Influence on Mycotox® NG effects on relative weights of some internal organs in Pekin ducks with experimentally reproduced aflatoxicosis В1

Contamination of poultry feeds with mycotoxins is a global problem faced by poultry industry due to increased demands and availability of poor-quality cereals. The aim of the present study was to evaluate the beneficial effects of a mycotoxin binder (Mycotox NG) on relative weights of internal organs in Pekin ducks with experimental aflatoxicosis. The birds were divided into one control and six experimental groups (n=10) as follows: group І (0 mg/kg AFB1 without Mycotox NG); group ІI (0.5 g/kg Mycotox NG); group ІІI (1.0 g/kg Mycotox NG); group IV (0.2 mg/kg AFB1); group V (0.4 mg/kg AFB1); group VI (0.2 mg/kg AFB1 + 0.5 g/kg Mycotox NG) and group VII (0.4 mg/kg AFB1 + 1.0 g/kg Mycotox NG). Trial duration was 42 days. It was established that ducks fed AFB1-contaminated feed had increased relative weights of liver, kidneys, pancreas, heart, gizzard and proventriculus compared to the control group. At the same time, the relative weights of immunocompetent organs (thymus, spleen and bursa of Fabricius) were reduced. The addition of Mycotox NG to the feed contaminated with AFB1 compensated partly the changes in relative weights of visceral organs. The results from the present study demonstrated that the tested toxin binder could be effective for reduction of toxic effects of aflatoxins in domestic ducks.

Probability-of-decision interval 3+3 (POD-i3+3) design for phase I dose finding trials with late-onset toxicity

Late-onset toxicities often occur in phase I trials investigating novel immunotherapy and molecular targeted therapies. For trials with cohort based designs (such as modified toxicity probability interval, Bayesian optimal interval, and i3+3), patients are often turned away since the current cohort are still being followed without definite dose-limiting toxicities, which results in prolonged trial duration and waste of patient resources. In this paper, we incorporate a probability-of-decision framework into the i3+3 design and allow real-time dosing inference when the next patient becomes available. Both follow-up time for the pending patients and time to dose-limiting toxicities for the observed patients are used in calculating the posterior probability of each possible dosing decision. An intensive simulation study is conducted to evaluate the operating characteristics of the newly proposed probability-of-decision-i3+3 design under various dosing scenarios and patient accrual settings. Results show that the probability-of-decision-i3+3 design achieves comparable safety and reliability performances but much shorter trial duration compared to the complete designs.

Modeling Clinical Trial Attrition Using Machine Intelligence: A driver analytics case study using 1,325 trials representing one million patients

The amount of time and resources invested in bringing novel therapeutics to market has increased year over year with fewer successful treatments reaching patients. In the lifecycle of drug development, the clinical phase is a major contributor to this decreasing efficiency in the development of clinical trials. One major barrier to the successful execution of a randomized control trial (RCT) is the attrition of patients who no longer participate in a trial either following enrollment or randomization. To address this problem, we have assembled a unique dataset by integrating multiple public databases including ClinicalTrials.gov and Aggregate Analysis of ClincalTrials.gov (AACT) to assemble a trial sponsor-independent dataset. This data spans 20 years of clinical trials and over 1 million patients (3,175 cohorts consisting of 1,020,085 patients and 79 curated features) in the respiratory domain and enabled a data-driven approach to identify top features influencing patient attrition in a trial. Top Features included Duration of Trial, Duration of Treatment, Indication, and Number of Adverse Events. We evaluated multiple machine learning models and found the best performance on the Test Set with Random Forest (Test subset: n=637 cohorts; RMSE 6.64). We envisage that our work will enable clinical trial sponsors to optimize trial run time by better anticipating and correcting for potential patient attrition using patient-centric strategies to improve patient engagement, thus enabling new therapies to be delivered to patients more quickly.

1048. Double-Blind, Randomized, Placebo-Controlled Phase 2b Multicenter Trial of V160, a Replication-Defective Human Cytomegalovirus (CMV) Vaccine

Background Preventing congenital cytomegalovirus infection (CMVi) is an important unmet need. Natural maternal immunity to CMV acquired prior to pregnancy appears to reduce fetal transmission. In a Phase 1 trial, V160, a replication-defective CMV vaccine expressing the pentameric complex, induced humoral and cell-mediated immune (CMI) responses comparable to natural immunity. Methods Healthy, CMV-seronegative women aged 16–35 years were randomized 1:1:1 to receive double-blind V160 in a 3- or 2-dose regimen or placebo. Primary and secondary endpoints were efficacy in reducing the incidence of CMVi with 3-dose or 2-dose regimens of V160 vs placebo, respectively, using a fixed-event design. Monthly urine and saliva samples were collected to identify CMVi by polymerase chain reaction (PCR) with a single positive sample considered evidence of infection. Immunoglobulin G (IgG) binding to glycoprotein B (gB) and CMV-specific neutralizing antibody (NAb) were measured in all participants, and CMI responses were measured in a subset. Injection-site and systemic adverse events (AEs) were collected for 5 days and 14 days, respectively, after each vaccination and serious AEs were collected for the trial duration. Results 2200 women from 7 countries were enrolled (of 7458 screened). Over 80% of participants received all doses, and compliance with saliva and urine samples was > 95%. Vaccine efficacy (VE) of 42.4% (95% CI -13.5, 71.1%) was demonstrated in the 3-dose group vs placebo. In the 2-dose group, VE was -32.0% (95% CI -135.0, 25.0%). Both the quantity and duration of CMV shedding in urine and saliva among cases of CMVi decreased in the 3-dose, but not the 2-dose group vs placebo. Both V160 regimens elicited humoral and CMI responses detected by CMV-specific NAb, gB IgG, and ELISpot, which peaked at Month 7 and continued to be detectable at Month 24. Mild to moderate AEs were more frequently reported in V160 vs placebo recipients, but no vaccine-related serious AEs or deaths were reported. Conclusion V160 was well tolerated and immunogenic, but neither the 3-dose nor 2-dose regimen demonstrated significant efficacy against CMVi as defined in this trial. The quantity and duration of CMV shedding was reduced in the 3-dose group, suggesting V160 may improve immune control of viral replication after CMVi. Disclosures Rituparna Das, MD, Merck & Co, Inc. (Employee) Daniel Blazquez-Gamero, MD, MSD (Other Financial or Material Support, Fees for lectures in educational activities) Soren Gantt, MD, Altona Diagnostics (Research Grant or Support)Merck (Consultant, Grant/Research Support)Meridian Biosciences (Research Grant or Support)Moderna (Consultant, Research Grant or Support)VBI Vaccines Inc (Research Grant or Support) Oliver Bautista, PhD, Merck & Co, Inc. (Employee) Karen Beck, RN, BSN, Merck & Co, Inc. (Employee) Anthony Conlon, PhD, Merck & Co, Inc. (Employee) Daniel Rosenbloom, PhD, Merck & Co, Inc. (Employee) Dai Wang, PhD, Merck & Co, Inc. (Employee) Michael Ritter, BA, Merck & Co, Inc. (Employee) Beth Arnold, MS, Merck & Co, Inc. (Employee, Shareholder) Paula Annunziato, MD, Merck & Co, Inc. (Employee) Kevin Russell, MD, MTM&H, Merck & Co., Inc. (Employee, Shareholder)

Betaine supplementation fails to improve body composition: a systematic review and meta-analysis

Previous studies evaluating the effects of betaine supplementation on body composition offer contradictory findings. This systematic review and meta-analysis assessed the effects of betaine supplementation on body composition indices (body mass [BM], body mass index [BMI], body fat percentage [BFP], fat mass [FM], fat-free mass [FFM]), and dietary intakes. Studies examining the effects of betaine supplementation on body composition and dietary intakes published up to August 2021 were identified through PubMed, the Cochrane Library, Web of Science, Embase, SCOPUS, and Ovid databases. Betaine supplementation failed to significantly affect BM [(WMD: −0.40 kg, 95% CI: −1.46 to 0.64), p=0.447], BMI [(WMD: −0.05 kg/m2, 95% CI: −0.36 to 0.25), p=0.719], BFP [(WMD: 0.26%, 95% CI: −0.82 to 1.36), p=0.663], FM [(WMD: −0.57 kg, 95% CI: −2.14 to 0.99), p=0.473], and FFM [(WMD: 0.61 kg, 95% CI: −1.27 to 2.49), p=0.527]. Subgroup analyses based on participant’s age (<40 and >40 years), sex, BMI, trial duration (<8 and ≥8 weeks), betaine supplementation dosage (<4 and ≥4 g), and health status (healthy or unhealthy) demonstrated similar results. Other than a potential negligible increase in protein intake (WMD: 3.56 g, 95% CI: 0.24 to 6.88, p=0.035), no changes in dietary intakes were observed following betaine supplementation compared to control. The present systematic review and meta-analysis does not show any beneficial effects of betaine supplementation on body composition indices (BM, BMI, FM, and FFM).

Cognitive Composites for Genetic Frontotemporal Dementia: GENFI-Cog

Background: Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) and recommend on recruitment and duration in clinical trial design.Methods: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR® plus NACC-FTLD≥0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier groups and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD=0.5 to ≥1 (and therefore how long a trial would need to be). Results: Results from the logistic regression analyses resulted in different composite scores for each mutation carrier group. The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after three years ~50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥1.DISCUSSION: We created gene-specific cognitive composite scores for C9orf72, GRN and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.

Metacognitive monitoring and metacognitive strategies of gifted and average children on dealing with deductive reasoning task

In this paper, we inquire into possible differences between children with exceptionally high intellectual abilities and their average peers as regards metacognitive monitoring and related metacognitive strategies. The question whether gifted children surpass their typically developing peers not only in the intellectual abilities, but also in their level of metacognitive skills, has not been convincingly answered so far. We sought to examine the indicators of metacognitive behavior by means of eye-tracking technology and to compare these findings with the participants’ subjective confidence ratings. Eye-movement data of gifted and average students attending final grades of primary school (4th and 5th grades) were recorded while they dealt with a deductive reasoning task, and four metrics supposed to bear on metacognitive skills, namely the overall trial duration, mean fixation duration, number of regressions and normalized gaze transition entropy, were analyzed. No significant differences between gifted and average children were found in the normalized gaze transition entropy, in mean fixation duration, nor - after controlling for the trial duration – in number of regressions. Both groups of children differed in the time devoted to solving the task. Both groups significantly differed in the association between time devoted to the task and the participants’ subjective confidence rating, where only the gifted children tended to devote more time when they felt less confident. Several implications of these findings are discussed.

Extracting the Auditory Attention in a Dual-Speaker Scenario From EEG Using a Joint CNN-LSTM Model

Human brain performs remarkably well in segregating a particular speaker from interfering ones in a multispeaker scenario. We can quantitatively evaluate the segregation capability by modeling a relationship between the speech signals present in an auditory scene, and the listener's cortical signals measured using electroencephalography (EEG). This has opened up avenues to integrate neuro-feedback into hearing aids where the device can infer user's attention and enhance the attended speaker. Commonly used algorithms to infer the auditory attention are based on linear systems theory where cues such as speech envelopes are mapped on to the EEG signals. Here, we present a joint convolutional neural network (CNN)—long short-term memory (LSTM) model to infer the auditory attention. Our joint CNN-LSTM model takes the EEG signals and the spectrogram of the multiple speakers as inputs and classifies the attention to one of the speakers. We evaluated the reliability of our network using three different datasets comprising of 61 subjects, where each subject undertook a dual-speaker experiment. The three datasets analyzed corresponded to speech stimuli presented in three different languages namely German, Danish, and Dutch. Using the proposed joint CNN-LSTM model, we obtained a median decoding accuracy of 77.2% at a trial duration of 3 s. Furthermore, we evaluated the amount of sparsity that the model can tolerate by means of magnitude pruning and found a tolerance of up to 50% sparsity without substantial loss of decoding accuracy.

Cost-Effectiveness Analysis of Local Treatment in Oligometastatic Disease

BackgroundIn certain malignancies, patients with oligometastatic disease benefit from radical ablative or surgical treatment. The SABR-COMET trial demonstrated a survival benefit for oligometastatic patients randomized to local stereotactic ablative radiation (SABR) compared to patients receiving standard care (SC) alone. Our aim was to determine the cost-effectiveness of SABR.Materials and MethodsA decision model based on partitioned survival simulations estimated costs and quality-adjusted life years (QALY) associated with both strategies in a United States setting from a health care perspective. Analyses were performed over the trial duration of six years as well as a long-term horizon of 16 years. Model input parameters were based on the SABR-COMET trial data as well as best available and most recent data provided in the published literature. An annual discount of 3% for costs was implemented in the analysis. All costs were adjusted to 2019 US Dollars according to the United States Consumer Price Index. SABR costs were reported with an average of $11,700 per treatment. Deterministic and probabilistic sensitivity analyses were performed. Incremental costs, effectiveness, and cost-effectiveness ratios (ICER) were calculated. The willingness-to-pay (WTP) threshold was set to $100,000/QALY.ResultsBased on increased overall and progression-free survival, the SABR group showed 0.78 incremental QALYs over the trial duration and 1.34 incremental QALYs over the long-term analysis. Treatment with SABR led to a marginal increase in costs compared to SC alone (SABR: $304,656; SC: $303,523 for 6 years; ICER $1,446/QALY and SABR: $402,888; SC: $350,708 for long-term analysis; ICER $38,874/QALY). Therapy with SABR remained cost-effective until treatment costs of $88,969 over the trial duration (i.e. 7.6 times the average cost). Sensitivity analysis identified a strong model impact for ongoing annual costs of oligo- and polymetastatic disease states.ConclusionOur analysis suggests that local treatment with SABR adds QALYs for patients with certain oligometastatic cancers and represents an intermediate- and long-term cost-effective treatment strategy.