End Point Research Articles

Insulin Efsitora versus Degludec in Type 2 Diabetes without Previous Insulin Treatment.

Insulin efsitora alfa (efsitora) is a new basal insulin designed for once-weekly administration. Data on safety and efficacy have been limited to small, phase 1 or phase 2 trials. We conducted a 52-week, phase 3, parallel-design, open-label, treat-to-target trial involving adults with type 2 diabetes who had not previously received insulin. Participants were randomly assigned in a 1:1 ratio to receive efsitora or degludec. The primary end point was the change in the glycated hemoglobin level from baseline to week 52; we hypothesized that efsitora would be noninferior to degludec (noninferiority margin, 0.4 percentage points). Secondary and safety end points included the change in the glycated hemoglobin level in subgroups of participants using and not using glucagon-like peptide-1 (GLP-1) receptor agonists, the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter in weeks 48 through 52, and hypoglycemic episodes. A total of 928 participants underwent randomization (466 to the efsitora group and 462 to the degludec group). The mean glycated hemoglobin level decreased from 8.21% at baseline to 6.97% at week 52 with efsitora (least-squares mean change, -1.26 percentage points) and from 8.24% to 7.05% with degludec (least-squares mean change, -1.17 percentage points) (estimated treatment difference, -0.09 percentage points; 95% confidence interval [CI], -0.22 to 0.04), findings that showed noninferiority. Efsitora was noninferior to degludec with respect to the change in the glycated hemoglobin level in participants using and not using GLP-1 receptor agonists. The percentage of time that the glucose level was within the target range was 64.3% with efsitora and 61.2% with degludec (estimated treatment difference, 3.1 percentage points; 95% CI, 0.1 to 6.1). The rate of combined clinically significant or severe hypoglycemia was 0.58 events per participant-year of exposure with efsitora and 0.45 events per participant-year of exposure with degludec (estimated rate ratio, 1.30; 95% CI, 0.94 to 1.78). No severe hypoglycemia was reported with efsitora; six episodes were reported with degludec. The incidence of adverse events was similar in the two groups. In adults with type 2 diabetes who had not previously received insulin, once-weekly efsitora was noninferior to once-daily degludec in reducing glycated hemoglobin levels. (Funded by Eli Lilly; QWINT-2 ClinicalTrials.gov number, NCT05362058.).

Liraglutide for Children 6 to

No medications are currently approved for the treatment of nonmonogenic, nonsyndromic obesity in children younger than 12 years of age. Although the use of liraglutide has been shown to induce weight loss in adults and adolescents with obesity, its safety and efficacy have not been established in children. In this phase 3a trial, which consisted of a 56-week treatment period and a 26-week follow-up period,we randomly assigned children (6 to <12 years of age) with obesity, in a 2:1 ratio, to receive either once-daily subcutaneous liraglutide at a dose of 3.0 mg (or the maximum tolerated dose) or placebo, plus lifestyle interventions. The primary end point was the percentage change in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters). The confirmatory secondary end points were the percentage change in body weight and a reduction in BMI of at least 5%. A total of 82 participants underwent randomization; 56 were assigned to the liraglutide group and 26 to the placebo group. At week 56, the mean percentage change from baseline in BMI was -5.8% with liraglutide and 1.6% with placebo, representing an estimated difference of -7.4 percentage points (95% confidence interval [CI], -11.6 to -3.2; P<0.001). The mean percentage change in body weight was 1.6% with liraglutide and 10.0% with placebo, representing an estimated difference of -8.4 percentage points (95% CI, -13.4 to -3.3; P = 0.001), and a reduction in BMI of at least 5% occurred in 46% of participants in the liraglutide group and in 9% of participants in the placebo group (adjusted odds ratio, 6.3 [95% CI, 1.4 to 28.8]; P = 0.02). Adverse events occurred in 89% and 88% of participants in the liraglutide and placebo groups, respectively. Gastrointestinal adverse events were more common in the liraglutide group (80% vs. 54%); serious adverse events were reported in 12% and 8% of participants in the liraglutide and placebo groups, respectively. Among children (6 to <12 years of age) with obesity, treatment with liraglutide for 56 weeks plus lifestyle interventions resulted in a greater reduction in BMI than placebo plus lifestyle interventions. (Funded by Novo Nordisk; SCALE Kids ClinicalTrials.gov number, NCT04775082.).

Longitudinal Changes of Clinical, Imaging, and Fluid Biomarkers in Preataxic and Early Ataxic Spinocerebellar Ataxia Type 2 and 7 Carriers.

Brain MRI abnormalities and increases in neurofilament light chain (NfL) have mostly been observed in cross-sectional studies before ataxia onset in polyglutamine spinocerebellar ataxias. Our study aimed to identify longitudinal changes in biological, clinical, and/or imaging biomarkers in spinocerebellar ataxia (SCA) 2 and SCA7 carriers over 1 year. We studied SCA2 and SCA7 carriers and controls (expansion-negative relatives) at the Paris Brain Institute. Inclusion criteria included Scale for the Assessment and Rating of Ataxia (SARA) scores between 0 and 15. Assessments at baseline, 6 months, and 12 months comprised neurologic, quality of life, orofacial motor, neuropsychological, and ophthalmologic examinations, along with gait and oculomotor recordings, brain MRI, CSF, and blood sampling. The primary outcome was the longitudinal change in these assessments over 1 year. We included 15 SCA2 carriers, 15 SCA7 carriers, and 10 controls between May 2020 and April 2021. At baseline, the ages were similar (41 [37, 46] for SCA2, 38 [28.5, 39.8] for SCA7, and 39.5 [31, 54.5] for controls, p = 0.78), as well the sex (p = 0.61); SARA scores were low but different (4 [1.25, 6.5] in SCA2, 2 [0, 11.5] in SCA7, and 0 in controls, p < 0.01). Pons and medulla volumes were smaller in SCAs (p < 0.05) and cerebellum volume only in SCA2 (p = 0.01). Plasma NfL levels were higher in SCA participants (SCA2: 14.2 pg/mL [11.52, 15.89], SCA7: 15.53 [13.27, 23.23]) than in controls (4.88 [3.56, 6.17], p < 0.001). After 1-year follow-up, in SCA2, there was significant pons (-144 ± 60 mm3) and cerebellum (-1,508 ± 580 mm3) volume loss and a worsening of gait assessment; in SCA7, SARA score significantly increased (+1.3 ± 0.4) and outer retinal nuclear layer thickness decreased (-15.4 ± 1.6 μm); for both SCA groups, the orofacial motor assessment significantly worsened. For preataxic and early ataxic carriers, the strongest longitudinal deterioration on outcome measures was orofacial motility in SCA2 and retinal thickness in SCA7. Despite the limitation of the small sample size, we detected annual changes in preataxic and early ataxic SCA individuals across brain MRI imaging, clinical scores, gait parameters, and retinal thickness. These parameters could serve as potential end points for future therapeutic trials in the preataxic phase. ClinicalTrials.gov NCT04288128.

Using weight loss to predict outcome and define a humane endpoint in preclinical sepsis studies

Preclinical mouse models are critical for understanding the pathophysiological response to infections and developing treatment strategies for sepsis. In keeping with ethical values, researchers follow guidelines to minimize the suffering of the mice. Weight loss is a criteria used as a humane end point, but there is no official recommendation for a maximum weight loss leading to euthanasia. To evaluate whether the thresholds used in daily practice are optimal, we performed a comprehensive retrospective analysis of data generated over 10 years with > 2300 mice used in models of infection with Listeria monocytogenes, Streptococcus pneumoniae, Candida albicans and H1N1 influenza virus. Weight loss segregated mice that survived from those that did not. Statistical analyses revealed that lowering the weight loss thresholds used (none, 30% or 20%) would have increased mortality rates due to the sacrifice of mice that survived infections (p < 0.01–0.001). Power calculations showed high variability and reduction of power as weight loss thresholds approached 20% for S. pneumoniae and L. monocytogenes models. Hence, weight loss thresholds need to be adapted to each model of infection used in a laboratory. Overall, weight loss is a valuable predictor of mortality that contributes to the robustness of composite scores. To our knowledge, this is the most extensive study exploring the relationship between weight loss threshold and sepsis outcome. It underscores the importance of the infection-model-specific evaluation of weight loss for use in clinical scores defining humane endpoints to minimize mouse suffering without compromising statistical power and scientific objectives.

UAV path planning based on bird flock migration

Unmanned aerial vehicle, generally referred to as UAV, due to its high-performance and low-cost characteristics, it is particularly widely used in both military and civil applications, and is often used to perform a variety of complex missions. Trajectory planning is the basis for UAVs to realize autonomous flight, which ensures that UAVs avoid obstacles and threatening areas when performing tasks, and guarantees the safe execution of tasks. The operation of a UAV requires finding the safest and most efficient trajectory from a starting point to a specified end point based on several specific constraints. Current UAV trajectory planning algorithms, such as swarm algorithm, particle swarm algorithm, and ant colony algorithm, have been widely recognized, but still have many limitations when they are applied to complex and variable terrain. Therefore, this paper proposes an improved UAV trajectory planning algorithm based on simulated bird migration, and uses matlab for simulation and algorithm evaluation. The simulation results indicate that the improved search strategy is effective, the algorithm can find a better solution in each iteration, and the search strategy of the algorithm can effectively guide the algorithm towards a more optimized region. Overall, this algorithm has high research value in both military and civilian fields.

Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study.

The randomized, open-label, global phase III TROPION-Lung01 study compared the efficacy and safety of datopotamab deruxtecan (Dato-DXd) versus docetaxel in patients with pretreated advanced/metastatic non-small cell lung cancer (NSCLC). Patients received Dato-DXd 6 mg/kg or docetaxel 75 mg/m2 once every 3 weeks. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Objective response rate, duration of response, and safety were secondary end points. In total, 299 and 305 patients were randomly assigned to receive Dato-DXd or docetaxel, respectively. The median PFS was 4.4 months (95% CI, 4.2 to 5.6) with Dato-DXd and 3.7 months (95% CI, 2.9 to 4.2) with docetaxel (hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.91]; P = .004). The median OS was 12.9 months (95% CI, 11.0 to 13.9) and 11.8 months (95% CI, 10.1 to 12.8), respectively (HR, 0.94 [95% CI, 0.78 to 1.14]; P = .530). In the prespecified nonsquamous histology subgroup, the median PFS was 5.5 versus 3.6 months (HR, 0.63 [95% CI, 0.51 to 0.79]) and the median OS was 14.6 versus 12.3 months (HR, 0.84 [95% CI, 0.68 to 1.05]). In the squamous histology subgroup, the median PFS was 2.8 versus 3.9 months (HR, 1.41 [95% CI, 0.95 to 2.08]) and the median OS was 7.6 versus 9.4 months (HR, 1.32 [95% CI, 0.91 to 1.92]). Grade ≥3 treatment-related adverse events occurred in 25.6% and 42.1% of patients, and any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8.8% and 4.1% of patients, in the Dato-DXd and docetaxel groups, respectively. Dato-DXd significantly improved PFS versus docetaxel in patients with advanced/metastatic NSCLC, driven by patients with nonsquamous histology. OS showed a numerical benefit but did not reach statistical significance. No unexpected safety signals were observed.

Twice-Yearly Depemokimab in Severe Asthma with an Eosinophilic Phenotype.

Depemokimab is an ultra-long-acting biologic therapy with enhanced binding affinity for interleukin-5 that may enable effective 6-month dosing intervals. In these phase 3A, randomized, placebo-controlled replicate trials, we evaluated the efficacy and safety of depemokimab in patients with severe asthma and an eosinophilic phenotype characterized by a high eosinophil count (≥300 cells per microliter in the previous 12 months or ≥150 cells per microliter at screening) and a history of exacerbations despite the receipt of medium- or high-dose inhaled glucocorticoids. Patients were randomly assigned in a 2:1 ratio to receive either depemokimab (at a dose of 100 mg subcutaneously) or placebo at weeks 0 and 26, plus standard care. The primary end point was the annualized rate of exacerbations at 52 weeks. Secondary end points, which were analyzed in a hierarchical manner to adjust for multiplicity, included the change from baseline in the score on the St. George's Respiratory Questionnaire (SGRQ), the forced expiratory volume in 1 second, and asthma symptom reports at 52 weeks. Across the two trials, 792 patients underwent randomization and 762 were included in the full analysis; 502 were assigned to receive depemokimab and 260 to receive placebo. The annualized rate of exacerbations was 0.46 (95% confidence interval [CI]), 0.36 to 0.58) with depemokimab and 1.11 (95% CI, 0.86 to 1.43) with placebo (rate ratio, 0.42; 95% CI, 0.30 to 0.59; P<0.001) in SWIFT-1 and 0.56 (95% CI, 0.44 to 0.70) with depemokimab and 1.08 (95% CI, 0.83 to 1.41) with placebo (rate ratio, 0.52; 95% CI, 0.36 to 0.73; P<0.001) in SWIFT-2. No significant between-group difference in the change from baseline in the SGRQ score was observed in either trial, so no statistical inference was drawn on subsequent secondary end points. The proportion of patients with any adverse event was similar in the two groups in both trials. Depemokimab reduced the annualized rate of exacerbations among patients with severe asthma with an eosinophilic phenotype. (Funded by GSK; SWIFT-1 and SWIFT-2 ClinicalTrials.gov numbers, NCT04719832 and NCT04718103.).

Clopidogrel Versus Aspirin as Chronic Maintenance Antiplatelet Monotherapy in Patients After Percutaneous Coronary Intervention With Chronic Kidney Disease: A Post Hoc Analysis of the HOST-EXAM Trial.

Clopidogrel monotherapy improved clinical outcomes compared with aspirin monotherapy during a chronic maintenance period in patients who underwent coronary stenting in the HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Extended Antiplatelet Monotherapy) trial. However, it is uncertain whether the beneficial effect of clopidogrel over aspirin is different according to the renal function. We conducted a post hoc analysis of the HOST-EXAM trial. Chronic kidney disease (CKD) was defined as baseline estimated glomerular filtration rate <60 mL/min per 1.73 m2. The primary end point was a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium bleeding type ≥3, during the 2-year follow up. Among the 5438 patients enrolled in the HOST-EXAM trial, 4844 patients (mean age, 63.3±10.6 years; 74.9% men) with a baseline creatinine value were analyzed in this study. A total of 508 (10.5%) patients had CKD, who were at higher risk of the primary end point compared with those without CKD (hazard ratio [HR], 2.01 [95% CI, 1.51-2.67]). Clopidogrel monotherapy was associated with a lower rate of the primary end point in both patients with CKD (HR, 0.74 [95% CI, 0.44-1.25]) and patients without CKD (HR, 0.71 [95% CI, 0.56-0.91]). No significant interaction was observed between the treatment effect and CKD status (P for interaction=0.889). During the chronic maintenance period after coronary stenting, the risk of thrombotic and bleeding events was significantly higher in patients with CKD compared with those without CKD. There was no statistical difference in the treatment effect of clopidogrel monotherapy in those with versus without CKD.

Preworkout dietary nitrate magnifies training-induced benefits to physical function in late postmenopausal women: a randomized pilot study.

To inform end points for future work, we explored the utility of preworkout (i.e., an acute dose before training) beetroot juice (BRJ) combined with exercise (BRJ + EX) to augment indices of physical function in postmenopausal women compared with exercise only (EX). A two-arm pilot study was used to compare 24 postmenopausal women following an 8-wk, circuit-based exercise intervention. Participants were randomized to BRJ + EX (n = 12) or EX (n = 12). BRJ + EX participants consumed 140 mL of BRJ 120-180 min (only) before training for 7 wk, then discontinued during the final week to mitigate carryover effects. Physical function indices were 6-min walk test (6MWT), estimated V̇o2peak, heart rate recovery (HRR), and maximal knee extensor power (Pmax). A treadmill task was used to measure V̇o2 on-kinetics wherein mean response time (MRT) coincided with the duration to reach 63% of steady-state V̇o2. Results showed greater changes (Δ) among BRJ + EX participants for 6MWT distance (40 ± 23 m vs. 8 ± 25 m; P = 0.003, d = 1.35), ΔV̇o2peak (1.5 ± 0.9 mL·kg-1·min-1 vs. 0.3 ± 1.0 mL·kg-1·min-1; P = 0.008, d = 1.20), and ΔHRR (-10 ± 6 beats/min vs. -1 ± 9 beats/min; P = 0.017, d = 1.05). Large and medium effect sizes favoring BRJ + EX were detected for ΔPmax (P = 0.07, d = 0.83) and ΔMRT (P = 0.257, d = 0.50), respectively. In postmenopausal women, BRJ + EX appears to magnify some adaptive benefits to physical function including aerobic capacity and recovery beyond that of training without BRJ. Investigation into contributing mechanisms is needed.NEW & NOTEWORTHY Though exercise training represents the principal strategy to combat age-related decline, the attendant effects of menopause weaken aspects of exercise adaptation compared with premenopausal women and age-matched men. Here we provide important initial evidence that preworkout (i.e., an acute dose before training) beetroot juice coupled with an 8-wk, circuit-based exercise training intervention may uniquely benefit late postmenopausal women by enhancing indices of physical function including aerobic capacity and recovery.

Nurse-Supported Self-Directed Cognitive Behavioral Therapy for Insomnia

Cognitive behavioral therapy for insomnia (CBTi) is the standard of care for treating insomnia disorder, but access is limited. Alternative approaches are needed to expand access to the standard of care. To examine the effectiveness of a nurse-supported, self-directed behavioral insomnia intervention for decreasing insomnia severity and improving sleep outcomes among veterans, a population with considerable mental health comorbidity. This randomized clinical trial included 178 patients with insomnia disorder who were recruited from a Veterans Affairs hospital (Durham VA Healthcare System) from September 2019 to April 2022 and randomized following baseline assessment; follow-ups were conducted at 8 weeks (primary end point) and 6 months. Data analysis was primarily conducted during the summer of 2023 and concluded in May 2024. Six weekly phone calls from a nurse interventionist plus assigned treatment manual readings covering CBTi treatment components. The health education manual focused on health topics but not sleep. The primary outcome was the Insomnia Severity Index (score range, 0-28; remission <8; differential improvement of 3 points targeted) score assessed at 8 weeks postrandomization. Secondary outcomes were sleep outcomes, depression, fatigue, treatment response, and remission. Of 178 study participants, the mean (SD) age was 55.1 (13.2) years, and 128 (71.9%) identified as men. At 8 weeks, Insomnia Severity Index scores decreased by an estimated mean (SE) of 5.7 (0.51) points in the intervention group and 2.0 (0.47) points in the control group, a differential mean improvement of 3.7 points (95% CI, -5.0 to -2.4; P < .001). Differences were sustained at 6 months (mean, -2.8; 95% CI, -4.4 to -1.3; P < .001). The intervention also resulted in greater improvements at 8 weeks postrandomization in diary sleep onset latency, wake after sleep onset, and sleep efficiency and actigraphy sleep efficiency; these differences were sustained at 6 months. At 8 weeks, depression and fatigue were significantly reduced, and the odds of treatment response and remission were greater in the intervention group compared with controls. This randomized clinical trial found that despite greater prevalence of mental health conditions and sleep difficulties among veterans, a nurse-supported self-directed CBTi was more effective than health education control for reducing insomnia severity and improving sleep outcomes. Although less effective than therapist-delivered CBTi, findings were comparable with other trials using modified CBTi protocols. ClinicalTrials.gov Identifier: NCT03727438.

Midterm outcomes of the Viabahn VBX balloon-expandable covered stent for fenestrations during complex endovascular aortic aneurysm repair

ObjectivesThe optimal bridging stent for fenestrations during complex endovascular aortic aneurysm repair (EVAR) has not been defined. At our institution, the Viabahn VBX is frequently used given its availability and mechanical and heparin-bonding characteristics. This study aimed to assess the performance of the Viabahn VBX vs the iCast balloon-expandable covered stents as bridging stents for fenestrations during complex EVAR. MethodsA retrospective study of consecutive patients undergoing complex EVAR between 2015 and 2021 was performed. Celiac arteries (CAs), superior mesenteric arteries (SMAs), left renal arteries, and right renal arteries stented with fenestrations were grouped according to the type of bridging stent, VBX vs iCast. Target vessels (TV) stented with a branch or scallop were excluded. The primary end points included primary patency and freedom from TV instability. ResultsA total of 292 patients undergoing complex EVAR were treated using VBX or iCast with a mean follow-up of 190 days (interquartile range, 36-384 days) for the VBX cohort and 804 days (interquartile range, 384-1507 days) for the iCast cohort. A total of 677 TVs were stented, including 134 CAs (20%), 175 SMAs (26%), 182 left RAs (27%), 186 right RAs (27%), and 12 additional vessels (2%). Proximal reinforcement was more frequent with VBX than with iCast stent (23% vs 2.4%; P < .0001). There was no difference in primary patency rates at 2 years between VBX and iCast stent for CA (100% vs 96.4%; P = .32), SMA (97.8% vs 100%; P = .14), and the RAs (96.7% vs 99.4%; P = .11). There was no difference between VBX and iCast in the cumulative incidence of type Ic and type IIIc endoleaks (3.2% vs 5.6%; P = .69) or freedom from TV instability at 2 years. ConclusionsViabahn VBX stents are a safe and effective option as bridging stents in fenestrations during complex EVAR with comparable midterm outcomes to iCast stents. However, proximal stent reinforcement may be required with VBX stent to ensure adequate sealing at the fenestrations. Longer follow-ups and larger series are required to assess long-term outcomes and durability.

Lee–Yang edge singularities in QCD via the Dyson–Schwinger equations

We take the Dyson–Schwinger Equation approach of QCD for the quark propagator at complex chemical potential to study the QCD phase transition. The phase transition line of the (2+1)\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$(2+1)$$\\end{document}-flavor QCD matter in the imaginary chemical potential region is computed via a simplified truncation scheme, whose curvature is found to be consistent with the one at real chemical potential. Moreover, the computation in the complex chemical potential plane allows us to determine the location of the Lee–Yang edge singularities. We show explicitly that the critical end point coincides with the Lee–Yang edge singularities on the real μB\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mu _{B} $$\\end{document} axis. We also investigate the scaling behavior of the singularities and discuss the possibility of extrapolating the CEP from a certain range of chemical potential.

Ibrutinib plus rituximab and mini-CHOP in older patients with newly diagnosed DLBCL: a phase 2 ALLG study

AbstractThe multicenter, prospective phase 2 Australasian Leukaemia & Lymphoma Group NHL29 trial was conducted to assess the addition of ibrutinib to R-mini-CHOP (dose attenuated R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients aged ≥75 years with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Treatment consisted of six 21-day cycles of ibrutinib–R-mini-CHOP followed by two 21-day cycles of R-ibrutinib. Coprimary end points were deliverability and 2-year overall survival (OS). The median average relative total dose and average relative dose intensity for the entire regimen were both 97% (interquartile range, 82-100 and 88-100, respectively). With a median follow-up of 35.5 months, the 2-year OS was 68% (95% confidence interval [CI], 55.6-77.4) with a 2-year progression-free survival (PFS) of 60.0% (95% CI, 47.7-70.3). Median OS and PFS were 72 months (95% CI, 35 to not reached) and 40 months (95% CI, 20.4 to not reached), respectively. The overall response rate was 76% (61/79) of patients, with a complete response rate of 71% (56/79). Deaths occurred in 34 of 79 patients (43%), including 17 from progressive disease and 5 treatment related. Overall, 67% patients experienced at least 1 serious adverse event. Most common adverse events were infections and diarrhea (the majority grade 1-2). In both health-related quality of life measures, there was an improvement in functional and symptom scales, median health state classification score, and median visual analogue scale in responders over time. In conclusion, this study showed that the addition of ibrutinib to R-mini-CHOP was both deliverable and efficacious in elderly DLBCL patients.

The role of radiomics analysis in the assessment of renal nodules on CT

PurposeTo develop a radiomics model for the characterization of renal nodules on CT.MethodsPatients who underwent surgical resection of renal nodules, with preoperative CT (LightSpeed VCT, GE) with contrast agent (Iopamidol 370; 1.5 ml/kg) and availability of a histopathological report, were retrospectively included. Renal lesions were segmented by two radiologists in consensus, in the arterial phase on the axial section with greater diameter. The radiomics analysis was performed with validated software (PyRadiomics on Syngo.via Frontier, Siemens) by applying normalization, resampling (1,1,1), setting bin width (15), and applying padding (2). The extracted features were used for training and testing machine learning models (random forest and support vector machine (end point: clear cell carcinoma, ccRCC).Results45 patients were included (mean age 56 years; 34/45 ccRCC). SVM e RF models obtained an AUC of 0.84 and accuracy of 0.87 and 0.80, respectively, in the testing phase.ConclusionRadiomics analysis is feasible and effective in the characterization of renal lesions on CT.

Association of Urinary Metals With Cardiovascular Disease Incidence and All-Cause Mortality in the Multi-Ethnic Study of Atherosclerosis (MESA).

Exposure to metals has been associated with cardiovascular disease (CVD) end points and mortality, yet prospective evidence is limited beyond arsenic, cadmium, and lead. In this study, we assessed the prospective association of urinary metals with incident CVD and all-cause mortality in a racially diverse population of US adults from MESA (the Multi-Ethnic Study of Atherosclerosis). We included 6599 participants (mean [SD] age, 62.1 [10.2] years; 53% female) with urinary metals available at baseline (2000 to 2001) and followed through December 2019. We used Cox proportional hazards models to estimate the adjusted hazard ratio and 95% CI of CVD and all-cause mortality by baseline urinary levels of cadmium, tungsten, and uranium (nonessential metals), and cobalt, copper, and zinc (essential metals). The joint association of the 6 metals as a mixture and the corresponding 10-year survival probability was calculated using Cox Elastic-Net. During follow-up, 1162 participants developed CVD, and 1844 participants died. In models adjusted by behavioral and clinical indicators, the hazard ratios (95% CI) for incident CVD and all-cause mortality comparing the highest with the lowest quartile were, respectively: 1.25 (1.03, 1.53) and 1.68 (1.43, 1.96) for cadmium; 1.20 (1.01, 1.42) and 1.16 (1.01, 1.33) for tungsten; 1.32 (1.08, 1.62) and 1.32 (1.12, 1.56) for uranium; 1.24 (1.03, 1.48) and 1.37 (1.19, 1.58) for cobalt; 1.42 (1.18, 1.70) and 1.50 (1.29, 1.74) for copper; and 1.21 (1.01, 1.45) and 1.38 (1.20, 1.59) for zinc. A positive linear dose-response was identified for cadmium and copper with both end points. The adjusted hazard ratios (95% CI) for an interquartile range (IQR) increase in the mixture of these 6 urinary metals and the corresponding 10-year survival probability difference (95% CI) were 1.29 (1.11, 1.56) and -1.1% (-2.0, -0.05) for incident CVD and 1.66 (1.47, 1.91) and -2.0% (-2.6, -1.5) for all-cause mortality. This epidemiological study in US adults indicates that urinary metal levels are associated with increased CVD risk and mortality. These findings can inform the development of novel preventive strategies to improve cardiovascular health.

Bladder-Preserving Trimodality Treatment for High-Grade T1 Bladder Cancer: Results From Phase II Protocol NRG Oncology/RTOG 0926.

To investigate the use of radiation with radiosensitizing chemotherapy following repeated transurethral resection (trimodality therapy) as an alternative to radical cystectomy in T1 bladder cancer which has failed Bacillus Calmette-Guerin (BCG). Patients with recurrent T1 bladders who had failed BCG and were recommended to undergo cystectomy were treated with trimodality therapy. The primary end point was 3-year freedom from cystectomy. Secondary end points were distant metastasis at 3 and 5 years, local recurrence, disease-specific and overall survival (OS), and safety. This single-arm phase II study enrolled 37 patients. Efficacy and safety were evaluated in 34 patients after three exclusions. The median follow-up was 5.1 years. The 3-year freedom from cystectomy rate was 88% (lower one-sided 97.5% confidence limit [CI], 72%), meeting the primary study goal. OS at 3 and 5 years was 69% (95% CI, 54 to 85) and 56% (95% CI, 39 to 74), respectively. The distant metastasis rates at 3 and 5 years were 12% (95% CI, 4 to 26) and 19% (95% CI, 7 to 34), respectively. Eight patients died due to urothelial cancer, 12 exhibited local recurrence at 3 years (cumulative incidence: 32%; 95% CI, 17 to 48), 18 experienced grade 3 adverse events, mostly hematological, and one developed grade 4 neutropenia. Trimodality therapy is an effective potential alternative to radical cystectomy for recurrent high-grade T1 urothelial cancer of the bladder. At 3 years, 88% of the patients remained free of cystectomy.

Magrolimab plus rituximab in relapsed/refractory indolent non-Hodgkin lymphoma: 3-year follow-up of a phase 1/2 trial

AbstractRelapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) is generally considered incurable with current treatment options. Previous phase 1b/2 results showed combining magrolimab (anti–cluster-of-differentiation [CD] 47 antibody) with the anti-CD20 antibody rituximab (M+R) has antitumor activity against R/R iNHL. We report 3-year follow-up data from this phase 1b/2 study assessing long-term safety and efficacy of M+R in R/R iNHL. After magrolimab priming, 4 patient groups in phase 1b M+R received 10 to 45-mg/kg magrolimab doses with 375 mg/m2 rituximab. Phase 2 explored 30 and 45 mg/kg magrolimab. Primary end points were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory analysis included circulating tumor DNA, biomarkers of magrolimab tumor penetration, and drug target expression assessments. Of 46 patients treated in phase 1b/2, 42 had follicular lymphoma and 4 had marginal zone lymphoma. All patients experienced ≥1 any-grade TEAE, and 44 reported ≥1 treatment-related TEAE. No additional toxicities were reported during long-term follow-up, and there were no treatment-related deaths. Median follow-up was 36.7 (range, 1.2-62.3) months. The ORR was 52.2%, with 30.4% achieving a complete response. The median DOR was 15.9 months, and median time-to-response was 1.8 months. Median PFS and OS were 7.4 (95% confidence interval, 4.8-13.0) months and not reached, respectively. These results demonstrate the long-term safety and efficacy of M+R in patients with iNHL and support further exploration of CD47-based treatment combinations. This trial was registered at www.ClinicalTrials.gov as #NCT02953509.

Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs.

The advent of new therapeutic modalities highlighted deficiencies in the traditional maximum tolerated dose approach for oncology drug dose selection and prompted the Food and Drug Administration (FDA)'s Project Optimus initiative, which suggests that sponsors take a holistic approach, including efficacy, safety, and pharmacokinetic (PK) and pharmacodynamic data, in conjunction with integrated exposure-response (ER) analyses. However, this method comes with an inherent challenge of the collation of the multisource data. To address this issue, an ER-based clinical utility score (CUS) framework, combining benefit and risk into a single measurement, was developed. Model-predicted outcomes for each clinically relevant end point, informed by ER modeling, are converted to a CUS using a user-defined utility function. Thereafter, individual CUS is integrated into a single score with user-defined weighting for each end point. The user-defined weighting feature allows the user to incorporate expert knowledge/understanding into weighing the product's benefit versus risk profile. To validate the framework, data were leveraged from over 50 oncology programs from 2019 to 2023 on the basis of FDA new drug application/biologics license application review packages and/or related literature studies. Five representative cases were selected for in-depth evaluation. Results showed that the optimal benefit-risk ratio (highest CUS) was consistently observed at PK exposures synonymous with recommended doses. A recurring theme across cases was a greater emphasis on safety over efficacy in oncology drug dose determination. The ER-based CUS framework offers a strategic tool to navigate the complexities of dose selection in oncology programs. It serves as a pillar to the importance of integrative data analysis, aligning with the vision of Project Optimus, and demonstrates its potential in guiding dose optimization by balancing therapeutic benefits against risk.

Temporal Shoreline Changes From 1984 to 2022 Along Beymelek Beach and Beymelek Lagoon, Antalya, Türkiye

Coastal zones are important transition zones between land and sea, and the shoreline is subject to dynamic change on both spatial and temporal scales. Accurate measurement and modelling of the shoreline is therefore essential for coastal sustainability and coastal zone management. In this study, the shoreline change of Beymelek Beach and Beymelek Lagoon was analyzed over both short and long periods by using End Point Rate (EPR), Net Shoreline Movement (NSM) and Linear Regression Rate (LRR) statistics from the Digital Shoreline Analyses System (DSAS) tool. The long-term shoreline statistics of the Beymelek Beach indicates that the maximum shoreline accretion was 128.4 m for NSM and 4.3 m/yr for EPR, while the maximum shoreline erosion was -62.6 m for NSM, and -1.8 m/yr for LRR in 1984 and 2022. The maximum shoreline erosion rate of Beymelek Lagoon was -148.5 m for NSM and the maximum shoreline accretion was 5.3 m for NSM between 1984 and 2022. As a result, Beymelek Beach and Beymelek Lagoon have experienced significant shoreline changes over both short and long time periods. Therefore, determining the shoreline change in the study area is crucial for making efficient decisions about the coastal zone and contributing to its sustainability.

DEVELOPMENT OF LEAK DETECTION METHODS FOR USE IN FIELD PIPELINE TRANSPORT

Today, most existing leak detection methods are effective only for stationary operating conditions of pipelines. During transient (dynamic) pumping modes, a significant decrease in the sensitivity of the methods occurs, or inoperability of leak detection systems (LDS) based on them is observed.Accordingly, for the operation of the LDS in the presence of transient processes in pipelines, it is necessary to use special approaches that take into account the features and interrelation of the monitored indicators of the dynamically changing pumping regime with each other. One solution to this problem is the use of a dynamic thermal-hydraulic model of the pipeline, which makes it possible to calculate pumping indicators at intermediate and boundary points of the pipeline at each moment in time.The article presents the developed digital model of a pipeline transporting single-phase flows, as a system of equations obtained from the laws of conservation of mass, momentum and energy. The model describes all significant processes and effects during the movement of the pumped flow through a pipeline and allows you to calculate the main characteristics of the flow, including finding the pressure and temperature distributions along the pipeline route.The method for detecting leaks from field pipelines operating under transient (dynamic) conditions is to compare the actual measured flow rate at the end point of the pipeline with the flow rate calculated using a dynamic model of this pipeline, into which the measured pumping indicators at the inlet of a real object are previously transferred. If there are significant deviations between the calculated pumping flow rate at the outlet of the pipeline in the model and the flow rate measured at the pipeline, a leak is concluded.In order to check the performance of the proposed solutions, modeling of leaking pipelines was carried out in specialized software at various flow rates, media viscosities and leak volumes. Based on the data obtained, a conclusion was made about the efficiency of the developed method.Thus, thanks to the proposed approach, it will be possible to promptly detect and eliminate leaks and withdrawals through unauthorized taps on field pipelines operating in unsteady mode, which in turn will significantly reduce operating costs associated with eliminating the consequences of failures.