MCH Leadership Training Program: An Innovative Application of an Implementation Science Framework.

INTRODUCTION: MCH training programs in schools of public health provide specialized training to develop culturally competent and skilled MCH leaders who will play key roles in public health infrastructure. Previous literature has reported on the effectiveness of MCH training programs (e.g., number of trainees, improvement in knowledge/skills); less attention has been devoted to understanding factors influencing program implementation during times of rapid change, while considering internal and external contexts (e.g., global pandemic, social unrest, uncertainty of funding, mental health issues, and other crises). PURPOSE: This article describes a graduate-level MCH leadership training program and illustrates how an implementation science framework can inform the identification of determinants and lessons learned during one year of implementation of a multi-year program. ASSESSMENT: Findings reveal how CFIR can be applicable to a MCH training program and highlight how constructs across domains can interact and represent determinants that serve as both a barrier and facilitator. Key lessons learned included the value of accountability, flexibility, learner-centeredness, and partnerships. CONCLUSION: Findings may apply to other programs and settings and could advance innovative training efforts that necessitate attention to the multi-level stakeholder needs (e.g., student, program, institution, community, and local/regional/national levels). Applying CFIR could be useful when interpreting process and outcome evaluation data and transferring findings and lessons learned to other organizations and settings. Integrating implementation science specifically into MCH training programs could contribute to the rigor, adaptability, and dissemination efforts that are critical when learning and sharing best practices to expand leadership capacity efforts that aim to eliminate MCH disparities across systems.

Form Follows Function: A New Structure for a School of Public Health in the 21st Century.

National discussions around education in public health in the early 2010s and the subsequent revisions to accreditation criteria for schools of public health in 2016 resulted in a dramatic shift away from the traditional 5 core discipline model in requirements for core curricula and the offering of specific master of public health degrees. With greater flexibility and opportunities for innovation, the College of Public Health at the University of South Florida embarked on a reexamination of its organizational structure, which, like many accredited schools, was based on the old 5 core discipline model. A transparent, inclusive, and deliberative process ultimately resulted in the elimination of departments in favor of a unified faculty whose collective discipline is public health. Decisions made along the way, unexpected opportunities that arose in the implementation, as well as challenges and early results are discussed.

Correction: Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain.

[This corrects the article DOI: 10.1371/journal.pbio.2001882.].

Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF-06446846 reveals a previously unexpected tunability of the human ribosome that allows small molecules to specifically block translation of individual transcripts.

Channeling Our Legacy into Our Future: The Importance of the MCH Pipeline Training Program.

The MCH Pipeline Program, created in 2006, creates an important opportunity to identify and encourage undergraduate students from underrepresented populations to consider career paths in maternal and child health. These programs provide didactic instruction, experiential learning, and mentorship to a diverse group of young scholars in order to both enhance their opportunities to pursue graduate or professional degree training in the myriad professions that make up the MCH workforce and to provide them with essential grounding in the history, context and mission of MCH. The leaders of the funded programs meet periodically to exchange ideas; on this occasion, the author was asked to address the group responding to the question "what knowledge or skills are critical for emerging undergraduate scholars?". Placing these programs squarely in their historical context, her remarks are provided here to encourage others to consider developing programs for undergraduate students who may be enlisted to join the MCH profession.

The Foundation of the Future of MCH.

The accompanying article on the Future of Public Health is a timely call to action. It reminds us of our strong roots and also compels us to consider larger societal issues in pursuing our shared goals.

Discovery of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1-carboxamides as small molecule inhibitors of PCSK9.

A series of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1-carboxamides were identified as small molecule PCSK9 mRNA translation inhibitors. Analogues from this new chemical series, such as 4d and 4g, exhibited improved PCSK9 potency, ADME properties, and in vitro safety profiles when compared to earlier lead structures.

Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis.

Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18 F-isotopologue validated our liver-targeting approach.

Anticipating change, sparking innovation: framing the future.

As the 100th anniversary of the 1915 Welch-Rose report approaches, the Association of Schools and Programs of Public Health (ASPPH) has been pursuing two initiatives to spark innovation in academic partnerships for enhancing population health: (1) Framing the Future: The Second 100 Years of Education for Public Health and (2) Reconnecting Public Health and Care Delivery to Improve the Health of Populations. We describe how ASPPH-member schools and programs accredited by the Council on Education for Public Health, along with their extraordinarily diverse array of partners, are working to improve education that better prepares health professionals to meet 21st-century population health needs.

Our practice is our passion: development and delivery of a 21st-century doctor of public health program.

Twenty-first century advances have significantly altered the functions of public health professionals, resulting in a need for advanced level training in community health leadership and practice-oriented research without interruption of professional careers. We present an example of an innovative Doctor of Public Health (DrPH) program developed at the University of South Florida College of Public Health. This program incorporates 21st century public health competencies within a competency-based curricular model, delivered in a hybrid format (fall or spring online delivery and a 1-week face-to-face summer institute) in collaboration between academic and practice-based public health professionals at local and national levels. This revised competency-based program is an example of how to meet the needs of the 21st century public health practitioners while maintaining their connections to the practice world.

Breaking the silence of sharing data in medical research.

Data sharing is highly advocated in the scientific community, with numerous organizations, funding agencies, and journals promoting transparency and collaboration. However, limited research exists on actual data sharing practices. We conducted a comprehensive analysis of the intent to share individual participant data (IPD) in a total of 313,990 studies encompassing clinical trials and observational studies obtained from ClinicalTrials.gov, spanning the period from 2000 to 2023. Our study found that only 10.3% of principal investigators (PIs) expressed intent to share IPD. Clinical trials were more likely to share data than observational studies (odds ratio, OR = 1.98, 95% CI: 1.92-2.04). Large sample size studies were 1.69 times more likely to share data than small ones (95% CI: 1.65-1.73). Studies registered after 2018 were 1.6 times more likely to share data (95% CI: 1.57-1.64) than before 2019. NIH and other US Federal agency-funded studies had 1.49 times higher odds of sharing data (95% CI: 1.43-1.55) than other funders. USA-based studies were 1.53 times more likely to share data (95% CI: 1.49-1.57) than out of USA. Biological trials were 1.58 times more likely to share data than drug and other trials (95% CI: 1.51-1.66). Phase III trials had the highest odds, 2.47 times, of sharing data (95% CI: 2.38-2.56) than non-Phase III trials.

Design and synthesis of aryl sulfonamide-based nonsteroidal mineralocorticoid receptor antagonists.

Hit-to-lead medicinal chemistry efforts are described starting from a screening hit 1, leading to a new class of aryl sulfonamide-based MR antagonist, exemplified by 17, that possesses favourable MR binding affinity, selectivity profile against closely related NHRs, physicochemical properties and metabolic stability.

The Florida Investigation of Primary Late Preterm and Cesarean Delivery: the accuracy of the birth certificate and hospital discharge records.

(1) Assess the accuracy of public health data sources used to investigate primary late preterm cesarean delivery (PLPCD) and (2) compare differences in data accuracy by hospital PLPCD rate classification. This analysis uses data from the Florida Investigation of Late Preterm and Cesarean Delivery (FILPCD), an investigation of singleton, PLPCD's that occurred from 2006 to 2007 in hospitals classified with either a low or high PLPCD rate (high rate 39.4-58.3 %, low rate 11.9-25.1 %). Three data sources were validated with maternal medical records: birth certificates, hospital discharge data, and combined birth certificate and hospital discharge data. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa values were calculated. A summary measure of kappa values was compared by hospital PLPCD rate classification using the paired sample Wilcoxon signed rank test. Large variations in accuracy of data elements were found by hospital PLPCD rate classification, with low PLPCD rate hospitals demonstrating higher overall data accuracy. The summary measure of agreement was significantly higher for low PLPCD rate hospitals compared to high PLPCD rate hospitals (0.60 vs. 0.50, p < 0.01). Accurate estimates of CD and late preterm birth are vital for public health practitioners and policy makers who seek to address the growing concern over recent increases in CD and late preterm birth. Understanding the potential for systematic differences in reporting accuracy by hospital PLPCD rate is important to data quality improvement efforts.

Identification of Morpholino-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-ones as Nonsteroidal Mineralocorticoid Antagonists.

A novel series of morpholine-based nonsteroidal mineralocorticoid receptor antagonists is reported. Starting from a pyrrolidine HTS hit 9 that possessed modest potency but excellect selectivity versus related nuclear hormone receptors, a series of libraries led to identification of morpholine lead 10. After further optimization, cis disubstituted morpholine 22 was discovered, which showed a 45-fold boost in binding affinity and corresponding functional potency compared to 13. While 22 had high clearance in rat, it provided sufficient exposure at high doses to favorably assess in vivo efficacy (increased urinary Na+/K+ ratio) and safety. In contrast to rat, the dog and human MetID and PK profiles of 22 were adequate, suggesting that it could be suitable as a potential clinical asset.

Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents.

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, 7l demonstrated an improved safety profile vs lead 7f. We hypothesize that the improved safety profile is related to diminished binding of 7l to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of 7l stalling of off-target proteins.