Non-responder Group Research Articles

Plasma essential amino acid levels in first episode psychosis at baseline and after antipsychotic treatment

This study assessed plasma levels of essential amino acids (EAA) in drug-naïve first episode psychosis (FEP) patients at diagnosis and after 10 weeks of antipsychotic treatment. Forty FEP patients were enrolled at baseline, with blood samples collected before and after a 10-week antipsychotic treatment period. Plasma EAA levels were measured using an LC/MS/MS method. Psychotic symptoms were evaluated using standardized inventories before and after treatment. A decrease in BPRS score of more than 40% was used to indicate treatment response. Thirty-five healthy volunteers served as the control group. Baseline plasma levels of Thr, Met, Leu, Lys, His, and Tyr were higher in FEP patients than in healthy controls. After 10 weeks of treatment, Leu, His, and Tyr increased further, primarily in treatment-responsive patients. Conversely, Val level was lower than controls in patients at baseline and remained unchanged after treatment. Increased EAA levels were correlated with lower (less severe) scores in positive symptom scales. Treatment non-responders had persistently low Tyr/large neutral amino acid (LNAA) ratio. Tyr/LNAA ratio increased after treatment, specifically in treatment-responders. Phe/Tyr ratio decreased post-treatment in both responder and non-responder groups. Elevated EAA levels in FEP patients may signify compensatory responses to increased physiological demand for neurotransmitters or energy. Combining specific EAA supplementation with antipsychotic treatment may enhance treatment response in these patients.

Efficacy of single anastomosis sleeve-ileal bypass in weight control and resolution of type 2 diabetes mellitus – a retrospective cohort study

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder exacerbated by obesity. Single Anastomosis Sleeve-Ileal Bypass (SASI) has emerged as a promising metabolic bariatric procedure that combines sleeve gastrectomy and ileal bypass, facilitating substantial weight loss and T2DM remission through restrictive and malabsorptive mechanisms. This study aims to evaluate the effects of SASI on T2DM remission, weight loss, and safety in one year follow-up. A retrospective cohort study analyzed 31 patients with obesity and T2DM who underwent SASI. Data collected included demographic characteristics, preoperative and postoperative BMI, HbA1c levels, and bariatric outcomes, including %TWL and T2DM changes. The mean age was 45 years, with a mean preoperative BMI of 40.7 kg/m². One year postoperatively, the mean %EWL was 85.6% and %TWL was 31.7%. T2DM remission was achieved in 24 (77.4%) patients, improvement in 4 (12.9%), and no change in 3 (9.7%). Hypertension improved in 21 (87.5%) patients, with 12 (50%) achieving remission. Significant reductions in BMI and HbA1c levels were observed (p < 0.001). Responders (R) and non-responders (NR) groups showed significant differences in postoperative BMI and %EWL (p = 0.007, p = 0.023). One patient experienced a Clavien-Dindo Grade III complication; no deaths occurred. SASI is an effective and safe procedure for treating T2DM, resulting in significant weight loss and metabolic improvements over a one-year follow-up. SASI seems to be a favorable option for T2DM management in metabolic bariatric surgery.

Infiltrations of plasma cells in synovium predict inadequate response to Adalimumab in Rheumatoid Arthritis patients

ObjectiveRheumatoid arthritis (RA) is a clinically heterogeneous and complex autoimmune disease, making the prediction of therapeutic responses a significant challenge. This study aims to assess the role of clinical and synovial biomarkers in predicting poor response to adalimumab treatment in RA patients.MethodsThis single-center prospective study included 56 RA patients who had an inadequate response to methotrexate (MTX). At baseline, comprehensive assessments including complete blood count, liver and kidney function tests, blood glucose levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), as well as counts of swollen and tender joints, Health Assessment Questionnaire (HAQ) score, pain visual analogue scale (VAS) scores, and DAS28-CRP scores were conducted. Synovial biopsies were performed, followed by an efficacy evaluation at 12 weeks of adalimumab treatment. Patients not meeting the ACR20 criteria were classified into the non-responder group, with the remainder categorized as the responder group.ResultsOut of the participants, 24 (42.9%) failed to achieve ACR20 with adalimumab treatment. Non-responders exhibited higher infiltration of plasma cells in the synovium. Multivariate logistic regression analysis identified the presence of plasma cells as an independent risk factor for inadequate response to adalimumab.ConclusionInadequate responses to adalimumab in RA patients were associated with increased plasma cell infiltrations in the synovium. These findings suggest a promising target for tailored therapies in rheumatoid arthritis.

Predicting blood pressure response to renal denervation based on a new approach.

Identifying predictors of blood pressure (BP) response to renal denervation (RDN) is crucial for patient selection. According to Wilder's principle, baseline BP predicts BP change after any antihypertensive intervention. Thus, any observed BP change after RDN is the sum of the BP change depending on the baseline BP and the specific BP reduction due to RDN. Based on this concept, we propose a new definition of BP responders. In our center, 148 patients with uncontrolled hypertension underwent RDN, and 24-h ambulatory BP (ABP) was measured at baseline, and 6 months after the procedure. The decrease in 24-h systolic BP (SBP) correlated with baseline SBP (P = <0.001, r = -0.374). We determined the RDN-specific effect by subtracting the predicted SBP decrease from the observed SBP decrease. The cohort was divided into RDN responders, neutral responders, and nonresponders. Our study population had a mean age of 59 ± 10.4 years and was 74% male. The RDN-specific (residual) 24-h ABP decreased by -14.9 ± 6.3/-8.2 ± 3.8 mmHg (responder group), 1.0 ± 3.2/0.2 ± 1.9 mmHg (neutral group), and 14.2 ± 10.4/8.3 ± 3.9 mmHg (nonresponder group) 6 months after RDN. Responders had fewer antihypertensive medications (P = 0.018), higher baseline office heart rate (HR) (P = 0.019), higher 24-h ambulatory HR (P = 0.003), lower BMI (P < 0.038), and absence of type 2 diabetes (T2D) (P = 0.020). Our definition of BP responders to RDN separates baseline BP-related changes from RDN-specific changes. Positive predictors for BP response to RDN include low BMI, fewer antihypertensive medications, high baseline office HR, high 24-h ambulatory HR, and absence of T2D.

Why Is the Group of Non-responders to Cardiac Resynchronization Therapy so Large? Some Ethical and Medical Aspects of the Topic

The aim of this single centre study (“St. Ekaterina” Hospital) is to assess the effect of a second successful cardiac resynchronization therapy (CRT) in patients who had already had an unsuccessful implantation of a CRT system at other medical centres in Bulgaria and were defined as “non-responders”. This is a prospective observational study. The patients have previously had an unsuccessful implantation of a left ventricular (LV) lead or the latter has not been placed in the target vessel. After the successful implantation of a new LV lead in another target vessel, the post-procedure criteria for echocardiographic (EchoCG) and clinical response were monitored. Over the period 2017–2019, 18 CRT systems have been implanted in 18 patients with an average age 65±1 years with initial heart failure (HF) according to the Classification of the New York Heart Association (NYHA) class III. The average LV ejection fraction (LVEF) was 28±1%. After the successful implantation of a new LV lead, patients presented with HF class II–III and LVEF 36±1%. In the new “upgrading” procedure, 15 patients (83%) had a good clinical and EchoCG response, and two of those 15 patients were “super responders”. The remaining three patients (17%) were “poor responders”. After the good clinical and echocardiographic response to the therapy with a second successful implantation of a LV lead in another target vessel, an important question arises, whether all “non-responders” to the CRT are actually supposed to be defined as such.

Myocardial single photon emission computed tomography imaging to identify non-responders to cardiac resynchronization therapy in patients with non-left bundle branch block

Abstract Background Non-response to cardiac resynchronization therapy (CRT) is an important issue in the treatment of heart failure with reduced ejection fraction (HFrEF) and non-left bundle branch block (LBBB). Although the QRS duration and morphology are crucial parameters for selecting CRT candidates, electrocardiogram (ECG) markers may inadequately represent the mechanical activation patterns within the heart. Owing to limitations associated with the ECG criteria, there is increasing interest in advanced multimodality imaging to improve patient selection. Recently, myocardial single-photon emission computed tomography imaging (G-MPI) is used for assessing left ventricular (LV) dyssynchrony. This technique is mostly automatic and has high intra- and inter-observer reproducibility and repeatability. Objectives This study aimed to examine whether preoperative G-MPI evaluation could predict non-responsiveness to CRT in patients with HFrEF with non-LBBB. Methods Between January 2021 and December 2022, 128 patients underwent CRT, of whom 73 with pre-operative evaluation using G-MPI were selected. Forty-three patients with non-LBBB (21 and 22 CRT responders and non-responders, respectively) were assessed. These patients were divided into CRT responder and non-responder groups. We evaluated the cut-off and clinical impact of pre-operative G-MPI parameters in predicting non-responsiveness to CRT. In addition, 30 patients with LBBB were analyzed. Results Among patients with non-LBBB, CRT responders and non-responders showed no significant differences in baseline characteristics, except for the LV dimension. A receiver operating characteristic curve analysis identified 108° and 27.7° as the optimal cut-offs for the bandwidth and phase standard deviation (SD), respectively, to predict non-responsiveness to CRT (area under the curve [AUC]=0.762; 95% confidence interval [CI]: 0.601–0.923 and AUC=0.742; 95% CI: 0.576–0.909, respectively). A multivariate analysis revealed that a cut-off bandwidth of ≥108° and phase SD of ≥27.7° are independent predictors of non-responsiveness to CRT in patients with non-LBBB (hazard ratios 5.65; 95% CI: 1.53–20.9; P=0.009). In contrast, there were no relationships between G-MPI parameters and non-responsiveness to CRT in patients with LBBB. Conclusions Pre-operative G-MPI findings were associated with non-responsiveness to CRT in patients with non-LBBB. The identification of potentially nonresponsive patients could influence patient management and alter outcomes.

Investigation of Blood Count-Based Inflammatory Biomarkers as Predictors of Response to Dupilumab Treatment in Patients with Chronic Rhinosinusitis with Nasal Polyps

Background/Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease often resistant to standard treatments. Dupilumab, a monoclonal antibody targeting the IL-4α receptor, has shown efficacy in CRSwNP, but a significant subset of patients do not respond to this therapy. This study aims to investigate pretreatment complete blood count (CBC)-based inflammatory biomarkers as predictors of response to dupilumab in patients with CRSwNP. Methods: This mono-centric, retrospective, single-arm longitudinal cohort study included 80 patients with uncontrolled CRSwNP who received dupilumab treatment at the Medical University of Graz. Patients were classified into responder and non-responder groups based on a reduction of &gt;1 in nasal polyp score (NPS) and a sinonasal outcome test-22 (SNOT-22) score &lt;40 points at six months. Pretreatment CBC-derived biomarkers, including eosinophil count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation indices including the aggregate inflammation systemic index (AISI), systemic inflammation index (SII), and systemic inflammation response index (SIRI), were analyzed for their predictive value. Results: Of the 80 patients, 72.5% were classified as responders, while 27.5% were non-responders. A significant positive correlation was found between baseline eosinophil count and NPS reduction (p = 0.027), suggesting that higher eosinophil levels may predict higher NPS reduction in dupilumab treatment. However, no significant associations were observed between NLR, PLR, and systemic inflammation indices with treatment outcomes. Conclusions: Pretreatment eosinophil count may serve as a potential biomarker for predicting nasal polyp reduction in dupilumab treatment of CRSwNP. Other CBC-based inflammatory markers did not show significant predictive value. Further prospective studies are needed to validate these findings and explore additional, reliable biomarkers to optimize treatment outcomes for CRSwNP patients.

Preventive treatment effects on brain structures and functions in patients with chronic migraine: A multimodel magnetic resonance imaging study.

Patients with chronic migraine (CM) often exhibit structural and functional alterations in pain-matrix regions, but it remains unclear how preventive treatment affects these changes. Therefore, this study aimed to investigate the structural and functional changes in pain-matrix regions in CM patients after 6-month treatment. A total of 24 patients with CM and 15 healthy controls were recruited for this study. Patients were divided into responder group (N = 9) and non-responder group (N = 15). After completing the Migraine Disability Assessment (MIDAS) questionnaire, all patients underwent whole-brain high-resolution T1-weighted images, diffusion-weighted imaging, and resting-state functional magnetic resonance imaging at baseline and 6-month follow-up. Whole brain gray matter volume and white matter diffusion indices were analyzed using voxel-based analysis. Structural and functional connectivity analyses were performed to understand brain changes in patients after 6-month preventive treatment. The responder group exhibited significantly higher MIDAS scores than the non-responder group at baseline, but no significant difference between the two groups at follow-up. No significant interval change was noted in gray matter volume, white matter diffusion indices, and structural connectivity in CM patients after 6-month treatment. Nonetheless, the functional connectivity was significantly increased between occipital, temporal lobes and cerebellum, and was significantly decreased between parietal and temporal lobes after 6-month preventive treatment. We concluded that resting-state functional connectivity was suitable for investigating the preventive treatment effect on CM patients.

Effects of vagal nerve stimulation parameters on heart rate variability in epilepsy patients.

Vagal nerve stimulation (VNS) is used as an alternative treatment in drug-resistant epilepsy patients. Effects of VNS on the cardiac autonomic system are controversial. In this study, we aimed to investigate the relationship between VNS parameters and heart rate variability (HRV) in epilepsy patients who underwent VNS treatment. Our study included 31 patients who underwent VNS for drug-resistant epilepsy. Patients were divided into groups according to response to VNS and VNS parameters. All patients underwent 24-h Holter ECG. The mean age of 31 VNS-treated epilepsy patients included in the study was 33.87 ± 7.6 years. When patients were grouped according to VNS response, 25 patients were in the VNS responder group and six patients were in the VNS-nonresponder group. When comparing Holter parameters in the VNS responder and non-responder groups, the median HF was significantly lower in the VNS responder group. VNS duration and signal frequency had a positive effect on LF/HF, while output and off time had a negative effect on LF/HF. When ROC analysis was performed to determine the cut-off values of the parameters for the VNS-responsive state, the AUC value of the HF parameter was 0.780, which was statistically significant. The cut-off value to distinguish response to VNS was 156.9. In conclusion, the effects of VNS parameters on HRV parameters are quite complex. However, the conclusion is that VNS is a neuromodulation method that affects the autonomic system in a complex way. Different levels of VNS parameters may also contribute to this effect. Furthermore, HRV parameters can be used as biomarkers to predict the patient population that may benefit from VNS.

Predictive biomarkers for low-dose IL-2 therapy efficacy in systemic lupus erythematosus: a clinical analysis

BackgroundLow-dose IL-2 (Ld-IL2) has shown favorable therapeutic effects in systemic lupus erythematosus (SLE) therapy. However, previous clinical trials reported an SLE Responder Index-4 (SRI-4) response rate of 65.52%-68%, with approximately half failing to achieve the primary endpoint by week 24. Our study aims to determine the real-world use of Ld-IL2 and to identify determinants of its effectiveness in SLE.MethodsWe pooled data from 342 SLE patients undergoing sequential Ld-IL2 treatment, with 314 persisting for over 3 months were included in effectiveness and prediction analyses. All patients were categorized into responder (n = 136) and non-responder group (n = 178) according to SRI-4. Lupus Low Disease Activity State (LLDAS) was also analyzed to validate our results.ResultsRash, lower complement 3 (C3), and renal involvement including urine protein, urine occult blood and urine casts emerged as prominent predictors of achieving SRI-4. Adjusting for baseline values using the ratio of change to baseline revealed significant differences in CD4 + T cell immune profiles between responders and non-responders. ROC analysis confirmed a satisfactory performance of rash, renal involvement, percentage change of CD4 + T cells, and C3 in predicting SRI-4, yielding an AUC of 0.933. LLDAS analysis showed that hematological involvements and lower CLA + Treg were potent predictive markers in LLDAS attainment. Conversely, renal involvement failed to have significant association in achieving LLDAS. The analysis of background therapy in SLE patients showed that MMF was more likely to reach the SRI-4 response with the combination of Ld-IL2.ConclusionsThese findings uncovered the predictors of Ld-IL2 treatment efficacy in SLE patients and provided guidance to physicians for rational utilization.

Efficacy and safety of orelabrutinib in relapsed/refractory idiopathic multicentric Castleman disease: A single-centre, retrospective study.

Idiopathic multicentric Castleman disease (iMCD) is a rare and heterogeneous lymphoproliferative disorder that lacks standardised treatment options for patients with refractory or relapsed (r/r) disease. Blocking Bruton's tyrosine kinase (BTK) has emerged as a promising therapeutic approach for iMCD without depleting B cells. This single-centre, retrospective study enrolled 10 patients with r/r iMCD who were treated with orelabrutinib, a novel, next-generation BTK inhibitor. The median age at orelabrutinib initiation was 48 (range: 31-58) years. The overall response rate was 70% (7/10 patients, 95% CI: 34.8-93.3), with 20% (n = 2) achieving complete response and 50% (n = 5) achieving partial response. The median time to response was 9.8 (range: 5.9-20.5) months. Patients in the non-responder group also demonstrated a continuous improvement in haemoglobin (91-105 g/L) and albumin (32-38 g/L) levels at month 12 of treatment despite not fulfilling response criteria. No grade 3 or higher adverse events occurred during the median time to the next treatment of 29.0 (range: 15.0-36.2) months. No patient mortality was recorded during the median follow-up duration of 32.8 (range: 15.0-36.9) months. In conclusion, orelabrutinib is a safe and effective regimen for r/r iMCD.

Interstitial lung disease associated with anti-aminoacyl-tRNA synthetase syndrome: quantitative evaluation of CT after initial treatment and long-term follow-up.

Visual evaluation of interstitial lung disease (ILD)-related changes can generate intra- and inter-observer errors. However, recent deep learning (DL) algorithm advances have facilitated accurate lung segmentation, lesion characterization, and quantification. To evaluate the treatment response and long-term course in ILD associated with anti-aminoacyl-tRNA synthetase syndrome (anti-ARS ILD) using a DL algorithm. Patients with anti-ARS ILD who underwent both pre- and post-initial-treatment computed tomography (CT) (n = 68) were divided into two groups (responders and non-responders) according to forced vital capacity improvement after initial treatment. We also analyzed the CT images of patients for whom long-term follow-up CT (>5 years) was performed after post-treatment CT (n = 43). DL analysis was used to classify CT imaging features into five patterns: normal; ground-glass opacity (GGO); consolidation; fibrotic lesions; and emphysema. The initial responder group had a larger volume of consolidation. Consolidation and GGO volumes decreased after initial treatment in both groups. However, whole-lung and normal-area volumes increased in the responder group; conversely, there was no significant increase in the non-responder group. At the long-term follow-up, fibrotic lesions significantly increased in both groups. The emphysema pattern increased significantly in both groups after initial treatment and long-term follow-up. Six of 26 (23.1%) responders and 8 of 17 (47.1%) non-responders were judged as having progressive pulmonary fibrosis. DL-based analysis facilitated the chronological evaluation of anti-ARS ILD. During the long-term follow-up, anti-ARS ILD was associated with chronological progression, regardless of initial treatment efficacy.

Predicting response to immunotherapy in oral squamous cell carcinoma via a CT-based radiomics model

BackgroundTo investigate whether radiomics models derived from pretreatment CT could help to predict response to immunotherapy in oral squamous cell carcinoma (OSCC).MethodsRetrospectively, a total of 40 patients with measurable OSCC were included. The patients were divided into responder group and non-responder group according to the comparison of pre-treatment and post-treatment CT findings. Radiomics features were extracted from pre-treatment CT images, and optimal features were selected by univariate analysis and the least absolute shrinkage and selection operator (LASSO) regression analysis. Neural network, support vector machine, random forest and logistic regression models were used to predict response to immunotherapy in OSCC, and leave-one-out cross validation was employed to assess the performance of the classifiers. The area under the curve (AUC), accuracy, sensitivity and specificity were calculated to quantify the predictive efficacy.ResultsA total of 7 features were selected to build models upon machine learning methods. By comparing different machine learning based models, the neural network model achieved the best predictive ability, with an AUC of 0.864, an accuracy of 82.5%, a sensitivity of 82.5%, and a specificity of 82.5%.ConclusionsThe pretreatment CT-based radiomics model showed good performance in predicting response to immunotherapy in OSCC. Pretreatment CT-based radiomics model might provide an alternative approach for the selection of patients who benefit from immunotherapy.

Gut microbiota as a prognostic biomarker for unresectable hepatocellular carcinoma treated with anti-PD-1 therapy.

To investigate the relationship between the gut microbiome and the response to anti-PD-1-based combination therapy in unresectable hepatocellular carcinoma (HCC). We aimed to identify potential non-invasive biomarkers and new strategies to modulate immunotherapy in HCC. In this study, fresh stool samples and clinical data were collected from unresectable HCC patients treated with anti-PD-1-based combination therapy at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2020 and December 2021. The patients were divided into two groups based on their response to treatment: the treatment responder group (R group) and the treatment non-responder group (NR group). The composition and diversity of the gut microbiome were bioinformatically analyzed by using the Whole Genome Shotgun strategy, including taxonomic composition analysis, Alpha diversity analysis, Beta diversity analysis, and differentially enriched bacterial taxa analysis. Differentially enriched bacterial taxa between R and NR groups were identified based on the magnitude of the linear discriminant analysis effect size (LEfSe) and analyzed for their impact on the survival of the patient. A total of 45 eligible patients with unresectable HCC treated with anti-PD-1-based combination therapy participated in this study. The gut microbiological composition and Alpha diversity of patients were not statistically different, but there was a statistically significant difference in Beta diversity between the R and NR groups. (PERMANOVA tests, P = 0.006). We further identified 56 enriched bacterial taxa in the R group and 44 enriched bacterial taxa in the NR group based on the LEfSe analysis (LDA >2.66, P< 0.05). Patients with a high abundance of Collinsella genus, Ruminococcus_AM4211, and Ruminococcus_AF25_28AC had a longer median PFS and median OS compared to those with low abundance (P < 0.05). On the contrary, the median PFS and OS of patients with a high abundance of Bacteroides_AF20_13LB and Veillonella_atypica were significantly shorter than those of patients with low abundance (P < 0.05). The multivariate analysis showed that the abundance of Bacteroides_AF20_13LB and Ruminococcus_ AF25_28AC was independent related factors for PFS, and the abundance of Bacteroides_AF20_13LB was an independent related factor of OS. The enrichment of specific gut microbiota affected clinical efficacy and survival benefits in HCC treated with anti-PD-1 therapy and may be a promising non-invasive gut microbial biomarker and a new strategy for modulating immunotherapy in HCC.

Evaluating the predictive efficacy of real-time 3D echocardiography in cardiac resynchronization therapy

BackgroundThe aim of this study is to assess the predictive efficacy of real-time three-dimensional echocardiography (RT-3DE) and QRS wave duration in determining the response to cardiac resynchronization therapy (CRT) and assessing left ventricular systolic function pre- and post-CRT device implantation.MethodA total of 51 patients with heart failure undergoing CRT at the Second Affiliated Hospital of Nantong University between January 1, 2013, and October 31, 2020, were enrolled in this study. Traditional two-dimensional echocardiography and RT-3DE were performed pre and post-CRT, with QRS wave width data from electrocardiograms and additional clinical information collected. Patients were categorized into CRT responder (n = 36) and CRT non-responder (n = 15) groups based on their response to CRT device implantation. Comparative analyses were conducted on the general characteristics of both groups, as well as the predictive efficacy of RT-3DE and QRS wave width for CRT responsiveness and left ventricular systolic function. Data on the standard deviation (Tmsv16-SD, Tmsv12-SD, Tmsv6-SD) and maximum difference (Tmsv16-Dif, Tmsv12-Dif, Tmsv6-Dif) of left ventricular end-systolic volume (LVESV) at segments 16, 12, and 6, as well as QRS wave width, were collected and analyzed.ResultsThe indicators Tmsv6-Dif, Tmsv12-Dif, Tmsv16-Dif, Tmsv6-SD, Tmsv12-SD, Tmsv16-SD, and QRS wave width exhibited significantly higher values in the CRT responder group when compared to the CRT non-responder group (P < 0.05). Among these, Tmsv16-SD demonstrated superior predictive performance for post-CRT response, with a sensitivity of 88.9%, specificity of 80.0%, and a diagnostic cut-off value of 6.19%. This predictive capability exceeded that of the conventional indicator, QRS wave width.ConclusionRT-3DE enables accurate prediction of post-CRT patient response and significantly facilitates quantitative assessment of CRT therapy efficacy.

Qingchang suppository ameliorates mucosal inflammation in ulcerative colitis by inhibiting the differentiation and effector functions of Th1 and Th17 cells

Ethnopharmacological relevanceQing Chang Suppository (QCS), a traditional Chinese medicine formula, has been shown to effectively alleviate mucosal inflammation in patients with ulcerative colitis (UC). While the mechanism of QCS appears to be related to the regulation of CD4+T cell subset responses, direct evidence demonstrating that QCS inhibits Th1 and Th17 cell activation in UC (particularly based on human data) remains lacking. Additionally, the precise mechanisms through which QCS affects these cells have yet to be fully elucidated. Aim of studyThis study aimed to investigate the effects of QCS on Th1 and Th17 cell responses in UC and to explore the underlying mechanisms. Materials and methodsTwenty-eight patients with mild-to-moderate UC were recruited and treated with QCS for 12 weeks. Symptoms were assessed every two weeks, with sigmoidoscopies performed at baseline and at week 12. Intestinal mucosal biopsies and peripheral blood (PB) were collected at these time points. At the end of the trial, patients were categorized into responder and non-responder groups based on a modified Mayo disease activity index score. Healthy controls (HCs) were defined as subjects without IBD or colorectal carcinoma but with colon polyps. The frequencies of IFN-γ+CD4+T cells and IL-17A+CD4+T cells in PB and colonic mucosa were measured using flow cytometry. The expression levels and localization of T-bet, RORγT, IFN-γ, TNF-α, and IL-17A were determined via immunofluorescence, and JNK signaling activation was assessed through immunoblotting and immunohistochemistry. All parameters were compared across the three groups. ResultsAt week 12, responders showed a significant reduction in colonic mucosal inflammation compared to baseline, accompanied by decreased frequencies of IFN-γ+CD4+T and IL-17A+CD4+ T cells in both PB and the colonic epithelial layer. Notably, Th1 and Th17 cell activity around intestinal epithelial cells (IECs) was nearly undetectable, as evidenced by the diminished expression of T-bet, RORγT, IFN-γ, TNF-α, and IL-17A. Additionally, JNK phosphorylation in these cells was significantly reduced. In contrast, non-responders exhibited no meaningful improvement; colonic pathology remained unchanged, and elevated levels of IFN-γ+CD4+T and IL-17A+CD 4+T cells persisted in both the PB and colonic epithelial layer. The presence of Th1 and Th17 cells and their associated cytokines around IECs remained substantial, and there was no significant change in JNK activation. ConclusionQCS attenuates mucosal inflammation in UC patients by inhibiting the differentiation and effector functions of Th1 and Th17 cells, primarily through the regulation of the JNK signaling pathway.

First real-world study on the effectiveness and tolerability of rimegepant for acute migraine therapy in Chinese patients

BackgroundRimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is indicated for acute and preventive migraine treatment in the United States and other countries. However, there is a lack of prospective real-world evidence for the use of rimegepant in Chinese migraine patients.MethodsThis was a single-arm, prospective, real-world study. While taking rimegepant to treat migraine attacks as needed, eligible participants were asked to record their pain intensity, functional ability, and accompanying symptoms for a single attack at predose and 0.5, 1, 2, 24, and 48 h postdose via a digital platform. Adverse events (AEs) during the rimegepant treatment period were recorded and analysed. The percentages of participants who experienced moderate to severe pain at predose and 0.5, 1, 2, 24, and 48 h postdose were assessed. Additionally, the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose were analysed. In addition, the total cohort (full population, FP) was stratified into a prior nonresponder (PNR) group to observe the effectiveness and safety of rimegepant for relatively refractory migraine and a rimegepant and eptinezumab (RE) group to observe the effectiveness and safety of the combination of these drugs.ResultsBy November 24th, 2023, 133 participants (FP, n = 133; PNR group, n = 40; RE group, n = 28) were enrolled, and 99 participants (FP, n = 99; PNR group, n = 30; RE group, n = 23) were included in the analysis. Rimegepant was effective in treating migraine in the FP and both subgroups, with a significant decreasing trend in the percentages of participants experiencing moderate to severe pain postdose (p < 0.05) and a marked increase in the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose compared with predose. AEs were reported by 6% of participants in the FP, and all AEs were mild.ConclusionsIn the real world, rimegepant is effective in the acute treatment of migraine patients in China. The low incidence rate of AEs highlighted the favourable tolerability profile of rimegepant.Trial registrationClinicaltrials.gov NCT05709106. Retrospectively registered on 2023-02-01.Graphical

Increased levels of Escherichia-Shigella and Klebsiella in the gut contribute to the responsivity of placebo analgesia

Placebo analgesia is observed in both humans and animals. Given the complexity of placebo analgesia involving a variety of neurobiological, psychological, and psychosocial processes, further investigation into its underlying mechanisms is essential. Gut microbiota has been implicated in the responsivity of placebo analgesia, but its precise role remains unknown and warrants further investigations. Here, we conducted a conditioning training model with chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in mice, associating parecoxib with different cues. Hierarchical clustering analysis of placebo analgesia behaviors was employed to classify mice into responders and non-responders phenotypes. Approximately 40% of CFA mice undergoing conditioning training exhibited placebo analgesia. Notably, placebo analgesia responders displayed reduced anxiety-like behaviors. 16S rRNA results revealed a distinct composition of gut microbiota composition among the control, placebo analgesia non-responders and responders groups. Notably, levels of Escherichia Shigella and Klebsiella in the gut were increased considerably in the placebo analgesia responders as compared to both control and non-responders groups. In conclusion, placebo analgesia responders demonstrated marked analgesia, reduced anxiety-like behaviors, and increased levels of Escherichia-Shigella and Klebsiella, implying a potential linkage between gut microbiota and placebo analgesia.

Perturbational complexity index in assessing responsiveness to rTMS treatment in patients with disorders of consciousness: a cross-over randomized controlled trial study

BackgroundDisorders of Consciousness (DoC) caused by severe brain injuries represent a challenging clinical entity, which is easy to misdiagnosis and lacks effective treatment options. Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive neuroelectric stimulation method that shows promise in improving consciousness for DoC, especially in minimally conscious state (MCS). However, there is little evidence of its effectiveness, especially in RCT studies.MethodsTwenty MCS patients participated in a double-blind, randomized, crossover, sham-controlled clinical study to evaluate the safety and efficacy of rTMS for MCS. Subjects were randomized into two groups: one group received rTMS-active for 10 consecutive days (n = 10), and the other group received rTMS-sham for 10 consecutive days (n = 10). After a 10-day washout period, the two groups were crossed over and received the opposite treatment. the rTMS protocol consisted of 2,000 pulses per day in the left dorsolateral prefrontal cortex (L-DLPFC), sent at 10 Hz. The stimulation intensity was 90% of the resting motor threshold. Coma Recovery Scale Revised (CRS-R), the main evaluation index, was evaluated before and after each phase in a double-blind manner. Meanwhile RS-EEG and TMS-EEG data were acquired and relative alpha power (RAP), and perturbational complexity index based on state transitions (PCIst) were caculated.ResultsOne-way ANOVA revealed significantly higher scores in rTMS-active treatment compared to rTMS-sham across various measures, including CRS-R total score, RAP, PCIst (all P < 0.05). Among the 20 MCS patients, 7 (35%) were identified as responders following rTMS treatment. Compared to rTMS-sham, responder scores for CRS-R, RAP, and PCIst (all P < 0.05) were significantly elevated after rTMS-active treatment. Conversely, there was no significant difference observed in non-responders. Furthermore, post-hoc analysis revealed that baseline PCIst was significantly higher in responders than non-responders. Upon a 6-month follow-up, CRS-R scores significantly increased in all 20 patients (P = 0.026). However, the responder group exhibited a more favorable prognosis compared to the non-responder group (P = 0.031).ConclusionsApplying 10 Hz rTMS to L-DLPFC significantly increased consciousness level in MCS patients. PCIst is a neurophysiological index that has the potential to evaluate and predict therapeutic efficacy.Trial registrationwww.ClinicalTrials.gov, identifier: NCT05187000.

Systematic analysis of serum peptidase inhibitor 3 in psoriasis diagnosis and treatment.

Psoriasis is a chronic inflammatory skin disease. To date, there are no serum biomarkers for psoriasis that have been validated to diagnose or treat psoriasis. Peptidase inhibitor 3 (PI3) levels in serum were measured using chemiluminescence immunoassay (CLIA) in two independent cohorts including healthy controls (HC) and patients diagnosed with chronic urticaria (CU), chronic eczema (CE), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriatic arthritis (PsA), or psoriasis vulgaris (PV). Receiver operating characteristic (ROC) curve analysis determined the diagnostic performance of PI3 in patients with psoriasis. The correlation between PI3 levels and the Psoriasis Area Severity Index (PASI) score was analyzed using the Spearman correlation method. Additionally, the study evaluated PI3 expression and treatment response of PV patients 12weeks before and after topical treatment with calcipotriol betamethasone and calcipotriol ointment (T#1) or topical therapy plus PSORI-CM01 granules (T#2). In cohort #1, PI3 levels effectively discriminate PV patients from HC and CU patients, with AUCs of 0.909 and 0.840, respectively. In cohort #2, AUCs for detecting PV patients among HC, CU, CE, SLE, and RA patients were 0.940, 0.926, 0.802, 0.989, and 0.951, respectively. For PsA patients, AUCs were 0.989, 0.986, 0.910, 1.000, and 0.984 compared to HC, CU, CE, SLE, and RA patients, respectively. In both cohorts, PI3 levels correlated significantly with PASI scores in PV patients (cohort #1, r = 0.433; cohort #2, r = 0.634) and PsA patients (cohort #2, r = 0.718). Moreover, univariate logistic regression analyses revealed that PV patients with higher PI3 expression had a significantly higher risk of treatment resistance, with an odds ratio of 3.45 [95% confidence interval (CI) 1.54, 7.74, p = 0.003]. Finally, PI3 levels decreased nearly 35-fold more in the responder than in the non-responder group before and after treatment. Serological PI3 is a reliable biomarker for PV diagnosis and may have the potential to predict and monitor the progression of PV before and after treatment. Key Points • This study validated PI3's diagnostic performance in two independent psoriasis cohorts using CLIA. • PI3 expression is significantly correlated with the psoriasis severity and with patients who benefited from the treatments. • Serological PI3 is a reliable biomarker for psoriasis diagnosis and may have the potential to monitor the psoriasis progression with and without treatments.