Traditional Endpoints Research Articles

A proposed multi-domain, digital model for capturing functional status and health-related quality of life in oncology.

Whereas traditional oncology clinical trial endpoints remain key for assessing novel treatments, capturing patients' functional status is increasingly recognized as an important aspect for supporting clinical decisions and assessing outcomes in clinical trials. Existing functional status assessments suffer from various limitations, some of which may be addressed by adopting digital health technologies (DHTs) as a means of collecting both objective and self-reported outcomes. In this mini-review, we propose a device-agnostic multi-domain model for oncology capturing functional status, which includes physical activity data, vital signs, sleep variables, and measures related to health-related quality of life enabled by connected digital tools. By using DHTs for all aspects of data collection, our proposed model allows for high-resolution measurement of objective data as patients navigate their daily lives outside of the hospital setting. This is complemented by electronic questionnaires administered at intervals appropriate for each instrument. Preliminary testing and practical considerations to address before adoption are also discussed. Finally, we highlight multi-institutional pre-competitive collaborations as a means of successfully transitioning the proposed digitally enabled data collection model from feasibility studies to interventional trials and care management.

Comparison between Bispectral Index-guided Propofol Induction and Clinically-guided Induction in Adult Hypertensive Patients Undergoing Elective Laparoscopic Surgery: A Randomised Controlled Study

Introduction: Traditional clinical endpoints for propofol induction often led to unintentional overdose, leading to haemodynamic instability, delayed recovery, and other complications. Bispectral Index monitoring could potentially prevent undesired haemodynamic changes like hypotension. Aim: To compare BIS-guided propofol induction with clinically guided propofol induction. Materials and Methods: A randomised controlled study was conducted in the Department of Anaesthesiology at Apollo Hospitals, Guwahati, Assam, India, between December 7, 2020 and December 6, 2021, on adult hypertensive patients undergoing elective laparoscopic surgeries. The Clinical Group (n=30) received propofol induction based on clinical guidance, and the Bispectral index group (n=30) underwent Bispectral Index (BIS) guided induction. Demographic variables, the dose of drug required for BIS 50, and the total amount of drug consumed were recorded. After the administration of each dose, Systolic BP (SBP), Diastolic BP (DBP), Mean Arterial BP (MAP), Heart Rate (HR), and SpO2 were recorded. Frequencies and percentages were used to describe qualitative data, whereas the mean and standard deviation were used to express quantitative data. Parametric tests included unpaired t-tests for comparison between groups. A p-value of <0.05 was considered statistically significant. Results: Total 60 patients with 30 in each group, were studied. There was a steady fall in SBP, DBP, and MAP with successive incremental doses of 0.5 mg in both groups. Mean SBP was comparable between the two groups at dosages of 1 mg/ kg, 1.5 mg/kg, and 2 mg/kg. At 2.5 mg/kg, the clinical group had a significantly lower SBP (p=0.0001). Mean DBP was comparable in both groups at doses of 2 mg/kg and 2.5 mg/ kg but significantly lower in the BIS group at 1 mg/kg and at 1.5 mg/kg (p=0.003, p=0.01). Mean MAP was comparable at doses of 2 and 2.5 mg/kg but significantly lower in the BIS group at doses of 1 mg/kg and 1.5 mg/kg (p=0.007, p=0.02). Mean HR was comparable between the two groups at doses of 1 and 1.5 mg/kg. HR showed an increase in group CL and a gradual drop in group BIS with incremental doses. Mean HR was significantly lower in the group BIS at doses of 2 mg/kg and 2.5 mg/kg (p=0.001, p=0.001). The BIS group required a substantially lower total dose of propofol compared to the CL group (158.63±30.57 mg vs. 118.23±28.53 mg, p=0.0001). Conclusion: BIS-guided propofol induction leads to more stable haemodynamics during induction. It helps to titrate propofol administration, which, in turn, reduces the frequency of propofol overdose and its subsequent adverse effects on haemodynamic stability. The total dose of propofol consumed is also reduced.

Patient, Relative and Staff Experiences of Clinical Trial Participation in Neurooncology: "Maybe You Can Also Show the Positive, No Matter How It Ends".

There is a lack of evidence regarding how patients with malignant brain tumor and their relatives experience participation in neurooncological clinical trials. Similarly, insights from the perspective of trial staff caring for this group of patients are missing. This study aims to investigate patient, relative and trial staff experiences regarding participation in clinical neurooncological trials. Within a qualitative exploratory study, 29 semi-structured interviews with brain tumor patients, relatives and trial staff were conducted and analyzed using reflexive thematic analysis (RTA) by Braun and Clarke. A patient researcher and patient council were involved in data analysis and interpretation. Four themes were developed reflecting significant aspects of the trial experience: 1. "It all revolves around hope"; 2. "Trial participation: experiencing unique medical care"; 3. "Everyone's roles are changing"; 4. "Communication as a possible area of conflict". Experiencing trial participation and general medical treatment were found to be interconnected to such a degree that they were often not meaningfully distinguished by patients and relatives. In addition to assessing traditional endpoints for patient outcomes, we recommend increased emphasis on investigating the impact of the "soft" components constituting trial participation. Due to the interconnectedness of medical treatment and trial participation, we recommend further investigation in comparison to experiences in regular care. A deeper understanding of trial participation is needed to inform improvements for patient experiences and staff satisfaction alongside medical and scientific progress.

Artificial Intelligence Technology Enabling Innovation in Museum Public Cultural Service Models

Abstract In this paper, we constructed an artificial intelligence model of environment perception and human body perception, and after filtering the irrelevant information in the environment, we collected and analyzed the three-dimensional information of the environment to realize the intelligent perception of the environment. Aiming at the transient noise that may occur in the robot’s operating environment, a time threshold is added on the basis of the traditional double threshold endpoint detection algorithm, which effectively eliminates the influence of transient noise on endpoint detection and realizes non-contact continuous speech recognition. Then the data of the perceived human body was analyzed to understand the perception of the human body by artificial intelligence. Finally, a model for museum public cultural innovation services was constructed based on AI, and the effects of AI on public cultural services were analyzed. The results show that people’s overall perception of intelligent services is 4.305 points, and the perceived functionality, perceived ease of use, perceived pleasantness, and level of intelligence have a significant positive correlation with the quality of public cultural services, with β-values of 0.286, 0.206, 0.068, and 0.378, respectively, and p<0.05.

Molecular responses of sponge larvae exposed to partially weathered condensate oil

Anthropogenic inputs of petroleum hydrocarbons into the marine environment can have long lasting impacts on benthic communities. Sponges form an abundant and diverse component of benthic habitats, contributing a variety of important functional roles; however, their responses to petroleum hydrocarbons are largely unknown. This study combined a traditional ecotoxicological experimental design and endpoint with global gene expression profiling and microbial indicator species analysis to examine the effects of a water accommodated fraction (WAF) of condensate oil on a common Indo-Pacific sponge, Phyllospongia foliascens. A no significant effect concentration (N(S)EC) of 2.1 % WAF was obtained for larval settlement, while gene-specific (N(S)EC) thresholds ranged from 3.4 % to 8.8 % WAF. Significant shifts in global gene expression were identified at WAF treatments ≥20 %, with larvae exposed to 100 % WAF most responsive. Results from this study provide an example on the incorporation of non-conventional molecular and microbiological responses into ecotoxicological studies on petroleum hydrocarbons.

WITHDRAWN: Digital microfluidics as an emerging tool for bacterial protocols

Three dimensional models of cell culture enables researchers to recreate aspects of tumour biology not replicated by traditional two dimensional techniques. Here we describe a protocol to enable automated high throughput phenotypic profiling across panels of patient derived glioma stem cell spheroid models. We demonstrate the use of both live/dead cell end-points and monitor the dynamic changes in the cell cycle using cell lines expressing the FUCCI cell cycle reporter. Together, these assays provide additional insight into the mechanism of action of compound treatments over traditional cell viability assay endpoints.

Frailty assessment: An emerging concept in aged People Living with HIV (PLHIV).

As the life expectancy of People Living with HIV (PLHIV) has improved with effective antiretroviral treatment (ART), they now face the challenges of accelerated ageing. Frailty is an emerging concept in the management of PLHIV and up to 28% of PLHIV are identified as frail. Frailty is a determinant of adverse clinical outcomes and is a complex clinical endpoint that has not been studied in India. This exploratory study was done to evaluate frailty and its determinants among PLHIV in India. This was a cross-sectional study in 76 PLHIV aged 50 years or more. All the study subjects underwent a comprehensive clinical assessment. The Fried's criteria and Veterans Aging Cohort Study (VACS) Index were used to evaluate for frailty. Socio-demographic, clinical, immunological, and virological variables were assessed for their association with frailty. The study was registered under Clinical Trials Registry-India (ICMR-NIMS): REF/2019/05/025616. The mean age of the subjects was 56.05 ± 5.8 years (range 50-76), and males constituted 81.57% (62/76) of the subjects and majority (60.53%) were underweight. On frailty assessment, 57.89% of the PLHIV were identified as prefrail/frail. Frailty had a significant association with low CD4 count (P = 0.0001) and number of comorbidities (P = 0.017) especially when comorbidities ≥2 (P = 0.04) and polypharmacy (P = 0.033). VACS index, polypharmacy, and low CD4 count ≤200 cells/mm3 were strong predictors of frailty. On multivariate regression analysis, CD4 count ≤200 emerged as the strongest independent predictor of frailty. The study highlighted the high prevalence of frailty and under nutrition among aged PLHIV. The study emphasizes the need for a shift away from traditional clinical endpoints to other outcome measures for a holistic approach to PLHIV.

Security in the Internet of Things (Iot): A Review, Block Chain Applications

The rise of smart technologies in various domains such as homes, cities, and other interconnected systems has propelled the Internet of Things (IoT) into a realm of immense influence, potential, and expansion. Cisco Inc. has forecasted a staggering 50 billion connected devices by 2020, underscoring the rapid proliferation of IoT. Despite this growth, a significant concern looms over the security of these IoT devices, as many are susceptible to hacking and compromise. Their limited computational, storage, and networking capabilities render them more vulnerable compared to traditional endpoint devices like smartphones, tablets, and computers.This paper examines and categorizes the major security challenges facing IoT devices. It reviews prevalent security issues within the layered architecture of IoT, encompassing networking, communication, and management protocols. The paper also delineates the security prerequisites for IoT and surveys current attacks, threats, and state-of-the-art solutions. Additionally, it presents a comparative analysis of IoT security challenges and existing solutions found in the literature.Furthermore, the paper delves into the potential of blockchain, the foundational technology behind bitcoin, as a pivotal tool for addressing numerous security issues in IoT. It discusses how blockchain can enhance security in IoT ecosystems. The paper concludes by outlining open research problems and ongoing challenges in IoT security, underscoring the need for continued innovation in this domain.

Patient-Defined Symptom Burden and Treatment Utilization in a Home-Reported Outcomes (HRO) Study in Sickle Cell Disease (SCD)

Introduction: Sickle cell disease (SCD) is a complex genetic disorder exhibited by diverse symptoms and treatment needs. Past studies have assessed the impact of SCD on patients' symptoms and disease management through patient-reported outcome (PRO) surveys, qualitative interviews, and eDiaries. Challenges associated with point-in-time data capture can hinder researchers' ability to capture the individualistic SCD experience. With the emergence of therapies like voxelotor (Oxbryta),which binds to sickle hemoglobin to reduce hemolysis and anemia, real-world evidence data can be used to close the gap between traditional endpoints and patients' experience of SCD. Objectives: The Ascend Study was designed with a flexible patient-reported data collection approach to understand day-to-day burden by collecting home-reported outcomes (HROs) through the Folia Health mobile and web-based platform. The objectives of the Ascend Study were to 1) Identify the most important symptoms-of-interest to individuals living with SCD; and 2) Understand treatments-in-use among participants taking and not taking voxelotor. Methods: The Advarra IRB-approved study used clinic referrals and community-based organizations to enroll a target of 75 participants. Individuals were eligible if diagnosed with SCD of any genotype residing in the US, aged 13 years and above (self-reported), and caregivers of children aged 4 to 12. Participants selected symptoms and treatments relevant to their individual SCD experience to routinely track in the platform for 3 months on a weekly basis, reporting treatment usage and changes in symptom severity on a 1 to 10 Likert scale. Monthly check-in surveys were conducted to review overall health. Participants could monitor symptom severity history, set treatment reminders, and generate graphs and insight reports in-platform. The study team analyzed active participants, defined as those who completed the study start survey, routine tracking weekly, and at least 2 of 3 monthly check-in surveys. Summary statistics of symptom tracking and treatment usage (including dosage) and subgroup analyses were performed for individuals taking voxelotor and those not taking it. Voxelotor usage was captured through an initial survey, including respective therapy start date (See Table 1). Results: 66 (80.4%) of 84 participants enrolled became active participants and, on average, selected 4.16 (SD=3.25) treatments as part of their routine and tracked a total of 88 distinct treatments. Folic acid was the most frequently selected (n=56) and tracked treatment. 11 types of pain medications were tracked by participants. The average person tracked 4.05 (SD=3.24) different treatments during the study, 2.19 (SD=1.24) of those pain-related. On average, participants taking voxelotor had lower total exposure to NSAID and opioid medication. Participants selected 6.41 (SD=2.84) symptom types and tracked 8.5 (SD=6.07) symptoms during the study. Majority of participants selected fatigue, chronic pain, and trouble concentrating (see Table 2). Participants on voxelotor tracked symptoms at an average of 3.58/10 severity (SD=1.07); those not on voxelotor tracked an average of 5.06/10 severity (SD=0.75). Fatigue was the most frequently tracked symptom overall (3,648 tracks), with an average of 55 fatigue tracks per participant over the 3-month period. This was closely followed by chronic pain (3,572 tracks). 91% (n=60) of all participants tracked each of these symptoms at least once. ‘Chest tightness or pain’ emerged as another important symptom that was tracked by 15 of 66 participants, at an average of 59 tracks per participant. Conclusion: Overall, the ASCEND study underscores the importance of understanding the holistic experience of individuals with SCD and highlights the need for individualized care approaches. Collecting HROs through a novel mobile and web-based platform gives direct insight into the symptom profiles and treatment patterns in SCD, which can lead to a focus towards improved management strategies and better quality of life for individuals living with this complex genetic disorder. These findings have the potential to contribute to the development of more patient-centered approaches to SCD management and help inform providers about the most important symptoms and treatment needs of their patients.

Avoidance behavior of Hyalella azteca in response to three common-use insecticides

Non-target organisms in aquatic environments may experience lethal or sublethal effects following exposure to contaminants. Most protocols and regulations, however, are designed to provide protection from lethal effects and are thus based on conventional estimates of population lethality. The relative lack of reliable behavioral endpoints makes it challenging to implement regulations that are similarly protective against sublethal toxicity. The objective of this study was to quantify the avoidance behavior of Hyalella azteca when exposed to three insecticides—bifenthrin (B), chlorpyrifos (C), and permethrin (P)—at a range of estimated lethal concentrations. A two-choice behavioral arena was used for each chemical to quantify H. azteca activity and time spent in either uncontaminated sediment or sediment spiked at concentrations reflecting estimated 48-h lethal concentrations (LC50, LC25, and LC10). For all three insecticides, naïve H. azteca demonstrated a preference for the uncontaminated sediment over the contaminated sediment at the LC50 (B: 312 ng/gOC; C: 1265 ng/gOC; P: 5042 ng/gOC) and LC25 (B: 230 ng/gOC; C: 859 ng/gOC; P: 3817 ng/gOC), spending significantly more time in the uncontaminated side of the arena. H. azteca did not avoid sediment at LC10 (B: 204 ng/gOC; C: 609 ng/gOC; P: 1515 ng/gOC) levels, indicating the existence of a potential threshold of detection. Despite the lack of substrate preference at this exposure level, H. azteca were nevertheless more active (i.e., increased zone-switching) when exposed to bifenthrin at the LC10, suggesting a possible irritation response (e.g., movement after exposure) to this chemical. Our results provide evidence that H. azteca exhibit innate avoidance responses to sediments contaminated with common insecticides at concentrations below those represented by traditional toxicological endpoints (e.g., LC50). The sensitivity and ease with which this behavioral endpoint can be assayed demonstrates the potential utility of behavioral endpoints in toxicological assessments using model organisms.

RdRp activity test using CRISPR/Cas13a enzyme (RACE) for screening of SARS-CoV-2 inhibitors

The coronavirus disease 2019 pandemic has highlighted the need for efficient antiviral drug screening technologies, particularly for targeting RNA-dependent RNA polymerase (RdRp). Here, we present a novel RdRp activity assay using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 13a (Cas13a) enzyme (RACE) for screening of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibitors. This is the first application of the CRISPR/Cas complex for RdRp activity-based drug screening. The RACE system combines RdRp, RNA template, target inhibitor, CRISPR/Cas13a, and reporter probe, enabling accurate detection of the inhibitory effect on RdRp activity. This is demonstrated by the system's ability to provide half-maximal inhibitory concentration values of 7.5 ± 0.5 and 8.9 ± 0.6 μM for remdesivir triphosphate and C646, respectively. In addition, the RACE system requires a detection time of 5 min, making it more efficient than traditional endpoint assays. The real-time fluorometric output of the RACE system allows monitoring of reactions, providing insight into the kinetics of RdRp activity. Furthermore, the versatility of the RACE system extends to lateral flow assay formats, improving convenience. We anticipate that the RACE system has the potential to identify antiviral compounds that target RdRp, thereby accelerating the development of effective antiviral therapies.

The Value of Progression-Free Survival at Three Years as a Primary Endpoint for Studies on Radiotherapy in Patients with Locally Advanced Cervical Cancer: Individual Patient Data and Validation From 27 Randomized Trials

A traditional endpoint for locally advanced cervical cancer (LACC) clinical trials is overall survival (OS) with five years of follow-up. At present, many clinical trials evaluating concurrent chemoradiotherapy combined with immunotherapy for LACC are underway in worldwide. The use of a shorter-term endpoint could significantly speed the translation of research findings into practice. The primary hypothesis was that PFS with three years of follow-up (PFS36) is an appropriate primary endpoint to replace OS with five years of follow-up (5-year OS). The primary hypothesis was developed from our individual data, was further investigated using phase III randomized controlled trials (RCTs), and then externally validated by phase II trials and retrospective studies up to 2022. Correlation analysis at the treatment-arm level was performed between 2-, 3-, 4-, and 5-year PFS rates and 5-year OS, using the Pearson correlation coefficient r in weighted linear regression, with weight equal to patient size. The MEDLINE, Embase, and PubMed databases, together with the Cochrane Central Register of Controlled Trials, were searched from January 1, 1999, to February 2, 2023. Articles eligible for inclusion contained complete survival data. A total of 613 patients with histologically confirmed, FIGO 2009 stage IB-IVA cervical cancer who underwent radiotherapy at our institute from January 2010 to December 2013 were eligible. Individual patient data were pooled to explore the correlation between PFS and the OS trend. The recurrence rates for years 1 through 5 were 12.9%, 7.3%, 3%, 2.3%, and 1.8%, respectively. The median recurrence time was 13 months and the median time from recurrence to death was 12.2 months. Within all the recurrence, 47.3% of recurrences occurred during the first year, 71.4% in the first two years, and 85% in the first three years. Patients who did not achieve PFS36 had a 5-year OS rate of 30.3%. In contrast, a 5-year OS rate of 98.2% was observed in patients who achieved PFS36. Further data were extracted from 27 RCTs on locally advanced cervical cancer. The trials included 57 arms, with a pooled sample size of 7,692 patients. Formal measures of surrogacy were satisfied. Quality control was performed, where studies with a high risk of bias were excluded. In trial-level surrogacy, PFS36 (r2, 0.778) was associated with 5-year OS. The correlation between PFS36 and OS was externally validated using independent phase II trials and retrospective data. In total, 23 studies representing 5,174 patients were included. PFS36 (r2, 0.719) was found to be associated with OS. The patients who achieved PFS36 had excellent outcomes, whereas patients that experienced earlier progression had poor survival. A significant correlation was found between PFS36 and 5-year OS in clinical trials on patients with locally advanced cervical cancer. These results suggest that PFS36 is an appropriate endpoint for LACC clinical trials of radiotherapy-based regimens.

Combined toxicity of fluorescent silica nanoparticles with cadmium in Ceriodaphnia dubia: Interactive effects of natural organic matter and green algae feeding

The environmental risks of silica nanoparticles (SiNP) reported in the literature are contradictory and bring into question its safety for use in consumer applications. Organisms are never exposed to NPs alone in the real environment, while studies of the combined toxicity of SiNP are limited. To address this, we compared the acute toxicity of fluorescent core-shell SiNPs alone and in mixtures with Cd2+ to Ceriodaphnia dubia in the absence and presence of NOM. We identified biodistribution and feeding behaviour in addition to the traditional endpoints. NOM increased the colloidal stability of SiNPs in reconstituted water. In immobility tests, no significant effects were observed from Cd2+ exposure with NOM and varying concentrations of SiNPs. A similar pattern of curve dose-response was observed for varying concentrations of SiNPs and increasing Cd2+ concentration and constant NOM. Fluorescence microscopy verified a dose-dependent bioaccumulation of SiNPs in C. dubia. Co-exposure to 10 mg L−1 SiNP with NOM and Cd2+ resulted in a stimulated stress feeding response at the lower Cd2+ concentrations which declined at the higher dose due to a functional impairment of the digestive tract. Alterations in feeding behaviour and the increasing bioaccumulation of SiNP indicate a potential ecological risk for Ceriodaphnia dubia from the mixture exposure.

Antibacterial Effect of Topically Administered Tranexamic Acid in Large Joint Arthroplasty

Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine and is commonly used as an antifibrinolytic agent in large joint surgery, such as knee arthroplasty, to minimize blood loss and its associated complications. Some studies have suggested that perioperative intravenous TXA application lowers the incidence of postoperative infections after hip and knee arthroplasty. While its effects on bacteria are not its primary purpose, more research is needed further to elucidate the extent of TXA’s impact on bacterial inhibition and its clinical relevance. In order to determine possible inhibitory effects, 22 clinically relevant bacterial strains were exposed to different TXA concentrations. Two different assays were performed: a microdilution assay with traditional endpoint measurements and a kinetic growth assay for a time-dependent susceptibility assessment. With the microdilution technique, a growth inhibitory effect became evident at higher TXA concentrations (50 and 100 mg/mL) on eight tested bacterial strains, of which four demonstrated absence of growth at 100 mg/mL, suggesting minimal inhibitory concentration. However, the kinetic growth assay revealed more specific TXA-induced dynamic changes in the bacterial growth of all tested bacterial strains. This study showed that TXA affects the growth dynamics of bacteria by altering their lag phase duration, exponential growth rate, and population density and may contribute to the prevention of implant-associated infections.

Feasibility of advanced composite endpoint analysis: Post-hoc insights from the vitamin intervention for stroke prevention randomized control trial

Background and aimsStroke is a major cause of mortality and disability, highlighting the importance of prevention. Clinical trials play an important role in evaluating interventions that can maximize stroke prevention. Traditional composite endpoints (TCE) used in clinical trials have limitations, as they pool together events of varying clinical importance. Weighted composite endpoints (WCE) have emerged as a solution to address these limitations and provide more accurate assessments of outcomes. In this study, we investigate the use of WCE in a previously reported negative clinical trial for stroke prevention. Methods and resultsWe analyzed data from the Vitamin Intervention for Stroke Prevention (VISP) trial, which compared high dose and low dose multivitamin therapy. We utilized weighted methods to analyze time-to-event outcomes with censoring. The primary outcomes of interest were time to nonfatal stroke, nonfatal coronary events, and death. We calculated modified Kaplan-Meier (KM) curves for each intervention group. We also performed a modified log-rank test to assess significant differences based on the weighted KM curves. The analysis included 3668 VISP trial participants, and most remained event-free throughout the study period. The TCE KM curve showed no significant difference in outcomes between high dose and low dose groups. Similarly, the WCE KM curves, with different weights assigned to each outcome, did not reveal significant differences in outcomes between the studied groups. ConclusionThis post-hoc analysis confirms the negative trial results of VISP and demonstrates the feasibility of using WCE in assessing nutrition-based interventions for stroke prevention.

Metabolomic responses in freshwater benthic invertebrate, Chironomus tepperi, exposed to polyethylene microplastics: A two-generational investigation

The accumulation of microplastics (MPs) in sediments could pose risks to benthic organisms and their progeny. Here, we examined effects on traditional apical endpoints along with changes to whole body metabolite profiles induced by irregular shaped polyethylene MPs (1–45 µm) at environmentally relevant concentrations (125, 250, 500 and 1000 MPs/kg sediment) in Chironomus tepperi using a two-generation exposure regime. Survival and emergence of C. tepperi were negatively affected in the parental generation at the two highest concentrations, whereas endpoints associated with growth were only impacted at 1000 MPs/kg sediment. Metabolites associated with several amino acid and energy metabolism pathways were present at lower abundances at the highest exposure concentration suggesting an overall impact on bioenergetics which relates to the inhibition of food acquisition or nutrient assimilation caused by ingestion of MPs, rather than a traditional receptor-mediated toxicity response. In contrast, no significant effects on apical endpoints were observed in the continuous exposure of first filial generation, and lactic acid was the only metabolite that differed significantly between groups. Larvae in unexposed conditions showed no differences in survival or metabolite profiles suggesting that effects in the parental generation do not carry over to the next filial generation. The findings provide evidence on the underlying impacts of MP ingestion and potential adaption to MP exposure of C. tepperi.

Reduced Fasting Duration in Cynomolgus Monkeys Enhances Animal Welfare During Toxicology Studies.

During toxicology studies, fasting animals prior to clinical pathology blood collection is believed to reduce variability in some clinical chemistry analytes. However, fasting adds stress to animals that are already stressed from the administration of potentially toxic doses of the test article. The purpose of this study was to assess the impacts of different fasting durations on cynomolgus monkeys' welfare during toxicology studies. To this end, we assessed the cynomolgus monkeys traditional and ancillary clinical pathology endpoints at different fasting times. We showed that most clinical pathology endpoints were largely comparable between different fasting times suggesting that cynomolgus monkeys could be fasted for as little as 4 hours for toxicology studies, as longer fasting times (up to 20 hours) resulted in stress, dehydration, and significant decreases in blood glucose- changes that impacts animal welfare. Shorter fasting times were associated with higher triglycerides variability among individual animals. Therefore, we propose that shorter fasting time (i.e., 4 hours) should be adequate for most toxicology studies except when: (1) parameters that could be affected by non-fasting conditions are important for safety and pharmacodynamic assessments (i.e., glucose and lipids) and (2) fasting would be needed for the bioavailability of an orally administered test article.

Re-irradiation for recurrent head and neck cancer: Freedom from cancer recurrence rate.

e18077 Background: Salvage re-irradiation (rRT) for patients with locoregionally recurrent head and neck cancer (rHNC) remains challenging. Methods: A retrospective analysis was performed on patients who received rRT between 2011 and 2018. The co-primary endpoint of the study was 2-year freedom from cancer recurrence rate (FCRR) and overall survival (OS), and secondary endpoints were 2-year disease free survival (DFS), local failure (LF), regional failure (RF), distant metastases (DM), and RTOG grade 3≥ late toxicities. Results: A total of 49 cases [nasopharygeal (n = 12); laryngeal (n = 12); oral cavity (n = 11); salivary gland (n = 9); and skin (n = 5)] were identified, adjuvant or definitive rRT were delivered to 22 and 27 patients, respectively. Various rRT fractionation schedules were used and 35/49 (71%) of patients received concurrent chemotherapy. The median follow-up after rRT was 30 months. The 2-year OS, DFS, LF, RF, and DM and FCRR were 64%, 51%, 28%, 32%, 9%, and 39% respectively. MVA showed that poor performance status (PS: 1-2 vs 0) and age > 52 years were predictive of worse OS. While, poor PS (1-2 vs 0) and total dose of rRT < 60Gy were predictive of worse DFS. Late RTOG toxicity of grade 3≥ was reported in 9(18.3%) patients. Conclusions: FCRR at 2 years after salvage rRT for rHNC was higher than other traditional endpoints and could be an important new endpoint to be included in the rRT studies. rRT for rHNC at our cohort was successful; with a manageable level of late sever toxicity.

The value of progression-free survival at three years as a primary endpoint for studies on radiotherapy in patients with locally advanced cervical cancer: Individual patient data from Chinese National Cancer Center and validation from 27 global randomized trials.

5534 Background: A traditional endpoint for locally advanced cervical cancer (LACC) clinical trials is overall survival with five years of follow-up (5-year OS). The use of a shorter-term endpoint could significantly speed the translation of research findings into practice. The primary hypothesis was that PFS with three years of follow-up (PFS36) is an appropriate primary endpoint to replace 5-year OS. Methods: The primary hypothesis was developed from our individual data, was further investigated using phase III randomized controlled trials (RCTs), and then externally validated by phase II trials and retrospective studies up to 2022. Correlation analysis at the treatment-arm level was performed between 2-, 3-, 4-, and 5-year PFS rates and 5-year OS. Correlation analysis was performed using the Pearson correlation coefficient r in weighted linear regression, with weight equal to patient size. The MEDLINE, Embase, and PubMed databases, together with the Cochrane Central Register of Controlled Trials, were searched from January 1, 1999, to February 2, 2023. Articles eligible for inclusion contained complete survival data. Results: A total of 613 patients with histologically confirmed, FIGO 2009 stage IB–IVA cervical cancer who underwent radiotherapy at our institute from January 2010 to December 2013 were eligible. Individual patient data were pooled to explore the correlation between PFS and the OS trend. The recurrence rates for years 1 through 5 were 12.9%, 7.3%, 3%, 2.3%, and 1.8%, respectively. The median recurrence time was 13 months and the median time from recurrence to death was 12.2 months. Within all the recurrence, 47.3% of recurrences occurred during the first year, 71.4% in the first two years, and 85% in the first three years. Patients who did not achieve PFS36 had a 5-year OS rate of 30.3%. In contrast, a 5-year OS rate of 98.2% was observed in patients who achieved PFS36. Further data were extracted from 27 randomized phase III trials on LACC. The trials included 57 arms, with a pooled sample size of 7,692 patients. In trial-level surrogacy, PFS36 (r2, 0.778) was associated with 5-year OS. Sensitivity analysis demonstrated reasonable overall consistency. The correlation between PFS36 and OS was externally validated using independent phase II trials and retrospective data. In total, 23 studies representing 5,174 patients were included. PFS (r2, 0.719) was found to be associated with 5-year OS. Conclusions: A significant correlation was found between PFS36 and 5-year OS in clinical trials on patients with locally advanced cervical cancer. This correlation was found both within patients and across trials. These results suggest that PFS36 is an appropriate endpoint for LACC trials of radiotherapy-based regimens.

Experimental Research on Reconstruction Techniques for Instantaneous Regression Rate of Hybrid Rocket Motor with Single-Port Wagon Wheel Fuel Grain

This study investigated reconstruction techniques for building the instantaneous fuel regression rate of the hybrid rocket motor (HRM). Specifically, an experiment in a laboratory 500 N-class hybrid rocket motor with single-port wagon wheel fuel grain, operated with hydrogen peroxide (HP) and hydroxyl-terminated polybutadiene (HTPB) based fuel (including Al), was carried out. A piece of post-processing software was developed to reconstruct the instantaneous regression rate and other performance parameters of the HRM during the firing test. The results produced by the reconstruction techniques are in good agreement with experimental data obtained by traditional methods, with a maximum error of less than 5.75%. Moreover, compared with the traditional endpoint method, the reconstruction method had a significant advantage, which could ascertain the sensitivity of the regression rate to changes in the oxidizer mass flux and fit the formula of regression rate in a single firing test. Additionally, digital image processing techniques were employed to determine the axial distribution of the fuel regression rate after the test using computed tomography (CT) scanning. This served to verify the accuracy of the instantaneous reconstruction calculation. The error in the average regression rate between CT scanning and the reconstruction calculation was 1.91%, proving that the CT scanning and pixel statistic method of the calculating regression rate was practical for characterizing the axial distribution of the average regression rate during the firing test. In summary, the main objective of this study was to reconstruct the transient parameters of hybrid rocket motor with single-port wagon wheel fuel grain using reconstruction techniques, and to fit the formula of the regression rate through a single-firing test. Furthermore, this paper proposes a modified reconstruction method that is essential for investigating fuel regression rate during the firing test of HRMs.