SUMO-dependent transcriptional repression by Sox2 inhibits the proliferation of neural stem cells.

Sox2 is known for its roles in maintaining the stem cell state of embryonic stem cells and neural stem cells. In particular, it has been shown to slow the proliferation of these cell types. It is also known for its effects as an activating transcription factor. Despite this, analysis of published studies shows that it represses as many genes as it activates. Here, we identify a new set of target genes that Sox2 represses in neural stem cells. These genes are associated with centrosomes, centromeres and other aspects of cell cycle control. In addition, we show that SUMOylation of Sox2 is necessary for the repression of these genes and for its repressive effects on cell proliferation. Together, these data suggest that SUMO-dependent repression of this group of target genes is responsible for the role of Sox2 in regulating the proliferation of neural stem cells.

Fasting before Intra-Gastric Dosing with Antigen Improves Intestinal Humoral Responses in Syrian Hamsters.

Oral vaccines, unlike injected, induce intestinal secretory immunoglobulin A (sIgA) mimicking our natural defense against gut pathogens. We previously observed sIgA responses after administering the Clostridioides difficile colonisation factor CD0873 orally in enteric capsules to hamsters. Enteric-coated capsules are designed to resist dissolution in the stomach and disintegrate only at the higher pH of the small intestine. However, the variable responses between animals led us to speculate suboptimal transit of antigens to the small intestine. The rate of gastric emptying is a controlling factor in the passage of oral drugs for subsequent availability in the small intestine for absorption. Whilst in humans, food delays gastric emptying, in rats, capsules can empty quicker from fed stomachs than from fasted. To test in hamsters if fasting improves the delivery of antigens to the small intestine, as inferred from the immune responses generated, 24 animals were dosed intragastrically with enteric capsules containing recombinant CD0873. Twelve hamsters were fasted for 12 h prior to each dose and the other 12 fed. Significantly higher sIgA titres, with significantly greater bacterial-adherence-blocking activity, were detected in small intestinal lavages in the fasted group. We conclude that fasting in hamsters improves intestinal delivery leading to more robust responses.

Evaluation of strategies to support implementation of a hospital walking program: protocol for a type III effectiveness-implementation hybrid trial.

BACKGROUND: STRIDE is a supervised walking program designed to address the negative consequences of immobility during hospitalization for older adults. In an 8-hospital stepped wedge randomized controlled trial, STRIDE was associated with reduced odds of hospital discharge to skilled nursing facility. STRIDE has the potential to become a system-wide approach to address hospital-associated disability in Veteran's Affairs; however, critical questions remain about how best to scale and sustain the program. The overall study goal is to compare the impact of two strategies on STRIDE program penetration (primary), fidelity, and adoption implementation outcomes. METHODS: Replicating Effective Programs will be used as a framework underlying all implementation support activities. In a parallel, cluster randomized trial, we will use stratified blocked randomization to assign hospitals (n = 32) to either foundational support, comprised of standard, low-touch activities, or enhanced support, which includes the addition of tailored, high-touch activities if hospitals do not meet STRIDE program benchmarks at 6 and 8 months following start date. All hospitals begin with foundational support for 6 months until randomization occurs. The primary outcome is implementation penetration defined as the proportion of eligible hospitalizations with ≥ 1 STRIDE walks at 10 months. Secondary outcomes are fidelity and adoption with all implementation outcomes additionally examined at 13 and 16 months. Fidelity will be assessed for STRIDE hospitalizations as the percentage of eligible hospital days with "full dose" of the program, defined as two or more documented walks or one walk for more than 5 min. Program adoption is a binary outcome defined as ≥ 5 patients with a STRIDE walk or not. Analyses will also include patient-level effectiveness outcomes (e.g., discharge to nursing home, length of stay) and staffing and labor costs. We will employ a convergent mixed-methods approach to explore and understand pre-implementation contextual factors related to differences in hospital-level adoption. DISCUSSION: Our study results will dually inform best practices for promoting successful implementation of an evidence-based hospital-based walking program. This information may support other programs by advancing our understanding of how to apply and scale-up national implementation strategies. TRIAL REGISTRATION: This study was registered on June 1, 2021, at ClinicalTrials.gov (identifier NCT04868656 ).

Adaptations and early adoption of a family caregiver intervention in the Veterans Affairs Health Care System: A multimethod pragmatic approach for national scaling.

OBJECTIVE: To examine the relationship between site-level adaptation and early adoption of Caregivers Finding Important Resources, Support, and Training (FIRST) training during national implementation across diverse Veteran Health Administration (VA) medical centers. DATA SOURCES AND STUDY SETTING: We enrolled and evaluated 25 VA medical centers (VAMCs). Along with administrative data on site characteristics, we examined site-reported data on adaptations and intervention adoption, defined as ≥4 training classes delivered to ≥5 caregivers at 6 months from April through October 2022. STUDY DESIGN: A type III hybrid implementation-effectiveness cluster randomized controlled trial, randomized VAMCs 1:1 to receive foundational (low-touch) implementation support (n = 12) or the addition of enhanced (high-touch) implementation support (n = 13). DATA COLLECTION/EXTRACTION METHODS: At key implementation phases, VAMCs were asked to report adaptations including content, contextual modifications (format, setting, personnel, and population), and training of providers. We describe site-level adaptations by arm and by organizational characteristics that included VAMC complexity level, staffing, rurality, and organizational readiness to change. We used qualitative comparative analysis to identify unique adaptations that contributed to intervention adoption at 6 months. PRINCIPAL FINDINGS: VAMCs randomized to receive enhanced support reported slightly more adaptations than those randomized to foundational support. At 6 months, VAMCs with two or more adaptations adopted Caregivers FIRST at a higher rate than those with fewer adaptations (90% vs. 44%). Staffing adaptations (e.g., who delivered the intervention), format and content (e.g., modified delivery pace), and referring provider training were unique adaptations to adopting sites. CONCLUSIONS: Site-level adaptations were diverse and occurred more frequently in sites with early adoption of Caregivers FIRST. Future research should identify best practices of supporting and monitoring intervention adaptation. Understanding the role of adaptation in early adoption success could assist other healthcare systems in implementing interventions for caregivers.

Site-initiated adaptations in the implementation of an evidence-based inpatient walking program.

BACKGROUND: There is increasing recognition of the importance of maximizing program-setting fit in scaling and spreading effective programs. However, in the context of hospital-based mobility programs, there is limited information on how settings could consider local context and modify program characteristics or implementation activities to enhance fit. To fill this gap, we examined site-initiated adaptations to STRIDE, a hospital-based mobility program for older Veterans, at eight Veterans Affairs facilities across the United States. METHODS: STRIDE was implemented at eight hospitals in a stepped-wedge cluster randomized trial. During the pre-implementation phase, sites were encouraged to adapt program characteristics to optimize implementation and align with their hospital's resources, needs, and culture. Recommended adaptations included those related to staffing models, marketing, and documentation. To assess the number and types of adaptations, multiple data sources were reviewed, including implementation support notes from site-level support calls and group-based learning collaborative sessions. Adaptations were classified based on the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME), including attention to what was adapted, when, why, and by whom. We reviewed the number and types of adaptations across sites that did and did not sustain STRIDE, defined as continued program delivery during the post-implementation period. RESULTS: A total of 25 adaptations were reported and classified across seven of the eight sites. Adaptations were reported across five areas: program documentation (n = 13), patient eligibility criteria (n = 5), program enhancements (n = 3), staffing model (n = 2), and marketing and recruitment (n = 2). More than one-half of adaptations were planned. Adaptations were common in both sustaining and non-sustaining sites. CONCLUSIONS: Adaptations were common within a program designed with flexible implementation in mind. Identifying common areas of planned and unplanned adaptations within a flexible program such as STRIDE may contribute to more efficient and effective national scaling. Future research should evaluate the relationship between adaptations and program implementation.