bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring a local genetic interaction network using evolutionary replay experiments
Authors: Vignogna Ryan C. , Buskirk Sean W. , Lang Gregory I.
Published: January 2021

Understanding how genes interact is a central challenge in biology. Experimental evolution provides a useful, but underutilized, tool for identifying genetic interactions, particularly those that involve non-loss-of-function mutations or mutations in essential genes. We previously identified a strong positive genetic interaction between specific mutations inKEL1(P344T) andHSL7(A695fs) that arose in an experimentally-evolvedSaccharomyces cerevisiaepopulation. Because this genetic interaction is not phenocopied by gene deletion, it was previously unknown. Using “evolutionary replay” experiments we identified additional mutations that have positive genetic interactions with thekel1-P344T mutation. We replayed the evolution of this population 672 times from six timepoints. We identified 30 populations where thekel1-P344T mutation reached high frequency. We performed whole-genome sequencing on these populations to identify genes in which mutations arose specifically in thekel1-P344T background. We reconstructed mutations in the ancestral andkel1-P344T backgrounds to validate positive genetic interactions. We identify several genetic interactors withKEL1, we validate these interactions by reconstruction experiments, and we show these interactions are not recapitulated by loss-of-function mutations. Our results demonstrate the power of experimental evolution to identify genetic interactions that are positive, allele specific, and not readily detected by other methods, and sheds light on a previously under-explored region of the yeast genetic interaction network.
Bidirectional, unlike unidirectional transport, allows transporting axonal cargos against their concentration gradient
Authors: Kuznetsov Ivan A. , Kuznetsov Andrey V.
Published: January 2021

Even though most axonal cargos are synthesized in the soma, the concentration of many of these cargos is larger at the presynaptic terminal than in the soma. This requires transport of these cargos from the soma to the presynaptic terminal or other active sites in the axon. Axons utilize both bidirectional (for example, slow axonal transport) and unidirectional (for example, fast anterograde axonal transport) modes of cargo transport. Bidirectional transport seems to be less efficient because it requires more time and takes more energy to deliver cargos. In this paper, we studied a family of models which differ by the modes of axonal cargo transport (such as anterograde and retrograde motor-driven transport and passive diffusion) as well as by the presence or absence of pausing states. The models are studied to investigate their ability to describe axonal transport against the cargo concentration gradient. We argue that bidirectional axonal transport is described by a higher-order mathematical model, which allows imposing cargo concentration not only at the axon hillock but also at the axon terminal. The unidirectional transport model allows only for the imposition of cargo concentration at the axon hillock. Due to the great lengths of the axons, anterograde transport mostly relies on molecular motors, such as kinesins, to deliver cargos synthesized in the soma to the terminal and other active sites in the axon. Retrograde transport can be also motor-driven, in which case cargos are transported by dynein motors. If cargo concentration at the axon tip is higher than at the axon hillock, retrograde transport can also occur by cargo diffusion. However, because many axonal cargos are large or they assemble in multiprotein complexes for axonal transport, the diffusivity of such cargos is very small. We investigated the case of a small cargo diffusivity using a perturbation technique and found that for this case the effect of diffusion is limited to a very thin diffusion boundary layer near the axon tip. If cargo diffusivity is decreased in the model, we show that without motor-driven retrograde transport the model is unable to describe a high cargo concentration at the axon tip. To the best of our knowledge, our paper presents the first explanation for the utilization of seemingly inefficient bidirectional transport in neurons.
Mechanism of activation and regulation of Deubiquitinase activity in MINDY1 and MINDY2
Authors: Rehman Syed Arif Abdul , Armstrong Lee A. , Lange Sven M. , Kristariyanto Yosua Adi , Grawert Tobias W. , Knebel Axel , Svergun Dmitri I. , Kulathu Yogesh
Published: January 2021

Of the eight distinct polyubiquitin chains that can be assembled, K48-linked ubiquitin is the most well-understood linkage and modification of proteins with K48 chains targets the modified protein for degradation. By removing ubiquitin from substrates or trimming ubiquitin chains, deubiquitinases (DUBs) can modulate the outcome of ubiquitylation. MINDY1 and MINDY2 are members of the MINDY family of DUBs that have exquisite specificity for cleaving K48-linked polyubiquitin. Being recently discovered DUBs, we have a poor understanding of their catalytic mechanism. By analysing crystal structures of MINDY1 alone and in complex with monoubiquitin or K48-linked ubiquitin chains, we here reveal how substrate interaction relieves autoinhibition and activates the DUB. Further, our analyses reveal a non-canonical catalytic triad composed of Cys-His-Thr and explain how these DUBs sense both ubiquitin chain length and linkage type to trim K48-linked ubiquitin chains. Our findings highlight the multiple layers of regulation modulating DUB activity in MINDY1 and MINDY2.

Synopsis

Structure of MINDY1 in complex with K48-linked diUb reveals how K48-linked polyUb is recognized and cleaved

The Cys loop mediates autoinhibition of the DUB and substrate binding at the S1 and S1’ sites relieves autoinhibition and activates the enzyme for catalysis

MINDY1 uses a non-canonical catalytic triad composed of Cys-His-Thr

MINDY1 has five ubiquitin binding sites within its catalytic domain and switches from exo to endo cleavage in a ubiquitin chain length-dependent manner
Activation of the vagal anti-inflammatory reflex by remote ischaemic conditioning in humans: experimental cross-over study
Authors: May Shaun M. , Chiang Eric , Reyes Anna , Martir Gladys , Patel Amour , Karmali Shamir , Patel Sanjiv , West Simeon , del Arroyo Ana Gutierrez , Gourine Alexander V. , Ackland Gareth L.
Published: January 2021

BACKGROUND

Non-invasive approaches in humans that may activate the vagal anti-inflammatory reflex are lacking. Neurons within the dorsal motor vagal nucleus (DMVN) activate both the vagal anti-inflammatory reflex (which regulates leukocyte trafficking by controlling neutrophil surface CD11b expression) and cardioprotection afforded by remote ischemic conditioning (RIC). We tested the hypothesis that RIC recruits vagal activity and activates the anti-inflammatory reflex in humans by reducing neutrophil (CD16+)CD11b expression.

METHODS

Participants (age:50±19 years; 53% female) underwent ultrasound-guided injection of local anaesthetic within the brachial plexus before applying 37×8 min cycles of brachial artery occlusion using a blood pressure cuff (RICblock). RIC was repeated 6 weeks later without brachial plexus block. Masked analysers quantified vagal activity (heart rate variability) before, and 10 minutes after, the last RIC cycle. The primary outcome was RR-interval, compared between RICblock and RIC. Secondary outcomes were time-domain, frequency-domain, and flow cytometric quantification of CD16+CD11b expression in whole blood (incubated with lipopolysaccharide (LPS) or saline) compared between RICblock and RIC.

RESULTS

RIC increased RR-interval (lowered heart rate) by 40ms (95% confidence intervals (95%CI):13-66; n=17; P=0.003). RR-interval did not change after RICblock (mean difference:20ms (95%CI:-11 to 50); P=0.19). High-frequency (vagal) modulation of heart rate was reduced after RICblock, but preserved after RIC (P<0.001). indicating RIC preserved vagal activity. LPS-induced CD16+CD11b+ expression was lower after RIC (3615 median fluorescence units (95%CI:475-6754); P=0.026), compared with 2331 units (95%CI:-3921 to 8582); P=0.726) after RICblock.

CONCLUSION

RIC recruits the vagal anti-inflammatory reflex, which requires intact afferent signalling from the peripheral tissue undergoing ischaemia/reperfusion to increase vagal tone and reduce neutrophil activation.

TRIAL REGISTRATION

researchregistry6482.
Oscillations support short latency co-firing of neurons during human episodic memory formation
Authors: Roux Frédéric , Parish George , Chelvarajah Ramesh , Rollings David T. , Sawlani Vijay , Hamer Hajo , Gollwitzer Stephanie , Kreiselmeyer Gernot , Wal Marije Ter , Kolibius Luca , Staresina Bernhard , Wimber Maria , Self Matthew W. , Hanslmayr Simon
Published: January 2021

Theta and gamma oscillations in the medial temporal lobe are suggested to play a critical role for human memory formation via establishing synchrony in neural assemblies. Arguably, such synchrony facilitates efficient information transfer between neurons and enhances synaptic plasticity, both of which benefit episodic memory formation. However, to date little evidence exists from humans that would provide direct evidence for such a specific role of theta and gamma oscillations for episodic memory formation. Here we investigate how oscillations shape the temporal structure of neural firing during memory formation in the medial temporal lobe. We measured neural firing and local field potentials in human epilepsy patients via micro-wire electrode recordings to analyze how brain oscillations promote co-incidences of firing between neurons during successful and unsuccessful encoding of episodic memories. The results show that phase-coupling of neurons to faster theta and gamma oscillations correlates with co-firing at short latencies (∼20-30 ms) and occurs during successful memory formation. Phase-coupling at slower oscillations in these same frequency bands, in contrast, correlates with longer co-firing latencies and occurs during memory failure. Thus, our findings provide evidence which implicate neural oscillations into the synchronization of neural firing in the medial temporal lobe during the encoding of episodic memories.
Comprehensive in situ mapping of human cortical transcriptomic cell types
Authors: Langseth Christoffer Mattsson , Gyllborg Daniel , Miller Jeremy A. , Close Jennie L. , Long Brian , Lein Ed S. , Hilscher Markus M. , Nilsson Mats
Published: January 2021

The ability to spatially resolve the cellular architecture of human cortical cell types over informative areas is essential to understanding brain function. We combined in situ sequencing gene expression data and single-nucleus RNA-sequencing cell type definitions to spatially map cells in sections of the human cortex via probabilistic cell typing. We mapped and classified a total of 59,816 cells into all 75 previously defined subtypes to create a first spatial atlas of human cortical cells in their native position, their abundances and genetic signatures.
DeepSVP: Integration of genotype and phenotype for structural variant prioritization using deep learning
Authors: Althagafi Azza , Alsubaie Lamia , Kathiresan Nagarajan , Mineta Katsuhiko , Aloraini Taghrid , Almutairi Fuad , Alfadhel Majid , Gojobori Takashi , Alfares Ahmad , Hoehndorf Robert
Published: January 2021

Motivation

Structural genomic variants account for much of human variability and are involved in several diseases. Structural variants are complex and may affect coding regions of multiple genes, or affect the functions of genomic regions in different ways from single nucleotide variants. Interpreting the phenotypic consequences of structural variants relies on information about gene functions, haploinsufficiency or triplosensitivity, and other genomic features. Phenotype-based methods to identifying variants that are involved in genetic diseases combine molecular features with prior knowledge about the phenotypic consequences of altering gene functions. While phenotype-based methods have been applied successfully to single nucleotide variants as well as short insertions and deletions, the complexity of structural variants makes it more challenging to link them to phenotypes. Furthermore, structural variants can affect a large number of coding regions, and phenotype information may not be available for all of them.

Results

We developed DeepSVP, a computational method to prioritize structural variants involved in genetic diseases by combining genomic and gene functions information. We incorporate phenotypes linked to genes, functions of gene products, gene expression in individual celltypes, and anatomical sites of expression, and systematically relate them to their phenotypic consequences through ontologies and machine learning. DeepSVP significantly improves the success rate of finding causative variants in several benchmarks and can identify novel pathogenic structural variants in consanguineous families.

Availability

https://github.com/bio-ontology-research-group/DeepSVP

Contact

robert.hoehndorf@kaust.edu.sa
In-frame deletion of SPECC1L microtubule binding domain results in embryonic tissue movement and fusion defects
Authors: Goering Jeremy P. , Wenger Luke W. , Stetsiv Marta , Moedritzer Michael , Hall Everett G. , Isai Dona Greta , Jack Brittany , Umar Zaid , Rickabaugh Madison K. , Czirok Andras , Saadi Irfan
Published: January 2021

Embryonic morphogenesis of the neural tube, palate, ventral body wall and optic fissure require precise sequence of tissue movement and fusion, which if incomplete, leads to anencephaly/exencephaly, cleft palate, omphalocele and coloboma, respectively. These are genetically heterogeneous birth defects, so there is a continued need to identify etiologic genes. Patients with autosomal dominantSPECC1Lmutations show syndromic malformations, including hypertelorism, cleft palate and omphalocele. TheseSPECC1Lmutations cluster in the second coiled-coil domain (CCD2), which facilitates association with microtubules. To study SPECC1L function in mice, we first generated a null allele (Specc1lΔEx4) lacking the entire SPECC1L protein. Homozygous mutants for these truncations died perinatally without cleft palate or exencephaly. Given the clustering of human mutations in CCD2, we hypothesized that targeted perturbation of CCD2 may be required. Indeed, homozygotes for in-frame deletions involving CCD2 (Specc1lΔCCD2) resulted in ~50% exencephaly and ~50% cleft palate. Interestingly, these two phenotypes are never observed in the same embryo. Examination of embryos with and without exencephaly revealed that the oral cavity was narrower in exencephalic embryos, which allowed palatal shelves to elevate despite their defect. In contrast to an evenly distributed subcellular expression pattern, mutant SPECC1L-ΔCCD2 protein showed abnormal subcellular localization, decreased overlap with microtubules, increased actin bundles, and dislocated non-muscle myosin II to the cell cortex. Thus, we show that perturbations of CCD2 in the context of full SPECC1L protein affects tissue fusion dynamics, indicating that humanSPECC1LCCD2 mutations are gain-of-function. Improper SPECC1L subcellular localization appears to disrupt connections between actomyosin and microtubule networks, which in turn may affect cell alignment and coordinate movement during tissue morphogenesis.
Use of continuous sample translation to reduce radiation damage for XPCS studies of protein diffusion
Authors: Lurio Laurence B. , Thurston George M. , Zhang Qingteng , Narayanan Suresh , Dufresne Eric M.
Published: January 2021

An experimental setup to measure X-ray photon correlation spectroscopy during continuous sample translation is presented and its effectiveness as a means to avoid sample damage in dynamics studies of protein diffusion is evaluated. X-ray damage from focused coherent synchrotron radiation remains below tolerable levels as long as the sample is translated through the beam sufficiently quickly. Here it is shown that it is possible to separate sample dynamics from the effects associated with the transit of the sample through the beam. By varying the sample translation rate, the damage threshold level, D
thresh = 1.8 kGy, for when beam damage begins to modify the dynamics under the conditions used, is also determined. Signal-to-noise ratios, R
sn ≥ 20, are obtained down to the shortest delay times of 20 µs. The applicability of this method of data collection to the next generation of multi-bend achromat synchrotron sources is discussed and it is shown that sub-microsecond dynamics should be obtainable on protein samples.
NMR spectroscopy in wine authentication: An official control perspective
Authors: Solovyev Pavel A. , Fauhl‐Hassek Carsten , Riedl Janet , Esslinger Susanne , Bontempo Luana , Camin Federica
Published: January 2021

Wine authentication is vital in identifying malpractice and fraud, and various physical and chemical analytical techniques have been employed for this purpose. Besides wet chemistry, these include chromatography, isotopic ratio mass spectrometry, optical spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy, which have been applied in recent years in combination with chemometric approaches. For many years, 2H NMR spectroscopy was the method of choice and achieved official recognition in the detection of sugar addition to grape products. Recently, 1H NMR spectroscopy, a simpler and faster method (in terms of sample preparation), has gathered more and more attention in wine analysis, even if it still lacks official recognition. This technique makes targeted quantitative determination of wine ingredients and nontargeted detection of the metabolomic fingerprint of a wine sample possible. This review summarizes the possibilities and limitations of 1H NMR spectroscopy in analytical wine authentication, by reviewing its applications as reported in the literature. Examples of commercial and open‐source solutions combining NMR spectroscopy and chemometrics are also examined herein, together with its opportunities of becoming an official method.
Histamine accumulation in dairy products: Microbial causes, techniques for the detection of histamine‐producing microbiota, and potential solutions
Authors: Moniente Marta , García‐Gonzalo Diego , Ontañón Ignacio , Pagán Rafael , Botello‐Morte Laura
Published: January 2021

Histamine poisoning is a significant public health and safety concern. Intoxication from ingestion of food containing high amounts of histamine may cause mild or severe symptoms that can even culminate in cardiac arrest. Nonetheless, although histamine levels in dairy products are not subject to any regulation, important outbreaks and severe adverse health effects have been reported due to intake of dairy products with a high histamine content, especially ripened cheeses. Histamine, a biogenic amine, can accumulate in dairy products as a result of the metabolism of starter and nonstarter lactic acid bacteria, as well as yeasts that contribute to the ripening or flavoring of the final product, or even as a result of spoilage bacteria. The aim of this review is to describe the microbiological causes of the presence of histamine in fermented milk products, and to propose control measures and potential methods for obtaining histamine‐free dairy products. Thus, this manuscript focuses on histamine‐producing microbiota in dairy products, highlighting the detection of histamine‐producing bacteria through traditional and novel techniques. In addition, this review aims to explore control measures to prevent the access of histamine‐producing microbiota to raw materials, as well as the formation of histamine in dairy products, such as a careful selection of starter cultures lacking the ability to produce histamine, or even the implementation of effective food processing technologies to reduce histamine‐producing microbiota. Finally, the removal of histamine already formed in dairy products through histamine‐degrading microorganisms or by enzymatic degradation will also be explored.
A review of microbes and chemical contaminants in dairy products in sub‐Saharan Africa
Authors: Akinyemi Muiz O. , Ayeni Kolawole I. , Ogunremi Omotade R. , Adeleke Rasheed A. , Oguntoyinbo Folarin A. , Warth Benedikt , Ezekiel Chibundu N.
Published: January 2021

Animal milk types in sub‐Saharan Africa (SSA) are processed into varieties of products using different traditional methods and are widely consumed by households to support nutritional intake and diet. Dairy products contain several microorganisms, their metabolites, and other chemical compounds, some with health benefits and many others considered as potential health hazards. Consumption of contaminated milk products could have serious health implications for consumers. To access the safety of milk products across SSA, studies in the region investigating the occurrences of pathogens as well as chemical compounds such as heat stable toxins and veterinary drug residues in animal milk and its products were reviewed. This is done with a holistic view in light of the emerging exposome paradigm for improving food safety and consumer health in the region. Herein, we showed that several published studies in SSA applied conventional and/or less sensitive methods in detecting microbial species and chemical contaminants. This has serious implications in food safety because the correct identity of a microbial species and accurate screening for chemical contaminants is crucial for predicting the potential human health effects that undermine the benefits from consumption of these foods. Furthermore, we highlighted gaps in determining the extent of viral and parasitic contamination of milk products across SSA as well as investigating multiple classes of chemical contaminants. Consequently, robust studies should be conducted in this regard. Also, efforts such as development cooperation projects should be initiated by all stakeholders including scientists, regulatory agencies, and policy makers to improve the dairy product chain in SSA in view of safeguarding consumer health.
Molidustat for anemia correction in Japanese patients undergoing hemodialysis: a single‐arm, phase 3 study
Authors: Akizawa Tadao , Nobori Kiyoshi , Matsuda Yoshimi , Hayashi Yasuhiro , Hayasaki Takanori , Yamamoto Hiroyasu
Published: January 2021

Molidustat, an orally administered hypoxia‐inducible factor prolyl‐hydroxylase inhibitor, is under development for the treatment of anemia of CKD. This 24‐week, phase 3, single‐arm, multicenter study evaluated the efficacy and safety of molidustat in Japanese patients with renal anemia who were undergoing hemodialysis and who were not receiving an erythropoiesis‐stimulating agent. Twenty‐five patients received molidustat at a starting dose of 75 mg once daily, which was adjusted to maintain a Hb target of ≥10.0 to <12.0 g/dL. The mean rates of Hb increase from baseline and week 0 to the first dose change up to week 8 were −0.030 and 0.080 g/dL/week, respectively. By week 24, 89% of patients had a Hb level within target range. No adverse events of special interest were reported. Treatment with dose‐titrated molidustat for 24 weeks was well tolerated in Japanese patients undergoing hemodialysis, and no new safety signal was observed. Clinicaltrials.gov identifier: NCT03351166.
Social media in interventional radiology
Authors: Wang Michael T. , Foo Michelle , Maingard Julian , Kok Hong Kuan , Lamanna Anthony , Jhamb Ashu , Brooks Mark , Asadi Hamed
Published: January 2021

Introduction

Social media provides opportunities for Interventional Radiologists to share research, communicate with colleagues, provide health information and advertise their clinical practice. This study aims to examine the online and social media presence of currently practicing Australian Interventional Radiologists.

Methods

Systematic Google searches were undertaken in May 2019 and updated in May 2020 to identify practicing Interventional Radiologists in Australia. Comprehensive searches of practice websites and social media platforms (Facebook, LinkedIn, Twitter, ResearchGate, YouTube) were undertaken for each Interventional Radiologist.

Results

There were 265 Interventional Radiologists identified as currently practising in Australia, including 209 Interventional Radiologists (excluding Interventional Neuroradiologists), 49 Interventional Neuroradiologists and 7 that practise across both Interventional Radiology and Interventional Neuroradiology. 72% of Interventional Radiologists had at least one social media account, with LinkedIn the most widely used social media platform (60%). There was a significant negative correlation between the total number of social media accounts and years in practice (P = 0.04). Across the states, a higher population per IR was positively correlated with a higher average number of social media accounts per IR (P = 0.04). Interventional Neuroradiologists had a significantly higher average number of social media accounts compared to Interventional Radiologists (1.94 vs 1.29, P < 0.01).

Conclusions

Most Australian Interventional Radiologists have a readily identifiable social media presence. There is potential for further utilisation of social media for academic, educational and business purposes.
ALKrearrangements as mechanisms of acquired resistance to osimertinib inEGFRmutant non‐small cell lung cancer
Authors: Hou Helei , Sun Dantong , Zhang Chuantao , Liu Dong , Zhang Xiaochun
Published: January 2021

Non‐small cell lung cancer (NSCLC) patients harboringEGFRsensitive mutations may benefit from treatment with EGFR TKIs. Osimertinib, which is an irreversible third‐generation EGFR TKI, has demonstrated a convincing efficacy, irrespective of whether it is used in first‐ or second‐line treatment. The acquired resistance mechanisms to osimertinib are highly complicated, and a variety of potential molecular mechanisms have been discovered, including C797S. Here, we determined thatALKrearrangement might be an underlying mechanism contributing to acquired resistance to osimertinib. In our report, a 60‐year‐old female patient with lung adenocarcinoma with anEGFRmutation was administered multiple treatments, including first‐line gefitinib and second‐line osimertinib. According to the next‐generation sequencing (NGS) assay after osimertinib failure, the emergence of anALKrearrangement was considered to be a potentially acquired resistance mechanism to osimertinib. The combination of osimertinib and crizotinib then maintained a six‐month stable disease.VEGFAamplification was identified after osimertinib plus crizotinib treatment, and chemotherapy plus bevacizumab achieved a continuous stable disease over 21 months. In this study, we also summarized previously reported cases and concluded thatALKrearrangement is a rare but critical resistance mechanism to osimertinib. After failure of combined treatment with osimertinib plus crizotinib, comprehensive molecular profiling should be performed, and chemotherapy plus bevacizumab might be an optimal treatment especially for patients harboringVEGFAamplification.
Pharmacokinetics and safety of pegylated recombinant human granulocyte colony‐stimulating factor in children with acute leukaemia
Authors: Liu Xi‐Ting , Zhao Yan‐Xia , Jia Guang‐Wei , Yang Fan , Zhang Chuan‐Zhou , Han Bing , Dai Jian‐Hua , Han Yue‐Qin , Tang Bo‐Hao , Yang Xin‐Mei , Shi Hai‐Yan , Zhou Yue , Sui Zhong‐Guo , Chen Jian‐Zhong , van den Anker Johannes N. , Zhao Wei
Published: January 2021

Aims

This open‐label, phase I study evaluated the pharmacokinetics and safety of pegylated recombinant human granulocyte colony‐stimulating factor (PEG‐rhG‐CSF) for the treatment of chemotherapy‐induced neutropenia in children with acute leukaemia.

Methods

PEG‐rhG‐CSF was administered as a single 100 mcg/kg (3 mg maximum dose) subcutaneous injection at the end of each chemotherapy period when neutropenia occurred. Blood samples were obtained from patients treated with PEG‐rhG‐CSF. PEG‐rhG‐CSF serum concentrations were determined by an enzyme‐linked immunosorbent assay. Population pharmacokinetic (PPK) analysis was implemented using the nonlinear mixed‐effects model. Short‐term safety was evaluated through adverse events collection (registered at clinicaltrials.gov identifier: 03844360).

Results

A total of 16 acute leukaemia patients (1.8–13.6 years) were included, of whom two (12.5%) had grade 3 neutropenia, six (37.5%) had grade 4 neutropenia, and eight (50.0%) had severe neutropenia. For PPK modelling, 64 PEG‐rhG‐CSF serum concentrations were obtainable. A one‐compartment model with first‐order elimination was used for pharmacokinetic data modelling. The current weight was a significant covariate. The median (range) of clearance (CL) and area under the serum concentration–time curve (AUC) were 5.65 (1.49–14.45) mL/h/kg and 16514.75 (6632.45–54423.30) ng·h/mL, respectively. Bone pain, pyrexia, anaphylaxis and nephrotoxicity were not observed. One patient died 13 days after administration, and the objective assessment of causality was that an association with PEG‐rhG‐CSF was “possible”.

Conclusions

The AUC of PEG‐rhG‐CSF (100 mcg/kg, 3 mg maximum dose) in paediatric patients with acute leukaemia were similar to those of PEG‐rhG‐CSF (100 mcg/kg) in children with sarcoma. PEG‐rhG‐CSF is safe, representing an important therapeutic option for chemotherapy‐induced neutropenia in paediatric patients with acute leukaemia.
No association between use of angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers prior to hospital admission and clinical course of COVID‐19 in the COvid MEdicaTion (COMET) study
Authors: Sablerolles Roos S. G. , Hogenhuis Freija E. F. , Lafeber Melvin , van de Loo Bob P. A. , Borgsteede Sander D. , Boersma Eric , Versmissen Jorie , van der Kuy Hugo ,   COMET Research Team
Published: January 2021

Since the outbreak of SARS‐CoV‐2, also known as COVID‐19, conflicting theories have circulated on the influence of angiotensin‐converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) on incidence and clinical course of COVID‐19, but data are scarce. The COvid MEdicaTion (COMET) study is an observational, multinational study that focused on the clinical course of COVID‐19 (i.e. hospital mortality and intensive care unit [ICU] admission), and included COVID‐19 patients who were registered at the emergency department or admitted to clinical wards of 63 participating hospitals. Pharmacists, clinical pharmacologists or treating physicians collected data on medication prescribed prior to admission. The association between the medication and composite clinical endpoint, including mortality and ICU admission, was analysed by multivariable logistic regression models to adjust for potential confounders. A total of 4870 patients were enrolled. ACEi were used by 847 (17.4%) patients and ARB by 761 (15.6%) patients. No significant association was seen with ACEi and the composite endpoint (adjusted odds ratio [OR] 0.94; 95% confidence interval [CI] 0.79 to 1.12), mortality (OR 1.03; 95%CI 0.84 to 1.27) or ICU admission (OR 0.96; 95%CI 0.78 to 1.19) after adjustment for covariates. Similarly, no association was observed between ARB and the composite endpoint (OR 1.09; 95%CI 0.90 to 1.30), mortality (OR 1.12; OR 0.90 to 1.39) or ICU admission (OR 1.21; 95%CI 0.98 to 1.49). In conclusion, we found no evidence of a harmful or beneficial effect of ACEi or ARB use prior to hospital admission on ICU admission or hospital mortality.
Change in the regulatory framework for zolpidem: What is the impact on the landscape of the prescription of sedative medications? The French national ZORRO study
Authors: Istvan Marion , Caillet Pascal , Rousselet Morgane , Guerlais Marylène , Laforgue Edouard‐Jules , Gérardin Marie , Jolliet Pascale , Feuillet Fanny , Victorri‐Vigneau Caroline
Published: January 2021

Aims

In recent years, zolpidem has been the subject of numerous reports of misuse, abuse and dependence. In view of these risks, the French drug agency (ANSM) decreed in April 2017 the implementation of secure prescription pads. The objective of this study was to evaluate the impact of this regulatory measure on the prescription of zolpidem and other sedative medications (zopiclone, benzodiazepines and antihistamines) in long‐term users of zolpidem and associated factors.

Methods

We performed a historical cohort study using data from the Generalist Sample of Beneficiaries (EGB). All patients aged over 18 years old who were long‐term users (at least 3 months) before the measure were enacted. We analysed the reimbursement trajectories of zolpidem, zopiclone, benzodiazepines and antihistamines (hydroxyzine and alimemazine) up to 2 years after the measure using a state sequence analysis.

Results

Overall, 2502 patients were analysed. A four‐cluster typology was identified: continuation of zolpidem (n = 1044, 42%), discontinuation of sedative medications (n = 766, 31%), change to zopiclone (n = 537, 21%) and change to hypnotic benzodiazepines (n = 155, 6%). The most frequently prescribed hypnotic benzodiazepine was lormetazepam. We identified age, sex, treatment for psychiatric or addictive disorder and volume of zolpidem use before the measure as factors associated with different reimbursement trajectories after the regulatory change.

Conclusion

The regulatory change for zolpidem prescriptions reduced exposure to zolpidem among long‐term users and also had a broad impact on prescriptions of other sedative medications. Switching to other medications that also present a potential risk of abuse or dependence should be carefully monitored.
Capmatinib in Japanese patients with MET exon 14 skipping–mutated or MET‐amplified advanced NSCLC: GEOMETRY mono‐1 study
Authors: Seto Takashi , Ohashi Kadoaki , Sugawara Shunichi , Nishio Makoto , Takeda Masayuki , Aoe Keisuke , Moizumi Sanae , Nomura Satoshi , Tajima Takeshi , Hida Toyoaki
Published: January 2021

MET mutations leading to exon 14 skipping (METΔex14) are strong molecular drivers for non–small‐cell lung cancer (NSCLC). Capmatinib is a highly potent, selective oral MET inhibitor that showed clinically meaningful efficacy and a manageable safety profile in a global phase II study (GEOMETRY mono‐1, NCT02414139) in patients with advanced METΔex14‐mutated/MET‐amplified NSCLC. We report results of preplanned analyses of 45 Japanese patients according to MET status (METΔex14‐mutated or MET‐amplified) and line of therapy (first‐ [1L] or second‐/third‐line [2/3L]). The starting dose was 400 mg twice daily. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee. A key secondary endpoint was duration of response (DOR). Among METΔex14‐mutated patients, in the 1L group, one patient achieved partial response (DOR of 4.24 months) and the other had stable disease. In the 2/3L group, the ORR was 36.4% (95% confidence interval [CI] 10.9%‐69.2%), median DOR was not evaluable, and progression‐free survival was 4.70 months. One patient (2/3L group) showed partial resolution of brain lesions per independent neuroradiologist review. In MET‐amplified patients with a MET gene copy number of ≥10, the ORR was 100% (2/2 patients) in the 1L group and 45.5% (5/11 patients) in the 2/3L group, with DOR of 8.2 and 8.3 months, respectively. Common treatment‐related adverse events among the 45 Japanese patients were blood creatinine increased (53.3%), nausea (35.6%), and oedema peripheral (31.1%); most were grade 1/2 severity. In conclusion, capmatinib was effective and well tolerated by Japanese patients with METΔex14/MET‐amplified NSCLC, consistent with the overall population.
NAFLD exacerbates cholangitis and promotes cholangiocellular carcinoma in mice
Authors: Maeda Shin , Hikiba Yohko , Fujiwara Hiroaki , Ikenoue Tsuneo , Sue Soichiro , Sugimori Makoto , Matsubayashi Mao , Kaneko Hiroaki , Irie Kuniyasu , Sasaki Tomohiko , Chuma Makoto
Published: January 2021

Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition, affecting up to 25% of the population worldwide. NAFLD has been linked to several conditions, including hepatic inflammation, fibrosis, and hepatocellular carcinoma (HCC), however the role of NAFLD in cholangitis and the development of cholangiocellular carcinoma (CCC) remains poorly understood. This study investigated whether a high‐fat diet (HFD) promotes cholangitis and the development of CCC in mice. We used liver‐specific E‐cadherin gene (CDH1) knockout mice, CDH1∆Liv, which develop spontaneous inflammation in the portal areas along with periductal onion skin‐like fibrosis, similar to that of primary sclerosing cholangitis (PSC). An HFD or normal diet (ND) was fed to CDH1∆Liv mice for 7 mo. In addition, CDH1∆Liv mice were crossed with LSL‐KrasG12D mice, fed an HFD, and assessed in terms of liver tumor development. The extent of cholangitis and number of bile ductules significantly increased in mice fed an HFD compared with ND‐administered CDH1∆Liv mice. The numbers of Sox9 and CD44‐positive stem cell‐like cells were significantly increased in HFD mice. LSL‐KrasG12D /CDH1∆Liv HFD mice exhibited increased aggressiveness along with the development of numerous HCC and CCC, whereas LSL‐KrasG12D/CDH1∆Liv ND mice showed several macroscopic tumors with both HCC and CCC components. In conclusion, NAFLD exacerbates cholangitis and promotes the development of both HCC and CCC in mice.
Skraban‐Deardorff syndrome: Six new cases of WDR26‐related disease and expansion of the clinical phenotype
Authors: Cospain Auriane , Schaefer Elise , Faoucher Marie , Dubourg Christèle , Carré Wilfrid , Bizaoui Varoona , Assoumani Jessica , Van Maldergem Lionel , Piton Amélie , Gérard Bénédicte , Tran Mau‐Them Frédéric , Bruel Ange‐Line , Faivre Laurence , Demurger Florence , Pasquier Laurent , Odent Sylvie , Fradin Mélanie , Lavillaureix Alinoë
Published: January 2021

Skraban‐Deardorff syndrome (a disease related to variations in the WDR26 gene; OMIM #617616) was first described in a cohort of 15 individuals in 2017. The syndrome comprises intellectual deficiency, severe speech impairment, ataxic gait, seizures, mild hypotonia with feeding difficulties during infancy, and dysmorphic features. Here, we report on six novel heterozygous de novo pathogenic variants in WDR26 in six probands. The patients' phenotypes were consistent with original publication. One patient displayed marked hypotonia with an abnormal muscle biopsy; this finding warrants further investigation. Gait must be closely monitored, in order to highlight any musculoskeletal or neurological abnormalities and prompt further examinations. Speech therapy and alternative communication methods should be initiated early in the clinical follow‐up, in order to improve language and oral eating and drinking.
Child protection policy: Understanding drivers of violence affecting children in Côte d’Ivoire
Authors: Ballet Jérôme , Konaté Francis , Kouamé Séverin Yao , Maternowska Catherine , Olié Louis
Published: January 2021

Motivation

Since the campaign launched by UNICEF in 2013, the momentum for measuring violence has grown significantly. Such studies generally measure risk and protective factors at the individual and interpersonal levels, but often overlook the critical institutional and structural drivers of violence.

Purpose

This article demonstrates how socioeconomic transformations, including “modern” forms of violence fuelled by social fragmentation, armed conflict and urbanization, are important conditions favouring violence against children.

Approach and methods

The article offers a systematic literature review following protocols in the original Multi‐Country Study on the Drivers of Violence Affecting Children, an approach first proposed by the UNICEF Office of Research ‐ Innocenti.

Findings

We underline two main changes among the drivers of violence in Côte d’Ivoire: economic crisis and urbanization, which combine to foster a climate of violence; and politico‐military crisis, which also creates a fertile ground for violence and its acceptance.

Policy implications

Child protection policy in Côte d’Ivoire is out of step with the evolution of the social context. It is mainly oriented towards “traditional” practices, which contrast with newer forms of violence developed over the past 30 years. The article shows that the country’s child protection policy does not take these changes sufficiently into account, and argues for policy change.
Predicting socio‐economic and biodiversity impacts of invasive species: Red Imported Fire Ant in the developing western Pacific
Authors: Gruber Monica A. M. , Janssen‐May Sharon , Santoro Davide , Cooling Meghan , Wylie Ross
Published: January 2021

Effective biosecurity and pest management are fundamental to sustainable development. Invasive ants pose significant risks to the environment and economy, which are well‐managed by biosecurity agencies in developed countries. However, a comprehensive view of the potential impacts of invasive ants in developing Pacific Island Countries and Territories (PICTs) is lacking. We quantified the potential costs of the Red Imported Fire Ant (Solenopsis invicta Buren) across multiple sectors using an extrapolation analysis. Overall, we estimated that the impacts of Red Imported Fire Ant on developing PICTs could amount to over USD 329 million annually, corresponding to approximately 0.7% of combined GDP. Over half of the costs were predicted to result from impacts on the agriculture sector, a major source of employment and subsistence. We found that over 350 highly threatened species could be at risk from Red Imported Fire Ant. We would expect countries with Least Developed Country status and relatively low GDP to be least able to respond to an incursion of these ants, and as a result the costs could be higher than we have extrapolated. Red Imported Fire Ant could therefore potentially have considerable impact on the on‐going development of the region.
Association between external female genital mutilation and securing paternity in a spider
Authors: Nakata Kensuke
Published: January 2021

Males sometimes injure their partner physically or physiologically during mating. While harmful mating is assumed to incur fitness costs, it is thought to confer increased paternity for males; this advantage may have driven the evolution of harmful mating. To date, two spider species are known to exhibit external female genital mutilation (EFGM), in which males remove a scape, a small projection on female's external genitalia, to secure their paternity. This study investigated whether a similar phenomenon occurs in Cyclosa ginnaga to assess whether EFGM is commonly associated with paternity securing in spiders. Two consecutive staged mating using a unmated female and two males was conducted and female genitalia was inspected after mating. Results showed that while EFGM occurred among C. ginnaga, the mutilation rate was less than half that of the two previously studied species. Mated females, irrespective of whether they experienced mutilation, attacked the second males that courted them. Consequently, most mating trials ended without successful copulation due to the retreat of the second male, and EFGM was seldom responsible for the failure of the second mating. These results do not support the hypothesis that EFGM evolved because it secured paternity for mutilator males.
Evolution of a public sector audit office: Evidence from the Republic of Fiji
Authors: Nath Nirmala , Van Peursem Karen A. , Lowe Alan
Published: January 2021

The Office of the Auditor General, Republic of Fiji was founded in 1970 on audit principles and national laws inspired by its former British colonial power. The Fijian Office operates in a challenging national context of coup‐determined regimes, military authority and ethnically‐dividing social practices. The purpose of this study is to uncover the processes and dynamics that explain how this Office remains a stable institution despite its challenging environment. We seek to understand how members of Fiji's Office of the Auditor General comprehend their role, find meaning in their actions and negotiate their authority in the context of powerful others. Our approach is qualitative and employs data from 28 interviews conducted over 12 years and historical documents. Our findings take into account wider social processes and reveal that through shared commitment and international associationism the Office of the Auditor General comes to absorb the norms and values of its westernised professional organizations. The contribution of the study is in revealing how external professional bodies and an empowered internal rationale can construct an institutional discourse that offers the potential for social stability even where local resistance is strong.
Social capital and the business models of financial cooperatives: Evidence from Japanese Shinkin banks
Authors: Chronopoulos Dimitris K. , Sobiech Anna L. , Wilson John O. S.
Published: January 2021

We investigate the link between social capital and business model choice of financial cooperatives (Shinkin banks) in Japan. We identify two forms of business model, which concentrate on the issuance of loans funded by deposits (traditional) and the investment and management of large investment portfolios (new).Traditionalbusiness models are more likely to emerge in geographic areas with higher levels of social capital. These findings are robust after controlling for bank‐ and prefecture‐level characteristics (such as unemployment, population and income) that may influence bank business model choice. We repeat our analysis for a sample of shareholder‐oriented (regional) banks, but fail to establish any relationship between social capital and this organisational form. Overall, our findings suggest that financial cooperatives in high‐social‐capital areas are more likely to adhere to a traditional model of financial intermediation focused on lending which promotes community and economic development.