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.

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.

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.

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?".

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.

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

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

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.

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 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.

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: and delivered in the first semester and and delivered in the second semester.

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.

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.

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.

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.

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.

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.

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.

Framing the future by mastering the new public health.

This commentary describes the Framing the Future task force of the Association of Schools and Programs of Public Health in recognition of the rapidly changing environment for education in public health.