bluuebunny/crossref_metadata_2025 huggingface dataset:
Ticagrelor versus clopidogrel in stent-assisted coil embolization of unruptured intracranial aneurysms
Authors: Chien Shuo-Chi , Chen Ching-Chang , Chen Chun-Ting , Wang Alvin Yi-Chou , Hsieh Po-Chuan , Yeap Mun-Chun , Liu Zhuo-Hao , Wang Yu-Chi , Liu Yu-Tse
Published: November 2021

Background

Dual antiplatelet therapy is widely used for stent-assisted coil embolization (SACE) for unruptured intracranial aneurysms (UIAs) to prevent thromboembolic events (TEs). Compared to clopidogrel associated with aspirin, knowledge of the safety and efficacy of ticagrelor is lacking in large studies to date.

Methods

A retrospective cohort study was conducted from January 2016 to December 2018 with at least one year of follow-up in a single institution and systemic review.

Results

Altogether, 153 patients with UIA receiving SACE were separated into two groups: 113 patients receiving clopidogrel plus aspirin and 40 patients receiving ticagrelor plus aspirin. Acute in-stent thrombotic events were noted in two patients in the clopidogrel group (1.77%) and none in the ticagrelor group (0%). Additionally, one patient (0.88%) in the clopidogrel group had an early ischemic stroke (<3 months). Delayed ischemic stroke was noted in 6 patients (5.31%) in the clopidogrel group and 3 patients (7.50%) in the ticagrelor group. There were no major hemorrhagic events in either group. The two groups showed no significant differences with regard to ischemic stroke or hemorrhagic stroke.

Conclusion

Compared to the clopidogrel based regimen, ticagrelor can also reduce TEs without increasing bleeding tendency for SACE of UIAs. Ticagrelor combined with low-dose aspirin is a safe and effective alternative option for SACE.
Numerical study of natural convection nanofluids flow in tilted cavities with a partially thermally heat source
Authors: Benyoucef Djamila , Noui Samira , Djaraoui Afaf
Published: November 2021

Numerically, natural convection heat transfer of nanofluids in a two-dimensional tilt square enclosure was investigated, with a partial heat source embedded on the bottom wall subject to a fixed heat flux. The remaining portions of the horizontal bottom wall are assumed to be adiabatic, while the upper horizontal wall and the vertical ones are supposed to be at a relatively low temperature. Using the finite volume method and the SIMPLER algorithm, the governing equations have been discretized and solved. Simulations have been carried out for more than one nanoparticle and base fluid, a range of Rayleigh numbers ([Formula: see text] Ra [Formula: see text]), various values of heat source length and location (0.2 [Formula: see text]  B [Formula: see text] 0.8 and 0.2 [Formula: see text]  D [Formula: see text] 0.5, respectively), solid volume fraction ([Formula: see text]) as well as tilt angle ([Formula: see text]). The results indicate that the heat transfer performance increases by adding nanoparticles into the base fluid. An optimum solid volume fraction raises and reduces the heat transfer rate and maximum temperature of the surface heat source. respectively. Moreover, the results show a significant impact of the tilt angle on the flow, temperature patterns, and the heat transfer rate with a specific tilt angle depending to the pertinent parameters.
Using finite element analysis to discuss the study of drawing of servo stamping curve
Authors: Chen Dyi-Cheng , Yeh Yu-Kuan
Published: November 2021

This study employed different molding parameter combinations, the Taguchi method, ANOVA, and response surface methodology to perform experiments. Finite element analysis was executed to find the optimum molding parameters and increase the depth of drawing molding. The material is aluminum alloy 6016, and the servo press was adopted for the experiments. The factors influencing the drawing molding including punch fillet radius, die fillet radius, die clearance, molding curve, and mold temperature were determined. To find the optimum combination of parameters and to design 16 experimental combinations, the L16 orthogonal array of the Taguchi method was employed. According to the experimental results, the optimum parameters include punch fillet radius of 8.5 mm, die fillet radius of 8.5 mm, clearance of 1.5 t, curve 3, and the mold temperature of 20°C. Using the optimum parameter combination the molding depth could be increased greatly and the thickness ratio could be improved.
Rivaroxaban versus aspirin for prevention of covert brain infarcts in patients with embolic stroke of undetermined source: NAVIGATE ESUS MRI substudy
Authors: Sharma Mukul , Smith Eric E , Pearce Lesly A , Perera Kanjana S , Kasner Scott E , Yoon Byung-Woo , Ameriso Sebastian F , Puig Josep , Damgaard Dorte , Fiebach Jochen B , Muir Keith W , Veltkamp Roland C , Toni Danilo S , Shamalov Nikolay , Gagliardi Rubens J , Mikulik Robert , Engelter Stefan T , Bereczki Daniel , O’Donnell Martin J , Saad Feryal , Shoamanesh Ashkan , Berkowitz Scott D , Mundl Hardi , Hart Robert G ,   On behalf of the NAVIGATE ESUS MRI Substudy Investigators
Published: November 2021

Background

Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown.

Aims

To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies.

Methods

At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression.

Results

Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52–1.7).

Conclusions

Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide. Registration: https://www.clinicaltrials.gov . Unique identifier: NCT 02313909
Estimating nocturnal stroke onset times by magnetic resonance imaging in the WAKE-UP trial
Authors: Cheng Bastian , Pinnschmidt Hans , Königsberg Alina , Schlemm Eckhard , Boutitie Florent , Ebinger Martin , Endres Matthias , Fiebach Jochen B , Fiehler Jens , Galinovic Ivana , Lemmens Robin , Muir Keith W , Pedraza Salvador , Puig Josep , Simonsen Claus Z , Thijs Vincent , Wouters Anke , Gerloff Christian , Thomalla Götz
Published: November 2021

Background

Fluid-attenuated inversion recovery (FLAIR) sequences have gained a role to guide treatment of patients with unknown time of stroke symptom onset. Evolution of signal intensities in FLAIR is associated with time since stroke onset with continuous linear increases.

Aims

Estimating symptom onset during night-sleep in patients from the WAKE-UP trial based on relative signal intensities FLAIR (FLAIR-rSI) from acute stroke lesions an independent dataset (PRE-FLAIR study).

Methods

FLAIR-rSI was quantified in stroke lesions in PRE-FLAIR and WAKE-UP. The PRE-FLAIR study was a multicenter observational trial establishing FLAIR as a surrogate parameter for time since stroke onset. WAKE-UP was a randomized controlled trial that revealed a benefit for alteplase in patients selected based on a DWI-FLAIR mismatch. Stroke onset times were recorded in PRE-FLAIR and used to fit a linear regression model with FLAIR-rSI, adjusted for patient age and lesion volume. The model was applied to FLAIR-rSI of stroke lesions to estimate onset times in those patients enrolled in WAKE-UP who had symptom onset during night-sleep.

Results

FLAIR-rSI was quantified in 399 patients from PRE-FLAIR. Linear regression indicated a significant association of age ( p = 0.001), lesion volume ( p = 0.005) and FLAIR-rSI ( p < 0.001) with time since symptom onset (adjusted R2 = 0.179). In 813 patients from WAKE-UP, distribution of times of last seen well, symptom recognition and MRI examination were recorded. Median times of last seen well were 1 h before midnight (IQR 2.4 h) and symptom recognition 7 h after midnight (IRQ 2.2 h). Based on the FLAIR-rSI profiles, we estimated median stroke onset 6.1 h after midnight (IQR 2.7 h).

Conclusion

Nocturnal strokes during night-sleep may predominantly occur during the early morning hours. Our results are in line with evidence of characteristic diurnal patterns of cardiovascular events.
Upper lip bite test compared to modified Mallampati test in predicting difficult airway in obstetrics: A prospective observational study
Authors: Moslemi Farnaz , Khan Zahid Hussain , Alizadeh Elham , Khamnian Zhila , Eftekhar Negar , Hosseini Mohammad-Salar , Mahmoodpoor Ata
Published: November 2021

Difficult airway and intubation can have dangerous sequela for patients if not managed promptly. This issue is even more challenging among obstetric patients. Several studies have aimed to determine whether the test to predict a difficult airway or difficult intubation, is higher in accuracy. This study aims to compare the upper lip bite test with the modified Mallampati test in predicting difficult airway among obstetric patients. During this prospective observational study, 184 adult pregnant women, with ASA physical status of II, were enrolled. Difficult intubations of Cormack-Lehane grade III and IV were defined as difficult airways and difficult intubation in this study. Upper lip bite test, modified Mallampati test, thyromental distance and sternomental distance were noted for all patients. Modified Mallampati test, upper lip bite test and sternomental distance had highest specificity. Based on regression analysis, body mass index and Cormack-Lehane grade have a significant association. Modified Mallampati test was the most accurate test for predicting difficult airway. The best cut-off points of thyromental distance and sternomental distance in our study were 5cm and 15cm, respectively, by receiver operating characteristic curve analysis. Based on the results of the present study, it can be concluded that in the obstetric population, modified Mallampati test is practically the best test for predicting difficult airway. However, combining this test with upper lip bite test, thyromental distance and sternomental distance might result in better diagnostic accuracy.
Effects of Materialism on Brand-Related User-Generated Content and Positive WOM on Social Media
Authors: Nguyen Han , Martin Brett A. S. , Kerr Gayle
Published: November 2021

This research investigates how materialism as a personality trait can impact consumers’ intention to create brand-related user-generated content (UGC) and positive WOM on Facebook. The research involved three studies. Study 1 was an online survey investigating the association between materialism and brand-related UGC and positive WOM creation on Facebook. Study 2 tested the mediating role of the perception of brand symbolism for the effect of materialism on brand-related UGC and positive WOM creation. Study 3 was an online experiment which manipulated materialism. It demonstrated that the perception of brand symbolism mediated the effect of materialism on brand-related UGC and positive WOM creation on Facebook. These findings show how materialism influences whether consumers create content about brands to express self-identity. They also show researchers and managers how to target consumers to encourage them to create brand-related UGC and positive WOM on social media. Specifically, by emphasising materialistic cues, marketers can enhance consumers’ perception of brand symbolism which can motivate consumers to create brand-related UGC and positive WOM.
Short-Term Training in Mindfulness Predicts Helping Behavior Toward Racial Ingroup and Outgroup Members
Authors: Berry Daniel R. , Wall Catherine S. J. , Tubbs Justin D. , Zeidan Fadel , Brown Kirk Warren
Published: November 2021

A randomized controlled trial tested whether mindfulness training would increase lab-based and in vivo spontaneous helping behaviors toward racial outgroup members. First, across conditions, those scoring higher in baseline trait mindfulness showed higher levels of preintervention lab-based and ecological momentary assessment (EMA)-based helping behavior. Next, short-term (4-day) training in mindfulness, relative to a well-matched sham meditation training, increased interracial helping behavior in a lab-based simulation. Finally, among people scoring lower in a basic form of trait mindfulness at baseline—that is, with greater room for improvement—mindfulness training predicted higher postintervention in vivo helping behavior reported via EMA. However, neither training condition alone attenuated preferential helping toward racial ingroup members. These findings indicate, for the first time, that mindfulness and its training fosters helping behavior toward strangers and acquaintances regardless of their racial ingroup or outgroup status, but preferential helping of racial ingroup members remains.
An exploration of ECtHR jurisprudence governing the administration of release processes for life and long-term sentence prisoners: Perspectives from the United Kingdom
Authors: Coffey Ger
Published: November 2021

The purpose of the research themes examined in this article is to contribute to the ongoing debate pertaining to substantive criminal laws and procedures governing sentence reviews of prolonged detention for life and long-term sentence prisoners in accordance with Article 5(4) ECHR. The incompatibility of whole life irreducible sentences with Article 3 ECHR is examined through the lens of the ECtHR judgment in Vinter, Moore and Bamber v United Kingdom. The analyses of ECtHR jurisprudence is heavily skewed towards the administration of indeterminate life, and by analogy long-term determinate sentences, in the United Kingdom which is an outlier jurisdiction in a European context given that, in conjunction with Turkey, it accounts for the majority of persons serving life sentences. The article focuses on pertinent ECHR provisions and associated ECtHR jurisprudence, with perspectives from the United Kingdom on their implementation as a case study. While key themes are disinterred from the ECtHR’s jurisprudence that will presumably inform sentence review procedures in European states, a broader analysis of release systems operative in a European context is beyond the scope of the article.
Iterative reconstruction improves image quality and reduces radiation dose in trauma protocols; A human cadaver study
Authors: Godt Johannes Clemens , Johansen Cathrine K , Martinsen Anne Catrine T , Schulz Anselm , Brøgger Helga M , Jensen Kristin , Stray-Pedersen Arne , Dormagen Johann Baptist
Published: November 2021

Background

Radiation-related cancer risk is an object of concern in CT of trauma patients, as these represent a young population. Different radiation reducing methods, including iterative reconstruction (IR), and spilt bolus techniques have been introduced in the recent years in different large scale trauma centers.

Purpose

To compare image quality in human cadaver exposed to thoracoabdominal computed tomography using IR and standard filtered back-projection (FBP) at different dose levels.

Material and methods

Ten cadavers were scanned at full dose and a dose reduction in CTDIvol of 5 mGy (low dose 1) and 7.5 mGy (low dose 2) on a Siemens Definition Flash 128-slice computed tomography scanner. Low dose images were reconstructed with FBP and Sinogram affirmed iterative reconstruction (SAFIRE) level 2 and 4. Quantitative image quality was analyzed by comparison of contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR). Qualitative image quality was evaluated by use of visual grading regression (VGR) by four radiologists.

Results

Readers preferred SAFIRE reconstructed images over FBP at a dose reduction of 40% (low dose 1) and 56% (low dose 2), with significant difference in overall impression of image quality. CNR and SNR showed significant improvement for images reconstructed with SAFIRE 2 and 4 compared to FBP at both low dose levels.

Conclusions

Iterative image reconstruction, SAFIRE 2 and 4, resulted in equal or improved image quality at a dose reduction of up to 56% compared to full dose FBP and may be used a strong radiation reduction tool in the young trauma population.
The Benefits of Living With Close Others: A Longitudinal Examination of Mental Health Before and During a Global Stressor
Authors: Sisson Natalie M. , Willroth Emily C. , Le Bonnie M. , Ford Brett Q.
Published: November 2021

For better or worse, the people one lives with may exert a powerful influence on one’s mental health, perhaps especially during times of stress. The COVID-19 pandemic—a large-scale stressor that prompted health recommendations to stay home to reduce disease spread—provided a unique context for examining how the people who share one’s home may shape one’s mental health. A seven-wave longitudinal study assessed mental health month to month before and during the pandemic (February through September 2020) in two diverse samples of U.S. adults ( N = 656; N = 544). Preregistered analyses demonstrated that people living with close others (children and/or romantic partners) experienced better well-being before and during the pandemic’s first 6 months. These groups also experienced unique increases in ill-being during the pandemic’s onset, but parents’ ill-being also recovered more quickly. These findings highlight the crucial protective function of close relationships for mental health both generally and amid a pandemic.
Bionanocomposites based on a covalent network of chitosan and edge functionalized graphene layers
Authors: Barbera Vincenzina , Torrisi Giulio , Galimberti Maurizio
Published: November 2021

In this study, carbon papers and aerogels were prepared from chitosan and graphene layers with aldehydic edge functional groups (G-CHO) able to form chemical bonds with chitosan and thus to form a crosslinked network. A high surface area graphite was edge functionalized with hydroxyl groups (G-OH) through the reaction with KOH. G-CHO, with 4.5 mmol/g of functional group, was prepared from G-OH by means of the Reimer-Tieman reaction. Characterization of the graphitic materials was performed with elemental analysis, titration, X-ray analysis, Raman spectroscopy and by estimating their Hansen solubility parameters. CS and G-CHO were mixed with mortar and pestle and carbon papers and aerogels were obtained from a stable acidic water suspension through casting and liophilization, respectively. Free standing and foldable carbon papers and monolithic aerogels based on a continuous covalent network between G-CHO and CS were prepared. G-CHO, which had about 22 stacked layers, was extensively exfoliated in the carbon paper, as confirmed by the absence of the 002 reflection of the graphitic crystallites in the XRD pattern. Carbon paper was found to be resistant to solvents and to be stable for pH ⩾ 7. Composites revealed electrical conductivity. The covalent network between the graphene layers and CS, suggested by the IR findings, accounts for these results. This work demonstrates the effectiveness of a continuous covalent network between chitosan and graphene layers edge functionalized with tailor made functional groups for the preparation of carbon papers and aerogels and paves the way for the scale up of such a type of composites.
Book review: Devesh Kapur and Madhav Khosla (Eds.), Regulation in India: Design, Capacity, Performance
Authors: Echeverri-Gent John
Published: November 2021

Devesh Kapur and Madhav Khosla (Eds.), Regulation in India: Design, Capacity, Performance (New Delhi: Bloomsbury, 2019), 407 pp. ₹739. ISBN 978-93-88630-66-5.
COVID-19 Vaccine Willingness and Hesitancy Among Marshallese Pacific Islanders
Authors: McElfish Pearl A. , Willis Don E. , Bogulski Cari , Kelen Meetu , Riklon Sheldon , Alik Eldon , Laelan Melisa , Brown April L. , Sinclair Ka’imi A. , Andersen Jennifer A. , Amick Benjamin C. , Williams Mark
Published: November 2021

COVID-19 has disproportionally burdened racial and ethnic minorities. Minority populations report greater COVID-19 vaccine hesitancy; however, no studies document COVID-19 vaccine willingness among Marshallese or any Pacific Islander group, who are often underrepresented in research. This study documents United States (US) Marshallese Pacific Islanders’: willingness to get the COVID-19 vaccine, willingness to participate in vaccine trials, and sociodemographic factors associated with willingness. From July 27, 2020-November 22, 2020, a convenience sample of US Marshallese adults were recruited through e-mail, phone calls, and a Marshallese community Facebook page to participate in an online survey. Of those surveyed (n = 120), 32.5% were extremely likely to get the COVID-19 vaccine; 20.8% were somewhat likely; 14.2% were unlikely or very unlikely; and 26.7% stated they did not know or were not sure. Only 16.7% stated they were willing to participate in a COVID-19 vaccine trial. Vaccine willingness was positively associated with older age, higher income, and longer US residence. Health insurance status and having a primary care provider were positively associated with vaccine willingness. Findings demonstrate within-group variation in COVID-19 vaccine willingness.
One year follow-up and exploratory analysis of a patient-centered interdisciplinary care intervention for multimorbidity
Authors: Fortin Martin , Stewart Moira , Almirall José , Berbiche Djamal , Bélanger Mathieu , Katz Alan , Ryan Bridget L , Wong Sabrina T , Zwarenstein Merrick
Published: November 2021

Context

Interventions for people with multimorbidity have obtained mixed results. We aimed to document the long-term effect of an intervention for people with multimorbidity.

Methods

284 patients (18–80 years) presenting three or more chronic conditions were recruited from seven family medicine groups in the Saguenay-Lac St-Jean region, Quebec, Canada. The patient-centered intervention was based on motivational approach and self-management support. Outcomes were evaluated in a one-year pre-post study design with questionnaires that included the Health Education Questionnaire (heiQ), the Self-Efficacy for Managing Chronic Diseases, the Veteran RAND-12 Health Survey (VR-12), the EuroQoL 5-Domains questionnaire, the Kessler six item Psychological Stress Scale, and measures of smoking habit, physical activity, healthy eating and alcohol consumption. Subgroup analyses by age, number of conditions, sex, and income were also conducted.

Results

The heiQ domain of emotional wellbeing improved significantly. Improvement was also observed for the VR-12 and the K6. Among the health behaviours, only healthy eating was improved. Subgroup analyses in this exploratory study suggest that younger patients, those with lower number of chronic conditions or higher incomes may respond better in relation to self-management, health status and health behaviours.

Conclusion

One year after the intervention, participants significantly improved a variety of outcomes. Subgroup analyses suggest that younger patients, those with lower number of chronic conditions or higher incomes may respond better in relation to self-management, health status and health behaviours. This suggests that future interventions should be tailored to patients’ characteristics including age, sex, income and number of conditions.
Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: results from a large multicenter study
Authors: Middeke Jan M. , Metzeler Klaus H. , Röllig Christoph , Krämer Michael , Eckardt Jan-Niklas , Stasik Sebastian , Greif Philipp A. , Spiekermann Karsten , Rothenberg-Thurley Maja , Krug Utz , Braess Jan , Krämer Alwin , Hochhaus Andreas , Brümmendorf Tim H. , Naumann Ralph , Steffen Björn , Einsele Hermann , Schaich Markus , Burchert Andreas , Neubauer Andreas , Görlich Dennis , Sauerland Cristina , Schäfer-Eckart Kerstin , Schliemann Christoph , Krause Stefan W. , Hänel Mathias , Frickhofen Norbert , Noppeney Richard , Kaiser Ulrich , Kaufmann Martin , Kunadt Desiree , Wörmann Bernhard , Sockel Katja , von Bonin Malte , Herold Tobias , Müller-Tidow Carsten , Platzbecker Uwe , Berdel Wolfgang E. , Serve Hubert , Baldus Claudia D. , Ehninger Gerhard , Schetelig Johannes , Hiddemann Wolfgang , Bornhäuser Martin , Stölzel Friedrich , Thiede Christian
Published: November 2021

Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.
Using chest CT scan and unsupervised machine learning for predicting and evaluating response to lumacaftor-ivacaftor in people with cystic fibrosis
Authors: Campredon Alienor , Battistella Enzo , Martin Clémence , Durieu Isabelle , Mely Laurent , Marguet Christophe , Belleguic Chantal , Murris-Espin Marlène , Chiron Raphaël , Fanton Annlyse , Bui Stéphanie , Reynaud-Gaubert Martine , Reix Philippe , Hoang-Thi Trieu-Nghi , Vakalopoulou Maria , Revel Marie-Pierre , Da Silva Jennifer , Burgel Pierre-Régis , Chassagnon Guillaume
Published: November 2021

Objectives

Lumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator known to improve clinical status in people with cystic fibrosis (CF). This study aimed to assess lung structural changes after one year of lumacaftor-ivacaftor treatment, and to use unsupervised machine learning to identify morphological phenotypes of lung disease that are associated with response to lumacaftor-ivacaftor.

Methods

Adolescents and adults with CF from the French multicenter real-world prospective observational study evaluating the first year of treatment with lumacaftor-ivacaftor were included if they had pretherapeutic and follow-up chest computed tomography (CT)-scans available. CT scans were visually scored using a modified Bhalla score. A k-mean clustering method was performed based on 120 radiomics features extracted from unenhanced pretherapeutic chest CT scans.

Results

A total of 283 patients were included. The Bhalla score significantly decreased after 1 year of lumacaftor-ivacaftor (−1.40±1.53 points compared with pretherapeutic CT; p<0.001). This finding was related to a significant decrease in mucus plugging (−0.35±0.62 points; p<0.001), bronchial wall thickening (−0.24±0.52 points; p<0.001) and parenchymal consolidations (−0.23±0.51 points; p<0.001). Cluster analysis identified 3 morphological clusters. Patients from cluster C were more likely to experience an increase in percent predicted forced expiratory volume in 1 sec (ppFEV1) ≥5 under lumacaftor–ivacaftor than those in the other clusters (54% of responders versus 32% and 33%; p=0.01).

Conclusion

One year treatment with lumacaftor-ivacaftor was associated with a significant visual improvement of bronchial disease on chest CT. Radiomics features on pretherapeutic CT scan may help in predicting lung function response under lumacaftor-ivacaftor.
The emerging role of proteases in α1-antitrypsin deficiency and beyond
Authors: Fazleen Aishath , Wilkinson Tom
Published: November 2021

α1-Antitrypsin deficiency (AATD) has been historically under-recognised and under-diagnosed; recently it has begun to receive greater interest in terms of attempts at deeper elucidation of pathology and treatment options. However, the concept of disease phenotypes within AATD (emphysema, chronic bronchitis, bronchiectasis or a combination of phenotypes) has not been proposed or studied. Of the three neutrophil serine proteases, neutrophil elastase was historically believed to be the sole contributor to disease pathology in AATD. Recently, Proteinase-3 has been increasingly studied as an equal, if not greater, contributor to the disease process. Cathepsin G, however, has not been extensively evaluated in this area. Matrix metalloproteinases have also been mentioned in the pathogenesis of AATD but have not been widely explored. This article considers the available evidence for differential protease activity in patients with AATD, including the contribution to distinct phenotypes of the disease. Owing to limited literature in this area, extrapolations from studies of other chronic lung diseases with similar phenotypes, including COPD and bronchiectasis, have been made. We consider a new framework of understanding defined by protease-driven endotypes of disease which may lead to new opportunities for precision medicine.
Asc-Seurat: analytical single-cell Seurat-based web application
Authors: Pereira W. J. , Almeida F. M. , Conde D. , Balmant K. M. , Triozzi P. M. , Schmidt H. W. , Dervinis C. , Pappas G. J. , Kirst M.
Published: November 2021

Background

Single-cell RNA sequencing (scRNA-seq) has revolutionized the study of transcriptomes, arising as a powerful tool for discovering and characterizing cell types and their developmental trajectories. However, scRNA-seq analysis is complex, requiring a continuous, iterative process to refine the data and uncover relevant biological information. A diversity of tools has been developed to address the multiple aspects of scRNA-seq data analysis. However, an easy-to-use web application capable of conducting all critical steps of scRNA-seq data analysis is still lacking.

We present Asc-Seurat, a feature-rich workbench, providing an user-friendly and easy-to-install web application encapsulating tools for an all-encompassing and fluid scRNA-seq data analysis. Asc-Seurat implements functions from the Seurat package for quality control, clustering, and genes differential expression. In addition, Asc-Seurat provides a pseudotime module containing dozens of models for the trajectory inference and a functional annotation module that allows recovering gene annotation and detecting gene ontology enriched terms. We showcase Asc-Seurat’s capabilities by analyzing a peripheral blood mononuclear cell dataset.

Conclusions

Asc-Seurat is a comprehensive workbench providing an accessible graphical interface for scRNA-seq analysis by biologists. Asc-Seurat significantly reduces the time and effort required to analyze and interpret the information in scRNA-seq datasets.
Genome-wide characterization and analysis of WRKY transcription factors in Panax ginseng
Authors: Di Peng , Wang Ping , Yan Min , Han Peng , Huang Xinyi , Yin Le , Yan Yan , Xu Yonghua , Wang Yingping
Published: November 2021

Background

Panax ginseng is a well-known medicinal plant worldwide. As an herbal medicine, ginseng is also known for its long lifecycle, which can reach several decades. WRKY proteins play regulatory roles in many aspects of biological processes in plants, such as responses to biotic or abiotic stress, plant development, and adaptation to environmental challenges. Genome-wide analyses of WRKY genes in P. ginseng have not been reported.

Results

In this study, 137 PgWRKY genes were identified from the ginseng genome. Phylogenetic analysis showed that the PgWRKYs could be clustered into three primary groups and five subgroups. Most of the PgWRKY gene promoters contained several kinds of hormone- and stress-related cis-regulatory elements. The expression patterns of PgWRKY genes in 14 different tissues were analyzed based on the available public RNA-seq data. The responses of the PgWRKY genes to heat, cold, salt and drought treatment were also investigated. Most of the PgWRKY genes were expressed differently after heat treatment, and expression trends changed significantly under drought and cold treatment but only slightly under salt treatment. The coexpression analysis of PgWRKY genes with the ginsenoside biosynthesis pathway genes identified 11 PgWRKYs that may have a potential regulatory role in the biosynthesis process of ginsenoside.

Conclusions

This work provides insights into the evolution, modulation and distribution of the WRKY gene family in ginseng and extends our knowledge of the molecular basis along with modulatory mechanisms of WRKY transcription factors in ginsenoside biosynthesis.
Euthanasia in advanced dementia; the view of the general practitioners in the Netherlands on a vignette case along the juridical and ethical dispute
Authors: Schuurmans Jaap , Crol Chantalle , Chabot Boudewijn , Olde Rikkert Marcel , Engels Yvonne
Published: November 2021

Background

In the Netherlands, euthanasia has been regulated by law since 2002. In the past decade, a growing number of persons with dementia requested for euthanasia, and more requests were granted. A euthanasia request from a patient with advanced dementia (PWAD) can have a major impact on a general practitioner (GP). We aimed to get insights in the views of Dutch GPs on euthanasia concerning this patient group.

Methods

A postal survey was sent to 894 Dutch GPs. Questions were asked about a case vignette about a PWAD who was not able to confirm previous wishes anymore. Quantitative data were analyzed with descriptive statistics.

Results

Of the 894 GPs approached, 422 (47.3%) completed the survey. One hundred seventy-eight GPs (42.2%) did not agree with the statement that an Advance Euthanasia Directive (AED) can replace an oral request if communication with the patient concerned has become impossible. About half of the respondents (209; 49.5%) did not agree that the family can initiate a euthanasia trajectory, 95 GPs (22.5%) would accept such a family initiative and 110 GPs (26.1%) would under certain conditions.

Discussion

In case of a PWAD, when confirming previous wishes is not possible anymore, about half of the Dutch GPs would not accept an AED to replace verbal or non-verbal conformation nor consider performing euthanasia; a minority would. Our study shows that, probably due to the public debate and changed professional guidelines, conflicting views have arisen among Dutch GPs about interpretation of moral, ethical values considering AED and PWADs.
Independent associations of thyroid-related hormones with hepatic steatosis and insulin resistance in euthyroid overweight/obese Chinese adults
Authors: Ma Danyan , Zeng Jinyang , Huang Bingkun , Yan Fangfang , Ye Jiawen , Chen Yun , Zeng Xiying , Zheng Xin , Xiao Fangsen , Lin Mingzhu , Liu Changqin , Li Zhibin
Published: November 2021

Purpose

The aim of the study is to explore the independent association of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) with hepatic steatosis and insulin resistance.

Methods

A cross-sectional study of 88 overweight/obese adults who underwent anthropometric measurements [BMI, waist circumference (WC) and waist-to-height ratio (WHtR)], hepatic steatosis assessment (FibroScan) and thyroid-related hormones tests was conducted from 2018 to 2020 in Xiamen, China.

Results

Subjects with increasing tertiles of FT3 showed significantly higher levels of controlled attenuation parameter (CAP) ((295.4 ± 44.1, 290.1 ± 68.2 and 331.7 ± 43.6 (dB/m) for tertile 1–3, respectively, p = 0.007) and fatty liver index (FLI) score (47.7 (33.9–60.8), 61.5 (45.1–88.9) and 90.5 (84.5–94.8), respectively, p < 0.001). FT3 significantly and positively correlated with obesity index (BMI, WC, and WHtR), homeostatic model assessment of insulin resistance (HOMA-IR) and hepatic steatosis (CAP and FLI). Multivariable linear regression analyses with adjustment for potential confounding factors showed FT3 was independently associated with BMI (regression coefficient (β (95%CI): 0.024 (0.004–0.043), p = 0.020), HOMA-IR (β (95%CI): 0.091 (0.007–0.174), p = 0.034), CAP (β (95%CI): 25.45 (2.59–48.31), p = 0.030) and FLI (β (95%CI): 0.121 (0.049–0.194), p = 0.001). Neither FT4 nor TSH was significantly associated with any indicators of obesity, insulin resistance or hepatic steatosis.

Conclusions

Increased FT3, but not FT4 or TSH, was independently associated with higher risks of hepatic steatosis and insulin resistance in euthyroid overweight/obese Chinese adults.

Trial registration Registration is not applicable for our study.
A fatal case of acute encephalopathy in a child due to coxsackievirus A2 infection: a case report
Authors: Nagai Tomonori , Hanaoka Nozomu , Katano Harutaka , Konagaya Masami , Tanaka-Taya Keiko , Shimizu Hiroyuki , Mukai Toshiji , Fujimoto Tsuguto
Published: November 2021

Background

Certain types of enteroviruses, including coxsackieviruses, cause encephalitis, and other neurological complications. However, these pathogens rarely cause fatal infections, especially in immunocompetent infants. In this study, we present a rare case of acute encephalopathy caused by coxsackievirus A2 (CV-A2), which progressed rapidly in a previously healthy female child.

Case presentation

In June 2013, a 26-month-old female child from Kanagawa, Japan, was found unresponsive during sleep. She was healthy until that morning. Her temperature was 37 °C at 08:00. She was feeling fine and went to the nursery that same morning. However, her condition worsened around noon. Therefore, she went home and slept at around 13:00. Surprisingly, after 2 h, her parents checked on her and found that she was lying on her back and was not breathing. Hence, she was immediately taken to a hospital by ambulance, but she was declared dead on arrival at the hospital. Subsequently, pathological autopsy and pathogenetic analysis, including multiple pathogen detection real-time PCR, were conducted to investigate the cause of death. The examination results revealed that she had an infectious respiratory disease and acute encephalopathy due to a CV-A2 infection.

Conclusions

Based on our findings, we concluded that a previously healthy girl who had no immediate history of underlying medical condition were susceptible to death by acute encephalopathy due to CV-A2 infections. We proposed this conclusion because the patient’s condition progressed rapidly in less than 2 h and eventually led to her death. This is the first report on an acute encephalitis-dependent death in a child due to CV-A2 infection.
Depression, anxiety, PTSD, and OCD after stillbirth: a systematic review
Authors: Westby Cèline Lossius , Erlandsen Andrea Røsberg , Nilsen Sondre Aasen , Visted Endre , Thimm Jens C.
Published: November 2021

Background

This systematic review aimed to provide an updated summary of studies investigating depression, anxiety, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD) in parents after stillbirth (from 20 weeks gestational age until birth).

Methods

A literature search was conducted in the databases Web of Science and PsychINFO. Main inclusion criteria were 1) peer-reviewed, quantitative, English-language articles published from 1980; (2) studies investigating depression, anxiety, PTSD, or OCD among parents following stillbirth; and (3) studies defining stillbirth as equal to or after 20 weeks of gestation.

Results

Thirteen quantitative, peer-reviewed articles were eligible for inclusion. Selected articles investigated depression, anxiety, and PTSD, while no studies on OCD met our inclusion criteria. The majority of studies investigated women, while only two studies included men. The results indicated heightened short- and long-term levels of depression, anxiety, and PTSD in parents after stillbirth compared to those of parents with live birth. Studies investigating predictors found that social support, marital status, negative appraisals, and variables related to care and management after stillbirth affected levels of symptoms.

Conclusions

Parents who experience stillbirth have a considerably higher risk of reporting symptoms of depression, anxiety, and PTSD compared with parents with live births. More longitudinal studies are needed to increase our knowledge of how symptoms develop over time, and more research on fathers, transgender, non-binary and gender fluid individuals is needed. Research on the association between stillbirth and OCD is also warranted. Knowledge of the severity of anxiety, depression, and PTSD after stillbirth, and predictors associated with symptom severity could provide healthcare professionals with valuable information on how to provide beneficial postpartum care.
Mapping the EORTC QLQ-C30 to EQ-5D-3L in patients with breast cancer
Authors: Gray Laura A. , Hernandez Alava Monica , Wailoo Allan J.
Published: November 2021

Background

The types of outcomes measured collected in clinical studies and those required for cost-effectiveness analysis often differ. Decision makers routinely use quality adjusted life years (QALYs) to compare the benefits and costs of treatments across different diseases and treatments using a common metric. QALYs can be calculated using preference-based measures (PBMs) such as EQ-5D-3L, but clinical studies often focus on objective clinician or laboratory measured outcomes and non-preference-based patient outcomes, such as QLQ-C30. We model the relationship between the generic, preference-based EQ-5D-3L and the cancer specific quality of life questionnaire, QLQ-C30 in patients with breast cancer. This will result in a mapping that allows users to convert QLQ-C30 scores into EQ-5D-3L scores for the purposes of cost-effectiveness analysis or economic evaluation.

Methods

We use data from a randomized trial of 602 patients with HER2-positive advanced breast cancer provided 3766 EQ-5D-3L observations. Direct mapping using adjusted, limited dependent variable mixture models (ALDVMM) is compared to a random effects linear regression and indirect mapping using seemingly unrelated ordered probit models. EQ-5D-3L was estimated as a function of the summary scales of the QLQ-C30 and other patient characteristics.

Results

A four component mixture model outperformed other models in terms of summary fit statistics. A close fit to the observed data was observed across the range of disease severity. Simulated data from the model closely aligned to the original data and showed that mapping did not significantly underestimate uncertainty. In the simulated data, 22.15% were equal to 1 compared to 21.93% in the original data. Variance was 0.0628 in the simulated data versus 0.0693 in the original data. The preferred mapping is provided in Excel and Stata files for the ease of users.

Conclusion

A four component adjusted mixture model provides reliable, non-biased estimates of EQ-5D-3L from the QLQ-C30, to link clinical studies to economic evaluation of health technologies for breast cancer. This work adds to a growing body of literature demonstrating the appropriateness of mixture model based approaches in mapping.
Study protocol of an open-label, single arm phase II trial investigating the efficacy, safety and quality of life of neoadjuvant chemotherapy with liposomal irinotecan combined with Oxaliplatin and 5-fluorouracil/Folinic acid followed by curative surgical resection in patients with hepatic Oligometastatic adenocarcinoma of the pancreas (HOLIPANC)
Authors: Gebauer Florian , Damanakis Alexander Ioannis , Popp Felix , Quaas Alexander , Kütting Fabian , Lutz Katrin , Held Swantje , Deuß Burkhard , Göser Tobias , Waldschmidt Dirk , Bruns Christiane
Published: November 2021

Background

According to current guidelines, treatment of patients with hepatic oligometastasis in pancreatic cancer is not reflected and systemic chemotherapy is recommended in those patients. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from clinical trials addressing this particular patient group is not available.

Methods

In this single arm, phase-2 trial, survival data from patients receiving neoadjuvant chemotherapy followed by R0/R1 resection will be compared to historic data from patients with oligometastatic adenocarcinoma of the pancreas.

The clinical trial will focus on a well-defined patient collective with metastatic load limited to the liver as target organ with a maximum of five metastases. The combination of liposomal irinotecan (nal-IRI), oxaliplatin (OX) and 5-fluouracil (5-FU)/folinic acid (FA) (nal-IRI + OX+ 5-FU/FA, NAPOX) was chosen as neoadjuvant chemotherapy; the choice was based on an ongoing clinical study in which NAPOX appeared manageable, with promising anti-tumor activity in first-line treatment of patients with metastatic pancreatic adenocarcinoma.

In total 150 patients will be enrolled for this trial with an aim of 55 patients receiving a complete macroscopic synchronous tumor and metastatic resection.

Discussion

This is the first clinical study to prospectively evaluate the value of multimodality therapy concepts in oligometastatic pancreatic cancer.

Trial registration numbers

EudraCT 2019–002734-37; NCT04617457.