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.

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.

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.

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.

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.].

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.

Application of the Intervention Mapping Framework to Develop an Integrated Twenty-first Century Core Curriculum-Part Three: Curriculum Implementation and Evaluation.

Public health professionals have been challenged to radically reform public health training to meet evolving demands of twenty-first century public health. Such a transformation requires a systems thinking approach with an interdisciplinary focus on problem solving, leadership, management and teamwork, technology and information, budgeting and finance, and communication. This article presents processes for implementing and evaluating a revised public health curriculum and outlines lessons learned from this initiative. To date, more than 200 students have participated in the initial pilot testing of this program. A rigorous process and outcome evaluation plan was developed and employed. Results from the evaluation were used to enhance the resulting curriculum. Specifically, all instructional materials were evaluated by both the students who received the materials and the faculty who presented the materials. As each successive pilot is delivered, both enrollment and faculty involvement has increased. Through this process, the value of committed faculty, the importance of engaging learners in the evaluation of an education program, and the need to implement curriculum that has been carefully evaluated and evidence-informed in nature has emerged. We credit our successful transformation of the Masters in Public Health core to the challenge provided by the Framing the Future task force, the commitment of our College of Public Health leadership, the engagement of our faculty, and the time we allowed for the process to unfold. Ultimately, we believe this transformed curriculum will result in better trained public health professionals, interdisciplinary practitioners who can see public health challenges in new and different ways.

Application of the Intervention Mapping Framework to Develop an Integrated Twenty-first Century Core Curriculum-Part Two: Translation of MPH Core Competencies into an Integrated Theory-Based Core Curriculum.

In the twenty-first century, the dynamics of health and health care are changing, necessitating a commitment to revising traditional public health curricula to better meet present day challenges. This article describes how the College of Public Health at the University of South Florida utilized the Intervention Mapping framework to translate revised core competencies into an integrated, theory-driven core curriculum to meet the training needs of the twenty-first century public health scholar and practitioner. This process resulted in the development of four sequenced courses: History and Systems of Public Health and Population Assessment I delivered in the first semester and Population Assessment II and Translation to Practice delivered in the second semester. While the transformation process, moving from traditional public health core content to an integrated and innovative curriculum, is a challenging and daunting task, Intervention Mapping provides the ideal framework for guiding this process. Intervention mapping walks the curriculum developers from the broad goals and objectives to the finite details of a lesson plan. Throughout this process, critical lessons were learned, including the importance of being open to new ideologies and frameworks and the critical need to involve key-stakeholders in every step of the decision-making process to ensure the sustainability of the resulting integrated and theory-based curriculum. Ultimately, as a stronger curriculum emerged, the developers and instructors themselves were changed, fostering a stronger public health workforce from within.

Application of the Intervention Mapping Framework to Develop an Integrated Twenty-First Century Core Curriculum-Part 1: Mobilizing the Community to Revise the Masters of Public Health Core Competencies.

Twenty-first century health challenges have significantly altered the expanding role and functions of public health professionals. Guided by a call from the Association of Schools and Programs of Public Health's (ASPPH) and the Framing the Future: The Second 100 Years of Education for Public Health report to adopt new and innovative approaches to prepare public health leaders, the University of South Florida College of Public Health aimed to self-assess the current Masters of Public Health (MPH) core curriculum with regard to preparing students to meet twenty-first century public health challenges. This paper describes how Intervention Mapping was employed as a framework to increase readiness and mobilize the COPH community for curricular change. Intervention Mapping provides an ideal framework, allowing organizations to access capacity, specify goals, and guide the change process from curriculum development to implementation and evaluation of competency-driven programs. The steps outlined in this paper resulted in a final set of revised MPH core competencies that are interdisciplinary in nature and fulfill the emergent needs to address changing trends in both public health education and challenges in population health approaches. Ultimately, the competencies developed through this process were agreed upon by the entire College of Public Health faculty, signaling one college's readiness for change, while providing the impetus to revolutionize the delivery of public health education at the University of South Florida.

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.

Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA).

The C-5 substituted 2,4-diaminoquinazoline RG3039 (compound 1), a member of a chemical series that was identified and optimized using an SMN2 promoter screen, prolongs survival and improves motor function in a mouse model of spinal muscular atrophy (SMA). It is a potent inhibitor of the mRNA decapping scavenger enzyme (DcpS), but the mechanism whereby DcpS inhibition leads to therapeutic benefit is unclear. Compound 1 is a dibasic lipophilic molecule that is predicted to accumulate in lysosomes. To understand if the in vivo efficacy is due to DcpS inhibition or other effects resulting from the physicochemical properties of the chemotype, we undertook structure based molecular design to identify DcpS inhibitors with improved physicochemical properties. Herein we describe the design, synthesis, and in vitro pharmacological characterization of these DcpS inhibitors along with the in vivo mouse CNS PK profile of PF-DcpSi (compound 24), one of the analogs found to be efficacious in SMA mouse model.

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.

A Small-Molecule Anti-secretagogue of PCSK9 Targets the 80S Ribosome to Inhibit PCSK9 Protein Translation.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that downregulates low-density lipoprotein (LDL) receptor (LDL-R) levels on the surface of hepatocytes, resulting in decreased clearance of LDL-cholesterol (LDL-C). Phenotypic screening of a small-molecule compound collection was used to identify an inhibitor of PCSK9 secretion, (R)-N-(isoquinolin-1-yl)-3-(4-methoxyphenyl)-N-(piperidin-3-yl)propanamide (R-IMPP), which was shown to stimulate uptake of LDL-C in hepatoma cells by increasing LDL-R levels, without altering levels of secreted transferrin. Systematic investigation of the mode of action revealed that R-IMPP did not decrease PCSK9 transcription or increase PCSK9 degradation, but instead caused transcript-dependent inhibition of PCSK9 translation. In support of this surprising mechanism of action, we found that R-IMPP was able to selectively bind to human, but not E. coli, ribosomes. This study opens a new avenue for the development of drugs that modulate the activity of target proteins by mechanisms involving inhibition of eukaryotic translation.

Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment.

Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.

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.