bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and risk factors of discomfort in infants with severe bronchiolitis
Authors: Leboucher Justine , Milési Christophe , Fumagalli Alice , Wroblewski Isabelle , Debillon Thierry , Mortamet Guillaume
Published: February 2022

Aim

The aim of this study was to assess the prevalence of discomfort in infants with severe bronchiolitis supported by noninvasive ventilation and to identify its potential risk factors.

Methods

A single‐centre retrospective observational study. Discomfort was assessed using the EDIN (Echelle de Douleur et d'Inconfort du Nouveau‐né) scale.

Results

Ninety‐one infants (median age 34 days [Interquartile IQR 19–55], 52 (57%) boys) were included in our study. Overall, no patient had a mean EDIN score higher than 8 on Days 1, 2 and 3. On Days 1 and 2, patients supported by bilevel positive airway pressure (BiPAP) had a higher EDIN score compared with other patients (3.3 [SD 2.5] versus 2.6 [SD 2.2] on Day 1 and 2.9 (SD 2.1) versus 2.3 (SD 2.2) on Day 2, both p < 0.001).

Conclusion

Patients with severe bronchiolitis and supported by any type of noninvasive ventilation had a low degree of discomfort during the first 3 days of ICU stay. Patients requiring bilevel noninvasive ventilation appeared to have a higher degree of discomfort, while we found no correlation between the level of discomfort and the degree of respiratory distress.
Neuromuscular recruitment strategies of the vastus lateralis according to sex
Authors: Guo Yuxiao , Jones Eleanor J. , Inns Thomas B. , Ely Isabel A. , Stashuk Daniel W. , Wilkinson Daniel J. , Smith Kenneth , Piasecki Jessica , Phillips Bethan E. , Atherton Philip J. , Piasecki Mathew
Published: February 2022

Aim

Despite males typically exhibiting greater muscle strength and fatigability than females, it remains unclear if there are sex‐based differences in neuromuscular recruitment strategies e.g. recruitment and modulation of motor unit firing rate (MU FR) at normalized forces and during progressive increases in force.

Methods

The study includes 29 healthy male and 31 healthy female participants (18‐35 years). Intramuscular electromyography (iEMG) was used to record individual motor unit potentials (MUPs) and near‐fibre MUPs from the vastus lateralis (VL) during 10% and 25% maximum isometric voluntary contractions (MVC), and spike‐triggered averaging was used to obtain motor unit number estimates (MUNE) of the VL.

Results

Males exhibited greater muscle strength (P < .001) and size (P < .001) than females, with no difference in force steadiness at 10% or 25% MVC. Females had 8.4% and 6.5% higher FR at 10% and 25% MVC, respectively (both P < .03), while the MUP area was 33% smaller in females at 10% MVC (P < .02) and 26% smaller at 25% MVC (P = .062). However, both sexes showed similar increases in MU size and FR when moving from low‐ to mid‐level contractions. There were no sex differences in any near‐fibre MUP parameters or in MUNE.

Conclusion

In the vastus lateralis, females produce muscle force via different neuromuscular recruitment strategies to males which is characterized by smaller MUs discharging at higher rates. However, similar strategies are employed to increase force production from low‐ to mid‐level contractions. These findings of similar proportional increases between sexes support the use of mixed sex cohorts in studies of this nature.
Review article: post‐TIPSS hepatic encephalopathy—current knowledge and future perspectives
Authors: Gairing Simon Johannes , Müller Lukas , Kloeckner Roman , Galle Peter R. , Labenz Christian
Published: February 2022

Background

In light of the global rise in the burden of chronic liver diseases and liver cirrhosis, the number of patients suffering from decompensation events is expected to increase. Transjugular intrahepatic portosystemic shunts (TIPSS) provide effective long‐term symptom control and may prolong transplant‐free survival in portal hypertension‐driven recurrent ascites and variceal bleeding. New‐onset or recurrent hepatic encephalopathy (HE) after TIPSS insertion (post‐TIPSS HE) represents the most severe post‐interventional complication.

Aims

To provide insight into the epidemiology and risk factors for post‐TIPSS HE and scrutinize the current state of the art in treatment and drug therapy options.

Methods

We conducted a literature search on post‐TIPSS HE in patients with liver cirrhosis.

Results

Post‐TIPSS HE occurs in up to 54.5% of cases and particularly early recurrent HE is associated with a dismal prognosis. In recent years, several risk factors for the development of post‐TIPSS HE have been identified. These include not only parameters reflecting liver function (model for end‐stage liver disease score/Child‐Pugh score) as well as cognitive dysfunction caused by minimal HE but also extrahepatic factors such as sarcopenia and common medications such as proton pump inhibitors. In addition, new data on the benefit of rifaximin and of smaller stent grafts emerged and may improve the prevention of post‐TIPSS HE.

Conclusions

Careful selection of TIPSS candidates is of utmost importance to reduce the risk of post‐TIPSS HE. In this narrative review, we provide a concise overview of the current epidemiology and risk factors of the treatment options for post‐TIPSS HE.
Joint Gene Network Construction by Single-Cell RNA Sequencing Data
Authors: Dong Meichen , He Yiping , Jiang Yuchao , Zou Fei
Published: February 2022

In contrast to differential gene expression analysis at the single-gene level, gene regulatory network (GRN) analysis depicts complex transcriptomic interactions among genes for better understandings of underlying genetic architectures of human diseases and traits. Recent advances in single-cell RNA sequencing (scRNA-seq) allow constructing GRNs at a much finer resolution than bulk RNA-seq and microarray data. However, scRNA-seq data are inherently sparse, which hinders the direct application of the popular Gaussian graphical models (GGMs). Furthermore, most existing approaches for constructing GRNs with scRNA-seq data only consider gene networks under one condition. To better understand GRNs across different but related conditions at single-cell resolution, we propose to construct Joint Gene Networks with scRNA-seq data (JGNsc) under the GGMs framework. To facilitate the use of GGMs, JGNsc first proposes a hybrid imputation procedure that combines a Bayesian zero-inflated Poisson model with an iterative low-rank matrix completion step to efficiently impute zero-inflated counts resulted from technical artifacts. JGNsc then transforms the imputed data via a nonparanormal transformation, based on which joint GGMs are constructed. We demonstrate JGNsc and assess its performance using synthetic data. The application of JGNsc on two cancer clinical studies of medulloblastoma and glioblastoma gains novel insights in addition to confirming well-known biological results.
An exploration of instructors' and students' perspectives on remote delivery of courses during the COVID‐19 pandemic
Authors: Chen Victoria , Sandford Adam , LaGrone Matthew , Charbonneau Kayla , Kong Jessica , Ragavaloo Shenoa
Published: February 2022

The world‐wide pivot to remote learning due to the exogenous shocks of COVID‐19 across educational institutions has presented unique challenges and opportunities. This study documents the lived experiences of instructors and students and recommends emerging pathways for teaching and learning strategies post‐pandemic. Seventy‐one instructors and 122 students completed online surveys containing closed and open‐ended questions. Quantitative and qualitative analyses were conducted, including frequencies, chi‐square tests, Welch Two‐Samples t‐tests, and thematic analyses. The results demonstrated that with effective online tools, remote learning could replicate key components of content delivery, activities, assessments, and virtual proctored exams. However, instructors and students did not want in‐person learning to disappear and recommended flexibility by combining learning opportunities in in‐person, online, and asynchronous course deliveries according to personal preferences. The paper concludes with future directions and how the findings influenced our planning for Fall 2021 delivery. The video abstract for this article is available at https://www.youtube.com/watch?v=F48KBg_d8AE.

Practitioner notes

What is already known about this topic

Emergency Remote Teaching (ERT) allowed institutions across the world to continue teaching and learning at all levels of education during the COVID‐19 pandemic. However, this form of delivery, created under conditions of uncertainty, was developed out of an urgency to keep education going rather than maintaining it at the same level.

What this paper adds

This study comes after ERT, and is situated between ERT and the return to campus, with some social distancing restrictions still active, in a delivery method widely viewed as “remote delivery”.

This is a case study of an entire Canadian higher education institution that implemented remote learning for over one full academic year, documenting and examining instructors' and students' experiences and challenges of the remote learning course delivery format.

Quantitative and qualitative data were collected to provide a holistic overview of instructors' and students' experiences of delivery method and assessments including the use of face‐tracking proctoring software.

Implications for practice and/or policy

Compared to ERT, remote delivery was a thoughtful and deliberate way to transform in‐person courses into virtual learning experiences.

Instructors and students were able to successfully replicate many features of in‐person learning and assessments experiences in remote delivery of courses by using effective online tools to teach and learn.

As a result, instructors and students called for the use of elements of remote delivery to create more flexible learning opportunities by combining in‐person, live streaming, and asynchronous learning options.
How far are we from predicting multi‐drug interactions during treatment for COVID‐19 infection?
Authors: Lozano Benjamin , Santibáñez Javier , Severino Nicolás , Saldias Cristina , Vera Magdalena , Retamal Jaime , Torres Soledad , Barrera Nelson P.
Published: February 2022

Seriously ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and hospitalized in intensive care units (ICUs) are commonly given a combination of drugs, a process known as multi‐drug treatment. After extracting data on drug–drug interactions with clinical relevance from available online platforms, we hypothesize that an overall interaction map can be generated for all drugs administered. Furthermore, by combining this approach with simulations of cellular biochemical pathways, we may be able to explain the general clinical outcome. Finally, we postulate that by applying this strategy retrospectively to a cohort of patients hospitalized in ICU, a prediction of the timing of developing acute kidney injury (AKI) could be made. Whether or not this approach can be extended to other diseases is uncertain. Still, we believe it represents a valuable pharmacological insight to help improve clinical outcomes for severely ill patients.
The ester derivatives obtained by C‐ring modification of podophyllotoxin‐induced apoptosis and inhibited proliferation in Hemangioma Endothelial Cells via downregulation of PI3K/Akt signaling pathway
Authors: Zhao Yan , Li Danyao , Han Yun , Wang Haohao , Du Rui , Yan Zhaowei
Published: February 2022

Infantile hemangioma (IH) is a common benign endothelial cell tumor in infants and young children, sometimes accompanied by potential complications, and may develop into malignant tumors. Hemangioma endothelial cells (HemECs) are one of the main components of IH. Podophyllotoxin (PPT) has been reported to have many pharmacological activities, especially anti‐tumor, but its high toxicity, poor water solubility, and serious gastrointestinal side effects limit its clinical application. In this study, we have designed and synthesized 20 ester derivatives by introducing Boc‐amino acids or organic acids at the C‐4 position of podophyllotoxin through esterification reactions. The cytotoxicity of these compounds was evaluated on HemECs. Changes in cell proliferation and apoptotic signaling pathways were studied by DAPI staining, colony formation assay, migration assay, measurement of reactive oxygen species (ROS) levels flow cytometry, and Western blot analysis. We found that eight of the compounds were more potent than PPT. Of these, compound V‐31 was the most active (IC50 = 0.079 ± 0.0049 µM). Further research indicated that compound V‐31 inhibited its proliferation and migration, increased the level of ROS in cells, and induced apoptosis by downregulating p‐PI3K, p‐Akt, and Bcl‐2, and upregulating cleaved caspase‐3 and Bax. Our research provides the first insight into the application of PPT derivatives in HemECs, may provide an effective medicine for IH treatment.
Gene profiling reveals a contact allergy signature in most positive Amerchol L‐101 patch test reactions
Authors: Ljungberg Silic Linda , Lefevre Marine‐Alexia , Bergendorff Ola , De Bernard Simon , Nourikyan Julien , Buffat Laurent , Nosbaum Audrey , Bruze Magnus , Nicolas Jean‐François , Svedman Cecilia , Vocanson Marc
Published: February 2022

Background

Diagnosis of contact allergy (CA) to Amerchol L‐101 (AL‐101), a marker for lanolin allergy, is problematic. Positive patch test reactions are frequently doubtful or weakly positive and difficult to associate with clinical relevance.

Objective

To gain further insight on the allergic or irritant nature of skin reactions induced by AL‐101 patch test.

Methods

We re‐tested in a dose–response fashion, 10 subjects with AL‐101 CA and performed comprehensive transcriptomic analysis (gene arrays, quantitative real‐time polymerase chain reaction [qRT‐PCR]) of samples of their skin reactions.

Results

Eight of the 10 CA subjects reacted positively upon re‐test, whereas two did not react. Most of AL‐101 positive patch tests expressed an allergy signature with strong activation of gene modules associated with adaptive immunity and downregulation of cornification pathway genes. In addition, the breadth of gene modulation correlated with the magnitude of patch test reactions and the concentration of AL‐101 applied. However, we observed that some of the positive patch test reactions to AL‐101 expressed no/few allergy biomarkers, suggesting the induction of an irritant skin inflammation in these samples.

Conclusions

This study confirms that AL‐101 is an allergen that can cause both contact allergy and contact irritation. Our results also highlight that molecular profiling might help to strengthen clinical diagnosis.
COVID‐19 vaccine acceptability among people in Australia who inject drugs: Update from the 2021 Illicit Drug Reporting System interviews
Authors: Price Olivia , Dietze Paul M. , Maher Lisa , Crawford Sione , Peacock Amy
Published: February 2022

People who inject drugs may be at higher risk of COVID‐19 transmission and more severe negative health outcomes following COVID‐19 infection. Early research on hypothetical COVID‐19 vaccines suggests this population may be less likely to accept vaccination. This commentary extends this research by presenting vaccine intention data from Illicit Drug Reporting System interviews conducted in June–July 2021, in the early stages of vaccine rollout, with people in Australia who inject drugs (N = 888). Half the sample (48%, n = 419) reported that they were hesitant to receive the COVID‐19 vaccine, with key barriers relating to vaccine safety and side effect concerns. This level of hesitancy is substantially higher than that of the general population at a similar time. While we note that the subsequent Delta variant‐driven third wave of cases in Australia and efforts to increase population vaccination coverage may have altered intent in this group, this level of hesitancy warrants a targeted strategy to mitigate vaccine‐related concerns and maximise uptake. Ideally, this should comprise an inclusive health response that is peer‐led, with peer‐based organisations ideally positioned to direct immunisation service delivery and provide vaccine‐related messaging.
Dispersal models alert on the risk of non‐native species introduction by Ballast water in protected areas from the Western Antarctic Peninsula
Authors: Dulière Valérie , Guillaumot Charlène , Lacroix Geneviève , Saucède Thomas , López‐Farran Zambra , Danis Bruno , Schön Isa , Baetens Katrijn
Published: February 2022

Aim

The Western Antarctic Peninsula is challenged by climate change and increasing maritime traffic that together facilitate the introduction of marine non‐native species from warmer regions neighbouring the Southern Ocean. Ballast water exchange has been frequently reported as an introduction vector. This study uses a Lagrangian approach to model the passive drift of virtual propagules departing from Ballast water hypothetic exchange zones, at contrasting distances from the coasts.

Location

Western Antarctic Peninsula.

Methods

Virtual propagules were released over the 2008–2016 period and at three distances from the nearest coasts: 200 (convention for the management of Ballast Water, 2004), 50 or 11 nautical miles (NM).

Results

Results show that exchanging Ballast water at 200 NM considerably reduces the arrival of propagules in proposed marine protected areas of the western side of the Antarctic Peninsula. On the eastern side, propagules can reach north‐eastern marine protected areas within a few days due to strong currents for all tested scenarios. Seasonal and yearly variations indicate that exceptional climate events could influence the trajectory of particles in the region. Ballast water should be exchanged at least 200 NM offshore on the western side of the Antarctic Peninsula and avoided on the eastern side to limit particle arrival in proposed marine protected areas. Focusing on Deception Island, our results suggested that the Patagonian crab (Halicarcinus planatus) observed in 2010 could have been introduced in case of Ballast water exchange at 50 NM or less from the coast.

Main conclusions

This study highlights the importance of respecting Ballast water exchange convention to limit the risk of non‐native species introduction. Ballast water exchange should be operated at least at 200 NM from the coasts, which further limits particle arrival in shallow water areas. This is especially important in the context of a more visited and warmer Southern Ocean.
Intra‐individual variability in task performance after cognitive training is associated with long‐term outcomes in children
Authors: Cubillo Ana , Hermes Henning , Berger Eva , Winkel Kirsten , Schunk Daniel , Fehr Ernst , Hare Todd A.
Published: February 2022

The potential benefits and mechanistic effects of working memory training (WMT) in children are the subject of much research and debate. We show that after five weeks of school‐based, adaptive WMT 6–9 year‐old primary school children had greater activity in prefrontal and striatal brain regions, higher task accuracy, and reduced intra‐individual variability in response times compared to controls. Using a sequential sampling decision model, we demonstrate that this reduction in intra‐individual variability can be explained by changes to the evidence accumulation rates and thresholds. Critically, intra‐individual variability is useful in quantifying the immediate impact of cognitive training interventions, being a better predictor of academic skills and well‐being 6–12 months after the end of training than task accuracy. Taken together, our results suggest that attention control is the initial mechanism that leads to the long‐run benefits from adaptive WMT. Selective and sustained attention abilities may serve as a scaffold for subsequent changes in higher cognitive processes, academic skills, and general well‐being. Furthermore, these results highlight that the selection of outcome measures and the timing of the assessments play a crucial role in detecting training efficacy. Thus, evaluating intra‐individual variability, during or directly after training could allow for the early tailoring of training interventions in terms of duration or content to maximise their impact.
What does an aetiological diagnosis actually mean?
Authors: Smithers‐Sheedy Hayley , Henry Georgina
Published: February 2022

This commentary is on the original article by Aravamuthan et al. on pages 723–733 of this issue.
Capturing the real‐world benefit of residual β‐cell function during clinically important time‐periods in established Type 1 diabetes
Authors: Taylor Guy S. , Shaw Andy C. , Smith Kieran , Wason James , McDonald Timothy J. , Oram Richard A. , Stevenson Emma , Shaw James A. M. , West Daniel J.
Published: February 2022

Aims

Many individuals with type 1 diabetes retain residual β‐cell function, with increased endogenous insulin secretion associated with reduced hyperglycaemia, hypoglycaemia and glycaemic variability. However, it is unknown when these improvements occur during the day. Dysglycaemia is common in overnight and postprandial periods and associated with diabetes complications. Therefore, this study aimed to determine the influence of residual β‐cell function upon nocturnal and postprandial glycaemic control in established type 1 diabetes.

Methods

Under free‐living conditions, 66 participants wore a blinded continuous glucose monitor (CGM), kept a food diary, and completed a stimulated urine C‐peptide creatinine (UCPCR) test. Nocturnal, and postprandial CGM outcomes (participant means and discrete event analysis) were compared between UCPCR groups: undetectable (Cpepund), low (Cpeplow: 0.001–0.19 nmol/mmol) and high (Cpephigh: ≥0.2 nmol/mmol).

Results

Greater β‐cell function was associated with incremental improvements in glycaemia. Cpephigh spent significantly greater time in normoglycaemia than Cpepund overnight (76 ± 20% vs. 58 ± 20%, p = 0.005) and 0–300 mins postprandially (68 ± 22% vs. 51 ± 22%, p = 0.045), while also having reducing nocturnal variability (SD 1.12 ± 0.41 vs. 1.52 ± 0.43 mmol/L, p = 0.010). Analysis of individual events, controlling for diabetes duration, BMI, basal insulin, use of a continuous or flash glucose monitor and (for postprandial) meal type, carbohydrate and bolus insulin intake, replicated the group findings, additionally demonstrating Cpepund had increased hyperglycaemia versus Cpeplow overnight and increased postprandial hypoglycaemic events compared with Cpephigh. For all participants, breakfast had a significantly higher incremental area under the curve than lunch and dinner.

Conclusions

Residual β‐cell function is associated with improved nocturnal and postprandial glycaemic control. These data may be of clinical importance for identifying specific periods and individuals where further glycaemic management strategies would be beneficial.
Comparing the comparators: How should the quality of education offered by online universities be evaluated?
Authors: Brasher Andrew , Whitelock Denise , Holmes Wayne , Pozzi Francesca , Persico Donatella , Manganello Flavio , Passarelli Marcello , Sangrà Albert
Published: February 2022

Comparing universities and courses is of interest to a variety of stakeholders including potential students, policy makers, news and media organisations, ranking providers, and universities themselves. There are a range of existing university ranking schemes that provide comparisons (e.g. Academic Ranking of World Universities) but typically these are designed with face‐to‐face teaching and learning in mind. There is also a growing number of quality assurance tools and approaches aimed at ensuring the quality of online education This article reports on an analysis of a range of quality assurance systems for online higher education institutions and courses, together with variety of ranking systems targeting conventional universities—with the aim of establishing what they measure, and the metrics used to assess quality. The findings from this analytical study were compared with a meta‐analysis of the literature about how students choose their university in order to understand how these instruments influence current student opinion and can be used more proactively by universities themselves. The findings reveal: (1) current ranking systems are of limited value for most potential undergraduate students, particularly with reference to online education, (2) comparison systems that can be of value to students from a variety of different backgrounds are likely to be complex to set up and run, and (3) quality indicators that promote both formative and summative evaluation may be beneficial to both institutions and students.
Suv39h1 regulates memory stability by inhibiting the expression of Shank1 in hippocampal newborn neurons
Authors: Chen Qi‐Nan , Ding Xin‐Lu , Guo Xiu‐Xian , Zhou Gang , Guan Ji‐Song
Published: February 2022

Adult newborn neurons are involved in memory encoding and extinction, but the neural mechanism is unclear. We found the adult newborn neurons at 4 weeks are recruited by learning and subjected to epigenetic regulations, consequently reducing their ability to be re‐recruited later. After removal of the epigenetic blockage, Suv39h1 KO mice showed an increased recruiting number of aged newborn neurons and enhanced flexibility in learning tasks. Besides NRXN1, we found SHANK1, the synaptic scaffold protein, is one of the major targets of Suv39h1, regulating memory stability. Expression of Shank1 is transiently engaged to enhance synaptogenesis during learning and is strongly suppressed by Suv39h1 from 5 h after learning. Exogenously overexpression of Shank1 in dentate gyrus increased the density of mushroom spines and decreased the persistency of old memories. Our study indicated the activity‐regulated epigenetic modification in newly matured newborn neurons in hippocampus insulates temporally distinct experiences and stabilizes old memories.
An improved Amplex Red‐based fluorometric assay of phenol oxidases and peroxidases activity: A case study on Haplic Chernozem
Authors: Khosrozadeh Sajedeh , Dorodnikov Maxim , Reitz Thomas , Blagodatskaya Evgenia
Published: February 2022

The initial steps of complex organic matter degradation in soil comprise several oxidative processes catalysed by phenol oxidases and peroxidases. Commonly, their activity is determined by colorimetric approaches based on a range of substrates, making comparison between studies difficult. To improve this shortcoming, we conducted a calibration procedure for assessing phenol oxidase and peroxidase activities in soils by a sensitive fluorometric assay. This assay is based on the colourless and non‐fluorescent Amplex Red® reagent as a substrate, which forms a fluorescent product, resorufin, upon oxidation. Commercially available resorufin was used as a standard for calibration. We applied Michaelis–Menten kinetics to determine functional traits of phenol oxidases and peroxidases in a case study on Haplic Chernozem from different land‐use and climate treatments of a field experiment. The kinetic parameters, limit of detection and limit of quantification demonstrated a high sensitivity of the fluorometric assay to differences caused by these treatments. For the total oxidative enzymes, the catalytic efficiency (Kcat, calculated as Vmax/Km) was 30% higher in the cropland compared with the pasture plot. However, compared with soil samples collected from ambient climatic conditions, Kcat of total oxidoreductases was 60% lower in cropland exposed to elevated air temperature and drought. The phenol oxidase activity was substantially higher than peroxidase activity in cropland land use. However, higher Kcat of peroxidase than phenol oxidase resulted in 60% faster substrate turnover under both climatic conditions. In our case study, the Amplex Red‐based assay enabled rapid and high‐throughput analyses of phenol oxidase and peroxidase activity in soil. The sensitivity of this assay for soil enzymology applications needs further testing for a larger range of soils and environmental conditions.

Highlights

A novel fluorometric assay of phenol oxidase and peroxidase activity in soil is proposed

Resorufin fits very well for calibration simplifying the comparisons between studies

Phenol oxidase and peroxidase displayed apparent Michaelis–Menten kinetics

Amplex Red was sensitive for land‐use and climate treatments on Haplic Chernozem
Patterns of molar agenesis associated with p.P20L and p.R77Q variants in PAX9
Authors: Intarak Narin , Theerapanon Thanakorn , Porntaveetus Thantrira , Shotelersuk Vorasuk
Published: February 2022

Nonsyndromic tooth agenesis is associated with variants in several genes. There are numerous genotype‐phenotype publications involving many patients and kindreds. Here, we identified six Thai individuals in two families with nonsyndromic tooth agenesis, performed exome sequencing, and conducted functional experiments. Family 1 had four affected members carrying the heterozygous PAX9 variant, c.59C>T (p.Pro20Leu). The p.Pro20Leu was previously reported in two families having four and three affected members. These seven cases and Proband‐1 had agenesis of at least three third molars. Family 2 comprised two affected members with agenesis of all 12 molars. Both individuals were heterozygous for c.230G>A (p.Arg77Gln) in PAX9, which has not been reported previously. This variant is predicted to be damaging, evolutionarily conserved, and resides in the PAX9 linking peptide. The BMP4 RNA levels in Proband‐1′s leukocytes were not significantly different from those in the controls, whereas BMP4 levels observed in Proband‐2 were significantly increased. Moreover, the p.Arg77Gln variant demonstrated nuclear localization similar to the wild‐type but resulted in significantly impaired transactivation of BMP4, a PAX9 downstream gene. In conclusion, we demonstrate that the PAX9 p.Pro20Leu is highly associated with absent third molars, while the novel PAX9 p.Arg77Gln impairs BMP4 transactivation and is associated with total molar agenesis.
DRAMing for autophagy
Authors: Leytens Alexandre , Dengjel Jörn
Published: February 2022

Autophagy, a catabolic lysosomal recycling pathway, is often found dysregulated in human diseases. Whereas its prime cell stress‐related function is cytoprotection, autophagy has also been linked to the activation of apoptosis and cell death. One group of proteins which participates in the orchestration of autophagy and apoptosis is the family of DRAM proteins. In the current issue of The FEBS Journal, Barthet et al. uncover a compensatory crosstalk between the two newest members of the family, DRAM‐4 and DRAM‐5, the latter one regulating autophagic activity.

Comment on https://doi.org/10.1111/febs.16365
Experimental evaluation of plastic wake on growing fatigue cracks from the analysis of residual displacement fields
Authors: Vasco‐Olmo Jose M. , Díaz Francisco A. , Camacho‐Reyes Alonso , James Neil , Antunes Fernando V.
Published: February 2022

A growing fatigue crack gives rise to a plastically deformed wake of material that envelops the crack. In this work, the plastic wake extent during fatigue crack growth is experimentally quantified by analyzing the crack tip displacement fields measured with digital image correlation. A novel technique based on use of a yield criterion is proposed that uses the undamaged state of the specimen as the reference state in the image processing. The plastic wake was identified by differentiation of the residual displacement fields obtained with a near‐zero load level to avoid any rigid body motion. The plastic wake extent was then found by assuming that the boundary between the elastic and plastic regions would occur when the equivalent stress was higher than the yield stress of the material. The results presented can contribute to a better understanding of the mechanisms driving fatigue crack propagation.
Genetic variants at the chromosomal region 2q21.3 underlying inhibitor development in patients with severe haemophilia A
Authors: Spena Silvia , Cairo Andrea , Pappalardo Emanuela , Gorski Marcin M. , Garagiola Isabella , Hassan Shermarke , Gualtierotti Roberta , Peyvandi Flora
Published: February 2022

Introduction

Inhibitor development affects about 30% of patients with severe haemophilia A (HA) and results from different environmental and genetic risk factors. Previously, we identified the missense variant rs3754689 in the LCT gene linked with this predisposition. Since rs3754689 variant is benign and is located in a conserved haplotype region, we hypothesized that the association signal captured by this variant is located in coinherited, neighbouring genes.

Aim

To identify novel genetic risk factors associated with inhibitor development in coding regions of R3HDM1, UBXN4, CXCR4, MCM6, DARS and miR128‐1 genes.

Methods

Targeted sequencing was performed in 246 severe HA patients (72 with and 174 without inhibitor): 181 previously and 65 newly enrolled.

Results

Forty‐one common and 152 rare variants passed the quality control. Logistic regression analysis of common variants identified rs3754689 and four additional variants (.011 < P < .047; FDR ranging .2‐.38). Logistic regression analysis performed only in the 220 Italian patients showed similar results (.004 < P < .05; FDR ranging .12‐.22). Three of these variants (rs3213892 and rs3816155 in the LCT intron 13 and rs961360 in the R3HDM1 intron10‐exon11 junction) may affect the expression of UBXN4 and R3HDM1, respectively. Rare variants did not show association with inhibitor development. Identified variants were not replicated in the multi‐ethnic SIPPET cohort of 230 severe HA patients.

Conclusion

Due to the limited sample size that may be responsible of the high FDR values, we could not confirm with certainty the analysed association. Further evaluation of the expression levels of analysed genes will confirm or not their role in inhibitor development.
Electronic diaries in the management of haemophilia gene therapy: Perspective of an expert group from the German, Austrian and Swiss Society on Thrombosis and Haemostasis (GTH)
Authors: Miesbach Wolfgang , Eichler Hermann , Holstein Katharina , Holzhauer Susanne , Klamroth Robert , Knöfler Ralf , Male Christoph , Olivieri Martin , Oldenburg Johannes , Tiede Andreas
Published: February 2022

Introduction

Gene therapy (GT) is becoming a realistic treatment option for patients with haemophilia. Outside clinical trials, the complexity and potential complications of GT will pose unprecedented challenges to haemophilia care centres.

Aim

To explore the potential use of electronic tools to improve the delivery of GT under real‐world conditions.

Methods

Considering the hub‐and‐spoke model, the GTH working group on GT considered the entire patient pathway and reached consensus on requirements for an integrative software tool to secure documenting and sharing information between treaters, pharmacies and patients.

Results

Six steps of the gene therapy process were identified, each requiring completion of the previous step as a prerequisite for entry. The responsibilities of GT dosing and follow‐up treatment centres, read/write access rules, and the minimum data set were outlined. Data contributed by patients through mobile devices was also considered.

Conclusion

Important information needs to be shared between patients and treatment centres in a real‐world GT hub‐and‐spoke model. Collecting and sharing this information in well‐organised electronic applications will not only improve patient care but also enable national and international data collection in clinical registries.
Blink reflex: A practical test to evaluate the trigeminal nerve injury following percutaneous balloon compression for the treatment of trigeminal neuralgia
Authors: Ma Chengwen , Tian Fuyu , Zhou Le , Gu Junxiang , Zhang Xi , Quan Junjie , Qu Jianqiang , Yan Xianxia
Published: February 2022

Objective

To evaluate the blink reflex (BR) in estimating the potential injury of trigeminal nerve following percutaneous balloon compression (PBC) surgery, and to determine the association between BR alterations and early surgical outcomes.

Methods

In this single‐center, prospective before‐and‐after study, a total of 74 patients who had primary trigeminal neuralgia and scheduled for PBC between October 2020 and June 2021 were prospectively included. BR testing and facial sensory assessment were performed pre‐ and post‐PBC. The latency and the area under the curve (AUC) of pre‐ and postoperative R1 (R1pre/R1post) and R2 (R2pre/R2post) were measured.

Results

The BR components were noticeably delayed or diminished following PBC. R1post was elicited in only 26 patients, and absent in 48 patients. The residual R1post had markedly reduced AUC (median difference [Hodges–Lehmann]: −59.5, 95% confidence interval [CI]: −217.5 to −6.9, p = 0.023). Compared with R2pre, the latency of R2post was considerably delayed (mean difference: 4.3, 95% CI: 2.9 to 5.7, p < 0.001) and the AUC was greatly suppressed (median difference [Hodges–Lehmann]: −388.4, 95% CI: −548.4 to −259.5, p < 0.001). After PBC, 58 patients had immediate total pain relief, and 16 had partial relief. The absence of R1post was found in 46 of 58 (79.3%) patients with complete remission, whereas in only 2 of 16 (12.5%) patients with partial relief. Association analysis showed that the absence of R1post was strongly associated with total pain relief (46/58 [79.3%] vs. 2/16 [12.5%], odds ratio [OR]: 26.8, 95% CI: 5.4 to 134.5, Cramér's V: 0.6, p < 0.001). The latency of R2post in patients with total relief was significantly delayed (mean difference: 2.5, 95% CI: 0.3 to 4.6, p = 0.028). Patients experienced graded facial numbness after PBC, of whom 31 reported mild numbness (Grades I–II) and 43 reported more severe numbness (Grades III–IV). The absence of R1post was significantly associated with facial numbness severity, 33/43 (76.7%) in Grades III–IV vs. 15/31 (48.4%) in Grades I–II (OR: 0.284, 95% CI: 0.105 to 0.771, Cramér's V: 0.3, p = 0.012). In patients with more severe numbness, the latency of R2post was significantly delayed (mean difference: 2.7, 95% CI: 0.1 to 5.3, p = 0.043), and the reduction of AUC was much greater (median difference [Hodges–Lehmann]: 17.2, 95% CI: 0.5 to 35.4, p = 0.041).

Conclusion

Both R1 and R2 were significantly diminished after PBC and these alterations were associated with early surgical outcomes, suggesting that the BR is useful in evaluating trigeminal injury following PBC and could provide objective information about early prognosis.
Assessing attack‐related fear in headache disorders—Structure and psychometric properties of the Fear of Attacks in Migraine Inventory
Authors: Klan Timo , Bräscher Anne‐Kathrin , Klein Silja , Diezemann‐Prößdorf Anke , Guth Anna‐Lena , Gaul Charly , Witthöft Michael
Published: February 2022

Objective

This study aimed to develop a self‐report questionnaire for the assessment of attack‐related fear in migraine, and to determine its factor structure as well as its psychometric properties by the primary analysis of a cross‐sectional survey’s data.

Background

High fear of attacks in migraine increases the burden of disease and is assumed to have a negative impact on the course of the disease. Little is known about the structure and dimensionality of attack‐related fear, and a valid instrument for the comprehensive assessment is lacking.

Methods

Based on a literature search and interviews with persons with migraine as well as with experienced practitioners, a 46‐item self‐report questionnaire, the Fear of Attacks in Migraine Inventory (FAMI) was developed. A cross‐sectional online survey comprising an assessment of diagnostic criteria of migraine and a battery of questionnaires including the FAMI was conducted (N = 387 persons with migraine, 364/387 [94.1%] women, M = 40.9 [SD = 13.1] years, migraine without aura: 153/387 [39.5%], migraine with aura: 85/387 [22.0%], and chronic migraine: 149/387 [38.5%]).

Results

Item selection led to 29 items for the FAMI. Exploratory factor analysis resulted in three clearly interpretable factors (fear of negative consequences; attention and anticipation; fear‐avoidance); a confirmatory factor analysis yielded an acceptable to good model fit (χ2(3) = 1328.84, p = 0.001, χ2/df = 3.55, RMSEA = 0.085, SRMR = 0.073, CFI = 0.98, and TLI = 0.97). Reliability was good (fear‐avoidance, ω = 0.85; attention and anticipation, ω = 0.88) to excellent (fear of negative consequences, ω = 0.91). Correlational analyses confirmed the convergent validity of the FAMI.

Conclusions

The FAMI appears suitable and promising for the assessment of attack‐related fear in migraine research and clinical care.
Vocal traits of shorebird chicks are related to body mass and sex
Authors: Kostoglou Kristal N. , Miller Edward H. , Weston Michael A. , Wilson David R.
Published: February 2022

Acoustic communication is critical during early life phases in precocial birds; for example, adult alarm calls can elicit antipredator behaviour in young, and chick vocalizations can communicate information to parents about chick identity, condition, location, sex or age. We opportunistically recorded Red‐capped Plover Charadrius ruficapillus and Southern Masked Lapwing Vanellus miles novaehollandiae distress calls of chicks while they were in the hand and analysed the calls to determine whether call structure is related to sex or body mass (a proxy for age). Our study provides the first evidence for charadriid chicks of (1) a sexual difference in call structure and rate and (2) gradual growth‐related changes in call structure and rate, across chicks. We provide a foundation for further studies of shorebird vocalizations during growth, which may elucidate the development and functional significance of such vocalizations.
Changes in transcriptome of goat muscle during frozen, ice‐temperature and chilled storage within 7 days
Authors: Xiao Yu , Shen Qian , Gu Minghui , Jiao Yang , Liu Yongfeng
Published: February 2022

This study aimed to use high‐throughput Illumina Hiseq4000 sequencing to reveal transcriptome changes of longissimus thoracis of goats in frozen storage (−20 to −18°C, FS), ice‐temperature storage (−1.5 to −0.5°C, IS) and chilled storage (2–4°C, CS) within 7 days postmortem. Hierarchical cluster and correlation analysis showed that transcriptome of FS changed little, and IS was suitable for 7 days’ storage. There were 27 continuously differentially expressed genes (DEGs) (fold change ≥2, P < 0.05) over time, and 10 genes were up‐regulated and 17 genes were down‐regulated. Among them, expression amounts of WTIP, PLK3, LOC108635411 and NHSL1 were negatively correlated with shear force, L*, a* and b*, respectively, and CD3E was positively correlated with a*. Bioinformatics analysis indicated that DEGs with increasing storage temperature were mainly involved in energy production and conversion, phosphorylation and apoptosis. This study provided a new perspective for understanding the underlying mechanism of goat meat quality after slaughter.
Improving τf and thermal conductivity of Ba(Zn1/3Nb2/3)O3 microwave dielectric ceramics by ordered domain engineering
Authors: Shi Rui Da , Liu Lu , Zhu Xiao Li , Chen Xiang Ming
Published: February 2022

The effects of B‐site 1:2 ordering and ordered domain structure upon temperature coefficient of resonant frequency and thermal conductivity were systematically investigated for Ba(Zn1/3Nb2/3)O3 microwave dielectric ceramics. These characteristics could be significantly improved by the means of ordered domain engineering. The temperature coefficient of resonant frequency apparently reduced with increasing ordering degree (from 32.07 ppm/°C for disordered samples to 28.03 ppm/°C for samples with ordering degree of 0.886), while the thermal conductivity significantly increased (from 3.23 W m−1 K−1 to 3.72 W m−1 K−1) at room temperature. The increased thermal conductivity resulted from the reduced phonon scattering, while the improved temperature coefficient of resonant frequency was due to the increased bond covalency, which contributed to the decreased . The present results will provide an efficient way to improve the performance of microwave dielectric ceramics for resonator applications for 5G mobile communication system.
The influence of the processing parameters on the reactive flash sintering of ZrO2‐CeO2
Authors: Ingraci Neto Rubens Roberto , Kardoulaki Erofili , Valdez James Anthony
Published: February 2022

Reactive flash sintering (RFS) is a method that was recently developed to produce dense single‐phase bulk ceramic parts through solid‐state reactions in a single‐step that only takes a few minutes. The influence of the RFS parameters on the phase purity of a simple mixed oxide, (Zr0.8,Ce0.2)O2, was investigated. Parameters such as furnace temperature, furnace atmosphere, electric current density, and alternating current (AC) or direct current (DC) were examined. It was found that (Zr0.8,Ce0.2)O2 pellets with high densities, above 90% of its theoretical density, can be produced by RFS in a few minutes when RFS occurs under oxidizing atmospheres, AC fields with current densities of 100 mA·mm−2, and at a furnace temperature of 1200°C. Reducing conditions such as Ar‐H2 atmosphere and DC fields, low furnace temperatures, and low current densities resulted in phase impurities and poor reactions between the ZrO2 and the CeO2 powders. These results show that RFS is a useful method to produce mixed oxides, but it is very sensitive to the processing parameters. This is the first time that the influence of most of the RFS processing parameters has been studied systematically. Thus, the present work aims to provide guidelines on selecting the right processing parameters when exploring RFS.
‘Closer to the Market’: EU Research Governance and Symbolic Power
Authors: Gengnagel Vincent , Zimmermann Katharina , Büttner Sebastian M.
Published: February 2022

Adding to vital debates in EU Studies about the executive power of European governance, this article analyses the influence of EU research funding in the social sciences. The standardization and enforcement of norms, principles, and language codes, we argue, play a crucial role in EU governance. Applying a mixed‐method approach, we show that mastery of the ‘EU language game’ does more than help scholars obtain EU funding; it also generates individual and disciplinary frictions, since it requires a subtle re‐orientation of social‐scientific research towards political goals. Our study sheds light on strategies used by scientists who find themselves enmeshed in this language game, from euphoric adaptation to reluctant lip service. Since these academic strategies play out in the relative autonomy of liberal EU governance, the explicit focus on market integration is accompanied by a less explicit interest in matters of political representation and identity formation.