A qualitative exploration of disseminating research findings among public health researchers in China.

BACKGROUND: Research dissemination is essential to accelerate the translating of evidence into practice. Little is known about dissemination among Chinese public health researchers. This study aimed to explore the understanding and practices of disseminating research findings and to identify barriers and facilitators that influence dissemination activities to non-research audiences. METHODS: This study deployed an exploratory qualitative design with purposive and snowball sampling. One focus group with 5 participants and 12 in-depth interviews were conducted with participants working in diverse fields from universities (n = 10), the National Chinese Center for Disease Control and Prevention (n = 4), the Chinese National Cancer Center (n = 1), the Chinese National Center for Cardiovascular Disease (n = 1), and China office of a global research institute (n = 1) from May to December 2021 to reach saturation. Data were initially analyzed using inductive thematic analysis. The designing for dissemination (D4D) logic model was then used to organize themes and subthemes. Two coders independently coded all transcripts and discussed disparities to reach a consensus. RESULTS: Out of 17 participants, 12 misunderstood the concept of dissemination; 14 had disseminated to non-research audiences: 10 to the public, 10 to practitioners, and 9 to policymakers. We identified multiple barriers to dissemination to non-research audiences across four phases of the D4D logic model, including low priority of dissemination, limited application of D4D strategies, insufficient support from the research organizations, practice settings, and health systems, and overemphasis on academic publications. CONCLUSIONS: There was a lack of understanding and experience of dissemination, indicating a lack of emphasis on active dissemination in China. We provide implications for raising awareness, building capacity, facilitating multidisciplinary collaboration, providing incentives and infrastructure, changing climate and culture, establishing communication and executive networks, and accelerating systematic shifts in impact focus.

Using National Public Health Accreditation to Explore Quality Improvement and Performance Management in Small Local Health Departments.

CONTEXT: This article focuses on 4 small local health departments (LHDs) that were in the process of seeking Public Health Accreditation Board (PHAB) reaccreditation or Pathways Recognition using PHAB Standards & Measures Version 2022. OBJECTIVE: The objective of this study was to explore the experiences of 4 small LHDs related to Quality Improvement (QI) and Performance Management (PM) in their pursuit of PHAB reaccreditation or Pathways Recognition. DESIGN: A team of researchers conducted 22 qualitative interviews with health department leaders and staff. Findings relative to QI/PM represent an embedded case study since they were part of a larger investigation. SETTING: The research team conducted interviews remotely with health departments located in the West and Midwest. PARTICIPANTS: Participants included adults at least 18 years old and employed in 1 of 4 health departments. MAIN OUTCOME MEASURES: Emergent themes from this qualitative investigation included using QI/PM tracking systems, building staff buy-in for QI/PM, integrating QI/PM into daily work, and advice for other health departments regarding QI/PM. RESULTS: Participants suggested that tracking systems helped them manage QI/PM processes. Staff buy-in for QI/PM was strengthened by building a sense of ownership of the process and connecting improvement processes to outcomes. Health departments integrated QI/PM into daily work by leadership modeling and communicating expectations. Advice for other health departments included finding a QI system that was easy to follow and recognizing the role of QI/PM in improving performance to better support the wellbeing of the community. CONCLUSIONS: QI/PM are important tools for health department effectiveness. Participants affirmed that the primary purposes of QI/PM are to enhance internal processes and improve community health outcomes. Study findings demonstrate how 4 small health departments integrated QI/PM into their public health practice.

Stepwise Stiffening/Softening of and Cell Recovery from Reversibly Formulated Hydrogel Interpenetrating Networks.

Biomechanical contributions of the extracellular matrix underpin cell growth and proliferation, differentiation, signal transduction, and other fate decisions. As such, biomaterials whose mechanics can be spatiotemporally altered- particularly in a reversible manner- are extremely valuable for studying these mechanobiological phenomena. Herein, a poly(ethylene glycol) (PEG)-based hydrogel model consisting of two interpenetrating step-growth networks is introduced that are independently formed via largely orthogonal bioorthogonal chemistries and sequentially degraded with distinct recombinant sortases, affording reversibly tunable stiffness ranges that span healthy and diseased soft tissues (e.g., 500 Pa-6 kPa) alongside terminal cell recovery for pooled and/or single-cell analysis in a near "biologically invisible" manner. Spatiotemporal control of gelation within the primary supporting network is achieved via mask-based and two-photon lithography; these stiffened patterned regions can be subsequently returned to the original soft state following sortase-based secondary network degradation. Using this approach, the effects of 4D-triggered network mechanical changes on human mesenchymal stem cell morphology and Hippo signaling, as well as Caco-2 colorectal cancer cell mechanomemory using transcriptomics and metabolic assays are investigated. This platform is expected to be of broad utility for studying and directing mechanobiological phenomena, patterned cell fate, and disease resolution in softer matrices.

LDB1 establishes multi-enhancer networks to regulate gene expression.

How specific enhancer-promoter pairing is established is still mostly unclear. Besides the CTCF/cohesin machinery, only a few nuclear factors have been studied for a direct role in physically connecting regulatory elements. Here, we show via acute degradation experiments that LDB1 directly and broadly promotes enhancer-promoter loops. Most LDB1-mediated contacts, even those spanning hundreds of kb, can form in the absence of CTCF, cohesin, or YY1 as determined via the use of multiple degron systems. Moreover, an engineered LDB1-driven chromatin loop is cohesin independent. Cohesin-driven loop extrusion does not stall at LDB1 occupied sites but may aid the formation of a subset of LDB1 anchored loops. Leveraging the dynamic reorganization of nuclear architecture during the transition from mitosis to G1-phase, we establish a relationship between LDB1-dependent interactions in the context of TAD organization and gene activation. Lastly, Tri-C and Region Capture Micro-C reveal that LDB1 organizes multi-enhancer networks to activate transcription. This establishes LDB1 as a direct driver of regulatory network inter-connectivity.

YY1-controlled regulatory connectivity and transcription are influenced by the cell cycle.

Few transcription factors have been examined for their direct roles in physically connecting enhancers and promoters. Here acute degradation of Yin Yang 1 (YY1) in erythroid cells revealed its requirement for the maintenance of numerous enhancer-promoter loops, but not compartments or domains. Despite its reported ability to interact with cohesin, the formation of YY1-dependent enhancer-promoter loops does not involve stalling of cohesin-mediated loop extrusion. Integrating mitosis-to-G1-phase dynamics, we observed partial retention of YY1 on mitotic chromatin, predominantly at gene promoters, followed by rapid rebinding during mitotic exit, coinciding with enhancer-promoter loop establishment. YY1 degradation during the mitosis-to-G1-phase interval revealed a set of enhancer-promoter loops that require YY1 for establishment during G1-phase entry but not for maintenance in interphase, suggesting that cell cycle stage influences YY1's architectural function. Thus, as revealed here for YY1, chromatin architectural functions of transcription factors can vary in their interplay with CTCF and cohesin as well as by cell cycle stage.

The Kinematics of Proal Chewing in Rats.

Chewing kinematics are well-documented in several mammal species with fused mandibular symphyses, but relatively understudied in mammals with an unfused symphysis, despite the fact that more than half of extant Mammalia have an unfused mandibular symphysis. The Wistar brown rat (Rattus norvegicus) is widely used in human health research, including studies of mastication or neurological studies where mastication is the output behavior. These animals are known to have unfused mandibular symphyses and proal jaw (rostrocaudal) motion during occlusion, but the lack of high resolution, 3-dimensional analysis of rat chewing leaves the functional significance of symphyseal mobility unknown. We used biplanar fluoroscopy and the X-ray reconstruction of moving morphology workflow to quantify chewing kinematics in 3 brown rats, quantifying overall jaw kinematics, including motions about the temporomandibular joint and unfused mandibular symphysis. During occlusion, the teeth and the mandibular condyle translate almost exclusively anteriorly (proal) during occlusion, with little motion in any other degrees of freedom. At the symphysis, we observed minimal flexion throughout the chew cycle. Overall, there are fundamental differences in jaw kinematics between rats and other mammals and therefore rats are not an appropriate proxy for ancestral mammal jaw mechanics. Additionally, differences between humans and rat chewing kinematics must be considered when using rats as a clinical model for pathological feeding research.

Experimental evidence that activewear retail imagery elicits physiological, attentional and self-reported markers of body image threat in women.

Online apparel retail imagery is a prominent threat to women's body image, particularly segments such as activewear which emphasize the value of women's bodies. In a within-subjects experiment, we exposed women (N = 128) to imagery randomly selected from activewear, casualwear and homewares websites and measured their gaze behavior, physiological arousal, as well as subjective emotional states and body image ratings. Exposure to activewear retail imagery elicited significantly lower body image ratings, a higher negative emotional state, and a lower positive emotional state compared to the other website imagery conditions. Physiological arousal was significantly higher for both apparel imagery conditions compared to the homewares imagery condition. Body biased gaze behavior was significantly higher for the activewear imagery condition compared to the casualwear imagery condition. Notably, body shame moderated the self-reported but not the physiological experimental effects, such that women with higher body shame experienced stronger adverse changes in their body image and emotional state ratings following activewear exposure. Correlations revealed that self-reported experimental responses to activewear imagery were strongly associated with self-objectification, appearance comparison, disordered eating and body image coping attitudes. Thus, exposure to popular apparel may play a role in maintaining maladaptive body image attitudes and behaviors in women.

Core outcomes in nerve surgery: development of a core outcome set for common peroneal (fibular) neuropathy.

OBJECTIVE: Common peroneal (fibular) neuropathy is the most common mononeuropathy of the lower extremity. Despite this, there are surprisingly few studies on the topic, and a knowledge gap remains in the literature. As one attempts to address this knowledge gap, a core outcome set (COS) is needed to guide the planning phases of future studies to allow synthesis and comparability of these studies. The objective of this study was to develop the COS-common peroneal neuropathy (CoPe) using a modified Delphi approach. METHODS: A 5-stage approach was used to develop the COS-CoPe: 1) stage 1, consortium development; 2) stage 2, a literature review to identify potential outcome measures; 3) stage 3, a Delphi survey to develop consensus on outcomes for inclusion; 4) stage 4, a Delphi survey to develop definitions; and 5) stage 5, a consensus meeting to finalize COS and definitions. The study followed the COS-STAndards for Development (COS-STAD) recommendations. RESULTS: The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 23 participants, all neurological surgeons, representing 13 countries. The final COS-CoPe consisted of 31 data points/outcomes covering domains of demographics, diagnostics, patient-reported outcomes, motor/sensory outcomes, and complications. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 12 months. The consensus optimal time points for assessment were preoperatively and 3, 6, 12, and 24 months postoperatively. CONCLUSIONS: The COINS Consortium developed a consensus COS and provided definitions, methods of implementation, and time points for assessment. The COS-CoPe should serve as a minimum set of data that should be collected in all future neurosurgical studies on common peroneal neuropathy. Incorporation of this COS should help improve consistency in reporting, data synthesis, and comparability, and should minimize outcome reporting bias.

Equipping the Public Health Workforce of the Future: Evaluation of an Evidence-Based Public Health Training Delivered Through Academic-Health Department Partnerships.

OBJECTIVE: Maintaining a skilled public health workforce is essential but challenging given high turnover and that few staff hold a public health degree. Situating workforce development within existing structures leverages the strengths of different organizations and can build relationships to address public health challenges and health equity. We implemented and evaluated an innovative, sustainable model to deliver an established evidence-based public health (EBPH) training collaboratively among Prevention Research Centers (PRC), local and state health departments, and Public Health Training Centers (PHTC). DESIGN: Quantitative data: quasi-experimental, 1-group pre-post. Qualitative data: cross-sectional. Data were collected between December 2021 and August 2022. SETTING: Four US sites, each a partnership between a PRC, local or state health department, and a PHTC. PARTICIPANTS: Governmental public health staff and representatives from other organizations that implement public health programs in practice settings. MAIN OUTCOME MEASURES: Course participants completed a pre- and postcourse survey self-rating 14 skills on a 5-point Likert scale. Differences were analyzed using mixed effects linear models. In-depth interviews (n = 15) were conducted with course faculty and partners to understand: (1) resources contributed, (2) barriers and facilitators, (3) benefits and challenges, and (4) resources needed to sustain this model. Interviews were transcribed verbatim, and a thematic analysis identified themes. RESULTS: Statistically significant increases in all skills were observed from pre- to postcourse (n = 241 at post, 90% response). The skills with the largest increases were understanding economic evaluation enough to inform decision-making (mean change = 1.22, standard error [SE] = 0.05) and developing an action plan (mean change = 1.07, SE = 0.07). Facilitators to delivering the course included having a shared goal of workforce development, existing course curricula, and dedicated funding for delivering the course. CONCLUSIONS: Collaborative delivery of the EBPH training can ameliorate the effects of high staff turnover, strengthen academic-practice relationships, and promote population-wide health and health equity.

Identification of Small-Molecule Antagonists Targeting the Growth Hormone Releasing Hormone Receptor (GHRHR).

The growth hormone-releasing hormone receptor (GHRHR) belongs to Class B1 of G protein-coupled receptors (GPCRs). Class B1 GPCR peptides such, as growth hormone-releasing hormone (GHRH), have been proposed to bind in a two-step model, where first the C-terminal region of the peptide interacts with the extracellular domain of the receptor and, subsequently, the N-terminus interacts with the seven transmembrane domain of the receptor, resulting in activation. The GHRHR has recently been highlighted as a promising drug target toward several types of cancer and has been shown to be overexpressed in prostate, breast, pancreatic, and ovarian cancer. Indeed, peptide GHRHR antagonists have displayed promising results in many cancer models. However, no nonpeptide GHRHR-targeting compounds have yet been identified. We have utilized several computational tools to target GHRHR and identify potential small-molecule compounds directed at this receptor. These compounds were validated in vitro using a cyclic adenosine monophosphate (cAMP) ELISA to measure activity at the GHRHR. In vitro results suggest that several of the novel small-molecule compounds could inhibit GHRH-induced cAMP accumulation. Preliminary analysis of the specificity/selectivity of one of the most effective hit compounds indicated that the effect seen was via inhibition of the GHRHR. We therefore report the first nonpeptide antagonists of GHRHR and propose a structural basis for inhibition induced by the compounds, which may assist in the future design of lead GHRHR compounds for treating disorders attributed to dysregulated/aberrant GHRHR signaling.

Peptide-enabled ribonucleoprotein delivery for CRISPR engineering (PERC) in primary human immune cells and hematopoietic stem cells.

Peptide-enabled ribonucleoprotein delivery for CRISPR engineering (PERC) is a new approach for ex vivo genome editing of primary human cells. PERC uses a single amphiphilic peptide reagent to mediate intracellular delivery of the same pre-formed CRISPR ribonucleoprotein enzymes that are broadly used in research and therapeutics, resulting in high-efficiency editing of stimulated immune cells and cultured hematopoietic stem and progenitor cells (HSPCs). PERC facilitates nuclease-mediated gene knockout, precise transgene knock-in, and base editing. PERC involves mixing the CRISPR ribonucleoprotein enzyme with peptide and then incubating the formulation with cultured cells. For efficient transgene knock-in, adeno-associated virus (AAV) bearing homology-directed repair template DNA may be included. In contrast to electroporation, PERC is appealing as it requires no dedicated hardware and has less impact on cell phenotype and viability. Due to the gentle nature of PERC, delivery can be performed multiple times without substantial impact to cell health or phenotype. Here we report methods for improved PERC-mediated editing of T cells as well as novel methods for PERC-mediated editing of HSPCs, including knockout and precise knock-in. Editing efficiencies can surpass 90% using either Cas9 or Cas12a in primary T cells or HSPCs. Because PERC calls for only three readily available reagents - protein, RNA, and peptide - and does not require dedicated hardware for any step, PERC demands no special expertise and is exceptionally straightforward to adopt. The inherent compatibility of PERC with established cell engineering pipelines makes this approach appealing for rapid deployment in research and clinical settings.

Comparative CNS Pharmacology of the Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Tolebrutinib is a covalent BTK inhibitor designed and selected for potency and CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied a translational approach to evaluate three BTK inhibitors in Phase 3 clinical development in MS with respect to their relative potency to block BTK-dependent signaling and exposure in the CNS METHODS: We used in vitro kinase and cellular activation assays, alongside pharmacokinetic sampling of cerebrospinal fluid (CSF) in the non-human primate cynomolgus to estimate the ability of these candidates (evobrutinib, fenebrutinib, and tolebrutinib) to block BTK-dependent signaling inside the CNS. RESULTS: In vitro kinase assays demonstrated that tolebrutinib reacted with BTK 65-times faster than evobrutinib, while fenebrutinib, a classical reversible antagonist with a Ki value of 4.7 nM and slow off-rate (1.54 x 10-5 s-1), also had an association rate 1760-fold slower (0.00245 µM-1 * s-1). Estimates of cellular potency were largely consistent with the in vitro kinase assays, with an estimated IC50 of 0.7 nM for tolebrutinib against 33.5 nM for evobrutinib and 2.9 nM for fenebrutinib. We then observed that evobrutinib, fenebrutinib, and tolebrutinib achieved similar levels of exposure in non-human primate CSF after oral doses of 10 mg/kg. However, tolebrutinib CSF exposure (4.8 ng/mL) (kp,uu CSF=0.40) exceeded the IC90 (the estimated concentration inhibiting 90% of kinase activity) value, while evobrutinib (3.2 ng/mL) (kp,uu CSF=0.13) and fenebrutinib (12.9 ng/mL) (kp,uu CSF=0.15) failed to reach the estimated IC90 values. CONCLUSIONS: Tolebrutinib was the only candidate of the three that attained relevant CSF exposure in non-human primates.

Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes.

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state regulatory potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbor distinctive transcription factor binding motifs that are similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we show that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

Closing the gap: advancing implementation science through training and capacity building.

In their article on "Navigating the Field of Implementation Science Towards Maturity: Challenges and Opportunities," Chambers and Emmons describe the rapid growth of implementation science along with remaining challenges. A significant gap remains in training and capacity building. Formats for capacity building include university degree programs, summer training institutes, workshops, and conferences. In this letter, we describe and amplify on five key areas, including the need to (1) identify advanced competencies, (2) increase the volume and reach of trainings, (3) sustain trainings, (4) build equity focused trainings, and (5) develop global capacity. We hope that the areas we highlight will aid in addressing several key challenges to prioritize in future efforts to build greater capacity in implementation science.

Early safety of endoscopic sleeve gastroplasty in super obesity (body mass index > 50).

BACKGROUND: The prevalence of super obesity (body mass index [BMI] > 50) continues to rise. However, the adoption of bariatric surgery in this population remains very low. There are limited studies evaluating the utility of endoscopic sleeve gastroplasty (ESG) in super obesity. OBJECTIVES: The purpose of this study is to evaluate the short-term safety profile of ESG in patients with super obesity using data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database. SETTING: United States. METHODS: We retrospectively analyzed patients who underwent ESG and sleeve gastrectomy (SG) from 2016 to 2021. Patients with BMI >50 who underwent ESG were compared to ESG patients with BMI <50 and also SG patients with BMI >50. Primary outcomes included the incidence of severe adverse events (AEs), hospital readmission, reintervention, and reoperation within 30 days of the primary procedure. Secondary outcomes included procedure time, hospital length of stay, and total body weight loss at 30 days. RESULTS: There were no significant differences in AE, reoperations, hospital readmissions, or reinterventions for patients with super obesity undergoing ESG, compared to patients with BMI below 50. Mean total body weight loss was greater in patients with super obesity. There were no significant differences in AEs for patients with super obesity who underwent ESG versus SG, although ESG patients had more hospital readmissions, reinterventions, and reoperations. CONCLUSIONS: ESG may be performed safely, with comparable safety to SG, in patients with BMI as high as 70. However, further studies are needed to validate the feasibility and long-term efficacy prior to clinical implementation.

Who Benefits? A Mixed Methods Study Assessing Community Use of a Major Metropolitan Park During the COVID-19 Pandemic.

By providing spaces for recreation, physical activity, social gatherings, and time in nature, urban parks offer physical, mental, and social benefits to users. However, many urban residents face barriers to park use. The COVID-19 pandemic introduced new potential barriers to urban park access and use, including changes to daily life and employment, closure of park amenities and restrictions to public movement, and risk from the coronavirus itself. The mixed-methods PARCS study measured use and perceptions of a large urban park in St. Louis, Missouri before, during, and after local COVID-19 contingency measures and restrictions. We examine data from 1,157 direct observation assessments of park usership, an online survey of park users (n=561), interviews with key stakeholders (n=27), four focus groups (n=30), and a community-based participatory research sub-study (n=66) to comprehensively characterize the effects of the COVID-19 pandemic on park use. Park users who felt unsafe from the coronavirus experienced 2.65 higher odds of reducing park use. However, estimated park visits during COVID-19 contingency measures (n=5,023,759) were twice as high as post-contingency (n=2,277,496). Participants reported using the park for physical activity, recreation, time in nature, and socializing during the contingency period. Black, Hispanic/Latino, and young people were less likely to visit the park than others, suggesting an additional, disproportionate impact of the pandemic on minoritized and socioeconomically disadvantaged communities. This study highlights the role of public spaces like parks as resources for health and sites where urban health inequities can be alleviated in times of public crisis.

Evidence That Pervasive Body Gaze Behavior in Heterosexual Men Is a Social Marker for Implicit, Physiological, and Explicit Sexual Assault Propensities.

Deliberate and effortful attempts to gaze at the bodies of women is emerging as a valuable marker of sexual objectification in men. Some preliminary evidence suggests that pervasive body gaze behavior may also accompany insidious attitudes which can facilitate sexual assault. The present study aimed to further explore this potential by examining pervasive body gaze associations with explicit, implicit, and physiological sexual assault propensity measures. We presented 110 heterosexual male participants with images of fully and partially dressed women with and without injuries while measuring their skin conductance responses. We also captured implicit and explicit sexual assault measures in addition to self-reported pervasive body gaze behavior. Pervasive body gaze behavior was significantly correlated with rape myth acceptance attitudes, prior perpetration of sexual assault, a stronger implicit association between erotica and aggression, and lower physiological reactivity during exposure to partially dressed injured women. These findings suggest that body gaze towards women could be a behavioral marker for inclinations to victim blame, preferences for rough sexual conduct, and a physiological desensitization towards female victims. This study further validates a five item self-reported body gaze measure as a valuable tool for detecting deviant sexual objectification attitudes and affective states. As such, measurement and observation of body gaze behavior could be useful for developing risk assessments, estimating intervention efficacy, and enhancing public awareness.

Exposure to preference-matched alcohol advertisements from national sports broadcasts increases short-term alcohol consumption inclinations in risky drinkers.

BACKGROUND: In Australia, sports broadcasting is afforded special alcohol advertising rights during daytime hours, which raises public health concerns, including short-term increases in alcohol consumption among the broad viewership of national sporting codes. METHODS: We conducted a content analysis across a sample of nationally televised finals matches (N = 16) from the Australian Football League (AFL) and the National Rugby League (NRL) to determine the prevalence of alcohol advertising video clips during these broadcasts. We also conducted an online experiment exposing participants (N = 345) to a randomly selected alcohol advertisement and measured the immediate effects on self-reported alcohol craving and drinking intentions. RESULTS: The prevalence of alcohol advertising video clips during AFL broadcasts was 3.9% and 1.8% for NRL. While, overall, alcohol advertisement video clip exposure did not impact craving or drinking intentions, a modest increase in craving was found for a subsample of risky drinking participants (N = 107) who also reported a preference for the specific alcoholic beverage being advertised. CONCLUSIONS: Video alcohol advertisements occurred less than 1 in 20 advertisements on average and exposure to alcohol advertising elicited a low, yet measurable, short-term increase in alcohol inclinations, among vulnerable adult drinkers when a desirable alcoholic beverage advertisement is viewed. SO WHAT?: Given that alcohol advertisements are most likely to increase consumption among risky drinkers, health messaging during sports broadcasts needs to specifically target these individuals.

Reimagining Public Health: Mapping A Path Forward.

The COVID-19 pandemic and other ongoing public health challenges have highlighted deficiencies in the US public health system. The United States is in a unique moment that calls for a transformation that builds on Public Health 3.0 and its focus on social determinants of health and partnerships with diverse sectors while also acknowledging how the pandemic altered the landscape for public health. Based on relevant literature, our experience, and interviews with public health leaders, we describe seven areas of focus within three broad categories to support transformational change. Contextual areas of focus include increasing accountability and addressing politicization and polarization. Topical areas of focus highlight prioritizing climate change and sharpening the focus on equity. Technical areas of focus include advancing data sciences, building the workforce, and enhancing communication capacity. A transformed public health system will depend highly on leadership, funding incentives, and both bottom-up and top-down approaches. A broad effort is needed by public health agencies, governments, and academia to accelerate the transition to a next phase for public health.

Fluorinated perhexiline derivative attenuates vascular proliferation in pulmonary arterial hypertension smooth muscle cells.

Increased proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs) is recognised as a universal hallmark of pulmonary arterial hypertension (PAH), in part related to the association with reduced pyruvate dehydrogenase (PDH) activity, resulting in decreased oxidative phosphorylation of glucose and increased aerobic glycolysis (Warburg effect). Perhexiline is a well-recognised carnitine palmitoyltransferase-1 (CPT1) inhibitor used in cardiac diseases, which reciprocally increases PDH activity, but is associated with variable pharmacokinetics related to polymorphic variation of the cytochrome P450-2D6 (CYP2D6) enzyme, resulting in the risk of neuro and hepatotoxicity in 'slow metabolisers' unless blood levels are monitored and dose adjusted. We have previously reported that a novel perhexiline fluorinated derivative (FPER-1) has the same therapeutic profile as perhexiline but is not metabolised by CYP2D6, resulting in more predictable pharmacokinetics than the parent drug. We sought to investigate the effects of perhexiline and FPER-1 on PDH flux in PASMCs from patients with PAH. We first confirmed that PAH PASMCs exhibited increased cell proliferation, enhanced phosphorylation of AKTSer473, ERK 1/2Thr202/Tyr204 and PDH-E1αSer293, indicating a Warburg effect when compared to healthy PASMCs. Pre-treatment with perhexiline or FPER-1 significantly attenuated PAH PASMC proliferation in a concentration-dependent manner and suppressed the activation of the AKTSer473 but had no effect on the ERK pathway. Perhexiline and FPER-1 markedly activated PDH (seen as dephosphorylation of PDH-E1αSer293), reduced glycolysis, and upregulated mitochondrial respiration in these PAH PASMCs as detected by Seahorse analysis. However, both perhexiline and FPER-1 did not induce apoptosis as measured by caspase 3/7 activity. We show for the first time that both perhexiline and FPER-1 may represent therapeutic agents for reducing cell proliferation in human PAH PASMCs, by reversing Warburg physiology.