Main outcomes of OECD/NEA THAI-2 project on hydrogen risk and source term investigations: Data application for code validation and containment safety assessment

Influence of boron carbide on core degradation during severe accidents in LWRs

The last two decades have seen tremendous advancements in tools like CRISPR, single-molecule sequencing technologies, optical genome mapping, single-cell omics techniques, etc. Genomic analyses of multiple individuals become important to address medical questions and advances in genomic technologies and methods directly contribute to improved outcomes in disease research and healthcare. Genome-wide association studies conducted in the past inform us about the limitations of technologies in analyzing factors contributing to human traits and diseases using only short-read amplicon sequencing technologies, especially in repetitive genomic stretches where the likelihood of structural variations is higher. While short-read sequencing is a highly evolved technology, the discovery of causative variants with it alone is impeded by its read length and depending on the assay, is limited to gene coding regions, and less penetrative variants are often missed. In a recent report, it was found that only about one in three known genetic disorders in children have been diagnosed successfully with short-read sequencing (SRS, including whole exome and whole genome assays). On the other hand, building evidence that variants occurring in extragenic regions are found to be driving mutations for diseases shows that there is a need to capture both intergenic and extragenic information. Long-read platforms including optical genome mapping and Pacific Biosciences (PacBio) or Oxford Nanopore Technology (ONT) sequencers have advantages like improved contiguity, long-range haplotype phasing, and therefore, identification of structural variants associated with diseases, especially where alleles extend beyond typical read length. They are better suited to capture large structural variations, their genotypes, and copy number alterations but some practical challenges, like lack of base-level resolution for optical mapping, high error rates, cost per sample, low throughput, and resource-heavy informatics analysis for long-read sequencing, prevent routine adoption long-read platforms. Targeted interrogation of the genome in lieu of the whole genome alleviates some of the above challenges. CRISPR-Cas9-based targeting methods offer programmability and thus are being increasingly used for long-read platforms. This thesis discusses novel applications of CRISPR-Cas9 nickase-based experimental methods for targeted interrogation of genomic features on long-read sequencing and optical mapping platforms. First, the linked-pair sequencing strategy enabled by CRISPR-Cas9n chemistry is described. Here, orderly fragmentation of DNA molecules is performed using CRISPR-Cas9n and pairs of sgRNA in such a way that produced fragments share identical termini. This strategy is capable of greater multiplicity and can assemble critical genetic loci effectively. The validity and efficacy of the method for sequencing were first demonstrated on a lambda phage model and Haemophilus influenzae model, and later for sequencing a cancer panel in the human genome containing 100 full-length gene sequences. When the designed linker sequences contained heterozygous genetic variants, long haplotypes could be established. These whole-gene haplotypes enable the study of genetic variants at non-coding regulatory elements and the detection of any allele-specific effects. The use of Cas9n to introduce nicks allowed for preferential ligation of sequencing adapters resulting in significant enrichment of target regions. Second, multicolor whole genome labeling for optical mapping technique, enabled by CRISPR-Cas9n, is described. Here, Cas9n is used to make directed nicks at target sites to incorporate fluorophores. This technique was used in the detection and quantification of known biomarkers (telomeres and D4Z4 units) and in finding the locations of LINE-1 insertions across the genome With Cas9-mediated nick-labeling, it is possible to target and fluorescently label any 20mer or the combination of multiple 20mers across the whole genome, especially in repetitive regions lacking DLE motifs. Custom maps can be generated to enable precise detection of breakpoints and interrogate the repetitive sequences; this enables more in-depth analysis of SVs than was previously possible. Application of this method in the interrogation of exogenic DNA integrations in the host genome for gene therapy validation and safety assessment is also demonstrated. Finally, additional applications of Cas9n chemistry using both long-read sequencing and optical genome mapping platforms together are demonstrated. Multicolor Cas9n-mediated labeling chemistry is leveraged to create high-density optical maps with an increased resolution for use in structural variant analysis, calling breakpoints, and scaffolding genome assemblies. Such high-density optical maps can also be used to study interactions of Cas9 with target DNA.

Cancer drug resistance remains a formidable challenge in modern oncology, necessitating innovative therapeutic strategies. The convergence of intricate regulatory networks involving long non-coding RNAs, microRNAs, and pivotal signaling pathways has emerged as a crucial determinant of drug resistance. This review underscores the multifaceted roles of lncRNAs and miRNAs in orchestrating gene expression and cellular processes, mainly focusing on their interactions with specific signaling pathways. Dysregulation of these networks leads to the acquisition of drug resistance, dampening the efficacy of conventional treatments. The review highlights the potential therapeutic avenues unlocked by targeting these non-coding RNAs. Developing specific inhibitors or mimics for lncRNAs and miRNAs, alone or in combination with conventional chemotherapy, emerges as a promising strategy. In addition, epigenetic modulators, immunotherapies, and personalized medicine present exciting prospects in tackling drug resistance. While substantial progress has been made, challenges, including target validation and safety assessment, remain. The review emphasizes the need for continued research to overcome these hurdles and underscores the transformative potential of lncRNA-miRNA interplay in revolutionizing cancer therapy.

Safety assessments and environmental impact statements for nuclear fuel cycle facilities require an estimate of potential airborne releases caused by accidents. Aerosols generated by accidents are being investigated by Pacific Northwest Laboratory to develop methods for estimating source terms from these accidents. Experiments were run by spilling viscous solutions and slurries to determine the mass and particle-size distribution of the material made airborne. In all cases, 1 L of solution was spilled from a height of 3 m. Aqueous solutions of sucrose (0 to 56%) gave a range of viscosities from 1.3 to 46 cp. The percent of spill mass made airborne from the spills of these solutions ranged from 0.001 to 0.0001. The mass of particles made airborne decreased as solution viscosity increased. Slurry loading ranged from 25 to 51% total solids. The maximum source airborne (0.0046 wt %) occurred with the slurry that had the lightest loading of soluble solids. The viscosity of the carrying solution also had an impact on the source term from spilling slurries. The effect of surface tension on the source term was examined in two experiments. Surface tension was halved in these spills by adding a surfactant. The maximum weight percent airborne from these spills was 0.0045, compared to 0.003 for spills with twice the surface tension. The aerodynamic mass medium diameters for the aerosols produced by spills of the viscous solutions, slurries, and low surface tension liquids ranged from 0.6 to 8.4 ..mu..m, and the geometric standard deviation ranged from 3.8 to 28.0.

BackgroundAnimal experimental studies and previous randomized trials suggest an improvement in mortality and neurological function with temperature regulation to hypothermia after cardiac arrest. According to a systematic review, previous trials were small, had a risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management (TTM) strategy is not known. To prevent outcome reporting bias, selective reporting and data-driven results, we present the a priori defined detailed statistical analysis plan as an update to the previously published outline of the design and rationale for the TTM trial.MethodsThe TTM trial is an investigator-initiated, multicenter, international, randomized, parallel-group, and assessor-blinded clinical trial of temperature management in 950 adult unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients are randomized to a TTM of either 33°C or 36°C after return of spontaneous circulation. The primary outcome is all-cause mortality at maximal follow-up (until end of the trial and a minimum of 180 days). The main secondary outcomes are the composite outcome of all-cause mortality and poor neurological function (Cerebral Performance Category (CPC) 3 and 4, and modified Rankin Scale (mRS) 4 and 5) at hospital discharge and at 180 days; and assessment of safety and harm: bleeding, infections, electrolyte and metabolic disorders, seizures, cardiac arrhythmia, and renal replacement therapy.ConclusionThe TTM trial investigates potential benefit and harm of two target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.Trial registrationClinicalTrials.gov identifier: NCT01020916

Accident analysis with MELCOR-fusion code for DONES lithium loop and accelerator

A three-dimensional neutronic modelling of the LMJ facility has been performed. The Monte Carlo transport code TRIPOLI is used to obtain the neutron spectra required for the inventory code FISPACT. Nodal activation responses and time-dependent decay gamma spectra are produced and used as source terms for further treatment by TRIPOLI for a range of engineering and safety assessments. It is shown that three-dimensional neutronic and nodal activation can be performed in a convenient way and the results obtained by this procedure will serve as a data-base for design and S&E analysis.

Background:We aim to study the treatment of psoriasis vulgaris with moving cupping.Methods:We will search PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, Wanfang Database, and Chinese Biomedical Literature Database of randomized controlled trials beginning from their inception to August 2020. The primary outcomes are that PASI score and clinical effective rate will be the main outcome indicators. Additional outcome is The Quality of life index score and safety assessment will be considered a secondary outcome. Two independent authors will based on the Cochrane system evaluation manual 5.1.0 version of RCT bias risk assessment tool to evaluate the risk of bias among the final included studies. And we will use the RevMan 5.3 software to analysis data.Results:This study will provide an assessment of the current state of moving cupping for the psoriasis vulgaris, aiming to show the efficacy and safety of this treatment.Conclusion:This study will provide evidence to judge whether moving cupping is an effective therapy for psoriasis vulgaris.Inplasy registration number:INPLASY2020120061.

BackgroundThe number of people with an alcohol use disorder (AUD) was recently estimated to be 63.5 million worldwide. The global burden of disease and injury attributable to alcohol is considerable: about 3 million deaths, namely one in 20, were caused by alcohol in 2015. At the same time, AUD remains seriously undertreated.In this context, alternative or adjunctive therapies such as brain stimulation could play an important role. The early results of studies using repetitive transcranial magnetic stimulation (rTMS) suggest that stimulations delivered to the dorsolateral prefrontal cortex significantly reduce cravings and improve decision-making processes in various addictive disorders. We therefore hypothesize that rTMS could lead to a decrease in alcohol consumption in patients with AUD.Methods/designWe report the protocol of a randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy of rTMS on alcohol reduction in individuals diagnosed with AUD. The study will be conducted in 2 centers in France. Altogether, 144 subjects older than 18 years and diagnosed with AUD will be randomized to receive 5 consecutive twice-daily sessions of either active or sham rTMS (10 Hz over the right DLPFC, 2000 pulses per day). The main outcomes of the study will be changes in alcohol consumption within the 4 weeks after the rTMS sessions. Secondary outcome measures will include changes in alcohol consumption within the 24 weeks, alcohol cravings, clinical and biological improvements, effects on mood and quality of life, and cognitive and safety assessments, and, for smokers, an assessment of the effects of rTMS on tobacco consumption.DiscussionSeveral studies have observed a beneficial effect of rTMS on substance use disorders by reducing craving, impulsivity, and risk-taking behavior and suggest that rTMS may be a promising treatment in addiction. However, to date, no studies have included sufficiently large samples and sufficient follow-up to confirm this hypothesis. The results from this large randomized controlled trial will give a better overview of the therapeutic potential of rTMS in AUD.Trial registrationClinicalTrials.gov NCT04773691. Registered on 26 February 2021https://clinicaltrials.gov/ct2/show/NCT04773691?term=trojak&draw=2&rank=5.

Subcutaneously administered repronex® in oligoovulatory female patients undergoing ovulation induction is as effective and well tolerated as intramuscular human menopausal gonadotropin treatment

Pharmacokinetics, Safety, and Tolerability of Single Oral Doses of a Novel Oxytocin Receptor Antagonist—Cligosiban—in Development for Premature Ejaculation: Three Randomized Clinical Trials in Healthy Subjects

BACKGROUNDEarly detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE, a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15,067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days due to significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine: 1) whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and 2) whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial using proteomics.METHODSA nested case-control analysis of paired plasma samples, at baseline and at 3-months, was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls, 1:1. Main outcomes were: 1) a survey of 1,129 proteins for discovery of biological pathways altered by torcetrapib, 2) a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure or death.RESULTSPlasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the two treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared to the atorvastatin only arm by +1.08% (p=0.0004). Thirty-seven proteins changed in the direction of increased risk out of 49 proteins previously associated with cardiovascular and mortality risk.CONCLUSIONSHeretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.

With the rapid growth of bridge engineering in energy, transportation, and communication, the importance of bridge construction is increasingly evident. However, due to the complex and hazardous construction environment, safety concerns have become a focal point. Recent progress in a comprehensive scientific assessment of bridge construction safety has introduced various evaluation methods, including risk assessment, Analytic Hierarchy Process, fuzzy comprehensive evaluation, and the application of big data and machine learning. Despite this, challenges like inconsistent indicators, insufficient data, and neglect of human factors persist. To address these, this paper uses regression analysis and establishes a regression decision tree model for bridge construction safety assessment, proving more accurate and reliable than other methods.

Nuclear Heating Measurement in Critical Facilities and Experimental Validation of Code and Libraries – An Application to Prompt and Delayed γ Nuclear Data Needs

Gamma camera imaging is one of prevalent diagnostic imaging tool for nuclear medicine. Although gamma camera imaging widely used for diagnostic imaging, quantification of gamma camera imaging is difficult due to scattered radiation. Compton scattering is always a problematic phenomenon in gamma camera imaging. In previous study, Siemens symbia scintillation camera was modeled for assessment of septal penetration photons and validation of Monte Carlo simulation code for the Siemens scintillation camera. In this study, optimal energy window for triple energy window (TEW) scatter correction method was assessed in gamma camera for <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">99m</sup> Tc, <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">131</sup> I radioisotopes using GATE simulation. Siemens Symbia T2 SPECT/CT scanner was used throughout to acquire planar data. These dataset were then reconstructed by FBP. Energy window was set for various main energy window width (10, 15, 20%) and sub energy window width (3 and 5keV). The point source was positioned at 8 positions. The triple energy window method estimated the scatter fraction in the photopeak from the counts acquired in two adjacent narrow windows. Linear interpolation between the two sub-windows could be used to obtain the following trapezoidal approximation of the scatter counts: C <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">s</sub> = (C <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">left</sub> /W <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">s</sub> + C <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">right</sub> /W <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">s</sub> ) × W <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m</sub> /2 For <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">99m</sup> Tc, 20% of main energy window and 5 keV of sub energy window and For <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">131</sup> I , 10% of main energy window and 5 keV of sub energy window was optimal for implementation of TEW. This result of present study provide optimal energy window for <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">131</sup> I scintigraphy data and would be helpful for quantification of <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">131</sup> I. Further study, experimental study will be performed for validation of this simulation result.