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ID PMID Title PublicationDate abstract
34678409 Hip Gluteus Medius Tears Are Associated With Lower Femoral Neck-Shaft Angles and Higher Ac 2022 May PURPOSE: 1) To assess the possible relationship between the morphology of femur or acetabulum and the gluteus medius pathology. 2) To analyze the outcome of isolated arthroscopic treatment of femoroacetabular impingement (FAI) for patients with radiographic gluteus medius tear. METHODS: We performed a retrospective study of FAI patients who underwent arthroscopy between January 2016 to December 2019. Demographic data, such as sex, age, body mass index (BMI), symptom duration, were collected. Radiographic parameters, including alpha angle, lateral center-edge angle (LCEa), femur neck-shaft angle (NSa), gluteus medius pathology, were also collected. Exclusion criteria were previous hip conditions, such as osteoarthritis (Tönnis grade > 1), rheumatoid arthritis, ankylosing spondylitis, snapping hip, previous surgery on the ipsilateral hip, or incomplete data. We followed up these patients with radiographic gluteus medius tear. No surgical procedure for gluteus medius was performed. The minimum follow-up period was 13 months. Patient-reported outcomes, such as modified Harris Hip score (mHHS), visual analog scale (VAS), and patient acceptable symptom state (PASS), as well as physical examination data, including tenderness at the greater trochanter, abductor weakness, limping gait, and positive Trendelenburg sign or test, were gathered preoperatively and postoperatively. RESULTS: A total of 569 hips (314, 55.2% male) were collected eventually, with a mean age of 36.5 ± 10.4 years (range: 13.0 to ∼65.0). Gluteus medius pathology was found in 209 (36.7%) hips, including 41 (7.2%) partial-thickness tears and 10 (1.8%) complete tears. The NSa of the normal, tendinosis, partial tear, and complete tear groups was 133.8 ± 4.7°, 130.6 ± 3.8°, 129.4 ± 3.9°, and 129.6 ± 3.4°, respectively (P < .001). The LCEa of each group was 31.7 ± 35.7°, 33.3 ± 6.5°, 34.9 ± 6.8°, and 33.7 ± 8.1°, respectively (P = .004). On multivariable logistic regression analysis, lower NSa and higher LCEa were identified as risk factors for developing gluteus medius pathology (P < .001). For patients with gluteus medius tear, two cases were lost to follow-up and two cases had incomplete data. The mean follow-up period of the remaining 47 hips was 29.5 ± 12.9 (range: 13 to 59) months. The mHHS improved from 54.8 ± 19.1 to 90.1 ± 6.7 points (P < .001), and VAS decreased from 6.8 ± 1.6 to 3.0 ± 1.6 points (P < .001). Forty-two cases met the threshold of PASS, with a rate of 89%. The abductor strength increased from 4.1 ± 1.00 to 4.6 ± .7 grades (P = .002). However, for patients with a completely torn gluteus medius, improvement of abductor strength was not significant statistically (3.4 ± .9 to 3.9 ± .9, P = .234). CONCLUSION: There was a correlation between lower NSa/higher LCEa and gluteus medius pathology. Isolated arthroscopic treatment of FAI for patients with radiographic gluteus medius tear can gain satisfactory patient-reported outcomes. LEVEL OF EVIDENCE: Therapeutic case series, IV.
34968661 Qingluotongbi formula regulates the LXRα-ERS-SREBP-1c pathway in hepatocytes to alleviate 2022 Apr 6 ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii Hook. f. (TW) is widely used to treat autoimmune and inflammatory diseases; however, its development and application is limited by its significant association with liver injury. The compound formula Qingluotongbi (QLT) employs TW as its main component and is used to treat rheumatoid arthritis with no adverse reactions, suggesting that QLT may reduce the liver toxicity of TW. AIM OF THE STUDY: We examined whether TW interferes with lipid metabolism to induce liver injury, and evaluated the protective effect of QLT in in vivo and in vitro experiments. MATERIALS AND METHODS: After administration of QLT and its ingredients, HepaRG cells and SD rats were tested for biochemical indicators, hepatocytes lipid changes, and rat liver pathological changes, and then we analyzed for the gene expression of liver X receptor α (LXRα), endoplasmic reticulum stress (ERS) key proteins, sterol regulatory element binding protein-1c (SREBP-1c), and lipid-synthesizing enzymes. In HepaRG cells, the protein expression of glucose-regulated protein 78 kDa (GRP78) and LXRα was detected after addition of an LXRα inhibitor, LXRα agonist, and ERS inhibitor. RESULTS: TW caused significant elevation of biochemical indicators and lipid droplet deposition in hepatocytes, as well as upregulated the gene expression of LXRα, ERS key proteins, SREBP-1c, and lipid-synthesizing enzymes in both in vitro and in vivo settings, and caused liver injury in rats. QLT can alleviate the lipotoxic liver injury caused by TW. LXRα agonist further activated ERS induced by TW, whereas LXRα inhibitor significantly reduced ERS and lipotoxic injury induced by TW in HepaRG cells. CONCLUSIONS: TW upregulated LXRα to activate ERS and increased the gene expression of SREBP-1c and lipid-synthesizing enzymes, leading to increased lipid synthesis in hepatocytes to result in liver injury. QLT inhibited the LXRα-ERS-SREBP-1c pathway and reduced abnormal lipid synthesis in hepatocytes and the hepatotoxicity of TW.
34961705 Safety and pharmacokinetics of Roscovitine (Seliciclib) in cystic fibrosis patients chroni 2022 May BACKGROUND: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects. METHODS: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks). RESULTS: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group. CONCLUSION: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.
35082139 Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: V 2022 Jan 26 OBJECTIVE: To investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk. DESIGN: Vitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design. SETTING: Nationwide in the United States. PARTICIPANTS: 25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment. INTERVENTIONS: Vitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence. MAIN OUTCOME MEASURES: The primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others. RESULTS: 25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease. CONCLUSIONS: Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo). STUDY REGISTRATION: ClinicalTrials.gov NCT01351805 and NCT01169259.
35030495 VECTOR: An algorithm for the detection of COVID-19 pneumonia from velcro-like lung sounds. 2022 Mar The coronavirus disease 2019 (COVID-19) has severely stressed the sanitary systems of all countries in the world. One of the main issues that physicians are called to tackle is represented by the monitoring of pauci-symptomatic COVID-19 patients at home and, generally speaking, everyone the access to the hospital might or should be severely reduced. Indeed, the early detection of interstitial pneumonia is particularly relevant for the survival of these patients. Recent studies on rheumatoid arthritis and interstitial lung diseases have shown that pathological pulmonary sounds can be automatically detected by suitably developed algorithms. The scope of this preliminary work consists of proving that the pathological lung sounds evidenced in patients affected by COVID-19 pneumonia can be automatically detected as well by the same class of algorithms. In particular the software VECTOR, suitably devised for interstitial lung diseases, has been employed to process the lung sounds of 28 patient recorded in the emergency room at the university hospital of Modena (Italy) during December 2020. The performance of VECTOR has been compared with diagnostic techniques based on imaging, namely lung ultrasound, chest X-ray and high resolution computed tomography, which have been assumed as ground truth. The results have evidenced a surprising overall diagnostic accuracy of 75% even if the staff of the emergency room has not been suitably trained for lung auscultation and the parameters of the software have not been optimized to detect interstitial pneumonia. These results pave the way to a new approach for monitoring the pulmonary implication in pauci-symptomatic COVID-19 patients.
34846307 What Are the All-Cause Survivorship Rates and Functional Outcomes in Patients Younger Than 2022 Mar 1 BACKGROUND: Approximately one-fourth of TKAs will be performed in patients 55 years or younger within the next decade. Postoperative outcomes for younger patients who had a knee arthroplasty were systematically reviewed in 2011; however, numerous studies evaluating young patients who had both a TKA and unicompartmental knee arthroplasty (UKA) have been reported in the past decade. Therefore, to better counsel this growing population of young patients undergoing knee arthroplasty, an updated understanding of their expected postoperative outcomes is warranted. QUESTIONS/PURPOSES: In this systematic review, we evaluated (1) all-cause survivorship, (2) reasons for revision, (3) patient-reported outcomes, and (4) return to physical activity and sport in patients 55 years or younger undergoing primary TKA or UKA. METHODS: A comprehensive search of PubMed, Medline, SportDiscus, and CINAHL was performed to identify all original studies evaluating outcomes after primary knee arthroplasty for young patients (55 years of age or younger) from inception until March 2021. The following keywords were used: knee, arthroplasty, replacement, pain, function, revision, survivorship, sport, physical activity, and return to play. Only original research studies that were related to knee arthroplasty and reported postoperative outcomes with a minimum 1-year follow-up for patients 55 years or younger were included. Unpublished materials, publications not available in English, and studies with a primary diagnosis of rheumatoid arthritis were excluded. The Methodological Index for Non-Randomized Studies (MINORS) score was used to evaluate the study quality of case series and comparative studies, while the Cochrane Risk of Bias tool and the Jadad scale were used for randomized studies. The primary outcomes of interest for this study were all-cause survivorship rate, reasons for all-cause revision, Knee Society and Knee Society Function scores (minimum clinically important difference [MCID] 7.2 and 9.7, respectively), WOMAC scores (MCID 10), Tegner scores (no reported MCID for knee arthroplasty), and return to physical activity or sport. Knee Society and Knee Society Function scores range from 0 to 100, with scores from 85 to 100 considered excellent and below 60 representing poor outcomes. All-cause survivorship rate and reasons for revision were both reported in 17 total studies. Knee Society scores were presented in 19 and Knee Society Function scores were reported in 18 included studies. WOMAC scores and Tegner scores were each found in four included studies, and return to physical activity and return to sport analyses were performed in seven studies. Overall, 21 TKA studies and five UKA studies were included in this analysis, featuring 3095 TKA knees and 482 UKA knees. RESULTS: Kaplan-Meier estimates of all-cause survivorship ranged from 90% to 98% at 5 to 10 years of follow-up after TKA and from 84% to 99% (95% CI 93% to 98%) at 10 years to 20 years post-TKA. All-cause UKA survivorship was 90% at 10 years and 75% at 19 years in the largest Kaplan-Meier estimate of survivorship for patients younger than 55 who underwent UKA. Common reasons for revision in TKA patients were polyethylene wear/loosening, aseptic tibial loosening, and infection, and in UKA patients the common reasons for revision were knee pain, aseptic loosening, progression of knee osteoarthritis, and polyethylene wear/loosening. Knee Society scores ranged from 85 to 98 for 5-year to 10-year follow-up and ranged from 86 to 97 at 10-year to 20-year follow-up in TKA patients. Knee Society Function scores ranged from 70 to 95 for 5-year to 10-year follow-up and ranged from 79 to 86 at 10-year to 20-year follow-up. Return to physical activity and sport was reported variably; however, most patients younger than 55 have improved physical activity levels after knee arthroplasty relative to preoperative levels. CONCLUSION: Although all-cause survivorship rates were frequently above 90% and patient-reported outcome scores were generally in the good to excellent range, several studies reported long-term survivorship rates from 70% to 85% and fair patient-reported outcome scores, which must be factored into any preoperative counseling with patients. We could not control for surgeon volume in this report, and prior research suggests that increasing volume is associated with less frequent complications; in addition, the studies we included were variably affected by selection bias, transfer bias, and assessment bias, which makes it likely that the findings of our review represent best-case estimates. To limit the frequency of revision in patients younger than 55 years undergoing TKA, clinicians should be cautious of polyethylene wear/loosening, aseptic tibial loosening, and infection, while knee pain and progression of knee osteoarthritis are also common reasons for revision in patients younger than 55 undergoing UKA. Further research should isolate younger knee arthroplasty patients and evaluate postoperative activity levels while accounting for preoperative physical activity and sport participation. LEVEL OF EVIDENCE: Level IV, therapeutic study.
35155868 Urine Single-Cell RNA Sequencing in Focal Segmental Glomerulosclerosis Reveals Inflammator 2022 Feb INTRODUCTION: Individuals with focal segmental glomerular sclerosis (FSGS) typically undergo kidney biopsy only once, which limits the ability to characterize kidney cell gene expression over time. METHODS: We used single-cell RNA sequencing (scRNA-seq) to explore disease-related molecular signatures in urine cells from subjects with FSGS. We collected 17 urine samples from 12 FSGS subjects and captured these as 23 urine cell samples. The inflammatory signatures from renal epithelial and immune cells were evaluated in bulk gene expression data sets of FSGS and minimal change disease (MCD) (The Nephrotic Syndrome Study Network [NEPTUNE] study) and an immune single-cell data set from lupus nephritis (Accelerating Medicines Partnership). RESULTS: We identified immune cells, predominantly monocytes, and renal epithelial cells in the urine. Further analysis revealed 2 monocyte subtypes consistent with M1 and M2 monocytes. Shed podocytes in the urine had high expression of marker genes for epithelial-to-mesenchymal transition (EMT). We selected the 16 most highly expressed genes from urine immune cells and 10 most highly expressed EMT genes from urine podocytes as immune signatures and EMT signatures, respectively. Using kidney biopsy transcriptomic data from NEPTUNE, we found that urine cell immune signature and EMT signature genes were more highly expressed in FSGS biopsies compared with MCD biopsies. CONCLUSION: The identification of monocyte subsets and podocyte expression signatures in the urine samples of subjects with FSGS suggests that urine cell profiling might serve as a diagnostic and prognostic tool in nephrotic syndrome. Furthermore, this approach may aid in the development of novel biomarkers and identifying personalized therapies targeting particular molecular pathways in immune cells and podocytes.
34971632 Increased sensitivity of gp210 autoantibody detection using a newly designed gp210 antigen 2022 Feb OBJECTIVES: The detection of autoantibody to glycoprotein 210 (gp210 Ab) against a 15 amino-acid peptide epitope by enzyme-linked immunosorbent assay (ELISA) has been widely used in the diagnosis of primary biliary cholangitis (PBC). However, this small peptide antigen presents spatial limitations for antibody access, which reduces the sensitivity of autoantibody detection. A recombinant gp210 antigen was constructed for increased sensitivity in antibody detection is described here. METHODS: The gp210 C terminal 18 amino acid coding sequence was ligated to the modified C-terminal 108 amino acid coding sequence of human serum albumin (mHSA108) and produced as a recombinant gp210 antigen mHSA108-gp210-C18. Measurements of gp210 Ab using the gp210 C-terminal 25 amino acid peptide (gp210-C25) and mHSA108-gp210-C18 by in-house ELISA were compared. ELISAs with mHSA108-gp210-C18 and commercial INOVA kit for gp210 Ab detection were also compared in PBC patients and healthy controls. The correlation between the two assays was analyzed and their efficiency in diagnosing was compared. RESULTS: Of 86 PBC samples, 35 (40.70%) and 44 (52.33%) positive samples were detected for anti-gp210 Ab using gp210-C25 and mHSA108-gp210-C18, respectively. Of 252 samples from PBC, 114 (45.24%) were positive for mHSA108-gp210-C18 ELISA whereas 94 (37.3%) for commercial ELISA (INOVA). All positive samples detected with commercial ELISA kit were also tested positive in mHSA108-gp210-C18 ELISA. Among 374 patients with other autoimmune diseases, anti-gp210 Ab were detected by mHSA108-gp210-C18 ELISA in 0.95% systemic lupus erythematosus (SLE) patients (2/210), 13.04% rheumatoid arthritis (RA) patients (13/97), and 1.47% of Sjögren's Syndrome (SS) patients (1/67). CONCLUSIONS: Compared to the gp210 peptide antigen, the sensitivity of the ELISA system using mHSA108-gp210-C18 antigen was improved. The novel gp210 antigen could be useful for screening patients known to be at increased risk of developing PBC.
34675423 Co-varying neighborhood analysis identifies cell populations associated with phenotypes of 2022 Mar As single-cell datasets grow in sample size, there is a critical need to characterize cell states that vary across samples and associate with sample attributes, such as clinical phenotypes. Current statistical approaches typically map cells to clusters and then assess differences in cluster abundance. Here we present co-varying neighborhood analysis (CNA), an unbiased method to identify associated cell populations with greater flexibility than cluster-based approaches. CNA characterizes dominant axes of variation across samples by identifying groups of small regions in transcriptional space-termed neighborhoods-that co-vary in abundance across samples, suggesting shared function or regulation. CNA performs statistical testing for associations between any sample-level attribute and the abundances of these co-varying neighborhood groups. Simulations show that CNA enables more sensitive and accurate identification of disease-associated cell states than a cluster-based approach. When applied to published datasets, CNA captures a Notch activation signature in rheumatoid arthritis, identifies monocyte populations expanded in sepsis and identifies a novel T cell population associated with progression to active tuberculosis.
34893469 EULAR points to consider for the use of imaging to guide interventional procedures in pati 2022 Jun OBJECTIVES: To develop evidence-based Points to Consider (PtC) for the use of imaging modalities to guide interventional procedures in patients with rheumatic and musculoskeletal diseases (RMDs). METHODS: European Alliance of Associations for Rheumatology (EULAR) standardised operating procedures were followed. A systematic literature review was conducted to retrieve data on the role of imaging modalities including ultrasound (US), fluoroscopy, MRI, CT and fusion imaging to guide interventional procedures. Based on evidence and expert opinion, the task force (25 participants consisting of physicians, healthcare professionals and patients from 11 countries) developed PtC, with consensus obtained through voting. The final level of agreement was provided anonymously. RESULTS: A total of three overarching principles and six specific PtC were formulated. The task force recommends preference of imaging over palpation to guide targeted interventional procedures at peripheral joints, periarticular musculoskeletal structures, nerves and the spine. While US is the favoured imaging technique for peripheral joints and nerves, the choice of the imaging method for the spine and sacroiliac joints has to be individualised according to the target, procedure, expertise, availability and radiation exposure. All imaging guided interventions should be performed by a trained specialist using appropriate operational procedures, settings and assistance by technical personnel. CONCLUSION: These are the first EULAR PtC to provide guidance on the role of imaging to guide interventional procedures in patients with RMDs.
35503679 Are Neighborhood Characteristics Associated With Outcomes After THA and TKA? Findings From 2022 May 3 BACKGROUND: Non-White patients have higher rates of discharge to an extended care facility, hospital readmission, and emergency department use after primary THA and TKA. The reasons for this are unknown. Place of residence, which can vary by race, has been linked to poorer healthcare outcomes for people with many health conditions. However, the potential relationship between place of residence and disparities in these joint arthroplasty outcomes is unclear. QUESTIONS/PURPOSES: (1) Are neighborhood-level characteristics, including racial composition, marital proportions, residential vacancy, educational attainment, employment proportions, overall deprivation, access to medical care, and rurality associated with an increased risk of discharge to a facility, readmission, and emergency department use after elective THA and TKA? (2) Are the associations between neighborhood-level characteristics and discharge to a facility, readmission, and emergency department use the same among White and Black patients undergoing elective THA and TKA? METHODS: Between 2007 and 2018, 34,008 records of elective primary THA or TKA for osteoarthritis, rheumatoid arthritis, or avascular necrosis in a regional healthcare system were identified. After exclusions for unicompartmental arthroplasty, bilateral surgery, concomitant procedures, inability to geocode a residential address, duplicate records, and deaths, 21,689 patients remained. Ninety-seven percent of patients in this cohort self-identified as either White or Black, so the remaining 659 patients were excluded due to small sample size. This left 21,030 total patients for analysis. Discharge destination, readmissions within 90 days of surgery, and emergency department visits within 90 days were identified. Each patient's street address was linked to neighborhood characteristics from the American Community Survey and Area Deprivation Index. A multilevel, multivariable logistic regression analysis was used to model each outcome of interest, controlling for clinical and individual sociodemographic factors and allowing for clustering at the neighborhood level. The models were then duplicated with the addition of neighborhood characteristics to determine the association between neighborhood-level factors and each outcome. The linear predictors from each of these models were used to determine the predicted risk of each outcome, with and without neighborhood characteristics, and divided into tenths. The change in predicted risk tenths based on the model containing neighborhood characteristics was compared to that without neighborhood characteristics.The change in predicted risk tenth for each outcome was stratified by race. RESULTS: After controlling for age, sex, insurance type, surgery type, and comorbidities, we found that an increase of one SD of neighborhood unemployment (odds ratio 1.26 [95% confidence interval 1.17 to 1.36]; p < 0.001) was associated with an increased likelihood of discharge to a facility, whereas an increase of one SD in proportions of residents receiving public assistance (OR 0.92 [95% CI 0.86 to 0.98]; p = 0.008), living below the poverty level (OR 0.82 [95% CI 0.74 to 0.91]; p < 0.001), and being married (OR 0.80 [95% CI 0.71 to 0.89]; p < 0.001) was associated with a decreased likelihood of discharge to a facility. Residence in areas one SD above mean neighborhood unemployment (OR 1.12 [95% CI [1.04 to 1.21]; p = 0.002) was associated with increased rates of readmission. An increase of one SD in residents receiving food stamps (OR 0.83 [95% CI 0.75 to 093]; p = 0.001), being married (OR 0.89 [95% CI 0.80 to 0.99]; p = 0.03), and being older than 65 years (OR 0.93 [95% CI 0.88 to 0.98]; p = 0.01) was associated with a decreased likelihood of readmission. A one SD increase in the percentage of Black residents (OR 1.11 [95% CI 1.00 to 1.22]; p = 0.04) and unemployed residents (OR 1.15 [95% CI 1.05 to 1.26]; p = 0.003) was associated with a higher likelihood of emergency department use. Living in a medically underserved area (OR 0.82 [95% CI 0.68 to 0.97]; p = 0.02), a neighborhood one SD above the mean of individuals using food stamps (OR 0.81 [95% CI 0.70 to 0.93]; p = 0.004), and a neighborhood with an increasing percentage of individuals older than 65 years (OR 0.90 [95% CI 0.83 to 0.96]; p = 0.002) were associated with a lower likelihood of emergency department use. With the addition of neighborhood characteristics, the risk prediction tenths of the overall cohort remained the same in more than 50% of patients for all three outcomes of interest. When stratified by race, neighborhood characteristics increased the predicted risk for 55% of Black patients for readmission compared with 17% of White patients (p < 0.001). The predicted risk tenth increased for 60% of Black patients for emergency department use compared with 21% for White patients (p < 0.001). CONCLUSION: These results can be used to identify high-risk patients who might benefit from preemptive interventions to avoid these particular outcomes and to create more realistic, comprehensive risk adjustment models for value-based care programs. Additionally, this study demonstrates that neighborhood characteristics are associated with greater risk for these outcomes among Black patients compared with White patients. Further studies should consider that race/ethnicity and neighborhood characteristics may not function independently from each other. Understanding this link between race and place of residence is essential for future racial disparities research. LEVEL OF EVIDENCE: Level III, therapeutic study.
34562595 Emerging evidence of Toll-like receptors as a putative pathway linking maternal inflammati 2022 Jan Inflammation is increasingly recognised to play a major role in gene-environment interactions in neurodevelopmental disorders (NDDs). The effects of aberrant immune responses to environmental stimuli in the mother and in the child can affect neuroimmune signalling that is central to brain development. Toll-like receptors (TLR) are the best known innate immune pattern and danger recognition sensors to various environmental threats. In animal models, maternal immune activation (MIA), secondary to inflammatory factors including maternal gestational infection, obesity, diabetes, and stress activate the TLR pathway in maternal blood, placenta, and fetal brain, which correlate with offspring neurobehavioral abnormalities. Given the central role of TLR activation in animal MIA models, we systematically reviewed the human evidence for TLR activation and response to stimulation across the maternal-fetal interface. Firstly, we included 59 TLR studies performed in peripheral blood of adults in general population (outside of pregnancy) with six chronic inflammatory factors which have epidemiological evidence for increased risk of offspring NDDs, namely, obesity, diabetes mellitus, depression, low socio-economic status, autoimmune diseases, and asthma. Secondly, eight TLR studies done in human pregnancies with chronic inflammatory factors, involving maternal blood, placenta, and cord blood, were reviewed. Lastly, ten TLR studies performed in peripheral blood of individuals with NDDs were included. Despite these studies, there were no studies which examined TLR function in both the pregnant mother and their offspring. Increased TLR2 and TLR4 mRNA and/or protein levels in peripheral blood were common in obesity, diabetes mellitus, depression, autoimmune thyroid disease, and rheumatoid arthritis. To a lesser degree, TLR 3, 7, 8, and 9 activation were found in peripheral blood of humans with autoimmune diseases and depression. In pregnancy, increased TLR4 mRNA levels were found in the peripheral blood of women with diabetes mellitus and systemic lupus erythematosus. Placental TLR activation was found in mothers with obesity or diabetes. Postnatally, dysregulated TLR response to stimulation was found in peripheral blood of individuals with NDDs. This systematic review found emerging evidence that TLR activation may represent a mechanistic link between maternal inflammation and offspring NDD, however the literature is incomplete and longitudinal outcome studies are lacking. Identification of pathogenic mechanisms in MIA could create preventive and therapeutic opportunities to mitigate NDD prevalence and severity.
34748866 Bioactive chemical constituents, in vitro anti-proliferative activity and in vivo toxicity 2022 Feb 10 ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma singularis Gagnep is a Vietnamese medicinal plant which has been commonly used as a medicinal remedy in traditional and folk medicines for improving health as well as for treating some diseases, like rheumatoid arthritis, kidney failure. However, pharmacological effects, including anti-cancer activity and the safety of this plant has not been fully investigated. AIM OF THE STUDY: This study aimed to investigate the in vitro anti-growth activity of an extract derived from Curcuma singularis rhizome extract (CSE) against cell lines as well as determine its phytochemical composition. The other goal of our study was to assess the safety of CSE in rats. MATERIALS AND METHODS: The main constituents in the extract were identified and quantitatively analyzed. The in vitro cytotoxicity of CSE was evaluated in several cancer and normal cell lines. The apoptotic activity of CSE and the expression of the apoptosis-related genes were investigated in AGS cells to clarify the underlying molecular mechanisms. The in vivo toxicity of CSE was assessed via acute and subacute oral studies on Sprague-Dawley rats, respectively according to the guidelines 425 and 407 of the Organization for Economic Cooperation and Development (OECD). The drug-related toxicity signs, mortality, body and organ weights were recoreded during the experimental period. In addition, the selected hematological and biochemical parameters, and histological alterations were determined at the end of the subacute toxicity test. RESULTS: Germacrone, ar-turmerone, and curcumol were three sesquiterpene components found in the extract. CSE showed cytotoxic effects in different cancer cells, but had minimal effects on normal cells. Apoptosis in AGS cells was caused by CSE in a concentration-dependent pattern through increase of Bax/Bcl-2 ratio, and release of cytochrome c, which leads to activation of caspase-3/-7, caspase-9, as well as cleavage of PARP. In the acute toxicity test, no signs of toxicity and no mortality were recorded in rats at both doses of 1000 and 5000 mg/kg. In the subacute toxicity study, CSE showed no drug-related adverse effects on water and food consumption, body and organ weights. CSE at a dose of 1000 mg/kg slightly increased WBC and platelet values in female rats, while it increased WBC values in male rats in all tested doses. The decrease of total cholesterol and triglyceride levels were found in female rats treated CSE at doses of 250 or 500 mg/kg. In addition, the increase of serum ALT and AST levels in rats treated at the dose of 1000 mg/kg were noted. No significant changes in histopathological structures of kidneys, spleen, heart and lungs, except liver tissue with minor modifications was found. CONCLUSIONS: Our findings indicated that CSE exhibited in vitro anti-proliferative effects on AGS cells by mainly activating the caspase-dependent mitochondrial apoptotic pathway. CSE also showed in vivo toxicity signals at the dose of 1000 mg/kg with proven minor hepatic injuries, which should be avoided the high dose for prolonged use. Curcuma singularis rhizomes may be used as a chemotherapeutic agent for the treatment of gastric cancer with in vitro anti-cancer investigation and in vivo biological safety evaluation.
35500440 Increased angiopoietin-like 4 expression ameliorates inflammatory bowel diseases via suppr 2022 Jul 5 Angiopoietin-like 4 (ANGPTL4) is involved in inflammation-associated diseases, such as rheumatoid arthritis, type 2 diabetes, atherosclerosis, and chronic obstructive pulmonary disease. The role of ANGPTL4 in the pathogenesis of inflammatory bowel disease (IBD) remains unknown. Here, the plasma ANGPTL4 levels peaked on days 3 and 5, and expression of ANGPTL4 of inflamed colons peaked on days 5 and 7 in mice with dextran sulfate sodium (DSS)-induced colitis. Simultaneously, CD8(+)T cells in the inflamed colons peaked at day 5 but declined at day 7. However, the ANGPTL4(-/-) mice treated with DSS exhibited exacerbated colitis with more CD8(+)T cells and macrophages infiltrating the colons. The exogenous ANGPTL4 protein protected the mice against DSS-induced colitis with less CD8(+)T cell and macrophage recruitment in the colons. In addition, recombinant ANGPTL4 directly downregulated the IFN-γ and NKG2D expression of CD8(+)T cells but had no effects on the CD86 expression and TNF-α secretion of macrophages ex vivo. Adding ANGPTL4 protein into ANGPTL4(-/-) mice almost blocked the onset of DSS-induced colitis. In parallel, the plasma ANGPTL4 levels were elevated in patients with Crohn's disease and ulcerative colitis at mild/moderate stage and restored to normal levels in IBD patients at a severe stage. The higher ANGPTL4 expression in the inflamed colons of patients with IBD was correlated with lower CD8(+) cell infiltration, whereas no associations with macrophages. Our results demonstrated the compensatory protective effect of ANGPTL4 on IBD development at least via the downregulation of CD8(+)T cell activities. Adding the ANGPTL4 protein would have beneficial effects to retard the progression of IBD.
35138894 Surface Ig variable domain glycosylation affects autoantigen binding and acts as threshold 2022 Feb 11 The hallmark autoantibodies in rheumatoid arthritis are characterized by variable domain glycans (VDGs). Their abundant occurrence results from the selective introduction of N-linked glycosylation sites during somatic hypermutation, and their presence is predictive for disease development. However, the functional consequences of VDGs on autoreactive B cells remain elusive. Combining crystallography, glycobiology, and functional B cell assays allowed us to dissect key characteristics of VDGs on human B cell biology. Crystal structures showed that VDGs are positioned in the vicinity of the antigen-binding pocket, and dynamic modeling combined with binding assays elucidated their impact on binding. We found that VDG-expressing B cell receptors stay longer on the B cell surface and that VDGs enhance B cell activation. These results provide a rationale on how the acquisition of VDGs might contribute to the breach of tolerance of autoreactive B cells in a major human autoimmune disease.
34729921 Screening for potential quality markers of Callerya nitida var. hirsutissima. Z.Wei based 2022 Jan Callerya nitida var. hirsutissima. Z.Wei is a classical, traditional Chinese herbal medicine mostly used to treat rheumatoid arthritis. Recent reports suggest that inconsistent and poor-quality control levels have primarily affected the therapeutic efficacy. Therefore, the aim of the current study was to investigate the active chemical ingredients, stability of components in blood, pharmacokinetics, and pharmacodynamics to specify the potential markers for quality control and quality evaluation of Callerya nitida. The active components in vitro and in vivo were obtained by ultra-high-performance liquid chromatography-mass spectrometry. Moreover, the changes of the bioactive components in the blood were monitored over time (0-24 h) in order to identify stable active components. On this basis, the pharmacokinetic characteristics of these ingredients combined with the anti-inflammatory activity were determined to screen out the potential markers for ensuring the quality control of Callerya nitida. The identified four components, such as calycosin, daidzein, formononetin, and 5-hydroxymethylfurfural, have the characteristics of intrinsic components, clearly defined structures, high exposure values, and in vivo stability, which are important for the therapeutic activity of pharmacologically active materials. Therefore, they can be used as potential markers to control the quality levels of Callerya nitida.
35566564 Importance of Vaccination against SARS-CoV-2 in Patients with Interstitial Lung Disease As 2022 Apr 26 OBJECTIVES: To describe the frequency of COVID-19 and the effect of vaccination in patients with interstitial lung disease and systemic autoimmune disease (ILD-SAD) and to identify factors associated with infection and severity of COVID-19. METHODS: We performed a cross-sectional multicenter study of patients with ILD-SAD followed between June and October 2021. The main variable was COVID-19 infection confirmed by a positive polymerase chain reaction (PCR) result for SARS-CoV-2. The secondary variables included severity of COVID-19, if the patient had to be admitted to hospital or died of the disease, and vaccination status. Other variables included clinical and treatment characteristics, pulmonary function and high-resolution computed tomography. Two logistic regression was performed to explore factors associated with "COVID-19" and "severe COVID-19". RESULTS: We included 176 patients with ILD-SAD: 105 (59.7%) had rheumatoid arthritis, 49 (27.8%) systemic sclerosis, and 22 (12.54%) inflammatory myopathies. We recorded 22/179 (12.5%) SARS-CoV-2 infections, 7/22 (31.8%) of them were severe and 3/22 (13.22%) died. As to the vaccination, 163/176 (92.6%) patients received the complete doses. The factors associated with SARS-CoV-2 infection were FVC (OR (95% CI), 0.971 (0.946-0.989); p = 0.040), vaccination (OR (95% CI), 0.169 (0.030-0.570); p = 0.004), and rituximab (OR (95% CI), 3.490 (1.129-6.100); p = 0.029). The factors associated with severe COVID-19 were the protective effect of the vaccine (OR (95% CI), 0.024 (0.004-0.170); p < 0.001) and diabetes mellitus (OR (95% CI), 4.923 (1.508-19.097); p = 0.018). CONCLUSIONS: Around 13% of patients with ILD-SAD had SARS-CoV-2 infection, which was severe in approximately one-third. Most patients with severe infection were not fully vaccinated.
35057907 Association of Lipoprotein(a) With Atherosclerotic Plaque Progression. 2022 Jan 25 BACKGROUND: Lipoprotein(a) [Lp(a)] is associated with increased risk of myocardial infarction, although the mechanism for this observation remains uncertain. OBJECTIVES: This study aims to investigate whether Lp(a) is associated with adverse plaque progression. METHODS: Lp(a) was measured in patients with advanced stable coronary artery disease undergoing coronary computed tomography angiography at baseline and 12 months to assess progression of total, calcific, noncalcific, and low-attenuation plaque (necrotic core) in particular. High Lp(a) was defined as Lp(a) ≥ 70 mg/dL. The relationship of Lp(a) with plaque progression was assessed using linear regression analysis, adjusting for body mass index, segment involvement score, and ASSIGN score (a Scottish cardiovascular risk score comprised of age, sex, smoking, blood pressure, total and high-density lipoprotein [HDL]-cholesterol, diabetes, rheumatoid arthritis, and deprivation index). RESULTS: A total of 191 patients (65.9 ± 8.3 years of age; 152 [80%] male) were included in the analysis, with median Lp(a) values of 100 (range: 82 to 115) mg/dL and 10 (range: 5 to 24) mg/dL in the high and low Lp(a) groups, respectively. At baseline, there was no difference in coronary artery disease severity or plaque burden. Patients with high Lp(a) showed accelerated progression of low-attenuation plaque compared with low Lp(a) patients (26.2 ± 88.4 mm(3) vs -0.7 ± 50.1 mm(3); P = 0.020). Multivariable linear regression analysis confirmed the relation between Lp(a) and low-attenuation plaque volume progression (β = 10.5% increase for each 50 mg/dL Lp(a), 95% CI: 0.7%-20.3%). There was no difference in total, calcific, and noncalcific plaque volume progression. CONCLUSIONS: Among patients with advanced stable coronary artery disease, Lp(a) is associated with accelerated progression of coronary low-attenuation plaque (necrotic core). This may explain the association between Lp(a) and the high residual risk of myocardial infarction, providing support for Lp(a) as a treatment target in atherosclerosis.
35039938 Association between serum miR-221-3p and intravenous immunoglobulin resistance in children 2022 Jan 18 OBJECTIVES: Intravenous immunoglobulin (IVIG) resistance was a major cause of coronary artery lesions in children with Kawasaki disease (KD). However, the cause of IVIG resistance in KD remains unknown. miR-221-3p has been confirmed involved in cardiovascular diseases and rheumatoid arthritis. The purpose of this study was to investigate the association between miR-221-3p and IVIG resistance in children with KD. METHODS: Fifty-five KD patients and 29 healthy controls (HCs) were enrolled in this study. KD patients were divided into group of sensitive to IVIG (IVIG-response, n = 42) and group of resistant to IVIG (IVIG-resistance, n = 13), group of 10 KD patients with coronary artery lesions (CALs, KD-CALs) and group of 10 sex- and age-matched KD patients without CALs (KD-NCALs). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the levels of miR-221-3p. RESULTS: Compared with the HCs group, miR-221-3p were significantly increased in the KD group (p < 0.05), and the IVIG-resistance group had higher levels of miR-221-3p than those in the IVIG-response group (p < 0.05). CRP (C-reactive protein), PCT (procalcitonin), NLR (neutrophil-lymphocyte ratio) were positively correlated with miR-221-3p in KD patients. In addition, the group of IVIG resistance had a higher level of Kobayashi Score (p < 0.001). The receiver operating characteristic curve showed that miR-221-3p had a better value for diagnosis IVIG resistance in children with KD than Kobayashi Score with the AUC of 0.811 (95% CI, 0.672-0.951), 0.793 (95% CI, 0.618-0.968), respectively. Additionally, miR-221-3p was elevated (p < 0.05) and showed an AUC value of 0.83 (95% CI, 0.648-1.000, p < 0.05) for the prediction of the complication of coronary artery abnormalities in the group of KD with CALs. CONCLUSIONS: miR-221-3p might be involved in the pathogenesis of KD and IVIG resistance and miR-221-3p can be used as a new potential biomarker to predict IVIG resistance in children with KD.
35579694 ATP spreads inflammation to other limbs through crosstalk between sensory neurons and inte 2022 Jun 6 Neural circuits between lesions are one mechanism through which local inflammation spreads to remote positions. Here, we show the inflammatory signal on one side of the joint is spread to the other side via sensory neuron-interneuron crosstalk, with ATP at the core. Surgical ablation or pharmacological inhibition of this neural pathway prevented inflammation development on the other side. Mechanistic analysis showed that ATP serves as both a neurotransmitter and an inflammation enhancer, thus acting as an intermediary between the local inflammation and neural pathway that induces inflammation on the other side. These results suggest blockade of this neural pathway, which is named the remote inflammation gateway reflex, may have therapeutic value for inflammatory diseases, particularly those, such as rheumatoid arthritis, in which inflammation spreads to remote positions.
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