Conditional probabilities of post-release events for hazardous materials pipelines

Pipelines are commonly considered a safe alternative for the transportation of hazardous materials. However, in case of failure, pipelines still pose major risks to the environment and to the population potentially exposed. The aim of the present work is to provide occurrence probabilities of the intermediate and final events following the accidental release of hazardous materials from pipelines. A collection of incidents and accidents occurred worldwide in connection with the use of onshore long-distance pipeline networks, has been gathered to make up a specific database for the analysis of incidents in pipelines. A qualitative and quantitative analysis of the data has allowed to develop detailed event trees for the different classes of hazardous materials, and to calculate the probability of occurrence of the final outcomes. The investigation has also aimed at identifying, for each type of release, the relationship between the final events and the causes of the pipeline failure. The results obtained represent a useful and needed starting point in Quantitative Risk Analysis of hazardous materials transportation via pipelines.Peer ReviewedPostprint (author's final draft

Midazolam nasal spray to treat intermittent, stereotypic episodes of frequent seizure activity: pharmacology and clinical role, a comprehensive review.

An intranasal formulation of midazolam, Nayzilam, has been FDA-approved to treat intermittent, stereotypic episodes of frequent seizure activity. Nayzilam is easy to administer and can quickly treat seizures that occur outside of the hospital. The intra-nasal route of administration allows non-medical personal to administer the drug which makes it more accessible and user-friendly in the event of a seizure. Many studies have indicated quick cessation of seizures with Nayzilam compared to rectal diazepam, which has been the standard of care treatment. Nayzilam has been proven to be safe and effective for acute seizures in children, deeming it a revolutionary alternative in times where intravenous administration is not possible

Rimegepant for the treatment of migraine.

Migraine is a common form of primary headache, affecting up to 1 in every 6 Americans. The pathophysiology is an intricate interplay of genetic factors and environmental influence and is still being elucidated in ongoing studies. The trigeminovascular system is now known to have a significant role in the initiation of migraines, including the release of pain mediators such as CGRP and substance P. Traditional treatment of migraine is usually divided into acute and preventive treatment. Acute therapy includes non-specific therapy, such as NSAIDs and other analgesics, which may provide relief in mild to moderate migraines. 5-HT1 agonists may provide relief in severe migraine, but are not universally effective and carry a significant side-effect profile with frequent redosing requirement. Prophylactic therapy may reduce the occurrence of acute migraine attacks in selected patients, but does not completely eliminate it. More recently, CGRP antagonism has been studied and shown to be effective in both abortion and prevention of migraine. Novel medications, targeting CGRP, divide into CGRP antibodies and receptor antagonists (gepants). Rimegepant, a second-generation gepant, has shown efficacy in several clinical trials in treating acute migraine. Ongoing trials are also evaluating its role in migraine prophylaxis, and results are promising. It is also generally safer for use than existing options, does not appear to increase the chance of developing chronic migraines, and carries a very tolerable side effects profile. It is a part of a growing arsenal in migraine treatment, and may present the silver bullet for treatment of this disease

Review of Interventional Therapies for Refractory Pediatric Migraine.

This is a review of the latest and seminal evidence in pediatric migraine. It covers the etiology and pathophysiology known today, and then will review treatment options, efficacy and safety, quality of data and indications. Though migraine is usually regarded as an infliction in adults, it is not uncommon in the pediatric population and affects up to 8% of children. Children may experience migraine differently than adults, and present not only with headache but also frequent gastrointestinal symptoms. They are frequently shorter in duration than in adults. Traditional migraine treatment in adults is less effective in children. In this population, adjunct therapies - such as interventional techniques - should be considered when traditional treatment fails, including Botulinum Toxin A (BTA) injections, peripheral nerve and ganglion blocks. BTA injections are FDA approved for migraine prophylaxis in adults, but currently not in children; however, recent evidence shows efficacy and safety in pediatric migraine management. Nerve blocks stop nociceptive afferent fibers through injection of local anesthetics, and it may be associated with the local injection of corticosteroids. Although more common in adults, recent data suggests they are safe and effective in children and adolescents. Blocking the sphenopalatine ganglion can be achieved through nasal approach, and achieves a similar action by blocking the entire ganglion. Interventional techniques may provide a key component in the alleviation of this otherwise debilitating chronic migraine pain. Though most studies have been performed in adults, new studies provide encouraging results for treatment in children

First Dark Matter Search with Nuclear Recoils from the XENONnT Experiment

We report on the first search for nuclear recoils from dark matter in the form of weakly interacting massive particles (WIMPs) with the XENONnT experiment, which is based on a two-phase time projection chamber with a sensitive liquid xenon mass of 5.9 ton. During the (1.09±0.03)  ton yr exposure used for this search, the intrinsic 85Kr and 222Rn concentrations in the liquid target are reduced to unprecedentedly low levels, giving an electronic recoil background rate of (15.8±1.3)  events/ton yr keV in the region of interest. A blind analysis of nuclear recoil events with energies between 3.3 and 60.5 keV finds no significant excess. This leads to a minimum upper limit on the spin-independent WIMP-nucleon cross section of 2.58×10$^{−47}$  cm$^2$ for a WIMP mass of 28  GeV/c$^2$ at 90% confidence level. Limits for spin-dependent interactions are also provided. Both the limit and the sensitivity for the full range of WIMP masses analyzed here improve on previous results obtained with the XENON1T experiment for the same exposure

An approximate likelihood for nuclear recoil searches with XENON1T data

The XENON collaboration has published stringent limits on specific dark matter – nucleon recoil spectra from dark matter recoiling on the liquid xenon detector target. In this paper, we present an approximate likelihood for the XENON1T 1 t-year nuclear recoil search applicable to any nuclear recoil spectrum. Alongside this paper, we publish data and code to compute upper limits using the method we present. The approximate likelihood is constructed in bins of reconstructed energy, profiled along the signal expectation in each bin. This approach can be used to compute an approximate likelihood and therefore most statistical results for any nuclear recoil spectrum. Computing approximate results with this method is approximately three orders of magnitude faster than the likelihood used in the original publications of XENON1T, where limits were set for specific families of recoil spectra. Using this same method, we include toy Monte Carlo simulation-derived binwise likelihoods for the upcoming XENONnT experiment that can similarly be used to assess the sensitivity to arbitrary nuclear recoil signatures in its eventual 20 t-year exposure

Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B cell acute lymphoblastic leukemia

B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. As predicted by its prenatal origin, infant B-ALL (iB-ALL) shows an exceptionally silent DNA mutational landscape, suggesting that alternative epigenetic mechanisms may substantially contribute to its leukemogenesis. Here, we have integrated genome-wide DNA methylome and transcriptome data from 69 patients with de novo MLL-rearranged leukemia (MLLr) and non-MLLr iB-ALL leukemia uniformly treated according to the Interfant-99/06 protocol. iB-ALL methylome signatures display a plethora of common and specific alterations associated with chromatin states related to enhancer and transcriptional control in normal hematopoietic cells. DNA methylation, gene expression, and gene coexpression network analyses segregated MLLr away from non-MLLr iB-ALL and identified a coordinated and enriched expression of the AP-1 complex members FOS and JUN and RUNX factors in MLLr iB-ALL, consistent with the significant enrichment of hypomethylated CpGs in these genes. Integrative methylome-transcriptome analysis identified consistent cancer cell vulnerabilities, revealed a robust iB-ALL–specific gene expression–correlating dmCpG signature, and confirmed an epigenetic control of AP-1 and RUNX members in reshaping the molecular network of MLLr iB-ALL. Finally, pharmacological inhibition or functional ablation of AP-1 dramatically impaired MLLr-leukemic growth in vitro and in vivo using MLLr-iB-ALL patient–derived xenografts, providing rationale for new therapeutic avenues in MLLr-iB-ALL.We thank CERCA/Generalitat de Catalunya (SGR180) and Fundació Josep Carreras-Obra Social la Caixa for their institutional support. Financial support for this work was obtained from the European Research Council (CoG-2014-646903 and PoC-2018-811220 to PM), the Spanish Ministry of Economy and Competitiveness (SAF-2019-108160-R and SAF2016-76758-R to PM and IV, respectively), the Spanish Association against cancer (AECC-CI-2015 and PROYE18061FERN to CB and MFF), the Fundación Uno entre Cienmil (to PM), the Health Institute Carlos III (ISCIII/FEDER, PI17/01028, PI15/00892, PI18/01527 to CB and AFF/MFF, respectively). We also acknowledge the Plan de Ciencia, Tecnología e Innovación from the Asturias Government cofunding 2018–2022/FEDER (IDI/2018/146to MFF). MFF also acknowledges funding from Fundación General CSIC (0348_CIE_6_E). PM also acknowledges financial support from Fundación Leo Messi. JRT and MV are supported by Juan de la Cierva fellowships by the Spanish Ministry of Science and Innovation (FJCI-2015-26965, IJC2018-36825-I, IJCI-2017-3317) and IUOPA-ISPA-FINBA (The IUOPA is supported by the Obra Social Cajastur-Liberbank, Spain). RTR is supported by a fellowship from the AECC scientific foundation. RFP and PSO are supported by the Severo Ochoa program (BP17-114 and BP17-165, respectively).Peer reviewe

Searching for Heavy Dark Matter near the Planck Mass with XENON1T

Multiple viable theoretical models predict heavy dark matter particles with a mass close to the Planck mass, a range relatively unexplored by current experimental measurements. We use 219.4 days of data collected with the XENON1T experiment to conduct a blind search for signals from multiply interacting massive particles (MIMPs). Their unique track signature allows a targeted analysis with only 0.05 expected background events from muons. Following unblinding, we observe no signal candidate events. This Letter places strong constraints on spin-independent interactions of dark matter particles with a mass between 1×10$^{12}$ and 2×10$^{17}$  GeV/c$^{2}$. In addition, we present the first exclusion limits on spin-dependent MIMP-neutron and MIMP-proton cross sections for dark matter particles with masses close to the Planck scale

Search for Coherent Elastic Scattering of Solar ⁸B Neutrinos in the XENON1T Dark Matter Experiment

We report on a search for nuclear recoil signals from solar 8B neutrinos elastically scattering off xenon nuclei in XENON1T data, lowering the energy threshold from 2.6 to 1.6  keV. We develop a variety of novel techniques to limit the resulting increase in backgrounds near the threshold. No significant 8B neutrinolike excess is found in an exposure of 0.6  t×y. For the first time, we use the nondetection of solar neutrinos to constrain the light yield from 1–2 keV nuclear recoils in liquid xenon, as well as nonstandard neutrino-quark interactions. Finally, we improve upon world-leading constraints on dark matter-nucleus interactions for dark matter masses between 3 and 11  GeV c−2 by as much as an order of magnitude