bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitrogen fertilizer-regulated plant-fungi interaction is related to root invertase-induced hexose generation
Authors: Sun Kai , Zhang Wei , Yuan Jie , Song Shi-Li , Wu Hao , Tang Meng-Jun , Xu Fang-Ji , Xie Xing-Guang , Dai Chuan-Chao
Published: July 2020

The mechanisms underlying nitrogen (N)-regulated plant-fungi interactions are not well understood. N application modulates plant carbohydrate (C) sinks and is involved in the overall plant-fungal association. We hypothesized that N regulates plant-fungi interactions by influencing the carbohydrate metabolism. The mutualistic fungus Phomopsis liquidambaris was found to prioritize host hexose resources through in vitro culture assays and in planta inoculation. Rice-Ph. liquidambaris systems were exposed to N gradients ranging from N-deficient to N-abundant conditions to study whether and how the sugar composition was involved in the dynamics of N-mediated fungal colonization. We found that root soluble acid invertases were activated, resulting in increased hexose fluxes in inoculated roots. These fluxes positively influenced fungal colonization, especially under N-deficient conditions. Further experiments manipulating the carbohydrate composition and root invertase activity through sugar feeding, chemical treatments and the use of different soil types revealed that the external disturbance of root invertase could reduce endophytic colonization and eliminate endophyte-induced host benefits under N-deficient conditions. Collectively, these results suggest that the activation of root invertase is related to N deficiency-enhanced endophytic colonization via increased hexose generation. Certain combinations of farmland ecosystems with suitable N inputs could be implemented to maximize the benefits of plant-fungi associations.
Target-oriented full-waveform inversion using Marchenko redatumed wavefields
Authors: Cui Tianci , Rickett James , Vasconcelos Ivan , Veitch Ben
Published: July 2020

Full-waveform inversion (FWI) has demonstrated increasing success in estimating medium properties, but its computational cost still poses challenges in moving towards high-resolution imaging of targets at depth. Here, we propose a target-oriented FWI method that inverts for the medium parameters confined within an arbitrary region of interest. Our method is novel in terms of both local wavefield modelling and data redatuming, in order to build a target-oriented objective function which is sensitive to the target medium only without further assumptions about the medium outside. Based on the convolution-type representation theorem, our local forward modelling operator propagates wavefields within the target medium only while providing full acoustic coupling between the target medium and the surrounding geology. A key requirement of our local FWI method is that the subsurface wavefields surrounding and inside the target be as accurate as possible. As such, the subsurface wavefields are retrieved by the Marchenko method, which can redatum the single-sided surface reflection data to the target zone while preserving both primary and multiple reflections, with minimal a priori knowledge of the full-domain medium. Given a sufficiently accurate initial velocity macromodel, our numerical examples show that our local FWI method resolves the reservoir zone of a 2-D Barrett Unconventional P-wave velocity model much more efficiently than the conventional full-domain FWI without significantly sacrificing accuracy. Our method may further enable FWI approaches to high-resolution imaging of subsurface targets.
Interventions to strengthen the leadership capabilities of health professionals in Sub-Saharan Africa: a scoping review
Authors: Johnson Oliver , Begg Kerrin , Kelly Ann H , Sevdalis Nick
Published: July 2020

Leadership is a critical component of a health system and may be particularly important in Sub-Saharan Africa, where clinicians take on significant management responsibilities. However, there has been little investment in strengthening leadership in this context, and evidence is limited on what leadership capabilities are most important or how effective different leadership development models are. This scoping review design used Arksey and O’Malley’s approach of identifying the question and relevant studies, selection, charting of data, summarizing of results and consultation. A comprehensive search strategy was used that included published and unpublished primary studies and reviews. Seven databases were searched, and papers written in English and French between 1979 and 2019 were included. Potential sources were screened against inclusion and exclusion criteria. Data were grouped into common categories and summarized in tables; categories included conceptual approach to leadership; design of intervention; evaluation method; evidence of effectiveness; and implementation lessons. The findings were then analysed in the context of the review question and objectives. Twenty-eight studies were included in the review out of a total of 495 that were initially identified. The studies covered 23 of the 46 countries in Sub-Saharan Africa. The leadership development programmes (LDPs) described were diverse in their design. No consistency was found in the conceptual approaches they adopted. The evaluation methods were also heterogeneous and often of poor quality. The review showed how rapidly leadership has emerged as a topic of interest in health care in Sub-Saharan Africa. Further research on this subject is needed, in particular in strengthening the conceptual and competency frameworks for leadership in this context, which would also inform better evaluation. Our findings support the need for LDPs to be accredited, better integrated into existing systems and to put greater emphasis on institutionalization and financial sustainability from their early development.
The Phosphodiesterase-4 Inhibitor Roflumilast, a Potential Treatment for the Comorbidity of Memory Loss and Depression in Alzheimer’s Disease: A Preclinical Study in APP/PS1 Transgenic Mice
Authors: Wang Hao , Zhang Fang-fang , Xu Yong , Fu Hua-rong , Wang Xiao-dan , Wang Lei , Chen Wei , Xu Xiao-yan , Gao Yong-feng , Zhang Ji-guo , Zhang Han-Ting
Published: July 2020

Background

Depression is highly related to Alzheimer’s disease (AD), yet no effective treatment is available. Phosphodiesterase-4 (PDE4) has been considered a promising target for treatment of AD and depression. Roflumilast, the first PDE4 inhibitor approved for clinical use, improves cognition at doses that do not cause side effects such as emesis.

Methods

Here we examined the effects of roflumilast on behavioral dysfunction and the related mechanisms in APPswe/PS1dE9 transgenic mice, a widely used model of AD. Mice at 10 months of age were examined for memory in the novel object recognition and Morris water-maze tests and depression-like behavior in the tail-suspension test and forced swimming test before killing for neurochemical assays.

Results

In the novel object recognition and Morris water-maze, APPswe/PS1dE9 mice showed significant cognitive declines, which were reversed by roflumilast at 5 and 10 mg/kg orally once per day. In the tail-suspension test and forced swimming test, the AD mice showed prolonged immobility time, which was also reversed by roflumilast. In addition, the staining of hematoxylin–eosin and Nissl showed that roflumilast relieved the neuronal cell injuries, while terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling analysis indicated that roflumilast ameliorated cell apoptosis in AD mice. Further, roflumilast reversed the decreased ratio of B-cell lymphoma-2/Bcl-2-associated X protein and the increased expression of PDE4B and PDE4D in the cerebral cortex and hippocampus of AD mice. Finally, roflumilast reversed the decreased levels of cyclic AMP (cAMP) and expression of phosphorylated cAMP response element-binding protein and brain derived neurotrophic factor in AD mice.

Conclusions

Together, these results suggest that roflumilast not only improves learning and memory but also attenuates depression-like behavior in AD mice, likely via PDE4B/PDE4D-mediated cAMP/cAMP response element-binding protein/brain derived neurotrophic factor signaling. Roflumilast can be a therapeutic agent for AD, in particular the comorbidity of memory loss and depression.
Mechanisms of Colonization Resistance Against Clostridioides difficile
Authors: Pike Colleen M , Theriot Casey M
Published: July 2020

Clostridioides difficile is an urgent antimicrobial-resistant bacterium, causing mild to moderate and sometimes life-threatening disease. Commensal gut microbes are critical for providing colonization resistance against C difficile and can be leveraged as non-antibiotic alternative therapeutics for the prevention and treatment of C difficile infection.
Arrival of the rare carbapenemase OXA-204 in Canada causing a multispecies outbreak over 3 years
Authors: Gobeille Paré Sarah , Mataseje Laura F , Ruest Annie , Boyd David A , Lefebvre Brigitte , Trépanier Pascale , Longtin Jean , Dolce Patrick , Mulvey Michael R
Published: July 2020

Objectives

To investigate a persistent multispecies OXA-204 outbreak occurring simultaneously in multiple distant hospitals in the province of Quebec, Canada.

Methods

OXA-204 carbapenemase-producing Enterobacterales (CPE) isolated from multiple hospitals between January 2016 and October 2018 were included in the study. An epidemiological inquiry was conducted in order to elucidate possible transmission routes and a putative source. Isolates were characterized by standardized antibiotic susceptibility testing and by WGS, using Illumina short-read data and MinION long-read data.

Results

The outbreak comprised 65 patients and 82 isolates from four hospital sites. Most patients were ≥65 years old, had multiple comorbidities and had received antibiotics recently. The infection to colonization ratio was 1:20. No persistent environmental reservoir was identified. The most frequent organism was Citrobacter freundii (n = 78), followed by Klebsiella spp. (n = 3) and Escherichia coli (n = 1). WGS analysis showed 77/78 C. freundii isolates differing by 0–26 single nucleotide variants (SNVs). Results of WGS analysis showed blaOXA-204 was present on three plasmids types (IncX1, IncA/C2 and IncFII/FIB/A/C2) and on a prophage. All C. freundii isolates harboured multiple copies of blaOXA-204, both on the chromosome and a plasmid. Plasmid IncFII/FIB/A/C2 was observed in all three species.

Conclusions

Transfer of OXA-204 plasmids likely occurred between species within the same patient, highlighting the plasticity of these plasmids and potential for widespread dissemination. OXA-204 carbapenemase has been introduced into Quebec and has rapidly disseminated. Although the infection to colonization ratio was low in this outbreak, this carbapenemase has been associated with severe infection elsewhere.
Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial
Authors: Abbaspour Kasgari Hamideh , Moradi Siavash , Shabani Amir Mohammad , Babamahmoodi Farhang , Davoudi Badabi Ali Reza , Davoudi Lotfollah , Alikhani Ahmad , Hedayatizadeh Omran Akbar , Saeedi Majid , Merat Shahin , Wentzel Hannah , Garratt Anna , Levi Jacob , Simmons Bryony , Hill Andrew , Tirgar Fakheri Hafez
Published: July 2020

Background

New therapeutic options are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). Repurposing existing pharmaceuticals provides an immediate treatment opportunity. We assessed the efficacy of sofosbuvir and daclatasvir with ribavirin for treating patients with COVID-19.

Methods

This was a single-centre, randomized controlled trial in adults with moderate COVID-19 admitted to the Ghaem Shahr Razi Hospital in Mazandaran Province, Iran. Patients were randomly assigned to 400 mg sofosbuvir, 60 mg daclatasvir and 1200 mg ribavirin (intervention group) or to standard care (control group). The primary endpoint of this study was length of hospital stay. This study is registered by IRCT.ir under the ID: IRCT20200328046886N1.

Results

Between 20 March 2020 and 8 April 2020, 48 patients were recruited; 24 patients were randomly assigned to the intervention group and 24 to the control group. The median duration of hospital stay was 6 days in both groups (P = 0.398). The number of ICU admissions in the sofosbuvir/daclatasvir/ribavirin group was not significantly lower than the control group (0 versus 4, P = 0.109). There was no difference in the number of deaths between the groups (0 versus 3, P = 0.234). The cumulative incidence of recovery was higher in the sofosbuvir/daclatasvir/ribavirin arm (Gray’s P = 0.033).

Conclusions

This randomized trial was too small to make definitive conclusions. There were trends in favour of the sofosbuvir/daclatasvir/ribavirin arm for recovery and lower death rates. However, there was an imbalance in the baseline characteristics between the arms. Larger randomized trials should be conducted to investigate this treatment further.
Commentary: Reflections on the COVID-19 Pandemic and Health Disparities in Pediatric Psychology
Authors: Valenzuela Jessica , Crosby Lori E , Harrison Roger R
Published: July 2020

The COVID-19 (2019 novel coronavirus) pandemic has had a significant economic, social, emotional, and public health impact in the United States. A disturbing trend is that Black, Indigenous, and/or People of Color (BIPOC) are disproportionately contracting coronavirus, as well as dying from COVID-19. Objective/Methods The pandemic has the potential to entrench and magnify existing health disparities and families marginalized across multiple demographic intersections such as race/ethnicity, class, immigration status, are especially vulnerable. These inequities have been further underscored by the recent murders of Black Americans by police and a resulting spotlight on racial injustice in the United States. Results Efforts to lessen the spread of the virus, have resulted in changes in pediatric primary and subspecialty service delivery which may affect access for BIPOC communities. BIPOC trainees including those with debt or caregiving responsibilities may be faced with new barriers resulting in delays in completion of their training. Further, clinical, community-based, and translational research has been disrupted by heightened safety precautions and social distancing which may affect BIPOC representation in research downstream. Conclusion In our roles as clinicians, supervisors, trainees, and researchers in primary and subspecialty care as well as in academia, pediatric psychologists have an ethical responsibility to address the disproportionate burden of this pandemic on vulnerable communities and to allocate our time and resources to ensuring health equity now and in the aftermath of COVID-19.
Laparoscopic management of an ascending colon hernia through the foramen of Winslow
Authors: Buisset Cyrille , Postillon Agathe , Aziz Sandrine , Bilbault Florian , Hoch Guillaume , Nesseler Jean-Philippe , Johann Marc
Published: July 2020

Herniation through the foramen of Winslow is rare, with a non-specific clinical presentation and his diagnosis may be difficult. A 44-year-old female was admitted with an acute epigastric abdominal pain. A computed tomography showed an internal hernia of the colon in the lesser sac. Laparoscopic reduction of the herniated contents and the fixation of the ascending colon with several non-absorbable sutures were performed. Twenty months after surgery, the patient has not experienced any recurrence. Computed tomography helps practitioners to the preoperative diagnosis of herniation through the foramen of Winslow, to the viability of the herniated contents and presence of occlusion. In case of herniation through the foramen of Winslow favored by a mobile ascending colon with a misapposition of the right Told fascia, the fixation of the colon with a non-absorbable suture was safe and may prevent the risk of recurrent internal hernia and colonic volvulus.
Constraining the second half of reionization with the Ly β forest
Authors: Keating Laura C , Kulkarni Girish , Haehnelt Martin G , Chardin Jonathan , Aubert Dominique
Published: July 2020

We present an analysis of the evolution of the Lyman-series forest into the epoch of reionization using cosmological radiative transfer simulations in a scenario where reionization ends late. We explore models with different mid-points of reionization and gas temperatures. We find that once the simulations have been calibrated to match the mean flux of the observed Lyman-α (Ly α) forest at 4 < z < 6, they also naturally reproduce the distribution of effective optical depths of the Lyman-β (Ly β) forest in this redshift range. We note that the tail of the largest optical depths that is most challenging to match corresponds to the long absorption trough of ULAS J0148+0600, which we have previously shown to be rare in our simulations. We consider the evolution of the Lyman-series forest out to higher redshifts, and show that future observations of the Ly β forest at z > 6 will discriminate between different reionization histories. The evolution of the Ly α and Ly γ forests are less promising as a tool for pushing studies of reionization to higher redshifts due to the stronger saturation and foreground contamination, respectively.
Hypermassive black holes have faint broad and narrow emission lines
Authors: Bhat Harshitha K , Chakravorty Susmita , Sengupta Dhrubojyoti , Elvis Martin , Datta Sudeb Ranjan , Roy Nirupam , Bertemes Caroline , Ferland Gary , Ezhikode Savithri H
Published: July 2020

The extreme ultraviolet region (EUV) provides most of the ionization that creates the high equivalent width (EW) broad and narrow emission lines (BELs and NELs) of quasars. Spectra of hypermassive Schwarzschild black holes (HMBHs; MBH ≥ 1010 M⊙) with α-discs, decline rapidly in the EUV suggesting much lower EWs. Model spectra for BHs of mass 106–1012 M⊙ and accretion rates 0.03 ≤ Lbol/LEdd ≤ 1.0 were input to the cloudy photoionization code. BELs become ∼100 times weaker in EW from MBH ∼ 108 M⊙ to MBH ∼ 1010 M⊙. The high-ionization BELs (O vi 1034 Å, C iv 1549 Å, and He ii 1640 Å) decline in EW from MBH ≥ 106 M⊙, reproducing the Baldwin effect, but regain EW for MBH ≥ 1010 M⊙. The low-ionization lines (Mg ii 2798 Å, H β 4861 Å, and H α 6563 Å) remain weak. Lines for maximally spinning HMBHs behave similarly. Line ratio diagrams for the BELs show that high O vi/H β and low C iv/H α may pick out HMBH, although O vi is often hard to observe. In NEL BPT diagrams, HMBHs lie among star-forming regions, except for highly spinning, high accretion rate HMBHs. In summary, the BELs expected from HMBHs would be hard to detect using the current optical facilities. From 100 to 1012 M⊙, the emission lines used to detect active galactic nuclei (AGNs) only have high EW in the 106–109 M⊙ window, where most AGNs are found. This selection effect may be distorting reported distributions of MBH.
Effects of density on the oxygen ionization equilibrium in collisional plasmas
Authors: Dufresne R P , Del Zanna G , Badnell N R
Published: July 2020

The ion populations most frequently adopted for diagnostics in collisional plasmas are derived from the density independent coronal approximation. In higher density, lower temperature conditions, ionization rates are enhanced once metastable levels become populated, and recombination rates are suppressed if ions recombine into Rydberg levels. As a result, the formation temperatures of ions shift, altering the diagnostics of the plasma. To accurately model the effect of ionization from metastable levels, new electron impact ionization cross-sections have been calculated for oxygen, both for direct ionization and excitation–auto-ionization of the ground and metastable levels. The results have been incorporated into collisional radiative modelling to show how the ionization equilibrium of oxygen changes once metastable levels become populated. Suppression of dielectronic recombination has been estimated and also included in the modelling, demonstrating the shifts with density in comparison to the coronal approximation. The final results for the ionization equilibrium are used in differential emission measure modelling to predict line intensities for many lines emitted by O ii–O vi in the solar transition region. The predictions show improved agreement by 15–40 per cent for O ii, O vi, and the intercombination lines of O iii–O v, when compared to results from coronal approximation modelling. While there are still discrepancies with observations of these lines, this could, to a large part, be explained by variability in the observations.
Star formation in luminous LoBAL quasars at 2.0 < z < 2.5
Authors: Wethers Clare F , Kotilainen Jari , Schramm Malte , Schulze Andreas
Published: July 2020

Low-ionization broad absorption line quasars (LoBALs) mark an important, yet poorly understood, population of quasars showing direct evidence for energetic mass outflows. We outline a sample of 12 luminous (Lbol > 1046 ergs−1) LoBALs at 2.0 < z < 2.5 – a key epoch in both star formation and black hole accretion, which have been imaged as part of a targeted program with the Herschel Spectral and Photometric Imaging REceiver (SPIRE). We present K-band NOTCam spectra for three of these targets, calculating their spectroscopic redshifts, black hole masses, and bolometric luminosities, and increasing the total number of LoBAL targets in our sample with spectral information from five to eight. Based on FIR observations from Herschel SPIRE, we derive prolific star formation rates (SFRs) ranging 740–2380 M⊙ yr−1 for the detected targets, consistent with LoBALs existing in an evolutionary phase associated with starburst activity. Furthermore, an upper limit of <440 M⊙ yr−1 is derived for the non-detections, meaning moderate-to-high SFRs cannot be ruled out, even among the undetected targets. Indeed, we detect an enhancement in both the SFRs and FIR fluxes of LoBALs compared to HiBAL and non-BAL quasars, further supporting the evolutionary LoBAL paradigm. Despite this enhancement in SFR, however, the environments of LoBALs appear entirely consistent with the general galaxy population at 2.0 < z < 2.5.
Gaia white dwarfs within 40 pc II: the volume-limited Northern hemisphere sample
Authors: McCleery Jack , Tremblay Pier-Emmanuel , Gentile Fusillo Nicola Pietro , Hollands Mark A , Gänsicke Boris T , Izquierdo Paula , Toonen Silvia , Cunningham Tim , Rebassa-Mansergas Alberto
Published: July 2020

We present an overview of the sample of Northern hemisphere white dwarfs within 40 pc of the Sun detected from Gaia Data Release 2 (DR2). We find that 521 sources are spectroscopically confirmed degenerate stars, 111 of which were first identified as white dwarf candidates from Gaia DR2 and followed up recently with the William Herschel Telescope and Gran Telescopio Canarias. Three additional white dwarf candidates remain spectroscopically unobserved and six unresolved binaries are known to include a white dwarf but were not in our initial selection in the Gaia DR2 Hertzsprung–Russell diagram. Atmospheric parameters are calculated from Gaia and Pan-STARRS photometry for all objects in the sample, confirming most of the trends previously observed in the much smaller 20 pc sample. Local white dwarfs are overwhelmingly consistent with Galactic disc kinematics, with only four halo candidates. We find that DAZ white dwarfs are significantly less massive than the overall DA population ($\overline{M}_\mathrm{DAZ}$ = 0.59 M⊙, $\overline{M}_\mathrm{DA}$ = 0.66 M⊙). It may suggest that planet formation is less efficient at higher mass stars, producing more massive white dwarfs. We detect a sequence of crystallized white dwarfs in the mass range from 0.6 $\lesssim M/\mbox{$\mathrm{M}_\odot $}\ \lesssim$ 1.0 and find that the vast majority of objects on the sequence have standard kinematic properties that correspond to the average of the sample, suggesting that their nature can be explained by crystallization alone. We also detect 26 double degenerates and white dwarf components in 56 wide binary systems.
Thermal inertias of pebble-pile comet 67P/Churyumov–Gerasimenko
Authors: Arakawa Sota , Ohno Kazumasa
Published: July 2020

The Rosetta mission to comet 67P/Churyumov–Gerasimenko has provided new data to better understand what comets are made of. The weak tensile strength of the cometary surface materials suggests that the comet is a hierarchical dust aggregate formed through gravitational collapse of a bound clump of small dust aggregates so-called ‘pebbles’ in the gaseous solar nebula. Since pebbles are the building blocks of comets, which are the survivors of planetesimals in the solar nebula, estimating the size of pebbles using a combination of thermal observations and numerical calculations is of great importance to understand the planet formation in the outer Solar system. In this study, we calculated the thermal inertias and thermal skin depths of the hierarchical aggregates of pebbles, for both diurnal and orbital variations of the temperature. We found that the thermal inertias of the comet 67P/Churyumov–Gerasimenko are consistent with the hierarchical aggregate of cm- to dm-sized pebbles. Our findings indicate that the icy planetesimals may have formed via accretion of cm- to dm-sized pebbles in the solar nebula.
Augmented base pairing networks encode RNA-small molecule binding preferences
Authors: Oliver Carlos , Mallet Vincent , Gendron Roman Sarrazin , Reinharz Vladimir , Hamilton William L , Moitessier Nicolas , Waldispühl Jérôme
Published: July 2020

RNA-small molecule binding is a key regulatory mechanism which can stabilize 3D structures and activate molecular functions. The discovery of RNA-targeting compounds is thus a current topic of interest for novel therapies. Our work is a first attempt at bringing the scalability and generalization abilities of machine learning methods to the problem of RNA drug discovery, as well as a step towards understanding the interactions which drive binding specificity. Our tool, RNAmigos, builds and encodes a network representation of RNA structures to predict likely ligands for novel binding sites. We subject ligand predictions to virtual screening and show that we are able to place the true ligand in the 71st–73rd percentile in two decoy libraries, showing a significant improvement over several baselines, and a state of the art method. Furthermore, we observe that augmenting structural networks with non-canonical base pairing data is the only representation able to uncover a significant signal, suggesting that such interactions are a necessary source of binding specificity. We also find that pre-training with an auxiliary graph representation learning task significantly boosts performance of ligand prediction. This finding can serve as a general principle for RNA structure-function prediction when data is scarce. RNAmigos shows that RNA binding data contains structural patterns with potential for drug discovery, and provides methodological insights for possible applications to other structure-function learning tasks. The source code, data and a Web server are freely available at http://rnamigos.cs.mcgill.ca.
The duties of a resulting trustee
Authors: Collings Matthew
Published: July 2020

The precise duties surrounding express trusts have caused issues enough (as we explore in this journal)—but what of the duties of resulting trustees? They have been considered in the authorities, and have been the subject of academic commentary, but have nevertheless remained somewhat opaque. A recent judgment in the Court of Appeal in Singapore (its highest court) has thoroughly traversed the principal English and Commonwealth authorities and collated the academic articles. It provides a comprehensive and valuable insight into the duties of resulting trustees.
Granger Causality of the Electroencephalogram Reveals Abrupt Global Loss of Cortical Information Flow during Propofol-induced Loss of Responsiveness
Authors: Pullon Rebecca M. , Yan Lucy , Sleigh Jamie W. , Warnaby Catherine E.
Published: July 2020

Background

It is a commonly held view that information flow between widely separated regions of the cerebral cortex is a necessary component in the generation of wakefulness (also termed “connected” consciousness). This study therefore hypothesized that loss of wakefulness caused by propofol anesthesia should be associated with loss of information flow, as estimated by the effective connectivity in the scalp electroencephalogram (EEG) signal.

Methods

Effective connectivity during anesthesia was quantified by applying bivariate Granger to multichannel EEG data recorded from 16 adult subjects undergoing a slow induction of, and emergence from, anesthesia with intravenous propofol. During wakefulness they were conducting various auditory and motor tasks. Functional connectivity using EEG coherence was also estimated.

Results

There was an abrupt, substantial, and global decrease in effective connectivity around the point of loss of responsiveness. Recovery of behavioral responsiveness was associated with a comparable recovery in information flow pattern (expressed as normalized values). The median (interquartile range) change was greatest in the delta frequency band: decreasing from 0.15 (0.21) 2 min before loss of behavioral response, to 0.06 (0.04) 2 min after loss of behavioral response (P < 0.001). Regional decreases in information flow were maximal in a posteromedial direction from lateral frontal and prefrontal regions (0.82 [0.24] 2 min before loss of responsiveness, decreasing to 0.17 [0.05] 2 min after), and least for information flow from posterior channels. The widespread decrease in bivariate Granger causality reflects loss of cortical coordination. The relationship between functional connectivity (coherence) and effective connectivity (Granger causality) was inconsistent.

Conclusions

Propofol-induced unresponsiveness is marked by a global decrease in information flow, greatest from the lateral frontal and prefrontal brain regions in a posterior and medial direction. Loss of information flow may be a useful measure of connected consciousness.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain
Authors: Verret Michael , Lauzier François , Zarychanski Ryan , Perron Caroline , Savard Xavier , Pinard Anne-Marie , Leblanc Guillaume , Cossi Marie-Joëlle , Neveu Xavier , Turgeon Alexis F. ,   the Canadian Perioperative Anesthesia Clinical Trials (PACT) Group
Published: July 2020

Background

Widely used for acute pain management, the clinical benefit from perioperative use of gabapentinoids is uncertain. The aim of this systematic review was to assess the analgesic effect and adverse events with the perioperative use of gabapentinoids in adult patients.

Methods

Randomized controlled trials studying the use of gabapentinoids in adult patients undergoing surgery were included. The primary outcome was the intensity of postoperative acute pain. Secondary outcomes included the intensity of postoperative subacute pain, incidence of postoperative chronic pain, cumulative opioid use, persistent opioid use, lengths of stay, and adverse events. The clinical significance of the summary estimates was assessed based on established thresholds for minimally important differences.

Results

In total, 281 trials (N = 24,682 participants) were included in this meta-analysis. Compared with controls, gabapentinoids were associated with a lower postoperative pain intensity (100-point scale) at 6 h (mean difference, −10; 95% CI, −12 to −9), 12 h (mean difference, −9; 95% CI, −10 to −7), 24 h (mean difference, −7; 95% CI, −8 to −6), and 48 h (mean difference, −3; 95% CI, −5 to −1). This effect was not clinically significant ranging below the minimally important difference (10 points out of 100) for each time point. These results were consistent regardless of the type of drug (gabapentin or pregabalin). No effect was observed on pain intensity at 72 h, subacute and chronic pain. The use of gabapentinoids was associated with a lower risk of postoperative nausea and vomiting but with more dizziness and visual disturbance.

Conclusions

No clinically significant analgesic effect for the perioperative use of gabapentinoids was observed. There was also no effect on the prevention of postoperative chronic pain and a greater risk of adverse events. These results do not support the routine use of pregabalin or gabapentin for the management of postoperative pain in adult patients.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Androgenic Modulation of the Chloride Transporter NKCC1 Contributes to Age-dependent Isoflurane Neurotoxicity in Male Rats
Authors: Chinn Gregory A. , Sasaki Russell Jennifer M. , Yabut Nicole A. , Maharjan Deenu , Sall Jeffrey W.
Published: July 2020

Background

Cognitive deficits after perinatal anesthetic exposure are well established outcomes in animal models. This vulnerability is sex-dependent and associated with expression levels of the chloride transporters NKCC1 and KCC2. The hypothesis was that androgen signaling, NKCC1 function, and the age of isoflurane exposure are critical for the manifestation of anesthetic neurotoxicity in male rats.

Methods

Flutamide, an androgen receptor antagonist, was administered to male rats on postnatal days 2, 4, and 6 before 6 h of isoflurane on postnatal day 7 (ntotal = 26). Spatial and recognition memory were subsequently tested in adulthood. NKCC1 and KCC2 protein levels were measured from cortical lysates by Western blot on postnatal day 7 (ntotal = 20). Bumetanide, an NKCC1 antagonist, was injected immediately before isoflurane exposure (postnatal day 7) to study the effect of NKCC1 inhibition (ntotal = 48). To determine whether male rats remain vulnerable to anesthetic neurotoxicity as juveniles, postnatal day 14 animals were exposed to isoflurane and assessed as adults (ntotal = 30).

Results

Flutamide-treated male rats exposed to isoflurane successfully navigated the spatial (Barnes maze probe trial F[1, 151] = 78; P < 0.001; mean goal exploration ± SD, 6.4 ± 3.9 s) and recognition memory tasks (mean discrimination index ± SD, 0.09 ± 0.14; P = 0.003), unlike isoflurane-exposed controls. Flutamide changed expression patterns of NKCC1 (mean density ± SD: control, 1.49 ± 0.69; flutamide, 0.47 ± 0.11; P < 0.001) and KCC2 (median density [25th percentile, 75th percentile]: control, 0.23 [0.13, 0.49]; flutamide, 1.47 [1.18,1.62]; P < 0.001). Inhibiting NKCC1 with bumetanide was protective for spatial memory (probe trial F[1, 162] = 6.6; P = 0.011; mean goal time, 4.6 [7.4] s). Delaying isoflurane exposure until postnatal day 14 in males preserved spatial memory (probe trial F[1, 140] = 28; P < 0.001; mean goal time, 6.1 [7.0] s).

Conclusions

Vulnerability to isoflurane neurotoxicity is abolished by blocking the androgen receptor, disrupting the function of NKCC1, or delaying the time of exposure to at least 2 weeks of age in male rats. These results support a dynamic role for androgens and chloride transporter proteins in perinatal anesthetic neurotoxicity.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Volatile versus Total Intravenous Anesthesia for Cancer Prognosis in Patients Having Digestive Cancer Surgery
Authors: Makito Kanako , Matsui Hiroki , Fushimi Kiyohide , Yasunaga Hideo
Published: July 2020

Background

Previous experimental and clinical studies have shown that anesthetic agents have varying effects on cancer prognosis; however, the results were inconsistent among these studies. The authors compared overall and recurrence-free survival in patients given volatile or intravenous anesthesia for digestive tract cancer surgery.

Methods

The authors selected patients who had elective esophagectomy, gastrectomy, hepatectomy, cholecystectomy, pancreatectomy, colectomy, and rectal cancer surgery from July 2010 to March 2018 using the Japanese Diagnosis Procedure Combination database. Patients were divided into a volatile anesthesia group (desflurane, sevoflurane, or isoflurane with/without nitrous oxide) and a propofol-based total intravenous anesthesia group. The authors hypothesized that total intravenous anesthesia is associated with greater overall and recurrence-free survival than volatile anesthesia. Subgroup analyses were performed for each type of surgery.

Results

The authors identified 196,303 eligible patients (166,966 patients in the volatile anesthesia group and 29,337 patients in the propofol-based total intravenous anesthesia group). The numbers (proportions) of death in the volatile anesthesia and total intravenous anesthesia groups were 17,319 (10.4%) and 3,339 (11.4%), respectively. There were no significant differences between the two groups in overall survival (hazard ratio, 1.02; 95% CI, 0.98 to 1.07; P = 0.28) or recurrence-free survival (hazard ratio, 0.99; 95% CI, 0.96 to 1.03; P = 0.59), whereas instrumental variable analyses showed a slight difference in recurrence-free survival (hazard ratio, 0.92; 95% CI, 0.87 to 0.98; P = 0.01). Subgroup analyses showed no significant difference in overall or recurrence-free survival between the groups in any type of surgery.

Conclusions

Overall and recurrence-free survival were similar between volatile and intravenous anesthesia in patients having digestive tract surgery. Selection of the anesthetic approach for these patients should be based on other factors.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Calcium channel blockers in pancreatic cancer: increased overall survival in a retrospective cohort study
Authors: Tingle Samuel J. , Severs George R. , Moir John A.G. , White Steven A.
Published: July 2020

Repurposing commonly prescribed noncancer medications for use in oncology has substantial advantages over de-novo development of anticancer drugs. Calcium signalling has been implicated in many of the hallmarks of cancer. Previous in-vitro and in-vivo studies have shown that calcium channel blockers (CCBs) are able to promote apoptosis, inhibit proliferation and prevent invasion and metastasis in a variety of cancer types. This retrospective cohort study aimed to translate this into the clinic by investigating the effect of CCBs on survival in pancreatic cancer. One hundred sixty-four patients with unresectable pancreatic ductal adenocarcinoma were included. Data were collected on CCB prescription, and for a range of other potentially important prognostic factors: ECOG performance status, AJCC cancer stage, chemotherapy regimen, radiotherapy, age, hypertension and sex. Participants prescribed CCB (n = 30) were more likely to be older (P = 0.004) and have hypertension (P < 0.0005); baseline demographics were otherwise similar between groups. On adjusted cox regression patients prescribed CCBs demonstrated significantly improved overall survival; hazard ratio −0.496 (0.297–0.827; P = 0.007). Performance status (P < 0.0005), tumour stage (P < 0.0005), chemotherapy regimen (P < 0.0005), radiotherapy (0.002) and age (P = 0.012) were also independent predictors of survival. The Kaplan–Meier estimated median survival was 15.3 months for patients prescribed CCBs versus 10.1 months for patients not prescribed CCBs (P = 0.131). This study supports previous work suggesting CCBs may be beneficial in pancreatic cancer. Further work on larger datasets will allow for subgroup analysis delineating the effects of specific CCBs in combination with different forms of chemotherapy, paving the way for future prospective studies.
Psychological Attachment Orientations of Surrogate Decision-Makers and Goals-of-Care Decisions for Brain Injury Patients in ICUs
Authors: Knies Andrea K. , Zhang Qiang , Juthani Prerak , Tu Stephanie , Pach Jolanta , Martinez Aida , Monin Joan K. , Hwang David Y.
Published: July 2020

Objectives:

To determine whether ICU surrogates with “insecure” psychologic attachment orientations are more prone to requesting tracheostomy and gastrostomy (i.e., life-sustaining therapy) for severe acute brain injury patients with poor prognosis compared to surrogates with “secure” orientations.

Design:

Cross-sectional survey from November 2017 to August 2018.

Setting:

Single neuroscience ICU at an academic medical center.

Subjects:

Consecutive sample of surrogates of patients admitted to the ICU with a minimum length of stay of 24 hours.

Interventions:

None.

Measurements and Main Results:

We identified surrogates’ psychologic attachment orientation via a standard tool, the Relationship Questionnaire, and collected other surrogate and patient demographics. We also presented surrogates with a hypothetical scenario of an intubated severe acute brain injury patient with poor prognosis and asked each surrogate whether he or she would request life-sustaining therapy or comfort measures only. Fisher exact test was used to compare frequency of life-sustaining therapy selection between secure and insecure surrogates. Additionally, we conducted univariate and multivariate analyses to determine other independent predictors of life-sustaining therapy selection. Two-hundred seventy-five of 713 (38.6%) eligible respondents participated; 153 (55.6%) surrogates were secure, and 122 (44.4%) insecure. There was no significant difference in the proportion of secure respondents selecting life-sustaining therapy compared to insecure (18.3% vs 20.5%; p = 0.38). Although still nonsignificant, the observed difference was slightly greater for those with a specific “anxious” insecure subtype versus “nonanxious” (18.2% vs 23.0%; p = 0.41). Overall, a higher proportion of respondents selecting life-sustaining therapy (vs comfort measures only) reported feeling uncertain or very uncertain about the hypothetical decision (45.3% vs 9.5%; p < 0.001). In a multivariate model, nonwhite race and high religiosity were significant predictors of life-sustaining therapy selection.

Conclusions:

Although surrogate attachment orientation is not predictive of life-sustaining therapy selection, nonwhite race and high religiosity are. Future interventions designed to support severe acute brain injury surrogates could focus on surrogates prone to selecting life-sustaining therapy with high degrees of uncertainty.
Coronavirus Disease 2019 Pandemic Measures: Reports From a National Survey of 9,120 ICU Clinicians
Authors: Kleinpell Ruth , Ferraro David M. , Maves Ryan C. , Kane Gill Sandra L. , Branson Richard , Greenberg Steven , Doersam Jennifer K. , Raman Rameela , Kaplan Lewis J.
Published: July 2020

Importance:

Recent reports identify that among hospitalized coronavirus disease 2019 patients, 30% require ICU care. Understanding ICU resource needs remains an essential component of meeting current and projected needs of critically ill coronavirus disease 2019 patients.

Objectives:

This study queried U.S. ICU clinician perspectives on challenging aspects of care in managing coronavirus disease 2019 patients, current and anticipated resource demands, and personal stress.

Design, Setting, and Participants:

Using a descriptive survey methodology, an anonymous web-based survey was administered from April 7, 2020, to April 22, 2020 (email and newsletter) to query members of U.S. national critical care organizations.

Measurements and Main Results:

Through a 16-item descriptive questionnaire, ICU clinician perceptions were assessed regarding current and emerging critical ICU needs in managing the severe acute respiratory syndrome coronavirus 2 infected patients, resource levels, concerns about being exposed to severe acute respiratory syndrome coronavirus 2, and perceived level of personal stress. A total of 9,120 ICU clinicians responded to the survey, representing all 50 U.S. states, with 4,106 (56.9%) working in states with 20,000 or more coronavirus disease 2019 cases. The 7,317 respondents who indicated their profession included ICU nurses (n = 6,731, 91.3%), advanced practice providers (nurse practitioners and physician assistants; n = 334, 4.5%), physicians (n = 212, 2.9%), respiratory therapists (n = 31, 0.4%), and pharmacists (n = 30, 0.4%). A majority (n = 6,510, 88%) reported having cared for a patient with presumed or confirmed coronavirus disease 2019. The most critical ICU needs identified were personal protective equipment, specifically N95 respirator availability, and ICU staffing. Minimizing healthcare worker virus exposure during care was believed to be the most challenging aspect of coronavirus disease 2019 patient care (n = 2,323, 30.9%). Nurses report a high level of concern about exposing family members to severe acute respiratory syndrome coronavirus 2 (median score of 10 on 0–10 scale). Similarly, the level of concern reached the maximum score of 10 in ICU clinicians who had provided care to coronavirus disease 2019 patients.

Conclusions:

This national ICU clinician survey identifies continued concerns regarding personal protective equipment supplies with the chief issue being N95 respirator availability. As the pandemic continues, ICU clinicians anticipate a number of limited resources that may impact ICU care including personnel, capacity, and surge potential, as well as staff and subsequent family members exposure to severe acute respiratory syndrome coronavirus 2. These persistent concerns greatly magnify personal stress, offering a therapeutic target for professional organization and facility intervention efforts.
Response and Survival Outcomes to Ibrutinib Monotherapy for Patients With Waldenström Macroglobulinemia on and off Clinical Trials
Authors: Castillo Jorge J. , Gustine Joshua N. , Meid Kirsten , Flynn Catherine A. , Demos Maria G. , Guerrera Maria L. , Jimenez Cristina , Kofides Amanda , Liu Xia , Munshi Manit , Tsakmaklis Nicholas , Patterson Christopher J. , Xu Lian , Yang Guang , Hunter Zachary R. , Treon Steven P.
Published: July 2020

Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The approval was based on a single, multicenter, phase II trial in previously treated WM patients. We sought to evaluate whether there were differences in clinical characteristics, response, and survival outcomes to ibrutinib monotherapy between WM patients treated on and off clinical trials. Treatment naïve and previously treated patients who received ibrutinib monotherapy at our institution and participated in two prospective studies (ON trial; n = 72) or a prospective database (OFF trial; n = 157) were included. The median times from WM diagnosis to ibrutinib initiation were 3.1 and 3.5 years for ON and OFF trial patients, respectively (p = 0.38). Similar rates of categorical response at 6, 12, and 24 months and at best response were also observed between ON trial and OFF trial patients. The 4‐year PFS and OS rates for ON trial and OFF trial patients were 72% and 63%, respectively (log‐rank p = 0.14) and 83% and 81%, respectively (log‐rank p = 0.14). CXCR4 mutations impacted response and survival outcomes to ibrutinib monotherapy. The 4‐year rates of ibrutinib discontinuation in ON and OFF trial patients were 36% and 44%, respectively (p = 0.11). Ibrutinib is effective in the routine clinical care of both treatment‐naïve and previously treated WM patients. The findings of our study validate the efficacy of ibrutinib monotherapy reported in multiple phase II clinical trials.