bluuebunny/crossref_metadata_2025 huggingface dataset:
BRET sensors unravel thatPlasmodium falciparumserpentine receptor 12 (PfSR12) increases surface expression of mammalian GPCRs in HEK293 cells
Authors: Pereira Pedro H. S. , Brito Gabriela , Moraes Miriam S. , Kiyan Camila L. , Avet Charlotte , Bouvier Michel , Garcia Celia R. S.
Published: April 2020

Malaria causes millions of deaths worldwide and is considered a huge public health problem for underdeveloped countries. The most severe cases of malaria present complications of the host circulatory system, which may cause clogging and rupture of blood vessels, leading to death or important sequelae. Because of the previously suggested role of thrombin and platelet aggregation inPlasmodium falciparumbiology, we hypothesized that one of the GPCR-like proteins identified in the genome of the parasite,P. falciparumserpentine receptor 12 (PfSR12), could be a thrombin-activated GPCR. To test this hypothesis we used a series of Bioluminescence and Bioluminescence Resonance Energy Transfer (BRET)-based biosensors to investigate the signaling activity of PfSR12. Using an Obelin based biosensor, thrombin promoted a PfSR12-dependent cytosolic Ca2+rise in HEK293 cells. This Ca2+mobilization was accompanied by DAG formation and PKC activation as detected using DAG and PKC BRET-based biosensors indicating a Gq/PLC/IP3 signaling pathway. The role of Gq was confirm using Gq/11knockout HEK293 cells as well as the Gq-selective inhibitor, YM254890. Further investigation revealed that PfSR12 is not itself a thrombin receptor but rather promotes the increase of cell surface expression of an endogenous thrombin receptor. This chaperone-like effect was not selective for thrombin receptors as PfSR12 expression also promoted an increased muscarinic type 3 receptor (M3R)-promoted DAG and PKC responses. This increase response was accompanied by an increase in surface expression of M3R. Our data indicate that PfSR12 acts as a chaperone and increases the expression of several GPCRs resulting in increased responsiveness to various hormones of mammalian cells that could contribute to the deleterious effects ofPlasmodium falciparuminfection.
Selective amplification of ipRGC signals accounts for interictal photophobia in migraine
Authors: McAdams Harrison , Kaiser Eric A , Igdalova Aleksandra , Haggerty Edda B , Cucchiara Brett , Brainard David H , Aguirre Geoffrey K
Published: April 2020

Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood.

We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both, and rated the degree of visual discomfort produced by these stimuli while we also recorded pupil responses.

We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina, and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an amplification of integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an amplification of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex).

By revealing a dissociation in the amplification of discomfort versus pupil response, our findings suggest a post-retinal alteration in processing of ipRGC signals for photophobia in migraine.

Significance

The melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs) may contribute to photophobia in migraine. We measured visual discomfort and pupil responses to cone and melanopsin stimulation—the photoreceptor inputs to the ipRGCs—in people with and without migraine. We find that people with migraine do not differ from those without headaches in how cone and melanopsin signals are weighted and combined to produce visual discomfort. Instead, migraine is associated with an amplification of ipRGC signals for discomfort. This effect of migraine upon ipRGC signals is limited to photophobia, as we did not find an enhancement of pupil responses or a change in other behaviors linked to ipRGC function. Our findings suggest a post-retinal amplification of ipRGC signals for photophobia in migraine.
Cryo-EM structures of human TRPC5 reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site
Authors: Wright David J. , Simmons Katie J. , Johnson Rachel M. , Beech David J. , Muench Stephen P. , Bon Robin S.
Published: April 2020

TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered the first clinical trials. However, fundamental and translational studies require a better understanding of TRPC1/4/5 channel regulation by endogenous and exogenous factors. Although several potent and selective TRPC1/4/5 modulators have been reported, the paucity of mechanistic insights into their modes-of-action remains a barrier to the development of new chemical probes and drug candidates. The xanthine class of modulators includes the most potent and selective TRPC1/4/5 inhibitors described to date, as well as TRPC5 activators. Our previous studies suggest that xanthines interact with a, so far, elusive pocket of TRPC1/4/5 channels that is essential to channel gating. Targeting this pocket may be a promising strategy for TRPC1/4/5 drug discovery. Here we report the first structure of a small molecule-bound TRPC1/4/5 channel – human TRPC5 in complex with the xanthine Pico145 – to 3.0 Å. We found that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a bound phospholipid. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn2+ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators.
Identification of functionally-distinct macrophage subpopulations regulated by efferocytosis inDrosophila
Authors: Coates Jonathon Alexis , Brittle Amy , Armitage Emma Louise , Zeidler Martin Peter , Evans Iwan Robert
Published: April 2020

Macrophages are a highly heterogeneous population of cells, with this diversity stemming in part from the existence of tissue resident populations and an ability to adopt a variety of activation states in response to stimuli.Drosophilablood cells (hemocytes) are dominated by a lineage of cells considered to be the functional equivalents of mammalian macrophages (plasmatocytes). Until very recently plasmatocytes were thought to be a homogeneous population. Here, we identify enhancer elements that label subpopulations of plasmatocytes, which vary in abundance across the lifecourse of the fly. We demonstrate that these plasmatocyte subpopulations behave in a functionally-distinct manner when compared to the overall population, including more potent migratory responses to injury and decreased clearance of apoptotic cells within the developing embryo. Additionally, these subpopulations display differential localisation and dynamics in pupae and adults, hinting at the presence of tissue-resident macrophages in the fly. Our enhancer analysis also allows us to identify novel candidate genes involved in plasmatocyte behaviour in vivo. Misexpression of one such enhancer-linked gene (calnexin14D) in all plasmatocytes improves wound responses, causing the overall population to behave more like the subpopulation marked by thecalnexin14D-associated enhancer. Finally, we show that, we are able to modulate the number of cells within some subpopulations via exposure to increased levels of apoptotic cell death, thereby decreasing the number of plasmatocytes within more wound-responsive subpopulations. Taken together our data demonstrates the existence of macrophage heterogeneity inDrosophilaand identifies mechanisms involved in the specification and function of these plasmatocyte subpopulations. Furthermore, this work identifies key molecular tools with whichDrosophilacan be used as a highly genetically-tractable, in vivo system to study the biology of macrophage heterogeneity.
Three-dimensional Genome Organization Maps in Normal Haematopoietic Stem Cells and Acute Myeloid Leukemia
Authors: Wang Benny , Kong Lingshi , Babu Deepak , Choudhary Ruchi , Fam Winnie , Tng Jia Qi , Goh Yufen , Han Bertrand Wong Jern , Liu Xin , Song Fang Fang , Chia Priscella , Chan Ming Chun , An Omer , Tham Cheng Yong , Benoukraf Touati , Yang Henry , Wang Wilson , Chng Wee Joo , Tenen Daniel , Fullwood Melissa Jane
Published: April 2020

Acute Myeloid Leukemia (AML) is a highly lethal blood cancer arising due to aberrant differentiation of haematopoietic stem cells. Here we obtained 3D genome organization maps by Hi-C in the CD34+ haematopoietic stem cells from three healthy individuals and eight individuals with AML, and found that AML have increased loops to oncogenes compared with normal CD34+ cells. TheMEIS1oncogenic transcription factor is regulated by a Frequently Interacting Region (FIRE). This FIRE is only present in normal bone marrow samples, and four of eight AML sample. FIRE presence is associated withMEIS1expression. CRISPR excision of a FIRE boundary led to loss ofMEIS1and reduced cell growth. Moreover, MEIS1 can bind to the promoter ofHOXA9, and HOXA9 shows gain of Acute Myeloid Leukemia-specific super-enhancers that loop to theHOXA9promoter.

Significance

We found that Acute Myeloid Leukemias have more chromatin loops to oncogenes compared with normal blood stem cells. We identified heterogeneity in chromatin interactions at oncogenes, and heterogeneity in super-enhancers that loop to oncogenes, as two key epigenetic mechanisms that underlieMEIS1andHOXA9oncogene expression respectively.
Transient disruption of the inferior parietal lobule impairs the ability to attribute intention to action
Authors: Patri Jean-François , Cavallo Andrea , Pullar Kiri , Soriano Marco , Valente Martina , Koul Atesh , Avenanti Alessio , Panzeri Stefano , Becchio Cristina
Published: April 2020

Although it is well established that fronto-parietal regions are active during action observation, whether they play a causal role in the ability to infer others’ intentions from visual kinematics remains undetermined. In experiments reported here, we combined offline continuous theta-burst stimulation (cTBS) with computational modeling to reveal single-trial computations in the inferior parietal lobule (IPL) and inferior frontal gyrus (IFG). Participants received cTBS over the left anterior IPL and the left IFG pars orbitalis, in separate sessions, before completing an intention discrimination task (discriminate intention of observed reach-to-grasp acts) or a kinematic discrimination task (discriminate peak wrist height of the same acts) unrelated to intention. We targeted intentions-sensitive regions whose fMRI-measured activity accurately discriminated intention from the same action stimuli. We found that transient disruption of activity of the left IPL, but not the IFG, impaired the observer’s ability to judge intention from movement kinematics. Kinematic discrimination unrelated to intention, in contrast, was largely unaffected. Computational analyses revealed that IPL cTBS did not impair the ability to ‘see’ changes in movement kinematics, nor did it alter the weight given to informative versus non-informative kinematic features. Rather, it selectively impaired the ability to link variations in informative features to the correct intention. These results provide the first causal evidence that left anterior IPL maps kinematics to intentions.
NFATc acts as a non-canonical phenotypic stability factor for a hybrid epithelial/mesenchymal phenotype
Authors: Subbalakshmi Ayalur Raghu , Kundnani Deepali , Biswas Kuheli , Ghosh Anandamohan , Hanash Samir M , Tripathi Satyendra C , Jolly Mohit Kumar
Published: April 2020

Metastasis remains the cause of over 90% of cancer-related deaths. Cells undergoing metastasis use phenotypic plasticity to adapt to their changing environmental conditions and avoid therapy and immune response. Reversible transitions between epithelial and mesenchymal phenotypes - Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-Epithelial Transition (MET) - form a key axis of phenotypic plasticity during metastasis and therapy resistance. Recent studies have shown that the cells undergoing EMT/MET can attain one or more hybrid epithelial/mesenchymal (E/M) phenotypes, the process of which is termed as partial EMT/MET. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either epithelial or mesenchymal state. Thus, it is crucial to identify the factors and regulatory networks enabling such hybrid E/M phenotypes. Here, employing an integrated computational-experimental approach, we show that the transcription factor NFATc can inhibit the process of complete EMT, thus stabilizing the hybrid E/M phenotype. It increases the range of parameters enabling the existence of a hybrid E/M phenotype, thus behaving as a phenotypic stability factor (PSF). However, unlike previously identified PSFs, it does not increase the mean residence time of the cells in hybrid E/M phenotypes, as shown by stochastic simulations; rather it enables the co-existence of epithelial, mesenchymal and hybrid E/M phenotypes and transitions among them. Clinical data suggests the effect of NFATc on patient survival in a tissue-specific or context-dependent manner. Together, our results indicate that NFATc behaves as a non-canonical phenotypic stability factor for a hybrid E/M phenotype.
Evolution of predator foraging in response to prey infection favors species coexistence
Authors: Prosnier Loïc , Médoc Vincent , Loeuille Nicolas
Published: April 2020

As acknowledged by Optimal Foraging theories, predator diets depend on prey profitability. Parasites, ubiquitous in food webs, are known to affect simultaneously host vulnerability to predation and host energy contents, thereby affecting profitability. In this work, we study the eco-evolutionary consequences of prey infection by a non trophically-transmitted parasite, with a simple lifecycle, on predator diet. We also analyze the consequences for coexistence between prey, predators and parasites. We model a trophic module with one predator and two prey species, one of these prey being infected by a parasite, and distinguish between two effects of infection: a decrease in host fecundity (virulence effect) and an increase in vulnerability to predation (facilitation effect). Predator foraging may evolve toward specialist or generalist strategies, the latter being less efficient on a given resource. We show that the virulence effect leads to specialisation on the non-infected prey while the facilitation effect, by increasing prey profitability, favors specialisation on the infected prey. Combining the two effects at intermediate intensities promotes either generalist predators or the diversification of foraging strategies (coexistence of specialists), depending of trade-off shape. We then investigate how the evolution of predator diet affects the niche overlap between predator and parasite. We show that facilitation effects systematically lead to a high niche overlap, ultimately resulting in the loss of the parasite. Virulence effects conversely favor coexistence by allowing a separation of the predator and parasite niches.
Minimal biophysical model of combined antibiotic action
Authors: Kavčič Bor , Tkačik Gašper , Bollenbach Tobias
Published: April 2020

Phenomenological relations such as Ohm’s or Fourier’s law have a venerable history in physics, but are still scarce in biology. This situation restrains predictive theory. Here, we build on bacterial “growth laws,” which capture physiological feedback between translation and cell growth, to construct a minimal biophysical model for the combined action of ribosome-targeting antibiotics. Our model predicts drug interactions like antagonism or synergy solely from responses to individual drugs. We systematically refine the model by including direct physical interactions of different drugs on the ribosome. In a limiting case, our model provides a mechanistic underpinning for recent predictions of higher-order interactions derived using entropy maximization. It further makes parameter-free predictions for combined drug effects on cells carrying resistance genes and for drugs that mimic poor nutrient environments. We show experimentally that resistance genes can drastically alter drug interactions in notable agreement with our theoretical predictions. While minimal, the model is readily adaptable and opens the door to predicting interactions of second and higher-order in a broad range of biological systems.
Conceptual framework: factors enabling collaborative healthcare and social services integration
Authors: Cheng Siu Mee , Catallo Cristina
Published: April 2020

Purpose

A conceptual framework for collaboratively based integrated health and social care (IHSC) integration is proposed to aid in understanding how to accomplish IHSC.

Design/methodology/approach

This model is based on extant literature of successfully IHSC initiatives.

Findings

The model aims to identify enabling integration factors that support collaborative integration efforts between healthcare and social services organizations. These factors include shared goals and vision, culture, leadership, team-based care, information sharing and communications, performance measurement and accountability agreements, and dedicated resources and financing. It also identifies factors that act as external influencers that can support or hinder integration efforts among collaborating organizations. These factors are geographic setting, funding models, governance structures, and public policies. These factors are intended to ensure that a realist lens is applied when trying to understand and explain IHSC.

Originality/value

This model is intended to provide a framework to support research, policy and implementation efforts.
Validating network connectivity with observed movement in experimental landscapes undergoing habitat destruction
Authors: Poli Caroline , Hightower Jessica , Fletcher Robert J.
Published: April 2020

Maintaining the ability of organisms to move between suitable patches of habitat despite ongoing habitat loss is essential to conserving biodiversity. Quantifying connectivity has therefore become a central focus of conservation planning. A large number of metrics have been developed to estimate potential connectivity based on habitat configuration, matrix structure and information on organismal movement, and it is often assumed that metrics explain actual connectivity. Yet, validation of metrics is rare, particularly across entire landscapes undergoing habitat loss—a crucial problem that connectivity conservation aims to mitigate.

We leveraged a landscape‐scale habitat loss and fragmentation experiment to assess the performance of commonly used patch‐ and landscape‐scale connectivity metrics against observed movement data, test whether incorporating information about the matrix improves connectivity metrics and examine the performance of metrics across a gradient of habitat loss. We tested whether 38 connectivity metrics predict movement at the patch (i.e. patch immigration rates) and landscape (i.e., total movements) scale for a pest insect, the cactus bug Chelinidea vittiger, across 15 replicate landscapes.

Metrics varied widely in their ability to explain actual connectivity. At the patch scale, dPCflux, which describes the contribution of a patch to movement across the landscape independent of patch size, best explained immigration rates. At the landscape scale, total movements were best explained by a mesoscale metric that captures that distance between clusters of patches (i.e. modules). Incorporating the matrix did not necessarily improve the ability of metrics to predict actual connectivity. Across the habitat loss gradient, dPCflux was sensitive to habitat amount.

Synthesis and applications. Our study provides a much‐needed evaluation of network connectivity metrics at the patch and landscape scales, emphasizing that accurate quantification of connectivity requires the incorporation, not only of habitat amount but also habitat configuration and information on dispersal capability of species. We suggest that variation in habitat may often be more critical for interpreting network connectivity than the matrix, and advise that connectivity metrics may be sensitive to habitat loss and should therefore be applied with caution to highly fragmented landscapes. Finally, we recommend that applications integrate mesoscale configuration of habitat into connectivity strategies.
Determination of metmyoglobin in cooked tan mutton using Vis/NIR hyperspectral imaging system
Authors: Yuan Ruirui , Liu Guishan , He Jianguo , Ma Chao , Cheng Lijuan , Fan Naiyun , Ban Jingjing , Li Yue , Sun Yourui
Published: April 2020

In this study, the ENVI 4.6 software was used to obtain the spectral reflection value of samples. The outlier samples were eliminated by the Monte Carlo method, and then SPXY (sample set partitioning based on be x–y distances) was used to divide the calibration set and prediction set. The spectral images were pretreated and characteristic wavelengths were extracted. The spectral models of full and pretreated spectra and characteristic bands were established by partial least squares regression (PLSR) and principle component regression (PCR), and the optimal modeling combination was selected. The results showed that the modeling effect of the original spectrum was the best. In full‐PLSR model, the determination coefficient of the calibration set (Rc2), the determination coefficient of prediction set (Rp2), and the determination coefficient of interactive verification set (Rcv2) were 0.8804, 0.7375, and 0.7422, and root‐mean‐square error of calibration set (RMSEC), root‐mean‐square error of prediction (RMSEP), and root mean square error of interactive validation set (RMSECV) were 2.3630, 2.9607, and 3.4209, respectively. PLSR and PCR models were established to obtain the optimal models of CARS‐PLSR and PCR‐PLSR. In the CARS‐PLSR model, the Rc2, Rp2, and Rcv2 were 0.9135, 0.7654, and 0.8171, respectively, while RMSEC, RMSEP, and RMSECV were 2.0275, 2.9306, and 2.9262, respectively. In the iRF‐PCR model, Rc2, Rp2, and Rcv2 were 0.7952, 0.7372, and 0.7280, respectively, while RMSEC, RMSEP, and RMSECV were 3.0207, 2.8278, and 3.4288, respectively. This study has demonstrated that visible and near‐infrared hyperspectral imaging system can rapidly predict the content of metmyoglobin in cooked tan mutton.

Practical Application

This study has demonstrated that visible and near‐infrared (Vis/NIR) hyperspectral imaging system can rapidly predict the content of MetMb in cooked tan mutton. With the advantages of nondestructive, rapid, real‐time, Vis/NIR, hyperspectral imaging system can be widely expanded and applied to the detection of myoglobin in meat to evaluate the color of meat.
Adapting to a global pandemic through live virtual delivery of a cancer collaborative trial group conference: The TROG 2020 experience
Authors: McDowell Lachlan , Goode Susan , Sundaresan Puma
Published: April 2020

Introduction

The global COVID‐19 pandemic forced the cancellation of the TROG 2020 face to face Annual Scientific Meeting (ASM). It was instead delivered as a live virtual meeting with 6 days of planning. Here, we report the participants’ experience of this live virtual meeting.

Method

Participants were invited to complete custom‐developed, pre‐ and post‐meeting surveys to assess their expectations of and satisfaction with the live virtual format. Speakers and moderators were also invited to complete a custom‐developed satisfaction survey. The working parties of TROG (head/neck/skin, genitourinary, breast and lung) were also sampled.

Results

In total, 188/273 (69%) registered participants logged in to the live virtual meeting. The online engagement for each of the oral sessions ranged from 53 to 66%. There were 102 and 57 responders to the online pre‐ and post‐meeting surveys, respectively. The majority of pre‐meeting responders indicated a significant level of employer support to attend the virtual meeting. Post‐meeting satisfaction exceeded pre‐meeting expectations (‘very much’ and ‘quite a bit’; 86% vs. 54%; P < 0.0001). The majority indicated they would be ‘quite a bit’ or ‘very much’ interested in future live virtual meetings.

Conclusion

The TROG 2020 ASM was conducted as a live virtual meeting. Participant satisfaction and future interest in a live virtual meeting was high, indicating this is a viable platform for other CCTG’s faced with the decision to deliver virtual content at times of global public health threats.
Is NAFTA Trade‐Creating or Trade‐Diverting? A System GMM Approach
Authors: Heo Yoon , Doanh Nguyen Khanh
Published: April 2020

This paper estimates the trade creation and trade diversion effects of the North American Free Trade Agreement (NAFTA) using a panel data set of 77 countries for the period 1989–2016. We found that the formation of NAFTA has resulted in both import trade creation and diversion. However, the magnitude of trade creation is higher than that of trade diversion. On the sectoral level, trade creation and diversion occur in both agricultural and non‐agricultural imports, with trade creation exhibiting a higher magnitude. The magnitude of trade creation and diversion is found to be the highest for agricultural imports, which are followed by total and non‐agricultural imports, respectively.
Prevalence of epiretinal membranes in the ageing population using retinal colour images and SD‐OCT: the Alienor Study
Authors: Delyfer Marie‐Noëlle , Legout Pierre , Le Goff Mélanie , Blaizeau Marion , Rougier Marie‐Bénédicte , Schweitzer Cédric , Korobelnik Jean‐François , Delcourt Cécile
Published: April 2020

Purpose

To analyse and compare the prevalence of epiretinal membranes (ERMs) obtained using either standard retinal colour images or spectral‐domain optical coherence tomography (SD‐OCT) in a population‐based setting of French elderly subjects.

Methods

Six hundred twenty‐four subjects of the Alienor cohort aged 75 years or older underwent both colour fundus imaging and SD‐OCT examinations. The ERMs were graded from retinal images and SD‐OCT macular scans in a masked fashion. On SD‐OCT images, the early ERMs, mature contractile ERMs without foveal modifications and mature contractile ERMs with foveal alterations were distinguished.

Results

610 (97.8%) subjects had gradable SD‐OCT examinations, and 511 (81.9%) had gradable fundus images in at least one eye. According to colour photographs, 11.6% of participants had definite ERMs. From SD‐OCT images, 52.8% of the subjects had early ERMs, 7.4% had mature ERMs without foveal involvement, and 9.7% had mature ERMs with foveal alterations. Regardless of the imaging method used, the ERMs were more often observed in pseudophakic eyes than in phakic eyes. Comparison of ERM assessment using fundus photographs versus SD‐OCT images demonstrated that the specificity of retinal colour images was good (>89.3%), whereas the sensitivity remained low even though it increased with ERM severity on SD‐OCT images.

Conclusions

Spectral‐domain optical coherence tomography (SD‐OCT) examinations have high feasibility in this elderly population and are much more sensitive than standard colour images for ERM assessments, especially in the early stages of the disease. Our results further highlight the need to use SD‐OCT instead of colour retinal photographs for the classification of ERMs in epidemiological studies.
Simulation of advanced cataract surgery – validation of a newly developed test
Authors: Forslund Jacobsen Mads , Konge Lars , la Cour Morten , Holm Lars , Kjærbo Hadi , Moldow Birgitte , Saleh George M. , Thomsen Ann Sofia Skou
Published: April 2020

Purpose

To develop and investigate an Eyesi simulator‐based test for the more experienced cataract surgeon for evidence of validity.

Methods

The study was a prospective interventional cohort study and carried out at the Copenhagen Academy for Medical Education and Simulation. The Eyesi Simulator was used for the test which was developed by three expert cataract surgeons. Ten cataract surgeons (>250 surgeries performed) and ten ophthalmic residents performed two repetitions of the test. The test consisted of four modules: Iris Expansion Ring insertion – level 1, Iris Expansion Ring extraction – level 2, Capsulorhexis – level 3 and Anterior Vitrectomy – level 6.

Results

Internal consistency reliability showed Cronbach’s alpha of 0.63. Test–retest reliabilities were significant for Iris Expansion Ring extraction – level 2 (p = 0.012) and Capsulorhexis – level 3 (p = 0.018). Differences between the two groups were only significant in both repetitions for the Iris Expansion Ring extraction – level 2 (p < 0.001 and p = 0.041, respectively). Furthermore, we found a statistically significant difference between the mean module scores for novices and the more experienced surgeons for Iris Expansion Ring insertion – level 1 (p = 0.021) and Capsulorhexis – level 3 (p = 0.019) in the first repetition.

Conclusion

The investigated modules show evidence of validity within several aspects of Messick’s framework. However, the evidence is not strong enough to apply the test for certification purposes of cataract surgeons, but the modules may still be relevant in the training of advanced cataract surgical procedures.
The utility of multichannel intraluminal impedance‐pH testing in tailoring the management of paediatric gastro‐oesophageal reflux disease
Authors: Gunasagaran Hema Lattha , Varjavandi Vincent , Lemberg Daniel A. , Ooi Chee Y. , Gupta Nitin , Krishnan Usha
Published: April 2020

Aim

To determine whether combined multichannel intraluminal impedance and pH (MII‐pH) testing led to a change in management of children with gastro‐oesophageal reflux disease (GORD).

Methods

Retrospective chart review was done in all patients who underwent MII‐pH testing for GORD symptoms at Sydney Children's Hospital between 2008 and 2016. Changes to anti‐reflux medications and referral for anti‐reflux surgery were evaluated.

Results

There were 365 patients, 260 (71.2%) of whom were on acid‐suppressing therapy. The median age was 4.1 ± 4.8 years, 205 patients (56%) were males, 83 (22.7%) were infants (<1 year of age) and 145 (39.7%%) had comorbid conditions. We found 72.1% had abnormal MII‐pH results, of which 17.5% had abnormal acid reflux, 8.2% had abnormal number of retrograde bolus movements and 46.3% had hypersensitive oesophagus (positive symptom association only). Infants were significantly more likely to have abnormal MII‐pH results compared to older children (P = .04). Results of MII‐pH testing led to medication changes in 44.7% and referral for anti‐reflux surgery in 6.8% of patients.

Conclusion

Combined multichannel intraluminal impedance and pH testing is clinically useful in the management of children with symptoms of GORD and over half the patients had changes to their medical treatment or referral for anti‐reflux surgery based on the results of MII‐pH testing. It resulted in a treatment change in an additional 32% of patients over traditional pH‐metry.
Serum (1 → 3)‐β‐D‐glucan could be useful to rule out invasive candidiasis in neonates with an adapted cut‐off
Authors: Cliquennois Pauline , Scherdel Pauline , Lavergne Rose‐Anne , Flamant Cyril , Morio Florent , Cohen Jeremie F. , Launay Elise , Gras Le Guen Christele
Published: April 2020

Aim

We assessed the diagnostic accuracy of serum (1 → 3)‐β‐D‐glucan (BDG) for neonatal invasive candidiasis (NIC) using the recommended cut‐off usually used in adults for detecting invasive candidiasis and searched for an optimal cut‐off for ruling out NIC.

Methods

We conducted a prospective cross‐sectional study at Nantes University medical centre from January 2017 to July 2018. All consecutive newborn infants of less than 28 days of corrected age, with clinically suspected NIC, who underwent BDG assay, were included. Sensitivity and specificity were calculated by using the recommended cut‐off of 80 pg/mL. Receiver operating characteristic curve analysis was used to identify an optimal cut‐off value.

Results

We included 55 newborn infants with 61 episodes of suspected NIC. Their median gestational and chronological ages were 28.0 weeks (interquartile range [IQR] 26.4‐34.1) and 10.0 days (IQR 6.0‐22.0), respectively. Of 61 episodes, seven revealed NIC. Sensitivity and specificity were 85.7% (95% confidence interval [CI] 42.1%‐99.6%) and 51.9% (37.8%‐65.7%) with the recommended cut‐off, respectively. An optimal cut‐off of 174 pg/mL offered the same sensitivity but higher specificity 77.8% (64.4%‐88.0%).

Conclusion

The recommended cut‐off of 80 pg/mL was probably too low for ruling out NIC. A higher cut‐off might have been more appropriate.
Thromboembolic risk and anticoagulant therapy in COVID‐19 patients: emerging evidence and call for action
Authors: Kollias Anastasios , Kyriakoulis Konstantinos G. , Dimakakos Evangelos , Poulakou Garyphallia , Stergiou George S. , Syrigos Konstantinos
Published: April 2020

Emerging evidence shows that severe coronavirus disease 2019 (COVID‐19) can be complicated with coagulopathy, namely disseminated intravascular coagulation, which has a rather prothrombotic character with high risk of venous thromboembolism. The incidence of venous thromboembolism among COVID‐19 patients in intensive care units appears to be somewhat higher compared to that reported in other studies including such patients with other disease conditions. D‐dimer might help in early recognition of these high‐risk patients and also predict outcome. Preliminary data show that in patients with severe COVID‐19, anticoagulant therapy appears to be associated with lower mortality in the subpopulation meeting sepsis‐induced coagulopathy criteria or with markedly elevated d‐dimer. Recent recommendations suggest that all hospitalized COVID‐19 patients should receive thromboprophylaxis, or full therapeutic‐intensity anticoagulation if such an indication is present.
Architecture of the evaporite accumulation and salt structures dynamics in Tiddlybanken Basin, southeastern Norwegian Barents Sea
Authors: Hassaan Muhammad , Faleide Jan I. , Gabrielsen Roy H. , Tsikalas Filippos
Published: April 2020

An extensive, reprocessed two‐dimensional (2D) seismic data set was utilized together with available well data to study the Tiddlybanken Basin in the southeastern Norwegian Barents Sea, which is revealed to be an excellent example of base salt rift structures, evaporite accumulations and evolution of salt structures. Late Devonian–early Carboniferous NE‐SW regional extensional stress affected the study area and gave rise to three half‐grabens that are separated by a NW‐SE to NNW‐SSE trending horst and an affiliated interference transfer zone. The arcuate nature of the horst is believed to be the effect of pre‐existing Timanian basement grain, whereas the interference zone formed due to the combined effect of a Timanian (basement) lineament and the geometrical arrangement of the opposing master faults. The interference transfer zone acted as a physical barrier, controlling the facies distribution and sedimentary thickness of three‐layered evaporitic sequences (LES). During the late Triassic, the northwestern part of a salt wall was developed due to passive diapirism and its evolution was influenced by halite lithology between the three‐LES. The central and southeastern parts of the salt wall did not progress beyond the pedestal stage due to lack of halite in the deepest evaporitic sequence. During the Triassic–Jurassic transition, far‐field stresses from the Novaya Zemlya fold‐and‐thrust belt reactivated the pre‐salt Carboniferous rift structures. The reactivation led to the development of the Signalhorn Dome, rejuvenated the northwestern part of the salt wall and affected the sedimentation rates in the southeastern broad basin. The salt wall together with the Signalhorn Dome and the Carboniferous pre‐salt structures were again reactivated during post‐Early Cretaceous, in response to regional compressional stresses. During this main tectonic inversion phase, the northwestern and southeastern parts of the salt wall were rejuvenated; however, salt reactivation was minimized towards the interference transfer zone beneath the centre of the salt wall.
Immune‐checkpoint molecules on regulatory T‐cells as a potential therapeutic target in head and neck squamous cell cancers
Authors: Suzuki Susumu , Ogawa Tetsuya , Sano Rui , Takahara Taishi , Inukai Daisuke , Akira Satou , Tsuchida Hiromi , Yoshikawa Kazuhiro , Ueda Ryuzo , Tsuzuki Toyonori
Published: April 2020

Immune‐checkpoint inhibitors improve the survival of head and neck squamous cell carcinoma (HNSCC) patients. Although recent studies have demonstrated that the tumor immune microenvironment (TIME) has critical roles in immunotherapy, the precise mechanisms involved are unclear. Therefore, further investigations of TIME are required for the improvement of immunotherapy. The frequency of effector regulatory T‐cells (eTregs) and the expression of immune‐checkpoint molecules (ICM) on eTregs and conventional T‐cells (Tconvs) both in peripheral blood lymphocytes (PBL) and tumor‐infiltrating lymphocytes (TIL) from HNSCC patients were analyzed by flow cytometry and their distributions were evaluated by multi‐color immunofluorescence microscopy. High frequency eTreg infiltration into HNSCC tissues was observed and high expressions of CD25, FOXP3, stimulatory‐ICM (4‐1BB, ICOS, OX40 and GITR) and inhibitory‐ICM (programmed cell death‐1 [PD‐1] and cytotoxic T‐lymphocyte‐associated protein‐4 [CTLA‐4]) were found on invasive eTregs. In contrast, the expression of stimulatory‐ICM on Tconvs was low and the expression of inhibitory‐ICM was high. In addition, ICM‐ligands (programmed cell death‐1 [PD‐L1], galectin‐9 and CEACAM‐1) were frequently expressed on cancer cells. PD‐L1 and galectin‐9 were also expressed on macrophages. PD‐1+ T‐cells interacted with PD‐L1+ cancer cells or PD‐L1+ macrophages. This suggested that in TIL, eTregs are highly activated, but Tconvs are exhausted or inactivated by eTregs and immune‐checkpoint systems, and ICM and eTregs are strongly involved in the creation of an immunosuppressive environment in HNSCC tissues. These suggested eTreg targeting drugs are expected to be a combination partner with immune‐checkpoint inhibitors that will improve immunotherapy of HNSCC.
Cytotoxic effects of vitamins K1, K2, and K3 against human T lymphoblastoid leukemia cells through apoptosis induction and cell cycle arrest
Authors: Xu Wencheng , Wu Hongguang , Chen Shuhe , Wang Xiaoqin , Tanaka Sachiko , Sugiyama Kentaro , Yamada Haruki , Hirano Toshihiko
Published: April 2020

The present study was undertaken to evaluate cytotoxic effects of vitamin K1 (phylloquinone), vitamin K2 (menaquinones), and vitamin K3 (menadione) against human T lymphoblastoid leukemia cells, Jurkat T cells, MOLT‐4 cells, and P‐glycoprotein‐expressing multidrug‐resistant MOLT‐4/DNR cells. Vitamins K2 and K3, but not vitamin K1, reduced viabilities of Jurkat, MOLT‐4, and MOLT‐4/DNR cells. The influence potency of vitamin K3 was larger than that of vitamin K2 in all of the three cell lines. MOLT‐4/DNR cells seemed to be more sensitive toward the effects of vitamins K2 and K3. The cytotoxicity of vitamins K2 and K3 on these leukemia cells seems to be related to apoptosis induction and cell cycle arrest. Vitamin K2 and K3 treatment induced cleavage of PARP obviously. Moreover, vitamins K2 and K3 specifically down‐regulated the expressions of cyclin A2 in all of the three cell lines. However, the effects of vitamins K2 and K3 on the cell cycle profiling in Jurkat, MOLT‐4, and MOLT‐4/DNR cells varied with the cell type. Vitamins K2 and K3 also decreased the viability of mitogen‐activated human peripheral blood mononuclear cells. Our observations suggest that vitamins K2 and K3 have bilateral cytotoxic effects on activated human peripheral lymphocytes and the human leukemic T cells.
Information‐rich wheat markets in the early days of COVID‐19
Authors: Vercammen James
Published: April 2020

This paper uses the information implicit in commodity futures and options prices to infer market beliefs about the impact of early‐stages COVID‐19 on commodity market fundamentals. The particular commodity examined is soft red winter (SRW) wheat, and the timeframe is early February to late March 2020. The analysis highlights various adjustments in the cash and futures price of SRW wheat in light of surging short‐run demand from consumer hoarding of staple food products, and a weakening long‐run market from growing wheat stocks and an emerging global recession. This split is causing the forward curve to flatten and basis levels to invert. The change over time in the price of options on wheat futures reveals increased price volatility in response to growing uncertainty about the COVID‐19 impacts. Similarly, changes in the skewness of the option's volatility smile illustrate a shift in traders’ perception about risk in the right versus left tail of the price distribution.
Best treatments available for distal acquired lacrimal obstruction: A systematic review and meta‐analysis
Authors: Vinciguerra Alessandro , Nonis Alessandro , Giordano Resti Antonio , Bussi Mario , Trimarchi Matteo
Published: April 2020

Background

Epiphora is a common clinical sign whose primary cause is post‐canalicular lacrimal obstruction. Treatment is both surgical and non‐surgical. In the literature, there is some evidence to suggest that some treatments are superior to others, but there are no direct comparative data in this regard.

Objective of review

To analyse the success rates of all available treatments to resolve post‐canalicular acquired lacrimal obstruction.

Type of review:

Systematic review and meta‐analysis.

Search strategy:

A literature search was conducted in the US National Library of Medicine (PubMed), EMBASE, SCOPUS and Cochrane databases with a final search performed in January 2020.

Evaluation method:

The search strategy identified articles published later than 2000 with at least 50 procedures performed both surgically (external dacryocystorhinostomy [EXT‐DCR], endoscopic dacryocystorhinostomy [END‐DCR] and transcanalicular laser dacryocystorhinostomy [TCL‐DCR]) and non‐surgically (balloon dacryoplasty [DCP], probing‐stenting [SP] and polyurethane stent [PoS]). The primary outcome was functional success, defined as symptom resolution or less than MUNK 2 scale; in addition to this, the influence of adjunctive treatments, such as application of mitomycin C and post‐procedural silicone stenting, was evaluated.

Results

In total, 14 958 papers were selected, 440 of which were reviewed after screening; 55 were included after full‐text review, which involved 9337 procedures. Mean success rate was 48.9% (35.7%‐62.3%) for DCP, 54.4% (41.8%‐66.5%) for SP, 73.6% (59.7%‐84%) for PoS, 80% (75.1%‐84%) for TCL‐DCR, 89.8% (83.3%‐93.9%) for EXT‐DCR and 89.5% (87.2%‐91.5%) for END‐DCR. Among all procedures, a difference was noted between DCP and END‐DCR (P < .001), DCP and EXT‐DCR (P < .001), SP and END‐DCR (P < .001), SP and EXT‐DCR (P < .001), END‐DCR and PoS (P = .016), and END‐DCR and TCL‐DCR (P = .001); no differences were noted between END‐DCR and EXT‐DCR (P = 1.00), EXT‐DCR and PoS (P = .121) and EXT‐DCR and TCL‐DCR (P = .223). Considering surgical procedures, no differences were seen if a silicone stenting was applied, whereas, due to heterogeneity of the literature data, no statistical analysis was feasible for application of mitomycin C.

Conclusions

Our analyses suggest that, among all procedures available, END‐DCR and EXT‐DCR should be considered as treatments of choice to resolve distal acquired lacrimal obstruction.
Influence of dose and antiepileptic comedication on brivaracetam serum concentrations in patients with epilepsy
Authors: Hagemann Anne , Klimpel Dennis , Bien Christian G. , Brandt Christian , May Theodor W.
Published: April 2020

The aim of this study was to investigate the influence of concomitant antiepileptic drugs (AEDs) on brivaracetam (BRV) trough serum concentrations. A total number of 368 routinely collected blood samples from 148 inpatients from Mara Hospital (Bethel Epilepsy Center) and von Bodelschwingh Foundation Bethel were retrospectively evaluated. Generalized estimation equations (GEEs) were used for statistical analysis. GEE analyses showed that BRV trough serum concentrations were significantly lower in patients with strong enzyme‐inducing AEDs (carbamazepine, phenytoin, and/or phenobarbital/primidone, −49%), but were not affected by concomitant intake of oxcarbazepine or eslicarbazepine. Age and gender did not have a significant effect. An alternative GEE model analyzing the BRV level‐to‐dose ratios yielded comparable results. Our results from routine therapeutic drug monitoring data indicate that the effect of enzyme‐inducing AEDs on BRV serum concentrations is stronger than the 20%‐30% reduction in BRV exposure previously reported in pharmacokinetics studies. Further research is necessary to evaluate these differences and to elucidate possible clinical consequences.
Spray dryer processed graphene oxide/reduced graphene oxide for high‐performance supercapacitor
Authors: Karakoti Manoj , Jangra Ritu , Pandey Sandeep , Dhapola Pawan Singh , Dhali Sunil , Mahendia Suman , Singh Pramod K , Sahoo Nanda Gopal
Published: April 2020

This study deals with the utility of mini spray dryer process to improve the dispersibility, of graphene oxide(GO) and its application for high‐performance supercapacitor. Initially, the neutral solution of GO was obtained using the modified Hummer's method. After this, the prepared GO solution was processed by mini spray dryer to obtain a more purified, lighter, and dispersed form of GO which is named as spray dryer processed GO (SPGO). The SPGO thus obtained showed excellent dispersibility behavior with various solvents, which is not found in case of conventional oven drying. Furthermore, utility of SPGO and its reduced form (r‐SPGO) for supercapacitor applications have been investigated. Results obtained from the cyclic voltammetry(CV) analysis, impedance, and charge‐discharge behavior of supercapacitor fabricated using r‐SPGO shows enhanced features. Therefore, the simple spray dried GO and its reduced form, that is, r‐SPGO can be utilized as a potential candidate for the supercapacitor application. Herein, as synthesized SPGO exhibited the specific capacitance of 12.07 and 37.6 F/g with PVA‐H3PO4 and 1 mol/L H3PO4, respectively, at a scan rate of 5 mV/s. On the other hand, reduced form of SPGO, that is, r‐SPGO showed the specific capacitance of 27.16 and 230 F/g with PVA‐H3PO4 and 1 mol/L H3PO4, respectively.