Twist2 amplification in rhabdomyosarcoma represses myogenesis and promotes oncogenesis by redirecting MyoD DNA binding.

Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer composed of myoblast-like cells. Recently, we discovered a unique muscle progenitor marked by the expression of the Twist2 transcription factor. Genomic analyses of 258 RMS patient tumors uncovered prevalent copy number amplification events and increased expression of TWIST2 in fusion-negative RMS. Knockdown of TWIST2 in RMS cells results in up-regulation of MYOGENIN and a decrease in proliferation, implicating TWIST2 as an oncogene in RMS. Through an inducible Twist2 expression system, we identified Twist2 as a reversible inhibitor of myogenic differentiation with the remarkable ability to promote myotube dedifferentiation in vitro. Integrated analysis of genome-wide ChIP-seq and RNA-seq data revealed the first dynamic chromatin and transcriptional landscape of Twist2 binding during myogenic differentiation. During differentiation, Twist2 competes with MyoD at shared DNA motifs to direct global gene transcription and repression of the myogenic program. Additionally, Twist2 shapes the epigenetic landscape to drive chromatin opening at oncogenic loci and chromatin closing at myogenic loci. These epigenetic changes redirect MyoD binding from myogenic genes toward oncogenic, metabolic, and growth genes. Our study reveals the dynamic interplay between two opposing transcriptional regulators that control the fate of RMS and provides insight into the molecular etiology of this aggressive form of cancer.

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.

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.

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.

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.

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.

Automated Data Cleanup for Mass Cytometry.

Mass cytometry is an emerging technology capable of 40 or more correlated measurements on a single cell. The complexity and volume of data generated by this platform have accelerated the creation of novel methods for high-dimensional data analysis and visualization. A key step in any high-level data analysis is the removal of unwanted events, a process often referred to as data cleanup. Data cleanup as applied to mass cytometry typically focuses on elimination of dead cells, debris, normalization beads, true aggregates, and coincident ion clouds from raw data. We describe a probability state modeling (PSM) method that automatically identifies and removes these elements, resulting in FCS files that contain mostly live and intact events. This approach not only leverages QC measurements such as DNA, live/dead, and event length but also four additional pulse-processing parameters that are available on Fluidigm Helios™ and CyTOF® (Fluidigm, Markham, Canada) 2 instruments with software versions of 6.3 or higher. These extra Gaussian-derived parameters are valuable for detecting well-formed pulses and eliminating coincident positive ion clouds. The automated nature of this new routine avoids the subjectivity of other gating methods and results in unbiased elimination of unwanted events. © 2019 International Society for Advancement of Cytometry.

mTORC1/rpS6 signaling complex modifies BTB transport function: an in vivo study using the adjudin model.

Studies have shown that the mTORC1/rpS6 signaling cascade regulates Sertoli cell blood-testis barrier (BTB) dynamics. For instance, specific inhibition of mTORC1 by treating Sertoli cells with rapamycin promotes the Sertoli cell barrier, making it "tighter." However, activation of mTORC1 by overexpressing a full-length rpS6 cDNA clone (i.e., rpS6-WT, wild type) in Sertoli cells promotes BTB remodeling, making the barrier "leaky." Also, there is an increase in rpS6 and p-rpS6 (phosphorylated and activated rpS6) expression at the BTB in testes at stages VIII-IX of the epithelial cycle, and it coincides with BTB remodeling to support the transport of preleptotene spermatocytes across the barrier, illustrating that rpS6 is a BTB-modifying signaling protein. Herein, we used a constitutively active, quadruple phosphomimetic mutant of rpS6, namely p-rpS6-MT of p-rpS6-S235E/S236E/S240E/S244E, wherein Ser (S) was converted to Glu (E) at amino acid residues 235, 236, 240, and 244 from the NH2 terminus by site-directed mutagenesis, for its overexpression in rat testes in vivo using the Polyplus in vivo jet-PEI transfection reagent with high transfection efficiency. Overexpression of this p-rpS6-MT was capable of inducing BTB remodeling, making the barrier "leaky." This thus promoted the entry of the nonhormonal male contraceptive adjudin into the adluminal compartment in the seminiferous epithelium to induce germ cell exfoliation. Combined overexpression of p-rpS6-MT with a male contraceptive (e.g., adjudin) potentiated the drug bioavailability by modifying the BTB. This approach thus lowers intrinsic drug toxicity due to a reduced drug dose, further characterizing the biology of BTB transport function.

PU.1 Regulates Ig Light Chain Transcription and Rearrangement in Pre-B Cells during B Cell Development.

B cell development and Ig rearrangement are governed by cell type- and developmental stage-specific transcription factors. PU.1 and Spi-B are E26-transformation-specific transcription factors that are critical for B cell differentiation. To determine whether PU.1 and Spi-B are required for B cell development in the bone marrow, Spi1 (encoding PU.1) was conditionally deleted in B cells by Cre recombinase under control of the Mb1 gene in Spib (encoding Spi-B)-deficient mice. Combined deletion of Spi1 and Spib resulted in a lack of mature B cells in the spleen and a block in B cell development in the bone marrow at the small pre-B cell stage. To determine target genes of PU.1 that could explain this block, we applied a gain-of-function approach using a PU.1/Spi-B-deficient pro-B cell line in which PU.1 can be induced by doxycycline. PU.1-induced genes were identified by integration of chromatin immunoprecipitation-sequencing and RNA-sequencing data. We found that PU.1 interacted with multiple sites in the Igκ locus, including Vκ promoters and regions located downstream of Vκ second exons. Induction of PU.1 induced Igκ transcription and rearrangement. Upregulation of Igκ transcription was impaired in small pre-B cells from PU.1/Spi-B-deficient bone marrow. These studies reveal an important role for PU.1 in the regulation of Igκ transcription and rearrangement and a requirement for PU.1 and Spi-B in B cell development.

Fibroblast Growth Factor 21 Stimulates Pancreatic Islet Autophagy via Inhibition of AMPK-mTOR Signaling.

BACKGROUND: Islet autophagy plays a role in glucose/lipid metabolism in type 2 diabetes mellitus. Meanwhile, fibroblast growth factor 21 (FGF21) has been found to regulate insulin sensitivity and glucose homeostasis. Whether FGF21 induces islet autophagy, remains to be elucidated. This study aimed to explore the physiological roles and signaling pathways involved in FGF21-stimulated islet autophagy under glucolipotoxic conditions. METHODS: C57/BL6J mice were fed a standard diet or high-fat diet (HFD) for 12 weeks, and islets were isolated from normal and FGF21 knockout (KO) mice. Isolated islets and INS-1E cells were exposed to normal and high-concentration glucose and palmitic acid with/without FGF21 or AMPK inhibitor compound C. Real-time PCR, Western blot and immunohistochemistry/transmission electron microscopy were performed for the expression of targeted genes/proteins. RESULTS: HFD-treated mice showed increases in fasting plasma glucose, body weight and impaired glucose tolerance; islet protein expression of FGF21 was induced after HFD treatment. Protein expression levels of FGF21 and LC3-II (autophagy marker) were induced in mouse islets treated with high concentrations of palmitic acid and glucose, while phosphorylation of AMPK was reduced, compared with controls. In addition, induction of LC3-II protein expression was reduced in islets isolated from FGF21 KO mice. Furthermore, exogenous administration of FGF21 diminished phosphorylation of AMPK and stimulated protein expression of LC3-II. Consistently, compound C significantly induced increased expression of LC3-II protein. CONCLUSIONS: Our data indicate that glucolipotoxicity-induced FGF21 activation mediates islet autophagy via AMPK inhibition, and further consolidate the evidence for the FGF21/analog being a pharmacotherapeutic target for obesity and its related T2DM.

mTORC1/rpS6 regulates blood-testis barrier dynamics and spermatogenetic function in the testis in vivo.

The blood-testis barrier (BTB), conferred by Sertoli cells in the mammalian testis, is an important ultrastructure that supports spermatogenesis. Studies using animal models have shown that a disruption of the BTB leads to meiotic arrest, causing defects in spermatogenesis and male infertility. To better understand the regulation of BTB dynamics, we report findings herein to understand the role of ribosomal protein S6 (rpS6), a downstream signaling protein of mammalian target of rapamycin complex 1 (mTORC1), in promoting BTB disruption in the testis in vivo, making the barrier "leaky." Overexpression of wild-type rpS6 (rpS6-WT, the full-length cDNA cloned into the mammalian expression vector pCI-neo) and a constitutively active quadruple phosphomimetic mutant cloned into pCI-neo (p-rpS6-MT) vs. control (empty pCI-neo vector) was achieved by transfecting adult rat testes with the corresponding plasmid DNA using a Polyplus in vivo-jetPEI transfection reagent. On the basis of an in vivo functional BTB integrity assay, p-rpS6-MT was found to induce BTB disruption better than rpS6-WT did (and no effects in empty vector control), leading to defects in spermatogenesis, including loss of spermatid polarity and failure in the transport of cells (e.g., spermatids) and organelles (e.g., phagosomes), to be followed by germ exfoliation. More important, rpS6-WT and p-rpS6-MT exert their disruptive effects through changes in the organization of actin- and microtubule (MT)-based cytoskeletons, which are mediated by changes in the spatiotemporal expression of actin- and MT-based binding and regulatory proteins. In short, mTORC1/rpS6 signaling complex is a regulator of spermatogenesis and BTB by modulating the organization of the actin- and MT-based cytoskeletons.

Identification of a negative regulatory role for spi-C in the murine B cell lineage.

Spi-C is an E26 transformation-specific family transcription factor that is highly related to PU.1 and Spi-B. Spi-C is expressed in developing B cells, but its function in B cell development and function is not well characterized. To determine whether Spi-C functions as a negative regulator of Spi-B (encoded by Spib), mice were generated that were germline knockout for Spib and heterozygous for Spic (Spib(-/-)Spic(+/-)). Interestingly, loss of one Spic allele substantially rescued B cell frequencies and absolute numbers in Spib(-/-) mouse spleens. Spib(-/-)Spic(+/-) B cells had restored proliferation compared with Spib(-/-) B cells in response to anti-IgM or LPS stimulation. Investigation of a potential mechanism for the Spib(-/-)Spic(+/-) phenotype revealed that steady-state levels of Nfkb1, encoding p50, were elevated in Spib(-/-)Spic(+/-) B cells compared with Spib(-/-) B cells. Spi-B was shown to directly activate the Nfkb1 gene, whereas Spi-C was shown to repress this gene. These results indicate a novel role for Spi-C as a negative regulator of B cell development and function.

PU.1 opposes IL-7-dependent proliferation of developing B cells with involvement of the direct target gene bruton tyrosine kinase.

Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreΔPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-CreΔPB mice. Enriched pro-B cells from CD19-CreΔPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreΔPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreΔPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreΔPB pro-B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro-B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells.

Management of traumatic haemorrhage in the Berger's space of a 4-year-old child.

We are reporting an unusual case of haemorrhage in the Berger's space after an episode of blunt ocular trauma in an eye of a 4-year-old boy, who enjoyed premorbid normal vision. A secondary posterior subcapsular cataract developed as a complication of the haemorrhage after 6 months of observation. Surgery comprised cataract extraction, removal of a residual retrolenticular haematoma via opening of posterior continuous curvilinear capsulorhexis (CCC), anterior vitrectomy and placement of an intraocular lens. This yielded a reasonable visual outcome. Complete spontaneous resolution of haemorrhage in the Berger's space is unlikely and may cause secondary cataracts in children. We suggest early intervention in such conditions in order to prevent the development of amblyopia.

Genome-wide comparison of PU.1 and Spi-B binding sites in a mouse B lymphoma cell line.

BACKGROUND: Spi-B and PU.1 are highly related members of the E26-transformation-specific (ETS) family of transcription factors that have similar, but not identical, roles in B cell development. PU.1 and Spi-B are both expressed in B cells, and have been demonstrated to redundantly activate transcription of genes required for B cell differentiation and function. It was hypothesized that Spi-B and PU.1 occupy a similar set of regions within the genome of a B lymphoma cell line. RESULTS: To compare binding regions of Spi-B and PU.1, murine WEHI-279 lymphoma cells were infected with retroviral vectors encoding 3XFLAG-tagged PU.1 or Spi-B. Anti-FLAG chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) was performed. Analysis for high-stringency enriched genomic regions demonstrated that PU.1 occupied 4528 regions and Spi-B occupied 3360 regions. The majority of regions occupied by Spi-B were also occupied by PU.1. Regions bound by Spi-B and PU.1 were frequently located immediately upstream of genes associated with immune response and activation of B cells. Motif-finding revealed that both transcription factors were predominantly located at the ETS core domain (GGAA), however, other unique motifs were identified when examining regions associated with only one of the two factors. Motifs associated with unique PU.1 binding included POU2F2, while unique motifs in the Spi-B regions contained a combined ETS-IRF motif. CONCLUSIONS: Our results suggest that complementary biological functions of PU.1 and Spi-B may be explained by their interaction with a similar set of regions in the genome of B cells. However, sites uniquely occupied by PU.1 or Spi-B provide insight into their unique functions.

Acceptability of psychological treatment to Chinese- and Caucasian-Australians: Internet treatment reduces barriers but face-to-face care is preferred.

PURPOSE: Internet treatments have the potential to improve access, especially for cultural groups who face considerable treatment barriers. This study explored the perceived barriers and likelihood of using Internet and face-to-face treatments for depression among Chinese and Caucasian Australian participants. METHODS: Three-hundred ninety-five (289 Chinese, 106 Caucasian) primary care patients completed a questionnaire about depression history, previous help-seeking, perceived barriers to Internet and face-to-face treatment, and likelihood of using either treatment for depressive symptoms. RESULTS: Internet treatment reduced perceived barriers (including stigma, lack of motivation, concerns of bringing up upsetting feelings, time constraints, transport difficulties, and cost) for both groups to a similar degree, except for time constraints. There were heightened concerns about the helpfulness, suitability, and confidentiality of Internet treatments. Chinese participants and individuals with a probable depression history reported increased perceived barriers across treatments. Both Chinese and Caucasian groups preferred face-to-face treatment across depression severity. However, when age was controlled, there were no significant concerns about Internet treatment, and face-to-face treatment was only preferred for severe depression. Only 12 % of the entire sample refused to try Internet treatment for depression. Endorsement of perceived Internet treatment barriers (including concerns of bringing up upsetting feelings, that treatment would be unhelpful or unsuitable, lack of motivation, cost, cultural sensitivity, and confidentiality) reduced the likelihood to try Internet treatments. CONCLUSIONS: Internet treatment reduced perceived treatment barriers across groups, with encouraging support for Internet treatment as an acceptable form of receiving help. Negative concerns about Internet treatment need to be addressed to encourage use.

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.

Transcription factor KROX20 marks epithelial stem cells for hair follicle formation.

Epidermal stem cells control homeostasis and regeneration of skin and hair. In the hair follicle (HF) bulge of mammals, populations of slow-cycling stem cells regenerate the HF during cyclical rounds of anagen (growth), telogen (quiescence), and catagen (regression). Multipotent epidermal cells are also present in the HF above the bulge area, contributing to the formation and maintenance of sebaceous gland and upper and middle portions of the HF. Here, we report that the transcription factor Krox20 is enriched in an epidermal stem cell population located in the upper/ middle HF. Expression analyses and lineage tracing using inducible Krox20-CreERT showed that Krox20-lineage cells migrate out of this HF region and contribute to the formation of bulge in the HF, serving as ancestors of bulge stem cells. In vivo depletion of these cells arrests HF morphogenesis. This study identifies a novel marker for an epidermal stem cell population that is indispensable for hair homeostasis.

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.

Implementation of a primary-tertiary shared care model to improve the detection of familial hypercholesterolaemia (FH): a mixed methods pre-post implementation study protocol.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disorder of lipid metabolism and a preventable cause of premature cardiovascular disease. Current detection rates for this highly treatable condition are low. Early detection and management of FH can significantly reduce cardiac morbidity and mortality. This study aims to implement a primary-tertiary shared care model to improve detection rates for FH. The primary objective is to evaluate the implementation of a shared care model and support package for genetic testing of FH. This protocol describes the design and methods used to evaluate the implementation of the shared care model and support package to improve the detection of FH. METHODS AND ANALYSIS: This mixed methods pre-post implementation study design will be used to evaluate increased detection rates for FH in the tertiary and primary care setting. The primary-tertiary shared care model will be implemented at NSW Health Pathology and Sydney Local Health District in NSW, Australia, over a 12-month period. Implementation of the shared care model will be evaluated using a modification of the implementation outcome taxonomy and will focus on the acceptability, evidence of delivery, appropriateness, feasibility, fidelity, implementation cost and timely initiation of the intervention. Quantitative pre-post and qualitative semistructured interview data will be collected. It is anticipated that data relating to at least 62 index patients will be collected over this period and a similar number obtained for the historical group for the quantitative data. We anticipate conducting approximately 20 interviews for the qualitative data. ETHICS AND DISSEMINATION: Ethical approval has been granted by the ethics review committee (Royal Prince Alfred Hospital Zone) of the Sydney Local Health District (Protocol ID: X23-0239). Findings will be disseminated through peer-reviewed publications, conference presentations and an end-of-study research report to stakeholders.