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MABp1, an antibody that targets interleukin 1α, has been associated with antitumour activity and relief of debilitating symptoms in patients with advanced colorectal cancer. We sought to establish the effect of MABp1 with a new primary endpoint in patients with advanced colorectal cancer. Eligible patients for the double-blind phase of this ongoing, placebo-controlled, randomised, phase 3 trial, had metastatic or unresectable disease, Eastern Cooperative Oncology Group performance status score 1 or 2, systemic inflammation, weight loss, and other disease-related morbidities associated with poor prognosis, and were refractory to oxaliplatin and irinotecan. Patients were randomly assigned 2:1 to receive either MABp1 or placebo. Randomisation codes were obtained from a centrally held list via an interactive web response system. Patients received an intravenous infusion of 7·5 mg/kg MABp1 or placebo given every 2 weeks for 8 weeks. The primary endpoint was assessed in patients who received at least one dose of MABp1 or placebo (modified intention-to-treat population), and was a composite of stable or increased lean body mass and stability or improvement in two of three symptoms (pain, fatigue, or anorexia) at week 8 compared with baseline measurements. This study is registered with ClinicalTrials.gov, number NCT02138422. Patients were enrolled between May 20, 2014, and Sept 2, 2015. The double-blind phase of the study was completed on Nov 3, 2015. Of 333 patients randomly assigned treatment, 207 received at least one dose of MABp1 and 102 at least one dose of placebo. 68 (33%) and 19 (19%) patients, respectively, achieved the primary endpoint (relative risk 1·76, 95% CI 1·12–2·77, p=0·0045). The most common grade 3–4 adverse events in the MABp1 group compared with in the placebo group were anaemia (eight [4%] of 207 vs five [5%] of 102 patients), increased concentration of alkaline phosphatase (nine [4%] vs two [2%]), fatigue (six [3%] vs seven [7%]), and increased concentration of aspartate aminotransferase (six [3%] vs two [2%]). After 8 weeks, 17 (8%) patients in the MABp1 group and 11 (11%) in the placebo group had died, but no death was judged to be related to treatment. The incidence of serious adverse events was not significantly different in the MABp1 group and placebo groups (47 [23%] vs 33 [32%], p=0·07). The primary endpoint was a useful means of measuring clinical performance in patients. MABp1 might represent a new standard in the management of advanced colorectal cancer. XBiotech.

Inflammation is an important feature of the malignant phenotype and promotes angiogenesis, tumour invasiveness, metastases, and cachexia. We used a first-in-class, monoclonal antibody (MABp1) cloned from a human being to target interleukin-1α, a mediator of chronic inflammation. We aimed to assess the safety and tolerability of MABp1 for interleukin-1α blockade in a refractory cancer population. We did an open-label, dose-escalation, and phase 1 study of MABp1 in adults with metastatic cancer at the MD Anderson Clinical Center for Targeted Therapy (Houston, TX, USA). We used a standard 3+3 design to identify the maximum tolerated dose. Patients received MABp1 intravenously once every 3 weeks through four dose levels: 0·25 mg/kg, 0·75 mg/kg, 1·25 mg/kg, and 3·75 mg/kg. After the dose-escalation phase, a second dosing arm was started with dosing every 2 weeks at the maximum tolerated dose. The primary objectives were safety, tolerability, characterisation of the pharmacokinetic profile, and identification of the recommended phase 2 dose. Secondary endpoints included pharmacodynamic effects and antitumour activity. All patients who received at least one dose of MABp1 were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT01021072. Between March 15, 2010, and July 30, 2012, 52 patients with metastatic cancer (18 tumour types) received anti-interleukin-1α monotherapy in dose-escalation and expansion groups. MABp1 was well tolerated, with no dose-limiting toxicities or immunogenicity. Thus, the recommended phase 2 dose was concluded to be 3·75 mg/kg every 2 weeks. Pharmacokinetic data were consistent at all dose levels and showed no evidence of accumulation or increased clearance of MABp1 at increasing doses. For 42 assessable patients, median plasma interleukin-6 concentrations had decreased from baseline to week 8 by a median of 2·7 pg/mL (IQR −12·6 to 3·0; p=0·08). Of the 34 patients restaged, one patient had a partial response and ten had stable disease. 30 patients were assessable for change in lean body mass, which increased by a mean of 1·02 kg (SD 2·24; p=0·02) between baseline and week 8. The most common adverse events possibly related to the study drug were proteinuria (n=11; 21%), nausea (7; 13%), and fatigue (7; 13%). The most frequent grade 3–4 adverse events (regardless of relation to treatment) were fatigue (3; 6%), dyspnoea (2; 4%), and headache (2; 4%). Two patients (4%) had grade 5 events (death due to disease progression), which were unrelated to treatment. MABp1 was well tolerated, no dose-limiting toxicities were experienced in this study, and disease control was observed. Further study of MABp1 anti-interleukin-1α antibody therapy for advanced stage cancer is warranted. XBiotech.

Summary Background Advanced non-small cell lung cancer (NSCLC) patients were treated as part of a Phase I dose escalation and expansion study evaluating a true human monoclonal antibody targeting IL-1α (Xilonix), which is intended to modulate the malignant phenotype—inhibiting tumor growth, spread and offering relief of symptoms. Methods Sixteen NSCLC patients were included. Patients failed a median of 4 chemotherapy regimens, including 10/16 failing anti-EGFR therapy. Disease progression was evaluated using a multi-modal approach: tumor response, patient reported outcomes (EORTC-QLQC30), and lean body mass (LBM). Patients received infusions every 2 or 3 weeks until progression, and were followed 24 months to assess survival. Results There were no infusion reactions, dose-limiting toxicities, or deaths due to therapy. Albeit not statistically significant, there was a trend in IL-6 (−2.6 ± 18.5 (0.1 [−2.8–2.4]), platelet counts (−11 ± 54 (−4[−36.0–1.0]), CRP (−3.3 ± 30.2 (0.4 [−10.7–1.8]) and LBM (1.0 ± 2.5 (0.4 [−0.5–2.6]). Self-reported outcomes revealed reductions in pain, fatigue and improvement in appetite. Median survival was 7.6 (IQR 4.4–11.5) months, stratification based on prior anti-EGFR therapy revealed a median survival of 9.4 months (IQR 7.6–12.5) for those pretreated ( N  = 10) versus a survival of 4.8 months (IQR 4.3–5.7) for those without ( N  = 6, logrank p  = 0.187). Conclusion Xilonix was well tolerated, with gains in LBM and improvement in symptoms suggesting a clinically important response. Although not statistically significant, the survival outcomes observed for patients with and without prior anti-EGFR therapy raises intriguing questions about the potential synergy of IL-1α blockade and anti-EGFR therapy. Further study for this agent in NSCLC is warranted.

BackgroundDirect oral anticoagulants (DOACs) are contraindicated in patients with atrial fibrillation (AF) and mechanical cardiac valves. However, safety and efficacy are controversial in patients with biological cardiac valves.ObjectiveWe report the safety and feasibility of periprocedural and long-term treatment with DOACs in patients with biological valves undergoing ablation for AF.MethodsA total of 127 patients with AF and biological cardiac valve undergoing CA on uninterrupted DOAC were matched by gender and age with 127 patients with AF and biological cardiac valves undergoing CA on uninterrupted warfarin. All patients were anticoagulated for at least 3–4 weeks prior to ablation with either rivaroxaban (70%) or apixaban (30%), which were continued for at least 3 months and subsequently based on CHA2DS2-VASc score.ResultsMean age of the study population was 63.0 ± 10.9 with 66% being male. The majority of patients on NOACs had aortic valve replacement (59%), while mitral valve was replaced in 41% of patients, which did not differ from the matched cohort on coumadin (aortic valve 57% and mitral valve 43%, (p = 0.8) (p = 0.8), respectively). The CHADS2 score was ≥ 2 in 90 patients (71.0%) on DOAC and 86 patients in (68%) the control (p = 0.6) group. Patients underwent ablation predominantly with uninterrupted rivaroxaban [89 (70%)], while the remaining 38 patients (30%) underwent ablation while on apixaban. Two groin hematomas were observed periprocedurally in both groups. No stroke/transient ischemic attack (TIA) was observed both periprocedurally and at long-term follow-up in either group.ConclusionPeriprocedural and long-term administration of DOACs in patients with biological cardiac valves undergoing AF ablation appears as safe as warfarin therapy.

The CABANA trial reported that catheter ablation, when compared with drug therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest in patients with atrial fibrillation. Despite multiple limitations in study design, the CABANA trial still confirmed that catheter ablation of atrial fibrillation led to clinically important and significant improvements in quality of life at 12 months without increasing the risk of complications.

Diabetes, a significant global health crisis, is primarily driven in India by unhealthy diets and sedentary lifestyles, with rapid urbanization amplifying these effects through convenience-oriented living and limited physical activity opportunities, underscoring the need for advanced preventative strategies and technology for effective management. This study integrates Shapley Additive explanations (SHAPs) into ensemble machine learning models to improve the accuracy and efficiency of diabetes predictions. By identifying the most influential features using SHAP, this study examined their role in maintaining high predictive performance while minimizing computational demands. The impact of feature selection on model accuracy was assessed across ten models using three feature sets: all features, the top three influential features, and all except these top three. Models focusing on the top three features achieved superior performance, with the ensemble model attaining a better performance in most of the metrics, outperforming comparable approaches. Notably, excluding these features led to a significant decline in performance, reinforcing their critical influence. These findings validate the effectiveness of targeted feature selection for efficient and robust clinical applications.

This article is fully devoted to the numerical approximation of Cauchy-type integrals in the complex plane. A class of degree eight quadrature rules is formulated from a family of Gauss-type two-point rules based on the method of extrapolation. The basic rules are developed and then composite rules are constructed from the basic rules. The Error bounds for each rule are determined. The validity of the method has been demonstrated by the provision of numerical experiments and their results.

Multi-disease conditions strain the body’s defenses, complicating recovery and increasing mortality risk. Therefore, effective concurrent prevention of multiple diseases is essential for mitigating complications and improving overall well-being. Explainable artificial intelligence (XAI) with an advanced multimodal large language model (LLM) can create an interactive system enabling the general public to engage in natural language without any specialized knowledge prerequisites. Counterfactual explanation, an XAI method, offers valuable insights by suggesting adjustments to patient features to minimize disease risks. However, addressing multiple diseases simultaneously poses challenging barriers. This article proposes an interactive multi-disease prevention system that uses Google Gemini Pro, a multimodal LLM, and a non-dominated sorting genetic algorithm, namely NSGA-II, to overcome such problems. This system recommends changes in feature values to concurrently minimize the risk of diseases such as heart attacks and diabetes. The system facilitates personalized feature value selection, significantly reducing disease attack probabilities to as low as possible. Such an approach holds the potential to simultaneously address the unresolved issue of preventing and managing multiple diseases for the general public.

IntroductionWe investigated the feasibility to proactively stimulate subsequent closure of a patent foramen ovale (PFO) by injuring (mechanical trauma or radiofrequency [RF] energy) the opposing surfaces of the septum primum (SP) and septum secundum (SS).Methods1. Mechanical Injury: The interatrial septum of patients who underwent multiple left atrial (LA) ablations over 6 years, where a PFO was used for LA access, were examined. Patients whose PFO was absent during a later procedure were identified. Eleven patients with LA accessed via a PFO also underwent subsequent LA procedures. 2. Ablation: Ten patients undergoing ablation for drug-resistant atrial fibrillation (AF), who also had a PFO, were studied. RF delivery was extended along the upper SP. Transthoracic echocardiogram (TTE) bubble study was repeated after 3 months.Results1. Mechanical Injury: Seven were male with a mean age of 58.3 ± 9.99. LA size was 42.73 ± 3.52 mm. The mean left ventricular ejection fraction (EF) was 62 ± 7.4%. During the repeat procedure, in 4 patients, the PFO could not be visualized and the fossa ovalis (FO) was punctured. The fourth patient had three procedures. During the second procedure the PFO was accessed, but with difficulty. During the third procedure, it was no longer present. All four patients had subsequent TTE showing no PFO. 2. Ablation: Seven were male with a mean age of 61.1 ± 9.8 years. The mean EF and LA diameters were 55 ± 5% and 4.4 ± 0.8 cm respectively. The mean RF time was 5.4 ± 2.2 min. At 3 months, 9 patients out of 10 showed no interatrial communication.ConclusionInjury of tunnel surfaces of the SP and SS by mechanical trauma or ablation can fuse the foramen ovale.

Purpose Non-pulmonary vein (non-PV) triggers and left atrial (LA) scars perpetuate atrial fibrillation (AF) and limit the success rate of catheter ablation. In order to understand the genetic basis of these risk factors, we examined the association of selected single nucleotide polymorphisms (SNPs) with scar and non-PV triggers. Methods Four hundred AF patients (67 % male, 62 ± 12 years, LA size 45.3 ± 7 mm, 64 % non-paroxysmal) undergoing catheter ablation were prospectively enrolled. DNA extractions for 16 AF-related SNPS from blood samples were performed of which 371 DNA samples were available for genotyping. Multivariate logistic regression analysis was used for assessing predictive role of individual SNP, and logistic kernel-machine approach was applied to test the cumulative effect of multiple SNPs as a group with non-PV triggers and LA scar. False discovery rate (FDR) was computed for all candidate SNPs to address multiple testing. Results SNPs rs6599230 and rs6843082 were inversely associated (OR 0.68, p  = 0.04, and 0.62, p  = 0.01, respectively) whereas rs1448817 (OR 1.74, p  = 0.04) and rs7193343 (OR 1.66, p  = 0.02) predicted higher risk of non-PV triggers. Genotypes for rs6599230 and rs6843082 conferred 51 % reduction in the odds for non-PV triggers (combined OR 0.49, p  = 0.019), while rs1448817 and rs7193343 demonstrated a combined OR of 1.93, p  = 0.025. FDR was controlled at 16 % to adjust for multiple testing. For LA scar, inverse association was observed with rs1448817 (OR 0.29, p  = 0.006), rs17042171 (OR 0.27, p  = 0.032), rs3807989 (OR 0.54, p  = 0.017), and rs6843082 (OR 0.56, p  = 0.009). Two SNPs were associated with increased scar risk: rs17375901 (OR 3.68, p  = 0.03) and rs7193343 (OR 1.74, p  = 0.037). For global association of SNPs with left atrial scar FDR was controlled at ≤10 % to adjust for multiple testing. Conclusions This study has a strong clinical significance as it provides important insights into the molecular basis of pertinent therapeutic targets. Our findings demonstrate that the presence of certain genetic polymorphisms increases the risk of scar and non-PV triggers in AF patients. Therefore, PVAI alone will not be enough to eliminate the arrhythmia and the operators may need to identify and isolate the non-PV foci to maximize procedural success in patients carrying these risk variants. Clinical trial registration clinicaltrials.gov (NCT01751607)