Cycle Length Research Articles

Aerobic granular sludge sequencing batch reactor for high strength domestic wastewater treatment: Assessing kinetic models and microbial community dynamics

The study aims to treat high strength domestic wastewater (HSDW) and cultivate microbial granular sludge in a sequencing batch reactor (SBR). A bench-scale bioreactor was used for startup. Response surface methodology (RSM) was used to determine the ideal parameters for removing organic materials from HSDW. Organic loading rate (OLR) and cycle time were the independent variables taken into consideration, while the response variable was COD removal. Results from RSM revealed that the optimal conditions for achieving > 98 % COD and TP (>80) removal were a cycle length of 6 h and an OLR of 1.5 kgCOD/m3d. The Modified-Kincannon and the Grau second-order kinetic models were compared to the COD removal rate for the SBR system. The saturation rate constant (Ni) and maximal substrate removal rate (Vc) were proposed to be 6.8 g L−1 d−1 and 0.83 g L−1 d−1, respectively, based on the modified Stover-Kincannon model. The modified Stover-Kincannon (R2 = 0.93673) and Grau second order (R2 = 0.99219) models high correlation coefficient values show that the experimental results and the prediction for the microbial aerobic granular based SBR system accord well. It was discovered that the modified Stover-Kincannon model was less suitable than the Grau second order model. The system microbial community changed because of the granulation process, as the reactor design operation had a big impact on the community structure. Decreased filamentous bacteria favoured several taxa that have been found to exist in granular biomass that is appropriate for treating wastewater. This study sheds important light on the complex interactions that occur between microbial populations and operational variables all through the granulation process in SBR.

CycLight: Learning traffic signal cooperation with a cycle-level strategy

This study introduces CycLight, a novel cycle-level deep reinforcement learning (RL) approach for network-level adaptive traffic signal control (NATSC) systems. Traditional RL-based step-by-step traffic signal controllers, while precise and responsive, demand high computational resources for frequent data exchanges and can increase traffic accident risks due to disordered phase switching. Different from the step-by-step control strategy aforementioned, the proposed CycLight adopts a cycle-level strategy, optimizing cycle length and splits simultaneously using Parameterized Deep Q-Networks (PDQN) algorithm. This cycle-level approach effectively reduces the computational burden associated with frequent data communication, meanwhile enhancing the practicality and safety of real-world applications. Moreover, a decentralized framework is formulated for multi-agent cooperation, while attention mechanism is integrated to accurately assess the impact of the surroundings on the current intersection. CycLight is tested in a large synthetic traffic grid using the microscopic traffic simulation tool, Simulation of Urban MObility (SUMO). Experimental results not only demonstrate the superiority of CycLight over other state-of-the-art approaches but also showcase its robustness against information transmission delays.

Explicit coordinated signal control using soft actor–critic for cycle length determination

AbstractExplicit signal coordination carries prior knowledge of traffic engineering and is widely accepted for global implementation. With the recent popularity of reinforcement learning, numerous researchers have turned to implicit signal coordination. However, these methods inevitably require learning coordination from scratch. To maximize the use of prior knowledge, this study proposes an explicit coordinated signal control (ECSC) method using a soft actor–critic for cycle length determination. This method can fundamentally solve the challenges encountered by traditional methods in determining the cycle length. Soft actor–critic was selected among various reinforcement learning methods. A single agent was administered to the arterials. An action is defined as the selection of a cycle length from among the candidates. The state is represented as a feature vector, including the cycle length and features of each leg at every intersection. The reward is defined as departures that indirectly minimize system vehicle delays. Simulation results indicate that ECSC significantly outperforms the baseline methods, as evident in system vehicle delay across nearly all demand scenarios and throughput in high demand scenarios. The ECSC revitalizes explicit signal coordination and introduces new perspectives on the application of reinforcement learning methods in signal coordination.

Tachycardia with cycle length alternans in Ebstein's anomaly.

The tachycardia which presents with regularly irregular rhythm consists of a broad set of differential diagnoses. We present a case of cycle length alternans tachycardia in a patient, with Ebstein's anomaly and describe how a diagnosis was arrived at after careful analysis of electrocardiogram and EGMs.

Atg7 autophagy-independent role on governing neural stem cell fate could be potentially applied for regenerative medicine.

A literature review showed that Atg7 biological role was associated with the development and pathogenesis of nervous system, but very few reports focused on Atg7 role on neurogenesis at the region of spinal cord, so that we are committed to explore the subject. Atg7 expression in neural tube is incrementally increased during neurogenesis. Atg7 neural-specific knockout mice demonstrated the impaired motor function and imbalance of neuronal and glial cell differentiation during neurogenesis, which was similarly confirmed in primary neurosphere culture and reversely verified by Atg7 overexpression in unilateral neural tubes of gastrula chicken embryos. Furthermore, activating autophagy in neural stem cells (NSCs) of neurospheres did not rescue Atg7 deficiency-suppressed neuronal differentiation, but Atg7 overexpression on the basis of autophagy inhibition could reverse Atg7 deficiency-suppressed neuronal differentiation, which provides evidence for the existence of Atg7 role of autophagy-independent function. The underlying mechanism is that Atg7 deficiency directly caused the alteration of cell cycle length of NSCs, which is controlled by Atg7 through specifically binding Mdm2, thereby affecting neuronal differentiation during neurogenesis. Eventually, the effect of overexpressing Atg7-promoting neuronal differentiation was proved in spinal cord injury model as well. Taken together, this study revealed that Atg7 was involved in regulating neurogenesis by a non-autophagic signaling process, and this finding also shed light on the potential application in regenerative medicine.

Comparison Between Sotorasib with Docetaxel for the Treatment of Chinese Patients with Previously Treated NSCLC with KRASG12C Mutation: A Cost-Effectiveness Analysis to Inform Drug Pricing.

This study sought to investigate the affordable price of sotorasib among patients with previously treated advanced KRASG12C-mutant non-small cell lung cancer (NSCLC) through a cost-effectiveness analysis from the perspectives of both the Chinese healthcare system and the patients. We developed a Markov model spanning a 20-year time horizon with a cycle length of 21 days. Our data were derived from the CodeBreaK 200 clinical trial, supplemented with published literature, publicly available national databases, and local hospitals. The primary outcomes were the affordable prices of sotorasib which would result in the incremental cost-effectiveness ratios (ICERs) of sotorasib relative to docetaxel below the preset willing-to-pay (WTP) threshold. Sensitivity analyses were performed to evaluate the model's robustness. At the national level, from the perspective of the Chinese healthcare system and patients, the price of sotorasib should be lower than US$0.04673 and $0.03231, respectively, to make it affordable, which is equivalent to $1346 and $931 per box (120mg × 240 pieces). At the provincial level, the price ceiling of sotorasib/mg fluctuated between $0.04084 to $0.08061 from the Chinese healthcare system's perspective and between $0.02642 to $0.06620 from the patients' perspective. Probabilistic sensitivity analyses revealed that, as the price of sotorasib decreased, its likelihood of being cost-effective increased. Sotorasib might be a cost-effective therapy in China. The pharmaco-economic evidence generated from this study has significant implications not only for guiding the drug pricing of the upcoming sotorasib but also for determining the reimbursement ratio for its potential inclusion in the National Reimbursement Drugs List in the future.

The Use of High-Density UN Fuel in Heat-Pipe Microreactors

Heat-pipe microreactors (HPMRs) are very small-scale nuclear reactors that employ heat pipes (HPs) for heat removal. HPMRs can be easily integrated with other forms of renewable energies, can be used for emergency responses to disaster relief zones, can be deployed in remote locations not connected to the grid, and can be removed from sites and replaced by new ones. HPMRs can also be used for space missions as HPs do not rely on gravity for heat transfer. Conventional fuel materials, such as uranium oxide (UO2) and uranium oxycarbide (UCO), are currently considered in most existing HPMR designs, but ceramic uranium nitride (UN) fuel that has high uranium density, high thermal conductivity, and high melting point may become a better fuel candidate. Through neutronics calculations, this paper assesses the impact of using UN fuel in HPMRs with two different neutron spectra (fast and thermal) and two different fuel forms [traditional solid fuel pellets and TRi-structural-ISOtropic (TRISO) fuel compacts]. It was concluded that retrofitting HPMRs with UN fuel has the potential to reduce the initial 235U enrichment requirement by ~3 wt% (to keep the same cycle length) or increase the cycle length (by keeping the same initial 235U enrichment), which enables more compact and transportable HPMR core designs. However, using UN fuel decreases the control element worth [by up to 20% for the Special Purpose Reactor (SPR) and 5% for HP-MR] and is up to 80% more costly. Increasing 15N enrichment can further decrease the initial 235U enrichment requirement and increase the control element worth but is more costly. Compared to fast-spectrum HPMRs fueled with solid pellet fuels, retrofitting UN fuel is more suitable for thermal-spectrum HPMRs fueled with TRISO fuel compacts, where the neutron spectrum hardening caused by using UN is less significant.

The value of ripple mapping in the age of coherent mapping in scar-related atrial tachycardia.

An accurate display of scar-related atrial tachycardia (ATs) is a key determinant of ablation success. The efficacy of ripple mapping (RM) in identifying the mechanism and critical isthmus of scar-related ATs during coherent mapping is unknown. A total of 97 patients with complex ATs who underwent radiofrequency catheter ablation at our center between October 2018 and September 2022 were included. ATs was mapped using a multielectrode mapping catheter on the CARTO3v7 CONFIDENCE module. Coherent and RM were used to identify the reentrant circuit. The mechanisms of 128 ATs were analyzed retrospectively (84 anatomic-reentrant ATs and 44 non-anatomic reentrant ATs). The median AT cycle length was 264±25ms. The correct diagnosis was achieved in 83 ATs (68%) using only coherent mapping. Through coherent mapping plus RM, 114 ATs (84.2%) were correctly diagnosed (68% vs. 89%, p=.019). In non-anatomical reentrant ATs, 81% of the diagnostic rate was achieved by reviewing both coherent and ripple mapping compared to reviewing coherent mapping alone (81% vs. 52%, p=.03). Reviewing coherent mapping and ripple mapping showed a higher diagnostic rate in patients who underwent cardiac surgery than those with Coherent mapping alone (64% vs. 88%, p=.04). Coherent mapping combined with RM was superior to coherent mapping alone in identifying the mechanism of scar-related ATs post-cardiac surgery and non-anatomic reentrant ATs.

Long term reactivity operation for a high temperature testing reactor (HTTR) loaded with uranium nitride fuel

A High Temperature Testing Reactor (HTTR) is one of the fourth generation nuclear reactors, the reactor uses UO2 as typical fuel with different axial and radial enrichments. In the present research, uranium nitride (UN) is proposed as a fuel for the reactor for the same core enrichment distribution. The core multiplication factor, cycle length, discharge burnup are calculated and the results of UO2 fuel are compared with UN fuel results. Neutron spectrum, fissile isotopes behavior and Breeding capability are compared for the two fuel types. Kinetic parameters, Control rods and Burnable poisons worth are also evaluated. The results indicated that uranium nitride (UN) has a longer fuel cycle, higher breeding capability and harder thermal flux compared to UO2 fuel.

Exploring the mechanism of membrane fouling alleviation with furanone and its derivatives addition as quorum sensing inhibitors

Membrane fouling is still the primary bottleneck issue for the widespread application of anaerobic membrane bioreactor (AnMBR) and quorum quenching (QQ) strategy is one of the feasible approaches for its fouling alleviation. In this study, 2(5H)-furanone was applied as an efficient, cost-effective and non-toxic QSI in a laboratory-scale AnMBR, achieving not only a doubled membrane filtration cycle length but also ensuring relatively stable treatment performance and enhanced methane production. The retarded membrane fouling could result from reduced soluble microbial product (SMP) and extracellular polymer substance (EPS) concentration, decreased by 13.6 % and 26.8 % compared with that in conventional AnMBR. Meanwhile, the biocake morphology also suggest reduced biofilm thickness and less organic deposition on the QQ-AnMBR. The microbial diversity analyses indicated that 2(5H)-furanone addition can accumulate the fermentative and acetogenic bacteria (Propioniciclava, Longilinea and norank_f__Anaerolineaceae in both sludge mix suspensions and biocake) and methanogens (Methanosaeta in bulk sludge, Methanosaeta and Methanobacterium in the biocakes), improving the anaerobic process in AnMBR. Moreover, the relative abundance of norank_f__norank_o__SJA-15, a typical filamentous bacterium and fouling-related microbe, significantly reduced after 2(5H)-furanone addition in the bulk sludge of QQ-AnMBR. Additionally, this study elucidated the membrane fouling control mechanism by 2(5H)-furanone addition through metagenomic and molecular docking analyses. Results indicate that 2(5H)-furanone may control membrane fouling mainly through quorum sensing processes inhibition by (i) competition of 2(5H)-furanone and acyl-homoserine lactones (AHLs) for binding sites on QS receptor proteins, and (ii) quorum quenching with increased lactone enzymes abundance and decreased AHLs concentration. These findings offer valuable insights that can significantly contribute to the advancement of this technology with membrane fouling control.

Changes in Exhaled Carbon Dioxide during the Menstrual Cycle and Menopause

Introduction: The menstrual cycle (MC) reflects multifaceted hormonal changes influencing women’s metabolism, making it a key aspect of women’s health. Changes in hormonal levels throughout the MC have been demonstrated to influence various physiological parameters, including exhaled carbon dioxide (CO2). Lumen is a small handheld device that measures metabolic fuel usage via exhaled CO2. This study leverages exhaled CO2 patterns measured by the Lumen device to elucidate metabolic variations during the MC, which may hold significance for fertility management. Additionally, CO2 changes are explored in menopausal women with and without hormonal replacement therapy (HRT). Methods: This retrospective cohort study analyzed exhaled CO2 data from 3,981 Lumen users, including eumenorrheal women and menopausal women with and without HRT. Linear mixed models assessed both CO2 changes of eumenorrheal women during the MC phases and compared between menopausal women with or without HRT. Results: Eumenorrheic women displayed cyclical CO2 patterns during the MC, characterized by elevated levels during the menstrual, estrogenic and ovulation phases and decreased levels during post-ovulation and pre-menstrual phases. Notably, despite variations in cycle length affecting the timing of maximum and minimum CO2 levels within a cycle, the overall pattern remained consistent. Furthermore, CO2 levels in menopausal women without HRT differed significantly from those with HRT, which showed lower levels. Conclusion: This study reveals distinct CO2 patterns across MC phases, providing insights into hormonal influences on metabolic activity. Menopausal women exhibit altered CO2 profiles in relation to the use or absence of HRT. CO2 monitoring emerges as a potential tool for tracking the MC and understanding metabolic changes during menopause.

Loading pattern optimization of a PWR using newly developed Multi-Verse optimization algorithm

In the fuel management of nuclear reactors, which has a direct impact on power generation costs and environmental factors, it is essential to obtain an optimal arrangement of assemblies and core parameters. This complex task relies on both neutronics and thermal hydraulics. This research solves this by employing PARCS and COBRA-EN codes, alongside Multi-Verse Optimization algorithm (MVO) as a novel algorithm. Findings demonstrate the MVO algorithm has reliability and favorable convergence rate. Moreover, integrating the nodal expansion technique with MVO notably decreases the computational time for optimization in the loading pattern optimizations (LPOs). The optimized loading pattern aligns well with the findings in the literature. Also, using multi objective fitness function leads to improving core flatness, cycle length and safety parameters.

Unveiling Systemic Immune Inflammation Index Correlations in Women with Polycystic Ovary Syndrome: A Cross-sectional Study

Background: Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-age women that imposes metabolic and cardiovascular risks. Systemic immune inflammation index (SII), an inflammatory biomarker calculated from a complete blood count, was linked to many metabolic and cardiovascular illnesses. Objective: To evaluate the SII correlation with clinical, biochemical, and hormonal parameters characteristic of PCOS cases for screening and diagnostic values. Methods: For fifty PCOS patients who were eligible, we did a cross-sectional study and collected three types of information on each person: demographic information like age, menstrual cycle length, and body mass index (BMI); hormonal information like LH/FSH ratio, testosterone, and fasting insulin; and biochemical information like the homeostasis model assessment of insulin resistance (HOMA-IR), serum cholesterol, serum HDL, and serum LDL. The systemic inflammatory index (SII) was calculated from a complete blood count. Results: We found a strong positive correlation between SII and BMI, LH/FSH ratio, testosterone, fasting serum insulin, HOMA-IR, cholesterol, and LDL. However, the correlation between SII, HDL and menstrual cycle days was negative. Regarding the other parameters (HOMA-IR, testosterone, cholesterol, BMI, and LH/FSH ratio), the best subset regression model figures out how strongly SII is linked to each one. Conclusions: SII was strongly and significantly correlated to PCOS clinical, biochemical, and hormonal parameters, which makes it recommendable for screening. Its feasibility, affordability, and meaningful correlation inspired therapeutic and prognostic applications in practice.

PIPAC in patients with peritoneal metastases from gastrointestinal tract (PIPOX01): An open label, non-comparative phase 1/2 dose escalation and expansion trial

BackgroundDespite modern systemic chemotherapy, survival remains poor for patients with advanced isolated peritoneal metastases from the gastrointestinal tract. We aimed to assess the safety and efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin. Patients and methodsWe conducted a phase 1/2, open label, non-comparative, dose escalation and expansion trial of PIPAC with oxaliplatin in patients with a peritoneal cancer index (PCI) of more than 5, 13 and 15 for respectively a gastric, small bowel and colorectal primary cancer, and who had received at least three months of systemic chemotherapy. PIPAC cycle lengths were 4–6 weeks with systemic chemotherapy allowed 15 days after each PIPAC. PCI and oxaliplatin tumor concentration were assessed every PIPAC cycle. The main endpoints were tolerability, tumor response, and survival. ResultsBetween 2017 and 2020, 34 patients were enrolled in three centers, in this phase 1/2 study, of whom 25 were evaluable at the recommended dose determined in the phase I trial (90 mg/m2 plus systemic 5-FU). Before inclusion, patients received a median of 2 [1–4] chemotherapy lines and had a median PCI of 22.5 [7–29]. At this dose, the safety profile showed acceptable tolerability. Eight patients (32 %) had grade 3/4 treatment-related adverse events. Minor (grade 1/2) adverse events were mainly abdominal pain (n = 19, 76 %) and nausea (n = 16, 64 %). Median PFS was 6.1 months and median OS was 13 months. ConclusionIn patients with advanced and refractory peritoneal metastasis, PFS of 6.1 months is encouraging. A prospective randomized phase II study is required.

Cost-effectiveness of one-stop-shop [18F]Fluorocholine PET/CT to localise parathyroid adenomas in patients suffering from primary hyperparathyroidism.

We conducted a cost-effectiveness analysis in which we compared a preoperative [18F]Fluorocholine PET/CT-based one-stop-shop imaging strategy with current best practice in which [18F]Fluorocholine PET/CT is only recommended after negative or inconclusive [99mTc]Tc-methoxy isobutyl isonitrile SPECT/CT for patients suffering from primary hyperparathyroidism. We investigated whether the one-stop-shop strategy performs as well as current best practice but at lower costs. We developed a cohort-level state transition model to evaluate both imaging strategies respecting an intraoperative parathyroid hormone monitored treatment setting as well as a traditional treatment setting. The model reflects patients' hospital journeys after biochemically diagnosed primary hyperparathyroidism. A cycle length of twelve months and a lifetime horizon were used. We conducted probabilistic analyses simulating 50,000 cohorts to assess joint parameter uncertainty. The incremental net monetary benefit and cost for each quality-adjusted life year were estimated. Furthermore, threshold analyses regarding the tariff of [18F]Fluorocholine PET/CT and the sensitivity of [99mTc]Tc-methoxy isobutyl isonitrile SPECT/CT were performed. The simulated long-term health effects and costs were similar for both imaging strategies. Accordingly, there was no incremental net monetary benefit and the one-stop-shop strategy did not result in lower costs. These results applied to both treatment settings. The threshold analysis indicated that a tariff of €885 for [18F]Fluorocholine PET/CT was required to be cost-effective compared to current best practice. Both preoperative imaging strategies can be used interchangeably. Daily clinical practice grounds such as available local resources and patient preferences should inform policy-making on whether a hospital should implement the one-stop-shop imaging strategy.

On 2-factors with long cycles in 3-connected claw-free graphs

For a graph H, let δ(H) be the minimum degree and let c(H) be the length of a longest cycle in H. A 2-factor of H is a spanning subgraph of H in which every component is a cycle. In [Discrete Math. 313 (2013) 1934-1943], Čada and Chiba asked if H is a 3-connected claw-free graph of order n with δ(H) sufficiently large, does H have a 2-factor F such that c(F)≥min⁡{9δ(H)−3,n}? In this paper, to answer their question, we show that if H is a 3-connected claw-free graph of order n with δ(H)≥15, then H has a 2-factor F such that c(F)≥min⁡{9δ(H)−3,n}.

Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear. We employed a large animal model, the female landrace pig, and used multiple in vivo and ex vivo approaches including pharmacological challenges, electrophysiology, and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta, or combined alpha-beta blockade), ganglionic blockade (hexamethonium), nor inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened the action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate. GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signalling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pacemaking. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in people treated with GLP-1 RAs.

A phase 2/3 study of Bicycle toxin conjugate BT8009 targeting nectin-4 in patients with locally advanced or metastatic urothelial cancer (la/mUC): Duravelo-2.

TPS4619 Background: BT8009 is a Bicycle toxin conjugate (BTC), comprising a highly selective bicyclic peptide targeting nectin-4 linked to the cytotoxin monomethyl auristatin E (MMAE) via a cleavable linker. Nectin-4 is an adhesion molecule commonly expressed in many tumor types, including urothelial cancer (UC), and is a validated therapeutic target (Hoffman-Censits 2021). BT8009 has a low molecular weight and short plasma half-life, with potential to rapidly penetrate solid tumors and reduce toxicity by minimizing exposure to normal tissue (Rigby 2022). Results from the ongoing phase 1/2 clinical trial of BT8009 (NCT04561362) indicate preliminary antitumor activity and a tolerable safety profile in patients (pts) with advanced malignancies including UC (Baldini 2023). This global, open label, phase 2/3 multicenter adaptive study aims to evaluate the safety and efficacy of BT8009 as monotherapy, or combined with pembrolizumab (pembro), vs chemotherapy in pts with locally advanced or metastatic UC (la/mUC) (NCT06225596/BT8009-230; Duravelo-2). Methods: The trial will enroll up to 956 adult pts in 2 cohorts. Cohort 1 will include n≤641 previously untreated pts eligible for platinum-based chemotherapy. Cohort 2 will include n≤315 pts with ≥1 prior systemic therapy, excluding enfortumab vedotin or other MMAE-based therapy. Pts must have la/mUC of the renal pelvis, ureter, bladder, or urethra, ECOG performance status ≤2 (Cohort 1) or ≤1 (Cohort 2), and adequate organ function. Cohort 1 will be randomized 1:1:1 to receive: 1) BT8009 5 mg/m2 on days (D)1, 8, and 15 + pembro 200 mg on D1; 2) BT8009 6 mg/m2 on D1 and 8 + pembro 200 mg on D1; or 3) chemotherapy (gemcitabine + cisplatin / carboplatin, followed by avelumab maintenance). Cohort 2 will be randomized 1:1 to receive: 1) BT8009 5 mg/m2 on D1, 8, and 15 or 2) BT8009 6 mg/m2 on D1 and 8. Cycle lengths will be 21D (28D for avelumab). After 30 pts in each dose arm have 9 weeks follow-up, an interim analysis will determine the optimal dose of BT8009 + pembro (Cohort 1) or BT8009 monotherapy (Cohort 2) to be used for the rest of the study. An additional Cohort 2 arm, optimal dose of BT8009 + pembro, will open after completion of the interim analysis. Discontinuation criteria include planned completion of therapy, progressive disease, and intolerable toxicity. Primary endpoints are progression-free survival (PFS; Cohort 1) and objective response rate (ORR; Cohort 2) assessed by blinded independent central review. Secondary endpoints are ORR (Cohort 1), PFS (Cohort 2), and overall survival, duration of response, disease control rate, safety/tolerability, and health-related quality of life (Cohorts 1 and 2). Pharmacokinetics, incidence/titers of antidrug antibodies, and tumor/peripheral biomarkers are exploratory endpoints. Efficacy endpoints will be assessed per RECIST v1.1. This study is actively recruiting. Clinical trial information: NCT06225596 .

Performance Evaluation of Signalized Intersection- A Case study of Prithivi Chowk, Pokhara

Prithivi Chowk, a heavily trafficked signalized intersection in Pokhara, Nepal, currently relies on manual traffic control, leading to significant issues during peak hours. This study employs the Highway Capacity Manual (HCM) methodology to evaluate the intersection's performance, aiming to address congestion and recommend improvements. Data collected from July 10-12, 2023, during peak hours, indicated traffic volumes of 6369.5 PCU/h in the morning and 6275.5 PCU/h in the evening, demonstrating over-saturation. The analysis included 12 vehicular and 4 pedestrian directions, with peak hour factors of 0.942 and 0.954, respectively.Initial assessments of three lane configurations and signal phasing plans revealed all phase plans exceeded capacity, resulting in a Level of Service (LOS) 'F'. Subsequent evaluations involved geometric enhancements, such as adding lanes. Increasing lanes in the Eastbound Through, Northbound Right Turn, and Westbound Right Turn directions significantly improved performance, achieving LOS 'D' in the third iteration of Phase Plan I. Optimal signal timings were designed using the Webster method, resulting in cycle lengths of 123 seconds for the morning peak and 116 seconds for the evening peak. The study highlights critical challenges and proposes targeted measures to enhance traffic flow at Prithivi Chowk, offering valuable contributions to transportation engineering and urban planning in Nepal. These findings emphasize the need for systematic traffic management improvements to mitigate congestion and enhance intersection performance.

Disparities and outcomes of immune checkpoint inhibitor therapies in LMICs: Retrospective study on current state, efficacy, and challenges in Armenia.

e23315 Background: The escalating incidence of cancer in Armenia is a global trend, underscoring the urgency for innovative treatments, including immune checkpoint inhibitors (ICIs). This study, a first in the region, investigates ICIs' real-world impact, emphasizing the current state and critical gaps in access to care. Methods: We conducted a retrospective review of 224 patients, excluding 32, resulting in 192 patients treated with ICIs between 2017 and 2023 across four major oncology centres. The review covered demographic and clinical data, genetic testing, treatment regimens, and survival outcomes, analyzed using the STATA 18 BE. Results: The mean age of the patients was 61.4 years, with 69.27% being male. Lung cancer was the most common diagnosis (42.19%, n = 81), followed by melanoma (11.98%, n = 23) and gastric cancer (10.94%, n = 21). Survival outcomes varied, with melanoma patients exhibiting a mean overall survival (OS) of 33.26 months, lung cancer patients 19.69 months, and gastric cancer patients 20.50 months; the survival difference between patients with metastases and without was not statistically significant. Patients receiving ICIs in the second or later lines of treatment had a 2.12-fold lower chance of survival compared to those receiving them as first-line treatment (95% CI 1.16-3.88, p = 0.014). 78% of patients received ICIs in the metastatic setting and only 22% in curative. In two centres, among 185 patients with metastatic lung cancer, only 23.2% (43 patients) received ICIs, and of these, about 50% underwent mutation testing, with only 4 assessed via broad panel NGS. A significant 76.8% (142 patients) did not receive immunotherapy. Furthermore, 34% of those starting ICI treatment were forced to discontinue due to financial hardships. Pembrolizumab and Nivolumab were the most widely used agents, but the choice varies significantly between centres. Conclusions: The financial barrier is substantial: the cost of one pembro cycle on the black market, at $3,000, is 3.8 times the annual income of those at the national poverty line, more than twice the income of the lower middle-income class, and represents over 60% of the country's GDP per capita. Median cycle lengths for ICIs, such as 6.5 for Ipil+Nivo and 5.61 for Pembro, are below the NCCN's standard recommendations, highlighting the profound impact of financial constraints on treatment adherence and duration. This study reveals the stark reality of ICI accessibility and affordability in Armenia, where a significant portion of cancer patients are unable to benefit from these potentially life-extending treatments. Additionally, a preference bias towards selecting treatments without nationwide guidelines was observed, alongside the absence of a national E-health database, underscoring the need for policymaker attention, insurance adjustments, and more precise, prospective data collection.