Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death

BACKGROUND: We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone (GnRH), the master molecule regulating reproduction, and cognitive deficits during pathological aging, including Down syndrome and Alzheimer's disease. Olfactory and cognitive alterations, which persist in some COVID-19 patients, and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and thus lead to accelerated or exacerbated cognitive decline. METHODS: We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in post-mortem patient brains and human fetal tissue. FINDINGS: We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin, favouring post-COVID cognitive or neurological symptoms, and that changes in testosterone levels and body weight over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia called tanycytes highlighted at least two viable neuroinvasion routes. Furthermore, GnRH neurons themselves were dying in all patient brains studied, dramatically reducing GnRH expression. Human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to infection. INTERPRETATION: Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be responsible for serious reproductive, metabolic, and mental health consequences in long-COVID and lead to an increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups. FUNDING: European Research Council (ERC) grant agreements No 810331, No 725149, No 804236, the European Union Horizon 2020 research and innovation program No 847941, the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale de la Recherche en Santé (ANRS) No ECTZ200878 Long Covid 2021 ANRS0167 SIGNAL, Agence Nationale de la recherche (ANR) grant agreements No ANR-19-CE16-0021-02, No ANR-11-LABEX-0009, No. ANR-10-LABEX-0046, No. ANR-16-IDEX-0004, Inserm Cross-Cutting Scientific Program HuDeCA, the CHU Lille Bonus H, the UK Medical Research Council (MRC) and National Institute of Health and care Research (NIHR)

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy. (C) 2017 by American Society of Clinical Oncolog

Estimating the growth in Mordell-Weil ranks and Shafarevich-Tate groups over Lie extensions

Let E/Q be an elliptic curve, p > 3 a good ordinary prime for E, and K∞ a p-adic Lie extension of a number field k. Under some standard hypotheses, we study the asymptotic growth in both the Mordell–Weil rank and Shafarevich–Tate group for E over a tower of extensions K ₙ/ₖ inside K∞; we obtain lower bounds on the former, and upper bounds on the latter’s size

First demonstration of 30 eVee ionization energy resolution with Ricochet germanium cryogenic bolometers

The future Ricochet experiment aims to search for new physics in the electroweak sector by measuring the Coherent Elastic Neutrino-Nucleus Scattering process from reactor antineutrinos with high precision down to the sub-100 eV nuclear recoil energy range. While the Ricochet collaboration is currently building the experimental setup at the reactor site, it is also finalizing the cryogenic detector arrays that will be integrated into the cryostat at the Institut Laue Langevin in early 2024. In this paper, we report on recent progress from the Ge cryogenic detector technology, called the CryoCube. More specifically, we present the first demonstration of a 30~eVee (electron equivalent) baseline ionization resolution (RMS) achieved with an early design of the detector assembly and its dedicated High Electron Mobility Transistor (HEMT) based front-end electronics. This represents an order of magnitude improvement over the best ionization resolutions obtained on similar heat-and-ionization germanium cryogenic detectors from the EDELWEISS and SuperCDMS dark matter experiments, and a factor of three improvement compared to the first fully-cryogenic HEMT-based preamplifier coupled to a CDMS-II germanium detector. Additionally, we discuss the implications of these results in the context of the future Ricochet experiment and its expected background mitigation performance.Comment: 10 pages, 5 figures, 1 tabl

Fast neutron background characterization of the future Ricochet experiment at the ILL research nuclear reactor

The future Ricochet experiment aims at searching for new physics in the electroweak sector by providing a high precision measurement of the Coherent Elastic Neutrino-Nucleus Scattering (CENNS) process down to the sub-100 eV nuclear recoil energy range. The experiment will deploy a kg-scale low-energy-threshold detector array combining Ge and Zn target crystals 8.8 meters away from the 58 MW research nuclear reactor core of the Institut Laue Langevin (ILL) in Grenoble, France. Currently, the Ricochet collaboration is characterizing the backgrounds at its future experimental site in order to optimize the experiment's shielding design. The most threatening background component, which cannot be actively rejected by particle identification, consists of keV-scale neutron-induced nuclear recoils. These initial fast neutrons are generated by the reactor core and surrounding experiments (reactogenics), and by the cosmic rays producing primary neutrons and muon-induced neutrons in the surrounding materials. In this paper, we present the Ricochet neutron background characterization using $^3$He proportional counters which exhibit a high sensitivity to thermal, epithermal and fast neutrons. We compare these measurements to the Ricochet Geant4 simulations to validate our reactogenic and cosmogenic neutron background estimations. Eventually, we present our estimated neutron background for the future Ricochet experiment and the resulting CENNS detection significance.Comment: 14 pages, 14 figures, 1 tabl

Coherent elastic neutrino-nucleus scattering: Terrestrial and astrophysical applications

Coherent elastic neutrino-nucleus scattering (CE$\nu$NS) is a process in which neutrinos scatter on a nucleus which acts as a single particle. Though the total cross section is large by neutrino standards, CE$\nu$NS has long proven difficult to detect, since the deposited energy into the nucleus is $\sim$ keV. In 2017, the COHERENT collaboration announced the detection of CE$\nu$NS using a stopped-pion source with CsI detectors, followed up the detection of CE$\nu$NS using an Ar target. The detection of CE$\nu$NS has spawned a flurry of activities in high-energy physics, inspiring new constraints on beyond the Standard Model (BSM) physics, and new experimental methods. The CE$\nu$NS process has important implications for not only high-energy physics, but also astrophysics, nuclear physics, and beyond. This whitepaper discusses the scientific importance of CE$\nu$NS, highlighting how present experiments such as COHERENT are informing theory, and also how future experiments will provide a wealth of information across the aforementioned fields of physics

Coherent elastic neutrino-nucleus scattering: Terrestrial and astrophysical applications

Coherent elastic neutrino-nucleus scattering (CE$\nu$NS) is a process inwhich neutrinos scatter on a nucleus which acts as a single particle. Thoughthe total cross section is large by neutrino standards, CE$\nu$NS has longproven difficult to detect, since the deposited energy into the nucleus is$\sim$ keV. In 2017, the COHERENT collaboration announced the detection ofCE$\nu$NS using a stopped-pion source with CsI detectors, followed up thedetection of CE$\nu$NS using an Ar target. The detection of CE$\nu$NS hasspawned a flurry of activities in high-energy physics, inspiring newconstraints on beyond the Standard Model (BSM) physics, and new experimentalmethods. The CE$\nu$NS process has important implications for not onlyhigh-energy physics, but also astrophysics, nuclear physics, and beyond. Thiswhitepaper discusses the scientific importance of CE$\nu$NS, highlighting howpresent experiments such as COHERENT are informing theory, and also how futureexperiments will provide a wealth of information across the aforementionedfields of physics.<br

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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