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Background Potentially inappropriate medication (PIM) is associated with negative health outcomes and can serve as an indicator of treatment quality. Previous studies have identified social inequality in treatment but often relied on narrow understandings of social position or failed to account for mediation by differential disease risk among social groups. Understanding how social position influences PIM exposure is crucial for improving the targeting of treatment quality and addressing health disparities. This study investigates the association between social position and PIM, considering the mediation effect of long-term conditions. Methods and findings This cross-sectional study utilized data from the 2017 Danish National Health Survey, including 177,495 individuals aged 18 or older. Data were linked to national registers on individual-level. PIM was defined from the STOPP/START criteria and social position was assessed through indicators of economic, cultural, and social capital (from Bourdieu's Capital Theory). We analyzed odds ratios (ORs) and prevalence proportion differences (PPDs) for PIM using logistic regression, negative binomial regression, and generalized structural equation modeling. The models were adjusted for age and sex and analyzed separately for indicators of under- (START) and overtreatment (STOPP). The mediation analysis was conducted to separate direct and indirect effects via long-term conditions. Overall, 14.7% of participants were exposed to one or more PIMs, with START PIMs being more prevalent (12.5%) than STOPP PIMs (3.1%). All variables for social position except health education were associated with PIM in a dose-response pattern. Individuals with lower wealth (OR: 1.85 [95% CI 1.77, 1.94]), lower income (OR: 1.78 [95% CI 1.69, 1.87]), and lower education level (OR: 1.66 [95% CI 1.56, 1.76]) exhibited the strongest associations with PIM. Similar associations were observed for immigrants, people with low social support, and people with limited social networks. The association with PIM remained significant for most variables after accounting for mediation by long-term conditions. The disparities were predominantly related to overtreatment and did not relate to the number of PIMs. The study's main limitation is the risk of reverse causation due to the complex nature of social position and medical treatment. Conclusions The findings highlight significant social inequalities in PIM exposure, driven by both economic, cultural, and social capital despite a universal healthcare system. Understanding the social determinants of PIM can inform policies to reduce inappropriate medication use and improve healthcare quality and equity., Author(s): Amanda Paust 1,2,*, Claus Vestergaard 1, Susan M. Smith 3, Karina Friis 4, Stine Schramm 5, Flemming Bro 1,2, Anna Mygind 1, Nynne Bech Utoft 1, James Larkin 6, [...]

Lung maturation is not limited to proper structural development but also includes differentiation and functionality of various highly specialized alveolar cell types. Alveolar type 1 (AT1s) cells occupy nearly 95% of the alveolar surface and are critical for establishing efficient gas exchange in the mature lung. AT1 cells arise from progenitors specified during the embryonic stage as well as alveolar epithelial progenitors expressing surfactant protein C (Sftpcpos cells) during postnatal and adult stages. Previously, we found that Wnt5a, a non-canonical Wnt ligand, is required for differentiation of AT1 cells during the saccular phase of lung development. To further investigate the role of Wnt5a in AT1 cell differentiation, we generated and characterized a conditional Wnt5a gain-of-function mouse model. Neonatal Wnt5a gain-of-function disrupted alveologenesis through inhibition of cell proliferation. In this setting Wnt5a downregulated β-catenin-dependent canonical Wnt signaling, repressed AT2 (anti-AT2) and promoted AT1 (pro-AT1) lineage-specific gene expression. In addition, we identified 2 subpopulations of Sftpchigh and Sftpclow alveolar epithelial cells. In Sftpclow cells, Wnt5a exhibits pro-AT1 and anti-AT2 effects, concurrent with inhibition of canonical Wnt signaling. Interestingly, in the Sftpchigh subpopulation, although increasing AT1 lineage-specific gene expression, Wnt5a gain-of-function did not change AT2 gene expression, nor inhibit canonical Wnt signaling. Using primary epithelial cells isolated from human fetal lungs, we demonstrate that this property of Wnt5a is evolutionarily conserved. Wnt5a therefore serves as a selective regulator that ensures proper AT1/AT2 balance in the developing lung.

Lung development is precisely controlled by underlying gene regulatory networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD) - a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization. Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin's development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird's eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD. Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.

WNT5a is a mainly "non-canonical" WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (Wnt5aCAG) and examined the specific role of Wnt5a during the saccular and alveolar phases of lung development. The lack of Wnt5a in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal Wnt5a inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of Wnt5a inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors Ror1 and Ror2 in alveolar myofibroblasts recapitulated the Wnt5aCAG phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in Wnt5aCAG lungs. Finally, we show that WNT5a is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD.

Current evidence suggests that iron deficiency (ID) plays a key role in the pathogenesis of conditions presenting with restlessness such as attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS). In clinical practice, ID and iron supplementation are not routinely considered in the diagnostic work-up and/or as a treatment option in such conditions. Therefore, we conducted a scoping literature review of ID guidelines. Of the 58 guidelines included, only 9 included RLS, and 3 included ADHD. Ferritin was the most frequently cited biomarker, though cutoff values varied between guidelines and depending on additional factors such as age, sex, and comorbidities. Recommendations surrounding measurable iron biomarkers and cutoff values varied between guidelines; moreover, despite capturing the role of inflammation as a concept, most guidelines often did not include recommendations for how to assess this. This lack of harmonization on the interpretation of iron and inflammation biomarkers raises questions about the applicability of current guidelines in clinical practice. Further, the majority of ID guidelines in this review did not include the ID-associated disorders, ADHD and RLS. As ID can be associated with altered movement patterns, a novel consensus is needed for investigating and interpreting iron status in the context of different clinical phenotypes. [ABSTRACT FROM AUTHOR]

Background General practitioners (GPs) need robust, up-to-date evidence to deliver high-quality patient care. There is limited literature regarding the role of international GP professional organizations in developing and publishing clinical guidelines to support GPs clinical decision making. Objective To identify evidence-based guidance and clinical guidelines produced by GP professional organizations and summarize their content, structure, and methods of development and dissemination. Methods Scoping review of GP professional organizations following Joanna Briggs Institute guidance. Four databases were searched and a grey literature search was conducted. Studies were included if they were: (i) evidence-based guidance documents or clinical guidelines produced de novo by a national GP professional organization, (ii) developed to support GPs clinical care, and (iii) published in the last 10 years. GP professional organizations were contacted to provide supplementary information. A narrative synthesis was performed. Results Six GP professional organizations and 60 guidelines were included. The most common de novo guideline topics were mental health, cardiovascular disease, neurology, pregnancy and women's health and preventive care. All guidelines were developed using a standard evidence-synthesis method. All included documents were disseminated through downloadable pdfs and peer review publications. GP professional organizations indicated that they generally collaborate with or endorse guidelines developed by national or international guideline producing bodies. Conclusion The findings of this scoping review provide an overview of de novo guideline development by GP professional organizations and can support collaboration between GP organizations worldwide thus reducing duplication of effort, facilitating reproducibility, and identifying areas of standardization. Protocol registration Open Science Framework: https://doi.org/10.17605/OSF.IO/JXQ26. [ABSTRACT FROM AUTHOR]

Background: The inverse care law states that availability of good medical care varies inversely with the need for it in the population served. In 2019, the main medical union and the Department of Health in the Republic of Ireland (RoI), agreed on funding a social deprivation practice grant for general practices in urban deprived areas. Aim: To examine the implementation and impact of the social deprivation practice grant in participating general practices. Design & setting: A mixed-methods study with sequential design based in Irish general practice. Method: Data were collected using a questionnaire and online semi-structured interviews with GPs and practice staff. Data were analysed separately, and the findings compared to examine the extent to which they converged or diverged. Results: There were 25 survey responses and nine interviews. All practices reported the grant was beneficial and most practices utilised the grant to fund additional doctor hours (17/25). Both surveys and interviews indicated that a small amount of additional funding allowed additional clinical need in areas of deprivation to be addressed, but there were some barriers identified in accessing the grant and implementing planned expenditure. Conclusion: Delivery of health care in areas of socioeconomic deprivation presents significant challenges. While there were some problems with implementation, the introduction of a small, targeted grant for general practices in areas of social deprivation allowed those practices to enhance their services, with tailored initiatives seeking to meet the needs of their patient populations. [ABSTRACT FROM AUTHOR]