bluuebunny/crossref_metadata_2025 huggingface dataset:
EDESIA: Plants, Food and Health: A cross‐disciplinary PhD programme from crop to clinic
Authors: Clark Ian M. , Cassidy Aedin , Heppleston Audrey , Bal Mark , Morgan Yvie , Nicklin Alicia , Yue Yang , Zardkoohi Aryana , Martin Cathie
Published: June 2022

In an era where preventive medicine is increasingly important due to an ageing population and rising obesity, optimised diets are key to improving health and reducing risk of ill health. The Wellcome Trust‐funded, EDESIA: Plants, Food and Health: a cross‐disciplinary PhD programme from Crop to Clinic (218 467/Z/19/Z) focuses on investigating plant‐based nutrition and health, from crop to clinic, drawing on the world‐class interdisciplinary research expertise of partner institutions based on the Norwich Research Park (University of East Anglia, John Innes Centre, Quadram Institute and Earlham Institute). Through a rotation‐based programme, EDESIA PhD students will train in a wide range of disciplines across the translational pathway of nutrition research, including analyses of epidemiological datasets, assessment of nutritional bioactives, biochemical, genetic, cell biological and functional analyses of plant metabolites, in vitro analyses in tissue and cell cultures, investigation of efficacy in animal models of disease, investigation of effects on composition and functioning of the microbiota and human intervention studies. Research rotations add a breadth of knowledge, outside of the main PhD project, which benefits the students and can be brought into project design. This comprehensive PhD training programme will allow the translation of science into guidelines for healthy eating and the production of nutritionally improved food crops, leading to innovative food products, particularly for prevention and treatment of chronic diseases where age is a major risk factor. In this article, we summarise the programme and showcase the experiences of the first cohort of students as they start their substantive PhD projects after a year of research rotations.
Early ultrastructural lesions of anti‐neutrophil cytoplasmic antibody‐ versus complement‐associated vasculitis
Authors: Koike Haruki , Furukawa Soma , Mouri Naohiro , Fukami Yuki , Iijima Masahiro , Katsuno Masahisa
Published: June 2022

This study aims to describe electron microscopic findings of vasculitis associated with anti‐neutrophil cytoplasmic antibody (ANCA) and complement. Sural nerve biopsy specimens were obtained from 10 patients with microscopic polyangiitis (MPA), a representative ANCA‐associated vasculitis, and six patients with nonsystemic vasculitic neuropathy (NSVN), who were negative for ANCA but positive for complement deposition. In patients with MPA, attachment of neutrophils to epineurial vascular endothelial cells, migration of neutrophils to the extravascular space via the penetration of the endothelial layer, and release of neutrophil components to the extracellular space were observed. Such neutrophil‐associated lesions were not observed in patients with NSVN. Nonetheless, morphological changes in epineurial vascular endothelial cells, such as increases in cytoplasmic organelles and cytoplasmic protrusions into the vascular lumen, were observed in patients with NSVN. Since these findings were observed where light microscopy‐based findings suggestive of vasculitis (e.g., the disruption of vascular structures and fibrinoid necrosis) were absent, they were considered early lesions that preceded the formation of the so‐called necrotizing vasculitis. In conclusion, this study enabled the visualization of distinctive early ultrastructural lesions associated with ANCA and complement. Further studies are needed to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of vasculitis.
The consequences of climate change for dryland biogeochemistry
Authors: Osborne Brooke B. , Bestelmeyer Brandon T. , Currier Courtney M. , Homyak Peter M. , Throop Heather L. , Young Kristina , Reed Sasha C.
Published: June 2022

Drylands, which cover > 40% of Earth's terrestrial surface, are dominant drivers of global biogeochemical cycling and home to more than one third of the global human population. Climate projections predict warming, drought frequency and severity, and evaporative demand will increase in drylands at faster rates than global means. As a consequence of extreme temperatures and high biological dependency on limited water availability, drylands are predicted to be exceptionally sensitive to climate change and, indeed, significant climate impacts are already being observed. However, our understanding and ability to forecast climate change effects on dryland biogeochemistry and ecosystem functions lag behind many mesic systems. To improve our capacity to forecast ecosystem change, we propose focusing on the controls and consequences of two key characteristics affecting dryland biogeochemistry: (1) high spatial and temporal heterogeneity in environmental conditions and (2) generalized resource scarcity. In addition to climate change, drylands are experiencing accelerating land‐use change. Building our understanding of dryland biogeochemistry in both intact and disturbed systems will better equip us to address the interacting effects of climate change and landscape degradation. Responding to these challenges will require a diverse, globally distributed and interdisciplinary community of dryland experts united towards better understanding these vast and important ecosystems.
Loss of pod strings in common bean is associated with gene duplication, retrotransposon insertion and overexpression of PvIND
Authors: Parker Travis A. , Cetz Jose , de Sousa Lorenna Lopes , Kuzay Saarah , Lo Sassoum , Floriani Talissa de Oliveira , Njau Serah , Arunga Esther , Duitama Jorge , Jernstedt Judy , Myers James R. , Llaca Victor , Herrera‐Estrella Alfredo , Gepts Paul
Published: June 2022

Fruit development has been central in the evolution and domestication of flowering plants. In common bean (Phaseolus vulgaris), the principal global grain legume staple, two main production categories are distinguished by fibre deposition in pods: dry beans, with fibrous, stringy pods; and stringless snap/green beans, with reduced fibre deposition, which frequently revert to the ancestral stringy state. Here, we identify genetic and developmental patterns associated with pod fibre deposition.

Transcriptional, anatomical, epigenetic and genetic regulation of pod strings were explored through RNA‐seq, RT‐qPCR, fluorescence microscopy, bisulfite sequencing and whole‐genome sequencing.

Overexpression of the INDEHISCENT (‘PvIND’) orthologue was observed in stringless types compared with isogenic stringy lines, associated with overspecification of weak dehiscence‐zone cells throughout the pod vascular sheath. No differences in DNA methylation were correlated with this phenotype. Nonstringy varieties showed a tandemly direct duplicated PvIND and a Ty1‐copia retrotransposon inserted between the two repeats. These sequence features are lost during pod reversion and are predictive of pod phenotype in diverse materials, supporting their role in PvIND overexpression and reversible string phenotype.

Our results give insight into reversible gain‐of‐function mutations and possible genetic solutions to the reversion problem, of considerable economic value for green bean production.
DKK3/CKAP4 axis is associated with advanced stage and poorer prognosis in oral cancer
Authors: Katase Naoki , Kudo Kodai , Ogawa Kazuhiro , Sakamoto Yae , Nishimatsu Shin‐ichiro , Yamauchi Akira , Fujita Shuichi
Published: June 2022

Objective

We previously reported that dickkopf WNT signaling inhibitor 3 (DKK3) would modulate malignant potential of oral squamous cell carcinoma (OSCC) via activating Akt. Recently, cytoskeleton associated protein 4 (CKAP4) functions as receptor of DKK3, which activates Akt in esophageal squamous cell carcinoma, but its expression and function in OSCC were unclear.

Methods

We studied DKK3 and CKAP4 protein expression in OSCC tissue and investigated the correlation between protein expression and clinical data. We also investigated whether antibodies (Ab) for DKK3 or CKAP4 could suppress malignant potential of the cancer cells.

Results

DKK3/CKAP4 protein expression was observed in majority of OSCC cases and was associated with significantly higher T‐stage and TNM stage. Multivariate analysis revealed that DKK3 and CKAP4 were independent prognostic biomarkers for overall survival (OS) and disease‐free survival (DFS), respectively. Survival analyses revealed that DKK3‐positive cases and CKAP4‐positive cases showed significantly shorter OS and DFS, respectively, and that DKK3/CKAP4 double‐negative cases showed significantly favorable prognosis. Both anti‐DKK3Ab and anti‐CKAP4Ab could suppress cancer cell proliferation, migration, and invasion.

Conclusion

DKK3/CKAP4 axis is thought to be important in OSCC, and it would be a promising therapeutic target.
Biomechanical Study of Intramedullary Versus Extramedullary Implants for Four Types of Subtrochanteric Femoral Fracture
Authors: Wang Jie , Jia Haobo , Ma Xinlong , Ma Jianxiong , Lu Bin , Bai Haohao , Wang Ying
Published: June 2022

Objectives

To compare the biomechanical performance of proximal femoral nail anti‐rotation (PFNA), the “upside‐down” less invasive plating system (LISS), and proximal femoral locking plate (PFLP) in fixing different fracture models of subtrochanteric fractures.

Methods

Thirty composite femurs were divided into three equal groups (PFNA, PFLP, and reverse LISS). The implant‐femur constructs were tested under axial compression load (0–1400 N) from models I to IV, which represented the Seinsheimer type I subtrochanteric fracture, type IIIa subtrochanteric fracture with the posteromedial fragment reduced; type IIIa subtrochanteric fracture with the posteromedial fragment lost; and type IV subtrochanteric fracture, respectively. Axial stiffness was analyzed for each group. Each group was then divided into two subgroups, one of which underwent torsional and axial compression failure testing, while the other subgroup underwent axial compression fatigue testing. The torsional stiffness, failure load, and cycles to failure were analyzed.

Results

PFNA had the highest axial stiffness (F = 761.265, p < 0.0001) and failure load (F = 48.801, p < 0.0001) in model IV. The axial stiffness and failure load of the PFLP were significantly higher than those of the LISS (p < 0.0001, p = 0.001). However, no significant difference in axial stiffness was found between models I to III (model I: F = 2.439, p = 0.106; model II: F = 2.745, p = 0.082; model III: F = 0.852, p = 0.438) or torsional stiffness in model IV (F = 1.784, p = 0.187). In fatigue testing, PFNA did not suffer from construct failure after 90,000 cycles of axial compression. PFLP and LISS were damaged within 14,000 cycles, although LISS withstood more cycles than PFLP (t = 3.328, p = 0.01).

Conclusion

The axial stiffness of the three implants was similar in models I to III. The biomechanical properties of PFNA were the best of the three implants in terms of axial stiffness, failure load, and fatigue testing cycles in model IV. The axial stiffness and failure load of the PFLP were better than those of the reverse LISS, but PFLP had fewer cycles in the fatigue tests than the reverse LISS.
Transnasal Endoscopic and Transoral Approaches in the Biopsies of Ventral Atlas and Axis Vertebrae: A Comprehensive Retrospective Study for Preprocedural Scheme, Biopsy Procedure, Core Technique Analysis, Diagnostic Yield and Clinical Outcome
Authors: Shao Xianhao , Li Jianmin , Yang Qiang , Li Ka , Yao Yuan , Sun Feifei , Li Zhenfeng
Published: June 2022

Objective

This study aims to describe and analyze the transoral and transnasal approaches for pathologies of the ventral atlas and axis vertebrae, which are considered technically challenging regions for diagnostic biopsy.

Methods

A series of transnasal endoscopic approach (TNA) and transoral approach (TOA) biopsies for the pathologies of the first and second cervical vertebrae were conducted and retrospectively analyzed from July 2014 to May 2021. The depth of the biopsy trajectory was measured on computed tomography images for all nine patients (eight males and one female with an average age of 58.11 ± 11.60 years), as were the coronal, sagittal, and vertical biopsy safe ranges. The characteristics of each lesion, including radiographic features, blood supply, and destruction of anterior or posterior vertebral body edges, were evaluated to guide the biopsy. Four biopsy core techniques (BCTs), including “lesion perforating”, “aspiration”, “cutting‐and‐scraping” and “biopsy forceps utilization” were elaborated in this study. The biopsy procedures and periprocedural precautions were demonstrated. Patient demographics, clinical data, lesion characteristics, diagnostic yield, and complications were recorded for each case.

Results

Eight TOA biopsies for the axis vertebral body and one TNA biopsy for the atlas anterior arch were successfully performed and yielded adequate pathologies. All biopsies were organized based on the preprocedural radiographic measurements, which showed that the average length of biopsy trajectory and coronal, sagittal, and vertical safe biopsy ranges were 85.00 ± 5.88, 20.63 ± 4.75, 16.25 ± 1.49, and 24.63 ± 2.26 mm, respectively, and these corresponding data were 95, 36, 9, and 26 mm in the TNA patient. Six osteolytic lesions (66.7%), one osteoblastic lesion (11.1%), and two mixed lesions (22.2%) were observed, among which seven lesions had a rich blood supply. Biopsy forceps and core needles were utilized to obtain samples in six and three patients, respectively. All the TNA and TOA biopsies were performed with cooperative application of multiple BCTs under compound anatomic and stereotactic navigations. Intraprocedural or postprocedural complications occurred in no patients who underwent the biopsy in the follow‐up period (1–39 months). No significant differences were found between the preprocedural and postprocedural blood indexes and visual analogue scale scores.

Conclusion

With a sophisticated preprocedural arrangement, cooperative application of BCTs, and careful periprocedural precautions, transnasal endoscopic and transoral biopsies are two feasible, efficient, and well‐tolerated procedures that achieve satisfactory diagnostic yield, complication rate, and clinical outcome.
Identification of the novel HLA‐DPA1*01:88 allele by next‐generation sequencing
Authors: Tiziana Galluccio , Maria Pinto Rita , Giuseppe Testa , Andrea Di Luzio , Marco Andreani
Published: June 2022

The novel HLA‐DPA1*01:88 allele differs from HLA‐DPA1*01:03:01:05 by one nucleotide substitution in Exon 3.
Successful treatment of ivermectin overdose in a bearded dragon (Pogona vitticeps) using gastric lavage and intravenous lipid emulsion
Authors: DeMel Danielle , Gleeson Molly , Schachterle Karen , Thomer Amanda
Published: June 2022

Objective

To describe the clinical signs and outcome following ivermectin overdose in a bearded dragon. This case also describes the novel use of intravenous lipid emulsion (ILE) as a rescue therapy in reptiles, as well as the use of aggressive gastrointestinal decontamination.

Case Summary

A 4‐year‐old female intact bearded dragon (Pogona vitticeps) (0.6 kg) was admitted to the ICU at a specialty hospital following accidental overdose of 40 mg (66.7 mg/kg) of ivermectin enterally. The patient was physically inverted to allow passive reflux of the medication, then sedated for gastric lavage. A 20% ILE was administered intravenously due to the high risk for fatality. Additional treatments included 2 doses of activated charcoal, as well as SC fluids, enteral nutrition, and sucralfate. The patient was profoundly sedate until day 4 when mild improvements in mentation were noted. The patient started ambulating on its own on day 6 and was discharged from the hospital on day 13. The patient was alive 720 days postdischarge.

New or Unique Information Provided

This is the first case report describing the events following ivermectin overdose and the use of ILE therapy and activated charcoal in a bearded dragon. These therapies were tolerated with no adverse effects noted in this patient. This report provides evidence that complete recovery from ivermectin overdose is possible.
Influence of Psycho-social Support on Stakeholder Engagement in Lebanon’s School Community
Authors: Hourani Fidaa Nimer , Kotob Mazen Muhieddine
Published: June 2022

Psycho-social Support (PSS) is a practical approach to improve people's well-being affected by humanitarian crises. However, empirical research on how it can improve engagement within academic settings is still limited. To address this gap, the current study investigates the impact of the PSS Program in improving the stakeholders' engagement within the school community in Lebanon by implementing counseling and supportive activities or services. The study selected a mixed research design and a cross-sectional survey to answer the research questions and to test the hypotheses. In April 2021, a sample of 446 respondents was selected from among the school stakeholders in Lebanon using the convenience and purposive sampling techniques. Data collected was coded, cleaned, and entered into Statistical Package for Social Sciences (SPSS) for analysis. The study confirmed that PSS significantly influences stakeholder engagement that lead into stakeholder belongingness, and quality and equity of education. Based on the outcomes, the researcher recommended adopting the PSS program to better the quality of education and assist administrations with more details that improve stakeholder engagement in their schools. The study also shows best practices in the utilization of the PSS to inspire stakeholder engagement during emergencies. Findings are necessary to the ministry of education, school administrators, students, parents, and researchers interested in using PSS in school settings.
Mechanical Properties of Prismatic Li-Ion Batteries—Electrodes, Cells, and Stacks
Authors: Sahraei Elham , Keshavarzi Mohammad Mehdi , Zhang Xiaowei , Lai Benjamin
Published: June 2022

Mechanical abusive loadings, as an inevitable consequence of road accidents, can damage the embedded energy storage system in an electric vehicle and deform its constitutive parts, e.g., the lithium-ion batteries. Therefore, to study the mechanical responses of these batteries and avoid expensive testing equipment and rigorous safety percussions, researchers are propelled toward utilizing numerical models. Computationally cost-efficient homogenized finite element models that represent the whole battery in the form of a uniform medium are the most feasible solution, especially in large-scale battery stacks simulations. Compared to the other form factors of the batteries, prismatic cells have been understudied even though they have higher packaging efficiency, by making optimal use of space. In this article, a comprehensive homogenization and failure calibration method was developed for these prismatic cells. The homogenization was done through extensive uniaxial components tests of the jellyroll and the shell casing. In addition, biaxial tensile tests and simulations were used to calibrate strain-based failure criteria for the components. The calibrated homogenized model is validated in various punch loading scenarios and used in the characterization of the load–displacement responses and failure modes of the stacked cell configurations. In the stacked simulations, due to the cushion-like behavior of the other cells, the failure happens in higher values of displacement compared to a single cell. However, the normalized intrusion percentages for the battery stacks are lower compared to a single battery cell. This emphasizes the importance of the safety assessment of an electric vehicle based on the failure analysis of the battery stacks rather than a single cell. This goal would be feasible through simulations of only homogenized cell models in the stacked configurations, which are elaborated in this article for prismatic cells.
Conversion of Thermally Amplified Hydraulic Shock for Power Generation: Modeling and Experimental Analyses
Authors: Abebe Ashenafi , Tadesse Yilma , Beyene Asfaw
Published: June 2022

Hydraulic shock, also colloquially known as hydram, or hydraulic ram pump, or water hammer, or fluid hammer is a high-pressure shock wave that propagates at the speed of sound through a piping system when a fluid in motion is forced to change direction or stop abruptly. This destructive force can be converted into useful work, i.e., to pump the water to higher elevation, thereby increasing its potential energy, i.e., lifts the water using the high-pressure shockwave. Its low performance combined with affordability of fuels has put this otherwise longstanding technology in the backburner of science and research for a long time, yielding to electric or fuel powered pumps. However, growing concerns about the impacts of fossil fuel use on the environment as well as the rising price of electricity has generated a renewed interest in such technology. The ram pump’s operation in remote areas where the power grid is not available adds research value to the technology. In this paper, a novel approach, i.e., adding thermal energy to the flow to assist the water hammer pressure was modeled. Computational fluid dynamics (CFD) simulations were conducted using ansys. The results were validated experimentally in a 32 mm (27 mm internal diameter) drive pipe and a supply head of 2.18 m ram pump. The exhaust pressure can also be used to produce power using a hydraulic turbine, hence our claim of multi-purpose application as a theme of this project. The results between simulation and experiment were consistent, with only 6.99% error for pressure, and 10.16% for flowrate. The results show that pressure increased from 183.33 kPa to 342.32 kPa when thermally assisted to reach 106.75 °C. The experimental discharge flow increased from 11.72 l/min to 16.41 l/min for the corresponding temperature, a 42.01% increase. The system in power mode produced 91.28 W and 35.81 W with and without thermal infusion, respectively. The Rankine efficiency of thermally assisted hydraulic ram for combined application was above 10% whereas with power generation only, the efficiency was 1.4% at a net delivery head of 5 m for both scenarios. It was observed that in general, the efficiency increases proportionally with delivery flow.
The triumph and tragedy of the Higgs boson
Authors: Cho Adrian
Published: June 2022

Ten years ago, physicists found what they predicted. Little new has followed
Metalloproteinase-Dependent and TMPRSS2-Independent Cell Surface Entry Pathway of SARS-CoV-2 Requires the Furin Cleavage Site and the S2 Domain of Spike Protein
Authors: Yamamoto Mizuki , Gohda Jin , Kobayashi Ayako , Tomita Keiko , Hirayama Youko , Koshikawa Naohiko , Seiki Motoharu , Semba Kentaro , Akiyama Tetsu , Kawaguchi Yasushi , Inoue Jun-ichiro
Published: June 2022

To develop effective therapeutics against COVID-19, it is necessary to elucidate in detail the infection mechanism of the causative agent, SARS-CoV-2. SARS-CoV-2 binds to the cell surface receptor ACE2 via the spike protein, and then the spike protein is cleaved by host proteases to enable entry.
A High-Carbohydrate Diet Prolongs Dysbiosis and Clostridioides difficile Carriage and Increases Delayed Mortality in a Hamster Model of Infection
Authors: Bhute Shrikant S. , Mefferd Chrisabelle C. , Phan Jacqueline R. , Ahmed Muneeba , Fox-King Amelia E. , Alarcia Stephanie , Villarama Jacob V. , Abel-Santos Ernesto , Hedlund Brian P.
Published: June 2022

The effects of diet on CDI are not completely known. Here, we used a high-carbohydrate diet previously shown to protect mice against CDI to assess its effect on a hamster model of CDI and paradoxically found that it promoted dysbiosis,
C. difficile
carriage, and higher mortality.
Daily-Seasonal Variation in the Number of Remotely Observed, Pulsed, ULF Electromagnetic Earthquakes and the Spatial Distribution of Their Generation Zones on the Earth’s Surface
Authors: Dovbnya B. V.
Published: June 2022

Based on data from long-term observations at two geophysical observatories, Borok and College, distantly spaced in latitude and longitude, the results of remote observation of pulsed electromagnetic, ultralow-frequency (ULF) signals detected from distant earthquakes are analyzed withinminutes of the seismic event. The daily and seasonal dependences of the frequency of occurrence of precursors in observatories and the nature of the spatial distribution of their generation zones on the Earth’s surface are studied. Two maxima are distinguished in the daily distribution of the recurrence frequency: in the evening and morning hours of local time. In the seasonal course, there is a maximum in the spring and an increase in the winter months. In the spatial distribution, there is an uneven location of sources around the globe: they are grouped into separate zones and cells that reflect separate regions on the map with manifestations of seismoelectromagnetic activity. Examples are given to illustrate the appearance of precursors. It is noted that the dynamic spectra of signals from earthquakes occurring in different regions of the Earth’s surface were similar. They were repeated at different magnitudes and focus depths and were observed in one time interval allocated relative to the moment of the earthquake. The results of the analysis indicated the universality of the processes of the generation of impulsive precursors preceding an earthquake, as well as the fundamental possibility of a short-term warning (of a few minutes) of an approaching earthquake.
Adherence to the 2015 and 2020 British Society of Paediatric Endocrinology and Diabetes guidelines and outcomes in critically ill children with diabetic ketoacidosis: a retrospective cohort study
Authors: Edwards Victoria Mary , Procter Claire , Jones Andrew J , Randle Elise , Ramnarayan Padmanabhan
Published: June 2022

Objectives

To compare clinical management and key outcomes of critically ill children with diabetic ketoacidosis (DKA) in two cohorts (2015 cohort: managed according to the 2015 British Society of Paediatric Endocrinology and Diabetes (BSPED) guidelines; 2020 cohort: managed according to the 2020 BSPED guidelines).

Design

Retrospective cohort study using prospectively collected data.

Setting

A critical care advice and transport service based in London, and referring hospitals within the critical care network.

Patients

All children 0–17 years referred for advice and/or critical care transport with a clinical diagnosis of DKA over a 30-month period (from September 2018 to March 2021).

Interventions

None.

Main outcome measures

Admission to intensive care unit (ICU), clinically diagnosed cerebral oedema and death.

Results

There were significant differences in fluid and insulin administration practices between the 2015 and 2020 cohorts (fluid bolus >20 mL/kg: 3% vs 30%, p<0.001; median total fluid given in the first 24 hours: 84 mL/kg vs 117 mL/kg, p<0.01; starting insulin infusion rate 0.1 U/kg/hour: 54% vs 31%, p<0.01). However, these differences were consistent with guideline recommendations (initial fluid infusion rate within 5% of guideline-recommended rate: 80% in the 2015 group vs 84% in the 2020 group). There were no significant differences in outcomes (ICU admission: 26% vs 35%, p=0.2; cerebral oedema: 21% vs 23%, p=0.8).

Conclusions

Our study findings indicate that changes to fluid and insulin administration occurred after the 2020 BSPED guideline publication, with strong adherence to the guideline, but these changes were not associated with changes in key outcomes.
Prospectively evaluating maternal and fetal outcomes in the era of CFTR modulators: the MAYFLOWERS observational clinical trial study design
Authors: Jain Raksha , Magaret Amalia , Vu Phuong T , VanDalfsen Jill M , Keller Ashley , Wilson Alexandra , Putman Melissa S , Mayer-Hamblett Nicole , Esther Charles R , Taylor-Cousar Jennifer L
Published: June 2022

Introduction

Therapeutic advances have markedly increased life expectancy for those with cystic fibrosis (CF), resulting in a median predicted survival over 50 years. Consequently, people with CF (pwCF) are living through their reproductive years and the rate of pregnancy is rapidly rising. Despite the increased relevance of this topic, multicentre studies investigating the association between maternal health and choices made during pregnancy on maternal and fetal outcomes do not exist. Furthermore, there are very limited data on the outcomes following CF transmembrane conductance regulator (CFTR) modulator use during pregnancy and lactation.

Methods and analysis

Maternal andFetal Outcomes in theEra of Modulators(MAYFLOWERS) is a prospective, multicentre observational clinical trial which will enrol approximately 285 pregnant pwCF including those who are modulator ineligible and those who choose to continue or discontinue CFTR modulator therapy during pregnancy and lactation. The primary aim of this 35-month study is to assess whether lung function changes during pregnancy differ based on the continued use of modulators or other factors such as pre-existing comorbid conditions. Secondary objectives include evaluation of pregnancy related and obstetrical complications and changes in mental health.

Ethics and dissemination

The design of this study required special consideration of study burden on pregnant and lactating people with chronic illness in the setting of a substantial number of unanswered questions under these conditions. MAYFLOWERS is the first prospective clinical trial examining pregnancy in CF; the outcomes will guide providers on pregnancy management in pwCF and others with chronic respiratory disease.
Acceptability of a task sharing and shifting model between family physicians and physiotherapists in French multidisciplinary primary healthcare centres: a cross-sectional survey
Authors: Kechichian Amélie , Desmeules François , Girard Pauline , Pinsault Nicolas
Published: June 2022

Objectives

The rising prevalence of musculoskeletal disorders increases pressure on primary care services. In France, patients with musculoskeletal disorders are referred to physiotherapist (PT) by family physician (FP). To improve access to musculoskeletal care, a new model of task sharing and shifting is implemented between FPs and PTs for patients with acute low back pain. This new model enables French PTs to expand their usual scope of practice by receiving patients as first-contact practitioner, diagnosing low back pain, prescribing sick leave and analgesic medication. The aim of this study is to investigate the acceptability of FPs and PTs regarding this new model.

Design

A cross-sectional survey design was used. Acceptability was measured using a questionnaire on the perception of the model and the perception of PTs’ skills to manage low back pain. Descriptive analyses were performed to compare results among participants.

Setting

French FPs and PTs working in multidisciplinary primary healthcare centres were invited to complete an online survey.

Participants

A total of 174 respondents completed the survey (81 FPs and 85 PTs).

Results

A majority of participants had a positive perception of the task sharing and shifting model. A majority of the participants were mostly or totally favourable towards the implementation of the model (FPs: n=46, 82% and PTs: n=40, 82%). The perceived level of competencies of PTs to manage acute low back pain was high. The confidence level of FPs was higher than that of PTs regarding PTs’ ability to adequately diagnose low back pain, refer patient to physiotherapy and prescribe sick leave or analgesic medication.

Conclusion

Based on this limited sample of participants, there appears to be good acceptability of the task sharing and shifting model for acute low back pain. Additional studies are needed to better determine the factors affecting the acceptability of such a model.
Current therapies and new developments in NASH
Authors: Dufour Jean-François , Anstee Quentin M , Bugianesi Elisabetta , Harrison Stephen , Loomba Rohit , Paradis Valerie , Tilg Herbert , Wong Vincent Wai-Sun , Zelber-sagi Shira
Published: June 2022

Non-alcoholic steatohepatitis is becoming the most important aetiology for advanced liver disease. There has been important progress in the field in recent years and the complexity of the pathophysiology of NASH is better understood. Multiple non-invasive circulating and imaging biomarkers have been tested. The importance of lifestyle has been recognised and several drugs are being tested in clinical trials. This review addresses the challenges that healthcare professionals face in the management of NASH patients.
Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study
Authors: Marinelli Brett , Kim Edward , D'Alessio Antonio , Cedillo Mario , Sinha Ishan , Debnath Neha , Kudo Masatoshi , Nishida Naoshi , Saeed Anwaar , Hildebrand Hannah , Kaseb Ahmed O , Abugabal Yehia I , Pillai Anjana , Huang Yi-Hsiang , Khan Uqba , Muzaffar Mahvish , Naqash Abdul Rafeh , Patel Rahul , Fischman Aaron , Bishay Vivian , Bettinger Dominik , Sung Max , Ang Celina , Schwartz Myron , Pinato David J , Marron Thomas
Published: June 2022

Background

Immune checkpoint inhibitors (ICIs) have revolutionized treatment of advanced hepatocellular carcinoma. Integrated use of transarterial chemoembolization (TACE), a locoregional inducer of immunogenic cell death, with ICI has not been formally assessed for safety and efficacy outcomes.

Methods

From a retrospective multicenter dataset of 323 patients treated with ICI, we identified 31 patients who underwent >1 TACE 60 days before or concurrently, with nivolumab at a single center. We derived a propensity score-matched cohort of 104 patients based on Child-Pugh Score, portal vein thrombosis, extrahepatic metastasis and alpha fetoprotein (AFP) who received nivolumab monotherapy. We described overall survival (OS), progression-free survival (PFS), objective responses according to modified RECIST criteria and safety in the multimodal arm in comparison to monotherapy.

Results

Over a median follow-up of 9.3 (IQR 4.0–16.4) months, patients undergoing multimodal immunotherapy with TACE achieved a significantly longer median (95% CI) PFS of 8.8 (6.2–23.2) vs 3.7 (2.7–5.4) months (log-rank 0.15, p<0.01) in the monotherapy group. Multimodal immunotherapy with TACE demonstrated a numerically longer OS compared with ICI monotherapy with a median 35.1 (16.1–Not Evaluable) vs 16.6 (15.7–32.6) months (log-rank 0.41, p=0.12). In the multimodal treatment group, there were three (10%) grade 3 or higher adverse events (AEs) attributed to immunotherapy compared with seven (6.7%) in the matched ICI monotherapy arm. There were no AEs grade 3 or higher attributed to TACE in the multimodal treatment arm. At 3 months following each TACE in the multimodal arm, there was an overall objective response rate of 84%. There were no significant changes in liver functional reserve 1 month following each TACE. Four patients undergoing multimodal treatment were successfully bridged to transplant.

Conclusions

TACE can be safely integrated with programmed cell death 1 blockade and may lead to a significant delay in tumor progression and disease downstaging in selected patients.
Sonic hedgehog pathway for the treatment of inflammatory diseases: implications and opportunities for future research
Authors: Palla Marco , Scarpato Luigi , Di Trolio Rossella , Ascierto Paolo Antonio
Published: June 2022

The Sonic hedgehog (Shh) signaling pathway is an essential pathway in the human body that plays an important role in embryogenesis and tissue homeostasis. Aberrant activation of this pathway has been linked to the development of different diseases, ranging from cancer to immune dysregulation and infections.

Uncontrolled activation of the pathway through sporadic mutations or other mechanisms is associated with cancer development and progression in various malignancies, such as basal cell carcinoma, medulloblastoma, pancreatic cancer, breast cancer and small-cell lung carcinoma. Targeted inhibition of the pathway components has therefore emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Currently, two main components of the pathway, the smoothened receptor and the glioma-associated oncogene homolog transcriptional factors, have been investigated for the development of targeted drugs, leading to the marketing authorization of three smoothened receptor inhibitors for the treatment of basal cell carcinoma and acute myeloid leukemia.

The Shh pathway also seems to be involved in regulating the immune response, possibly playing a role in immune system evasions by tumors, development of autoimmune diseases, such as rheumatoid arthritis and Crohn’s disease, airway inflammation, and diseases related to aberrant activation of T-helper 2 cellular response, such as allergy, atopic dermatitis, and asthma.

Finally, the Shh pathway is involved in pathogen-mediated infection, including influenza-A and, more recently, SARS-CoV-2 viruses. Therefore, agents that inhibit the Shh signaling pathway might be used to treat pathogenic infections, shifting the therapeutic approach from strain-specific treatments to host-based strategies that target highly conserved host targets.
A homozygous variant inCHMP3is associated with complex hereditary spastic paraplegia
Authors: Cohen-Barak Eran , Danial-Farran Nada , Chervinsky Elana , Alimi-Kasem Ola , Zagairy Fadia , Livneh Ido , Mawassi Bannan , Hreish Maysa , Khayat Morad , Lossos Alexander , Meiner Vardiella , Ehilevitch Nina , Weiss Karin , Shalev Stavit
Published: June 2022

Background

Monogenic neurodegenerative diseases represent a heterogeneous group of disorders caused by mutations in genes involved in various cellular functions including autophagy, which mediates degradation of cytoplasmic contents by their transport into lysosomes. Abnormal autophagy is associated with hereditary ataxia and spastic paraplegia, amyotrophic lateral sclerosis and frontal dementia, characterised by intracellular accumulation of non-degraded proteins. We investigated the genetic basis of complex HSP in a consanguineous family of Arab-Muslim origin, consistent with autosomal recessive inheritance.

Methods

Exome sequencing was followed by variant filtering and Sanger sequencing for validation and familial segregation. Studies for mRNA and protein expression used real-time PCR and immunoblots. Patients’ primary fibroblasts were analysed using electron microscopy, immunofluorescence, western blot analysis and ectopic plasmid expression for its impact on autophagy.

Results

We identified a homozygous missense variant inCHMP3(Chr2:86507484 GRCh38 (NM_016079.4): c.518C>T, p.Thr173Ile), which encodes CHMP3 protein. Segregation analysis validated the presence of the homozygous variant in five affected individuals, while healthy family members were found either heterozygous or wild type for this variant. Primary patient’s fibroblasts showed significantly reduced levels of CHMP3. Electron microscopy disclosed accumulation of endosomes, autophagosomes and autolysosomes in patient’s fibroblasts, which correlated with higher levels of autophagy markers, p62 and LC3-II. Ectopic expression of wild-typeCHMP3in primary patient fibroblasts led to reduction of the p62 particles accumulation and number of endosomes and autophagosomes compared with control.

Conclusions

Reduced level of CHMP3 is associated with complex spastic paraplegia phenotype, through aberrant autophagy mechanisms.
Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis
Authors: Abdelhak Ahmed , Cordano Christian , Boscardin W John , Caverzasi Eduardo , Kuhle Jens , Chan Brandon , Gelfand Jeffrey M , Yiu Hao H , Oertel Frederike C , Beaudry-Richard Alexandra , Condor Montes Shivany , Oksenberg Jorge R , Lario Lago Argentina , Boxer Adam , Rojas-Martinez Julio C , Elahi Fanny M , Chan Jonah R , Green Ari J
Published: June 2022

Background

Chronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored.

Methods

Plasma neurofilament light chain (NfL) levels were measured from ReBUILD trial’s participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period.

Results

NfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=−0.035 [−0.068 to −0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values (B=0.003 [−0.0004 to 0.007], p=0.081). Based on a Cohen’s d of 0.248, a future 1:1 parallel-arm placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202 subjects per group to achieve 80% power.

Conclusions

In pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination.

Trial registration number

NCT02040298.
A Particle Swarm with Local Decision Algorithm for Functional Distributed Constraint Optimization Problems
Authors: Shi Meifeng , Liao Xin , Chen Yuan
Published: June 2022

Functional Distributed Constraint Optimization Problems (F-DCOPs) are a constraint processing framework for continuous variables in the multi-agent system. Particle swarm optimization-based F-DCOP (PFD) is a population-based algorithm to solve F-DCOP collaboratively. Although it can significantly reduce the computational overhead and memory requirements, its solution depends on the decision of root agent in the Breadth First Search (BFS) pseudo-tree and it is easy to fall into local optimum. To solve the above problems, this paper designed an improved PFD algorithm with Local Decision named PFD-LD, which effectively reduces the dependence on root agent through local decision. In addition, a mutation operator is used to avoid falling into local optimum. It is proved that PFD-LD is an anytime algorithm and local decision can expand the search of the solution space. Finally, the extensive experiments based on four types of benchmark problems show that the proposed algorithm outperforms state-of-the-art F-DCOP solving algorithms.
The symmetric Post Correspondence Problem, and errata for the freeness problem for matrix semigroups
Authors: Birget Jean-Camille , Talambutsa Alexey L.
Published: June 2022

In this paper, we define the symmetric Post Correspondence Problem (PCP) and prove that it is undecidable. As an application, we show that the original proof of undecidability of the freeness problem for [Formula: see text] integer matrix semigroups works for the symmetric PCP, but not for the PCP in general.
On Heegaard splittings of mapping torus and induced by open book decompositions
Authors: Du Kun
Published: June 2022

In this paper, we give a sufficient condition for a keen weakly reducible and unstabilized Heegaard splitting of mapping torus and a sufficient condition for an irreducible, unstabilized and strongly irreducible Heegaard splitting induced by open book decomposition.
A Machine Learning Study on the Role of Behavioral and Demographic Factors in Mining Injuries
Authors: Ravikumar Appani , Raju Gunda Yuga , Gupta Suprakash
Published: June 2022

Predictive models for work-related injuries in mines are complicated, with personal, technical, and societal aspects all playing a role. Numerous studies have reported that human behavior is a significant factor in mine injuries. Many researchers have opined that maintaining a high level of safe human behavior is a challenging task. In Indian mines, the risk management team uses hierarchy control charts to avoid incidents, but managing human behavioral factors which lead to injury is more challenging. Owing to these constraints, we attempted to find the significant human behavioral factors that lead to injury in mines. In this work, we try to develop predictive models using behavioral and demographic factors to predict mine workers’ injury status and evaluate the most significant factor. To investigate the relevance of behavioral characteristics in work-related injuries, we employed three machine learning models (neural networks, random forest, and K-NN) as well as two classic statistical approaches (linear and logistic regression) to compare their results and see which method performs better. We have collected data of six factors and injury status of 186 workers through a questionnaire survey. After data analysis, a detailed comparison between machine learning models and traditional methods shows that random forest performs better than other models. This study also found that demographic features and job dissatisfaction attitude are the leading influencing factors to work-related injuries. This work is beneficial to mine management in the present Indian mining scenario to devise appropriate countermeasures.
A STUDY OF LIVER BIOMECHANICAL RESPONSES UNDER CLASSICAL IMPACTS FOR VEHICLE OCCUPANTS
Authors: YUAN MIN , XIAO SEN , YANG JIKUANG , WU JINDONG , HOU JINGPU
Published: June 2022

Liver injury is one of the most fatal injuries in traffic accidents. To deeply study response characters of this injury under the unique impact condition, three impact tests are conducted based on the human body model and constraint systems of a car. This study is conducted based on the numerical method and adopts the orthogonal experimental design to deeply investigate the relationship between biomechanical responses and the impact loading variables. Data were collected and analyzed with the rotation of the liver in three planes and the distance change relative to the spine. Results show that in the near-side oblique impact, the maximum stress of the liver is captured as 10.041 MPa. In addition, the rotation angle of the liver in the three planes is the largest in the far-side oblique collision. In general, a more significant influence on the compression and movement of the liver is obtained from the near-side side collision, mainly because the door directly hits the left side of the occupant during crash process due to the limited space between door and occupant. In a far-side oblique collision, a buffering effect of the seat back to the driver does not play the role during the crash. As a result, the seatbelt slips off the occupant’s shoulder, resulting in a high displacement of the upper body. Thus, ensuring the restraint effect of the seatbelt may be a crucial problem for far-side oblique collision. This study can provide a reference to the occupant safety protection during vehicle accidents.