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Abstract Background Glaucoma is a leading cause of blindness, affecting retinal ganglion cells (RGCs) and their axons. By 2040, it is likely to affect 110 million people. Neuroinflammation, specifically through the release of proinflammatory cytokines by M1 microglial cells, plays a crucial role in glaucoma progression. Indeed, in post-mortem human studies, pre-clinical models, and ex-vivo models, RGC degeneration has been consistently shown to be linked to inflammation in response to cell death and tissue damage. Recently, Rho kinase inhibitors (ROCKis) have emerged as potential therapies for neuroinflammatory and neurodegenerative diseases. This study aimed to investigate the potential effects of three ROCKis (Y-27632, Y-33075, and H-1152) on retinal ganglion cell (RGC) loss and retinal neuroinflammation using an ex-vivo retinal explant model. Methods Rat retinal explants underwent optic nerve axotomy and were treated with Y-27632, Y-33075, or H-1152. The neuroprotective effects on RGCs were evaluated using immunofluorescence and Brn3a-specific markers. Reactive glia and microglial activation were studied by GFAP, CD68, and Iba1 staining. Flow cytometry was used to quantify day ex-vivo 4 (DEV 4) microglial proliferation and M1 activation by measuring the number of CD11b+, CD68+, and CD11b+/CD68+ cells after treatment with control solvent or Y-33075. The modulation of gene expression was measured by RNA-seq analysis on control and Y-33075-treated explants and glial and pro-inflammatory cytokine gene expression was validated by RT-qPCR. Results Y-27632 and H-1152 did not significantly protect RGCs. By contrast, at DEV 4, 50 µM Y-33075 significantly increased RGC survival. Immunohistology showed a reduced number of Iba1+/CD68+ cells and limited astrogliosis with Y-33075 treatment. Flow cytometry confirmed lower CD11b+, CD68+, and CD11b+/CD68+ cell numbers in the Y-33075 group. RNA-seq showed Y-33075 inhibited the expression of M1 microglial markers (Tnfα, Il-1β, Nos2) and glial markers (Gfap, Itgam, Cd68) and to reduce apoptosis, ferroptosis, inflammasome formation, complement activation, TLR pathway activation, and P2rx7 and Gpr84 gene expression. Conversely, Y-33075 upregulated RGC-specific markers, neurofilament formation, and neurotransmitter regulator expression, consistent with its neuroprotective effects. Conclusion Y-33075 demonstrates marked neuroprotective and anti-inflammatory effects, surpassing the other tested ROCKis (Y-27632 and H-1152) in preventing RGC death and reducing microglial inflammatory responses. These findings highlight its potential as a therapeutic option for glaucoma.

Abstract Introduction Even though the local tolerance of prostaglandin (PG) analogues has improved drastically since the introduction of preservative-free (PF) eye drops, prescription patterns still vary widely among practitioners and between countries and could have an impact on the ocular surface of treated patients and, in consequence, their adherence. The aim of this study is to explore the prescribing patterns of PG analogues monotherapy in France and to evaluate their impact on ocular surface status. Methods This was a national multicenter cross-sectional observational study that was conducted by 18 glaucoma experts in France. Patients over 18 years of age and receiving monotherapy with topical PG analogues for the treatment of ocular hypertension and/or glaucoma, with no history of prior glaucoma surgery, were consecutively selected from the glaucoma outpatient clinics of participating physicians and underwent an ocular surface examination. Results A total of 344 eyes of 344 patients were enrolled between November 2022 and November 2023. Prescribed PG monotherapy was PF in 271 (78.7%) patients. Clinical history and ocular surface evaluation indicated that 79.4% of the study population (n = 273) presented with at least one symptom or clinical sign of dry eye and that three patients out of four had an unstable tear film. Subgroup analysis comparing preserved and PF PG analogues showed a higher prevalence of conjunctival hyperemia and corneal staining in the preserved group. Multivariate analysis identified conjunctival hyperemia as consistently associated with preservative use (odds ratio = 7.654; p = 0.003 for moderate conjunctival hyperemia). Conclusions This study highlights the growing trend toward PF PG analogue prescriptions by specialists in France. However, ocular surface issues remain prevalent, impacting patient adherence and treatment efficacy. Comprehensive ocular surface examinations are crucial in glaucoma management to enhance long-term tolerance, compliance, and overall treatment success.

IntroductionLower cognitive functioning in old age has been associated with personality traits or systemic inflammatory markers. Associations have also been found between personality traits and inflammatory markers. However, no study has explored the inter-relationships between these three components simultaneously. The present study aims to better understand the inter-relationships among personality traits, inflammatory markers, and cognitive performance in elderly individuals without dementia.MethodsThis study utilizes a network analysis approach, a statistical method that allows visualization of the data’s unique pairwise associations. We performed a cross-sectional analysis on 720 elderly individuals without dementia, using data from Colaus|PsyColaus, a population-based study conducted in Lausanne, Switzerland. The Revised NEO Five-Factor Inventory (NEO-FFI-R) was used to assess personality traits, and interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were used as peripheral inflammatory markers. Cognitive domains were investigated using the Mini-Mental State Examination (MMSE), the Verbal Fluency Test, the Stroop Test, the DO40, and the Free and Cued Selective Reminding (FCSR) test.ResultsOpenness was associated with verbal fluency and Agreeableness with immediate free recall. In contrast, no association between inflammatory markers and personality traits or cognition was identified.DiscussionIn elderly individuals without dementia, a high level of Openness or Agreeableness was associated with executive functioning/semantic memory and episodic memory, respectively.

Previous studies indicate that children are exposed to different literacy experiences at home. Although these disparities have been shown to affect children's literacy skills, it remains unclear whether and how home literacy practices influence brain activity underlying word-level reading. In the present study, we asked parents of French children from various socioeconomic backgrounds (n = 66; 8.46 ± 0.36 years, range 7.52-9.22; 20 girls) to report the frequency of home literacy practices. Neural adaptation to the repetition of printed words was then measured using functional magnetic resonance imaging (fMRI) in a subset of these children (n = 44; 8.49 ± 0.33 years, range 8.02-9.14; 13 girls), thereby assessing how sensitive was the brain to the repeated presentation of these words. We found that more frequent home literacy practices were associated with enhanced word adaptation in the left posterior inferior frontal sulcus (r = 0.32). We also found that the frequency of home literacy practices was associated with children's vocabulary skill (r = 0.25), which itself influenced the relation between home literacy practices and neural adaptation to words. Finally, none of these effects were observed in a digit adaptation task, highlighting their specificity to word recognition. These findings are consistent with a model positing that home literacy experiences may improve children's vocabulary skill, which in turn may influence the neural mechanisms supporting word-level reading.

Abstract Antiplatelet therapy through inhibition of the adenosine diphosphate (ADP)/P2Y12 pathway is commonly used in the treatment of acute coronary syndrome (ACS). Although efficient in preventing platelet activation and thrombus formation, it increases the risk of bleeding complications. In patients with ACS receiving platelet aggregation inhibitors, that is, P2Y12 blockers (n = 923), we investigated the relationship between plasma and platelet‐associated CD40L levels and bleeding events (n = 71). Treatment with P2Y12 inhibitors in patients with ACS did not affect plasma‐soluble CD40L levels, but decreased platelet CD40L surface expression (pCD40L) and platelet‐released CD40L (rCD40L) levels in response to stimulation as compared to healthy controls. In vitro inhibition of the ADP pathway in healthy control platelets reduced both pCD40L and rCD40L levels. In a multivariable analysis, the reduced pCD40L level observed in ACS patients was significantly associated with the risk of bleeding occurrence (adjusted odds ratio = 0.15; 95% confidence interval = 0.034‐0.67). P2Y12 inhibitor‐treated (ticagrelor) mice exhibited a 2.5‐fold increase in tail bleeding duration compared with controls. A significant reduction in bleeding duration was observed on CD40L+/+ but not CD40L−/− platelet infusion. In addition, CD40L blockade in P2Y12 inhibitor–treated blood samples from a healthy human reduced thrombus growth over immobilized collagen under arterial flow. In conclusion, measurement of pCD40L may offer a novel approach to assessing bleeding risk in patients with ACS who are being treated with P2Y12 inhibitors.

A growing number of studies suggest that the frequency of numeracy experiences that parents provide at home may relate to children's mathematical development. However, the relation between home numeracy practices and children's numerical skills is complex and might depend upon both the type and difficulty of activities, as well as the type of math skills. Studies have also argued that this relation may be driven by factors that are not systematically controlled for in the literature, including socio-economic status (SES), parental math skills and children's IQ. Finally, as most prior studies have focused on preschoolers, it remains unclear to what extent there remains a relation between the home numeracy environment and math skills when children are in elementary school. In the present study, we tested an extensive range of math skills in 66 8-year-olds, including non-symbolic quantity processing, symbolic number understanding, transcoding, counting, and mental arithmetic. We also asked parents to complete a questionnaire about their SES, academic expectations, academic attitudes, and the numeracy practices that they provide at home. Finally, we measured their arithmetic fluency as a proxy for parental math skills. Over and above differences in socio-economic status, parental arithmetic fluency, child's IQ, and time spent with the child, we found a positive relation between the frequency of formal numeracy practices that were at or above grade level and two separate measures of mental arithmetic. We further found that the frequency of these advanced formal numeracy practices was related to parents' academic expectations. Therefore, our study shows that home numeracy experiences predict arithmetic skills in elementary school children, but only when those activities are formal and sufficiently challenging for children.

• RWJF FNS program used multi-pronged approach to support nurses completing accelerated PhD programs. • Scholars completed quantitative exit surveys, providing information about their satisfaction with the program, as well as details on their dissertation approaches. • Scholar program experiences were positive. • Despite stresses posed by accelerated PhD programs, scholars are well-situated to advance nursing science. • Findings suggest secondary data analyses work well for accelerated programs. Robert Wood Johnson Foundation Future of Nursing Scholars program used multi-pronged approach to support nurses completing accelerated PhD programs. The purpose of this manuscript was to describe scholars' experiences completing PhDs, their dissertation characteristics, program leadership development sessions, scholar perceptions of program components. Of 201 scholars, 157 (78%) completed quantitative exit surveys, providing: satisfaction with doctoral programs and FNS curricula, types of dissertation data used, dissertation formats. Interviews held with five scholars to capture representative themes. Scholars utilized primary and secondary data for dissertations; 53% primarily used secondary data. The majority (68%) used manuscript dissertation formats. Approximately 64% completely agreed program curricula helped prepare them for professional transitions, to work collaboratively, lead confidently. Proportion of FNS graduates (42%) pursuing postdoctoral positions exceeded national trends. Despite stresses posed by accelerated PhD programs, scholars are well-situated to advance nursing science. Findings suggest secondary data analyses work well for accelerated programs. Scholar program experiences were positive. [ABSTRACT FROM AUTHOR]

• Students in the RWJF FNS program were funded to complete the PhD within 3 years. • As of May 1, 2022, 181 scholars graduated with 20 scholars still enrolled. • The FNS program provided students with financial support, mentorship, and a concentrated leadership development program. • Nurses from 46 schools pursued their PhDs as Future of Nursing Scholars. Following the 2010 report, "The Future of Nursing: Leading Change, Advancing Health," Robert Wood Johnson Foundation created the Future of Nursing Scholars program to increase the number of PhD-prepared nurses who could assume leadership roles earlier in their careers by shortening the PhD education trajectory and developing leadership skills. The purpose of this paper is to describe the state of the field at program launch, the program development, and operations. A descriptive narrative was used, which relied on literature review focused on nursing PhD program completion and presentation of FNS program objectives and findings. Nurses from 46 schools pursued their PhDs as Future of Nursing Scholars. As of May 1, 2022, 181 scholars graduated with 20 scholars still enrolled. Preliminary results suggest accelerate PhD programs featuring intensive mentoring and financial support can produce well-prepared nurse researchers ready for postdoctoral positions and leadership roles. Program attributes including financial support and leadership development initiatives may be replicated. [ABSTRACT FROM AUTHOR]

Background/Objectives Lymphocytes play a critical role in visceral adipose tissue inflammation. The CD28 costimulatory molecule is required for lymphocyte activation and for the development of a functional regulatory T cells (Treg) compartment; however its role during obesity is unknown. Methods During diet-induced obesity, we investigated the effects of selective interference with CD28 signaling using knock-out mice (Cd28KO) and a CTLA4-Ig fusion protein inhibiting CD28-B7 interactions. Results Cd28 deficiency decreased pathogenic T-cells and Treg content within adipose tissue without changing macrophages number. Cd28KO epididymal but not subcutaneous fat was characterized by enlarged adipocytes, reduced levels of inflammatory cytokines and increased Glut4, adiponectin and lipogenic enzymes mRNA levels. This was associated with reduced inflammation, fat accumulation and enhanced glucose metabolism in liver. Weight gain and fasting glucose tolerance were not affected. CTLA4-Ig injections reduced the number T-cells in epididymal adipose tissue but not inflammatory cytokines levels and failed to improve liver fat accumulation. Conclusions Deletion of CD28 creates a new pro/anti-inflammatory balance in epididymal adipose tissue and liver and exerts a protective effect against hepatic steatosis. [ABSTRACT FROM AUTHOR]

Rationnel: Le lymphocyte T (LyT) participe à l’inflammation du tissu adipeux (TA) Son activation fait intervenir le système de costimulation CD28/B7. La déficience CD28 induit un défaut d’activation des LyT et une réduction des LyT régulateurs (LyTreg) dans les organes lymphoïdes. Nous avons étudié l’influence des LyT au cours de l’obésité en modulant le CD28. Matériels et méthodes: Des souris CD28KO et CD28KI (délétion de la portion intracytoplasmique) ont reçu une alimentation hyperlipidique. L’homéostasie des LyT et le statut métabolique ont été évalués. Résultats: Les populations CD3+, CD3+CD4+, CD3+CD8+ sont réduites et celle des LyTregs absente dans le TA CD28KO/KI comparé au TA WT. Un défaut d’activation moins prononcé des LyT est observé chez les CD28KI confronté au CD28KO dans la rate et le TA. Malgré un poids similaire aux WT, les CD28KO et KI présentent une sensibilité à l’insuline améliorée dans le TA avec une augmentation des gènes impliqués dans la lipogenèse et la signalisation insulinique. Le contenu en triglycérides du foie et les ARNm d’enzymes impliqués dans leur synthèse sont réduits chez les animaux déficients. Paradoxalement l’effet protecteur est plus important chez les CD28KI par comparaison au CD28KO avec des taux plus élevés d’IRS1, de gpam et de PPARγ dans le TA et une tolérance au glucose améliorée suggérant un rôle bénéfique d’une activation LyT résiduelle sur l’état inflammatoire du TA. En accord avec cette hypothèse le nombre de macrophages dans le TA ne diffère pas entre les groupes, par contre, les macrophages M2 CD206+, les niveaux d’ARNm CD206 et CD273, TGFβ, IL10, CXCL13 et CCL22 sont plus élevés dans le TA CD28KI comparé au TA CD28KO. Conclusion: Ces données soulignent l’importance des LyT et du CD28 dans les complications métaboliques de l’obésité. L’activation du LyT n’est pas indispensable au recrutement des macrophages dans le TA mais paraît nécessaire à leur polarisation. [ABSTRACT FROM AUTHOR]

Metabolic Syndrome (MS) predisposes to type 2 diabetes (T2D) and coronary heart disease (CAD). Elevated levels of the serpin PAI-1 are observed in MS, and epidemiological studies evidenced an association between increased PAI-1 levels, the risk of CAD and more recently T2D. However, it is still unknown whether PAI-1 is causally involved. To answer this point, we studied the potential effect of PAI-1 on Furin convertase, focusing on the processing of two Furin substrates: the insulin proreceptor (proIR) and proADAM-17. In Furin-defective LoVo cells, proIR was weakly processed, due to the lack of endogenous Furin activity. Overexpression of Furin greatly enhanced the maturation of proIR, which was inhibited by a synthetic convertase inhibitor. In Furin-transfected LoVo cells, expression of PAI-1 (wild-type or stabilized mutant) reduced proIR maturation. ProIR maturation was neither altered by the addition of exogenous recombinant PAI-1 to LoVo cells overexpressing Furin, nor by the coculture of Furin-only expressing cells with PAI-1-only expressing cells. These results suggest an intracellular inhibitory effect of PAI-1 on Furin. We also observed that PAI-1 expression in LoVo cells moderately inhibited Furin-dependent maturation of proADAM-17/TACE, an enzyme involved in the shedding of TNF and its receptors (TNFRs). As a result, the Furin-activated cleavage of TNF and both TNFRs by ADAM-17 was significantly reduced by PAI-1 expression. In conclusion, our results suggest a potential role of PAI-1 as a Furin inhibitor, which could give to PAI-1 a causative role in MS by regulating both insulin and TNF pathways. [Copyright &y& Elsevier]