An archaeal transcription factor EnfR with a novel 'eighth note' fold controls hydrogen production of a hyperthermophilic archaeon Thermococcus onnurineus NA1.

Thermococcus onnurineus NA1, a hyperthermophilic carboxydotrophic archaeon, produces H2 through CO oxidation catalyzed by proteins encoded in a carbon monoxide dehydrogenase (CODH) gene cluster. TON_1525 with a DNA-binding helix-turn-helix (HTH) motif is a putative repressor regulating the transcriptional expression of the codh gene cluster. The T55I mutation in TON_1525 led to enhanced H2 production accompanied by the increased expression of genes in the codh cluster. Here, TON_1525 was demonstrated to be a dimer. Monomeric TON_1525 adopts a novel 'eighth note' symbol-like fold (referred to as 'eighth note' fold regulator, EnfR), and the dimerization mode of EnfR is unique in that it has no resemblance to structures in the Protein Data Bank. According to footprinting and gel shift assays, dimeric EnfR binds to a 36-bp pseudo-palindromic inverted repeat in the promoter region of the codh gene cluster, which is supported by an in silico EnfR/DNA complex model and mutational studies revealing the implication of N-terminal loops as well as HTH motifs in DNA recognition. The DNA-binding affinity of the T55I mutant was lowered by ∼15-fold, for which the conformational change of N-terminal loops is responsible. In addition, transcriptome analysis suggested that EnfR could regulate diverse metabolic processes besides H2 production.

Adolescent Parvalbumin Expression in the Left Orbitofrontal Cortex Shapes Sociability in Female Mice.

The adolescent social experience is essential for the maturation of the prefrontal cortex in mammalian species. However, it still needs to be determined which cortical circuits mature with such experience and how it shapes adult social behaviors in a sex-specific manner. Here, we examined social-approaching behaviors in male and female mice after postweaning social isolation (PWSI), which deprives social experience during adolescence. We found that the PWSI, particularly isolation during late adolescence, caused an abnormal increase in social approaches (hypersociability) only in female mice. We further found that the PWSI female mice showed reduced parvalbumin (PV) expression in the left orbitofrontal cortex (OFCL). When we measured neural activity in the female OFCL, a substantial number of neurons showed higher activity when mice sniffed other mice (social sniffing) than when they sniffed an object (object sniffing). Interestingly, the PWSI significantly reduced both the number of activated neurons and the activity level during social sniffing in female mice. Similarly, the CRISPR/Cas9-mediated knockdown of PV in the OFCL during late adolescence enhanced sociability and reduced the social sniffing-induced activity in adult female mice via decreased excitability of PV+ neurons and reduced synaptic inhibition in the OFCL Moreover, optogenetic activation of excitatory neurons or optogenetic inhibition of PV+ neurons in the OFCL enhanced sociability in female mice. Our data demonstrate that the adolescent social experience is critical for the maturation of PV+ inhibitory circuits in the OFCL; this maturation shapes female social behavior via enhancing social representation in the OFCL SIGNIFICANCE STATEMENT Adolescent social isolation often changes adult social behaviors in mammals. Yet, we do not fully understand the sex-specific effects of social isolation and the brain areas and circuits that mediate such changes. Here, we found that adolescent social isolation causes three abnormal phenotypes in female but not male mice: hypersociability, decreased PV+ neurons in the left orbitofrontal cortex (OFCL), and decreased socially evoked activity in the OFCL Moreover, parvalbumin (PV) deletion in the OFCL in vivo caused the same phenotypes in female mice by increasing excitation compared with inhibition within the OFCL Our data suggest that adolescent social experience is required for PV maturation in the OFCL, which is critical for evoking OFCL activity that shapes social behaviors in female mice.

Mortality in patients with systemic lupus erythematosus: A meta-analysis of overall and cause-specific effects.

OBJECTIVES: Our objective was to assess the overall and cause-specific standardized mortality ratios (SMRs) among patients diagnosed with systemic lupus erythematosus (SLE). METHODS: An exhaustive systematic review was undertaken, encompassing studies that scrutinized SMRs, both overall and for specific causes, in patients diagnosed with SLE compared to the general populace. The databases of PUBMED, EMBASE, and Cochrane were meticulously searched to collate relevant literature. Following this comprehensive search, a meta-analysis was executed to methodically assess all-cause, sex-specific, ethnicity-specific, and cause-specific SMRs in individuals with SLE. RESULTS: The inclusion criteria were met by 29 studies encompassing 72,342 patients with SLE and documenting 7352 deaths. The meta-analysis disclosed a pronounced 2.87-fold elevation in the SMR for all-cause mortality in SLE patients relative to the general population (SMR, 2.866; 95% confidence interval [CI], 2.490-3.242; p < .001). Region-specific assessments showed variable all-cause SMRs, with Europe reporting 2.607 (95% CI, 1.939-3.275; p < .001), Asia revealing 3.043 (95% CI, 2.082-4.004; p < .001), and particularly high SMRs noted in North America and Oceania. Gender-focused analyses presented a pooled SMR of 3.261 (95% CI, 2.674-3.848; p < .001) for females, and 2.747 (95% CI, 2.190-3.304; p < .001) for males. Evaluations specific to cause of death illustrated notably elevated SMRs for renal disease (SMR, 4.486; 95% CI, 3.024-5.948; p < .001), infections (SMR, 4.946; 95% CI, 4.253-5.639; p < .001), cardiovascular diseases (CVD) (SMR, 2.931; 95% CI, 1.802-4.061; p < .001), cerebrovascular accidents (CVA) (SMR, 1.588; 95% CI, 0.647-2.528; p = .001), and cancer (SMR, 1.698; 95% CI, 0.871-2.525; p < .001). CONCLUSIONS: This meta-analysis underscores a significant 2.87-fold elevation in the SMR among patients with SLE compared to the general population, transcending differences in sex or geographical regions. Moreover, an appreciable increase in mortality due to specific causes, including renal disease, infection, CVD, CVA, malignancy, and neuropsychiatric SLE, accentuates the imperative for targeted interventions to mitigate these elevated risks in SLE patients.

BeStSel: webserver for secondary structure and fold prediction for protein CD spectroscopy.

Circular dichroism (CD) spectroscopy is widely used to characterize the secondary structure composition of proteins. To derive accurate and detailed structural information from the CD spectra, we have developed the Beta Structure Selection (BeStSel) method (PNAS, 112, E3095), which can handle the spectral diversity of ß-structured proteins. The BeStSel webserver provides this method with useful accessories to the community with the main goal to analyze single or multiple protein CD spectra. Uniquely, BeStSel provides information on eight secondary structure components including parallel ß-structure and antiparallel ß-sheets with three different groups of twist. It overperforms any available method in accuracy and information content, moreover, it is capable of predicting the protein fold down to the topology/homology level of the CATH classification. A new module of the webserver helps to distinguish intrinsically disordered proteins by their CD spectrum. Secondary structure calculation for uploaded PDB files will help the experimental verification of protein MD and in silico modelling using CD spectroscopy. The server also calculates extinction coefficients from the primary sequence for CD users to determine the accurate protein concentrations which is a prerequisite for reliable secondary structure determination. The BeStSel server can be freely accessed at https://bestsel.elte.hu.

Standardized mortality ratios in systemic sclerosis: a meta-analysis assessing overall and sex- and disease subtype-specific differences.

OBJECTIVE: This study aims to evaluate the overall and sex- and illness subtype-specific standardized mortality ratios (SMRs) in patients with systemic sclerosis (SSc). METHODS: We searched and examined studies that compared the overall and sex- and illness subtype-specific SMRs in patients with SSc to those in the general population using MEDLINE, EMBASE, and Cochrane databases (until May 2023). We then conducted a meta-analysis of the overall and sex- and illness subtype-specific SMRs in patients with SSc. RESULTS: Overall, 29 studies including 30,673 patients with SSc and 5582 deaths met the inclusion criteria. Patients with SSc had a higher overall SMR than that in the general population (SMR: 2.742, 95% confidence interval [CI]: 2.224-3.38091, p < 0.001). The SMR significantly increased in populations from Europe, North America, Asia, and Oceania according to regional stratification. A sex-specific meta-analysis revealed a substantial increase in the SMR in both men and women (SMR: 3.598, 95% CI: 3.097-4.180, p < 0.001; SMR: 2.833, 95% CI: 2.4384-3.292, p < 0.001, respectively) and the mortality rate was higher in men compared to women. A substantial increase in the SMR in diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) was observed in a disease subtype-specific meta-analysis. In addition, the SMR in the dcSSc group was higher than that in the lcSSc group (SMR: 4.726, 95% CI: 3.795-5.885, p < 0.001; SMR: 1.987, 95% CI: 1.586-2.489, p < 0.001, respectively). CONCLUSION: Our findings demonstrated that the mortality rate in patients with SSc was 2.74-times greater than that in the general population. The mortality rate was higher in men compared to women. Additionally, compared to patients with lcSSc, those with dcSSc showed much higher fatality rates.

Role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential biomarkers in Behçet's disease: a meta-analysis.

AIM: The mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have attracted interest as possible indicators of inflammation and disease activity in various diseases. This meta-analysis assessed the association between NLR, MPV, PLR, and Behçet's disease (BD) and their correlation with disease activity and thrombosis. METHODS: A thorough search of the Medline, Embase, and Cochrane databases was performed to identify relevant studies. Studies comparing NLR, MPV, and PLR between patients with BD and healthy controls, as well as studies examining these measures in connection with disease activity and thrombosis in BD satisfied the inclusion criteria. The standardized mean difference (SMD) and 95% confidence interval (CI) were used to calculate the effect sizes. RESULTS: This meta-analysis included 24 articles. The findings revealed no discernible differences in MPV between the BD and control groups (p = 0.992). NLR was substantially higher in the BD group than in the control group (p < 0.001). PLR was higher in the BD group than in the control group (p = 0.030), indicating that BD is associated with a larger PLR. Patients with active and inactive BD did not vary significantly in terms of disease activity according to the MPV. Comparing MPV between patients with BD with and without thrombosis showed no discernible changes. However, individuals with active BD had a considerably higher NLR and PLR than those with inactive BD (p = 0.003 and p = 0.005, respectively). The statistical significance threshold for the association between NLR, PLR, and thrombosis in patients with BD was not met. CONCLUSION: NLR and PLR can be regarded as general markers of inflammation according to the results of this meta-analysis.

Relative efficacy and safety of calcineurin inhibitor, mycophenolate mofetil, and azathioprine as maintenance therapies for lupus nephritis: a network meta-analysis.

OBJECTIVE: This study aimed to assess the relative efficacy and safety of calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and azathioprine (AZA) as maintenance therapies for lupus nephritis. METHODS: Randomized controlled trials (RCTs) examining the efficacy and safety of CNI, MMF, and AZA as maintenance therapies in patients with lupus nephritis were included. We performed a Bayesian random-effects network meta-analysis to combine the direct and indirect evidence from RCTs. RESULTS: Ten RCTs comprising 884 patients were included in the study. Although the difference was not statistically significant, MMF showed a trend toward a lower relapse rate compared with AZA (odds ratio [OR] 0.72, 95% credible interval [CrI] 0.45-1.22). Similarly, tacrolimus showed a trend toward a lower relapse rate compared with AZA (OR 0.85, 95% CrI 0.34-2.00). Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that MMF had the highest probability of being the best treatment based on the relapse rate, followed by CNI and AZA. The incidence of leukopenia in the MMF and CNI groups was significantly lower than that in the AZA group (OR 0.12, 95% CrI 0.04-0.34; OR 0.16, 95% CrI 0.04-0.50; respectively). Fewer patients with infections were observed in the MMF group than in the AZA group, although the difference was not statistically significant. The analysis of withdrawals due to adverse events showed a similar pattern. CONCLUSION: Lower relapse rates combined with a more favorable safety profile suggest that CNI and MMF are superior to AZA as maintenance treatments in lupus nephritis patients.

Comparison of the efficacy and safety of olokizumab at different dosages in patients with active rheumatoid arthritis: a network meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to assess the relative efficacy and safety of olokizumab at different dosages in patients with active rheumatoid arthritis (RA). METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of olokizumab administered intravenously to RA patients at 64 mg/kg every 2 or 4 weeks (Q2 or Q4W). RESULTS: Five RCTs comprising 2609 patients met the inclusion criteria. Both olokizumab Q2 and Q4W treatments achieved a significant American College of Rheumatology 20% response (ACR20) compared with the placebo (odds ratio [OR] 3.21, 95% credible interval [CrI] 2.53-4.09; OR 3.05, 95% CrI 2.43-3.86). However, olokizumab Q2W was associated with the most favorable surface using the cumulative ranking curve (SUCRA) for the ACR20 response rate. The ranking probability based on the SUCRA indicated that olokizumab Q2W had the highest probability of being considered the best treatment option for achieving the ACR20 response rate, followed by olokizumab Q4W, adalimumab, and placebo. The ACR50 and 70 response rates showed a similar distribution pattern to the ACR20 response rate, except that olokizumab Q4W had a higher-ranking probability than olokizumab Q2W for ACR50. The SUCRA rating likelihood of adverse events (AEs) and withdrawal due to AEs showed that a placebo was likely to be the best intervention. CONCLUSION: Both olokizumab Q2 and Q4W were efficacious and well-tolerated treatments for active RA.

All-cause and cause-specific mortality in rheumatoid arthritis: a meta-analysis.

OBJECTIVE: This study aimed to evaluate standardized mortality ratios (SMRs) for both all-cause and cause-specific mortality in patients with rheumatoid arthritis (RA). METHODS: We conducted an extensive search across the Medline, Embase, and Cochrane databases to identify studies investigating SMRs for all-cause and/or cause-specific mortality in individuals with RA compared to the general population. Subsequently, we performed a comprehensive meta-analysis, examining SMRs across various categories, including all-cause, sex-specific, ethnicity-specific, and cause-specific SMRs in RA patients. RESULTS: Seventeen studies involving 486,098 patients with RA and 63,988 deaths met the inclusion criteria. Patients with RA had a 1.522-fold increase in all-cause SMR (SMR 1.522, 95% CI 1.340-1.704, p < 0.001) compared to the general population. Stratification by ethnicity revealed that the all-cause SMR was 1.575 (95% CI 1.207-1.943) in Caucasians and 1.355 (95% CI 1.140-1.569) in Asians. The gender-specific meta-analysis revealed elevated SMR in both women and men. RA patients exhibited an increased risk of mortality attributed to cardiovascular disease (CVD), respiratory disease, infection, and cerebrovascular accidents (CVA). However, no significant increase in SMR was observed for mortality due to malignancy. CONCLUSION: This meta-analysis study highlights a 1.522-fold increase in SMR in patients with RA compared to that in the general population, irrespective of sex or region. Additionally, a notable increase in mortality associated with specific causes, including CVD, respiratory disease, infection, and CVA, underscores the critical need for targeted interventions to manage these heightened risks in patients with RA.

Association between systemic sclerosis and venous thromboembolism, pulmonary embolism, and deep vein thrombosis: a meta-analysis.

OBJECTIVE: This study aimed to analyze the published data pertaining to the correlation between venous thromboembolism (VTE) and systemic sclerosis (SSc). METHODS: We conducted manual searches and explored MEDLINE, EMBASE, and Cochrane databases to review papers reporting the risk of VTE in patients with SSc. A meta-analysis was performed exploring the relative risks (RRs) of deep vein thrombosis (DVT), pulmonary embolism (PE), and VTE in these individuals. RESULTS: Six trials that included 41,105 patients with SSc were eligible for inclusion. A meta-analysis of the six included studies revealed a statistically significant correlation (RR 2.372, 95% confidence interval [CI] = 1.608-3.500, p < 0.001) between the risk of VTE and SSc. Regional subgroup study revealed a strong correlation between SSc and VTE risk in Americans, Europeans, and Asians. Additionally, a significant correlation between SSc and PE risk was observed (RR 3.154, 95% CI = 1.320-7.539, p = 0.010). Finally, the meta-analysis revealed a substantial correlation (RR 5.190, 95% CI = 1.513-17.01, p = 0.009) between the risk of DVT and SSc. CONCLUSION: This meta-analysis showed that SSc is linked to an increased risk of DVT, PE, and VTE. This finding underscores the importance of close monitoring for the emergence of these conditions in patients with SSc.

Anatomical Exploration of the KI1 Acupoint: Implications for Medial and Lateral Plantar Nerve Stimulation.

Background and Objectives: This study aims to identify the precise anatomical location and therapeutic mechanisms of the KI1 acupoint (Yongquan) in relation to foot muscles and nerves, known for treating neurological disorders and pain. Materials and Methods: Dissection of six cadavers at Chungnam National University College of Medicine examined KI1's relation to the foot's four-layer structure. Results: The KI1 acupoint was located in the superficial and deep layers of the plantar foot, adjacent to significant nerves like the medial and lateral plantar nerves. Differences in the acupoint's exact location between genders were noted, reflecting variances in foot morphology. KI1 acupuncture was found to stimulate the muscle spindles and nerve fibers essential for balance and bipedal locomotion. This stimulation may enhance sensory feedback, potentially improving cognitive functions and balance control. Conclusions: This anatomical insight into KI1 acupuncture underpins its potential in neurological therapies and pain management.

Augmented humoral and cellular immunity against severe acute respiratory syndrome coronavirus 2 after breakthrough infection in kidney transplant recipients who received 3 doses of coronavirus disease 2019 vaccine.

Diminished immune response to coronavirus disease 2019 (COVID-19) vaccines and breakthrough infection (BI) is a major concern for solid organ transplant recipients. Humoral and cellular immune responses of kidney transplant (KT) recipients after a third COVID-19 vaccination were investigated compared to matched health care workers. Anti-severe acute respiratory syndrome coronavirus 2 spike protein antibody and severe acute respiratory syndrome coronavirus 2 specific interferon-gamma releasing assay (IGRA) were assessed. A total of 38 KT recipients, including 20 BI and 18 noninfection, were evaluated. In the KT BI group, antibody titers were significantly increased (median 5 to 724, binding antibody units/mL (P = 0.002) after the third vaccination, but IGRA responses were negligible. After BI, antibody titers increased (median 11 355 binding antibody unit/mL; P < 0.001) and there was a significant increase of IGRA responses to spike proteins (Spike1-Nil, median 0.05 to 0.41 IU/mL; P = 0.009). Antibody titers and IGRA responses were significantly higher in the BI than in the noninfection group after 6 months. Immune responses were stronger in the health care worker than in the KT cohort, but the gap became narrower after BI. In conclusion, KT recipients who experienced BI after 3 COVID-19 vaccinations acquired augmented humoral and cellular immune responses.

Association between functional FCGR3A F158V and FCGR2A R131H polymorphisms and responsiveness to rituximab in patients with autoimmune diseases: a meta-analysis.

OBJECTIVES: To investigate the association between the functional Fc gamma receptor 3 A (FCGR3A) V158F and FCGR2A R131H polymorphisms and rituximab therapy in patients with autoimmune diseases. METHODS: We searched the Medline, Embase, and Cochrane databases for relevant articles. We conducted a meta-analysis of the association between FCGR3A V158F and FCGR2A R131H polymorphisms and responsiveness to rituximab in patients with autoimmune diseases. RESULTS: Eleven studies, consisting of 661 responders and 267 non-responders for FCGR3A V158F polymorphism and 156 responders and 89 non-responders for FCGR2A R131H polymorphism, were included. The meta-analysis revealed a significant association between the FCGR3A V allele and responsiveness to rituximab (odds ratio [OR] = 1.600, 95% confidence interval [CI] = 1.268-2.018, P < 0.001). Furthermore, associations were found using the dominant and homozygous contrast models. Subgroup analysis showed an association between the FCGR3A V allele and responsiveness to rituximab in European, RA, ITP, small (<50) and large (≥50) groups, and short- (≤6 months) and long-term follow-up periods (≥6 months). These associations were also found in recessive, dominant or homozygous contrast models. Meta-analysis revealed no association between the FCGR2A R allele and responsiveness to rituximab (OR = 1.243, 95% CI = 0.825-1.873, P = 0.229). CONCLUSIONS: We demonstrated that the FCGR3A F158V polymorphism is associated with better responsiveness to rituximab therapy in patients with autoimmune diseases, indicating that individuals carrying the FCGR3A V allele will likely respond better to rituximab. However, FCGR2A R131H polymorphism was not associated with better response to rituximab.

Design and Evaluation of a Carrier-Free Prodrug-Based Palmitic-DEVD-Doxorubicin Conjugate for Targeted Cancer Therapy.

In the development of new drugs, typical polymer- or macromolecule-based nanocarriers suffer from manufacturing process complexity, unwanted systematic toxicity, and low loading capacity. However, carrier-free nanomedicines have made outstanding progress in drug delivery and pharmacokinetics, demonstrating most of the advantages associated with nanoparticles when applied in targeted anticancer therapy. Here, to overcome the problems of nanocarriers and conventional cytotoxic drugs, we developed a novel, carrier-free, self-assembled prodrug consisting of a hydrophobic palmitic (16-carbon chain n-hexadecane chain) moiety and hydrophilic group (or moiety) which is included in a caspase-3-specific cleavable peptide (Asp-Glu-Val-Asp, DEVD) and a cytotoxic drug (doxorubicin, DOX). The amphiphilic conjugate, the palmitic-DEVD-DOX, has the ability to self-assemble into nanoparticles in saline without the need for any carriers or nanoformulations. Additionally, the inclusion of doxorubicin is in its prodrug form and the apoptosis-specific DEVD peptide lead to the reduced side effects of doxorubicin in normal tissue. Furthermore, the carrier-free palmitic-DEVD-DOX nanoparticles could passively accumulate in the tumor tissues of tumor-bearing mice due to an enhanced permeation and retention (EPR) effect. As a result, the palmitic-DEVD-DOX conjugate showed an enhanced therapeutic effect compared with the unmodified DEVD-DOX conjugate. Therefore, this carrier-free palmitic-DEVD-DOX prodrug has great therapeutic potential to treat solid tumors, overcoming the problems of conventional chemotherapy and nanoparticles.

Association between Susceptibility to Systemic Lupus Erythematous and Polymorphisms in miR-146a and miR-499: A Meta-Analysis.

INTRODUCTION: This study aimed to determine whether miR-146a and miR-499 polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE). METHODS: We searched the MEDLINE, EMBASE, and Cochrane databases. We performed a meta-analysis on the association of miR-146a rs2910164, rs2431697, rs57095329, and miR-499 rs3746444 polymorphisms with susceptibility to SLE. RESULTS: Twenty-one studies from 17 reports, with 18,910 patients and 29,622 controls, were included in the meta-analysis. Meta-analysis revealed no association between SLE and the rs2910164 C allele (odds ratio [OR] = 0.999, 95% confidence interval [CI] = 0.816-1.222, p = 0.990). Stratification by ethnicity indicated no association between the miR-146a C allele and SLE in Arab or Latin American populations. The meta-analysis revealed an association between SLE and the miR-499 rs374644 CC + CT genotype in the overall group (OR = 1.313, 95% CI = 1.015-1.698, p = 0.038). Furthermore, meta-analysis revealed a significant association between SLE and the miR-146a rs2431697 C allele in the overall group (OR = 0.746, 95% CI = 0.697-0.798, p = 0.038). The miR-146a rs2431697 C allele is protective against SLE risk. Stratification by ethnicity indicated an association between the miR-146a rs2431697 C allele and SLE in Asian and European, but not Arab populations. The meta-analysis showed an association between the miR-146a rs57095329 G allele and SLE in Asian, but not Arab populations. DISCUSSION/CONCLUSION: This meta-analysis suggests that the miR-146a rs2431697 polymorphism is a protective factor against the risk of SLE, and that the miR-146a rs57095329 and miR-499 rs3746444 polymorphisms are associated with susceptibility to SLE. However, miR-146a rs2910164 was not associated with susceptibility to SLE.

Associations between blood IL-33 levels and IL-33 gene polymorphisms with susceptibility to systemic lupus erythematosus: A meta-analysis.

OBJECTIVES: This study investigated the relationship between circulating interleukin-33 (IL-33) levels and systemic lupus erythematosus (SLE) along with polymorphisms in the IL-33 gene and SLE susceptibility. METHOD: The MEDLINE, EMBASE, and Cochrane Library databases (to May 2023) were searched for relevant publications. Using a meta-analysis we investigated serum/plasma IL-33 levels in patients with SLE and controls, and the relationship between IL-33 rs1929992, rs1891385, rs7044343, rs1095498, and rs10975579 polymorphisms and the risk of developing SLE. RESULTS: Nine studies focusing on 1,935 patients with SLE were included. IL-33 levels were significantly higher in the SLE group than in the control group (SMD = 2.140, 95% CI = 1.068-3.212, p < .001). Asian, European, and Arab groups have shown increased IL-33 levels in SLE populations, according to ethnic stratification. Regardless of the sample size, variable adjustment, data format, or publication year, the subgroup analysis showed significantly higher IL-33 levels in the SLE group. This meta-analysis supported the significance of the link between SLE and the IL-33 rs1891385 C allele (OR, 1.525; 95% CI, 11.310-1.777; p = .010). A similar association was found between the IL-33 rs1891385 C/A polymorphism and SLE, using homozygote comparisons and dominant and recessive models. However, this meta-analysis found no association between the IL-33 polymorphisms rs1929992, rs7044343, rs1095498, and rs10975579 and susceptibility to SLE. CONCLUSIONS: This meta-analysis identified significantly higher levels of circulating IL-33 in patients with SLE as well as an association between IL-33 rs1891385 and SLE.

Systemic lupus erythematosus and toll-like receptor 9 polymorphisms: A meta-analysis of genetic association studies.

OBJECTIVE: This study aimed to examine whether polymorphisms in toll-like receptor 9 (TLR9) contribute to vulnerability to systemic lupus erythematosus (SLE). METHODS: We searched the MEDLINE, Embase, and Web of Science databases for relevant articles. We conducted a meta-analysis to examine the association between the TLR9 rs187084, rs352139, rs352140, and rs5743836 polymorphisms and SLE risk. RESULTS: A total of 5447 patients with SLE and 6588 control participants across 26 trials from 24 articles were included. The TLR9 rs187084 T allele was significantly associated with SLE (odds ratio, 1.146; 95% confidence interval, 1.033-1.273; p = 0.010). In a meta-analysis, the TLR9 rs187084 T allele was associated with SLE in the Asian population but not in the Arab population, demonstrating the existence of ethnicity-specific effects. Using homozygote contrast and recessive models, the researchers also found that the TLR9 rs187084 T/C polymorphism was associated with SLE. The TLR9 rs352139 G allele was not associated with SLE in this meta-analysis. After accounting for ethnic differences, we found that the TLR9 rs352139 G allele was not associated with SLE in Asians and Arabs. Furthermore, homozygote contrast and dominant models found no association between the TLR9 rs352139 G/A polymorphism and SLE. TLR9 polymorphisms at rs352140 and rs5743836 were not associated with an increased risk of SLE in any genetic prediction model, including people of Asian, European, or Latin American ancestry. CONCLUSIONS: SLE susceptibility is associated with the TLR9 rs187084 polymorphism in the Asian population and the rs187084, rs352139, rs352140, and rs5743836 polymorphisms in the Asian, European, and Latin American populations, respectively.

Treatment of active systemic lupus erythematosus with baricitinib: A meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to evaluate the safety and effectiveness of baricitinib in patients with systemic lupus erythematosus (SLE). METHODS: We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Register to find relevant publications. Using data from randomized controlled trials (RCTs), we performed a meta-analysis to investigate the safety and efficacy of baricitinib in patients with active SLE who did not respond well to standard treatments. RESULTS: A total of 1849 individuals (1235 experimental participants and 614 controls) from three RCTs on baricitinib were included. A reduction of ≥ 4 points from baseline in SLEDAI-2K score in the baricitinib 4 mg group was greater than the placebo group's reduction (odds ratio [OR] = 1.407, 95% confidence interval [CI] 1.123-1.763, p = .003). The baricitinib 4 mg group significantly outperformed the placebo group in terms of SLEDAI-2K remission of arthritis or rash (OR = 1.327, 95% CI = 1.059-1.663, p = .014). Other effectiveness outcomes such as the SRI4 response did not substantially improve in the baricitinib 4 mg group when compared with the placebo group. And there were no significant increase in the efficacy outcomes in the baricitinib 2 mg group than in the placebo group. However, there was a substantially higher incidence of severe adverse events (SAE) and serious infections in the baricitinib 4 mg group (OR = 1.493, 95% CI = 1.002-2.225, p = .049; OR = 2.303, 95% CI = 1.147-4.622, p = .019) compared to the placebo group. There were no differences between the baricitinib 2 mg and placebo groups in any of the safety outcome data. CONCLUSION: Meta-analysis reveals that baricitinib 4 mg is beneficial for treating active SLE in terms of a reduction of ≥ 4 points from baseline in SLEDAI-2K score and SLEDAI-2K remission of arthritis or rash. However, the higher frequency of SAEs and serious infections was observed in the group receiving baricitinib 4 mg.

Associations between circulating interleukin-17 levels and Behcet's disease and between IL-17 gene polymorphisms and disease susceptibility: a meta-analysis.

OBJECTIVES: To systematically investigate the relationship between circulating interleukin-17 (IL-17) levels and Behçet's disease (BD) and the associations between polymorphisms in IL17 genes and BD susceptibility. METHODS: We searched the Medline, Embase, and Cochrane databases for relevant articles. We performed a meta-analysis of serum/plasma IL-17 levels in BD patients and controls and evaluated the associations between IL17A rs4711998, rs8193036, and rs2275913 and IL17F rs763780 and rs2397084 polymorphisms and the risk of BD. RESULTS: Twelve studies, involving 901 patients with BD and 1,131 controls, were included. Our meta-analysis revealed that circulating IL-17 levels were significantly higher in the BD group than in the control group (SMD = 1.422, 95% confidence interval [CI] = 0.689-2.155, p<0.001). Subgroup analysis by data type indicated higher IL-17 levels in the BD group in both the original and calculated data populations. Stratification by publication year revealed significantly lower vitamin D levels in the SSc group in both recent and older publication years. No significant differences in IL-17 levels were observed between the active and inactive disease groups. We found no evidence of associations between BD and IL17A rs2275913, L17F rs763780, or rs2397084 polymorphisms. However, a significant association was found between BD and IL17A rs4711998 and rs8193036 polymorphisms in the pooled cohort of affected individuals compared to that in pooled controls (odds ratio [OR] = 1.347, 95% CI = 1.043-1.741, p<0.001; OR = 0.691, 95% CI = 0.542-0.880, p=0.003). CONCLUSIONS: This meta-analysis revealed significantly higher circulating IL-17 levels in BD patients and showed evidence of associations between IL17A rs4711998 and rs8193036 polymorphisms and BD.

Risk factors and clinical outcomes of cytomegalovirus diseases in hematologic malignancy patients without hematopoietic stem-cell transplantation.

PURPOSE: This study aims to evaluate the risk factors and prognosis for CMV diseases in hematologic malignancy patients without hematopoietic stem-cell transplantation (HSCT). METHODS: We performed a case-control study (1:2) between 2012 and 2022. Adults with pathologic-confirmed CMV diseases (n=60) among hematologic malignancy patients were matched and compared to whom without CMV disease. RESULTS: Lymphoma was the most common underlying malignancy, and gastrointestinal tract involvement was the most common CMV disease. In the case group, high-dose steroid administration and transfusion within one month before diagnosis were higher (p<0.001). Steroid administration (aOR=5.78; 95% confidence interval: 1.25-26.68, p=0.024), red blood cell transfusion within one month (aOR=14.63; 2.75-77.76, p=0.002), low BMI (aOR=13.46, 2.07-87.45, p=0.006), and hypoalbuminemia (aOR=26.48, 5.93-118.17, p<0.001) were independent risk factors associated with CMV disease. The 30-day mortality was higher in the case group and CMV disease was significantly associated with all-cause mortality (aOR=14.41, 3.23-64.31, p<0.001). CONCLUSION: In hematologic malignancy patients without HSCT, risk factors for CMV organ disease included high-dose steroid administration and RBC transfusion within one month, low BMI, and hypoalbuminemia. Overall mortality was significantly higher with CMV disease, and CMV disease occurrence was a significant risk factor for mortality.