Fenebrutinib, a Bruton's tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways.

BACKGROUND: Bruton's tyrosine kinase (BTK) is an intracellular signaling enzyme that regulates B-lymphocyte and myeloid cell functions. Due to its involvement in both innate and adaptive immune compartments, BTK inhibitors have emerged as a therapeutic option in autoimmune disorders such as multiple sclerosis (MS). Brain-penetrant, small-molecule BTK inhibitors may also address compartmentalized neuroinflammation, which is proposed to underlie MS disease progression. BTK is expressed by microglia, which are the resident innate immune cells of the brain; however, the precise roles of microglial BTK and impact of BTK inhibitors on microglial functions are still being elucidated. Research on the effects of BTK inhibitors has been limited to rodent disease models. This is the first study reporting effects in human microglia. METHODS: Here we characterize the pharmacological and functional properties of fenebrutinib, a potent, highly selective, noncovalent, reversible, brain-penetrant BTK inhibitor, in human microglia and complex human brain cell systems, including brain organoids. RESULTS: We find that fenebrutinib blocks the deleterious effects of microglial Fc gamma receptor (FcγR) activation, including cytokine and chemokine release, microglial clustering and neurite damage in diverse human brain cell systems. Gene expression analyses identified pathways linked to inflammation, matrix metalloproteinase production and cholesterol metabolism that were modulated by fenebrutinib treatment. In contrast, fenebrutinib had no significant impact on human microglial pathways linked to Toll-like receptor 4 (TLR4) and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) signaling or myelin phagocytosis. CONCLUSIONS: Our study enhances the understanding of BTK functions in human microglial signaling that are relevant to MS pathogenesis and suggests that fenebrutinib could attenuate detrimental microglial activity associated with FcγR activation in people with MS.

Assessing the effects of textile leachates in fish using multiple testing methods: From gene expression to behavior.

The textile industry, while of major importance in the world economy, is a toxic industry utilizing and emitting thousands of chemical substances into the aquatic environment. The aim of this project was to study the potentially harmful effects associated with the leaching of chemical residues from three different types of textiles: sportswear, children's bath towels, and denim using different fish models (cell lines, fish larvae and juvenile fish). A combination of in vitro and in vivo test systems was used. Numerous biomarkers, ranging from gene expression, cytotoxicity and biochemical analysis to behavior, were measured to detect effects of leached chemicals. Principle findings indicate that leachates from all three types of textiles induced cytotoxicity on fish cell lines (RTgill-W1). Leachates from sportswear and towels induced mortality in zebrafish embryos, and chemical residues from sportswear reduced locomotion responses in developing larval fish. Sportswear leachate increased Cyp1a mRNA expression and EROD activity in liver of exposed brown trout. Leachates from towels induced EROD activity and VTG in rainbow trout, and these effects were mitigated by the temperature of the extraction process. All indicators of toxicity tested showed that exposure to textile leachate can cause adverse reactions in fish. These findings suggested that chemical leaching from textiles from domestic households could pose an ecotoxicological threat to the health of the aquatic environment.

Dispensation des antirétroviraux pour une durée de plus d'un mois : retour sur une recherche exploratoire qualitative.

This article presents the results of a qualitative research on practices of dispensing antiretroviral medication concerning requests for greater than one month, for departure abroad. In spite of a strict regulation, a cartography shows a heterogeneity of its application leading to a great diversity of dispensing practices. This qualitative research with 22 pharmacies across the territory reveals relational and regulatory logics that contribute to this non-uniformity of practices. The concepts of embarrassment, professional commitment, regulatory concerns and personal relationships with patients largely explain the accommodations and crafts observed in this type of ARV dispensing request.

Clinical and Imaging Outcomes after Vitamin D Supplementation in Patients with Multiple Sclerosis: A Systematic Review.

The link between vitamin D and multiple sclerosis (MS) has been suggested in epidemiological, genetic, immunological, and clinical studies. The aim of the present systematic review of the literature was to assess the effects of vitamin D supplementation on clinical and imaging outcomes in patients with MS. The outcomes we assessed included relapse events, disability progression, and magnetic resonance imaging (MRI) lesions. The search was conducted using PubMed, ClinicalTrials.gov, and EudraCT databases, and it included records published up until 28 February 2023. The systematic review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. Nineteen independent clinical studies (corresponding to 24 records) were included in the systematic review. The risk of bias in randomized controlled trials (RCTs) was analyzed using the Cochrane risk-of-bias tool. Fifteen trials investigated relapse events, and most of them reported no significant effect of vitamin D supplementation. Eight of 13 RCTs found that vitamin D supplementation had no effect on disability [assessed by Expanded Disability Status Scale (EDSS) scores] compared to controls. Interestingly, recent RCTs reported a significant reduction in new MRI lesions in the central nervous system of MS patients during supplementation with vitamin D3.

Divergent functional outcomes of NLRP3 blockade downstream of multi-inflammasome activation: therapeutic implications for ALS.

NOD-Like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome modulation has emerged as a potential therapeutic approach targeting inflammation amplified by pyroptotic innate immune cell death. In diseases characterized by non-cell autonomous neurodegeneration including amyotrophic lateral sclerosis (ALS), the activation of several inflammasomes has been reported. Since functional redundancy can exist among inflammasome pathways, here we investigate the effects of NLRP3 inhibition on NLRP3, NLR family CARD Domain Containing 4 (NLRC4) and non-canonical pathways to understand whether NLRP3 blockade alone can mitigate pro-inflammatory cytokine release and pyroptotic cell death in contexts where single or multiple inflammasome pathways independent of NLRP3 are activated. In this study we do not limit our insights into inflammasome biology by solely relying on the THP-1 monocytic line under the LPS/nigericin-mediated NLRP3 pathway activation paradigm. We assess therapeutic potential and limitations of NLRP3 inhibition in multi-inflammasome activation contexts utilizing various human cellular systems including cell lines expressing gain of function (GoF) mutations for several inflammasomes, primary human monocytes, macrophages, healthy and Amyotrophic Lateral Sclerosis (ALS) patient induced pluripotent stem cells (iPSC)-derived microglia (iMGL) stimulated for canonical and non-canonical inflammasome pathways. We demonstrate that NLRP3 inhibition can modulate the NLRC4 and non-canonical inflammasome pathways; however, these effects differ between immortalized, human primary innate immune cells, and iMGL. We extend our investigation in more complex systems characterized by activation of multiple inflammasomes such as the SOD1G93A mouse model. Through deep immune phenotyping by single-cell mass cytometry we demonstrate that acute NLRP3 inhibition does not ameliorate spinal cord inflammation in this model. Taken together, our data suggests that NLRP3 inhibition alone may not be sufficient to address dynamic and complex neuroinflammatory pathobiological mechanisms including dysregulation of multiple inflammasome pathways in neurodegenerative disease such as ALS.

To what extent do people living with HIV, people on pre-exposure prophylaxis, doctors and pharmacists endorse 90-day dispensing of antiretroviral therapy in France?

JUSTIFICATION: The WHO 95-95-95 targets for 2030 do not imply that people living with HIV (PLHIV) achieve a good quality of life. The current 30-day dispensing interval for antiretroviral (ART) burdens the healthcare system. Lengthening dispensing intervals could alleviate this burden as well as enhance patient well-being. OBJECTIVES: To capture perceptions on 90-day dispensing interval (90D) for ART from the perspective of PLHIV, people on pre-exposure prophylaxis (PrEP), doctors, and pharmacists. METHODS: Multi-centre observational survey led in France from 16 to 20 October 2020, among doctors agreeing to participate via regional coordinated care organisations for HIV, all PLHIV or people on PrEP consulting these outpatient-clinic doctors, and pharmacists doing ART dispensing. RESULTS: The survey was completed by 220 doctors who saw 1087 people (999 PLHIV; 88 on PrEP) and 176 pharmacists from 55 centres. Among the PLHIV, 855 (85.6%, 95% CI: 83.2%-87.7%) and among the patients on PrEP, 70 (79.5%, 95% CI: 69.6%-87.4%) stated they would be interested in 90D. All in all, patients who were more likely to endorse 90D are those who opt exclusively for hospital dispensing (OR 3.22 [1.57-6.58]) and who rotate between hospital and community pharmacy dispensing (OR 3.29 [1.15-9.32]). Patients who were less likely to endorse 90-D were those who consult in a city located outside the 3 French high HIV prevalence regions (OR 0.66 [0.44-0.99]), receive 2 vs 1 pill QD regimens (OR 0.53 [0.31-0.91]), and anticipate at least one vs no limitation to 90D (OR 0.27 [0.17-0.42]). 90D was perceived as possible by 152 pharmacists (86.4%), including 8 (5%) without restriction, and 219 doctors (99.6%), including 42 (19.2%) regardless of PLHIV's immunovirologic status or social conditions (health insurance coverage, access to housing or accommodation, access to rights, resources). Comparison of the benefits and limitations of a 90-day ART dispensing interval as perceived by PLHIV and people on PrEP, doctors and pharmacists shows that doctors anticipate a higher number of benefits than people on ART and/or pharmacists, chiefly that 90D would be more convenient and create less risk of drug shortages and that patients would gain autonomy and a better quality of life. Pharmacists were found to clearly perceive the economic benefits (90D would be less expensive) but anticipate more drawbacks than doctors and the people on ART themselves: more administrative burdens, more non-dispensing if doses get lost, harder to track adherence and more drug-drug interaction issues, and more work as they shall have to warn the patient of potential risks of shortages due to the cost of the stock. CONCLUSION: A clear majority of PLHIV, people on PrEP, doctors, and pharmacists endorsed 90D of ART. Most patients thought that 90D would be a good option, whereas most pharmacists and doctors thought that eligibility for 90D dispensing should depend on immunovirologic factors and social condition criteria. Moreover, pharmacists thought it would be necessary to commit regulatory resources and a better follow-up on adherence and drug-drug interactions.

Pharmacist's role in HIV care in France. Implication for clinical improvement of people living with HIV worldwide.

In France, antiretroviral (ARV) treatment can be dispensed by hospital and/or community pharmacies. Since January 2016, an online patient medication file can be used to optimize dispensing, but medication interviews have not yet been incorporated into this system. To understand both people living with HIV (PLHIV) and their pharmacists' habits and expectations of patient medication file and interviews, two consecutive national surveys were organized. The first one, carried out in October 2016 in care centers, was an anonymous questionnaire for PLHIV. The second one was an online survey for community and hospital pharmacies conducted in February 2017. A total of 1137 PLHIV (68% men, of mean age 50.2 ± 11.5 years, CD4 count 671 ± 354, 90% with undetectable HIV viral load (VL) and 64.2% reporting comorbidities) and 246 pharmacies responded. While the existence of the online medication file is known by 58% of PLHIV, only 40% of pharmacists declare it to be systematically offered. It was offered to 120/694 (17%) PLHIV and 96 (80%) accepted it. Currently, 78 (7%) PLHIV feel well taken care of because they are offered medication interviews, 343/1078 (32%) would like to take advantage of this program, mainly those with a shorter ARV duration (OR ARV duration 0.97 [0.95-0.99]), a VL less often undetectable (OR undetectable VL 0.55 [0.31-0.98]), and those who feel anxious more often (OR anxious 2.38 [1.48-3.84]). These results suggest that better implementation of medication files and interviews will strengthen current clinical pathways.