bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic and functional analyses detect an EXT1 splicing pathogenic variant in a Chinese hereditary multiple exostosis (HME) family
Authors: Li Jianwei , Wang Zhiqiang , Han Yaxin , Jin Chengfang , Cheng Dalin , Zhou Yong‐An , Zhen Junping 
Published: February 2022

AbstractBackgroundHereditary multiple exostosis (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple cartilage‐covered tumors on the external surfaces of bones (osteochondromas). Most of HME cases result from heterozygous loss‐of‐function mutations in EXT1 or EXT2 gene.MethodsClinical examination was performed to diagnose the patients: Whole exome sequencing (WES) was used to identify pathogenic mutations in the proband, which is confirmed by Sanger sequencing and co‐segregation analysis: qRT‐PCR was performed to identify the mRNA expression level of EXT1 in patient peripheral blood samples: minigene splicing assay was performed to mimic the splicing process of EXT1 variants in vitro.ResultsWe evaluated the pathogenicity of EXT1 c.1056 + 1G > T in a Chinese family with HME. The clinical, phenotypic, and genetic characterization of patients in this family were described. The variant was detected by whole‐exome sequencing (WES) and confirmed by Sanger sequencing. Sequencing of the RT‐PCR products from the patient's blood sample identified a large deletion (94 nucleotides), which is the whole exome 2 of the EXT1 cDNA. Splicing assay indicated that the mutated minigene produced alternatively spliced transcripts, which cause a frameshift resulting in an early termination of protein expression.ConclusionsOur study establishes the pathogenesis of the splicing mutation EXT1 c.1056 + 1G > T to HME and provides scientific foundation for accurate diagnosis and precise medical intervention for HME.
Effects of Calcium Source, Inulin, and Lactose on Gut‐Bone Associations in an Ovarierectomized Rat Model
Authors: He Weiwei , Xie Zhuqing , Thøgersen Rebekka , Rasmussen Martin Krøyer , Zachariassen Line F. , Jørgensen Niklas Rye , Nørgaard Jan Værum , Andersen Henrik J. , Nielsen Dennis S. , Hansen Axel K. , Bertram Hanne Christine 
Published: February 2022

ScopeOsteoporosis poses a health challenge especially for postmenopausal women. This study aims to explore nutritional strategies to counteract bone demineralization in ovarierectomized (OVX) rats.Methods and ResultsOVX rats (n = 49) are fed with one of six different diets, where two different calcium sources (dairy calcium or calcium carbonate) are provided alone or in combination with either inulin (5%) or lactose (0.5%). In addition, a calcium‐deficient diet is included. Calcium supplementation increases intestinal concentrations of short‐chain fatty acids (SCFAs) and the abundance of fecal Acinetobacter and Propionibacterium. Accompanied with these effects, rats fed with calcium‐fortified diets have higher bone mineral density, bone mineral content and femur mechanical strength, lower serum levels of bone markers, and lower expression of calcium absorption‐related genes (transient receptor potential vanilloid type 6 (TRPV6), calcium‐binding protein (CaBP) compared with control. Inulin supplementation results in a markedly increased production of intestinal SCFAs, a decreased intestinal pH, an increased abundance of Allobaculum and Bifidobacterium, and an increased expression of Trpv6. Inulin and lactose show beneficial effects on spine bone.ConclusionCalcium modulates gut microbiome composition and function. A pronounced effect of inulin on metabolic activity in the gastrointestinal tract is evident, and lactose supplementation decreases jejunal pH that might be associated with slightly enhanced bone mineralization.
Garlic‐Derived Organosulfur Compounds Regulate Metabolic and Immune Pathways in Macrophages and Attenuate Intestinal Inflammation in Mice
Authors: Zhu Ling , Myhill Laura J. , Andersen‐Civil Audrey I. S. , Thamsborg Stig M. , Blanchard Alexandra , Williams Andrew R. 
Published: February 2022

AbstractScope: Garlic is a source of bioactive phytonutrients that may have anti‐inflammatory or immunomodulatory properties. The mechanism(s) underlying the bioactivity of these compounds and their ability to regulate responses to enteric infections remains unclear.Methods and Results: This study investigates if a garlic‐derived preparation (PTSO‐PTS) containing two organosulfur metabolites, propyl‐propane thiosulfonate (PTSO), and propyl‐propane thiosulfinate (PTS), regulate inflammatory responses in murine macrophages and intestinal epithelial cells (IEC) in vitro, as well as in a model of enteric parasite‐induced inflammation. PTSO‐PTS decreases lipopolysaccharide‐induced secretion of TNFα, IL‐6, and IL‐27 in macrophages. RNA‐sequencing demonstrates that PTSO‐PTS strongly suppresses pathways related to immune and inflammatory signaling. PTSO‐PTS induces the expression of a number of genes involved in antioxidant responses in IEC during exposure to antigens from the parasite Trichuris muris. In vivo, PTSO‐PTS does not affect T. muris establishment or intestinal T‐cell responses but significantly alters cecal transcriptomic responses. Notably, a reduction in T. muris‐induced expression of Tnf, Saa2, and Nos2 is observed.Conclusion: Garlic‐derived organosulfur compounds exert anti‐inflammatory effects in macrophages and IEC, and regulate gene expression during intestinal infection. These compounds and related organic molecules may thus hold potential as functional food components to improve gut health in humans and animals.
High‐Fat‐Diet‐Induced Extracellular Matrix Deposition Regulates Integrin—FAK Signals in Adipose Tissue to Promote Obesity
Authors: Chen Hui‐jian , Yan Xi‐yue , Sun Ao , Zhang Li , Zhang Jing , Yan You‐e 
Published: February 2022

ScopeHigh‐fat‐diet (HFD) is an important factor in obesity. Extracellular matrix (ECM) regulates white adipose tissue (WAT), but its mechanism is unknown.Methods and ResultsThis study uses three models—HFD‐fed mice, human with obesity, and 3T3‐L1 adipocytes with oleic acid (OA)/macromolecular crowders (MMC) treatment. Glucose and lipids metabolic disorders, increased collagen I/IV and laminin α2/4 (LAMA2/4), and upregulated integrins (ITGA1/ITGA7) – focal adhesion kinase (FAK) – c‐Jun N‐terminal kinase (JNK)/extracellular regulated protein kinase 1/2 (ERK1/2) signals in obese WAT from mice and human are observed. The upregulation of ECM – integrin – FAK signals is stronger in subcutaneous WAT than that in visceral WAT of mice, but these results are reversed in human. In vitro, oleic acid (OA) promotes lipid accumulation and upregulates collagen IV, LAMA4, and p‐JNK. MMC is used to induce ECM deposition in adipocytes. MMC promotes adipocyte differentiation and integrins – FAK – JNK/ERK1/2 signals. When FAK phosphorylation is inhibited, downstream p‐JNK is decreased. Inhibition of FAK phosphorylation reduces adipocyte differentiation, but MMC partially reverses this effect.ConclusionHFD‐induced ECM deposition, whose signals are transmitted into adipocytes through upregulating ITGA1/ITGA7, activates the phosphorylation of intracellular FAK – JNK/ERK1/2 signals, and promotes adipogenesis in WAT. This mechanism provides novel therapeutic targets to treat obesity.
Real‐time estimation of patient‐specific dose distributions for medical CT using the deep dose estimation
Authors: Maier Joscha , Klein Laura , Eulig Elias , Sawall Stefan , Kachelrieß Marc 
Published: February 2022

AbstractPurposeWith the rising number of computed tomography (CT) examinations and the trend toward personalized medicine, patient‐specific dose estimates are becoming more and more important in CT imaging. However, current approaches are often too slow or too inaccurate to be applied routinely. Therefore, we propose the so‐called deep dose estimation (DDE) to provide highly accurate patient dose distributions in real timeMethodsTo combine accuracy and computational performance, the DDE algorithm uses a deep convolutional neural network to predict patient dose distributions. To do so, a U‐net like architecture is trained to reproduce Monte Carlo simulations from a two‐channel input consisting of a CT reconstruction and a first‐order dose estimate. Here, the corresponding training data were generated using CT simulations based on 45 whole‐body patient scans. For each patient, simulations were performed for different anatomies (pelvis, abdomen, thorax, head), different tube voltages (80 kV, 100 kV, 120 kV), different scan trajectories (circle, spiral), and with and without bowtie filtration and tube current modulation. Similar simulations were performed using a second set of eight whole‐body CT scans from the Visual Concept Extraction Challenge in Radiology (Visceral) project to generate testing data. Finally, the DDE algorithm was evaluated with respect to the generalization to different scan parameters and the accuracy of organ dose and effective dose estimates based on an external organ segmentation.ResultsDDE dose distributions were quantified in terms of the mean absolute percentage error (MAPE) and a gamma analysis with respect to the ground truth Monte Carlo simulation. Both measures indicate that DDE generalizes well to different scan parameters and different anatomical regions with a maximum MAPE of 6.3% and a minimum gamma passing rate of 91%. Evaluating the organ dose values for all organs listed in the International Commission on Radiological Protection (ICRP) recommendation, shows an average error of 3.1% and maximum error of 7.2% (bone surface).ConclusionsThe DDE algorithm provides an efficient approach to determine highly accurate dose distributions. Being able to process a whole‐body CT scan in about 1.5 s, it provides a valuable alternative to Monte Carlo simulations on a graphics processing unit (GPU). Here, the main advantage of DDE is that it can be used on top of any existing Monte Carlo code such that real‐time performance can be achieved without major adjustments. Thus, DDE opens up new options not only for dosimetry but also for scan and protocol optimization.
On the proper use of structural similarity for the robust evaluation of medical image synthesis models
Authors: Gourdeau Daniel , Duchesne Simon , Archambault Louis 
Published: February 2022

AbstractPurposeTo propose good practices for using the structural similarity metric (SSIM) and reporting its value. SSIM is one of the most popular image quality metrics in use in the medical image synthesis community because of its alleged superiority over voxel‐by‐voxel measurements like the average error or the peak signal noise ratio (PSNR). It has seen massive adoption since its introduction, but its limitations are often overlooked. Notably, SSIM is designed to work on a strictly positive intensity scale, which is generally not the case in medical imaging. Common intensity scales such as the Houndsfield units (HU) contain negative numbers, and they can also be introduced by image normalization techniques such as the z‐normalization.MethodsWe created a series of experiments to quantify the impact of negative values in the SSIM computation. Specifically, we trained a three‐dimensional (3D) U‐Net to synthesize T2‐weighted MRI from T1‐weighted MRI using the BRATS 2018 dataset. SSIM was computed on the synthetic images with a shifted dynamic range. Next, to evaluate the suitability of SSIM as a loss function on images with negative values, it was used as a loss function to synthesize z‐normalized images. Finally, the difference between two‐dimensional (2D) SSIM and 3D SSIM was investigated using multiple 2D U‐Nets trained on different planes of the images.ResultsThe impact of the misuse of the SSIM was quantified; it was established that it introduces a large downward bias in the computed SSIM. It also introduces a small random error that can change the relative ranking of models. The exact values for this bias and error depend on the quality and the intensity histogram of the synthetic images. Although small, the reported error is significant considering the small SSIM difference between state‐of‐the‐art models. It was shown therefore that SSIM cannot be used as a loss function when images contain negative values due to major errors in the gradient calculation, resulting in under‐performing models. 2D SSIM was also found to be overestimated in 2D image synthesis models when computed along the plane of synthesis, due to the discontinuities between slices that is typical of 2D synthesis methods.ConclusionVarious types of misuse of the SSIM were identified, and their impact was quantified. Based on the findings, this paper proposes good practices when using SSIM, such as reporting the average over the volume of the image containing tissue and appropriately defining the dynamic range.
Multisystem screening reveals SARS‐CoV‐2 in neurons of the myenteric plexus and in megakaryocytes
Authors: Gray‐Rodriguez Sandra , Jensen Melanie P , Otero‐Jimenez Maria , Hanley Brian , Swann Olivia C , Ward Patrick A , Salguero Francisco J , Querido Nadira , Farkas Ildiko , Velentza‐Almpani Elisavet , Weir Justin , Barclay Wendy S , Carroll Miles W , Jaunmuktane Zane , Brandner Sebastian , Pohl Ute , Allinson Kieren , Thom Maria , Troakes Claire , Al‐Sarraj Safa , Sastre Magdalena , Gveric Djordje , Gentleman Steve , Roufosse Candice , Osborn Michael , Alegre‐Abarrategui Javier 
Published: February 2022

AbstractSARS‐CoV‐2, the causative agent of COVID‐19, typically manifests as a respiratory illness, although extrapulmonary involvement, such as in the gastrointestinal tract and nervous system, as well as frequent thrombotic events, are increasingly recognised. How this maps onto SARS‐CoV‐2 organ tropism at the histological level, however, remains unclear. Here, we perform a comprehensive validation of a monoclonal antibody against the SARS‐CoV‐2 nucleocapsid protein (NP) followed by systematic multisystem organ immunohistochemistry analysis of the viral cellular tropism in tissue from 36 patients, 16 postmortem cases and 16 biopsies with polymerase chain reaction (PCR)‐confirmed SARS‐CoV‐2 status from the peaks of the pandemic in 2020 and four pre‐COVID postmortem controls. SARS‐CoV‐2 anti‐NP staining in the postmortem cases revealed broad multiorgan involvement of the respiratory, digestive, haematopoietic, genitourinary and nervous systems, with a typical pattern of staining characterised by punctate paranuclear and apical cytoplasmic labelling. The average time from symptom onset to time of death was shorter in positively versus negatively stained postmortem cases (mean = 10.3 days versus mean = 20.3 days, p = 0.0416, with no cases showing definitive staining if the interval exceeded 15 days). One striking finding was the widespread presence of SARS‐CoV‐2 NP in neurons of the myenteric plexus, a site of high ACE2 expression, the entry receptor for SARS‐CoV‐2, and one of the earliest affected cells in Parkinson's disease. In the bone marrow, we observed viral SARS‐CoV‐2 NP within megakaryocytes, key cells in platelet production and thrombus formation. In 15 tracheal biopsies performed in patients requiring ventilation, there was a near complete concordance between immunohistochemistry and PCR swab results. Going forward, our findings have relevance to correlating clinical symptoms with the organ tropism of SARS‐CoV‐2 in contemporary cases as well as providing insights into potential long‐term complications of COVID‐19. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Social determinants of health and pediatric cancer survival: A systematic review
Authors: H. Tran Yvette , Coven Scott L. , Park Seho , Mendonca Eneida A. 
Published: February 2022

AbstractDespite treatment advancements and improved survival, approximately 1800 children in the United States will die of cancer annually. Survival may depend on nonclinical factors, such as economic stability, neighborhood and built environment, health and health care, social and community context, and education, otherwise known as social determinants of health (SDoH). Extant literature reviews have linked socioeconomic status (SES) and race to disparate outcomes; however, these are not inclusive of all SDoH. Thus, we conducted a systematic review on associations between SDoH and survival in pediatric cancer patients. Of the 854 identified studies, 25 were included in this review. In addition to SES, poverty and insurance coverage were associated with survival. More studies that include other SDoH, such as social and community factors, utilize prospective designs, and conduct analyses with more precise SDoH measures are needed.
Disparities in the acceptance of chromosomal microarray at the time of prenatal genetic diagnosis
Authors: Swanson Kate , Loeliger Kelsey B. , Chetty Shilpa P. , Sparks Teresa N. , Norton Mary E. 
Published: February 2022

AbstractObjectiveChromosomal microarray (CMA) increases the diagnostic yield of prenatal genetic diagnostic testing but is not universally performed. Our objective was to identify provider and patient characteristics associated with the acceptance of CMA at the time of prenatal genetic diagnostic testing.MethodsRetrospective cohort study of patients undergoing prenatal genetic diagnostic testing (chorionic villus sampling or amniocentesis) at a single institution between 2014 and 2020. Primary outcome was the acceptance of CMA based on the genetic counselor ,GC who saw the patient. Secondary analyses assessed patient characteristics associated with the acceptance of CMA.Results2372 participants were included. Fifty‐eight percent of participants accepted CMA. Acceptance of CMA varied significantly by GC, ranging from 31% to 90%. Patients with public insurance and those who identified as Black or Hispanic/Latina were less likely to have CMA performed (aOR 0.24, 95% CI 0.20–0.30, and 0.68, 95% CI 0.50–0.92). Even among those with a structural anomaly present, public insurance was associated with significantly lower odds of CMA being performed (aOR 0.39, 95% CI 0.25–0.61).ConclusionsAcceptance of CMA at the time of prenatal genetic diagnostic testing varied based on the GC performing the counseling. Public insurance was associated with lower frequency of accepting CMA.
The interacting physiology of COVID‐19 and the renin‐angiotensin‐aldosterone system: Key agents for treatment
Authors: Lumbers Eugenie R. , Head Richard , Smith Gary R. , Delforce Sarah J. , Jarrott Bevyn , H. Martin Jennifer , Pringle Kirsty G. 
Published: February 2022

AbstractSARS‐CoV‐2 interacting with its receptor, angiotensin‐converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS‐CoV‐2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole‐body response to maintain tissue perfusion. Tissue and circulating renin‐angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang‐(1‐7) by the enzyme ACE2. Ang‐(1‐7) has effects that are contrary to Ang II‐AT1R mediated effects. Thus, destruction of ACE2 by SARS‐CoV‐2 results in loss of control of the pro‐inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS‐CoV‐2 that is responsible for the pathogenesis of COVID‐19.
Life satisfaction among skilled transnational families before and during the COVID‐19 outbreak
Authors: Gerber Roxane , Ravazzini Laura 
Published: February 2022

AbstractInternational mobility has radically changed during the COVID‐19 pandemic. Among all types of families, transnational families might have particularly suffered in 2020 during lockdowns that restricted international visits to family members. This paper focuses on the life satisfaction of skilled migrants living in Switzerland before and during the COVID‐19 pandemic. In particular, we focus on those who live long‐distance transnational relationships with other family members. We investigate the impact of the COVID‐19 pandemic on self‐reported life satisfaction using the Swiss Migration‐Mobility Survey (MMS). We apply panel analyses using random effects over three waves of the MMS. We found that the COVID‐19 crisis negatively affected recently arrived migrants' well‐being in Switzerland in 2020. However, migrants in transnational arrangements with children abroad show higher levels of life satisfaction in 2020, in comparison with migrant non‐transnational families. When interacted with gender, this improvement of life satisfaction concerns mostly men, while women in transnational partnerships report a significantly lower level of life satisfaction in 2020.
Chemical characterization of non‐psychoactive Cannabis sativa L. extracts, in vitro antiproliferative activity and induction of apoptosis in chronic myelogenous leukaemia cancer cells
Authors: Anceschi Lisa , Codeluppi Alessandro , Brighenti Virginia , Tassinari Riccardo , Taglioli Valentina , Marchetti Lucia , Roncati Luca , Alessandrini Andrea , Corsi Lorenzo , Pellati Federica 
Published: February 2022

AbstractIn this study, extracts from non‐psychoactive Cannabis sativa L. varieties were characterized by means of ultra high‐performance liquid chromatography coupled with high‐resolution mass spectrometry (UHPLC‐HRMS) and their antiproliferative activity was assessed in vitro. The human chronic myelogenous leukaemia cell line K562 was chosen to investigate the mechanism of cell death. The effect on the cell cycle and cell death was analysed by flow cytometry. Proteins related to apoptosis were studied by western blotting. Mechanical properties of cells were assessed using the Micropipette Aspiration Technique (MAT). The results indicated that the cannabidiol (CBD)‐rich extract inhibited cell proliferation of K562 cell line in a dose‐dependent manner and induced apoptosis via caspase 3 and 7 activation. A significant decrease in the mitochondrial membrane potential was detected, together with the release of cytochrome c into the cytosol. The main apoptotic markers were not involved in the mechanism of cell death. The extract was also able to modify the mechanical properties of cells. Thus, this hemp extract and its pure component CBD deserve further investigation for a possible application against myeloproliferative diseases, also in association with other anticancer drugs.
Progression of pulmonary veno‐occlusive disease without pulmonary hypertension
Authors: Beshay Sarah , Humbert Marc , Barrios Roberto , Sahay Sandeep 
Published: February 2022

AbstractPulmonary veno‐occlusive disease (PVOD) is a progressively fatal disease with no definitive treatment options. PVOD can be a result of genetic mutation but can also be due secondary to exposure to solvents or chemotherapeutic agents. Generally, at the time of diagnosis PVOD is associated with hemodynamically confirmed pulmonary hypertension (PH). In this study, we describe a patient who was diagnosed with PVOD early in the disease without hemodynamically confirmed PH. She had histologically confirmed PVOD. Her clinical presentation posed management challenges and prednisone therapy was used to stabilize her disease. This case and some recently published reports highlight possible immune dysregulation in PVOD and role for immuno‐suppressive therapy in these patients.