I.V. MIDAZOLAM AS AN INDUCTION AGENT FOR ANAESTHESIA: A STUDY IN VOLUNTEERS

The central nervous and cardiovascular effects of midazolam 0.15 mg kg−1 were studied in 20 healthy, unpremedicated volunteers (10 male and 10 female). No important side-effects were noted and the venous tolerance to midazolam was excellent. Three minutes after injection mean systolic arterial pressure decreased from 121±(SEM) 2 mm Hg to 115±(SEM) 2 mm Hg and diastolic pressure from 78±2 to 70±2 mm Hg (P <0.05), and these effects persisted for at least 20 mm. Heart rate increased from 77±4 beat mm−1 to 90±3 and 88±3 beat mm−1 1 and 3 mm after the injection (P <0.05). Anterograde amnesia (40±3 min duration) and drowsiness (lasting 128±23 mm) were observed in all subjects. Loss of the eyelash reflex and apnoea were observed more often in the male group than in the female subjects. Midazolam 0.15 mg kg−1 was not sufficient to induce anaesthesia reliably in healthy unpretnedicated volunteer

Asymptotic solvability of an imaginary cubic oscillator with spikes

For the PT symmetric potential of Dorey, Dunning and Tateo we show that in the large angular momentum (i.e., strongly spiked) limit the low-lying eigenstates of this popular non-Hermitian problem coincide with the shifted Hermitian harmonic oscillators calculated at the zero angular momentum. This type of an approximate Hermitization is valid in all the domain where the spectrum of energies remains real. It proves very efficient numerically. The construction is asymmetric with respect to the sign of the subdominant square-root spike, and exhibits a discontinuity at the point where the PT symmetric regularization vanishes.Comment: 20 pages and 2 figure

Health workers’ perspectives on the quality of maternal and newborn health care around the time of childbirth: Results of the Improving MAternal Newborn carE in the EURO Region (IMAgiNE EURO) project in 12 countries of the World Health Organization European Region

Background Health workers’ (HWs’) perspectives on the quality of maternal and newborn care (QMNC) are not routinely collected. In this cross-sectional study, we aimed to document HWs’ perspectives on QMNC around childbirth in 12 World Health Organization (WHO) European countries. Methods HWs involved in maternal/neonatal care for at least one year between March 2020 and March 2023 answered an online validated WHO standards-based questionnaire collecting 40 quality measures for improving QMNC. A QMNC index (score 0–400) was calculated as a synthetic measure. Results Data from 4143 respondents were analysed. For 39 out of 40 quality measures, at least 20% of HWs reported a ‘need for improvement’, with large variations across countries. Effective training on healthy women/newborns management (n = 2748, 66.3%), availability of informed consent job aids (n = 2770, 66.9%), and effective training on women/newborns rights (n = 2714, 65.5%) presented the highest proportion of HWs stating ‘need for improvement’. Overall, 64.8% (n = 2684) of respondents declared that HWs numbers were insufficient for appropriate care (66.3% in Portugal and 86.6% in Poland), and 22.4% described staff censorship (16.3% in Germany and 56.7% in Poland). The reported QMNC index was low in all countries (Poland median (MD) = 210.60, interquartile range (IQR) = 155.71, 273.57; Norway MD = 277.86; IQR = 244.32, 308.30). The ‘experience of care’ domain presented in eight countries had significantly lower scores than the other domains (P 0.05). Multivariate analyses confirmed large QMNC variation by country. HWs with <10 years of experience, HWs from public facilities, and midwives rated QMNC with significantly lower scores (P < 0.001). Conclusions HWs from 12 European countries reported significant gaps in QMNC, lacking association with COVID-19 pandemic trends. Routine monitoring of QMNC and tailored actions are needed to improve health services for the benefit of both users and providers. Registration ClinicalTrials.gov NCT04847336. © (2024), (University of Edinburgh). All rights reserved.This study was supported by the Ministry of Health, Rome, Italy, in collaboration with the Institute for Maternal and Child Health, IRCCS ‘Burlo Garofolo,’ Trieste, Italy. Raquel Costa was supported by the Social European Fund and Foundation for Science and Technology under a post-doctoral grant (SFRH/BPD/117597/2016). Epidemiology Research Unit (EPIUnit) – UIDB/04750/2020, Laboratory for Integrative and Translational Research in Population Health (ITR) – LA/P/0064/2020, and Human-environment Interaction laboratory (HEI-Laboratory) – UIDB/05380/2020 (https://doi.org/10.54499/UIDP/05380/2020) are financed by Portuguese fundings through Fundação para a Ciência e a Tecnologia, Instituto publico

Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

Staff training to improve participant recruitment into surgical randomised controlled trials : A feasibility study within a trial (SWAT) across four host trials simultaneously

The PROMoting THE Use of SWATs (PROMETHEUS) programme was funded by the Medical Research Council (MRC) [grant number MR/R013748/1]. The DISC host trial is funded by the Health Technology Assessment Programme (Grant Ref: 15/102/04). IntAct is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership (Grant Ref: 14/150/62). The EME Programme is funded by the MRC and NIHR, with contributions from the CSO in Scotland and Health and Care Research Wales and the HSC R&D Division, Public Health Agency in Northern Ireland. PROFHER-2 is funded by the Health Technology Assessment Programme (Grant Ref: 16/73/03). START: REACTS is funded by the NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 16/61/18. The development of the training intervention was funded by the MRC Network of Hubs for Trials Methodology Research (MR/L004933/1- R53) and supported by the MRC ConDuCT-II Hub (Collaboration and innovation for Difficult and Complex randomized controlled Trials In Invasive procedures - MR/K025643/1). The online version of the training intervention was funded by the NIHR and is hosted on the NIHR Learn platform (https://learn.nihr.ac.uk/course/view.php?id=385). It is based on the face-to face GRANULE training course funded by the Bowel Disease Research Foundation in collaboration with the University of Birmingham, University of Bristol and former MRC ConDuCT-II Hub. This work was part-funded by the Wellcome Trust [ref: 204829] through the Centre for Future Health (CFH) at the University of York. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the MRC or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.Peer reviewedPublisher PD

Regional differences in the quality of maternal and neonatal care during the COVID-19 pandemic in Portugal: Results from the IMAgiNE EURO study

Objective: To compare women's perspectives on the quality of maternal and newborn care (QMNC) around the time of childbirth across Nomenclature of Territorial Units for Statistics 2 (NUTS-II) regions in Portugal during the COVID-19 pandemic. Methods: Women participating in the cross-sectional IMAgiNE EURO study who gave birth in Portugal from March 1, 2020, to October 28, 2021, completed a structured questionnaire with 40 key WHO standards-based quality measures. Four domains of QMNC were assessed: (1) provision of care; (2) experience of care; (3) availability of human and physical resources; and (4) reorganizational changes due to the COVID-19 pandemic. Frequencies for each quality measure within each QMNC domain were computed overall and by region. Results: Out of 1845 participants, one-third (33.7%) had a cesarean. Examples of high-quality care included: low frequencies of lack of early breastfeeding and rooming-in (8.0% and 7.7%, respectively) and informal payment (0.7%); adequate staff professionalism (94.6%); adequate room comfort and equipment (95.2%). However, substandard practices with large heterogeneity across regions were also reported. Among women who experienced labor, the percentage of instrumental vaginal births ranged from 22.3% in the Algarve to 33.5% in Center; among these, fundal pressure ranged from 34.8% in Lisbon to 66.7% in Center. Episiotomy was performed in 39.3% of noninstrumental vaginal births with variations between 31.8% in the North to 59.8% in Center. One in four women reported inadequate breastfeeding support (26.1%, ranging from 19.4% in Algarve to 31.5% in Lisbon). One in five reported no exclusive breastfeeding at discharge (22.1%; 19.5% in Lisbon to 28.2% in Algarve). Conclusion: Urgent actions are needed to harmonize QMNC and reduce inequities across regions in Portugal. © 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.Funding text 1: This work was supported by the Ministry of Health, Rome - Italy, in collaboration with the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste - Italy. This study was supported by Portuguese fundings through FCT - Fundação para a Ciência e a Tecnologia, IP, in the scope of the projects EPIUnit - UIDB/04750/2020, ITR - LA/P/0064/2020, and HEILab - UIDB/05380/2020, and by the European Social Fund (ESF) and FCT (SFRH/BPD/117597/2016; RC postdoctoral fellowship). We are grateful to the women who dedicated their time to complete the survey, to Associação Portuguesa pelos Direitos da Mulher na Gravidez e Parto (APDMGP) for support with survey dissemination and to nurse Louise Semião for assistance provided in back-translation of the questionnaires. Special thanks to the IMAgiNE EURO study group for their contribution to the development of this project and support for this manuscript.; Funding text 2: This work was supported by the Ministry of Health, Rome ‐ Italy, in collaboration with the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste ‐ Italy. This study was supported by Portuguese fundings through FCT ‐ Fundação para a Ciência e a Tecnologia, IP, in the scope of the projects EPIUnit ‐ UIDB/04750/2020, ITR ‐ LA/P/0064/2020, and HEILab ‐ UIDB/05380/2020, and by the European Social Fund (ESF) and FCT (SFRH/BPD/117597/2016; RC postdoctoral fellowship). We are grateful to the women who dedicated their time to complete the survey, to Associação Portuguesa pelos Direitos da Mulher na Gravidez e Parto (APDMGP) for support with survey dissemination and to nurse Louise Semião for assistance provided in back‐translation of the questionnaires. Special thanks to the IMAgiNE EURO study group for their contribution to the development of this project and support for this manuscript. ; Funding text 3: IMAgiNE EURO project was supported by the Ministry of Health, Rome ‐ Italy, in collaboration with the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste ‐ Italy. This study was supported by Fundação para a Ciência e a Tecnologia; European Social Fund (ESF) Funding informatio

The molecular basis of polysaccharide cleavage by lytic polysaccharide monooxygenases.

Lytic polysaccharide monooxygenases (LPMOs) are copper-containing enzymes that oxidatively break down recalcitrant polysaccharides such as cellulose and chitin. Since their discovery, LPMOs have become integral factors in the industrial utilization of biomass, especially in the sustainable generation of cellulosic bioethanol. We report here a structural determination of an LPMO-oligosaccharide complex, yielding detailed insights into the mechanism of action of these enzymes. Using a combination of structure and electron paramagnetic resonance spectroscopy, we reveal the means by which LPMOs interact with saccharide substrates. We further uncover electronic and structural features of the enzyme active site, showing how LPMOs orchestrate the reaction of oxygen with polysaccharide chains.We thank K. Rasmussen and R.M. Borup for experimental assistance, and MAXLAB, Sweden and the European Synchrotron Radiation Facility (ESRF), France, for synchrotron beam time and assistance. This work was supported by the UK Biotechnology and Biological Sciences Research Council (grant numbers BB/L000423 to P.D., G.J.D. and P.H.W., and BB/L021633/1 to G.J.D. and P.H.W.), Agence Française de l'Environnement et de la Maîtrise de l'Energie (grant number 1201C102 to B.H.), the Danish Council for Strategic Research (grant numbers 12-134923 to L.L.L. and 12-134922 to K.S.J.). Travel to synchrotrons was supported by the Danish Ministry of Higher Education and Science through the Instrument Center DANSCATT and the European Community's Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (grant agreement 283570). L.M., S.F., S.C. and H.D. were supported by Institut de Chimie Moléculaire de Grenoble FR 2607, LabEx ARCANE (ANR-11-LABX-0003-01), the PolyNat Carnot Institute and the French Agence Nationale de la Recherche (PNRB2005-11).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nchembio.202