Cartilage oligomeric matrix protein as a potential biomarker for knee osteoarthritis.

Aims: This study aimed to determine the expression and clinical significance of a cartilage protein, cartilage oligomeric matrix protein (COMP), in knee osteoarthritis (OA) patients. Methods: A total of 270 knee OA patients and 93 healthy controls were recruited. COMP messenger RNA (mRNA) and protein levels in serum, synovial fluid, synovial tissue, and fibroblast-like synoviocytes (FLSs) of knee OA patients were determined using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry. Results: COMP protein levels were significantly elevated in serum and synovial fluid of knee OA patients, especially those in the advanced stages of the disease. Serum COMP was significantly correlated with radiological severity as well as measures of body composition, physical performance, knee pain, and disability. Receiver operating characteristic curve analysis unveiled a diagnostic value of serum COMP as a biomarker of knee OA (41.64 ng/ml, area under the curve (AUC) = 1.00), with a sensitivity of 99.6% and a specificity of 100.0%. Further analysis uncovered that COMP mRNA expression was markedly upregulated in the inflamed synovium of knee OA, consistent with immunohistochemical staining revealing localization of COMP protein in the lining and sub-lining layers of knee OA inflamed synovium. Most notably, relative COMP mRNA expression in knee OA synovium was positively associated with its protein levels in serum and synovial fluid of knee OA patients. In human knee OA FLSs activated with tumour necrosis factor-alpha, COMP mRNA expression was considerably up-regulated in a time-dependent manner. Conclusion: All results indicate that COMP might serve as a supportive diagnostic marker for knee OA in conjunction with the standard diagnostic methods.

Elevated serum IL-34 is correlated with disease severity in patients with biliary atresia following Kasai portoenterostomy.

BACKGROUND: Biliary atresia (BA) is a severe congenital disorder with progressive obstructive cholangiopathy in young children. The inflammatory process has been recognized as one of the pathological mechanisms driving bile duct injury. Since interleukin-34 (IL-34) has been reportedly linked to several pathological liver disorders, including inflammation, the current study aimed to analyze circulating IL-34 and the association of circulating IL-34 with hepatic deterioration and clinical outcomes in post-Kasai BA children. METHODS: Circulating IL-34 levels were analyzed in 89 post-Kasai BA subjects and 45 healthy individuals using an ELISA. Liver stiffness (hardness) was measured by ultrasound elastography. RESULTS: Circulating IL-34 was substantially higher in BA children than in control individuals, particularly those with unfavorable outcomes including hepatic dysfunction, jaundice, and portal hypertension. In BA group, circulating IL-34 was positively correlated with liver stiffness (r = 0.515, p < 0.001), AST (r = 0.403, p < 0.001), ALT (r = 0.279, p = 0.008), total bilirubin (r = 0.224, p = 0.03), ALP (r = 0.255, p = 0.016), and serum IL-6 (r = 0.590, p < 0.001) but inversely correlated with albumin (r = -0.417, p < 0.001). Kaplan-Meier survival analysis showed that higher circulating IL-34 levels were significantly associated with reduced survival rates in BA subjects (p = 0.002). CONCLUSION: Higher circulating IL-34 values were directly associated with hepatic impairment and the BA severity, implicating thatserum IL-34 could be applied as a noninvasive marker for the monitoring of the severity in BA subjects following Kasai portoenterostomy and therapeutic efficacy.

Interleukin-1 family cytokines in liver cell death: a new therapeutic target for liver diseases.

INTRODUCTION: Liver cell death represents a basic biological process regulating the progression of liver diseases via distinct mechanisms. Accumulating evidence has uncovered participation of interleukin (IL)-1 family cytokines in liver cell death. Upon activation of cell death induced by hepatotoxic stimuli, IL1 family cytokines released by hepatic dead cells stimulate recruitment of immune cells, which in turn influence inflammation and subsequent liver injury, thus highlighting their potential as therapeutic targets in liver diseases. Enhancing our comprehension of mechanisms underlying IL1 family cytokine signaling in cell death responses could pave the way for novel therapeutic interventions aimed at addressing liver cell death-related liver pathologies. AREAS COVERED: This review summarizes the recent findings reported in preclinical and clinical studies on mechanisms of liver cell death, alongside participation of IL1 family members consisting of IL1α, ILß, IL18, and IL33 in liver cell death and their significant implications in liver diseases. EXPERT OPINION: Discovery of new and innovative therapeutic approaches for liver diseases will need close cooperation between fundamental and clinical scientists to better understand the multi-step processes behind IL1 family cytokines' contributions to liver cell death.

Economic cost of patients with trisomy 13, 18, and 21 in a tertiary hospital in Thailand.

The purpose of this study was to determine direct and indirect costs of patients with trisomy (T) 13, 18, and 21 in Thailand. Direct medical costs were obtained from Siriraj Informatics and Data Innovation Center (SiData+), Faculty of Medicine, Siriraj Hospital, and indirect costs were estimated using a human capital approach. About 241 patients with T21 had outpatient care visits and 124 patients received inpatient care. For T13 and T18, five and seven patients were analyzed for outpatient and inpatient cares, respectively. For patients with T13, T18, and T21 receiving outpatient care, total annual mean direct medical costs ranged from 183.2 USD to 655.2 USD. For inpatient care, average yearly direct medical costs varied between 2,507 USD to 14,790 USD. The mean and median increased with age. In outpatient care, costs associated with drugs and medical devices were a major factor for both T13 and T21 patients, whereas laboratory costs were substantial for T18 patients. For inpatient care, costs of drug and medical devices were the greatest for T13 patients, while service fee and operation costs were the highest for T18 and T21 patients, respectively. For outpatient care, adult patients with congenital heart disease (CHD) had significantly higher mean annual direct medical costs than those without CHD. However, all adult and pediatric patients with CHD receiving inpatient care had significantly higher costs. Patients with T13, T18, and T21 had relative lifetime costs of 22,715 USD, 11,924 USD, and 1,022,830 USD, respectively.

Efficacy of anti-tuberculosis drugs for the treatment of latent tuberculosis infection: a systematic review and network meta-analysis.

Despite the availability of three network meta-analyses (NMA) examining the efficacy, treatment completion, and adverse events associated with all latent tuberculosis infection (LTBI) treatments, there is currently no evidence to support the notion that the benefits of these treatments outweigh the potential risks. This NMA aimed to conduct a comprehensive comparison and update of the efficacy, treatment completion rates and adverse events associated with recommended treatment options for LTBI for individuals with confirmed LTBI, as outlined in the 2020 World Health Organization (WHO) Consolidated Guidelines for TB preventive treatment. A comprehensive search of the MEDLINE and Scopus databases was conducted until April 2023. The NMA was applied to estimate the risk difference and corresponding 95% confidence interval (CI) using a combination of direct and indirect evidence. The risk-benefit assessment was employed to evaluate the feasibility of the extra benefits in relation to the extra risks. The primary outcomes of interest in this study were active TB disease, completion rates, and adverse events. The meta-analysis incorporated data from 15 studies, which collectively demonstrated that the administration of a placebo resulted in a significant increase in the risk of developing TB disease by 1.279%, compared to the daily intake of isoniazid for 6 months (6H). Furthermore, treatment completion rates were significantly higher when using isoniazid plus rifapentine weekly for 3 months (3HP) and rifampicin daily for 4 months (4R), as compared to 6H. Considering adverse events, the combination of 3HP, 4R, and isoniazid administered daily for 9 months (referred to as 9H) significantly decreased adverse events by 4.53% in comparison to 6H. The risk-benefit assessment showed that alternative treatment regimens (9H, 4R, 3HR and 3HP) had a lower incidence of adverse events, while demonstrating a higher efficacy in preventing TB, as compared to 6H. This review indicates that there were no significant differences observed among various active treatment options in terms of their efficacy in preventing active TB. Moreover, completion rates were higher in 3HP and 4R, and a reduction in adverse events was observed in 3HP, 4R, and 9H.

Effect of vitamin D supplementation on circulating level of autophagosome protein LC3A, inflammation, and physical performance in knee osteoarthritis.

Aberrant autophagic activity is observed in osteoarthritic joints. Vitamin D was shown to alleviate not only osteoarthritis severity, but also autophagy process. However, the influence of vitamin D on autophagy in knee osteoarthritis (KOA) remains ambiguous. This study aimed to determine the effect of vitamin D2 on serum levels of autophagosome protein LC3A in patients with KOA and whether LC3A levels were correlated with serum 25-hydroxyvitamin D (25(OH)D) and clinical outcomes of patients with KOA. A total of 165 patients with KOA and 25 healthy controls were recruited. Vitamin D2 (ergocalciferol) was administered to patients with KOA at a weekly dosage of 40,000 IU. Serum LC3A, knee pain and functional scores, muscle strength, physical performance, and biochemical parameters were examined before and after 6 months of vitamin D2 supplementation. Serum LC3A levels were significantly higher in patients with KOA than healthy controls. In patients with KOA, vitamin D2 supplementation significantly decreased serum LC3A levels. Furthermore, baseline levels of serum LC3A were significantly associated with radiographic severity, pain and functional scores, total cholesterol, hs-CRP, IL-6, protein carbonyl, and serum 25(OH)D. After adjusting for established confounders, independent relationships among serum LC3A and radiographic severity, pain and functional scores, total cholesterol, hs-CRP, IL-6, protein carbonyl, and serum 25(OH)D were also observed. Vitamin D2 supplementation was shown to not only decrease serum levels of LC3A, inflammatory markers, as well as oxidative stress, but also improve muscle strength and physical performance in patients with KOA.

Economic evaluation of prenatal screening for fetal aneuploidies in Thailand.

Historically, there has been a lack of cost-effectiveness data regarding the inclusion of universal non-invasive prenatal testing (NIPT) for trisomy 21, 18, and 13 in the benefit package of the Universal Health Coverage (UHC) in Thailand. Therefore, this study aimed to perform the cost-benefit analysis of prenatal screening tests and calculate the budget impact that would result from the implementation of a universal NIPT program. A decision-tree model was employed to evaluate cost and benefit of different prenatal chromosomal abnormalities screenings: 1) first-trimester screening (FTS), 2) NIPT, and 3) definitive diagnostic (amniocentesis). The comparison was made between these screenings and no screening in three groups of pregnant women: all ages, < 35 years, and ≥ 35 years. The analysis was conducted from societal and governmental perspectives. The costs comprised direct medical, direct non-medical, and indirect costs, while the benefit was cost-avoidance associated with caring for children with trisomy and the loss of productivity for caregivers. Parameter uncertainties were evaluated through one-way and probabilistic sensitivity analyses. From a governmental perspective, all three methods were found to be cost-beneficial. Among them, FTS was identified as the most cost-beneficial, especially for pregnant women aged ≥ 35 years. From a societal perspective, the definitive diagnostic test was not cost-effective, but the other two screening tests were. The most sensitive parameters for FTS and NIPT strategies were the productivity loss of caregivers and the incidence of trisomy 21. Our study suggested that NIPT was the most cost-effective strategy in Thailand, if the cost was reduced to 47 USD. This evidence-based information can serve as a crucial resource for policymakers when making informed decisions regarding the allocation of resources for prenatal care in Thailand and similar context.

Effect of galectin-3 on synovial inflammation in knee osteoarthritis via stimulating phosphatidylinositol-3-kinase/Akt pathway.

Galectin-3 (Gal-3), a glycan-binding protein responsible for inflammation, has been reportedly implicated in inflammatory arthritis. This study aimed to determine clinical and pathological effects of Gal-3 on inflammation in knee osteoarthritis (OA). Gal-3 mRNA and protein levels in synoviocytes, synovium, synovial fluid, and plasma of knee OA patients were determined using real-time polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. Signaling mechanism underlying inflammatory effect of Gal-3 was further elucidated in human knee OA synoviocytes. Clinical study uncovered significant increases in plasma and synovial fluid Gal-3 levels in knee OA patients, particularly those with advanced-stage. In knee OA patients, plasma Gal-3 was significantly associated with radiographic severity and indicators of body composition, physical performance, and knee pain and disability. In the inflamed synovium of knee OA patients, further analysis depicted a marked up-regulation of Gal-3 mRNA expression, consistent with immunohistochemical analysis showing localization of Gal-3 protein in the lining and sublining layers of the inflamed synovium. An in vitro study unveiled that aberrant Gal-3 mRNA expression was regulated by tumor necrosis factor (TNF)-α in knee OA synoviocytes. Gal-3 significantly enhanced production of NO and IL-6, up-regulated mRNA expressions of IL-6, NF-κB, and MMP-13, and down-regulated mRNA expressions of ACAN and SOX-9 via stimulating Akt phosphorylation in knee OA synoviocytes. Gal-3 exerted an inflammatory action, which might emerge as a possible mediator of synovitis and cartilage degeneration in knee OA.

Host genetic polymorphisms involved in long-term symptoms of COVID-19.

Host genetic polymorphisms are recognized as a critical determinant of diversity in clinical symptoms of Coronavirus disease 2019 (COVID-19). Accordingly, this study aimed to determine possible associations between single nucleotide polymorphisms (SNPs) in 37 candidate genetic variants and clinical consequences of COVID-19 - especially long-term symptoms, Long COVID. A total of 260 COVID-19 patients, divided into mild (n = 239) and severe (n = 21) and further categorized based on the presence of Long COVID (no, n = 211; yes, n = 49), were recruited. Genotyping of selected polymorphisms responsible for viral entry, immune response, and inflammation was performed using MassARRAY system. Out of 37 SNPs, 9 including leucine zipper transcription factor like-1 (LZTFL1) rs10490770 C allele, LZTFL1 rs11385942 dupA allele, nicotinamide adenine dinucleotide synthetase-1 (NADSYN1) rs12785878 TT genotype, plexin A-4 (PLXNA4) rs1424597 AA genotype, LZTFL1 rs17713054 A allele, interleukin-10 (IL10) rs1800896 TC genotype and C allele, angiotensin converting enzyme-2 (ACE2) rs2285666 T allele, and plasmanylethanolamine desaturase-1 (PEDS1) rs6020298 GG genotype and G allele were significantly associated with an increased risk of developing Long COVID, whereas interleukin-10 receptor subunit beta (IL10RB) rs8178562 GG genotype was significantly associated with a reduced risk of Long COVID. Kaplan-Meier curve displayed that the above gene polymorphisms were significantly associated with cumulative rate of Long COVID occurrence. Polymorphisms in LZTFL1 rs10490770, LZTFL1 rs11385942, LZTFL1 rs17713054, NADSYN1 rs12785878, PLXNA4 rs1424597, IL10 rs1800896, ACE2 rs2285666, PEDS1 rs6020298, and IL10RB rs8178562 appear to be genetic factors involved in development of Long COVID.

Vitamin D and autophagy in knee osteoarthritis: A review.

Knee osteoarthritis (KOA), the highly prevalent degenerative disease affecting the joint, perpetually devastates the health of the elderly. Of various mechanisms known to participate in KOA etiology, apoptosis of chondrocytes is widely regarded as the primary cause of cartilage degradation. It has been suggested that the induction of autophagy in chondrocytes could potentially prolong the progression of KOA by modulating intracellular metabolic processes, which may be helpful for ameliorating chondrocyte apoptosis and eventual cartilage degeneration. Autophagy, a physiological process characterized by intracellular self-degradation, has been reportedly implicated in various pathologic conditions including KOA. Interestingly, vitamin D has been shown to regulate autophagy in human chondrocytes through multiple pathways, specifically AMPK/mTOR signaling pathway. This observation underscores the potential of vitamin D as a novel approach for restoring the functionality and survivability of chondrocytes in KOA. Supporting vitamin D's clinical significance, previous studies have demonstrated its substantial involvement in the symptoms and irregular joint morphology observed in KOA patients, strengthening potential therapeutic efficacy of vitamin D in treatment of KOA. Herein, the purpose of this review was to determine the mechanisms underlying the multi-processes of vitamin D implicated in autophagy in several cells including chondrocytes, which would bring unique insights into KOA pathogenesis.

Economic Evaluation of Screening Strategy for Latent Tuberculosis Infection (LTBI) in Contacts of Tuberculosis Patients: Systematic Review and Quality Assessment.

A tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be used to screen for latent tuberculosis infection (LTBI). Due to its low cost, TST has been used particularly in underdeveloped countries. The limitations of TST were poor specificity in populations with a high prevalence of Bacille Calmette-Guérin (BCG) vaccination and variability of test readers. IGRA is used as an alternative to TST in settings where higher costs can be supported. The lack of studies conducted in high TB incidence countries since previous review, and using relevant assessment tools of the quality appraisal make the need for updated studies and a more comprehensive systematic review. This study aimed to conduct a systematic review of published economic evaluations of screening strategies for LTBI in contacts of TB patients, assess the quality of these studies, and compare the assessment results related to a country's income level in order to provide information to other countries. The databases were searched in January 2022 including MEDLINE and Scopus. Two independent reviewers evaluated the included studies based on eligibility criteria, data extraction, and quality assessment. Eleven economic evaluations of LTBI diagnostic tests in TB contacts were included. Most studies were conducted in high-income countries (91%) and used cost-effectiveness analysis methods (73%). The quality assessment of reporting and data sources was appropriate, ranging from 71% to 89%. Interventions varied from study to study. The outcomes were cost per life years gained (27%), cost per quality-adjusted life year gained (27%), cost per TB case prevented (36%), and cost per close contact case (10%). In high-income countries which were not countries with high TB burden, the use of IGRA alone for screening TB contacts was cost-effective, whereas TST was cost-effective in only two studies. In comparison to TST, IGRA could reduce false-positive results, resulting in fewer patients undergoing TB treatment and preventive treatment.

Costs Associated with Adverse Drug Reactions Among HIV/TB Patients in Thailand.

Purpose: To assess the direct and indirect costs associated with adverse drug reactions (ADRs) in patients receiving treatment regimens for human immunodeficiency virus (HIV) infection and tuberculosis (TB) in selected Thai hospitals. Patients and Methods: This was a retrospective study conducted between October 2014 and September 2019 at three public hospitals in Thailand. Data were obtained from a medical database and spontaneous ADR reporting system of each study site. The out-of-pocket health payments and indirect costs were determined via interviewing. All costs were updated to 2021. Results: A total of 432 eligible patients who experienced ADRs due to HIV and TB treatment, and 93 patients were interviewed to determine direct non-medical and indirect costs. The average direct medical cost for ADR was USD 5.65 for mild cases, USD 156.54 for moderate cases, and USD 1,242.45 for severe cases. For direct non-medical costs, the average cost per episode was USD 27.29 in mild ADR, USD 70.86 in moderate ADR and USD 270.66 in severe ADR. The indirect cost incurred in each mild, moderate and severe ADR was USD 41.86, USD 89.34, and USD 552.60, respectively. The Stevens-Johnson syndrome (SJS) had the highest management costs. Conclusion: ADRs associated with anti-tuberculosis drugs and antiretroviral drugs seem to have a substantial economic impact from a societal perspective. These findings would be useful for increasing awareness and encouraging early avoidance of ADRs.

Mitochondrial DNA content as a diagnostic marker for antituberculosis drug-induced liver injury.

OBJECTIVES: This study aimed to investigate whether mitochondrial DNA (mtDNA) content, an index of mitochondrial dysfunction, was associated with clinical parameters indicating anti-tuberculosis (TB) drug-induced liver injury (ATDILI) in TB patients and could emerge as an ATDILI biomarker. METHODS: Leukocyte mtDNA content in 102 TB patients (49 ATDILI cases and 53 non-ATDILI cases) and 100 age-matched healthy controls was measured using real-time polymerase chain reaction. RESULTS: Compared with healthy controls, both TB patients with and without ATDILI had significantly decreased mtDNA content. Compared with the patients without ATDILI, mtDNA content was significantly increased in those with ATDILI. Higher mtDNA content was observed to be independently associated with increased susceptibility to ATDILI. Increased mtDNA content measured within 1-7 days of treatment was independently associated with elevated levels of serum aminotransferases assessed within 8-60 days of treatment. After initiating treatment within 1-7 days, mtDNA content was detected to be more sensitive and selective for differentiating TB patients with ATDILI from those without ATDILI than serum aminotransferases. Kaplan-Meier analysis revealed a significant correlation between elevated mtDNA content and increased rate of ATDILI occurrence in TB patients, attested by Cox regression analysis, adjusting for confounders. CONCLUSION: Changes in leukocyte mtDNA content would reflect ATDILI progression and could be used as a potential stratification tool for identifying TB patients at risk of ATDILI.

Economic Evaluation of Multiple-Pharmacogenes Testing for the Prevention of Adverse Drug Reactions in People Living with HIV.

Purpose: Pharmacogenetics (PGx) testing is one of the methods for determining whether individuals are at risk of adverse drug reactions (ADRs). It has been reported that multiple-PGx testing, a sequencing technology, has a higher predictive value than single-PGx testing. Therefore, this study aimed to determine the most cost-effective PGx testing strategies for preventing drug-induced serious ADRs in human immunodeficiency virus (HIV)-infected patients. Patients and Methods: Potential strategies, including 1) single-PGx esting (ie, HLA-B*57:01 testing before prescribing abacavir, HLA-B*13:01 testing before prescribing co-trimoxazole and dapsone, and NAT2 testing before prescribing isoniazid) and 2) multiple-PGx testing as a combination of four single-gene PGx tests in one panel, were all compared to no PGx testing (current practice). To evaluate total cost in Thai baht (THB) and quality-adjusted life years (QALYs) for each strategy-based approach to a societal perspective, a hybrid decision tree and Markov model was constructed. Incremental cost-effectiveness ratios (ICERs) were estimated. Uncertainty, threshold, and scenario analyses were all performed. Results: Before prescribing HIV therapy, providing single or multiple-PGx testing might save roughly 68 serious ADRs per year, and the number needed to screen (NNS) to avoid one serious ADR was 40. Consequently, approximately 35% and 40% of the cost of ADR treatment could be avoided by the implementation of single- and multiple-PGx testing, respectively. Compared with no PGx testing strategy, the ICERs were 146,319 THB/QALY gained for single-PGx testing and 152,014 THB/QALY gained for multiple-PGx testing. Moreover, the probability of multiple-PGx testing being cost-effective was 45% at the Thai willingness to pay threshold of 160,000 THB per QALY. Threshold analyses showed that multiple-PGx testing remained cost-effective under the range of cost, sensitivity at 0.95-1.00 and specificity at 0.98-1.00. Conclusion: Single and multiple-PGx testing might be cost-effective options for reducing the incidence of drug-induced serious ADRs in people living with HIV.

The Association of HLA-B*35 and GSTT1 Genotypes and Hepatotoxicity in Thai People Living with HIV.

Glutathione s-transferase (GST) is a family of drug-metabolizing enzymes responsible for metabolizing and detoxifying drugs and xenobiotic substances. Therefore, deletion polymorphisms of GSTs can be implicated in developing several pathological conditions, including antiretroviral drug-induced liver injury (ARVDILI). Notably, GST polymorphisms have been shown to be associated with ARVDILI risk. However, data on GST polymorphisms in the Thai population are limited. Therefore, this study investigated possible associations between GST genetic polymorphisms and ARVDILI development. A total of 362 people living with HIV (PLHIV) and 85 healthy controls from multiple centers were enrolled. GSTM1 and GSTT1 genetic polymorphisms were determined using polymerase chain reactions. In addition, HLA genotypes were determined using a sequence-based HLA typing method. After comparing GST genotypic frequencies, there was no significant difference between PLHIV and healthy volunteers. However, while observing the PLHIV group, GSTT1 wild type was significantly associated with a 2.04-fold increased risk of ARVDILI (95%CI: 1.01, 4.14; p = 0.045). Interestingly, a combination of GSTT1 wild type and HLA-B*35:05 was associated with a 2.28-fold higher risk of ARVDILI (95%CI: 1.15, 4.50; p = 0.02). Collectively, GSTT1 wild type and a combination of GSTT1 wild type plus HLA-B*35:05 were associated with susceptibility to ARVDILI in the Thai population.

Clusterin exacerbates interleukin-1ß-induced inflammation via suppressing PI3K/Akt pathway in human fibroblast-like synoviocytes of knee osteoarthritis.

This study aimed to examine, a multifaceted chaperon-like protein exerting anti-inflammatory action, clusterin (CLU), mRNA and protein levels in the systemic and local joint environment of knee osteoarthritis (OA) patients and to determine whether CLU inhibited interleukin (IL)-1ß-induced inflammation in knee OA fibroblast-like synoviocytes (FLSs) through modulating phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. CLU protein and mRNA expressions in the synovium and its protein levels in plasma and synovial fluid of knee OA patients were measured using immunohistochemistry, real-time PCR, and ELISA, respectively. Anti-inflammatory effect of CLU was further elucidated in knee OA FLSs treated with IL-1ß in the absence or presence of CLU, CLU alone, or PI3K inhibitor (LY294002) along with IL-1ß and CLU. In a clinical study, compared with knee OA patients without synovitis, CLU protein and mRNA were expressed in the synovium of knee OA patients with synovitis, especially those with high-grade, consistent with analyses of its plasma and synovial fluid levels. CLU mRNA and protein levels were both associated with synovitis severity. An in vitro study uncovered that CLU significantly alleviated IL-1ß-induced overproduction of nitric oxide and IL-6 in knee OA FLSs. Furthermore, CLU significantly attenuated inflammation and extracellular matrix degradation induced by IL-1ß via down-regulating expressions of IL-6, nuclear factor kappa B, and matrix metalloproteinase-13. Mechanistically, CLU significantly impeded IL-1ß-induced Akt phosphorylation in knee OA FLSs, in line with addition of LY294002 along with IL-1ß and CLU. These findings suggest that CLU may have potential as a novel therapeutic target for synovitis and cartilage destruction in knee OA.

Systemic cytokine profiles in biliary atresia.

BACKGROUND: Inflammation and immune dysregulation persuade biliary duct injury in biliary atresia (BA), a leading cause of pediatric liver transplantation given lack of specific biomarkers. We aimed to determine associations between systemic cytokine profiles and clinical parameters in BA patients and to identify potential BA biomarkers. METHODS: Systemic levels of 27 cytokines were measured in 82 BA patients and 25 healthy controls using a multiplex immunoassay. Relative mRNA expressions of candidate cytokines in 20 BA livers and 5 non-BA livers were assessed using quantitative real-time PCR. RESULTS: Higher levels of 17 cytokines including IL-1ß, IL-6, IL-7, IL-8, IL-9, IL-2, IL-15, eotaxin, IP-10, MCP-1, MIP-1α, MIP-1ß, G-CSF, IL-1ra, IL-4, IL-5, and IL-10 and lower levels of IFN-α and PDGF were significantly associated with BA. In BA patients, increased levels of IL-7, eotaxin, IP-10, and IL-13 were significantly associated with unfavorable outcomes including jaundice, fibrosis, and portal hypertension. Indeed, systemic levels of those cytokines were significantly correlated with clinical parameters indicating jaundice, fibrosis, and hepatic dysfunction in BA patients. Out of 27 cytokines, 4 (IL-8, IP-10, MCP-1, and PDGF) had potential as sensitive and specific biomarkers of BA. Of these, higher IL-8 levels were significantly associated with reduced survival of BA. In BA livers, relative mRNA expressions of IL-8, IP-10, and MCP-1 were significantly up-regulated. CONCLUSIONS: Higher levels of several cytokines including inflammatory cytokines, immunomodulatory cytokines, chemokines, and anti-inflammatory cytokines and lower levels of growth factors would reflect inflammatory and immune responses related to BA development. Among 27 cytokines, plasma IL-8 might have great potential as a diagnostic and prognostic biomarker for BA.

Cost-Utility Analysis of Molecular Testing for Tuberculosis Diagnosis in Suspected Pulmonary Tuberculosis in Thailand.

PURPOSE: Given the lack of economic evaluation study of molecular testing in Thailand, this study aimed to evaluate the cost-utility of molecular testing algorithms including Xpert MTB/RIF and the loop-mediated isothermal amplification (TB-LAMP) in the general population suspected of having pulmonary TB based on a societal perspective. METHODS: A hybrid decision tree Markov model using a 1-month cycle length was used to evaluate costs and outcomes of five TB diagnostic algorithms: 1) sputum smear microscopy (SSM) with culture and drug susceptibility testing (DST), 2) Xpert MTB/RIF add-on, 3) Xpert MTB/RIF initial, 4) TB-LAMP add-on, and 5) TB-LAMP initial during a lifetime period. All costs were calculated in 2021 Baht, and results were presented as an incremental cost-effectiveness ratio (ICER) for molecular testing compared with SSM with culture. One-way sensitivity and probability analyses were used to evaluate uncertainty input parameters. RESULTS: TB-LAMP was less expensive overall (6565 Baht) than Xpert MTB/RIF (7010 Baht) and SSM with culture (6845 Baht). Molecular testing was projected to improve quality adjusted life year (QALY) by 0.53 to 0.94 years. In comparison to SSM with culture and DST, providing an initial TB-LAMP test was the most preferred choice. Xpert MTB/RIF Initial had the lowest ICER (197 Baht per QALY gained), followed by TB-LAMP Add-on (993 Baht per QALY gained) and Xpert MTB/RIF Add-on (3940 Baht per QALY gained). One-way sensitivity analysis uncovered that sensitivity of TB-LAMP was greater than that of other parameters. CONCLUSION: Providing molecular testing including Xpert MTB/RIF and TB-LAMP as either initial or add-on test for TB diagnosis was more cost-effective than SSM with culture and DST in the general population with suspected pulmonary TB in Thailand. Our study could provide useful evidence to policymakers advocating for inclusion of molecular testing in the universal health coverage benefit package in Thailand.

Genetic polymorphisms of ACE1, ACE2, and TMPRSS2 associated with COVID-19 severity: A systematic review with meta-analysis.

Novel coronavirus disease 2019 (COVID-19) poses a global threat, due to its fluctuating frequency and lethality. Published data revealed associations of COVID-19 susceptibility and severity with host genetic polymorphisms in renin-angiotensin-aldosterone system (RAAS)-related genes including angiotensin-converting enzyme (ACE)1, ACE2, and transmembrane protease (TMPRSS)2. However, the findings remain inconclusive. Accordingly, we aimed to clarify associations of genetic variants in those genes with COVID-19 susceptibility and severity using a systematic review with meta-analysis. From inception through 1 July 2021, a literature search was performed using PubMed, Scopus, Web of Science, and Cochrane Library databases. Allelic distributions for each polymorphism were calculated as pooled odds ratios (OR) with 95% confidence intervals (CI) to assess the strength of association. A total of 3333 COVID-19 patients and 5547 controls from 11 eligible studies were included. From a systematic review, ACE1 rs1799752, ACE1 rs4646994, ACE2 rs2285666, and TMPRSS2 rs12329760 were identified as common polymorphisms of RAAS-related genes. Meta-analysis showed a significant association between TMPRSS2 rs12329760 C-allele and an increased risk of developing severe COVID-19 (OR = 1.32, 95% CI: 1.01, 1.73). Likewise, additional meta-analyses uncovered that both ACE1 rs4646994 DD-genotype and ACE2 rs2285666 GG-genotype carriers had a significantly increased risk of developing severe COVID-19 (OR = 2.06, 95% CI: 1.45, 2.93; OR = 2.14, 95% CI: 1.26, 3.66; respectively). Genetic polymorphisms of ACE1 rs4646994 DD-genotype, ACE2 rs2285666 GG-genotype, and TMPRSS2 rs12329760 CC-genotype and C-allele may serve as predictive models of COVID-19 severity.