A Sierra Leone 2021 Midwifery Clinical Training Needs Assessment: A Call to Action to Augment Clinical Precepting.

Objective: Sierra Leone has one of the highest maternal mortality and infant mortality rates globally. We share findings from a Midwifery Clinical Training Needs Assessment, conducted in 2021 as a collaboration between the Government of Sierra Leone and Seed Global Health. The assessment identified existing needs and gaps in midwifery clinical training at health facilities in Sierra Leone from various stakeholders' perspectives. Methods: The descriptive needs assessment utilized mixed methods, including surveys, focus group discussions (FGDs), interviews, and reviews of maternal medical records. Results: The following showed needs and gaps in labor and delivery management; record keeping; triage processes; clinical education for students, recent graduates, and preceptors; and lack of infrastructure and resources. Conclusion: The knowledge gained from this needs assessment can further the development of midwifery clinical training programs in Sierra Leone and other low-income countries facing similar challenges. We discuss the implication of our findings.

Embracing Social Engagement in Academic Medicine: Ongoing Challenges and How to Move Forward.

Academic medical centers have historically been defined by scientific discovery for health advancement. However, the mounting challenges of modern medicine are fueled by the social, economic, and political determinants of health that predict vulnerability and accelerate poor outcomes. To surmount looming threats to health, the academic medical mindset must equally prioritize social engagement-work that directly addresses the systemic social causes of health and illness-alongside the traditional pedagogy of laboratory-based, translational, and clinical research. Considerable barriers still exist, rooted in historical priorities and significant funding structured to reward scientific achievements. Academic medicine has the agency to support elements of restructuring to help prioritize research, education, and training to more prominently include social engagement. Crucial steps to ensure the success of this process include prioritizing financial commitments to community-engaged scholarship and programmatic work and rigorous recognition of faculty who work on socially engaged scholarship within promotion schemes. The COVID pandemic presents an unprecedented opportunity for academic medicine to reflect on the breadth of the work we promote and encourage, work that reflects all the complex elements of health-those that can be documented in a lab notebook and those rooted in social systems and structures that we have neglected for too long.

Functional analysis of clinical response to low-dose IL-2 in patients with refractory chronic graft-versus-host disease.

Patients with chronic graft-versus-host disease (cGVHD) have a paucity of regulatory CD4 T cells (CD4Tregs) that mediate peripheral tolerance. In clinical trials, daily low-dose interleukin-2 (IL-2) has been administered safely for prolonged periods in patients with steroid-refractory cGVHD. Peripheral CD4Tregs expand dramatically in all patients during IL-2 therapy but clinical improvement was observed in ∼50% of patients. Here, we examined the impact of low-dose IL-2 therapy on functional T-cell markers and the T-cell repertoire within CD4Tregs, conventional CD4 T cells (CD4Tcons), and CD8+ T cells. IL-2 had profound effects on CD4Tregs homeostasis in both response groups including selective expansion of the naive subset, improved thymic output, and increased expression of Ki67, FOXP3, and B-cell lymphoma 2 within CD4Tregs. Similar changes were not seen in CD4Tcons or CD8 T cells. Functionally, low-dose IL-2 enhanced, in vitro, CD4Treg-suppressive activity in both response groups, and all patient CD4Tcons were similarly suppressed by healthy donor CD4Tregs. High-throughput sequencing of the T-cell receptor ß (TCRß) locus demonstrated that low-dose IL-2 therapy increased TCR repertoire diversity and decreased evenness within CD4Tregs without affecting CD4Tcons or CD8 T cells. Using clone-tracking analysis, we observed rapid turnover of highly prevalent clones in CD4Tregs as well as the conversion of CD4Tcons to CD4Tregs. After 12 weeks of daily IL-2, clinical responders had a greater influx of novel clones within the CD4Treg compartment compared with nonresponders. Further studies to define the function and specificity of these novel CD4Treg clones may help establish the mechanisms whereby low-dose IL-2 therapy promotes immune tolerance.

Repurposing Hsp90 inhibitors as antibiotics targeting histidine kinases.

To address the growing need for new antimicrobial agents, we explored whether inhibition of bacterial signaling machinery could inhibit bacterial growth. Because bacteria rely on two-component signaling systems to respond to environmental changes, and because these systems are both highly conserved and mediated by histidine kinases, inhibiting histidine kinases may provide broad spectrum antimicrobial activity. The histidine kinase ATP binding domain is conserved with the ATPase domain of eukaryotic Hsp90 molecular chaperones. To find a chemical scaffold for compounds that target histidine kinases, we leveraged this conservation. We screened ATP competitive Hsp90 inhibitors against CckA, an essential histidine kinase in Caulobacter crescentus that controls cell growth, and showed that the diaryl pyrazole is a promising scaffold for histidine kinase inhibition. We synthesized a panel of derivatives and found that they inhibit the histidine kinases C. crescentus CckA and Salmonella PhoQ but not C. crescentus DivJ; and they inhibit bacterial growth in both Gram-negative and Gram-positive bacterial strains.

Are rare, long waiting times between rearrangement events responsible for the slowdown of the dynamics at the glass transition?

The dramatic slowdown of the structural relaxation at the glass transition is one of the most puzzling features of glass dynamics. Single molecule orientational correlation times show this strong Vogel-Fulcher-Tammann temperature dependence typical for glasses. Through statistical analysis of single molecule trajectories, we can identify individual glass rearrangement events in the vicinity of a probe molecule in the glass former poly(vinyl acetate) from 8 K below to 6 K above the glass transition temperature. We find that changes in the distribution of waiting times between individual glass rearrangement events are much less dramatic with temperature, the main difference being a small, but decisive number of increasingly long waiting times at lower temperatures. We notice similar individual, local relaxation events in molecular dynamics trajectories for a variety of glassy systems further from the glass transition, leading to waiting time distributions with similar features as those observed in the single molecule experiments. We show that these rare long waiting times are responsible for the dramatic increase in correlation time upon cooling.