Systemic and anti-nociceptive effects of prolonged lidocaine, ketamine, and butorphanol infusions alone and in combination in healthy horses

BACKGROUND: Prolonged drug infusions are used to treat horses with severe signs of pain, but can be associated with altered gastrointestinal transit. The purpose of this study was to determine the effects of prolonged constant rate infusions (CRI) of lidocaine (L), butorphanol (B), and ketamine (K) alone and in combination on gastrointestinal transit, behavior, and thermal nociceptive threshold in healthy horses. METHODS: Eight healthy adult horses were used in a randomized, cross-over, blinded, prospective experimental trial. Interventions were saline, L, K, B, LK, LB, BK, and LBK as an intravenous CRI for 96 hours. Drugs were mixed or diluted in saline; following a bolus, CRI rate was 0.15mL/kg/hr with drug doses as follows: L – 1.3 mg/kg then 3 mg/kg/hr; B – 0.018 mg/kg then 0.013 mg/kg/hr; K – 0.55 mg/kg then 0.5 mg/kg/hr. Two-hundred plastic beads were administered intragastrically by nasogastric tube immediately prior to the bolus. Feces were collected every 2 hours, weighed, and beads manually retrieved. Behavior was scored every 2 hours, vital parameters every 6 hours, and thermal nociceptive threshold every 12 hours for 96 hours. Drug concentrations in the LBK solution were tested every 6 hours for 72 hours. RESULTS: Four of 64 trials (3 LBK, 1 BK) were discontinued early due to signs of abdominal discomfort. There were no apparent differences between groups in vital parameters or thermal threshold. Transit time was delayed for LB and LBK with a corresponding decrease in fecal weight that was most severe in the final 24 hours of infusion. Significant changes in behavior scores, vital parameters, or thermal threshold were not observed. The concentration of each drug in the combined solution declined by less than 31% over the sampling period. CONCLUSIONS: Drug combinations containing butorphanol cause an apparent delay in gastrointestinal transit in healthy horses without substantially affecting somatic nociception at the doses studied. Combinations of lidocaine and ketamine may have less impact on gastrointestinal transit than infusions combined with butorphanol. Further work is needed to determine the effects of these drugs in painful or critically ill patients

The cost implications of continuous glucose monitoring in pregnant women with type 1 diabetes in 3 Canadian provinces: a posthoc cost analysis of the CONCEPTT trial

BACKGROUND: The Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial (CONCEPTT) found improved health outcomes for mothers and their infants among those randomized to self-monitoring of blood glucose (SMBG) with continuous glucose monitoring (CGM) compared with SMBG alone. In this study, we evaluated whether CGM or standard SMBG was more or less costly from the perspective of a third-party payer. METHODS: We conducted a posthoc analysis of data from the CONCEPTT trial (Mar. 25, 2013, to Mar. 22, 2016). Health care resource data from 215 pregnant women, randomized to CGM or SMBG, were collected from 31 hospitals in 7 countries. We determined resource costs posthoc based on prices from hospitals in 3 Canadian provinces (Ontario, British Columbia, Alberta). The primary outcome was the difference between groups in the mean total cost of care for mother and infant dyads, paid by each government (i.e., the third-party payer) from randomization to hospital discharge (time horizon). The secondary outcome included CGM and SMBG costs not paid by governments (e.g., glucose monitoring devices and supplies). RESULTS: The mean total cost of care was lower in the CGM group compared with the SMBG group in each province (Ontario: $13 270.25 v.$18 465.21, difference in mean total cost [DMT] -$5194.96, 95$9841 to -$1395; BC:$13 480.57 v. $18 762.17, DMT -$5281.60, 95% CI -$9964 to -$1382; Alberta: $13 294.39 v.$18 674.45, DMT -$5380.06, 95$10 216 to -$1490). There was no difference in the secondary outcome. INTERPRETATION: Government health care costs are lower when CGM is paid by the patient, driven by lower costs from reduced use of the neonatal intensive care unit in the CGM group; however, when governments pay for CGM equipment, there is no overall cost difference between CGM and SMBG. Governments should consider paying for CGM, as it results in improved maternal and neonatal outcomes with no added overall cost. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01788527

Cerebral venous thrombosis due to vaccine-induced immune thrombotic thrombocytopenia after a second ChAdOx1 nCoV-19 dose.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.Cerebral venous thrombosis (CVT) is the most common and severe manifestation of vaccine-induced immune thrombotic thrombocytopenia (VITT), which is a rare side effect of the SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (Vaxzevria, AstraZeneca/Oxford). The absolute risk of VITT and VITT-related CVT is estimated at 20 and 8 per million first doses of ChAdOx1 nCoV-19, respectively. So far, no definite VITT cases occurring after a second ChAdOx1 nCoV-19 vaccine dose have been reported, raising the question of whether VITT only occurs after a first dose. Two pharmacovigilance studies reported cases of thrombosis with thrombocytopenia after a second ChAdOx1 nCoV-19 dose, but because of lack of clinical data, none of these could be classified as VITT. Knowledge on whether VITT can occur after a second ChAdOx1 nCoV-19 dose is relevant for clinicians and policymakers, especially in low- and middle-income countries, which are currently the main users of adenovirus-based vaccines. We used data from the “CVT after SARS-CoV-2 vaccination” registry to identify VITT-related CVT cases occurring after a second ChAdOx1 nCoV-19 dose. Details of this registry have been published. Briefly, this ongoing study collects data on patients with CVT with symptom onset ≤28 days from SARS-CoV-2 vaccination, regardless of the type and dose of vaccine. The study is endorsed by the European Academy of Neurology and the European Stroke Organization. Investigators are instructed to report consecutive cases from their hospitals. The ethical review board of the Academic Medical Centre issued a waiver of formal approval for this observational study. Each center obtained local permission to carry out the study and acquired informed consent for the use of pseudonymized care data according to national law. We used the case definition criteria of the United Kingdom expert hematology panel to classify cases as definite, probable, possible, or unlikely VITT after ChAdOx1 nCoV-19 administration among CVT cases reported until 1 December 2021.This work was supported by The Netherlands Organisation for Health Research and Development (ZonMw, grant number 10430072110005) (J.M.C.) and the Dr. C. J. Vaillant Foundation (J.M.C.).info:eu-repo/semantics/publishedVersio

Differential limit on the extremely-high-energy cosmic neutrino flux in the presence of astrophysical background from nine years of IceCube data

We report a quasi-differential upper limit on the extremely-high-energy (EHE) neutrino flux above $5\times 10^{6}$ GeV based on an analysis of nine years of IceCube data. The astrophysical neutrino flux measured by IceCube extends to PeV energies, and it is a background flux when searching for an independent signal flux at higher energies, such as the cosmogenic neutrino signal. We have developed a new method to place robust limits on the EHE neutrino flux in the presence of an astrophysical background, whose spectrum has yet to be understood with high precision at PeV energies. A distinct event with a deposited energy above $10^{6}$ GeV was found in the new two-year sample, in addition to the one event previously found in the seven-year EHE neutrino search. These two events represent a neutrino flux that is incompatible with predictions for a cosmogenic neutrino flux and are considered to be an astrophysical background in the current study. The obtained limit is the most stringent to date in the energy range between $5 \times 10^{6}$ and $5 \times 10^{10}$ GeV. This result constrains neutrino models predicting a three-flavor neutrino flux of $E_\nu^2\phi_{\nu_e+\nu_\mu+\nu_\tau}\simeq2\times 10^{-8}\ {\rm GeV}/{\rm cm}^2\ \sec\ {\rm sr}$at$10^9\ {\rm GeV}$. A significant part of the parameter-space for EHE neutrino production scenarios assuming a proton-dominated composition of ultra-high-energy cosmic rays is excluded.Comment: The version accepted for publication in Physical Review

Post-Transplantation Cyclophosphamide for Graft-versus- Host Disease Prophylaxis in Multiple Myeloma Patients Who Underwent Allogeneic Hematopoietic Cell Transplantation:First Comparison by Donor Type. A Study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation

Graft-versus-host disease (GVHD) remains among the major causes of treatment failure in patients with multiple myeloma (MM) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). The use of post-transplantation cyclophosphamide (PT-Cy) is now a well-established and widely used method for GVHD prophylaxis after HLA haploidentical HCT. However, the rationale for using PT-Cy in the setting of matched donor transplantation is less apparent, given the lesser degree of bidirectional alloreactivity. In this retrospective study, we investigated the role of PT-Cy as GVHD prophylaxis in patients with multiple myeloma underoing allo-HCT, among different donor types, to determine cumulative incidence of acute and chronic GVHD and impact on engraftment, progression-free survival (PFS), GVHD-free/relapse- free survival (GRFS), overall survival (OS), and NRM A total of 295 patients with MM underwent allo-HCT using grafts from a matched related donor (MRD; n = 67), matched unrelated donor (MUD; n = 72), mismatched related or unrelated donor (MMRD/MMUD, 1 antigen; n = 27), or haploidentical donor (haplo; n = 129) using PT-Cy between 2012 and 2018. In addition to PT-Cy, agents used in GVHD prophylaxis included calcineurin inhibitors in 239 patients (81%), with mycophenolate mofetil in 184 of those 239 (77%). For grade II-IV acute GVHD, the cumulative incidence at day +100 was 30% (95% confidence interval [CI], 25% to 36%), 9% (95% CI, 5% to 12%) for grade III-IV acute GVHD, and 27% (95% CI, 21% to 32%) for chronic GVHD (limited, 21%; extensive, 6%), with no differences by donor type. The median time to neutrophil engraftment was 19d (95% CI, 18-19), with no significant difference by donor type. The median time to platelet engraftment was delayed in haploidentical donor graft recipients (27 days versus 21 days; P <.001). Two-year OS, PFS, GRFS, and NRM were 51% (95% CI, 45% to 58%), 26% (95% CI, 20% to 32%), 24% (95% CI, 18% to 30%), and 19% (95% CI, 14% to 24%), respectively, with no significant difference between different donor types. In multivariable analyses, compared with the haplo donors, the use of MRDs was associated with significantly better OS (hazard ratio [HR], 0.6; 95% CI, 0.38 to 0.95; P =.029), and the use of MUDs was associated with a significantly higher GRFS (HR, 0.63; 95% CI, 0.42 to 0.97; P =.034). There was a trend toward improved PFS with use of MUDs (HR, 0.69; 95% CI, 0.46 to 1.04; P =.08). Our data show that PT-Cy in MM patients undergoing allo-HCT resulted in low rates of acute and chronic GVHD and led to favorable survival, especially in the matched related donor setting

The Role of TiO2 Doping on RuO2-Coated Electrodes for the Water Oxidation Reaction

Electrochemical water splitting into H2 and O2 presents a significant and challenging energy loss due to the high overpotential required at the anode. Today, in industrially relevant applications, dimensionally stable anodes (DSA) based on the electrocatalytic active RuO2 are conventionally utilized. To enhance the resistance against corrosion, incorporation of TiO2 in the RuO2-coated electrodes is widely employed. In the present work we have used scanning electrochemical microscopy (SECM) to demonstrate that TiO2-doped RuO2-coated electrodes, in addition to being more durable, also show an electrocatalytic activity that is, on average, 13% higher as compared to the pure RuO2-coated electrodes. We also demonstrate that cracks in the pure RuO2 coating are the most active zones, probably because Ti from the Ti support has diffused into the first applied layer of the RuO2 coating. To reveal the nature of this enhanced activity for water oxidation displayed on TiO2-doped RuO2 electrodes, we have employed X-ray photoelectron spectroscopy (XPS) for material characterization. The results show that the electrocatalytic activity enhancement displayed on the mixed (Ru1–x:Tix)O2 coating is promoted through a charge transfer from the RuO2 to the TiO2, which provides new and more reactive sites designated as activated RuO2δ+.This study has partly been carried out in the framework of the European Commission FP7 Initial Training Network “ELCAT”, Grant Agreement No. 214936-2. Portions of this research were performed at SPring-8 with the approval of Japan Synchrotron Radiation Research Institute as Nanotechnology Support Project of the Ministry of Education, Culture, Sports, Science and Technology (Proposal No. 2007A2005 and 2008A1671/BL-47XU)

Gene Expression of the Tumour Suppressor LKB1 Is Mediated by Sp1, NF-Y and FOXO Transcription Factors

The serine/threonine kinase LKB1 is a tumour suppressor that regulates multiple biological pathways, including cell cycle control, cell polarity and energy metabolism by direct phosphorylation of 14 different AMP-activated protein kinase (AMPK) family members. Although many downstream targets have been described, the regulation of LKB1 gene expression is still poorly understood. In this study, we performed a functional analysis of the human LKB1 upstream regulatory region. We used 200 base pair deletion constructs of the 5′-flanking region fused to a luciferase reporter to identify the core promoter. It encompasses nucleotides −345 to +52 relative to the transcription start site and coincides with a DNase I hypersensitive site. Based on extensive deletion and substitution mutant analysis of the LKB1 promoter, we identified four cis-acting elements which are critical for transcriptional activation. Using electrophoretic mobility shift assays as well as chromatin immunoprecipitations, we demonstrate that the transcription factors Sp1, NF-Y and two forkhead box O (FOXO) family members FOXO3 and FOXO4 bind to these elements. Overexpression of these factors significantly increased the LKB1 promoter activity. Conversely, small interfering RNAs directed against NF-Y alpha and the two FOXO proteins greatly reduced endogenous LKB1 expression and phosphorylation of LKB1's main substrate AMPK in three different cell lines. Taken together, these results demonstrate that Sp1, NF-Y and FOXO transcription factors are involved in the regulation of LKB1 transcription

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected