Disease-specific Characteristics Research Articles

Biomarkers in bronchiectasis.

Bronchiectasis is a heterogeneous disease with multiple aetiologies and diverse clinical features. There is a general consensus that optimal treatment requires precision medicine approaches focused on specific treatable disease characteristics, known as treatable traits. Identifying subtypes of conditions with distinct underlying biology (endotypes) depends on the identification of biomarkers that are associated with disease features, prognosis or treatment response and which can be applied in clinical practice. Bronchiectasis is a disease characterised by inflammation, infection, structural lung damage and impaired mucociliary clearance. Increasingly there are available methods to measure each of these components of the disease, revealing heterogeneous inflammatory profiles, microbiota, radiology and mucus and epithelial biology in patients with bronchiectasis. Using emerging biomarkers and omics technologies to guide treatment in bronchiectasis is a promising field of research. Here we review the most recent data on biomarkers in bronchiectasis.

Enrichment of glioblastoma tumor microenvironment in a GZMK+ T cell population.

2065 Background: Glioblastoma (GBM) bears a survival estimate below 10% at 5 years, despite standard chemoradiation treatment. Trials evaluating immune checkpoint blockade (ICB) in gliomas have been disappointing so far, dealing with the unique immunosuppressive tumor microenvironment (TME) of the brain. Nevertheless, we have clinical evidence of ICB efficacy for brain metastases (BrM) of immunosensitive tumors. Even if both GBMs and BrM share the same organ-specific microenvironment, it is clear that disease-specific immune characteristics instruct differential response to ICB. Methods: By using advanced deep learning algorithms to combine public and in-house-generated single-cell RNA sequencing profiles, we analyzed immune infiltrate characteristics of 602949 CD45+ cells from 76 GBM, 30 BrM from different types of extracranial tumors (13 NSCLC, 12 melanoma, 2 ovarian, 1 breast, 1 colorectal and 1 renal carcinoma) and 3 normal brain samples. The analysis was restricted to newly diagnosed GBM, excluding recurrent and pre-treated cases. CD8+ cells underwent segregation into clusters based on log2 normalized expression levels of CD3E and CD8A (with expression values greater than 0). The data integration utilized DESC, a deep learning model founded on autoencoders, and subsequent examination was conducted within the Scanpy framework. Cluster analysis was executed employing the Leiden algorithm. Differentially expressed genes (DEGs) were pinpointed across clusters using the Wilcoxon test, with False Discovery Rate (FDR) correction carried out through the Benjamini-Hochberg procedure. Results: From CD45+CD3+ cells, we isolated CD8+ T cells and identified 7 informative CD8+ T cells clusters. Based on DEGs, we could appreciate T cells clusters that were also recapitulated in other extracranial malignancies. The most abundant subset was composed of GZMK+ effector T cells (Cluster 0: GZMK, GZMM, CD44, KLRG1, IL7R, GZMA, CXCR3), followed by putative tumor-specific tissue-resident memory cells (Cluster 1: GZMB, LAG3, CTLA4, TIGIT, CXCL13, ITGAE, ENTPD1, PDCD1, CD27, HLA-DRB1), stem-cell memory-like T cells (Cluster 3: IL7R, CCR7, JUNB, KLF2, TCF7) and a less represented cluster characterized by high expression of genes belonging to the HSP family (Cluster 4: HSPA1, HSPH1, HSPE1, HSPD1, IFN). Interestingly, while the majority of the identified clusters was equally represented in the 3 different tissues, the GZMK+ effector T cells cluster (Cluster 0) was found to be more represented in GBM compared to BrM and normal brain tissue. Conclusions: A GZMK+ effector T cells subpopulation, specifically enriched in GBM, has been poorly characterized in its function and spatial localization. Our data highlight the importance of studying the composition of the immune infiltrate in GBM with multi-omics approaches in order to uncover deep mechanisms of resistance to ICB and eventually provide hints on potential therapeutic targets.

Antegrade balloon dilatation of the duodenal papilla during laparoscopic cholecystectomy versus endoscopic retrograde cholangiography in patients with acute choledocholithiasis: a case control matched study

IntroductionIn acute obstructive common bile duct (CBD) stones endoscopic retrograde cholangiography for CBD stone removal before cholecystectomy (ChE) (‘ERC-first’) is the gold standard of treatment. Intraoperative antegrade balloon dilatation of the duodenal papilla during ChE with flushing of CBD stones to the duodenum (‘ABD-during-ChE’) may be an alternative ‘one-stop-shop’ treatment option. However, a comparison of outcomes of the ‘ABD-during-ChE’ technique and the’ERC-first’ approach has never been performed.MethodsRetrospective case control matched study of patients suffering from obstructive CBD stones (< 8 mm) without severe pancreatitis or cholangitis that underwent the traditional ‘ERC-first’ approach versus the ‘ABD-during-ChE’ technique. Primary endpoint was the overall Comprehensive Complication Index (CCI®) from diagnosis to complete CBD stone removal and performed ChE.ResultsA total of 70 patients were included (35 patients each in the ‘ERC first’- and ‘ABD-during-ChE’-group). There were no statistical significant differences in terms of demographics and disease specific characteristics between the two study groups. However, there was a not significant difference towards an increased overall CCI® in the ‘ERC-first’ group versus the ‘ABD-during-ChE’ group (14.4 ± 15.4 versus 9.8 ± 11.1, p = 0.225). Of note, six major complications (Clavien-Dindo classification ≥ IIIa) occurred in the ‘ERC-first’ group versus two in the ‘ABD-during-ChE’ group (17% versus 6%, p = 0.136). In addition, significantly more interventions and a longer overall time from diagnosis to complete clearance of bile ducts and performed ChE was found, when comparing the ‘ERC-first’ group and the ‘ABD-during-ChE’ group (3.7 ± 0.8 versus 1.1 ± 0.4, p < 0.001; 160.5 ± 228.6 days versus 12.0 ± 18.0 days, p < 0.001).ConclusionIn patients suffering from acute obstructive CBD stones smaller than 8 mm, compared to the ‘ERC-first’ approach, the ‘ABD-during-ChE’ technique resulted in significantly less interventions and reduced overall treatment time from diagnosis to complete clearance of bile ducts and performed ChE. This comes together with a strong trend of less intervention related complications in the ‘ABD-during-ChE’ group.

Extravertebral low back pain: a scoping review

BackgroundLow back pain (LBP) is one of the most common reasons for consultation in general practice. Currently, LBP is categorised into specific and non-specific causes. However, extravertebral causes, such as abdominal aortic aneurysm or pancreatitis, are not being considered.MethodsA systematic literature search was performed across MEDLINE, Embase, and the Cochrane library, complemented by a handsearch. Studies conducted between 1 January 2001 and 31 December 2020, where LBP was the main symptom, were included.ResultsThe literature search identified 6040 studies, from which duplicates were removed, leaving 4105 studies for title and abstract screening. Subsequently, 265 publications were selected for inclusion, with an additional 197 publications identified through the handsearch. The majority of the studies were case reports and case series, predominantly originating from specialised care settings. A clear distinction between vertebral or rare causes of LBP was not always possible. A range of diseases were identified as potential extravertebral causes of LBP, encompassing gynaecological, urological, vascular, systemic, and gastrointestinal diseases. Notably, guidelines exhibited inconsistencies in addressing extravertebral causes.DiscussionPrior to this review, there has been no systematic investigation into extravertebral causes of LBP. Although these causes are rare, the absence of robust and reliable epidemiological data hinders a comprehensive understanding, as well as the lack of standardised protocols, which contributes to a lack of accurate description of indicative symptoms. While there are certain disease-specific characteristics, such as non-mechanical or cyclical LBP, and atypical accompanying symptoms like fever, abdominal pain, or leg swelling, that may suggest extravertebral causes, it is important to recognise that these features are not universally present in every patient.ConclusionThe differential diagnosis of extravertebral LBP is extensive with relatively low prevalence rates dependent on the clinical setting. Clinicians should maintain a high index of suspicion for extravertebral aetiologies, especially in patients presenting with atypical accompanying symptoms.

E064 Identifying patients with pulmonary disease in a mixed connective tissue disease cohort

Abstract Background/Aims Respiratory involvement specifically interstitial lung disease (ILD) is a recognised complication of mixed connective tissue disease (MCTD), with a reported prevalence ranging from 40-78%. Surveillance for ILD in other connective tissue diseases such as systemic sclerosis is established clinical practice. Using guidelines recently published by the American College of Rheumatology (2023) we undertook a service evaluation to evaluate current practice for patients in our centre. Methods Electronic case notes were searched using key terms ‘mixed connective tissue disease’, ‘MCTD’ and ‘anti-RNP positive’ to identify patients seen between January 2021-2023. Patients identified were then compared against three MCTD classification criteria (Sharp et al, Alarcon-Sergovia et al and Kasukawa et al). To ensure a robust diagnosis, only those meeting the classification threshold on two or more criterion were included. Results 56 patients were identified however only 44 met two classification criteria and were subsequently included. Mean age was 47.3 years with 40/44 (91%) female. 28/44 (64%) had previous CT chest imaging. In the remaining 16/44 (46%), none had reported symptoms suggestive of ILD in preceding two years. 34/44 (77%) patients had previous pulmonary function testing. In those without, 1/10 had recently reported dyspnoea. 9/44 (20%) had identified MCTD-ILD of which 7/9 (30%) were on immunosuppression, 3/9 for predominant lung disease. Of those with ILD, 7/9 (78%) had had PFTs in the last year. No patients with ILD had undergone assessment for ambulatory desaturation. 7/9 (78%) patients with ILD had received specialist respiratory input, 1 had been seen in a general respiratory clinic, and in 1 case it was unknown. All patients with identified ILD who met established criteria for treatment were receiving immunosuppression. No patient met criteria for progressive fibrotic ILD. No specific disease characteristics (utilising clinical criterion from classification criteria) were demonstrated to have association with ILD (statistical analysis performed using the chi-squared test). No association was demonstrated in patients displaying anti- Ro52 and Ro60 positivity and ILD. Conclusion This evaluation has highlighted that patients with identified MCTD-ILD are being treated and monitored well. However further surveillance for pulmonary involvement both at baseline and then subsequent interval pulmonary function testing needs to improve. This may account for the lower prevalence of ILD in our MCTD cohort in comparison to the literature. Surveillance of pulmonary involvement should take place regardless of clinical disease manifestations displayed. We need to establish feasibility for ambulatory desaturation testing in those with ILD within our outpatient setting. With increasing immunomodulatory treatment available identifying patients with MCTD-ILD is imperative. Disclosure R. Benson: None. K. Mashida: None. M. Ahmad: None. L.G. Spencer: None. Z. McLaren: None. T. Barnes: None.

Developing MLP based prediction system for anticancer drug response using hybrid features of genomics and cheminformatics

Traditional cancer treatment methods have become less effective due to the increasing diversity of cancer types. To address this, precision medicine has gained support within the medical community. This approach tailors treatment to individual patients based on their specific disease characteristics. However, a major challenge lies in accurately predicting how a patient will respond to a specialized drug. Numerous machine learning-based predictive systems have been developed to address this challenge. These systems utilize genomic signatures and the chemical structure of drugs to predict drug activity. In this paper, we introduce a Multi-Layer Perceptron (MLP) based system for predicting the response of anticancer drugs. Our system utilizes hybrid features derived from both genetic expression and the chemical structure of drugs. It is developed using the well-known GDSC dataset (Genomics of Drug Sensitivity in Cancer). Our system achieved a lower Root Mean Square Error (RMSE) value of 0.889, in contrast to the RMSE value of 0.983 obtained by the current state-of-the-art (SOTA) system, SwNet. This indicates superior predictive accuracy. The findings suggest that our proposed research holds promise for the development of targeted drugs for anticancer treatments.

Development of diabetes complications within coordinated and structured primary healthcare (2011-2020): a 10 year retrospective cohort study of over 200,000 patients in Germany.

Diabetes is a growing, costly, and potentially preventable public health issue. In 2004, Germany introduced the GP-centred healthcare programme to strengthen primary care. To assess the hazards of the most common diabetes-related complications in patients enrolled in GP-centred healthcare in comparison to usual primary care. A retrospective cohort study based on German claims data (4 million members) from 2011 to 2020. 217,964 patients with diabetes were monitored from 2011-2020. Endpoints were blindness, amputation, myocardial infarction, stroke, coronary heart disease, dialysis, hypoglycaemia and all-case-mortality. Cox proportional-hazards regression models were used for multivariable analysis and adjusted for socio-demographic, practice- and disease-specific characteristics. Compared to usual care (n=98,609 patients), GP-centred healthcare (n=119,355 patients) showed a relative risk reduction of blindness of 12 %, and amputation of 20% over 10 years. The estimated impact of GP-centred healthcare on myocardial infarction, stroke, coronary artery disease, dialysis and mortality is significantly favourable in comparison to usual care. However, the proportional risk of hypoglycaemia (+1.2 %) in the interventional group is higher than in the usual care. Enrolment in GP-centred healthcare appears to result in a consistent reduction of the relative risk of diabetes-related complications over 10 years. The significant difference in contrast to usual care may be explained by robust, structured primary care provision, including the diabetes disease management programme and improved coordination and networking of care within primary and secondary care.

Strictureplasty may lead to increased preference in the surgical management of Crohn's disease: a case-matched study.

Resection and strictureplasty are the two surgical modalities used in the management of Crohn's disease (CD). The objective of this study was to compare morbidity and clinical recurrence between patients who underwent strictureplasty and patients who underwent resection. Patients with CD who underwent strictureplasty between January 2012 and December 2022 were enrolled. The patients were well matched with patients who underwent resection without strictureplasty. Patient- and disease-specific characteristics, postoperative morbidity, and clinical recurrence were also analyzed. A total of 118 patients who underwent a total of 192 strictureplasties were well matched to 118 patients who underwent resection. The strictureplasty group exhibited significantly less blood loss (30ml versus 50ml, p < 0.001) and stoma creation (2.5% versus 16.9%, p < 0.001). No significant difference was found regarding postoperative complications or length of postoperative stay. At the end of the follow-up, the overall rate of clinical recurrence was 39.4%, and no difference was observed between the two groups. Postoperative prophylactic use of biologics (odds ratio= 0.2, p < 0.001) was the only protective factor against recurrence. Strictureplasty does not increase the risk of complications or recurrence compared with resection. It represents a viable alternative to resection in selected patients, and as such, it should have a broader scope of indications and greater acceptance among surgeons.

Efficacy of transcatheter arterial embolization in treating nonvariceal gastric remnant bleeding: a retrospective 5-year study

BackgroundGastric remnant bleeding is a special case of upper gastrointestinal bleeding with certain specific disease characteristics, and some matters of transcatheter arterial embolization (TAE) for hemostasis need attention. In this study, we aimed to explore the clinical use of TAE in patients with nonvariceal gastric remnant bleeding and identify the factors influencing the clinical efficacy of these interventions.MethodsData were retrospectively analyzed from 42 patients for whom angiography and embolization were performed but could not be treated endoscopically or had failed endoscopic management in our department between January 2018 and January 2023 due to nonvariceal gastric remnant bleeding. We investigated the relationship between the incidence of re-bleeding and the following variables: sex, age, pre-embolization gastroscopy/contrast-enhanced computer tomography, embolization method, aortography performance, use of endoscopic titanium clips, and the presence of collateral gastric-supplying arteries.ResultsForty-two patients underwent 47 interventional embolizations. Of these, 16 were positive for angiographic findings, and 26 were negative. Based on arteriography results, different embolic agents were selected, and the technical success rate was 100%. The incidence of postoperative re-bleeding was 19.1% (9/47), and the overall clinical success rate was 81.0% (34/42). Logistic regression analysis of the relationship between the incidence of early re-bleeding following embolization and the proportion of collateral gastric supply arteries revealed an odds ratio of 10.000 (p = 0.014).ConclusionsUtilizing TAE for nonvariceal gastric remnant bleeding is safe and effective. The omission of collateral gastric-supplying arteries can lead to early re-bleeding following an intervention.

Comparison of patient-reported outcomes of physical activity and accelerometry in people with multiple sclerosis and ambulatory impairment: A cross-sectional study

BackgroundAccelerometers and patient-reported outcomes (PRO) are used to assess physical activity (PA) in people with multiple sclerosis (pwMS). So far it is unknown, however, whether these assessments represent mobility limitations in pwMS with mild and moderate to severe disability alike. The primary aim of the study was to assess the correlation between accelerometry and International Physical Activity Questionnaire (IPAQ) scores in pwMS with different degrees of ambulatory impairment. Taken its frequent use into account, the Godin Leisure Time Exercise Questionnaire (GLTEQ) was investigated as additional PRO. MethodsIn a prospective cohort of pwMS, correlational analyses were performed between the number of daily steps, time spent in light, moderate to vigorous PA (MVPA) and time spent sitting as assessed using accelerometry (ActiGraph®-GT3X), and the respective IPAQ and GLTEQ scores. Additionally, associations of PA with disease-specific characteristics, aerobic capacity (VO2peak), walking assessments (Timed 25-Foot Walk, T25FW; 2-Minute Walk Test, 2MWT) and walking perception (Multiple Sclerosis Walking Scale-12; MSWS-12) were explored. Patient subgroups with mild (Expanded Disability Status Scale; EDSS score <4.0) and moderate to severe disability (EDSS ≥4.0) were analysed for the impact of ambulatory impairment on PA. Multiple linear regression was used to determine predictors of PA. ResultsA total of 56 pwMS completed the study, with a mean (standard deviation, SD) age of 48.4 (10.3) years, disease duration of 14.8 (9.6) years and median (interquartile range) EDSS score of 3.5 (2.0 – 4.4). Moderate to weak correlations were found between daily step count and IPAQ total metabolic equivalent (MET) minutes/week (p < 0.001; r = 0.506), MVPA MET-minutes/week (p < 0.01; r = 0.479) and walking MET-minutes/week (p < 0.05; r = 0.372) in the total cohort. Time spent sitting was inversely correlated with total MET-minutes/week and MVPA MET-minutes/week (p < 0.05; r = -0.358 and r = -0.365). Subgroup analysis revealed, that daily step count was significantly correlated with total MET-minutes/week, MVPA MET-minutes/week and walking MET-minutes/week (p < 0.01, r = 0.569; p < 0.01, r = 0.531 and p < 0.05, r = 0.480, respectively) in the “mild disability” subgroup only, whereas time spent sitting was inversely correlated with total MET-minutes/week (p < 0.05; r = -0.582) in the “moderate to severe disability” subgroup. There was no association between objectively assessed PA and GLTEQ scores in any group. In the total cohort, moderate to weak correlations were found between daily step count and walking assessments (T25FW: p < 0.01, ρ = -0.508; 2MWT: p < 0.01, ρ=0.463) and MSWS-12 (p < 0.001; ρ = -0.609). Moderate to weak correlations were also observed between VO2peak and walking assessments (T25FW: p < 0.01; ρ = -0.516; 2MWT: p < 0.01, ρ=0.480). Multiple linear regression analysis identified disability and VO2peak as predictors of PA (p = 0.045; β=0.25 and p < 0.001; β=0.49). ConclusionSignificant associations of objective PA measurements using accelerometry with IPAQ were found only in pwMS with “mild disability”. In pwMS with “moderate to severe disability”, IPAQ did not reflect the objectively assessed amount of PA. In our cohort, GLTEQ showed no association with objectively assessed PA. Thus, an MS-specific self-reported questionnaire for assessing PA is warranted.

Postural Control Characteristics in Alzheimer's Disease, Dementia With Lewy Bodies, and Vascular Dementia.

Dementia often results in postural control impairment, which could signify central nervous system dysfunction. However, no studies have compared postural control characteristics among various types of dementia. This study aimed to compare static postural control in patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular dementia (VaD). Cross-sectional relationship between the clinical diagnoses (AD, DLB, VaD, or normal cognition [NC]) of outpatients at a memory clinic and their upright postural control characteristics were examined. In the postural control test, participants were instructed to maintain a static upright standing on a stabilometer for 60 seconds under the eyes-open and eyes-closed conditions. Forty postural control parameters, including distance, position, and velocity in the anterior-posterior and medio-lateral directions, derived from the trajectory of the center of mass sway, were calculated. The characteristics of each type of dementia were compared to those of NC, and the differences among the 3 types of dementia were evaluated using linear regression models. The study included 1789 participants (1206 with AD, 111 with DLB, 49 with VaD, and 423 with NC). Patients with AD exhibited distinct postural control characteristics, particularly in some distance and velocity parameters, only in the eyes-closed condition. Those with DLB exhibited features in the mean position in the anterior-posterior direction. In patients with VaD, significant differences were observed in most parameters, except the power spectrum. Patients with AD, DLB, and VaD display disease-specific postural control characteristics when compared to cognitively normal individuals.

Nivolumab monotherapy or combination with ipilimumab with or without cobimetinib in previously treated patients with pancreatic adenocarcinoma (CheckMate 032)

BackgroundPancreatic cancer is one of the deadliest cancer types and represents a major unmet medical need. CheckMate 032 investigated safety and efficacy of nivolumab monotherapy and nivolumab plus ipilimumab with/without...

Race and Odds of Surgery Offer in Small Bowel and Pancreas Neuroendocrine Neoplasms.

Despite existing society guidelines, management of pancreatic (PanNEN) and small bowel (SBNEN) neuroendocrine neoplasms remains inconsistent. The purpose of this study was to identify patient- and/or disease-specific characteristics associated with increased odds of being offered surgery for PanNEN and SBNEN. The Surveillance, Epidemiology, and End Results (SEER) Program database and the National Cancer Database (NCDB) were queried for patients with PanNEN/SBNEN. Demographic and pathologic data were compared between patients who were offered surgery and those who were not. Multivariate logistic regression was performed to identify factors independently associated with being offered surgery. In SEER, there were 3641 patients with PanNEN (54.7% were offered surgery) and 5720 with SBNEN (86.0% were offered surgery). On multivariate analysis of SEER, non-white race was associated with decreased odds of surgery offer for SBNEN [odds ratio (OR) 0.58, p < 0.001], but not PanNEN (p = 0.187). In NCDB, there were 28,483 patients with PanNEN (57.5% were offered surgery) and 42,675 with SBNEN (86.9% were offered surgery). On multivariate analysis of NCDB, non-white race was also associated with decreased odds of surgery offer for SBNEN (OR 0.61, p < 0.001) but not PanNEN (p = 0.414). This study's findings suggest that, in addition to previously reported disparities in surgical resection and surgery refusal rates, racial/ethnic disparities also exist earlier in the course of treatment, with non-white patients being less likely to be offered surgery for SBNEN but not for PanNEN; this is potentially due to discrepancies in rates of referral to academic centers for pancreas and small bowel malignancies.

Decline in Incidence of Extra-Articular Manifestations of Rheumatoid Arthritis: A Population-Based Cohort Study.

The focus of this study was to assess changes in the cumulative incidence of extra-articular manifestations of rheumatoid arthritis (ExRAs) and associated mortality risk. This study evaluated trends in occurrence of ExRAs using a population-based inception cohort that included all adult patients with incident rheumatoid arthritis (RA) from 1985 through 2014 meeting the 1987 American College of Rheumatology criteria. Patients were divided into two cohorts based on the incidence date of RA, 1985 to 1999 and 2000 to 2014. The occurrence of ExRAs was determined by manual chart review, and the 10-year cumulative incidence was estimated for each ExRA in both cohorts. Cox proportional hazard models were used to determine associations between specific demographic and RA disease characteristics and ExRAs and between ExRAs and mortality. There were 907 patients included, 296 in the 1985 to 1999 cohort and 611 in the 2000 to 2014 cohort. The 10-year cumulative incidence of any ExRA decreased significantly between the earlier and later cohorts (45.1% vs 31.6%, P < 0.001). This was largely driven by significant declines in subcutaneous rheumatoid nodules (30.9% vs 15.8%, P < 0.001) and nonsevere ExRAs (41.4% vs 28.8%, P = 0.001). Identified risk factors for the development of any ExRAs include rheumatoid factor positivity (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.43-2.86) and current smoking (HR 1.61, 95% CI 1.10-2.34). Mortality was increased in patients with either nonsevere (HR 1.83, 95% CI 1.18-2.85) or severe ExRAs (HR 3.05, 95% CI 1.44-6.49). The incidence of ExRAs has decreased over time. Mortality remains increased in patients with ExRAs.

Developing and externally validating multinomial prediction models for methotrexate treatment outcomes in patients with rheumatoid arthritis: results from an international collaboration

ObjectivesIn rheumatology, there is a clinical need to identify patients at high risk (>50%) of not responding to the first-line therapy methotrexate (MTX) due to lack of disease control or discontinuation due to adverse events (AEs). Despite this need, previous prediction models in this context are at high risk of bias and ignore AEs. Our objectives were to (i) develop a multinomial model for outcomes of low disease activity and discontinuing due to AEs 6 months after starting MTX, (ii) update prognosis 3-month following treatment initiation, and (iii) externally validate these models. Study Design and SettingA multinomial model for low disease activity (submodel 1) and discontinuing due to AEs (submodel 2) was developed using data from the UK Rheumatoid Arthritis Medication Study, updated using landmarking analysis, internally validated using bootstrapping, and externally validated in the Norwegian Disease-Modifying Antirheumatic Drug register. Performance was assessed using calibration (calibration-slope and calibration-in-the-large), and discrimination (concordance-statistic and polytomous discriminatory index). ResultsThe internally validated model showed good calibration in the development setting with a calibration-slope of 1.01 (0.87, 1.14) (submodel 1) and 0.83 (0.30, 1.34) (submodel 2), and moderate discrimination with a c-statistic of 0.72 (0.69, 0.74) and 0.53 (0.48, 0.59), respectively. Predictive performance decreased after external validation (calibration-slope 0.78 (0.64, 0.93) (submodel 1) and 0.86 (0.34, 1.38) (submodel 2)), which may be due to differences in disease-specific characteristics and outcome prevalence. ConclusionWe addressed previously identified methodological limitations of prediction models for outcomes of MTX therapy. The multinomial approach predicted outcomes of disease activity more accurately than AEs, which should be addressed in future work to aid implementation into clinical practice.

Shared and distinct abnormalities of brain magnetization transfer ratio in schizophrenia and major depressive disorder: a comparative voxel-based meta-analysis.

Patients with schizophrenia (SCZ) and major depressive disorder (MDD) share significant clinical overlap, although it remains unknown to what extent this overlap reflects shared neural profiles. To identify the shared and specific abnormalities in SCZ and MDD, we performed a whole-brain voxel-based meta-analysis using magnetization transfer imaging, a technique that characterizes the macromolecular structural integrity of brain tissue in terms of the magnetization transfer ratio (MTR). A systematic search based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in PubMed, EMBASE, International Scientific Index (ISI) Web of Science, and MEDLINE for relevant studies up to March 2022. Two researchers independently screened the articles. Rigorous scrutiny and data extraction were performed for the studies that met the inclusion criteria. Voxel-wise meta-analyses were conducted using anisotropic effect size-signed differential mapping with a unified template. Meta-regression was used to explore the potential effects of demographic and clinical characteristics. A total of 15 studies with 17 datasets describing 365 SCZ patients, 224 MDD patients, and 550 healthy controls (HCs) were identified. The conjunction analysis showed that both disorders shared higher MTR than HC in the left cerebellum ( P =0.0006) and left fusiform gyrus ( P =0.0004). Additionally, SCZ patients showed disorder-specific lower MTR in the anterior cingulate/paracingulate gyrus, right superior temporal gyrus, and right superior frontal gyrus, and higher MTR in the left thalamus, precuneus/cuneus, posterior cingulate gyrus, and paracentral lobule; and MDD patients showed higher MTR in the left middle occipital region. Meta-regression showed no statistical significance in either group. The results revealed a structural neural basis shared between SCZ and MDD patients, emphasizing the importance of shared neural substrates across psychopathology. Meanwhile, distinct disease-specific characteristics could have implications for future differential diagnosis and targeted treatment.

Propensity Score Matching Comparing Asciminib Versus Ponatinib in Chronic Myeloid Leukemia Patients Who Failed Prior Tyrosine Kinase Inhibitor Therapy

Background ASCEMBL trial has demonstrated superior efficacy of Asciminib (ASC) over Bosutinib in terms of molecular response, and event-free survival. Furthermore, ASC could reduce discontinuation rates due to lower occurrences of adverse events (7% vs 25%). However, it remains to be established how ASC would compare to Ponatinib (PON), which is frequently used in chronic myeloid leukemia (CML) practice for patients (pts) failing multiple lines of tyrosine kinase inhibitor (TKI) therapy. No prospective study has been performed or is ongoing comparing ASC vs PON, but alternatively, observational data can provide valuable insight on this topic. The propensity score is the probability of therapy assignment conditional on observed baseline characteristics. We performed a propensity score matching (PSM) analysis to balance the variables affecting the treatment choice among ASC vs PON therapy. The present study aimed to compare the therapeutic efficacy of ASC to PON in CML pts who failed prior TKIs concerning molecular response, failure-free survival (FFS), progression, and overall survival (OS). Patients and methods A total of 426 CML pts who had been treated with ASC or PON in 6 countries (Canada, Netherlands, Czech Republic, France, Argentine, and Italy) were included. In this preliminary report, data from 394 pts were analyzed. Primary endpoint was FFS at 1 year which was defined as the interval from TKI therapy start until treatment failure or death. Treatment outcomes were assessed for molecular response and long-term outcomes such as MR2 (BCR::ABL1 &amp;lt;1%IS or molecular response 2 log or deeper), MMR (BCR::ABL1 &amp;lt;0.1%IS or molecular response 3 log or deeper), MR4 (BCR::ABL1 &amp;lt;0.01%IS or molecular response 4 log or deeper), FFS, Progression, and OS. These parameters were evaluated in the overall population (n=394), resistant (n=254), or intolerant subgroups (n=126), T315I mutated (n=89) or non-T315I mutated subgroups (n=304), those having a past history of cardiovascular disease (CVD) (n=89) or not (n=304). For propensity score calculation, the following pre-treatment variables were selected using a binary logistic regression model: age, history of cardiovascular disease (CVD), disease phase, T315I mutation, and reason for failure to prior TKI line. 160 pts (i.e. 80 case-control pairs) were finally extracted through the PSM process within 0.2 of caliper difference. Results Significant differences were observed in various factors between ASC vs PON group, such as age (p&amp;lt;0.01), past history of CVD (p&amp;lt;0.01), previous TKI lines (p&amp;lt;0.01), presence of mutations (p=0.034), and reason for failure to prior TKI line (p&amp;lt;0.01). These differences ceased to exist when PSM was applied (Table 1). In the overall population, at 12 months, FFS was 46.7%, 95%CI [40.0-52.0%], MR2 62.6% [57.1-67.6%], MMR 44.7% [39.2-50.1%], MR4 28.6% [23.9-33.6%]), and OS 88.1% [84.1-91.1%]. In the overall population, PON group showed a lower FFS than ASC group (HR of PON 1.61, 95%CI [1.14-2.28], p=0.006), but, this difference was no significant when limited to the PSM selected pts. Figure 1 illustrates FFS in Asciminib vs Ponatinib-treated patients. In a subgroup of pts without T315I mutation, those on ASC showed higher FFS (HR of PON 1.82, [1.21-2.71], p=0.003), higher MR2 rate (HR of PON 0.69, [0.511-0.94], p=0.020), and higher MMR rate (HR of PON 0.677, [0.47-0.97], p=0.035). Additionally, in a subgroup of pts with a history of CVD those on ASC showed higher FFS (HR of PON 2.21, [1.19-4.10], p=0.011). Also, in pts in the chronic phase, ASC group showed higher FFS (HR of PON 1.77, [1.18-2.65], p=0.005), MR2 rate (HR of PON 0.73, [0.55-0.97], p=0.032), and MMR rate (HR of PON 0.71, [0.52-0.99], p=0.047). In the PSM balanced population, only MR2 rate was found to be significantly higher in favor of ASC (HR of PON 0.6, [0.39-0.93], p=0.022), while no significant differences were observed in all the other endpoints of interest. Conclusion From our current preliminary results, it can be established that ASC has at least equal efficacy to PON regarding FFS, MMR, MR4, progression, and OS which was confirmed in a PSM cohort. These findings contribute valuable insights to the understanding of ASC and PON treatments in pts with specific disease characteristics and may have implications for personalized therapy decisions in the absence of clinical trials comparing these drugs. Our aim is to expand our PSM cohort.

A new regional Rheumatic Heart Disease Registry: results of the first 2595 patients

Abstract Background Rheumatic Heart Disease (RHD) remains a major cause of morbidity and mortality in low- and middle-income countries. However, specific disease characteristics and progression varies in different regions. Purpose We here present preliminary results of a new regional RHD registry. Methods A total of 2595 consecutive patients with clinical and echocardiographic RHD were registered from March 2009 and February 2023, and their baseline clinical and echo characteristics, demographics, comorbidities, the pattern and severity of valvular involvement, intervention history and treatment practices were recorded. Follow-up ranged from 1 to 168 months (47±38.8) and was complete in 90.4% of the patients. Results The age of the patients ranged from 3-86 years (40.18±13.83). The majority was female (n=1765, 68%). At enrolment only 26 (1%) patients were on secondary penicillin prophylaxis. Symptoms were present in 73.8% (n=1916) of the patients (NYHA III: n=984, 37.9%). 2226 (85.8%) patients had moderate-to-severe multivalvular disease complicated by pulmonary hypertension (n=877, 33.8%), atrial fibrillation (AF) (n=750, 28.9%), cerebrovascular events (n=158, 6%), infective endocarditis (n=17, 0.66%) and thrombosis of valve prosthesis (n=14, 0.54%). Previous cardiac intervention was reported by 492 patients (19%). Regular 6 monthly follow-up at our centre for periods ranging from 1 to 168 months (47±38.8). During this period a total of 1309 (50.4%) patients underwent cardiac procedures. Balloon Mitral Valvuloplasty was performed in 289 patients (11.1%). Cerebrovascular events (n=92, 3.5%), LA thrombus (n=22, 0.85%), infective endocarditis (n=13, 0.5%) and thrombosis of valve prosthesis (n=19, 0.73%) occurred during follow-up. Patient mortality was 12.6% (n=328) during the study period (47±38.8 months). Penicillin prophylaxis rate was 63.3% (n=1742), however, only 15% of these patients followed the penicillin prophylaxis schedule. Conclusions In spite of continued cardiac care in this study, young patients with rheumatic heart disease have high morbidity and mortality. Further efforts to determine the exact causes involved and improve prognosis are warranted.

Factors Impacting Response to Olutasidenib in Patients with mIDH1 Acute Myeloid Leukemia

Introduction. Olutasidenib is an FDA-approved, targeted therapy for IDH1-mutated (mIDH1) AML. Among 147 patients with relapsed/refractory mIDH1 AML, 51 (35%) achieved a complete response (CR) or CR with partial hematologic recovery (CRh) after treatment with olutasidenib, with a duration of response of 25.9 months. We conducted sub-analyses to better understand which factors might be predictive of response to therapy. Methods. Patients were divided into groups based on achieving an overall response (CR, CRh, CRi, PR, MLFS) or having best response of stable disease or progression. Groups were compared to determine if there were baseline patient or disease characteristics that might predict attainment of an overall response to olutasidenib. The study was not powered to statistically evaluate subpopulations. Descriptive statistics are provided, and differences of 20% or more between groups were noted. Data cutoff date is June 2021. Results. As of data cutoff, 71 (48%) patients had achieved an overall response; the remaining 76 patients had stable disease (SD), clinical benefit (CB), disease progression (PD) or were not evaluated (due to short time on trial). Composite CR (CR, CRh, CRi) was achieved in 66/71 (93%) of overall responders, with PR and MLFS comprising only 3% of overall responders ( Table 1). With a median follow-up of 10.2 months (range 0.2-38.1), 20 responders were continuing treatment with ongoing responses at the time of data cutoff while 51 had discontinued; reasons for discontinuation were HSCT (n=14 all of whom had ongoing responses), disease progression (n=24), adverse event (n=8), physician decision (n=4) and protocol deviation (1). Responses to olutasidenib therapy were observed across a broad range of patient demographics and disease characteristics, most of which did not appear to impact the rate of response to olutasidenib ( Table 2). Bone marrow blast count at baseline correlated with response, with 63% of patients with baseline counts ≤40% achieving an overall response compared with 34% in those with baseline counts &amp;gt;40%. More patients with R132C (58%) and R132L/G/S (48%) mutations achieved an overall response compared to those with an R132H mutation (26%) However, a previous analysis showed that patients with the R132H mutation were more likely to have a FLT3 and/or NPM1 mutation, which are associated with a poor prognosis (de Botton S, et al, Blood 2021). Although fewer patients in the overall responder groups had FLT3 or NPM1 mutations compared with the non-responder group, 12/38 (32%) with NPM1 and 5/16 (31%) with FLT3 had an overall response. In addition, 2/5 (40%) patients with the TP53 co-mutation had an overall response to olutasidenib. While group outcomes for specific characteristics of disease may suggest a worse prognosis, individual patients treated with olutasidenib may achieve an overall response despite the impact of these negative factors. Two patients in this analysis had mIDH1-R132H mutations as well as FLT3 and NPM1 co-mutations and primary relapsed AML. One achieved a CRh and proceeded to transplant after a DOR of 15.5 months, and the other achieved a CRi lasting 1.3 months and then progressed. The baseline bone blast count was 53% in the first patient and 80% in the second. Two of the responders in this analysis had mIDH1-R132C and a TP53 co-mutation with refractory AML; one achieved a CR and proceeded to transplant after a DOR of 6 months, and the other had a PR and progressed after 3 months. The baseline bone blast count was 25% in the first patient and 65% in the second patient. Conclusions. This post-hoc analysis demonstrated that response to olutasidenib occurred across a wide variety of patient types and disease characteristics, including those generally associated with a poor prognosis. Baseline bone blast count was strongly predictive of response to treatment. Further evaluation of these observations is needed.

Contraindicated Drug Responses in Dravet Syndrome Brain Organoids Utilizing Micro Electrode Array Assessment Methods

Ensuring drug safety for patients with specific neurological disorders is of paramount importance. For instance, certain antiepileptic drugs (AEDs) are contraindicated in Dravet Syndrome (DS), which is characterized by a deficiency in Na+ channel function. Constructing in vitro assessment methods capable of detecting contraindicated drug responses and medication effects on neurons derived from DS patients is highly anticipated for drug safety assessment and therapeutic innovation. This study used micro electrode array (MEA) measurements with low-frequency analysis on human iPSC-derived DS organoids to investigate AED responses. When exposed to the contraindicated drugs carbamazepine and phenytoin, the number of network oscillations increased in DS organoids while maintaining oscillation intensity. Furthermore, carbamazepine administration appeared to enhance activities beyond oscillations which is partially consistent with findings in the DS mouse model. Conversely, treatment with the therapeutic drug sodium valproate resulted in a similar decrease in activity both in healthy and DS organoids. The frequency characteristics of spontaneous firings and AEDs responsiveness in DS organoids demonstrated partial correlation with typical electroencephalography patterns observed in vivo. In conclusion, this study, employing MEA measurements with low-frequency analysis, revealed contraindicated drug responses and disease-specific functional characteristics in DS organoids, effective for DS patient safety assessment, precision medicine, and antiepileptic drug screening.