Suboptimal management of rheumatoid arthritis in France: a real-world study based on data from the French National Health Data System.

OBJECTIVES: The emergence of targeted therapy is changing rheumatoid arthritis (RA) management, but real-world data remain limited. This study aimed to describe real-world RA treatment patterns using data from a French national claims database. METHODS: This longitudinal study used the French Permanent Representative Sample (Echantillon Généraliste des Bénéficiaires) claims database. Patients with RA were identified between 2013 and 2017, with treatment patterns, persistence and adherence described. RESULTS: The study population included 2553 patients with RA. Disease-modifying antirheumatic drugs (DMARDs) were prescribed for 1512 (59.2%) patients, of whom 721 (47.6%) did not require discontinuation or treatment switch. There were 377 (24.9%) treatment discontinuations and 114 patients (7.5%) switched to a targeted DMARD (biological and synthetic (Janus kinase inhibitor) DMARDs). Among the 2315 patients with RA in 2017, almost half (n=1102, 47.6%) were not treated with a DMARD. Most (85.7%) received symptomatic treatment (analgesics (81.0%), steroids (49.2%), non-steroidal anti-inflammatory drugs (39.5%)). Of the 1142 treatment initiations identified, 713 (62.4%) were conventional synthetic DMARDs (csDMARDs), with methotrexate being the most frequent (n=553, 48.45%). One-year persistence rates varied between 55.9% (49.2-62.0%) for tumour necrosis factor inhibitors, and 63.4% (59.6-67.0%) for csDMARDs. Treatment adherence, assessed through medication possession ratio, varied between 71.9% and 90.8%, with ≥80% being the adherence cut-off. Almost half of DMARD initiations were associated with long-term (>6 months), high-dose oral steroid use (~7 mg/day prednisone equivalent). CONCLUSION: Despite a diverse therapeutic arsenal, there remains a medical need that is not covered by current RA management, which is frequently compensated for by overprescription of steroids.

Retina and RPE lipid profile changes linked with ABCA4 associated Stargardt's maculopathy.

Stargardt maculopathy, caused predominantly by mutations in the ABCA4 gene, is characterized by an accumulation of non-degradable visual pigment derivative, lipofuscin, in the retinal pigment epithelium (RPE) - resulting in RPE atrophy. RPE is a monolayer tissue located adjacent to retinal photoreceptors and regulates their health and functioning; RPE atrophy triggers photoreceptor cell death and vision loss in Stargardt patients. Previously, ABCA4 mutations in photoreceptors were thought to be the major contributor to lipid homeostasis defects in the eye. Recently, we demonstrated that ABCA4 loss of function in the RPE leads to cell-autonomous lipid homeostasis defects. Our work underscores that an incomplete understanding of lipid metabolism and lipid-mediated signaling in the retina and RPE are potential causes for lacking treatments for this disease. Here we report altered lipidomic in mouse and human Stargardt models. This work provides the basis for therapeutics that aim to restore lipid homeostasis in the retina and the RPE.

Fermented Pineapple Juice Consumption Limits Metabolic Disorders Associated to Sugary Drinks on High-Fat Diet-Fed Mice.

SCOPE: Lactic acid fermentation (LAF) modulates the composition of food, leading to changes in safety, sensory, and nutritional properties. The effects of lactic fermented pineapple juice (FJ) supplementation on energetic metabolism of high-fat diet (HFD) fed mice are compared with either water (control), sweetened water (SW), bacteria in SW, and pineapple juice (J) supplementation. METHODS AND RESULTS: Drink consumption and body weight are measured during the 6 weeks of experiment, whereas glycemia and lipid content are determined at the beginning and at the end of the experiment. Total energy intake is similar between all groups though the volume of juice consumed is lower than that of SWs. Weight gain is higher for mice provided with sugary drinks (5.65 ± 1.32 to 7.74 ± 2.98 g) compared to water (4.68 ± 0.93 g). The FJ is less detrimental to blood carbohydrate regulation than other sugary drinks. Triglyceride (TG) and total cholesterol content are not modified following fermented juice or water consumption, contrarily to other sugary drinks. Whatever the drink, intestinal permeability is preserved. Lactic acid bacterium (LAB) population in feces is not affected by the beverage but species composition is modified. CONCLUSION: From a health perspective, FJ is preferable to other sugary drinks to limit metabolic disorders related to HFD.

Case Report of Bifid Ureter with a Blind Ending: Surgical Laparoscopic Management.

BACKGROUND The blind-ending branch of a bifid ureter is a rare congenital anomaly which is usually asymptomatic but can occasionally give rise to various symptoms, such as chronic abdominal pain. Diagnosis is most often confirmed radiologically, and treatment is usually conservative. Surgical resection of the blind ending of a bifid ureter should be considered in cases of persistent symptoms. CASE REPORT A female patient of 49 years of age presented with intermittent right lumbar pain, repetitive urinary infections and microscopic hematuria. We present here the diagnostic work-up of the case, leading to the identification of the existence of ureteral bifidity located at the lower third of the ureter and of a blind ending of the bifid ureter. Several regimens of various antibiotics failed to resolve the symptoms. It was decided to carry out a laparoscopic resection of the blind ending of the bifid ureter. We describe the practical procedures of the surgical operation and discuss briefly the embryological etiology and the physiopathology of the condition as well as the principal diagnostic modalities. Since the surgery, the patient has been symptom-free. CONCLUSIONS Despite being usually asymptomatic, the rare congenital anomaly of a bifid ureter with a blind ending can occasionally give rise to symptoms such as recurrent infections and persistent abdominal pain. Laparoscopic-based resection of the blind ending should be considered in such cases.

Antioxidant Activities of Co-Encapsulated Natal Plum (Carissa macrocarpa) Juice Inoculated with Ltp. plantarum 75 in Different Biopolymeric Matrices after In Vitro Digestion.

Biopolymeric systems that co-encapsulate probiotics and bioactive compounds ensure timely delivery in the gastrointestinal tract. Cyanidin 3-sambubioside is the dominant anthocyanin in Natal plum (Carissa macrocarpa). This study aims at the co-encapsulation of Natal plum (Carissa macrocarpa) juice inoculated with Lactiplantibacillus plantarum 75 (Ltp. plantarum 75) by freeze-drying using pea protein isolate, maltodextrin, and psyllium mucilage and evaluating their release in vitro. An encapsulation efficiency of >85% was noted in lactic acid bacteria (LAB) survival and anthocyanin content. Freeze-drying produced pinkish-red powder, rich in polyphenols and LAB (>6 Log CFU mL−1) after 14 days of storage. Natal plum juice + maltodextrin + pea protein isolate + psyllium mucilage + Ltp. plantarum 75 (NMPeaPsyB) showed the highest LAB population (6.74 Log CFU mL−1) with a survival rate of 81.9%. After digestion, NMPeaPsyB and NMPeaPsy had the highest LAB survival (>50%) at 67.5% and 67.5 ± 0.75%, respectively, and the highest bioaccessibility of cyanidin 3-sambubioside in Natal plum juice than the other co-encapsulation with other biopolymers. NMPeaPsy and NMPeaPsyB showed phenolic stability in the gastric phase and controlled release in the intestinal simulated phase. The antioxidant activities had strong correlations with cyanidin 3-sambubioside. The results confirmed that microencapsulation is important for improving stability and allowing for the development of functional foods.

Variability of Bacterial Homopolysaccharide Production and Properties during Food Processing.

Various homopolysaccharides (HoPSs) can be produced by bacteria: α- and ß-glucans, ß-fructans and α-galactans, which are polymers of glucose, fructose and galactose, respectively. The synthesis of these compounds is catalyzed by glycosyltransferases (glycansucrases), which are able to transfer the monosaccharides in a specific substrate to the medium, which results in the growth of polysaccharide chains. The range of HoPS sizes is very large, from 104 to 109 Da, and mostly depends on the carbon source in the medium and the catalyzing enzyme. However, factors such as nitrogen nutrients, pH, water activity, temperature and duration of bacterial culture also impact the size and yield of production. The sequence of the enzyme influences the structure of the HoPS, by modulating the type of linkage between monomers, both for the linear chain and for the ramifications. HoPSs' size and structure have an effect on rheological properties of some foods by their influence on viscosity index. As a consequence, the control of structural and environmental factors opens ways to guide the production of specific HoPS in foods by bacteria, either by in situ or ex situ production, but requires a better knowledge of HoPS production conditions.

AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration.

Late-onset retinal degeneration (L-ORD) is an autosomal dominant disorder caused by a missense substitution in CTRP5. Distinctive clinical features include sub-retinal pigment epithelium (RPE) deposits, choroidal neovascularization, and RPE atrophy. In induced pluripotent stem cells-derived RPE from L-ORD patients (L-ORD-iRPE), we show that the dominant pathogenic CTRP5 variant leads to reduced CTRP5 secretion. In silico modeling suggests lower binding of mutant CTRP5 to adiponectin receptor 1 (ADIPOR1). Downstream of ADIPOR1 sustained activation of AMPK renders it insensitive to changes in AMP/ATP ratio resulting in defective lipid metabolism, reduced Neuroprotectin D1(NPD1) secretion, lower mitochondrial respiration, and reduced ATP production. These metabolic defects result in accumulation of sub-RPE deposits and leave L-ORD-iRPE susceptible to dedifferentiation. Gene augmentation of L-ORD-iRPE with WT CTRP5 or modulation of AMPK, by metformin, re-sensitize L-ORD-iRPE to changes in cellular energy status alleviating the disease cellular phenotypes. Our data suggests a mechanism for the dominant behavior of CTRP5 mutation and provides potential treatment strategies for L-ORD patients.

Pre and Probiotics Involved in the Modulation of Oral Bacterial Species: New Therapeutic Leads in Mental Disorders?

This systematic review aims to identify probiotics and prebiotics for modulating oral bacterial species associated with mental disorders. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline, we search the electronic MEDLINE database published till January 2021 to identify the studies on probiotics and/or prebiotics for preventing and treating major oral dysbiosis that provokes mental disorders. The outcome of the search produces 374 records. After excluding non-relevant studies, 38 papers were included in the present review. While many studies suggest the potential effects of the oral microbiota on the biochemical signalling events between the oral microbiota and central nervous system, our review highlights the limited development concerning the use of prebiotics and/or probiotics in modulating oral dysbiosis potentially involved in the development of mental disorders. However, the collected studies confirm prebiotics and/or probiotics interest for a global or targeted modulation of the oral microbiome in preventing or treating mental disorders. These outcomes also offer exciting prospects for improving the oral health of people with mental disorders in the future.

Did the Brain and Oral Microbiota Talk to Each Other? A Review of the Literature.

This systematic review aims to investigate the role of the oral microbiome in the pathophysiology of mental health disorders and to appraise the methodological quality of research of the oral-brain axis which is a growing interest area. The PRISMA guideline was adopted, to carry out an electronic search through the MEDLINE database, to identify studies that have explored the role of the oral microbiome in the pathophysiology of mental health disorders published from 2000 up to June 2020. The search resulted in 140 records; after exclusions, a total of 22 papers were included in the present review. In accordance with the role of the oral microbiome in the pathophysiology of mental disorders, four mental disorders were identified: Alzheimer's disease, dementia, and cognitive disorders; autism spectrum disorder; Down's syndrome and mental retardation; and Bipolar disorders. Studies argue for correlations between oral microbiota and Alzheimer's disease, autism spectrum disorders, Down's syndrome, and bipolar disorders. This field is still under-studied, and studies are needed to clarify the biological links and interconnections between the oral microbiota and the pathophysiology of all mental health disorders. Researchers should focus their efforts to develop research on the oral-brain axis in the future.

Healthcare pathway and patients' expectations in pulmonary fibrosis.

Patients with pulmonary fibrosis want earlier referral to excellence centres and an improved network of care http://ow.ly/pidy30abNoH.

Molecular Dissection of the Interface between the Type VI Secretion TssM Cytoplasmic Domain and the TssG Baseplate Component.

The type VI secretion system (T6SS) is a multiprotein complex that catalyses toxin secretion through the bacterial cell envelope of various Gram-negative bacteria including important human pathogens. This machine uses a bacteriophage-like contractile tail to puncture the prey cell and inject harmful toxins. The T6SS tail comprises an inner tube capped by the cell-puncturing spike and wrapped by the contractile sheath. This structure is built on an assembly platform, the baseplate, which is anchored to the bacterial cell envelope by the TssJLM membrane complex (MC). This MC serves as both a tail docking station and a channel for the passage of the inner tube. The TssM transmembrane protein is a key component of the MC as it connects the inner and outer membranes. In this study, we define the TssM topology, highlighting a large but poorly studied 35-kDa cytoplasmic domain, TssMCyto, located between two transmembrane segments. Protein-protein interaction assays further show that TssMCyto oligomerises and makes contacts with several baseplate components. Using computer predictions, we delineate two subdomains in TssMCyto, including a nucleotide triphosphatase (NTPase) domain, followed by a 110-aa extension. Finally, site-directed mutagenesis coupled to functional assays reveals the contribution of these subdomains and conserved motifs to the interaction with T6SS partners and to the function of the secretion apparatus.

Altered expression of the poly(ADP-ribosyl)ation enzymes in uveal melanoma and regulation of PARG gene expression by the transcription factor ERM.

PURPOSE: Poly(ADP-ribosyl)ation is a reversible post-translational modification that requires the contribution of the enzymes poly(ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose) glycohydrolase (PARG). Our study explores expression and activity of PARP-1 and PARG in uveal melanoma cell lines with varying tumorigenic properties. METHODS: Gene profiling on microarrays was conducted using RNA prepared from the uveal melanoma cell lines T97, T98, T108, and T115. The activity of PARP-1 and PARG was monitored by enzymatic assays, whereas their expression was measured by Western blot and PCR. The PARG promoter was analyzed using promoter deletions and site-specific mutagenesis in transfection analyses. The transcription factors binding the PARG promoter were studied by electrophoretic mobility shift assay (EMSA) analyses. Suppression of PARP-1 and PARG expression was performed in T97 and T115 cells by RNAi, and their tumorigenic properties monitored by injections into athymic mice. RESULTS: Expression of PARP-1 was found to vary considerably between uveal melanoma cell lines with distinctive tumorigenic properties in vivo. Sp1 and the ETS protein ERM were shown to bind to the PARG gene promoter to ensure basal transcription in uveal melanoma. Importantly, suppression of PARG gene expression in T97 and T115 cells increased their capacity to form tumors in athymic mice, whereas suppression of PARP-1 significantly reduced or almost entirely abolished tumor formation. CONCLUSIONS: Our results suggest that while overexpression of PARP-1 may confer a proliferative advantage to aggressive uveal melanoma tumors, PARG may, on the other hand, support a tumor suppressor function in vivo.

Interactions between human plasma components and a xenogenic adenovirus vector: reduced immunogenicity during gene transfer.

By the time we are adolescents most of us have been in contact with several of the >50 human adenovirus (HAd) serotypes. These common subclinical infections lead to an efficient anti-adenovirus cross-reacting adaptive immunity. During gene therapy, the ubiquitous anti-adenovirus humoral response and complement activation will modify and dictate vector biodistribution, as well as the response to the virion and transgene(s). In this study, we assayed the interactions of a xenogenic adenovirus derived from canine serotype 2 (CAV-2) with naturally occurring human antibodies (Abs) and the complement system. In our cohort, we found class G immunoglobulins (Igs) that recognized the intact CAV-2 virion and the external virion proteins. However, the majority of donors had low or no neutralizing Abs, class A, or class M Igs. Purified anti-HAd serotype 5 Abs also recognized CAV-2 virion proteins. In addition, in spite of the presence of anti-CAV-2 IgGs, CAV-2 poorly activated the classical and alternative complement cascades. This atypical response was due to a block upstream of the component 3 (C3) convertase and interplay between the component 1 (C1) inhibitor, the C1q-C1r2-C1s2 complex and CAV-2. Our data demonstrate that some xenogenic adenovirus vectors, like CAV-2, could lead to notably different outcomes following systemic delivery.