Disease Severity Research Articles

РОЛЬ ИММУННОГО ОТВЕТА В РАЗВИТИИ ГИПОКСИЧЕСКИХ ОСЛОЖНЕНИЙ РЕСПИРАТОРНЫХ ИНФЕКЦИЙ НИЖНИХ ДЫХАТЕЛЬНЫХ ПУТЕЙ У ДЕТЕЙ

Pneumonia is one of the most common severe infectious diseases in pediatric practice. Hypoxia is common in children with pneumonia and is one of the main predictors of poor outcome. The role of the central link in the cellular response to hypoxia is played by the family of hypoxia-inducible factors (HIF). HIF-1α is the key regulator of both T- and B-lymphocyte functions. The processes of their maturation are accompanied by the formation of circular DNA fragments, TREC (T-cell Receptor Excision Circle) and KREC (Kappa-deleting Recombination Excision Circle). TREC and KREC are unable to replicate and serve as markers for naive lymphocyte production. In its turn, HIF-1α can be used as a marker for cellular hypoxia. The use of TREC and KREC in assessing the immune system in patients with various immunological and infectious pathologies has already been described. At the same time, HIF-1α has so far been little studied as yet. The purpose of this research was to analyze the scientific bibliographical data on the HIF-1α assessment as a marker for hypoxia as well as the quantitative level of TREC and KREC as markers for the adaptive immune response; to study the bibliographical sources on the effect of hypoxia on the immune response, including as part of lower respiratory tract infections. Methods used: bibliographical research in Scopus, PubMed and Google Scholar with keywords “TREC,” “KREC,” “HIF,” “hypoxia,” “pneumonia,” “immune response,” that was then followed by the search results’ systematization, analysis and synthesis. Results: the analysis of bibliographical sources had allowed the Authors to conclude that there is a possible close connection between acute hypoxia and the formation of an adequate immune response in infectious pathologies. Research in this area is still extremely scarce. At the same time, the prospects for this area determine the need for further fundamental and clinical research. Conclusion: it is of a great scientific and clinical interest to be able to non-invasively assess the degree of acute hypoxia during an ongoing infectious disease by examining urinary HIF-1α levels. Particularly promising is the assessment of the HIF-1α level not only as a regulator of tissue adaptation to acute hypoxia, but also as a modulator of the immune response. Taking into consideration the analyzed data, both TREC and KREC appear to be the optimal markers characterizing the functional state of the adaptive immune system.

Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn

BackgroundIn early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti–neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels.MethodsIn an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks’ gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN. The primary end point was live birth at 32 weeks’ gestation or later without intrauterine transfusions as assessed against a historical benchmark (0%; clinically meaningful difference, 10%).ResultsLive birth at 32 weeks’ gestation or later without intrauterine transfusions occurred in 7 of 13 pregnancies (54%; 95% confidence interval, 25 to 81) in the study. No cases of fetal hydrops occurred, and 6 participants (46%) did not receive any antenatal or neonatal transfusions. Six fetuses received an intrauterine transfusion: five fetuses at 24 weeks’ gestation or later and one fetus before fetal loss at 22 weeks and 5 days’ gestation. Live birth occurred in 12 pregnancies. The median gestational age at delivery was 36 weeks and 4 days. Of the 12 live-born infants, 1 received one exchange transfusion and one simple transfusion and 5 received only simple transfusions. Treatment-related decreases in the alloantibody titer and IgG level were observed in maternal samples and cord blood. No unusual maternal or pediatric infections were observed. Serious adverse events were consistent with HDFN, pregnancy, or prematurity.ConclusionsNipocalimab treatment delayed or prevented fetal anemia or intrauterine transfusions, as compared with the historical benchmark, in pregnancies at high risk for early-onset severe HDFN. (Funded by Janssen Research and Development; UNITY ClinicalTrials.gov number, NCT03842189.)

Polygenic Risk and Coronary Artery Disease Severity.

Coronary atherosclerotic burden and adverse coronary heart disease events are related phenotypes with likely shared genetic cause. We analyzed 6021 patients with available coronary angiography, genotyping, and exome sequencing data. We tested for associations of polygenic risk scores for coronary heart disease (PRSCHD) with multiple measures of coronary artery disease (CAD) severity. We assessed the interplay between PRSCHD and pathogenic/likely pathogenic variants in 3 familial hypercholesterolemia genes. We performed mediation analyses to explore whether CAD severity mediated the association of PRSCHD with prevalent coronary heart disease and incident myocardial infarction. A 1-SD increase in PRSCHD was associated with multiple measures of CAD severity, including the log Gensini score (β, 0.31 [95% CI, 0.28-0.33]). Carrying a pathogenic/likely pathogenic familial hypercholesterolemia variant was associated with a higher log Gensini score after adjustment for PRSCHD (β, 0.21 [95% CI, 0.03-0.38]). PRSCHD was associated with incident myocardial infarction over a mean follow-up of 9.2 years (hazard ratio, 1.20 [95% CI, 1.13-1.27]; P=5×10-10), and the Gensini score mediated 90% of this association. PRSCHD was associated with multiple measures of CAD severity. The association of PRSCHD with incident myocardial infarction was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the 2 phenotypes.

Investigation of the utility of smartphone-based gait analyses in discrimination between patients with Alzheimer's disease and Parkinson's disease.

To reveal the discriminative value of gait parameters between Alzheimer's disease (AD) and Parkinson's disease (PD) subjects. We included all consecutive patients with newly diagnosed AD and those with a diagnosis of PD who applied to our polyclinic between March 2022 and June 2022. The demographic and clinical features were evaluated during interviews. The gait analyses were performed using a quantitative, smartphone-based gait analyses program. Using this program, the step time (ST), step length (SL), step number (SN), gait velocity (GV), and cadence were measured in all individuals. Overall, 31 patients with AD and 45 with PD were enrolled in the analyses. The mean age of the AD group was higher according to those with PD. As expected, the Mini-Mental State Examination (MMSE) values were lower in the AD group. The comparative analyses of the gait parameters between groups did not reveal differences in any of the measures. The correlation analyses to investigate the possible association between the disease severity and gait parameters revealed that the MDS-UPDRS showed low negative correlations with SL and GV. Our findings suggest that the evaluation of gait using the gait analyses program does not contribute to the discrimination between AD and PD in clinical practice.

Plasma Extracellular Vesicles Derived from Pediatric COVID-19 Patients Modulate Monocyte and T Cell Immune Responses Based on Disease Severity.

The COVID-19 pandemic has caused significant morbidity and mortality globally. The role of plasma-derived extracellular vesicles (EVs) in pediatric COVID-19 patients remains unclear. We isolated EVs from healthy controls (n = 13) and pediatric COVID-19 patients (n = 104) with varying severity during acute and convalescent phases using serial ultracentrifugation. EV effects on healthy PBMCs, naïve CD4+ T cells, and monocytes were assessed through in vitro assays, flow cytometry, and ELISA. Our findings indicate that COVID-19 severity correlates with diverse immune responses. Severe acute cases exhibited increased cytokine levels, decreased IFNγ levels, and lower CD4+ T cell and monocyte counts, suggesting immunosuppression. EVs from severe acute patients stimulated healthy cells to express higher PDL1, increased Th2 and Treg cells, reduced IFNγ secretion, and altered Th1/Th17 ratios. Patient-derived EVs significantly reduced proinflammatory cytokine production by monocytes (p < .001 for mild, p = .0025 for severe cases) and decreased CD4+ T cell (p = .043) and monocyte (p = .033) populations in stimulated healthy PBMCs. This study reveals the complex relationship between immunological responses and EV-mediated effects, emphasizing the impact of COVID-19 severity. We highlight the potential role of plasma-derived EVs in early-stage immunosuppression in severe COVID-19 patients.

Perioperative Management of Pediatric Combined Heart and Liver Transplantation: A 17 year single center experience.

An increasing number of centers are undertaking combined heart and liver transplantation in adult and pediatric patients with congenital heart disease. The primary aim of this study was to describe the perioperative management of a single center cohort, identifying challenges and potential solutions. We conducted a retrospective review of all patients undergoing combined heart and liver transplantation at Stanford Children's Hospital from 2006 to 2022. Preoperative information included cardiac diagnosis, hemodynamics, and severity of liver disease. Intraoperative data included length of surgery, cardiopulmonary bypass time, and blood products transfused. Postoperative data included blood products transfused in the intensive care unit, time to extubation, length of intensive care unit stay, survival outcomes and 30-day adverse events. Eighteen patients underwent en bloc combined heart and liver transplantation at Stanford Children's Hospital from 2006 to 2022, and the majority 15 (83%) were transplanted for failing Fontan circulation with Fontan Associated Liver Disease. Median surgical procedure time was 13.4 [11.5, 14.5] h with a cardiopulmonary bypass time of 4.3 [3.9, 5.8] h. Median total blood products transfused in the operating room post cardiopulmonary bypass was 89.4 [63.9, 127.0] mLs/kg. Nine patients (50%) had vasoplegia during cardiopulmonary bypass. Activated prothrombin complex concentrates were used post cardiopulmonary bypass in 15 (83%) patients with a 30-day thromboembolism rate of 22%. Median time to extubation was 4.0 [2.8, 6.5] days, median intensive care unit length of stay 20.0 [7.8, 48.3] days and median hospital length of stay 54.0 [30.5, 68.3] days. Incidence of renal replacement therapy was 11%; however, none required renal replacement therapy by the time of hospital discharge. Neurological events within 30 days were 17% and the 30 day and 1 year survival was 89%. Perioperative challenges include major perioperative bleeding, unstable hemodynamics, and end organ injury including acute kidney injury and neurological events. Successful outcomes for en bloc combined heart and liver transplantation are possible with careful multidisciplinary planning, communication, patient selection, and integrated peri-operative management.

Efficient topical treatments of cutaneous lupus erythematosus: A systematic review and network meta-analysis.

Although cutaneous lupus erythematosus (CLE) has been treated with topical agents, there was no high-quality evidence of which agents were more effective, and which clinical scores were more suitable. On December 22nd, 2023, a search was conducted across five databases to identify randomized controlled trials (RCTs). Two authors independently screened the titles and abstracts of articles based on predetermined criteria. Selected articles were then assessed for inclusion in a blinded manner, with any disagreements resolved through consensus. Data were abstracted in duplicate, and a random-effects model was utilized for network meta-analysis. The certainty of the evidence was evaluated according to PRISMA guidelines, using the Grading of Recommendations Assessment, Development and Evaluation approach. The analysis was finalized in January 2024, with the primary outcome focused on the change in cutaneous lupus erythematosus disease area and severity index (CLASI) from baseline. Seven RCTs involving 231 participants were analyzed. The network meta-analysis (NMA) revealed that 4% nicotinamide demonstrated the highest probability of achieving the intended outcomes, with a mean difference (MD) of 3.10 and a 95% confidence interval (CI) of 1.99-4.21. Additionally, 0.05% clobetasol, 2% nicotinamide, and 0.1% tacrolimus also exhibited statistically significant differences, with MDs of 2.30 and 95% CIs of 0.73-3.88; 2.30 and 0.97-3.63; and 1.30 and 0.03-2.57, respectively. As data with a high level of evidence, NMAs demonstrated that 4% nicotinamide, 0.05% clobetasol, 2% nicotinamide, and 0.1% tacrolimus are statistically significant topical agents. CLASI may be an appropriate outcome to evaluate drug efficacy in CLE.

Exploring the Potential of a Tailored Executive Functioning Training Program for Children with Congenital Heart Disease: A Brief Report.

The aim of this pilot study was to explore whether executive functioning (EF) problems of children with severe congenital heart disease (CHD) could be improved through a personalized EF-training program. Eleven preschool-aged children (mean age = 62 months, SD = 6) received a standardized test battery. Eight children were eligible for training and six children participated in the training and posttest. Due to the small sample size, only effect sizes were analyzed. Clinically relevant improvements were found with large effect sizes. Findings indicate that a personalized EF-training program could be effective in improving EF of children with severe CHD. Further research is needed.

Different meanings of a three-point decline in MMSE score in Alzheimer's disease and depressive disorder.

The Mini-Mental State Examination (MMSE) is a composite scale that is included in diagnostic algorithms and in procedures to assess severity of cognitive impairment and efficacy of therapeutic interventions. It is unclear, however, whether the MMSE provides information about the same deficits in different diseases. To assess patterns of MMSE scores in patients with confirmed diagnosis of Alzheimer's disease or depressive disorder. We used data from a previously published cross-sectional retrospective observational clinical cohort study. The final analysis included only patients in whom biomarker analysis showed results characteristic of Alzheimer's disease (n = 167) and patients with depressive disorder in whom Alzheimer's disease had been ruled out by analysis of biomarkers (n = 69). A three-point decline in MMSE score from 30 to 27 reflected impairment of memory recall in patients with Alzheimer's disease, whereas it reflected impairments in calculation and memory recall in patients with depressive disorder. A further three-point decline in MMSE score from 27 to 24 predominantly reflected additional calculation impairment in patients with Alzheimer's disease. Our results indicate that memory performance is the most important measure of disease severity and the main contributor to the decline in MMSE score at onset of clinical manifestation of Alzheimer's disease. In general, this suggests that memory should be the primary measure used in routine clinical care and the primary endpoint in clinical trials involving patients with Alzheimer's disease at onset of clinical manifestation. Changes in other measures of cognition should prompt consideration of possible comorbidities as a cause, rather than the impact of Alzheimer's disease itself.

Alopecia areata exhibits cutaneous and systemic OX40 activation across atopic backgrounds.

Alopecia areata (AA) is a chronic, nonscarring hair-loss disorder associated with significant quality-of-life impairment and limited treatment options. AA has been recently linked to atopy and shown to exhibit both Th1- and Th2-driven inflammation. However, a comprehensive molecular and cellular characterization across blood and scalp compartments in both atopic and nonatopic patients is lacking. Lesional and nonlesional scalp biopsies obtained from AA patients with (n = 16) or without (n = 20) atopic history, and 17 demographically matched healthy controls were analyzed with RNA-seq, RT-PCR, and immunohistochemistry. Flow cytometry was also performed on peripheral blood mononuclear cells (PBMCs) from a subset of patients. Differential expression was defined using |fold-change| > 1.5 and false-discovery rate <0.05. AA scalp exhibited robust upregulation of Th1- (IFNG, CXCL9, CXCL10, CXCL11) and Th2-related products (CCL26, CCR4, IL10, IL13, TSLP, TNFRSF4/OX40) and shared downregulation of hair keratins, regardless of atopic background, with variable Th17/Th22 modulation. AA patients with atopy exhibited greater inflammatory tone and Th2-skewing (IL10, IL13, IL33, CCR4, CCL26). Disease severity correlated significantly with immune and hair keratin biomarkers and with perifollicular cellular infiltrates. Cutaneous OX40/OX40L upregulation was paralleled by increases in circulating OX40+ and OX40L+ leukocytes, regardless of atopic background. Our results suggest some atopy-associated immune differences in AA and highlight the OX40 axis as a potential novel therapeutic target that may broadly benefit AA patients.

Emerging multisystem biomarkers in hereditary transthyretin amyloidosis: a pilot study

Hereditary transthyretin (ATTRv) amyloidosis is a rare, adult-onset, progressive, multisystemic condition caused by TTR pathogenic variants. Reliable biomarkers are needed to allow early diagnosis and to monitor disease severity and progression. We measured serum concentrations of growth differentiation factor-15 (GDF-15) and uromodulin (Umod) in ATTRv patients to evaluate correlations with standard markers of disease severity (FAP stage and PND score). Blood samples were collected from 16 patients diagnosed with ATTRv amyloidosis and a verified TTR variant and from 26 healthy controls. ATTRv patients were stratified by clinical phenotype (neurologic vs. mixed), genotype (V30M vs. non-V30M), and disease severity. We found significantly higher levels of serum GDF-15 in ATTRv patients compared with controls. Mean serum Umod levels were significantly lower in patients with ATTRv than controls. A positive correlation was found between serum Umod and estimated glomerular filtration rate (eGFR), while an inverse correlation was found with cystatin C levels. Conversely, GDF-15 showed a negative correlation with eGFR, and a direct correlation with cystatin C levels. No correlation was demonstrated between GDF-15 or Umod levels and traditional cardiac biomarkers. The results identify alteration of serum levels of GDF-15 and Umod in ATTRv amyloidosis.

The Effects of Opioid Administration on Clostridioides Difficile Infection: A Retrospective Cohort Study.

Background: Clostridioides difficile (C. difficile) is a leading cause of healthcare-associated infections. Using opioids while infected with C. difficile may hypothetically lead to reduced clearance of the organism and higher risk of progressing to severe or fulminant infection. Objective: The objective of this study was to determine if opioid use leads to worsening of C. difficile infection. Methods: This was a single-center, retrospective cohort study of patients with C. difficile infection. The primary endpoint was progression to severe or fulminant disease, defined as serum creatinine greater than 1.5mg/dL or over 50% of baseline, white blood cells above 15,000 cells/mm3, shock requiring vasopressors, ileus, toxic megacolon, or vancomycin dose increase. Secondary outcomes included hospital length of stay and time to resolution of diarrhea. The groups were stratified based on average morphine milligram equivalents received during the treatment. Results: A total of 73 patients were included in the non-opioid group and 93 patients in the opioid group. The composite outcome occurred in 16 patients (21.9%) without opioids vs 26 patients (28.0%) with opioids; (P = 0.37). The average length of stay was 7.2 days without opioids and 9.3 days with opioids (P = 0.11) and the average time to resolution of diarrhea was 3.5 days without opioids and 5.5 days with opioids (P = 0.40). Conclusion: There was no significant difference in the rate of progression to severe or fulminant disease. There was a numerical trend towards increase in progression in patients who had opioids, primarily driven by those who had higher dosages of opioids used.

Clinical Features, Psychiatric Comorbidities and Treatments in Childhood OCD in terms of OCD Severity, Age and Gender

Objective: The aim of this study was to investigate the clinical features, psychiatric comorbidities, and treatments of childhood obsessive-compulsive disorder (OCD), with consideration given to OCD severity, gender and age. Method: The study included 104 children and adolescents between the ages of 6 and 17 who were diagnosed with OCD and followed up in Child and Adolescent Psychiatry outpatient clinics between 2016 and 2023. The study examined the sociodemographic characteristics, clinical features, comorbid psychiatric disorders, and treatment approaches of children and adolescents with OCD. Results: The sample had a mean age of 13.1 ± 2.7 years, and the mean age at onset of OCD was 11.9 ± 2.7 years (range: 5-17 years). Those with mild OCD had a significantly lower mean age at presentation and onset of OCD compared to those with moderate and severe OCD (p=0.012, p=0.02, respectively). Patients with severe OCD had longer illness duration (p=0.009) and outpatient follow-up (p=0.004) compared to those with moderate OCD. Boys had significantly higher rates of family history of psychiatric disorders (p=0.006), attention-deficit/hyperactivity disorder/oppositional defiant disorder (p=0.003), and tic disorder (p=0.035) comorbidity rates than girls, while girls had higher rates of anxiety disorders (p=0.022) comorbidity. The study found that repeating and counting compulsions were more common in adolescents than in preadolescents (p=0.003, all). Conclusion: These results suggest that clinical presentation and comorbidity may vary with disease severity, gender and age, in children and adolescents with OCD. Early intervention is crucial to prevent clinical progression, worsening, and mental health sequelae.

Contrastive machine learning reveals Parkinson’s disease specific features associated with disease severity and progression

Parkinson’s disease (PD) exhibits heterogeneity in terms of symptoms and prognosis, likely due to diverse neuroanatomical alterations. This study employs a contrastive deep learning approach to analyze Magnetic Resonance Imaging (MRI) data from 932 PD patients and 366 controls, aiming to disentangle PD-specific neuroanatomical alterations. The results reveal that these neuroanatomical alterations in PD are correlated with individual differences in dopamine transporter binding deficit, neurodegeneration biomarkers, and clinical severity and progression. The correlation with clinical severity is verified in an external cohort. Notably, certain proteins in the cerebrospinal fluid are strongly associated with PD-specific features, particularly those involved in the immune function. The most notable neuroanatomical alterations are observed in both subcortical and temporal regions. Our findings provide deeper insights into the patterns of brain atrophy in PD and potential underlying molecular mechanisms, paving the way for earlier patient stratification and the development of treatments to slow down neurodegeneration.

Rate of dupilumab use and symptom severity of patients with chronic rhinosinusitis with nasal polyposis after Draf 3 frontal sinusotomy.

The indications for endoscopic modified Lothrop procedure (Draf 3) in patients with refractory chronic rhinosinusitis with nasal polyposis (CRSwNP) remain unclear. This study evaluates the effectiveness of Draf 3 for refractory CRSwNP focusing on improvements in disease severity and need for subsequent dupilumab rescue therapy. Retrospective review of patients with CRSwNP undergoing Draf 3 surgery at a tertiary center between 2012 and 2022. Clinicodemographic variables were compared across those who did versus did not require rescue with postoperative dupilumab. Time to postoperative dupilumab rescue was analyzed and longitudinal disease-specific outcomes were measured using the sinonasal outcomes test (SNOT-22). Within 87 patients with CRSwNP, 24.1% had aspirin-exacerbated respiratory disease (AERD). Significant improvement in SNOT-22 score was found in CRSwNP with AERD (p<0.001) and without AERD (p=0.01) up to 24 months postoperative. 14.9% eventually required rescue with a dupilumab. More specifically, of 21 patients with AERD, 24.1% eventually required rescue with dupilumab. Dupilumab rescue was associated with a greater number of prior sinus surgeries (p=0.02), prior aspirin desensitization (p=0.02), and worse preoperative Lund-MacKay scores (p<0.001). No association between biologic rescue and frontal recess antero-posterior diameter was found (p=0.20). Draf 3 surgery in CRSwNP was associated with significant improvement in SNOT-22 score at 24 months. Furthermore, only 14.9% of patients required dupilumab rescue. Patients with AERD were more likely to require rescue with dupilumab even though 75.1% avoided treatment with the biologic over the study period.

Study of the Immune Infiltration and Sonic Hedgehog Expression Mechanism in Synovial Tissue of Rheumatoid Arthritis-Related Interstitial Lung Disease under Machine Learning CIBERSORT Algorithm.

Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is one of the common complications in patients with RA, which affects their quality of life. The CIBERSORT algorithm is widely employed to determine the proportion of immune cells (ICs) in diseased tissues, while the Sonic Hedgehog (Shh) signaling pathway, as an imperative regulatory factor, has also attracted attention in the pathology of RA-ILD. This work was to explore the mechanisms of RA-ILD immune infiltration and synovial tissue (ST) Shh expression based on the CIBERSORT algorithm. The differential genes of RA-ILD were subjected to pathway enrichment analysis using R language. The content and proportion of 22 types of ICs in RA-ILD lung tissues were analyzed using machine learning-based CIBERSORT algorithm. Meanwhile, immunoblotting was employed to detect and analyze the expression of Shh, Smoothened (Smo), and bone morphogenetic proteins (BMPs) proteins in ST samples from RA-ILD and Ctrl groups (RA patients without ILD). The hub target genes in the protein network associated with RA-ILD include BSG, CCL2, CTLA4, FGFBP1, GLI1, HHIP, HLA-DRB1, IFNAR1, IL17A, IL23A, IL-6, INPP4A, LILRB1, MUC5B, PADI4, PPM1A, PTCH1, PTPN22, RSPO4, Shh, SMO, STAT4, SUFU, TAOK2, TIMP2, and TWSG1, which are involved in multiple pathways, such as B cell regulation, transcription factors of the Shh pathway, and ST immune tolerance-related pathways. In the immunological analysis of RA-ILD using the CIBERSORT algorithm, HLA (r = -0.26), PTPN22 (r = -0.36), STAT4 (r = -0.18), IL-6 (r = -0.17), CTLA4 (r = -0.27), and PADI4 (r = -0.21) were all found to exhibit negative correlations with CD4+T cells (P < 0.05). Monocytes were found to be more abundant in RA-ILD patients' serum versus the Ctrl group. Shh, Smo, and BMP expressions were drastically lower in the RA-ILD group versus Ctrl group (P < 0.05). Significant immune cell infiltration was observed in the lung tissues of RA-ILD patients. Further analysis utilizing the CIBERSORT algorithm revealed alterations in the proportions of different IC subtypes, indicating their association with disease severity and prognosis. Moreover, there was a significant decrease in the expression levels of Shh, Smo, and BMP. These findings underscore the importance of immune cells in the pathophysiology of RA-ILD and suggest a potential involvement of the Shh signaling pathway in the pathogenesis of RA-ILD.

TLR8 is expressed in monocytes in contrast to plasmacytoid dendritic cells and mediates aberrant IL-10 responses in patients with systemic sclerosis (SSc).

Systemic sclerosis (SSc) is a severe rheumatic disease, causing fibrotic tissue rearrangement. Aberrant Toll-like receptor 8 (TLR8) transcripts in plasmacytoid dendritic cells (pDC) were recently linked to SSc pathogenesis, which is at least partially mediated by increased type I interferon (IFN-I) responses. Here, we addressed the functional role of TLR8 signaling in different immune cell subsets of patients with SSc. Monocytes, conventional dendritic cells (cDC), and pDC, from blood and skin of patients with SSc were analyzed for TLR8 protein expression. To assess TLR function, cytokine responses upon TLR7 and TLR8 stimulation were studied. To identify relevant alterations specific for SSc (n=16), patients with primary Sjögren's syndrome (pSS) (n=10) and healthy controls (HC) (n=13) were included into the study. In all individuals, TLR8 was expressed in monocytes and cDC, but not in pDC. The TLR8 expression levels were overall similar in patients with SSc, pSS, and HC. Additionally, in all study participants, TLR8 stimulation of pDC did not induce IFN-I expression. In contrast, monocytes from patients with SSc revealed increased interleukin-10 (IL-10) responses upon TLR8 (SSc vs.HC: p=0.0126) and TLR7/8 stimulation (SSc vs. HC: p=0.0170). TLR8 protein is not expressed in pDC of patients with SSc. Accordingly, they do not respond to TLR8 stimulation. In contrast, monocytes of patients with SSc respond to TLR8 stimulation with increased IL-10 responses. Therefore, TLR8 signaling in monocytes participates in SSc pathogenesis by conferring aberrant IL-10 expression.

A CT-based radiomics model for predicting lymph node metastasis in hepatic alveolar echinococcosis patients to support lymph node dissection

BackgroundHepatic alveolar echinococcosis (AE) is a severe zoonotic parasitic disease, and accurate preoperative prediction of lymph node (LN) metastasis in AE patients is crucial for disease management, but it remains an unresolved challenge. The aim of this study was to establish a radiomics model for the preoperative prediction of LN metastasis in hepatic AE patients.MethodsA total of 100 hepatic AE patients who underwent hepatectomy and hepatoduodenal ligament LN dissection at Qinghai Provincial People's Hospital between January 2016 and August 2023 were included in the study. The patients were randomly divided into a training set and a validation set at an 8:2 ratio. Radiomic features were extracted from three-dimensional images of the hepatoduodenal ligament LNs delineated on arterial phase computed tomography (CT) scans of hepatic AE patients. Least absolute shrinkage and selection operator (LASSO) regression was applied for data dimensionality reduction and feature selection. Multivariate logistic regression analysis was performed to develop a prediction model, and the predictive performance of the model was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA).ResultsA total of 7 radiomics features associated with LN status were selected using LASSO regression. The classification performances of the training set and validation set were consistent, with area under the operating characteristic curve (AUC) values of 0.928 and 0.890, respectively. The model also demonstrated good stability in subsequent validation.ConclusionIn this study, we established and evaluated a radiomics-based prediction model for LN metastasis in patients with hepatic AE using CT imaging. Our findings may provide a valuable reference for clinicians to determine the occurrence of LN metastasis in hepatic AE patients preoperatively, and help guide the implementation of individualized surgical plans to improve patient prognosis.

Circulating Cell-Free DNA Promotes Inflammation in Patients with Dermatomyositis with Anti-NXP2 Antibodies via the cGAS/STING Pathway.

Dermatomyositis (DM) is a rare type I interferon (IFN-I)-driven autoimmune disease, and anti-nuclear matrix protein 2 (NXP2) antibody is related to severe muscle disease and poor prognosis. Circulating cell-free DNA (ccf-DNA), including ccf-mitochondrial DNA and ccf-nuclear DNA, activates cGAS/STING pathway to induce IFN-I production in autoimmune diseases. We investigated whether serum-derived ccf-DNA played a pathogenic role on skeletal muscle in anti-NXP2 antibody-positive DM. Serum ccf-DNA levels were measured, and correlations between ccf-DNA and clinicopathological indicators were performed. RNA sequencing, immunofluorescence, western blotting and RT-qPCR were performed on skeletal muscle samples. The serum-induced expression of p-STING in C2C12 cells was assessed in vitro. We found that increased ccf-DNA levels were positively correlated with MYOACT scores in anti-NXP2 antibody-positive DM. RNA sequencing and immunofluorescence results revealed that the cytosolic DNA-sensing pathway was upregulated and that increased cytosolic dsDNA was colocalised with cGAS in skeletal muscle in anti-NXP2 antibody-positive DM. Western blot analysis revealed activation of the cGAS/STING pathway in patients with perifascicular atrophy (PFA) but not in patients without PFA. RT-qPCR showed increased IFN-I scores in both patients with PFA and patients without PFA. Sera from patients with PFA increased p-STING expression in C2C12 cells, and DNase I treatment and STING inhibitor efficiently inhibited p-STING expression, respectively. Increased ccf-DNA levels may be potential biomarkers for monitoring disease activity in anti-NXP2 antibody-positive DM. Activation of the cGAS/STING pathway is associated with PFA. Our findings identify the pathogenic role of ccf-DNA on skeletal muscle via the cGAS/STING pathway.

Tick-borne encephalitis vaccine breakthrough infections induce aberrant T cell and antibody responses to non-structural proteins

Tick-borne encephalitis virus (TBEV) vaccine breakthrough (VBT) infections are not uncommon in endemic areas. The clinical and immunological outcomes have been poorly investigated. We assessed the magnitude and specificity of virus-specific antibody and T cell responses after TBE in previously vaccinated subjects and compared the results with those of unvaccinated TBE patients and study subjects that received vaccination without VBT infection. Symptomatic TBEV infection of unvaccinated study subjects induced virus-specific antibody responses to the E protein and non-structural protein 1 (NS1) as well as T cell responses to structural and other non-structural (NS) proteins. After VBT infections, significantly impaired NS1-specific antibody responses were observed, while the virus-specific T cell responses to the NS proteins were relatively strong. VBT infection caused predominantly moderate to severe disease during hospitalization. The level of TBEV EDIII- and NS1-specific antibodies in unvaccinated convalescent patients inversely correlated with TBE severity and neurological symptoms early after infection.