Duration Of Treatment Research Articles

Lyme disease in UK primary care: a knowledge, attitude and practice survey.

Lyme disease (LD) cases in the UK most commonly present within the primary care setting. Despite an upward trend of incidence, little is known regarding general practitioner (GP) experience with diagnosis and treatment. This study aims to describe baseline primary care clinician Knowledge, Attitude and Practice (KAP) in Scotland and England. Online KAP survey on Lyme disease for UK based practising GPs. An online KAP questionnaire was developed for use in UK primary care. The survey was distributed through UK based research networks, professional societies and via social media. 191 complete responses were analysed (England n=130, Scotland n=61). The Scotland-based respondent group had more relevant consultations in the previous 3 years. Respondents from Scotland demonstrated a greater awareness that erythema migrans (EM) is pathognomonic for Lyme disease and that serological testing of this patient group is not indicated. Less common cardiac and neurological symptoms were not as well associated with Lyme disease by both respondent groups for the former and England-based respondents for the latter. Prescribing according to the National institute for Health and Care Excellence (NICE) guidance was identified in 70% of Scotland and 42% of England-based GP responses. Targeted resources may improve clinician confidence on exposure risk, symptom recognition, testing limitations and treatment dose and duration. Scotland-based respondents' better survey performance potentially reflects greater clinical exposure and public awareness of the disease, due to high endemicity within the nation.

Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists and cancer mortality. A real-world registry

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1ra) reduce cardiovascular events through different mechanisms, nevertheless, their association with cancer remains unclear. Purpose We aim to compare the combined treatment (SGLT2i and GLP1ra) with monotherapy regarding hospitalization or/and death for cancer in a general population and a subgroup of patients with cardiovascular disease (CVD). Methods Retrospective observational study of patients who were prescribed SGLT2i, GLP1ra, or both drugs. Multinomial propensity score was performed in all the population and in a subgroup of patients with CVD (atrial fibrillation [AF], heart failure [HF], coronary artery disease [CAD], peripheral arterial disease [PAD], or cerebrovascular accident [CVA]). The following variables were included to adjust the three groups: Sex, Age, Obesity, diabetes mellitus (DM), high blood pressure (HBP), dyslipidemia (DLP), CAD, HF, AF, and CVA. The three primary outcomes were (i) hospitalization for any cancer, (ii) death for any cancer, and (iii) the combined event in the included population and the subgroup of patients with CVD. The multivariate Cox regression analysis determined the hazard rate (HR) of age, sex, risk factors, and treatment for each outcome. Results We included 14709 patients (11366 with SGLT2i, 1016 with GLP1ra, and 2327 with both treatments) from the treatment initiation. The subgroup with CVD included 4957 (33.7%) patients (Fig 1). After 33 months of median follow-up, the incidence of cancer events was similar between patients with and without CVD (3.4% or 3.7%, respectively). Sex (male) and age were the main risk factors for the 3 outcomes in both groups. Combined treatment and its duration had a protector role for cancer mortality regarding monotherapy with SGLT2i or GLP1ra in all population (HR [95%CI]) 0.2216 [0.106-0.459]; p<0.001 or 0.1928 [0.071-0.519]; p=0.001, respectively) (Fig 2a) and in the subgroup of patients with CVD (HR [95%CI]) 0.279 [0.078-0.994]; p<0.049 or 0.129 [0.024-0.668]; p=0.014, respectively) (Fig 2b), but these results were not found for the outcome of hospitalization for cancer. The combined therapy concerning SGLT2i and duration of treatment showed a protective role against the combined event (HR [95%CI]) 0.709 [0.521-0.967]; p=0.029) and (HR [95%CI]) 0.991 [0.983-0.999]; p=0.032) in the general population but not in the group of CVD. A higher survival rate for any cancer mortality was observed in those patients with the combined therapy respect to monotherapy (SGLT2i or GLP1ra) in the general population (Fig 2c) and the subgroup of patients with CVD (Fig 2d). Conclusions Initiation of combined therapy vs. monotherapy was associated with a lower rate of cancer mortality in the general population and patients with CVD. Future clinical trials and mechanistic studies will clarify the possible role of these drugs on carcinogenesis.Figure 1Figure 2

The evolving treatment landscape of multiple myeloma in Portugal: A nation‐wide retrospective cohort study of real‐world clinical practice

AbstractObjectivesTo characterize variations in real‐world treatment patterns in multiple myeloma (MM) in Portugal over a 5‐year period.MethodsA retrospective cohort multicenter study using secondary data of national hospital drug consumption database from 11 Portuguese public hospitals between 2017 and 2022.ResultsNumber of MM‐treated patients increased 53% over 5 years (from 825 to 1266 patients). Constant slight predominance of male patients (55%), 82% over 60 years old (median age, 70 years), and half of newly diagnosed patients were transplant‐eligible. The highest growth rate was in second‐line treatments, with a sixfold increase in patients in fourth‐line or beyond. First‐line treatment pattern remained stable both in transplant‐eligible (bortezomib, cyclophosphamide and dexamethasone (VCd_, bortezomib, thalidomide and dexamethasone (VTd), and bortezomib, lenalidomide and dexamethasone (VRd)) and noneligible patients (bortezomib, melphalan and prednisolone (VMP), VCd, and lenalidomide, dexamethasone (Rd)). Maintenance therapy increased from 5% to 16%, shifting from thalidomide to lenalidomide. Second and third lines were dominated by daratumumab‐based regimens after 5 years. No standard of care in fourth‐line treatment. Treatment duration increased in transplant‐eligible due to maintenance therapy and in noneligible due to fourth‐line treatments. Patients moved from first‐ to second‐line more rapidly over time.ConclusionsThere was an increase in MM patients reaching advanced treatment lines and significant changes in the treatment patterns, driven by access to more effective frontline treatments and longer duration of treatment.

Cardiovascular events in CML patients treated with nilotinib: validation of the HFA-ICOS baseline risk score

Abstract Background The therapeutic landscape of chronic myeloid leukaemia (CML) has been transformed by tyrosine kinase inhibitors (TKI). Nilotinib, a potent 2nd generation TKI, showed higher rates of major molecular response than imatinib, however was associated with higher rates of cardiovascular (CV) toxicity. Objectives To describe the CV events associated with nilotinib in a real-world CML population and assess the predictive value of the HFA-ICOS baseline risk score in clinical practice. Methods The HFA-ICOS baseline risk was calculated (low, medium, high /very high) for patients with CML treated with nilotinib between 2006 and 2021. The incidence of all CV events, ischaemic events and Major CV Adverse Events (MACE) were reviewed and compared among the different risk groups. Results A total of two hundred and twenty-nine eligible patients were included in the analysis. The incidence of CV events, ischaemic events, and MACE, while on nilotinib, were 20.9% (95% CI: 15.7% to 26.2%), 12.7% (95% CI: 8.4% to 16.9%), and 12.2% (95% CI: 7.9% to 16.5%) respectively, following a median duration of treatment with nilotinib of 34.4 months for the entire cohort. Patients with a higher HFA-ICOS baseline risk score had higher rates of all CV events (low: 11.2%, medium: 28.2% [HR: 2.8, 95% CI: 1.2 to 6.2], high/very high: 32.4% [HR: 3.5, 95% CI: 1.8 to 6.8]), ischaemic events (low: 5.2%, medium: 17.9% [HR: 3.7, 95% CI: 1.2 to 10.9] , high/very high: 21.6% [HR: 3.7, 95% CI: 1.4 to 9.7]) and MACE (low: 7.8% , medium: 10.3% [HR:1.2, 95% CI: 0.38 to 4.1], high/very high: 20.2% [HR: 2.2, 95% CI: 0.9 to 5.3]). The predictive tool presented an 89% NPV, and an area under the ROC curve: 0.65 for all CV events, an NPV of 95% and AUC 0.68 for ischaemic events and NPV 92% and AUC 0.62 for MACE. Conclusions The HFA-ICOS risk stratification tool has been shown to be an efficient discriminator at low, medium and high/very high risk of developing cardiovascular events, with an overall positive trend towards increasing cardiotoxicity rates with rising risk categories. This study provides evidence to support the use of this predictive tool in nilotinib treated patients, as it also underscores the potential for further improvement in the overall discriminatory ability of the model.

Colchicine prevents post-ablation atrial fibrillation recurrence: a systematic review and meta-analysis

Abstract Background Catheter ablation for atrial fibrillation (AF) is a commonly performed procedure with appreciable effectiveness; however, post-AF ablation recurrence is often observed. The pathophysiology behind this recurrence is often inflammation and oxidative stress triggered during the ablation procedure. Colchicine is a potent anti-inflammatory agent that has emerged as a promising therapeutic for preventing post-ablation AF recurrence; however, the data available on its efficacy are limited. Purpose This meta-analysis aimed to investigate the outcomes of post-ablation AF patients who received colchicine in the postoperative period. Methods A comprehensive literature search spanning major bibliographic databases was conducted to retrieve studies comparing outcomes in post-ablation AF patients who received colchicine versus those who did not. The outcomes of interest included AF recurrence, pericarditis, gastrointestinal side effects, and hospitalization. AF recurrence was determined with a 12-lead electrocardiogram and/or Holter monitoring. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were pooled from all studies using the DerSimonian and Laird random-effects model. Statistical significance was set at p ≤ 0.05. Results Six studies were included with 1791 patients (721 in the colchicine group and 1070 in the placebo group). Patients who received colchicine had significantly lower odds of AF recurrence on follow-up [OR: 0.62; 95% CI: 0.48, 0.79; p=0.0001] but had higher gastrointestinal side effects [OR: 2.67; 95% CI: 1.00, 7.12; p=0.05]. There were no statistically significant differences in acute pericarditis [OR: 0.54; 95% CI: 0.27, 1.05; p=0.07] or hospitalization [OR: 1.03; 95% CI: 0.73, 1.45; p=0.87]. Conclusion Prophylactic use of colchicine after catheter ablation in patients with AF leads to a reduction in AF recurrence, albeit with increased gastrointestinal side effects such as diarrhea and nausea. Colchicine use did not lead to a reduction in the rates of pericarditis and hospitalization after ablation. Large randomized controlled trials are necessary to evaluate the efficacy of colchicine in the prevention of AF recurrence, particularly focusing on the dose and duration of treatment to optimize the side effect profile.

Real-World Experience with Diroximel Fumarate in Patients with Multiple Sclerosis: A Prospective Multicenter Study.

Current literature and a real-world study suggest that diroximel fumarate (DRF) is safer than dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS). However, no real-world study to date has significantly addressed the efficacy of this treatment. This study aims to elucidate the safety, tolerability, and efficacy of DRF in a real-world setting, utilizing data from a Spanish national registry of patients commencing DRF therapy post-market introduction. In this multicenter, prospective observational study, data were collected from MS patients who initiated DRF treatment. The study monitored demographic and clinical characteristics, safety outcomes (including adverse events, reasons for discontinuation, and lymphocyte counts), and efficacy outcomes (radiological and clinical activity). A total of 195 MS patients across 26 neurological departments were included, predominantly female (79.5%), with a mean age of 42.17 years, and a mean duration of treatment with DRF of 6.3 months. Most patients (70.3%) reported no adverse events, while gastrointestinal issues and flushing were the most common adverse events observed. The majority of patients (84.6%) continued with DRF treatment, with tolerability issues being the primary reason for discontinuation. Efficacy analysis showed low relapse rates post-DRF initiation, with most patients exhibiting stable or improved Expanded Disability Status Scale scores and radiological assessments demonstrating minimal activity. This comprehensive analysis provides valuable insights into the real-world application of DRF, confirming its safety and tolerability while offering preliminary evidence of its efficacy in managing MS.

Therapeutic effects of FGF21 mimetic bFKB1 on MASH and atherosclerosis in Ldlr-/-.Leiden mice.

Fibroblast growth factor 21 (FGF21) is a promising target for treatment of obesity-associated diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. We evaluated the effects of the bispecific anti-FGF21-β klotho (KLB) agonist antibody bFKB1 in a preclinical model of MASH and atherosclerosis. Low-density lipoprotein receptor knockout (Ldlr-/-).Leiden mice received a high-fat diet for 20 weeks, followed by treatment with an isotype control antibody or bFKB1 for 12 weeks. Effects on plasma risk markers and (histo)pathology of liver, adipose tissue, and heart were evaluated alongside hepatic transcriptomics analysis. bFKB1 lowered body weight (-21%) and adipose tissue mass (-22%) without reducing food intake. The treatment also improved plasma insulin (-80%), cholesterol (-48%), triglycerides (-76%), alanine transaminase (ALT: -79%), and liver weight (-43%). Hepatic steatosis and inflammation were strongly reduced (macrovesicular steatosis -34%; microvesicular steatosis -100%; inflammation -74%) and while the total amount of fibrosis was not affected, bFKB1 did decrease new collagen formation (-49%). Correspondingly, hepatic transcriptomics and pathway analysis revealed the mechanistic background underlying these histological improvements, demonstrating broad inactivation of inflammatory and profibrotic transcriptional programs by bFKB1. In epididymal white adipose tissue, bFKB1 reduced adipocyte size (-16%) and inflammation (-52%) and induced browning, signified by increased uncoupling protein-1 (UCP1) protein expression (8.5-fold increase). In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area (-38%). bFKB1 has strong beneficial metabolic effects associated with a reduction in hepatic steatosis, inflammation, and atherosclerosis. Analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration as well.

Osmotic Treatment of Orange and Pink Sweet Potato-Mass Transfer Rate and Efficiency

Sweet potatoes (Ipomoea batatas) are globally cultivated due to its adaptability, high nutritional value, and short growing season, tolerance to high-temperature soils, low fertility, and minimal pest or disease issues, making it a valuable asset to the food industry. Osmotic treatment, a renowned preservation technique requiring mild temperatures and minimal energy, has gained prominence. Over ten years of research at the Faculty of Technology Novi Sad has pioneered the use of sugar beet molasses as an effective osmotic solution for drying different herbs, fruits, vegetables, and meat. This study specifically focused on osmotically treating samples of pink and orange sweet potatoes in sugar beet molasses (80% w/w) to explore the influence of solution temperatures (20°C, 35°C, and 50°C) and osmotic treatment durations (1h, 3h, and 5h) on mass transfer rate and treatment efficiency. The Principal Component Analysis (PCA) and color correlation analysis were employed to illustrate the connections between different sweet potato samples. Findings indicate that the mass transfer rate peaks at the onset of the process. Particularly with the highest temperature after 1h of osmotic treatment The highest values for RWL and RSG (13.33±0.02, 1.85±0.04 and 11.51±0.02, accordingly) were obtained for both orange ((15.19±0.08 g/(gi.s.w.·s)·105and 4.53±0.06 g/(gi.s.w.·s)·105) and pink sweet potato ((9.91±0.02 g/(gi.s.w.·s)·105 and 3.78±0.04 g/(gi.s.w.·s)·105), respectively. Notably, diffusion is most rapid within the initial three hours, suggesting potential reductions in processing time aligned with these results.

A novel dynamic risk score to predict venous thromboembolism (VTE) recurrences after 3 months of anticoagulation in patients with incident VTE and without active cancer

Abstract Background Predicting the risk of recurrent venous thromboembolism (rVTE) during and following anticoagulation is complex. Current models lack the ability to adapt to changing patient conditions over time and fail to account for the direct impact of anticoagulation in real-world clinical settings. Purpose To develop a dynamic risk prediction model for rVTE to help clinicians decide on the duration of anticoagulant therapy in conjunction with a model for bleeding (also submitted to the conference). Methods UK Clinical Practice Research Datalink data (2001-2020) was used to generate a retrospective cohort with first VTE who had received 3 months of anticoagulation. Patient episodes of rVTE were evaluated. Covariates were collected at baseline and subsequently as time-varying data to capture changes post-VTE. Hazards with 95% confidence intervals (CI) were estimated and covariates included in a Fine & Gray model used as predictors of rVTE. An additive (logarithmic) scoring scheme was developed from subdistribution hazard ratios, discrimination (expressed by the C-statistic) estimated from 10-fold cross-validation. Results 51,465 patients with a first VTE were included; 4041 rVTE were identified in 200,698 person-years of observation. Incidence rates for rVTE were 2.01 per 100 person-years. Nineteen independent predictors of rVTE (recorded before or after the VTE diagnosis) were included in the model, 13 associated with increased risk and 6 with decreased risk, Table 1. Patients recognised as lower-risk, medium and higher-risk (10.5%, 37% and 52.5% of the population, respectively, at 90 days after first VTE, assuming no anticoagulation treatment) had an annualised rVTE incidence rate of 2.20, 3.84, and 7.44 per 100 person-years. The C-statistic for rVTE was 0.65 (95%CI, 0.64-0.66). The points scored can be added or subtracted to predict risk (Table 2). Conclusions Our dynamic risk score effectively identifies patients at risk of rVTE three months post their initial VTE diagnosis. It allows for continuous monitoring of risk, and modelling of treatment impact, providing clinicians with a pragmatic tool to help determine treatment duration, and adapt their strategies in response to evolving patient conditions.Table 1:Predictors for VTE recurrenceTable 2:VTE recurrence risk score

Feature importance explanation of prosthetic valve endocarditis through machine learning via SHAP

Abstract Introduction Diagnosing prosthetic valve endocarditis poses a significant challenge in daily clinical practice. Accurately identifying these patients is vital due to its treatment implications. Clinical and imaging assessment of suspected cases yields a substantial number of interrelated variables, which can be analyzed through machine learning techniques in order to improve diagnostic accuracy. Feature ranking facilitates identification and interpretability of relevant clinical and imaging variables in this task. Purpose To utilize machine learning feature ranking and modeling in order to improve interpretable identification of patients with prosthetic valve endocarditis. Methods 89 cases defined by the endocarditis team and 173 controls were analyzed. We implemented the SHapley Additive exPlanations (SHAP) method to evaluate feature importance. 5-fold cross-validated Xgboost models were trained and independently tested with additive clinical, echocardiographic and 18F-FDG PET/CT data. Performance was evaluated through confusion matrices, F1-scores and AUCs. These were compared against conventional logistic regression of the Duke Criteria classification. Results Mean age was 59.6 ± 15.7, with 29.7% women. 14 clinical (demographic, laboratory and cultures), 2 echocardiographic, and 5 PET/CT features were included. The XGBoost model trained with all additive features demonstrated an AUC of 0.91±0.1 and outperformed simpler models as well as the Duke classification model (AUC=0.85). The clinical variables alone achieved an AUC of 0.85±0.11, while integration with echocardiography enhanced its performance to 0.90±0.04 (Fig. 1). Feature ranking demonstrated that antibiotic treatment duration, positive blood cultures, valve type, weight and CRP were the most relevant clinical variables, while the presence of vegetation or abscess, and abnormal uptake and uptake focality on PET/CT represented the most relevant imaging variables (Fig. 2). Conclusion Machine learning-based feature ranking and modeling may significantly enhance identification of patients with prosthetic valve endocarditis beyond standard clinical criteria. Feature selection offers interpretable performance in identifying these cases, model testing in clinical decision support may be warranted.Fig. 1:Comparative AUC Analysis.Fig. 2:SHAP feature importance.

Safety and effectiveness of sodium-glucose co-transporter 2 inhibitors in active cancer patients with heart failure: results of the observational TOSCA trial

Abstract Background Sodium-glucose co-transporter 2 inhibitors (SGLT2i) currently represent a pillar of heart failure (HF) treatment. However, cancer patients have not been included in landmark randomized controlled trials (RCTs), and data on safety and effectiveness in this population are lacking. Purpose Purpose of present study was to evaluate safety and effectiveness of SGLT2i in active cancer patients with HF. Methods TOSCA is a multi-centre observational trial including patients (≥ 18 years) with active cancer (diagnosis < 3 years) receiving SGLT2i for HF treatment. Patients were enrolled in two (prospective and retrospective) cohorts. The primary endpoint was safety (incidence of known and unexpected side effects). The secondary endpoint was effectiveness (ejection fraction (EF) increase, New York Heart Association (NYHA) class change, HF-related events). Exploratory endpoints included drug-drug interactions with anticancer and supportive care drugs, treatment of cancer therapy-related cardiac dysfunction (CTRCD), and changes in NT-proBNP. Results Eighty-three pts were enrolled (59 prospective - 24 retrospective). Median age was 71 (range 44-92) yrs, M/F 48/52%. The main cancer sites were breast, gastrointestinal tract, and hematological malignancies. Most cases (62%) received an active treatment (mainly chemotherapy) while on SGLT2i. Prevalent aetiology was drug-induced HF (37%) with reduced EF as the prevalent clinical presentation (39%). Prescribed agents were dapagliflozin in 60% and empagliflozin in 40% of cases on top of conventional guideline-directed medical therapy, with a median treatment duration of 3 (range 3-25) months. The incidence of urinary tract infection was 2.5%. No cases of genital infection, hypoglycemia, diabetic ketoacidosis, acute renal injury, thrombosis, and bone fractures were reported. Mean overall EF slightly increased (44.1% vs. 46.6%), and NYHA class improved (class improvement in 16%). Unplanned cardiology visits (1.2%), i.v. diuretics (1.2%), coronary angiography (5%), emergency access (2.5%), and new HF episodes (3.7%) rates were low. SGLT2i appeared effective in 31 cases of CTRCD. A relative reduction in mean NT-proBNP levels (2748 vs 1125pg/mL) was observed. No drug-drug interactions were reported. Conclusions SGLT2i appear to be safe and effective in active cancer patients with HF, with potential cardioprotective effect. No new safety warnings were recorded.

Zibotentan in microvascular angina: a randomized, placebo-controlled, crossover trial

Abstract Background/Introduction Microvascular angina is a chronic condition characterized by abnormal myocardial blood flow leading to ischemic symptoms. Endothelin-1, a peptide secreted by endothelial cells, is a highly potent constrictor of the human coronary arterioles. Microvascular angina is associated with elevated circulating concentrations of endothelin-1, and prolonged exposure to ‘excess’ endothelin causes vasoconstriction and vascular remodelling. The chronic elevation of circulating endothelin-1 in microvascular angina may be influenced by genetic factors. Purpose Zibotentan, the most selective antagonist of the endothelin A receptor with no off-target binding to the endothelin B receptor, was evaluated in oncology trials and did not improve survival. We identified zibotentan as a potential disease-modifying therapy for patients suffering from microvascular angina. We hypothesized that zibotentan 10 mg daily for 12 weeks in addition to background medical therapy could be an efficacious and safe treatment for patients with microvascular angina. We further hypothesized that the SNP regulator of EDN1 gene expression, rs9349379 (G allele), could be a novel theragnostic biomarker. Methods The trial involved a prospective, multicentre, randomized, double-blind, placebo-controlled, sequential crossover design to assess the effects of zibotentan 10 mg or matched placebo, once daily for 12 weeks. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The secondary outcomes included exercise test parameters, health status questionnaires, safety (frequency and severity of severe adverse events (SAEs) and adverse events), feasibility (withdrawal rate), and biomarkers of efficacy (pharmacokinetics, pharmacodynamics). Results The study found no significant difference in exercise duration with zibotentan (-4.26 seconds; 95% CI: -19.60 to 11.06; P=0.5871). There was no effect on the secondary outcomes. However, for exploratory (mechanistic) outcomes, zibotentan increased plasma big endothelin-1, endothelin-1, and global myocardial blood flow, while reducing hemoglobin, diastolic, and systolic blood pressure (all p<0.001). Adverse events were more common during the zibotentan period (60.2%) compared to placebo (14.4%, p<0.001). Conclusion(s) In conclusion, daily administration of 10 mg zibotentan for 12 weeks did not enhance exercise duration and was commonly associated with adverse effects related to fluid retention. Further trials exploring lower zibotentan doses in combination with agents to mitigate fluid retention, and longer treatment durations, are warranted.

A novel dynamic risk score to predict Clinically Significant Bleeding (CSB) after 3 months of anticoagulation in patients with incident Venous ThromboEmbolism (VTE) and without active cancer

Abstract Background Predicting the risk of clinically significant bleeding (CSB), bleeding requiring hospitalisation or fatal bleeding, during and following anticoagulation is complex. Current models lack the ability to adapt to changing patient conditions over time and fail to account for the direct impact of anticoagulation in real-world clinical settings. Purpose To develop a dynamic risk prediction model for CSB to help clinicians decide on the duration of anticoagulant therapy in conjunction with a model for recurrences of VTE (also submitted to the conference). Methods UK Clinical Practice Research Datalink data (2001-2020) was used to generate a retrospective cohort with first VTE who had received 3 months of anticoagulation. Patient episodes of CSB and recurrent VTE were evaluated. Covariates were collected at baseline and subsequently as time-varying data to capture changes post-VTE. Hazards with 95% confidence intervals (CI) were estimated and covariates included in a Fine & Gray model used as predictors of CSB. An additive (logarithmic) scoring scheme was developed from subdistribution hazard ratios, discrimination (expressed by the C-statistic) estimated from 10-fold cross-validation. Results 51,621 patients with a first VTE were included; 3307 CSB were identified in 206,292 person-years of observation. Incidence rates for CSB were 1.60 per 100 person-years. 18 independent predictors of CSB (recorded before or after the VTE diagnosis) were included in the model, Table 1. Patients recognised as lower-risk, medium and higher-risk (67.5 %, 15.9 % and 16.7 % of the population, respectively, at 90 days after first VTE, assuming no anticoagulation treatment) had an annualised incidence rate of 0.84, 2.94, and 9.45 per 100 person-years. The C-statistic for CSB was 0.78 (95%CI, 0.77-0.79). The points scored can be added to predict risk (Table 2). Conclusions Our dynamic score effectively identifies patients at risk of CSB three months post their initial VTE diagnosis. It allows for continuous monitoring of risk, and modelling of treatment impact, providing clinicians with a pragmatic tool to help determine treatment duration, and adapt their strategies in response to evolving patient conditions.Table 1:Predictors for CSBTable 2:CSB risk score

Unsupervised machine learning identifies distinct phenotypes in cardiac complications of pediatric patients treated with anthracyclines

BackgroundAnthracyclines are essential in pediatric cancer treatment, but patients are at risk cancer therapy-related cardiac dysfunction (CTRCD). Standardized definitions by the International Cardio-Oncology Society (IC-OS) aim to enhance precision in risk assessment.ObjectivesCategorize distinct phenotypes among pediatric patients undergoing anthracycline chemotherapy using unsupervised machine learning.MethodsPediatric cancer patients undergoing anthracycline chemotherapy at our institution were retrospectively included. Clinical and echocardiographic data at baseline, along with follow-up data, were collected from patient records. Unsupervised machine learning was performed, involving dimensionality reduction using principal component analysis and K-means clustering to identify different phenotypic clusters. Identified phenogroups were analyzed for associations with CTRCD, defined following contemporary IC-OS definitions, and hypertensive response.ResultsA total of 187 patients (63.1% male, median age 15.5 years [10.4–18.7]) were included and received anthracycline chemotherapy with a median treatment duration of 0.66 years [0.35–1.92]. Median follow-up duration was 2.78 years [1.31–4.21]. Four phenogroups were identified with following distribution: Cluster 0 (32.6%, n = 61), Cluster 1 (13.9%, n = 26), Cluster 2 (24.6%, n = 46), and Cluster 3 (28.9%, n = 54). Cluster 0 showed the highest risk of moderate CTRCD (HR: 3.10 [95% CI: 1.18–8.16], P = 0.022) compared to other clusters. Cluster 3 demonstrated a protective effect against hypertensive response (HR: 0.30 [95% CI: 0.13– 0.67], P = 0.003) after excluding baseline hypertensive patients. Longitudinal assessments revealed differences in global longitudinal strain and systolic blood pressure among phenogroups.ConclusionsUnsupervised machine learning identified distinct phenogroups among pediatric cancer patients undergoing anthracycline chemotherapy, offering potential for personalized risk assessment.

A wearable real-time particulate monitor demonstrates that soaking hay reduces dust exposure.

Affordable particulate matter (PM) monitors suitable for use on horses will facilitate the evaluation of PM mitigation methods and improve the management of equine asthma. Calibrate a real-time wearable PM monitor (Black Beauty [BB]) and compare the PM exposures of horses fed dry or soaked hay. Laboratory calibration; complete cross-over feed trial. Side-by-side sampling with BB monitors and tapered element oscillating microbalances (TEOMs) was performed under varying concentrations of PM from alfalfa hay. Linear regression was used to derive a calibration formula for each unit based on TEOM PM measurements. Precision was evaluated by calculating the coefficient of variation and pairwise correlation coefficients between three BB monitors. PM exposure was measured at the breathing zone of 10 horses for 8 h after they were fed dry or soaked hay. Repeated measures generalised linear models were constructed to determine the effect of hay treatment and measurement duration (initial 20-min vs. 8-h) upon exposure to PM with diameters smaller than or equal to 10 μm (PM10) and 2.5 μm (PM2.5). BB monitor PM2.5 and PM10 measurements were linearly correlated with TEOM data (coefficient of determination r2 > 0.85 and r2 > 0.90 respectively), but underestimated PM2.5 mass concentrations by a factor of 4 and PM10 concentrations by a factor of 44. Measures from the three BB monitors had a coefficient of variation <15% and pairwise r > 0.98. Feeding soaked hay significantly reduced average PM2.5 exposures (20-min: dry: 160 μg/m3, soaked: 53 μg/m3, p < 0.0001; 8-h: dry: 76 μg/m3, soaked: 31 μg/m3, p = 0.0008) and PM10 exposures (20-min: dry: 2829 μg/m3, soaked: 970 μg/m3, p < 0.0001; 8-h: dry: 1581 μg/m3, soaked: 488 μg/m3, p = 0.008). No health outcome measures were collected. With appropriate corrections, the BB monitor can be used to estimate horse PM exposure. While 20-min measurements yielded higher estimates of exposure than 8-h measurements, both intervals demonstrate that soaking hay reduces PM exposures by more than 50%.

Long-term safety and efficacy of MBA-P01 for the treatment of glabellar lines: results from a multicenter, repeated-dose, open-label extension study

Purpose Following the introduction of new type of botulinum toxin (MBA-P01), a recent phase 3 study demonstrated that MBA-P01 showed comparable efficacy and safety to onabotulinumtoxin A for reducing glabellar lines. The primary objective of this study was to evaluate the long-term safety of repeated MBA-P01 administration for the treatment of glabellar lines. Materials and methods This multicenter, single-group, repeated-dose, long-term open-label extension study evaluated repeated treatment with MBA-P01 (20 U, five treatments over 16 months), with posttreatment evaluation performed up to 52 weeks. Results Based on the safety assessment results, no specific irreversible adverse reactions were associated with the safety profile of MBA-P01. Repeated treatment with MBA-P01 was effective for a treatment duration of 3–5 months. Conclusion In conclusion, multiple cycles of treatment of glabellar lines with MBA-P01 at a dose of 20 U were well tolerated. Clinical trial registration information: This study is registered in ClincalTrials.gov (NCT05321979).

Nail changes in patients receiving systemic isotretinoin therapy

In this study, it was aimed to describe isotretinoin-induced nail changes and increase patients’ treatment compliance. A total of 200 patients diagnosed with acne vulgaris were included in the study. 100 of the patients were started systemic isotretinoin treatment and 100 control patients were receiving topical acne treatment. Age and gender of all of the participants, duration of treatment, total doses per month, and type of nail changes were recorded. Patients with persistent nail changes were followed at the 3rd and 6th months after treatment. A total of 34 patients had nail changes in the isotretinoin group. These changes included onychoschizia (55.9%), leukonychia (11.8%), onychorexis (8.8%), median nail dystrophy (5.9%), pyogenic granulomas (5.9%), chronic paronychia and granulation tissue (5.9%), onycholysis (2.9%) and Beau’s line (2.9%). The rate of nail changes in the isotretinoin group was significantly higher than in the topical treatment group (34% vs. 11%, p:0.001). Isotretinoin increases the risk of nail changes, primarily onychoschizia. The risk of developing nail changes is not associated with treatment duration but is associated with the total cumulative dose. Nail findings induced by isotretinoin are completely reversible.

Factors associated with low hepatitis B surface antigen levels in chronic hepatitis B patients treated with nucleot(s)ide analogs.

Several studies have reported that chronic hepatitis B (CHB) patients with low hepatitis B surface antigen (HBsAg) levels (100 or 10IU/mL) at the cessation of nucleot(s)ide analogs (NA) have a favorable prognosis. In this retrospective study, we evaluated the duration of NA treatment and the factors associated with achieving these low HBsAg levels. We also examined the relationship between HBsAg and hepatitis B core-related antigen (HBcrAg) levels at the time of NA discontinuation and subsequent clinical outcomes. This study included 153 CHB patients who initiated NA therapy at our hospital, received treatment, and were followed up for over 1year. The cumulative incidence rates of achieving low HBsAg levels at 5 and 10years post-NA administration were as follows: 19.0% and 29.2% for HBsAg <100IU/mL, 13.8% and 17.6% for HBsAg <10IU/mL, and 9.5% and 13.5% for HBsAg <0.05IU/mL, respectively. Hepatitis B virus genotypes other than genotype C (hazard ratio [HR] 3.47; p<0.001) and an HBsAg level <1000IU/mL at the start of NA therapy (HR 2.49; p=0.008) were significantly associated with achieving HBsAg levels <100IU/mL. Among 27 patients who discontinued NA therapy, 5 patients with HBsAg levels <100IU/mL and HBcrAg levels <3logU/mL at the time of discontinuation did not experience virological relapse. The cumulative rates of achieving HBsAg levels <100IU/mL were relatively high. Discontinuation of NA may be considered based on HBsAg and HBcrAg levels during the course of NA therapy.

Long-term safety and efficacy of adjunctive lacosamide in the treatment of generalized onset tonic-clonic seizures: An open-label extension trial.

This study was undertaken to assess long-term safety, tolerability, and efficacy of lacosamide (LCM) as adjunctive therapy for generalized onset tonic-clonic seizures (GTCS) in patients aged ≥4 years with idiopathic generalized epilepsy (IGE). EP0012 (NCT02408549) was a phase 3, multicenter, open-label extension (OLE) trial. Patients were enrolled from SP0982 (NCT02408523). Trial duration was ≥2 years (adults) and ≤5 years (children). The trial consisted of a treatment period, ≤4-week taper period, and 30-day safety follow-up. Safety (primary) variables were incidence of treatment-emergent adverse events (TEAEs), discontinuations due to TEAEs, incidence of onset of absence or myoclonic seizures, and increase in days with absence or myoclonic seizures per 28 days. Efficacy (secondary) variable was percent change in GTCS frequency per 28 days. Kaplan-Meier estimated retention rates and analyses by number of lifetime antiseizure medications (ASMs) were performed post hoc. Overall, 239 patients (mean age = 27.9 years, 56.1% female, 18.4% children) were enrolled and received ≥1 dose of LCM in this OLE (median treatment duration = 3.2 years); 157 (65.7%) completed the trial, and 82 (34.3%) discontinued. The most common reason for discontinuation (≥10%) was withdrawn consent (30 [12.6%]). Kaplan-Meier estimated retention rate was 87%, 72%, and 60% at 1, 3, and 5 years, respectively. Overall, 222 (92.9%) patients reported TEAEs; 19 (7.9%) discontinued due to TEAEs. Few patients had an increase in number of days with absence or myoclonic seizures, or incidence of new absence or myoclonic seizures. Median percent change in GTCS frequency per 28 days from the combined baseline was -88.6% (range = -100.0 to 465.4, n = 238). Post hoc analyses demonstrated small numerical differences between patients with 1, 2, and ≥3 lifetime ASMs. The results support the use of long-term adjunctive LCM for GTCS in patients with IGE. Long-term adjunctive LCM was efficacious and well tolerated independent of the number of ASMs used before LCM initiation. ClinicalTrials.gov: NCT02408549.

Optimization of Production Parameters for Impact Strength of 3D-Printed Carbon/Glass Fiber-Reinforced Nylon Composite in Critical ZX Printing Orientation

Additive manufacturing (AM) methods are increasingly being adopted as an alternative for mass production. In particular, Fused Deposition Modeling (FDM) technology is leading the way in this field. However, the adhesion of the layers in products produced using FDM technology is an important issue. These products are particularly vulnerable to forces acting parallel to the layers and especially to impact strength. Most products used in the industry have complex geometries and thin walls. Therefore, solid infill is often required in production, and this production must take place in the ZX orientation. This study aims to optimize the impact strength against loads acting parallel to the layers (ZX orientation) of PA6, one of the most widely used materials in the industry. This orientation is critical in terms of mechanical properties, and the mechanical characteristics are significantly lower compared to other orientations. In this study, filaments containing pure PA6 with 15% short carbon fiber and 30% glass fiber were utilized. Additionally, the printing temperature, layer thickness and heat treatment duration were used as independent variables. An L9 orthogonal array was employed for experimental design and then each experiment was repeated three times to conduct impact strength tests. Characterization, Taguchi optimization, and factor analyses were performed, followed by fracture surface characterization by SEM. As a result, the highest impact strength was achieved with pure PA6 at 8.9 kJ/m2, followed by PA6 GF30 at 8.1 kJ/m2, and the lowest impact strength was obtained with PA6 CF15 at 6.258 kJ/m2. Compared to the literature and manufacturer datasheets, it was concluded that the impact strength values had significantly increased and the chosen experimental factors and their levels, particularly nozzle temperature, were effective.