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ID PMID Title PublicationDate abstract
35128827 Epigenetic Regulation of Nutrient Transporters in Rheumatoid Arthritis Fibroblast-like Syn 2022 Feb 6 OBJECTIVE: Since previous studies indicate that metabolism is altered in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), we undertook this study to determine if changes in the genome-wide chromatin and DNA states in genes associated with nutrient transporters could help to identify activated metabolic pathways in RA FLS. METHODS: Data from a previous comprehensive epigenomic study in FLS were analyzed to identify differences in genome-wide states and gene transcription between RA and osteoarthritis. We utilized the single nearest genes to regions of interest for pathway analyses. Homer promoter analysis was used to identify enriched motifs for transcription factors. The role of solute carrier transporters and glutamine metabolism dependence in RA FLS was determined by small interfacing RNA knockdown, functional assays, and incubation with CB-839, a glutaminase inhibitor. We performed (1) H nuclear magnetic resonance to quantify metabolites. RESULTS: The unbiased pathway analysis demonstrated that solute carrier-mediated transmembrane transport was one pathway associated with differences in at least 4 genome-wide states or gene transcription. Thirty-four transporters of amino acids and other nutrients were associated with a change in at least 4 epigenetic marks. Functional assays revealed that solute carrier family 4 member 4 (SLC4A4) was critical for invasion, and glutamine was sufficient as an alternate source of energy to glucose. Experiments with CB-839 demonstrated decreased RA FLS invasion and proliferation. Finally, we found enrichment of motifs for c-Myc in several nutrient transporters. CONCLUSION: Our findings demonstrate that changes in the epigenetic landscape of genes are related to nutrient transporters, and metabolic pathways can be used to identify RA-specific targets, including critical solute carrier transporters, enzymes, and transcription factors, to develop novel therapeutic agents.
35119769 Reduction of Cardiovascular Disease and Mortality versus Risk of New Onset Diabetes with S 2022 Feb 4 OBJECTIVE: Assess the effect of statin use on the risk of cardiovascular disease (CVD), all-cause mortality, and type 2 diabetes mellitus (T2DM) in patients with rheumatoid arthritis (RA). METHODS: We identified a cohort of patients with RA between 1989 and 2018, within the UK Clinical Practice Research Datalink (CPRD). We employed a prevalent new-user cohort design by which patients initiating statins were each matched to two concurrent non-users by the time-conditional propensity score (TCPS). Patients were followed until the occurrence of the composite endpoint of myocardial infarction, stroke, hospitalized heart failure or CVD-mortality, all-cause mortality and incident T2DM. The Cox proportional hazards model was used to estimate the hazard ratio of each outcome associated with as-treated statin use, with adjustment for TCPS deciles and imbalanced covariables. RESULTS: Among 1768 statin initiators and 3528 non-users, 63 vs. 340 CVD (3.0/100 person-years [PY] vs. 2.7/100 PY) and 62 vs. 525 deaths (2.8/100 PY vs. 4.1/100 PY) occurred, respectively. Incident T2DM was noted in 128 of 3608 statin initiators (3.0/100 PY) and 518 of 7208 non-users (2.0/100 PY). Statin initiation was associated with 32% (HR=0.68, 95% CI 0.51-0.90) reduction in CVD, 54% (HR=0.46, 95% CI 0.35-0.60) reduction in all-cause mortality, and 33% increase in T2DM (HR=1.33, 95% CI 1.09-1.63) risks. Number needed to treat/harm to prevent a CVD, all-cause mortality or to cause T2DM in 1-year was 102, 42, 127 respectively. CONCLUSION: Statins are associated with important reductions in CVD and mortality which outweigh the modest increase in T2DM risk in RA patients.
35389078 Development and validation of a self-administered questionnaire measuring essential knowle 2022 Apr 7 To develop and validate a questionnaire assessing patient knowledge in rheumatoid arthritis (RA). Knowledge considered essential for patients with RA was identified through a series of Delphi rounds among rheumatologists, health professionals (HPs), patients, and then reformulated to construct the knowledge questionnaire. Cross-sectional multicenter validation was performed in 12 rheumatology departments to assess internal validity (Kuder-Richardson coefficient), external validity, acceptability, reproducibility (Lin's concordance correlation coefficient) and sensitivity to change (difference in total score before and after patient education sessions). Associations between patient variables and knowledge levels were evaluated. RAKE (RA Knowledge questionnairE) is a self-administered 45-item questionnaire scored 0-100, with a 32-item short-form survey assessing knowledge of disease, comorbidity, pharmacological treatments, non-pharmacological treatments, self-care and adaptative skills. Of 130 patients included in the validation study, 108 were women. Acceptability was good with < 5% missing data. Internal validity coefficient was 0.90. Mean (standard deviation) long-form score was 72.8 ± 17.8, with lower scores in comorbidity and self-care and higher scores in adaptive skills. Reproducibility was good (0.86 [0.80; 0.92]). RAKE score was positively correlated with the patients' level of education and the HPs' opinion on the patients' knowledge. RAKE score showed good sensitivity to change: 66.8 ± 16.4 then 83.8 ± 12.7, representing a hedges effect size of 1.14 [95% CI 0.73; 1.55]. RAKE is an updated questionnaire assessing essential knowledge for patients with RA to enhance self-management according to current guidelines and the patients' perspective. RAKE can usefully inform patient education interventions, routine care and research.
34806155 Fine Comparison of the Efficacy and Safety Between GB242 and Infliximab in Patients with R 2022 Feb INTRODUCTION: This phase III trial (NCT04178850) evaluated the efficacy, safety, and immunogenicity of GB242, an infliximab biosimilar, vs. infliximab (Remicade(®)) reference product in patients with moderate-to-severe active rheumatoid arthritis (RA) combination with methotrexate (MTX) therapy. METHODS: Patients were randomized in a 1:1 ratio to receive either GB242 or INF (3 mg/kg). Therapeutic equivalence of clinical response according to the American College of Rheumatology 20% (ACR20) response rate at week 30 was declared if the two-sided 95% CI for the treatment difference was within ± 14%. The comparison of GB242 with INF also included the proportion of patients achieving a week 30 ACR 50 response, ACR70 response, change in Disease Activity Score 28 (DAS28), as well as safety and immunogenicity. RESULTS: A total of 570 subjects were randomized into GB242 (N = 285) or INF (N = 285) and 283 subjects in each group were analyzed. At week 30, the ACR20 was 62.54% for the GB242 group (95% CI 56.62-68.20%) and 56.89% for the INF group (95% CI 50.90-62.74%). The difference between the two groups was 5.65% with a 95% CI of - 2.48 to 13.74. ACR50 response was 37.12% for GB242 and 32.86% for INF at week 30. ACR70 response was 19.79% for GB242 and 16.96% for INF at week 30, respectively. The incidence of treatment-emergent adverse events was comparable (77.4% in GB242 vs. 80.2% in INF) and detection of antidrug antibodies (ADA) to infliximab up to week 30 (60.8% in GB242 vs. 59.4% in INF) was comparable. CONCLUSIONS: GB242 demonstrated equivalent efficacy to INF at week 30. Moreover, GB242 was well tolerated, with a similar immunogenicity and safety profile comparable to INF.
35171365 Altered levels of circulating CD8(+)CXCR5(+)PD-1(+)T follicular cytotoxic cells in primary 2022 Jun BACKGROUND: Circulating CD8(+) T-cells expressing the C-X-C chemokine receptor type 5 (CXCR5) (CD8(+)CXCR5(+)T), a recently identified follicular cytotoxic T cell subset, are involved in antiviral immunity and autoimmunity, but their abundance and role in the pathogenesis of primary Sjögren syndrome (pSS) are unknown. METHODS: Circulating CD8(+)CXCR5(+)T cell and CD8(+) regulatory T cells (CD8(+)Treg) were evaluated in 49 pSS patients (19 patients with pulmonary involvement) and 24 age- and sex-matched healthy controls (HCs) by flow cytometry. Orthogonal partial least squares discriminant analysis (OPLS-DA) was performed, and receiver operating characteristic curves (ROC) were generated to identify characteristic cell subsets. Spearman's correlation analysis was conducted to examine the relationships between CD8(+) T cell subsets and clinical features. RESULTS: The proportions and numbers of CD8(+)CXCR5(+), CD8 + CXCR5(+) programmed death 1-positive (PD-1(+)), and CD8(+)CXCR5(-)PD-1(+)T cells were significantly higher, whereas those of CD8(+)Treg were markedly lower, in pSS patients than HCs. The CD8(+)CXCR5(+)PD-1(+)T cell to CD8(+)Treg ratio had the greatest discriminatory power for pSS and HCs according to OPLS-DA and ROC analyses. The increased numbers of CD8(+)CXCR5(+)T cells and CD8(+)CXCR5(+)PD-1(+)T cells were strongly associated with those of CD4(+)CXCR5(+)T and B cells. The proportions and numbers of CD8(+)CXCR5(+)PD-1(+)T cells were increased in pSS patients with lung involvement. CONCLUSIONS: We identified a new CD8(+)CXCR5(+)PD-1(+)T subset, which was increased in abundance in pSS patients, particularly those with lung involvement, compared with HCs. Also, the CD8(+)CXCR5(+)PD-1(+)T to CD8(+)Treg ratio may be useful for identifying pSS. Our findings suggest that targeting follicular CD8(+)T cell subsets has therapeutic potential for pSS. Key Points • CD8+CXCR5+ T cells were expanded in the circulation of patients with pSS. • Reduced numbers CD8+Treg cells in pSS patients. • Increased CD8+CXCR5+PD-1+T cells in pSS patients with pulmonary involvement.
35526080 Impaired activation of STAT5 upon IL-2 stimulation in Tregs and elevated sIL-2R in Sjögre 2022 May 7 BACKGROUND: Interleukin-2 (IL-2) and the high-affinity IL-2 receptor (IL-2R) are essential for the survival of regulatory T cells (Tregs) which are the main players in immune tolerance and prevention of autoimmune diseases. Sjögren's syndrome (SS) is a chronic autoimmune disease predominantly affecting women and is characterised by sicca symptoms including oral and ocular dryness. The aim of this study was to investigate an association between IL-2R and Treg function in patients with SS of different severity defined by the salivary flow rate. METHODS: In a cross-sectional study, we determined plasma soluble IL-2R (sIL-2R) levels in women with SS (n=97) and healthy females (n=50) using ELISA. A subset of those (n=51) was screened for Treg function measured by the STAT5 signalling response to IL-2 using phospho-flow cytometry. RESULTS: We found that elevated plasma levels of sIL-2R were positively associated with the severity of SS reflected by a pathologically low salivary flow. Phospho-flow analysis revealed that patients with SS have a significantly lower frequency of pSTAT5(+) Tregs upon IL-2 stimulation compared with healthy individuals, while the frequency of Tregs and pSTAT5 in conventional T cells remained unchanged. In addition, we observed more pSTAT5(+) Tregs at baseline in patients with SS, which is significantly associated with seropositivity and elevated sIL-2R. CONCLUSIONS: Our data indicates that Tregs have a weakened immunosuppressive function in patients with SS due to impaired IL-2/IL-2R signalling capacity. This could mediate lymphocytic infiltration into salivary glands inducing sicca symptoms. We believe that sIL-2R could act as a useful indicator for SS and disease severity.
35634334 Comprehensive Analysis of the Relationships Between the Gut Microbiota and Fecal Metabolom 2022 The gut microbiota has been associated with primary Sjogren's syndrome (pSS), yet the biological implications of these associations are often elusive. We analyzed the fecal microbiota through 16S rRNA gene amplification and sequencing in 30 patients with pSS and 20 healthy controls (HCs); At the same time, the fecal metabolome was characterized by ultrahigh-performance liquid chromatography-mass spectrometry. In addition, correlation analyses of microbiota and metabolome data were performed to identify meaningful associations. We found that the microbiota composition of pSS patients was significantly different from that of HCs. The pSS gut microbiota is characterized by increased abundances of proinflammatory microbes, especially Escherichia-Shigella, and decreased abundances of anti-inflammatory microbes. Concerning the metabolome, a multivariate model with 33 metabolites efficiently distinguished cases from controls. Through KEGG enrichment analysis, we found that these metabolites were mainly involved in amino acid metabolism and lipid metabolism. The correlation analysis indicated that there were certain correlations between the microbiota and metabolism in pSS patients. In addition, an abundance of Escherichia-Shigella was found to be correlated with high levels of four metabolites (aflatoxin M1, glycocholic acid, L-histidine and phenylglyoxylic acid). Our research suggests that in pSS patients, the gut microbiota is characterized by a specific combination of proinflammatory changes and metabolic states. Escherichia-Shigella is a factor related to gut dysbiosis, which may promote intestinal damage and affect amino acid metabolism.
34614514 Rice bodies in the wrist. 2022 Jan 7 Rice bodies are a rare finding in medicine and offer a therapeutic challenge. As their occurrence varies over multiple rheumatic as well as infectious diseases, multiple hypotheses have been made about their origin. While rice bodies are most frequently reported in the shoulder and knee joints, flexor tendon synovitis with accompanying rice bodies is rarer. We report a case of extensive flexor tenosynovitis with rice bodies in the wrist in a 90-year-old patient with seronegative rheumatoid arthritis. The patient reported a 5-month history of painful swelling of the right wrist. Ultrasound showed pronounced swelling of the synovial tissue of the flexor tendons. Laboratory test were negative for rheumatology tests with normal C-reactive protein and sedimentation rates. T2-weighted magnetic resonance imaging demonstrated an extensive synovitis reaching from the distal forearm into the hand with inclusions, better known as rice bodies. Synovectomy including carpal tunnel release was performed with dissection of the mass revealing an extensive synovitis with a multitude of rice bodies. Histopathology showed lymphohistiocytic infiltrates consistent with rheumatoid nodules. After surgery, the patient regained full function of the wrist within 2 weeks without any pain or remaining mass in the affected limb.
35040085 The Conundrum of Psoriatic Arthritis: a Pathogenetic and Clinical Pattern at the Midpoint 2022 Jan 18 Psoriatic arthritis (PsA) is a chronic inflammatory condition characterized by psoriasis, synovitis, enthesitis, spondylitis, and the possible association with other extra-articular manifestations and comorbidities. It is a multifaceted and systemic disorder sustained by complex pathogenesis, combining aspects of autoinflammation and autoimmunity. Features of PsA autoinflammation include the role of biomechanical stress in the onset and/or exacerbation of the disease; the evidence of involvement of the innate immune response mediators in the skin, peripheral blood and synovial tissue; an equal gender distribution; the clinical course which may encounter periods of prolonged remission and overlapping features with autoinflammatory syndromes. Conversely, the role of autoimmunity is evoked by the association with class I major histocompatibility complex alleles, the polyarticular pattern of the disease which sometimes resembles rheumatoid arthritis and the presence of serum autoantibodies. Genetics also provide important insights into the pathogenesis of PsA, particularly related to class I HLA being associated with psoriasis and PsA. In this review, we provide a comprehensive review of the pathogenesis, genetics and clinical features of PsA that endorse the mixed nature of a disorder at the crossroads of autoinflammation and autoimmunity.
34662070 Peripheral Ulcerative Keratitis. 2022 Jan Peripheral ulcerative keratitis (PUK) affects the juxtalimbal cornea and classically presents with epithelial defect and stromal lysis. This inflammatory condition results in a complex interplay between host autoimmunity, the anatomy and physiology of the peripheral cornea, and the environment. The underlying cause could be local or systemic, infectious or noninfectious. PUK can be due to vasculitides and collagen vascular disease; rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and systemic lupus erythematosus (SLE) can account for up to 53% of PUK cases. PUK in scleritis is a poor prognostic factor. Progressive stromal lysis can cause corneal perforation, and in patients with an underlying autoimmune disease indicates significant morbidity and mortality. PUK without systemic association is known as Mooren's ulcer (MU) and contributes to 31.5% of PUK causes. Bowman first described it in 1849, followed by McKenzie in 1854, as an "ulcus roden" of the cornea. Mooren's ulcer occurs in the absence of scleritis and is a diagnosis of exclusion. Clinical signs begin in the peripheral cornea and progress centrally and circumferentially, with a distinctive overhanging edge.  PUK is important to diagnose as it can be the first presenting feature of a life-threatening systemic disease. Meticulous clinical investigation and multi-disciplinary management are required to ensure safe patient outcomes.
35242257 Pneumatosis intestinalis: Not always bowel ischemia. 2022 Apr Pneumatosis intestinalis or abnormal intramural gas within the digestive tract usually suggests bowel ischemia necessitating urgent surgery. We report the case of an 82-year-old female presenting with hypotension and nausea, with a past history of schizophrenia, low grade chronic lymphocytic leukemia, stroke, bronchitis and rheumatoid arthritis. Computed tomography performed demonstrated extensive submucosal gas within the entire small bowel, associated with free gas in the peritoneal cavity. Bowel ischemia was diagnosed radiologically. However, a benign diagnosis of fecal impaction was ultimately made due to the patient's stable clinical status. Clinical correlation and close monitoring of clinical status in this context is of greatest diagnostic assistance when encountered with this phenomenon, to prevent unnecessary harm to the patient.
35466876 Flavonoids as Sirtuin Modulators. 2022 Apr 22 Sirtuins (SIRTs) are described as NAD+-dependent deacetylases, also known as class III histone deacetylases. So far, seven sirtuin genes (SIRTS 1-7) have been identified and characterized in mammals and also known to occur in bacteria and eukaryotes. SIRTs are involved in various biological processes including endocrine system, apoptosis, aging and longevity, diabetes, rheumatoid arthritis, obesity, inflammation, etc. Among them, the best characterized one is SIRT1. Actually, small molecules seem to be the most effective SIRT modulators. Flavonoids have been reported to possess many positive effects favrable for human health, while a relatively less research has been reported so far on their funcions as SIRT modulation mechanisms. In this regard, we herein aimed to focus on modulatory effects of flavonoids on SIRTs as the most common secondary metabolites in natural products. Our literature survey covering the years of 2006-2021 pointed out that flavonoids frequently interact with SIRT1 and SIRT3 followed by SIRT6. It can be also concluded that some popular flavonoid derivatives, e.g. resveratrol, quercetin, and catechin derivatives came forward in terms of SIRT modulation.
35503162 Baricitinib: A Review in Moderate to Severe Atopic Dermatitis. 2022 May Baricitinib (Olumiant(®)) is an oral small molecule inhibitor of Janus kinase (JAK)1 and JAK2, which have been implicated in the pathogenesis of atopic dermatitis (AD). In phase III studies in adults with moderate to severe AD who were inadequately controlled with topical corticosteroids (TCS) or systemic treatments (e.g. ciclosporin), or for whom these therapies were not advisable, baricitinib, alone or in combination with TCS, achieved significant and/or clinically relevant improvements in multiple measures of disease severity, pruritus, skin pain, sleep disturbance and health-related quality of life (HR-QOL) over 16 weeks. Benefit onset was rapid, with efficacy generally sustained over the longer term (treatment duration ≤ 68 weeks). In this patient population, the safety profile of baricitinib was consistent with that established in the moderate to severe rheumatoid arthritis (RA) population. Although further longer-term data would be beneficial, current evidence indicates that baricitinib, alone or in combination with TCS, provides an oral alternative to subcutaneous biologics for the treatment of moderate to severe AD in adults who are candidates for systemic therapy.
35284738 Network Pharmacology-Based Analysis on the Effects and Mechanism of the Wang-Bi Capsule fo 2022 Mar 8 Wang-Bi capsule (WB) is a traditional Chinese medicine (TCM)-based herbal formula, and it has been used in the treatment of rheumatoid arthritis (RA) in China for many years. Additionally, WB is also used as a supplement to the treatment of osteoarthritis (OA) in clinical practice. Our research aimed to reveal the therapeutic effects and underling mechanism of WB on RA and OA through computational system pharmacology analysis and experimental study. Based on network pharmacology analysis, a total of 173 bioactive compounds interacted with 417 common gene targets related to WB, RA, and OA, which mainly involved the PI3K-Akt signaling pathway. In addition, the serine-threonine protein kinase 1 (AKT1) might be a core gene protein for the action of WB, which was further emphasized by molecular docking. Moreover, the anti-inflammatory activity of WB in vitro was confirmed by reducing NO production in lipopolysaccharide (LPS)-induced RAW264.7 cells. The anti-RA and OA effects of WB in vivo were confirmed by ameliorating the disease symptoms of collagen II-induced RA (CIA) and monosodium iodoacetate-induced OA (MIA) in rats, respectively. Furthermore, the role of the PI3K-Akt pathway in the action of WB was preliminarily verified by western blot analysis. In conclusion, our study elucidated that WB is a potentially effective strategy for the treatment of RA and OA, which might be achieved by regulating the PI3K-Akt pathway. It provides us with systematic insights into the effects and mechanism of WB on RA and OA.
35200126 Identification of RRM2 in peripheral blood mononuclear cells as a novel biomarker for the 2022 Feb 1 OBJECTIVES: Rheumatoid arthritis (RA) is a common autoimmune disease. However, the positive diagnosis value of the current biomarkers is unsatisfactory. Here, we aimed to identify RA-associated susceptibility genes and explore their potential as novel biomarkers for the diagnosis of RA. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from healthy controls and RA patients. RNA-seq and bioinformatics analyses were performed to identify the hub genes associated with RA. Then, the expression of hub genes was assessed in mRNA expression profiles from GEO datasets. Real time-quantitative PCR (RT-qPCR) was performed to further confirm the expression of the hub genes using the PBMCs that were collected from RA patients (n=47) and healthy controls (n=40). Finally, we evaluated the diagnostic potential of the candidate mRNAs. RESULTS: RNA-seq analyses revealed 178 dysregulated genes measured by changes in mRNAs between the healthy controls and the RA patients. We identified 3 candidate mRNAs, including ASPM, DTL and RRM2, all of which were highly expressed in RA. RRM2 showed a significant higher expression in remissive RA compared with active RA. Significant correlations were observed between DTL and IL-8, TNF-α which were tested in serum by ELISA, between RRM2 and CDAI, DAS-28, tender and swollen joints, respectively. The expression level of RRM2 was significantly higher in RA patients with the Anti-CCP- than with the Anti-CCP+. The AUC (RA vs. OA) value of RRM2 was 0.941 (p<0.0001; sensitivity=0.867; specificity=0.904). CONCLUSIONS: RRM2 showed high diagnosis efficiency for RA patients. Therefore, the findings provided a novel candidate biomarker for the diagnosis of RA.
35177322 Repeatability of quantitative MRI in patients with rheumatoid arthritis. 2022 Feb 14 INTRODUCTION: Rheumatoid arthritis (RA) affects 1% of the population and is principally associated with joint inflammation. It is suggested however that muscle involvement may be one of the earliest clinical features of RA. It is therefore important that techniques exist to accurately assess muscle health in those with RA to enable successful treatment. This study assesses the inter-rater and intra-rater repeatability of Diffusion Tensor MRI (DTI), 2-Point Dixon fat fraction, and T2 relaxation of the thigh muscle in patients with RA using manual regions of interest (ROI). METHODS: Nineteen patients (10/19 males; mean age 59; range 18-85) diagnosed with RA had an MRI scan of their hamstrings and quadriceps muscles to obtain fat fraction (FF), mean diffusivity (MD), fractional anisotropy (FA), and T2 quantitative measurements. Two raters DB & MF independently contoured ROIs for each patient. DB repeated the ROI for the same 19 patients after a 6-month hiatus to assess intra-rater repeatability. Inter-rater and intra-rater repeatability for the ROI measurements were compared using Inter Class Correlation (ICC) and Bland-Altman plots. RESULTS: There was excellent agreement for both inter-rater and intra-rater repeatability. ICC results ranged from 0.900 to 0.998 (P < 0.001), and intra-rater ICC results ranged from 0.977 to 0.999 (P < 0.001). Bland-Altman plots also showed excellent agreement. CONCLUSIONS: ICC measurements and Bland-Altman plots showed excellent repeatability and agreement with no statistically significant differences when assessing the inter-rater and intra-rater repeatability of FF, MD, FA, and T2 relaxation of the thigh muscle using manual regions of interest in patients with RA. IMPLICATIONS FOR PRACTICE: Manual ROI drawing does not introduce significant errors obtaining FF, MD, FA, and T2 MRI measurements in an RA population.
35018644 Determinants of long-term opioid prescribing in an urban population: A cross-sectional stu 2022 Jan 11 BACKGROUND: Opioid prescribing has more than doubled in the UK between 1998 and 2016. Potential adverse health implications include dependency, falls and increased health expenditure. AIM: To describe the predictors of long-term opioid prescribing (LTOP) (≥3 opioid prescriptions in a 90-day period). DESIGN AND SETTING: A retrospective cross-sectional study in 41 general practices in South London. METHOD: Multi-level multivariable logistic regression to investigate the determinants of LTOP. RESULTS: Out of 320 639 registered patients ≥18 years, 2679 (0.8%) were identified as having LTOP. Patients were most likely to have LTOP if they had ≥5 long-term conditions (LTCs) (adjusted odds ratio [AOR] 36.5, 95% confidence interval [CI] 30.4-43.8) or 2-4 LTCs (AOR 13.8, CI 11.9-16.1) in comparison to no LTCs, were ≥75 years compared to 18-24 years (AOR 12.31, CI 7.1-21.5), were smokers compared to nonsmokers (AOR 2.2, CI 2.0-2.5), were female rather than male (AOR 1.9, CI 1.7-2.0) and in the most deprived deprivation quintile (AOR 1.6, CI 1.4-1.8) compared to the least deprived. In a separate model examining individual LTCs, the strongest associations for LTOP were noted for sickle cell disease (SCD) (AOR 18.4, CI 12.8-26.4), osteoarthritis (AOR 3.0, CI 2.8-3.3), rheumatoid arthritis (AOR 2.8, CI 2.2-3.4), depression (AOR 2.6, CI 2.3-2.8) and multiple sclerosis (OR 2.5, CI 1.4-4.4). CONCLUSION: LTOP was significantly higher in those aged ≥75 years, with multimorbidity or specific LTCs: SCD, osteoarthritis, rheumatoid arthritis, depression and multiple sclerosis. These characteristics may enable the design of targeted interventions to reduce LTOP.
35655291 Marine-derived microbes and molecules for drug discovery. 2022 Jun 3 Increasing attention has been paid to marine-derived biomolecules as sources of therapeutics for autoimmune diseases. Nagasaki Prefecture has many islands and is surrounded by seas, straits, gulfs, bays, and coves, giving it the second longest coastline in Japan after Hokkaido. We have collected more than 20,000 marine microbes and have been preparing an original marine microbial extract library, which contains small and mid-size biomolecules that may penetrate cell membranes and interfere with the intracellular protein-protein interaction involved in the development of autoinflammatory diseases such as familial Mediterranean fever. In addition, we have been developing an indoor shark farming system to prepare shark nanobodies that could be developed as potential therapeutic agents for autoimmune diseases. Sharks produce heavy-chain antibodies, called immunoglobulin new antigen receptors (IgNARs), consisting of one variable domain (V(NAR)) and five constant domains (C(NAR)); of these, V(NAR) can recognize a variety of foreign antigens. A V(NAR) single domain fragment, called a nanobody, can be expressed in Escherichia coli and has the properties of an ideal therapeutic candidate for autoimmune diseases. Shark nanobodies contain complementarity-determining regions that are formed through the somatic rearrangement of variable, diversity, and joining segments, with the segment end trimming and the N- and P-additions, as found in the variable domains of mammalian antibodies. The affinity and diversity of shark nanobodies are thus expected to be comparable to those of mammalian antibodies. In addition, shark nanobodies are physically robust and can be prepared inexpensively; as such, they may lead to the development of highly specific, stable, effective, and inexpensive biotherapeutics in the future. In this review, we first summarize the history of the development of conventional small molecule drugs and monoclonal antibody therapeutics for autoimmune diseases, and then introduce our drug discovery system at Nagasaki University, including the preparation of an original marine microbial extract library and the development of shark nanobodies.
35239492 IPP: An Intelligent Privacy-Preserving Scheme for Detecting Interactions in Genome Associa 2022 Mar 3 Analyzing K-order Single Nucleotide Polymorphism (SNP) interactions through the statistics of Genome-Wide Association Studies (GWAS) is crucial for discovering pathogenic causes of human complex diseases and controlling risk genetic variants of diverse disorders. We propose a method based on Ant Colony Optimization (ACO) algorithm to detect gene interactions for GWAS - an Intelligent Privacy-Preserving scheme (IPP). Initially, we design a multi-objective search algorithm to discover the candidate SNP sets related to disease phenotype, which utilizes Differential Privacy (DP) method by disturbing the multi-objective function to construct a rational epistatic privacy protection strategy. Furthermore, the global path selection strategy composed of two probabilistic methods is proposed to reduce the probability of falling into the local optimum. We use simulated models and a real dataset of Rheumatoid Arthritis (RA) to compare IPP with four popular methods to detect K-order SNPs, the experimental results show that IPP can guarantee the search accuracy effectively and enhance the detecting ability of various models. Further, the privacy budget experiments indicate that the range of privacy budget in IPP is reasonable and make the framework more stable.
34283427 Undifferentiated Connective Tissue Disease. 2022 Jan The connective tissues play a crucial role within organs by supporting and binding several types of tissues. If these tissues are targeted by the immune system, a connective tissue disease may occur, resulting in a wide range of signs and symptoms. The connective tissue disease is an umbrella for a wide variety of diseases. For each one, there are diagnostic criteria. However, if the signs and symptoms of a patient do not meet any of these diagnostic criteria, the diagnosis of undifferentiated connective tissue disease will be established. Undifferentiated connective tissue disease is a clinical entity defined as serological and clinical manifestations of systemic autoimmune disease. However, not fulfilling any criteria of defined connective tissue disease such as systemic lupus erythematosus, mixed connective tissue disease, Sjögren syndrome, systemic sclerosis, polymyositis, dermatomyositis, or rheumatoid arthritis. In clinical practice, the presence of undifferentiated connective tissue disease can be common. The early phase of a major rheumatic disease was defined earlier by LeRoy et al. in 1980 as undifferentiated connective tissue disease in patients whose features did not meet other classification criteria.