or older for whom the suspected sepsis protocol was initiated during their acute care area admission. The evaluation focused on improvements in time to intravenous antibiotic administration and volume of fluid resuscitation compared with before protocol implementation. The protocol empowers the rapid response team to initiate sepsis management and includes pertinent laboratory tests, blood cultures, intravenous broad-spectrum antibiotic administration, and a crystalloid bolus (30 mL/kg) if indicated. RESULTS: A total of 32 patients were evaluated. Time to first-dose antibiotic administration was reduced by half (from 269 to 135 minutes). Eighteen patients met criteria for fluid resuscitation, with twice as many receiving appropriate fluid volumes compared with before protocol implementation. CONCLUSION: Implementation of the suspected sepsis protocol demonstrates the substantial role nurses have in optimizing patient care, especially in the timely treatment of sepsis.

The Impact of the COVID-19 Pandemic on Adolescent Mental Health and Substance Use.

PURPOSE: The aim of this study is to determine whether COVID-19-induced financial impact, stress, loneliness, and isolation were related to perceived changes in adolescent mental health and substance use. METHODS: Data were from Baseline (2018) and Wave 3 (2020; mean age = 14.8; 50% female) of 1,188 adolescents recruited from 12 Texas public middle schools as part of a randomized controlled trial. Participants were primarily Black (23%), Latinx (41%), Asian (11%), and White (9%). We assessed mental health and substance use (Baseline and Wave 3) and pandemic-related physical interaction, loneliness, stress, family conflict, and economic situation (Wave 3). RESULTS: COVID-19-induced stress and loneliness were linked to depression (beta = 0.074, p ≤ .001; beta = 0.132, p ≤ .001) and anxiety (beta = 0.061, p = .001; beta = 0.088, p ≤ .001) among ethnically diverse adolescents. Adolescents who did not limit their physical interactions due to COVID-19 had fewer symptoms of depression (beta = -0.036, p = .03); additionally, adolescents who did not restrict their socializing were substantially more likely to report using a variety of substances (e.g., for episodic heavy drinking; odds ratio = 1.81, p = .001). Increased use of a food bank was linked to depression (beta = 0.063, p ≤ .001) and a negative change in financial situation was linked to increased alcohol use (odds ratio = 0.70, p = .04) among adolescents. DISCUSSION: After controlling for prepandemic psychopathology and race/ethnicity, COVID-19 induced isolation, loneliness, stress, and economic challenges were linked to poor mental health and substance misuse. Substantial structural, community, school, and individual level resources are needed to mitigate the impact of the COVID-19 pandemic on adolescent psychosocial health.

CGG repeats trigger translational frameshifts that generate aggregation-prone chimeric proteins.

CGG repeat expansions in the FMR1 5'UTR cause the neurodegenerative disease Fragile X-associated tremor/ataxia syndrome (FXTAS). These repeats form stable RNA secondary structures that support aberrant translation in the absence of an AUG start codon (RAN translation), producing aggregate-prone peptides that accumulate within intranuclear neuronal inclusions and contribute to neurotoxicity. Here, we show that the most abundant RAN translation product, FMRpolyG, is markedly less toxic when generated from a construct with a non-repetitive alternating codon sequence in place of the CGG repeat. While exploring the mechanism of this differential toxicity, we observed a +1 translational frameshift within the CGG repeat from the arginine to glycine reading frame. Frameshifts occurred within the first few translated repeats and were triggered predominantly by RNA sequence and structural features. Short chimeric R/G peptides form aggregates distinct from those formed by either pure arginine or glycine, and these chimeras induce toxicity in cultured rodent neurons. Together, this work suggests that CGG repeats support translational frameshifting and that chimeric RAN translated peptides may contribute to CGG repeat-associated toxicity in FXTAS and related disorders.

A community-led mobile health clinic to improve structural and social determinants of health among (im)migrant workers.

BACKGROUND: Community-led interventions that address structural and social determinants of health are lacking among (im)migrant workers, especially seafood workers. This lack of medical attention is especially alarming given their high rate of injury and death. METHODS: Community-based participatory research (CBPR), a relational model that values the participants as equal partners in research, dissemination, and implementation, guided the interviews and mobile clinic. Seafood workers were engaged throughout data collection, analysis, and interpretation and played a significant role in moving the findings from research into actionable change. RESULTS: To address the lack of healthcare options for (im)migrants, and at the request of the seafood workers participating in the ongoing CBPR study, we successfully implemented and treated workers in our mobile clinic. DISCUSSION: Many of these individuals had not been seen by a healthcare provider in years, highlighting the importance of community trust and rapport building when addressing interconnected health and safety issues. CONCLUSIONS: Although CBPR and free (mobile) health clinics are in and of themselves not novel concepts, when applied to high-risk occupational settings with under-reached populations (e.g., (im)migrant workers), they have the ability to improve health and prevent injury. This intervention adds to the growing literature detailing the potential benefits of using CBPR, and meeting people where they are, especially with historically marginalized populations.

Mechanistic convergence across initiation sites for RAN translation in fragile X associated tremor ataxia syndrome.

Repeat associated non-AUG (RAN) translation of CGG repeats in the 5'UTR of FMR1 produces toxic proteins that contribute to fragile X-associated tremor/ataxia syndrome (FXTAS) pathogenesis. The most abundant RAN product, FMRpolyG, initiates predominantly at an ACG upstream of the repeat. Accurate FMRpolyG measurements in FXTAS patients are lacking. We used data-dependent acquisition and parallel reaction monitoring (PRM) mass spectrometry coupled with stable isotope labeled standard peptides to identify signature FMRpolyG fragments in patient samples. Following immunoprecipitation, PRM detected FMRpolyG signature peptides in transfected cells, and FXTAS tissues and cells, but not in controls. We identified two amino-terminal peptides: an ACG-initiated Ac-MEAPLPGGVR and a GUG-initiated Ac-TEAPLPGGVR, as well as evidence for RAN translation initiation within the CGG repeat itself in two reading frames. Initiation at all sites increased following cellular stress, decreased following eIF1 overexpression and was eIF4A and M7G cap-dependent. These data demonstrate that FMRpolyG is quantifiable in human samples and FMR1 RAN translation initiates via similar mechanisms for near-cognate codons and within the repeat through processes dependent on available initiation factors and cellular environment.

"Don't Know where to Go for Help": Safety and Economic Needs among Violence Survivors during the COVID-19 Pandemic.

The COVID-19 pandemic and related quarantine has created additional problems for survivors of interpersonal violence. The purpose of this study is to gain a preliminary understanding of the health, safety, and economic impacts of the COVID-19 pandemic on people that are experiencing or have previously experienced violence, stalking, threats, and/or abuse. An online survey, open from April to June 2020, was taken by people with safety concerns from interpersonal violence. Participants were recruited from IPV and sexual assault-focused agencies, state coalitions, and social media. Quantitative data were summarized using descriptive methods in SPSS and coding methods from thematic and content analysis was used to analyze qualitative data from open-ended questions. A total of 53 participants were recruited for the survey. Individuals with safety concerns have experienced increased challenges with health and work concerns, stress from economic instability, difficulties staying safe, and access resources and support. Over 40% of participants reported safety had decreased. Use of social media and avoidance strategies were the most common safety approaches used. Participants reported mixed experiences with virtual services. The COVID-19 pandemic has exacerbated existing structural concerns for survivors of violence like IPV and sexual assault. Increased support and economic resource access, coupled with modified safety planning and improved virtual approaches, would better help meet survivor needs.

On the Front Lines of the COVID-19 Pandemic: Occupational Experiences of the Intimate Partner Violence and Sexual Assault Workforce.

In the face of increasing risk for intimate partner violence (IPV) and sexual assault during the COVID-19 pandemic, there is an urgent need to understand the experiences of the workforce providing support to survivors, as well as the evolving service delivery methods, shifting safety planning approaches, and occupational stress of frontline workers. We addressed this gap by conducting an online survey of members of IPV and sexual assault workforce using a broad, web-based recruitment strategy. In total, 352 staff from 24 states participated. We collaborated with practitioner networks and anti-violence coalitions to develop the brief survey, which included questions about work and health, safety planning, and stress. We used chi-square, t-test, and ANOVA analysis techniques to analyze differences within position and demographic variables. For qualitative data, we used thematic analysis to analyze responses from four open-ended questions. The sample was majority female-identified (93.7%) and essential workers in dual IPV and sexual assault programs (80.7%). Findings demonstrated that since the pandemic began, IPV and sexual assault staff are experiencing more personal and professional stressors, perceive a decrease in client safety, and lack resources needed to help survivors and themselves. Common problems included a lack of food or supplies at home and work and housing and financial support for survivors. There was a 51% increase in the use of video conference for work, which contributed to workforce strain. Reductions in overall service capacity and a shift to remote service provision have implications for both survivors and staff. These findings suggest a critical need for additional training, infrastructure, and support for the IPV and sexual assault workforce. There is an urgent need to classify IPV and sexual assault staff as first responders and address the occupational stress associated with the COVID-19 pandemic.

Does chronotype explain daily timing of music behaviors?

We addressed how circadian rhythms influence daily musical activities of performing musicians, who exhibit fine temporal control. Music performances often occur in the evening and late at night; evidence suggests that composing musicians tend to be later chronotypes than non-composing musicians. However, chronotype and daily music-making in performing musicians have yet to be investigated. The current study examined chronotype in actively practicing and/or performing musicians and non-musicians, and whether it was related to the daily timing of music performance. To test influences of daily changes due to the global COVID-19 pandemic, disruptions to musical, athletic, social, and sleep habits were also measured. Performing musicians, active (practicing but non-performing) musicians, inactive musicians, and non-musicians, residing in Canada, completed a 7-day online daily activity and sleep diary in Summer 2020. There were more evening chronotypes than morning chronotypes in the sample. Active/performing musicians tended to be earlier chronotypes than all other groups. Musicians' chronotype, but not nightly sleep timing, predicted the time of day that musicians made music: Late chronotypes made music later in the day and early chronotypes made music earlier in the day. Music performance and practice amount decreased during the COVID-19 period, but the daily timing of these activities did not change. All participants reported later sleep onset during the COVID-19 period; the amount of social interaction decreased during the COVID-19 period, while exercise increased for some and decreased for others. No changes in the daily timing of exercise, social interaction, or morning wake-up were reported. These findings suggest that performing musicians may be slightly earlier chronotypes than non-performing musicians and non-musicians, despite music performances often occurring in the evening. Chronotype was related to the time of day of music-making independent of nightly sleep timing, suggesting that times of day for making music reflect an individual's circadian rhythm.

Improving Access to Kidney Transplantation: Perspectives From Dialysis and Transplant Staff in the Southeastern United States.

RATIONALE & OBJECTIVE: There are many barriers to meeting the goal of increasing kidney transplants in the United States. It is important to understand dialysis and transplant center providers' existing practices and identified barriers to increasing the number of dialysis patients who are evaluated for and get wait-listed for a transplant. STUDY DESIGN: Cross-sectional survey of dialysis unit and transplant center staff in End Stage Renal Disease Network 6 (Georgia, North Carolina, South Carolina). SETTING & PARTICIPANTS: Ninety-one transplant staff from all 9 transplant centers in the region and 421 dialysis staff from 421 facilities responded to the survey. PREDICTORS: N/A. OUTCOME: Provider perceptions of barriers faced by patients in the kidney transplant evaluation process and suggestions for improving care. ANALYTICAL APPROACH: Mixed methods. Descriptive analyses of responses to multiple-choice questions and qualitative analysis of open-ended survey responses. RESULTS: The top 5 barriers to kidney transplantation as reported by transplant staff were transportation (63.7%), low health literacy (50.5%), lack of understanding about the transplant process (37.4%), distance to transplant center (29.7%), and low socioeconomic status (28.6%). When asked how dialysis units can help patients complete the evaluation process, the most common responses from transplant center staff were educating patients about transplant (54%), helping patients through steps in the process (35%), and better communication with transplant centers (15%). When dialysis unit staff were asked what could be done to help the facility improve its transplant wait-list rate, the most common responses were educational materials for patients and staff (55%), better communication with transplant centers (12%), and transportation and financial assistance (9%). LIMITATIONS: Survey responses are from 1 end stage renal disease network. CONCLUSIONS: Dialysis units, transplant centers, and ESRD networks can work together to help patients address key barriers to transplantation to improve the country's transplantation rate.

SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity.

Transcribed CGG repeat expansions cause neurodegeneration in Fragile X-associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA-binding proteins (RBPs) into nuclear foci and undergo repeat-associated non-AUG (RAN) translation into toxic peptides. To identify proteins involved in these processes, we employed a CGG repeat RNA-tagging system to capture repeat-associated RBPs by mass spectrometry in mammalian cells. We identified several SR (serine/arginine-rich) proteins that interact selectively with CGG repeats basally and under cellular stress. These proteins modify toxicity in a Drosophila model of FXTAS. Pharmacologic inhibition of serine/arginine protein kinases (SRPKs), which alter SRSF protein phosphorylation, localization, and activity, directly inhibits RAN translation of CGG and GGGGCC repeats (associated with C9orf72 ALS/FTD) and triggers repeat RNA retention in the nucleus. Lowering SRPK expression suppressed toxicity in both FXTAS and C9orf72 ALS/FTD model flies, and SRPK inhibitors suppressed CGG repeat toxicity in rodent neurons. Together, these findings demonstrate roles for CGG repeat RNA binding proteins in RAN translation and repeat toxicity and support further evaluation of SRPK inhibitors in modulating RAN translation associated with repeat expansion disorders.