LPA-induced expression of CCN2 in muscular fibro/adipogenic progenitors (FAPs): Unraveling cellular communication networks.

Cellular Communication Network Factor 2, CCN2, is a profibrotic cytokine implicated in physiological and pathological processes in mammals. The expression of CCN2 is markedly increased in dystrophic muscles. Interestingly, diminishing CCN2 genetically or inhibiting its function improves the phenotypes of chronic muscular fibrosis in rodent models. Elucidating the cell-specific mechanisms behind the induction of CCN2 is a fundamental step in understanding its relevance in muscular dystrophies. Here, we show that the small lipids LPA and 2S-OMPT induce CCN2 expression in fibro/adipogenic progenitors (FAPs) through the activation of the LPA1 receptor and, to a lower extent, by also the LPA6 receptor. These cells show a stronger induction than myoblasts or myotubes. We show that the LPA/LPARs axis requires ROCK kinase activity and organized actin cytoskeleton upstream of YAP/TAZ signaling effectors to upregulate CCN2 levels, suggesting that mechanical signals are part of the mechanism behind this process. In conclusion, we explored the role of the LPA/LPAR axis on CCN2 expression, showing a strong cytoskeletal-dependent response in muscular FAPs.

Economic burden of nonadherence to standards of diabetes care.

OBJECTIVES: To evaluate the effect of nonadherence to American Diabetes Association (ADA) guidelines on health care expenditures for patients with type 2 diabetes (T2D). STUDY DESIGN: Retrospective cross-sectional cohort design, utilizing 2016-2018 Medical Expenditure Panel Survey data. METHODS: Patients with a diagnosis of T2D who completed the supplemental T2D care survey were included in the study. Participants were categorized based on adherence to the 10 processes in the ADA guidelines into adherent (≥ 9 processes) and nonadherent (≤ 6 processes) categories. Propensity score matching was employed using a logistic regression model. After matching, total annual health care expenditure change from baseline year was compared using a t test. Further, imbalanced variables were controlled for in a multivariable linear regression model. RESULTS: A total of 1619 patients representing 15,781,346 (SE = 438,832) individuals met the inclusion criteria, among whom 12.17% received nonadherent care. After propensity matching, those who received nonadherent care had $4031 higher total annual health care expenditures compared with their baseline year, whereas patients who received adherent care had $128 lower total annual health care expenditures compared with their baseline year. Further, multivariable linear regression adjusted for the imbalanced variables indicated that nonadherent care was associated with a mean (SE) $3470 ($1588) increase in the change from baseline health care expenditure. CONCLUSIONS: Nonadherence to the ADA guidelines results in a significant increase in health care expenditures among patients with diabetes. The economic impact of nonadherent care for T2D is a significant and extensive issue that needs to be addressed. These findings emphasize the importance of providing care based on ADA guidelines.

Activation of skeletal muscle FAPs by LPA requires the Hippo signaling via the FAK pathway.

Lysophosphatidic acid (LPA) is a lysophospholipid that signals through six G-protein coupled receptors (LPARs), LPA1 to LPA6. LPA has been described as a potent modulator of fibrosis in different pathologies. In skeletal muscle, LPA increases fibrosis-related proteins and the number of fibro/adipogenic progenitors (FAPs). FAPs are the primary source of ECM-secreting myofibroblasts in acute and chronic damage. However, the effect of LPA on FAPs activation in vitro has not been explored. This study aimed to investigate FAPs' response to LPA and the downstream signaling mediators involved. Here, we demonstrated that LPA mediates FAPs activation by increasing their proliferation, expression of myofibroblasts markers, and upregulation of fibrosis-related proteins. Pretreatment with the LPA1/LPA3 antagonist Ki16425 or genetic deletion of LPA1 attenuated the LPA-induced FAPs activation, resulting in decreased expression of cyclin e1, α-SMA, and fibronectin. We also evaluated the activation of the focal adhesion kinase (FAK) in response to LPA. Our results showed that LPA induces FAK phosphorylation in FAPs. Treatment with the P-FAK inhibitor PF-228 partially prevented the induction of cell responses involved in FAPs activation, suggesting that this pathway mediates LPA signaling. FAK activation controls downstream cell signaling within the cytoplasm, such as the Hippo pathway. LPA induced the dephosphorylation of the transcriptional coactivator YAP (Yes-associated protein) and promoted direct expression of target pathway genes such as Ctgf/Ccn2 and Ccn1. The blockage of YAP transcriptional activity with Super-TDU further confirmed the role of YAP in LPA-induced FAPs activation. Finally, we demonstrated that FAK is required for LPA-dependent YAP dephosphorylation and the induction of Hippo pathway target genes. In conclusion, LPA signals through LPA1 to regulate FAPs activation by activating FAK to control the Hippo pathway.

Emergent Social Capital during the Coronavirus Pandemic in the United States in Hispanics/Latinos.

The coronavirus pandemic has drastically impacted many groups that have been socially and economically marginalized such as Hispanics/Latinos in the United States (U.S.). Our aim was to understand how bonding social capital, bridging social capital, and trust played a role in Hispanics/Latinos over the course of the COVID-19 outbreak, as well as explore the negative consequences of social capital. We performed focus group discussions via Zoom (n = 25) between January and December 2021 with Hispanics/Latinos from Baltimore, MD, Washington, DC, and New York City, NY. Our findings suggest that Hispanics/Latinos experienced bridging and bonding social capital. Of particular interest was how social capital permeated the Hispanic/Latino community's socioeconomic challenges during the pandemic. The focus groups revealed the importance of trust and its role in vaccine hesitancy. Additionally, the focus groups discussed the dark side of social capital including caregiving burden and spread of misinformation. We also identified the emergent theme of racism. Future public health interventions should invest in social capital, especially for groups that have been historically marginalized or made vulnerable, and consider the promotion of bonding and bridging social capital and trust. When prospective disasters occur, public health interventions should support vulnerable populations that are overwhelmed with caregiving burden and are susceptible to misinformation.

Demographics of and Costs to Users of Chiropractic Services in the United States with Neck or Back Pain not Meeting Guideline-Based Minimum Treatment Frequency Thresholds.

Context: Acceptance of chiropractic services as an effective therapy for neck or back pain has been well established with randomized controlled trials (RCTs); however, there have been limited observations made on the treatment frequency patterns seen in the real world. Objective: The purpose of this study is to identify chiropractic users with neck or back pain who did not meet recommended treatment frequency guidelines and examine their demographics and chiropractic costs. Design: In this cross-sectional retrospective study, the nationally representative 2017 Medical Expenditure Panel Survey database was used. Setting: This study used nationally representative US survey data. Participants: Inclusion criteria were adults aged 18 years and older with a diagnosis of neck or back pain with one or more chiropractic visits in 2017. Outcomes Measures: Chiropractic utilization was categorized as concordant or discordant with treatment frequency guidelines; concordant was defined as 5 or more visits to a chiropractor within any 2-month time frame or at least 12 total visits during the year. Discordant was defined as circumstances not meeting concordant criteria. The groups were compared by demographics including age, sex, race, region, years of education, health insurance coverage, employment status, family income, presence of headache diagnosis, Charlson Comorbidity Index score and the presence of any limitation of physical function. Comparisons were made between the two groups using Chi-squared tests. Logistic regression was used to adjust for covariates. Results: There were 159 and 310 adults classified as concordant and discordant, respectively (weighted total: 1 849 108 [31.44%] and 4 032 541 [68.56%], with significantly different mean chiropractic costs of $2555 and $434, respectively. Significant independent predictors of discordant chiropractic utilization were race, years of education, family income and the presence of any limitation of physical function. Conclusions: Most chiropractic users with diagnosed neck or back pain were considered discordant with treatment frequency guidelines, which may indicate inefficiencies in treatment and inefficient use of healthcare resources.

The Effects of Yoga in Helping Cancer Patients and Caregivers Manage the Stress of a Natural Disaster: A Brief Report on Hurricane Harvey.

Background: This small qualitative study reports on the experiences of patients and family caregivers who participated in a dyadic yoga pilot trial while undergoing cancer treatment in the midst of Hurricane Harvey. Our primary purpose was to determine if participants implemented components of the program to cope with the stressors associated with Hurricane Harvey and if they perceived benefits from the yoga practices. Methods: We administered brief semistructured interviews to the dyads participating in a dyadic yoga pilot trial. Participants (n = 5 dyads) were asked to discuss their experience with Hurricane Harvey, including factors that helped them cope with the event while receiving treatment. Result: Patients had a mean age of 55.6 years, were mostly non-Hispanic White, male, and had advance stage head and neck cancer. Caregivers had a mean age of 58 years and were mainly non-Hispanic White and female. Analyses of the interviews revealed 2 overarching themes: (1) the storm's negative impact and (2) the use of yoga to cope with the hurricane-related stressors. Conclusions: Patient-caregiver dyads experienced psychological distress during the storm and/or its aftermath. Dyads used yoga techniques to cope with these psychological stressors. Yoga served as a means of social support as dyads either participated in these activities together or with other family members.

Caracterización de los modelos pedagógicos y su pertinencia en una educación contable crítica / Characterization of pedagogical models and their relevance in a critical accounting education / Caracterização de modelos pedagógicos e sua relevância em uma educação contábil crítica

Resumen En el presente documento se identifican los elementos, los actores y los intereses presentes en los modelos pedagógicos más relevantes en la literatura académica, en contraste con lo aplicado en la educación contable, con el fin de fundamentar un modelo pedagógico tendiente a una formación contable crítica, analítica, activa y propositiva. Para ello, se analizan las teorías y los modelos pedagógicos a través de los autores más citados por investigadores que describen las características de los procesos de aprendizaje desde distintas ciencias sociales, y en el ámbito de la educación contable se revisan artículos, libros y tesis que abordan las necesidades sociales del ejercicio profesional contable enfocando la revisión en las investigaciones dadas con posterioridad a la crisis económica del 2002 en Estados Unidos y aquellas publicaciones emitidas por organizaciones multilaterales que buscan guiar criterios de confiabilidad y comparabilidad de la profesión y la información contable a nivel internacional. Se concluye que los modelos pedagógicos que podrían tener un mayor impacto en la generación de contadores críticos, analíticos, proactivos y propositivos, son aquellos que otorgan un rol principal al estudiante y se enfocan en la formación de individuos que permitan el desarrollo social y económico de su entorno. Clasificación JEL: A22, I23.

Abstract This document identifies elements, actors and interests present in the most relevant pedagogical models in the academic literature, in contrast to what is applied in accounting education, in order to base a pedagogical model tending to a critical, analytical, active and proactive accounting education. For this, theories and pedagogical models are analyzed through of the authors most cited by researches books and thesis academics that investigate about the social necessities of the accounting professional activity focused in the researches that originate after the United States economic crisis the 2002 and the publications generated by multilateral organizations that guide the criteria's reliability and comparability of the accounting profession and information are reviewed, in order to support a pedagogical model tending to a critical, analytical, active and proactive accounting education. The conclusion of this study is that pedagogical models that could have a greater impact on the generation of critical, analytical, proactive and proactive accountants, are those that grant a main role to the student and focus on the training of individuals that allow the social and economic development of their environment. JEL Classification: A22, I23.

Resumo Este documento identifica os elementos, atores e interesses presentes nos modelos pedagógicos mais relevantes na literatura acadêmica, em contraste com o que é aplicado na educação contábil, a fim de fundamentar um modelo pedagógico tendendo a uma formação contábil crítica. , analítica, ativa e proativa. Para isso, as teorias e modelos pedagógicos são analisados através dos autores mais citados pelos pesquisadores que descrevem as características dos processos de aprendizagem das diferentes ciências sociais, e no campo da educação contábil, artigos, livros e teses são revisados. abordar as necessidades sociais da prática contábil focando revendo as investigações proferidas após a crise econômica de 2002 nos Estados Unidos e essas publicações emitidos por organismos multilaterais que buscam orientar critérios de fiabilidade e comparabilidade da profissão e as informações contábeis no nível internacional Conclui-se que os modelos pedagógicos que podem ter um grande impacto sobre a geração de contadores críticos, analíticos, pró-ativa e proposicional são aqueles que dão um papel de liderança para o aluno e se concentrar no treinamento de pessoas para permitir o desenvolvimento social e econômico seu ambiente. Classificações JEL: A22, I23.

Denervation-induced skeletal muscle fibrosis is mediated by CTGF/CCN2 independently of TGF-ß.

Muscular fibrosis is caused by excessive accumulation of extracellular matrix (ECM) that replaces functional tissue, and it is a feature of several myopathies and neuropathies. Knowledge of the biology and regulation of pro-fibrotic factors is critical for the development of new therapeutic strategies. Upon unilateral sciatic nerve transection, we observed accumulation of ECM proteins such as collagen and fibronectin in the denervated hindlimb, together with increased levels of the profibrotic factors transforming growth factor type ß (TGF-ß) and connective tissue growth factor (CTGF/CCN2). In mice hemizygous for CTGF/CCN2 or in mice treated with a blocking antibody against CTGF/CCN2, we observed reduced accumulation of ECM proteins after denervation as compared to control mice, with no changes in fibro/adipogenic progenitors (FAPs), suggesting a direct role of CTGF/CCN2 on denervation-induced fibrosis. During time course experiments, we observed that ECM proteins and CTGF/CCN2 levels are increased early after denervation (2-4 days), while TGF-ß signaling shows a delayed kinetics of appearance (1-2 weeks). Furthermore, blockade of TGF-ß signaling does not decrease fibronectin or CTGF levels after 4 days of denervation. These results suggest that in our model CTGF/CCN2 is not up-regulated by canonical TGF-ß signaling early after denervation and that other factors are likely involved in the early fibrotic response following skeletal muscle denervation.

APOE Genotype Differentially Modulates Effects of Anti-Aß, Passive Immunization in APP Transgenic Mice.

BACKGROUND: APOE genotype is the foremost genetic factor modulating ß-amyloid (Aß) deposition and risk of sporadic Alzheimer's disease (AD). Here we investigated how APOE genotype influences response to anti-Aß immunotherapy. METHODS: APPSW/PS1dE9 (APP) transgenic mice with targeted replacement of the murine Apoe gene for human APOE alleles received 10D5 anti-Aß or TY11-15 isotype control antibodies between the ages of 12 and 15 months. RESULTS: Anti-Aß immunization decreased both the load of fibrillar plaques and the load of Aß immunopositive plaques in mice of all APOE backgrounds. Although the relative reduction in parenchymal Aß plaque load was comparable across all APOE genotypes, APP/ε4 mice showed the greatest reduction in the absolute Aß plaque load values, given their highest baseline. The immunization stimulated phagocytic activation of microglia, which magnitude adjusted for the post-treatment plaque load was the greatest in APP/ε4 mice implying association between the ε4 allele and impaired Aß phagocytosis. Perivascular hemosiderin deposits reflecting ensued microhemorrhages were associated with vascular Aß (VAß) and ubiquitously present in control mice of all APOE genotypes, although in APP/ε3 mice their incidence was the lowest. Anti-Aß immunization significantly reduced VAß burden but increased the number of hemosiderin deposits across all APOE genotypes with the strongest and the weakest effect in APP/ε2 and APP/ε3 mice, respectively. CONCLUSIONS: Our studies indicate that APOE genotype differentially modulates microglia activation and Aß plaque load reduction during anti-Aß immunotherapy. The APOE ε3 allele shows strong protective effect against immunotherapy associated microhemorrhages; while, conversely, the APOE ε2 allele increases risk thereof.