Tobacco control interventions for populations living in subsidised, low-income housing: a scoping review.

OBJECTIVES: People living in subsidised low-income housing are more likely to smoke and experience secondhand smoke exposure compared to the general population. While tobacco control interventions have yielded substantial population health benefits, people living in subsidised housing experience a greater burden of tobacco-related harms. We synthesised existing peer-reviewed and grey literature to determine tobacco control interventions that have been implemented in subsidised housing globally, and to understand their impact on smoking and secondhand smoke exposure. METHODS: We searched five databases for peer-reviewed research, and Google Advanced for grey literature. We adhered to the JBI Scoping Review Methodology and Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. RESULTS: Fifty-seven sources met the eligibility criteria. The most common type of intervention was mandatory smoking bans covering all indoor spaces (n = 32), followed by cessation-focused interventions (n = 19). Interventions that indirectly addressed smoking were the least common (n = 6). Our findings suggest smoking bans can increase smoking cessation and reduce secondhand smoke exposure, especially if implemented alongside cessation support strategies. CONCLUSION: Tobacco control interventions targeting subsidised housing demonstrate positive effects on tobacco-related outcomes for residents and provide an important opportunity to address health disparities. Future research should examine the long-term impacts of the interventions, including potential unintended consequences, in varied subsidised housing contexts.

Evaluation of the Accuracy, Credibility, and Readability of Statin-Related Websites: Cross-Sectional Study.

BACKGROUND: Cardiovascular disease (CVD) represents the greatest burden of mortality worldwide, and statins are the most commonly prescribed drug in its management. A wealth of information pertaining to statins and their side effects is on the internet; however, to date, no assessment of the accuracy, credibility, and readability of this information has been undertaken. OBJECTIVE: This study aimed to evaluate the quality (accuracy, credibility, and readability) of websites likely to be visited by the general public undertaking a Google search of the side effects and use of statin medications. METHODS: Following a Google web search, we reviewed the top 20 consumer-focused websites with statin information. Website accuracy, credibility, and readability were assessed based on website category (commercial, not-for-profit, and media), website rank, and the presence or absence of the Health on the Net Code of Conduct (HONcode) seal. Accuracy and credibility were assessed following the development of checklists (with 20 and 13 items, respectively). Readability was assessed using the Simple Measure of Gobbledegook scores. RESULTS: Overall, the accuracy score was low (mean 14.35 out of 20). While side effects were comprehensively covered by 18 websites, there was little information about statin use in primary and secondary prevention. None of the websites met all criteria on the credibility checklist (mean 7.8 out of 13). The median Simple Measure of Gobbledegook score was 9.65 (IQR 8.825-10.85), with none of the websites meeting the recommended reading grade of 6, even the media websites. A website bearing the HONcode seal did not mean that the website was more comprehensive or readable. CONCLUSIONS: The quality of statin-related websites tended to be poor. Although the information contained was accurate, it was not comprehensive and was presented at a reading level that was too difficult for an average reader to fully comprehend. As such, consumers risk being uninformed about this pharmacotherapy.

Medicaid Expansion and Racial-Ethnic and Sex Disparities in Cardiovascular Diseases Over 6 Years: A Generalized Synthetic Control Approach.

BACKGROUND: Studies have suggested Medicaid expansion enacted in 2014 has resulted in a reduction in overall cardiovascular disease (CVD) mortality in the United States. However, it is unknown whether Medicaid expansion has a similar effect across race-ethnicity and sex. We investigated the effect of Medicaid expansion on CVD mortality across race-ethnicity and sex. METHODS: Data come from the behavioral risk factor surveillance system and the US Centers for Disease Control's Wide-ranging Online Data for Epidemiologic Research, spanning the period 2000-2019. We used the generalized synthetic control method, a quasi-experimental approach, to estimate effects. RESULTS: Medicaid expansion was associated with -5.36 (mean difference [MD], 95% confidence interval [CI] = -22.63, 11.91) CVD deaths per 100,000 persons per year among Blacks; -4.28 (MD, 95% CI = -30.08, 21.52) among Hispanics; -3.18 (MD, 95% CI = -8.30, 1.94) among Whites; -5.96 (MD, 95% CI = -15.42, 3.50) among men; and -3.34 (MD, 95% CI = -8.05, 1.37) among women. The difference in mean difference (DMD) between the effect of Medicaid expansion in Blacks compared with Whites was -2.18; (DMD, 95% CI = -20.20, 15.83); between that in Hispanics compared with Whites: -1.10; (DMD, 95% CI = -27.40, 25.20) and between that in women compared with men: 2.62; (DMD, 95% CI = -7.95, 13.19). CONCLUSIONS: Medicaid expansion was associated with a reduction in CVD mortality overall and in White, Black, Hispanic, male, and female subpopulations. Also, our study did not find any difference or disparity in the effect of Medicaid on CVD across race-ethnicity and sex-gender subpopulations, likely owing to imprecise estimates.

Monocyte Differentiation and Heterogeneity: Inter-Subset and Interindividual Differences.

The three subsets of human monocytes, classical, intermediate, and nonclassical, show phenotypic heterogeneity, particularly in their expression of CD14 and CD16. This has enabled researchers to delve into the functions of each subset in the steady state as well as in disease. Studies have revealed that monocyte heterogeneity is multi-dimensional. In addition, that their phenotype and function differ between subsets is well established. However, it is becoming evident that heterogeneity also exists within each subset, between health and disease (current or past) states, and even between individuals. This realisation casts long shadows, impacting how we identify and classify the subsets, the functions we assign to them, and how they are examined for alterations in disease. Perhaps the most fascinating is evidence that, even in relative health, interindividual differences in monocyte subsets exist. It is proposed that the individual's microenvironment could cause long-lasting or irreversible changes to monocyte precursors that echo to monocytes and through to their derived macrophages. Here, we will discuss the types of heterogeneity recognised in monocytes, the implications of these for monocyte research, and most importantly, the relevance of this heterogeneity for health and disease.

The association between provider encouragement and sodium consumption behaviors.

OBJECTIVE: To explore and describe the associations between provider encouragement and four sodium consumption behaviors. METHODS: We analyzed a 2016 Internet panel survey dataset of 954 socio-demographically diverse adults (age ≥18 years) living in Los Angeles County. Behaviors analyzed were current status of watching one's salt/sodium intake, frequency of adding salt to food, frequency of using a food/Nutrition Facts label to decide what food to purchase, and frequency of changing one's mind about buying a food product due to its sodium content. Multivariable logistic regression analyses examined the relationship between doctor/health professional (provider) encouragement and these sodium-related behaviors, controlling for self-reported health status and sociodemographic characteristics. RESULTS: Provider encouragement was positively associated with three of the four sodium consumption behaviors examined: currently watching salt/sodium intake (AOR=7.27, 95% CI=3.97-13.34); frequently using a food/Nutrition Facts label (AOR=1.70, 95% CI=1.09-2.64); and frequently changing one's mind about buying a food product due to its sodium content (AOR=2.29, 95% CI=1.45-3.63). CONCLUSIONS: Provider encouragement appears to have a salutary impact on sodium consumption among residents. PRACTICE IMPLICATIONS: Provider encouragement may represent an underutilized strategy for counseling patients about cardiovascular health and about the benefits of reducing sodium consumption.

Posttranscriptional Regulation in Response to Different Environmental Stresses in Campylobacter jejuni.

The survival strategies that Campylobacter jejuni (C. jejuni) employ throughout its transmission and infection life cycles remain largely elusive. Specifically, there is a lack of understanding about the posttranscriptional regulation of stress adaptations resulting from small noncoding RNAs (sRNAs). Published C. jejuni sRNAs have been discovered in specific conditions but with limited insights into their biological activities. Many more sRNAs are yet to be discovered as they may be condition-dependent. Here, we have generated transcriptomic data from 21 host- and transmission-relevant conditions. The data uncovered transcription start sites, expression patterns and posttranscriptional regulation during various stress conditions. This data set helped predict a list of putative sRNAs. We further explored the sRNAs' biological functions by integrating differential gene expression analysis, coexpression analysis, and genome-wide sRNA target prediction. The results showed that the C. jejuni gene expression was influenced primarily by nutrient deprivation and food storage conditions. Further exploration revealed a putative sRNA (CjSA21) that targeted tlp1 to 4 under food processing conditions. tlp1 to 4 are transcripts that encode methyl-accepting chemotaxis proteins (MCPs), which are responsible for chemosensing. These results suggested CjSA21 inhibits chemotaxis and promotes survival under food processing conditions. This study presents the broader research community with a comprehensive data set and highlights a novel sRNA as a potential chemotaxis inhibitor. IMPORTANCE The foodborne pathogen C. jejuni is a significant challenge for the global health care system. It is crucial to investigate C. jejuni posttranscriptional regulation by small RNAs (sRNAs) in order to understand how it adapts to different stress conditions. However, limited data are available for investigating sRNA activity under stress. In this study, we generate gene expression data of C. jejuni under 21 stress conditions. Our data analysis indicates that one of the novel sRNAs mediates the adaptation to food processing conditions. Results from our work shed light on the posttranscriptional regulation of C. jejuni and identify an sRNA associated with food safety.

Training Physician‒Scientists for Careers in Investigative Dermatology.

Physician‒scientists have made countless discoveries, and their dwindling numbers are a significant concern. Although dermatology has become an increasingly popular destination for physician‒scientist trainees, the proportion of trainees who pursue scientific research careers after training is among the lowest of all medical specialties. To investigate this problem, we surveyed a national cohort of dermatology educators, physician‒scientist track program directors, and National Institute of Arthritis and Musculoskeletal and Skin Diseases T32 directors for opinions regarding physician‒scientist training in dermatology. On the basis of these findings and to help address the issue, we propose a training practicum and provide a resource for funding opportunities to help guide trainees and institutions interested in supporting investigative dermatologists. We also discuss the important roles of department chairs and institutions in fashioning an environment conducive to physician‒scientist training. The information and recommendations provided in this paper may help to improve the recruitment, training, development, and retention of investigative dermatologists and future leaders in this field.

Hypertriglyceridemia: rationale, design and implementation of the Australian Hypertriglyceridemia Registry.

PURPOSE OF REVIEW: Hypertriglyceridemia (HTG) is a risk factor for atherosclerotic cardiovascular disease (ASCVD), aortic stenosis, hepatic steatosis and pancreatitis. We briefly review the aetiology and treatment of HTG and familial chylomicronemia syndrome (FCS), as well as the implementation of a clinical quality registry for improving care, the Australian Hypertriglyceridemia (AUSTRIG) Registry. RECENT FINDINGS: There is a need to improve the detection of individuals with severe HTG and FCS, who could benefit from more intense and novel treatments to prevent end-organ damage. Patient registries provide valuable data for advancing care of individuals with severe HTG at high risk of acute pancreatitis, steatohepatitis and ASCVD. However, there is a paucity of registries of such patients. We outline the design and implementation of the AUSTRIG Registry. SUMMARY: Clinical registries can be employed in many ways for improving outcomes for patients with HTG, through the collation and analysis of data for enabling health service planning, clinical trials and audits, and for better informing and empowering registrants.

Customizing Maxpar Direct Immune Profiling Assay with Additional Surface Marker and Intracellular Cytokine Staining Workflows for Expanded Mass Cytometry Panels.

Mass cytometry, or cytometry by time-of-flight (the basis for Fluidigm® CyTOF® technology), is a system for single-cell detection using antibodies tagged with metal probes. Without the need for compensation, the highly parametric Helios™ mass cytometer has a detection range of 135 distinct mass channels (75-209 Da). Optimized for mass cytometry, the Maxpar® Direct™ Immune Profiling Assay™ is a dry, metal-tagged antibody cocktail for immunophenotyping 37 immune cell populations found in human peripheral blood in a single tube. The Maxpar Direct Assay utilizes 31 mass channels for marker detection and live/dead viability staining, with at least 14 additional marker channels available from the Fluidigm catalog for flexible custom panel design. Here, we describe a workflow combining the assay with additional surface and intracellular cytokine antibodies for peripheral blood mononuclear cell (PBMC) staining using lanthanide-, bismuth-, and cadmium-tagged antibodies.

Crystallization of the Multi-Receptor Tyrosine Kinase Inhibitor Sorafenib for Controlled Long-Term Drug Delivery Following a Single Injection.

INTRODUCTION: A major challenge in cancer medicine is the safe and effective delivery of drugs to the right tissue at the right time. Despite being designed for greater target specificity, many drugs still result in side effects and lack of safety in patients following global dissemination. Therefore, to develop new, more effective formulations capable of improving specificity and reducing off-target effects, here we describe formulation of drug crystals, from even a very hydrophobic and otherwise difficult to solubilize small molecule chemical compound, capable of providing constant drug release for weeks following a single injection. METHODS: We chose to utilize the multi-tyrosine kinase inhibitor and multi-modal (anti-angiogenic and tumor cell cytotoxic) agent sorafenib, to combat aberrant angiogenesis and tumor growth which contribute to metastasis, ultimately responsible for poor patient outcomes. We tuned crystal size (surface area:volume ratios), imaged by SEM, to display controllability of drug delivery kinetics in in vitro drug release assays. RESULTS: Single and powder crystal X-ray diffraction (XRD) established that all crystals were the same polymorph and drug form. When utilized against an orthotopic triple negative breast cancer (TNBC) mouse model (4T1 in syngeneic BALB/c mice), we established anti-tumor activity from a single local, subcutaneous injection of crystalline sorafenib. CONCLUSION: From our findings, we support that engineering crystalline drug delivery systems has implications in the treatment of cancer or other diseases where high enough constitutive drug levels are needed to maintain target saturation and inhibition while also preventing emergence of drug resistance, which is a consequence often seen with suboptimal dosing. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12195-021-00708-6.

Nature versus Number: Monocytes in Cardiovascular Disease.

Monocytes play a key role in cardiovascular disease (CVD) as their influx into the vessel wall is necessary for the development of an atherosclerotic plaque. Monocytes are, however, heterogeneous differentiating from classical monocytes through the intermediate subset to the nonclassical subset. While it is recognized that the percentage of intermediate and nonclassical monocytes are higher in individuals with CVD, accompanying changes in inflammatory markers suggest a functional impact on disease development that goes beyond the increased proportion of these 'inflammatory' monocyte subsets. Furthermore, emerging evidence indicates that changes in monocyte proportion and function arise in dyslipidemia, with lipid lowering medication having some effect on reversing these changes. This review explores the nature and number of monocyte subsets in CVD addressing what they are, when they arise, the effect of lipid lowering treatment, and the possible implications for plaque development. Understanding these associations will deepen our understanding of the clinical significance of monocytes in CVD.

A Legislative/Legal History of Prescription Drug Advertising and Promotion Regulation.

PURPOSE: The communication by pharmaceutical companies of promotional messages about their products has long been controversial, but deemed to be necessary by the pharmaceutical industry so that health care professionals and in some cases patients/consumers can be made aware of the latest developments through the communication vehicles they are accustomed to seeing - in the case of health care professionals, through medical advertising, direct mail, visits by company representatives, and attendance at medical meetings, and in case of patients, through the news media and television advertising. On the other hand, critics argue that such promotion, which sometimes reduces complex medical issues to advertising slogans, is inappropriate for products intended to treat and cure diseases, and that health care professionals should learn about new products from peer-reviewed medical literature.  Consequently, advertising, and promotional programs are heavily regulated by the U.S. Food and Drug Administration (FDA). However, the laws themselves raise constitutional issues of infringement on free speech.  Over the past few years, a number of lawsuits have been decided that help clarify the role of the FDA and the extent of its authority in regulating what companies or their employees say about their products. These court decisions are important because they help define how health care professionals and patients/consumers receive medical information. METHODS: This overview is intended to identify, in non-technical language, some of the more controversial and challenging issues involved in the FDA's efforts to regulate marketing communications by drug companies and how the courts view them. RESULTS: The recent lawsuits often involve complex and far-reaching legal issues.  But when examined in toto, as this paper does, they have reflected a view by the courts that truthful and non-misleading statements by drug companies about their products can be legally communicated even when the medical information is not formally approved by the FDA and included in the FDA-approved labeling.  The lawsuits thus have led to an environment in which the FDA continues to oversee with great fervor the activities of drug companies in communicating medical information but at the same time having some flexibility in keeping health care professionals and patients up to date with th latest information about medical research and new therapeutic products. CONCLUSION: How pharmaceutical products are marketed has been deemed by the U.S. Congress to be important enough to need to be subject to federal regulation.  The issues create a tension between the need for medical information to be accurate and balanced, and the guarantees of free speech.  This review provides an important perspective on how this tension is being resolved, even as dramatic advances in both medical products and technology create new challenges.

Immunocartography: Charting vaccine-driven immunity by applying single cell proteomics to an in vitro human model.

The ability to measure immunomodulatory effects of a vaccine is crucial for novel vaccine design. While traditional animal models have been effective, a better understanding of the response in humans to new vaccines in pre-clinical development is critical for advancement to clinical trials. A translational methodology that can capture the complexity of a vaccine-driven response in a human model, which does not require human exposure, is needed. Here we have designed a platform that uses fresh human whole blood as a key component to study the adaptive immune memory response to vaccine formulations. The response is monitored by high-parameter single cell analysis using mass cytometry (Helios, CyTOF System), allowing for a rapid, in-depth characterization of antigen specific proliferation and expansion of preexisting memory T cells in concert with an innate adjuvant-driven response. In this work we demonstrate the capability of this platform to characterize biologically relevant changes in the cellular response across memory T-cells, B cells, monocytes, and NK cells, at an unprecedented level of detail. This approach that we call Immunocartography has the potential to transform the way new vaccines can be assessed before and throughout clinical development.

Identification of an RNA sponge that controls the RoxS riboregulator of central metabolism in Bacillus subtilis.

sRNAs are a taxonomically-restricted but transcriptomically-abundant class of post-transcriptional regulators. While of major importance for adaption to the environment, we currently lack global-scale methodology enabling target identification, especially in species without known RNA hub proteins (e.g. Hfq). Using psoralen RNA cross-linking and Illumina-sequencing we identify RNA-RNA interacting pairs in vivo in Bacillus subtilis, resolving previously well-described interactants. Although sRNA-sRNA pairings are rare (compared with sRNA-mRNA), we identify a robust example involving the conserved sRNA RoxS and an unstudied sRNA RosA (Regulator of sRNA A). We show RosA to be the first confirmed RNA sponge described in a Gram-positive bacterium. RosA interacts with at least two sRNAs, RoxS and FsrA. The RosA/RoxS interaction not only affects the levels of RoxS but also its processing and regulatory activity. We also found that the transcription of RosA is repressed by CcpA, the key regulator of carbon-metabolism in B. subtilis. Since RoxS is already known to be transcriptionally controlled by malate via the transcriptional repressor Rex, its post-transcriptional regulation by CcpA via RosA places RoxS in a key position to control central metabolism in response to varying carbon sources.

Bioanalysis in the Age of New Drug Modalities.

In the absence of regulatory guidelines for the bioanalysis of new drug modalities, many of which contain multiple functional domains, bioanalytical strategies have been carefully designed to characterize the intact drug and each functional domain in terms of quantity, functionality, biotransformation, and immunogenicity. The present review focuses on the bioanalytical challenges and considerations for RNA-based drugs, bispecific antibodies and multi-domain protein therapeutics, prodrugs, gene and cell therapies, and fusion proteins. Methods ranging from the conventional ligand binding assays and liquid chromatography-mass spectrometry assays to quantitative polymerase chain reaction or flow cytometry often used for oligonucleotides and cell and gene therapies are discussed. Best practices for method selection and validation are proposed as well as a future perspective to address the bioanalytical needs of complex modalities.

Monocyte Subset Recruitment Marker Profile Is Inversely Associated With Blood ApoA1 Levels.

Dyslipidemia promotes development of the atherosclerotic plaques that characterise cardiovascular disease. Plaque progression requires the influx of monocytes into the vessel wall, but whether dyslipidemia is associated with an increased potential of monocytes to extravasate is largely unknown. Here (using flow cytometry) we examined recruitment marker expression on monocytes from generally healthy individuals who differed in lipid profile. Comparisons were made between monocyte subsets, participants and relative to participants' lipid levels. Monocyte subsets differed significantly in their expression of recruitment markers, with highest expression being on either the classical or non-classical subsets. However, these inter-subset differences were largely overshadowed by considerable inter-participant differences with some participants having higher levels of recruitment markers on all three monocyte subsets. Furthermore, when the expression of one recruitment marker was high, so too was that of most of the other markers, with substantial correlations evident between the markers. The inter-participant differences were explained by lipid levels. Most notably, there was a significant inverse correlation for most markers with ApoA1 levels. Our results indicate that dyslipidemia, in particular low levels of ApoA1, is associated with an increased potential of all monocyte subsets to extravasate, and to do so using a wider repertoire of recruitment markers than currently appreciated.

Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling.

Schwannomas are tumors of the Schwann cells that cause chronic pain, numbness, and potentially life-threatening impairment of vital organs. Despite the identification of causative genes, including NF2 (Merlin), INI1/SMARCB1, and LZTR1, the exact molecular mechanism of schwannoma development is still poorly understood. Several studies have identified Merlin as a key regulator of the Hippo, MAPK, and PI3K signaling pathways; however, definitive evidence demonstrating the importance of these pathways in schwannoma pathogenesis is absent. Here, we provide direct genetic evidence that dysregulation of the Hippo pathway in the Schwann cell lineage causes development of multiple schwannomas in mice. We found that canonical Hippo signaling through the effectors YAP/TAZ is required for schwannomagenesis and that MAPK signaling modifies schwannoma formation. Furthermore, cotargeting YAP/TAZ transcriptional activity and MAPK signaling demonstrated a synergistic therapeutic effect on schwannomas. Our new model provides a tractable platform to dissect the molecular mechanisms underpinning schwannoma formation and the role of combinatorial targeted therapy in schwannoma treatment.

Genetically detoxified pertussis toxin displays near identical structure to its wild-type and exhibits robust immunogenicity.

The mutant gdPT R9K/E129G is a genetically detoxified variant of the pertussis toxin (PTx) and represents an attractive candidate for the development of improved pertussis vaccines. The impact of the mutations on the overall protein structure and its immunogenicity has remained elusive. Here we present the crystal structure of gdPT and show that it is nearly identical to that of PTx. Hydrogen-deuterium exchange mass spectrometry revealed dynamic changes in the catalytic domain that directly impacted NAD+ binding which was confirmed by biolayer interferometry. Distal changes in dynamics were also detected in S2-S5 subunit interactions resulting in tighter packing of B-oligomer corresponding to increased thermal stability. Finally, antigen stimulation of human whole blood, analyzed by a previously unreported mass cytometry assay, indicated broader immunogenicity of gdPT compared to pertussis toxoid. These findings establish a direct link between the conserved structure of gdPT and its ability to generate a robust immune response.

New insights into the neurofibroma tumor cells of origin.

Neurofibromatosis type I (NF1) is a debilitating inherited tumor syndrome affecting around 1 in 3000 people. Patients present with a variety of tumors caused by biallelic loss of the tumor suppressor neurofibromin (NF1), a negative regulator of Ras signaling. While the mechanism of tumor formation is similar in the majority of NF1 cases, the clinical spectrum of tumors can vary depending on spatiotemporal loss of heterozygosity of NF1 in cells derived from the neural crest during development. The hallmark lesions that give NF1 its namesake are neurofibromas, which are benign Schwann cell tumors composed of nervous and fibrous tissue. Neurofibromas can be found in the skin (cutaneous neurofibroma) or deeper in body near nerve plexuses (plexiform neurofibroma). While neurofibromas have been known to be Schwann cell tumors for many years, the exact timing and initiating cell has remained elusive. This has led to difficulties in developing animal models and successful therapies for NF1. A culmination of recent genetic studies has finally begun to shed light on the detailed cellular origins of neurofibromatosis. In this review, we will examine the hunt for neurofibroma tumor cells of origin through a historical lens, detailing the genetic systems used to delineate the source of plexiform and cutaneous neurofibromas. Through these novel findings, we can better understand the cellular, temporal, and developmental context during tumor initiation. By leveraging this data, we hope to uncover new therapeutic targets and mechanisms to treat NF1 patients.