bluuebunny/crossref_metadata_2025 huggingface dataset:
Research and scholarly methods: Subgroup analysis
Authors: Ding Qian , Wan Shaowei , Dowling Thomas C.
Published: February 2022

Subgroup analysis is designed to evaluate whether an intervention has differing effects according to baseline characteristics of participants in clinical trials. This approach can help identify subgroups of patient populations, within a single trial or across multiple trials (meta‐analysis), that may benefit from the intervention or can be hypothesis‐generating for future trials. Properly prespecified subgroup analyses can increase the effect size of subgroups and the legitimacy of P‐values in determining significance and hypothesis testing. However, many pitfalls and limitations exist and must be recognized, including post hoc data‐generating, multiple testing, selective reporting, and insufficient sample size. Failure to account for these limitations could lead to erroneous interpretations that adversely impact clinical decision‐making. This review will provide a general overview, best practices, and pitfalls to avoid for investigators involved in the design, conduct, or interpretation of subgroup analyses.
The Calcified Vasculature in Chronic Kidney Disease Secretes Factors that Inhibit Bone Mineralization
Authors: Mace Maria L. , Gravesen Eva , Nordholm Anders , Egstrand Soeren , Morevati Marya , Olgaard Klaus , Lewin Ewa
Published: February 2022

Vascular calcification and bone disorder progress simultaneously in chronic kidney disease (CKD). Still, how the complex pathological mechanisms are linked is only sparsely understood. Up to now, the focus has been on the disturbed bone metabolism in developing vascular calcification. However, our group has recently demonstrated that vascular calcification has negative effects on bone formation and mineralization as shown in the bone of normal recipient rats transplanted with the calcified aorta from CKD rats. In the present in vitro study, the hypothesis of a direct crosstalk between the vasculature and bone was examined. Calcified aortas from 5/6 nephrectomized rats and normal aortas from control rats were excised and incubated ex vivo. The calcified aorta secreted large amounts of sclerostin, dickkopf‐1 (Dkk1), and activin A. Both normal and calcified aortas secreted frizzle‐related protein 4 (SFRP4). Aorta rings were co‐incubated with the osteoblast‐like cell line UMR‐106. The calcified aorta strongly inhibited calcium crystal formation in UMR‐106 cells, together with a significant upregulation of the mineralization inhibitors osteopontin and progressive ankylosis protein homolog (ANKH). The strong stimulation of osteopontin was blocked by lithium chloride, indicating involvement of Wnt/β‐catenin signaling. The present in vitro study shows detrimental effects of the calcified aorta on bone cell mineralization. These findings support the hypothesis of an active role of the calcified vasculature in the systemic CKD–mineral and bone disorder (CKD‐MBD), resulting in a pathological vascular–bone tissue crosstalk. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Real‐time visualization and quantitation of cell death and cell cycle progression in 2D and 3D cultures utilizing genetically encoded probes
Authors: Varadarajan Shankara Narayanan , Mathew Krupa Ann , Chandrasekharan Aneesh , Lupitha Santhik Subhasingh , Lekshmi Asha , Mini Minsa , Darvin Pramod , Santhoshkumar T. R.
Published: February 2022

Cancer cells grown as 3D‐structures are better models for mimicking in vivo conditions than the 2D‐culture systems employable in drug discovery applications. Cell cycle and cell death are important determinants for preclinical drug screening and tumor growth studies in laboratory conditions. Though several 3D‐models and live‐cell compatible approaches are available, a method for simultaneous real‐time detection of cell cycle and cell death is required. Here we demonstrate a high‐throughput adaptable method using genetically encoded fluorescent probes for the real‐time quantitative detection of cell death and cell cycle. The cell‐cycle indicator cdt1‐Kusabira orange (KO) is stably integrated into cancer cells and further transfected with the Fluorescence Resonance Energy Transfer‐based ECFP‐DEVD‐EYFP caspase activation sensor. The nuclear cdt1‐KO expression serves as the readout for cell‐cycle, and caspase activation is visualized by ECFP/EYFP ratiometric imaging. The image‐based platform allowed imaging of growing spheres for prolonged periods in 3D‐culture with excellent single‐cell resolution through confocal microscopy. High‐throughput screening (HTS) adaptation was achieved by targeting the caspase‐sensor at the nucleus, which enabled the quantitation of cell death in 3D‐models. The HTS using limited compound libraries, identified two lead compounds that induced caspase‐activation both in 2D and 3D‐cultures. This is the first report of an approach for noninvasive stain‐free quantitative imaging of cell death and cell cycle with potential drug discovery applications.
Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review
Authors: Li Chun‐wei , Yu Kang , Shyh‐Chang Ng , Jiang Zongmin , Liu Taoyan , Ma Shilin , Luo Lanfang , Guang Lu , Liang Kun , Ma Wenwu , Miao Hefan , Cao Wenhua , Liu Ruirui , Jiang Ling‐juan , Yu Song‐lin , Li Chao , Liu Hui‐jun , Xu Long‐yu , Liu Rong‐ji , Zhang Xin‐yuan , Liu Gao‐shan
Published: February 2022

Age‐associated obesity and muscle atrophy (sarcopenia) are intimately connected and are reciprocally regulated by adipose tissue and skeletal muscle dysfunction. During ageing, adipose inflammation leads to the redistribution of fat to the intra‐abdominal area (visceral fat) and fatty infiltrations in skeletal muscles, resulting in decreased overall strength and functionality. Lipids and their derivatives accumulate both within and between muscle cells, inducing mitochondrial dysfunction, disturbing β‐oxidation of fatty acids, and enhancing reactive oxygen species (ROS) production, leading to lipotoxicity and insulin resistance, as well as enhanced secretion of some pro‐inflammatory cytokines. In turn, these muscle‐secreted cytokines may exacerbate adipose tissue atrophy, support chronic low‐grade inflammation, and establish a vicious cycle of local hyperlipidaemia, insulin resistance, and inflammation that spreads systemically, thus promoting the development of sarcopenic obesity (SO). We call this the metabaging cycle. Patients with SO show an increased risk of systemic insulin resistance, systemic inflammation, associated chronic diseases, and the subsequent progression to full‐blown sarcopenia and even cachexia. Meanwhile in many cardiometabolic diseases, the ostensibly protective effect of obesity in extremely elderly subjects, also known as the ‘obesity paradox’, could possibly be explained by our theory that many elderly subjects with normal body mass index might actually harbour SO to various degrees, before it progresses to full‐blown severe sarcopenia. Our review outlines current knowledge concerning the possible chain of causation between sarcopenia and obesity, proposes a solution to the obesity paradox, and the role of fat mass in ageing.
Incorporation of metallic particles in activated carbon used in lipase immobilization for production of isoamyl acetate
Authors: de Oliveira Thainá Peixoto , Santos Mateus Pereira Flores , Brito Mylena Junqueira Pinto , Veloso Cristiane Martins
Published: February 2022

BACKGROUND

Biotechnology has revolutionized the use of enzymes for application in industrial processes. The present work evaluated the effect of functionalizing activated carbon with metallic nanoparticles obtained from corn cob residue on lipase immobilization. The aim was to improve the enzymatic activity of the immobilized enzyme and subsequent application of derivatives in the synthesis of isoamyl acetate ester (banana flavor).

RESULTS

The activated carbon (CCAC) had a mesoporous structure and specific surface area of 1135 m2 g−1, characteristic of supports from precursor material with a high cellulose content, which was reduced in metalized carbon (CCACM) due to the insertion of metallic particles (760 m2 g−1). CCACM showed a slightly higher lipase absorptive capacity than CCAC (280.72 ± 0.27 mg g−1 and 276.46 ± 0.03 mg g−1, respectively). Furthermore, for derivatives the optimal reaction medium conditions were pH 7.0 and 30 °C, confirming the advantage associated with lipase immobilization, obtaining activity values of 84.0 ± 2.12 U, 72.3 ± 1.7 U and 31.4 ± 1.9 U, for lipase immobilized on CCACM, CCAC and native form, respectively. The derivatives showed potential application in the synthesis of isoamyl acetate ester, with conversions above 90% and stability during five cycles of use.

CONCLUSION

The activated carbon metallization process showed an increase in lipase immobilization efficiency and proved to be a promising support, since there was an increase in its enzymatic activity and the derivatives obtained showed potential application in aroma synthesis, reaching conversion above 90%. © 2022 Society of Chemical Industry (SCI).
Multithreshold multipartite graphs
Authors: Chen Guantao , Hao Yanli
Published: February 2022

We call a graph a ‐threshold graph if there are distinct real numbers and a mapping such that for any two vertices , we have that if and only if there are odd numbers such that . The least integer such that is a ‐threshold graph is called a threshold number of , and denoted by . The well‐known family of threshold graphs is a set of graphs with . Jamison and Sprague introduced the concept of ‐threshold graph, and proved that exists for every graph . They further obtained a number of interesting results on . In addition, they also proposed several unsolved problems and conjectures, including the following two.

Problem: Determine the exact threshold numbers of the complete multipartite graphs.

Conjecture: For all even , there is a graph with and . This is equivalent to that for all odd , there is a graph with and , where is the complement of .

In this short paper, we give a partial solution of the problem and confirm the conjecture.
Inhibition of the extracellular signal‐regulated kinase pathway reduces the inflammatory component in nucleus pulposus cells
Authors: Tekari Adel , Marazza Alessandro , Crump Katherine , Bermudez‐Lekerika Paola , Gantenbein Benjamin
Published: February 2022

Intervertebral disc (IVD) degeneration is a spinal disorder that triggers an inflammatory response and subsequent development of spinal pseudoarthrosis. The aim of the present study is to elucidate the role of the extracellular signal‐regulated kinase (ERK) pathway in inflammation‐induced IVD cells. Inflammatory human nucleus pulposus (NP) cells (NPCs) were induced using tumor necrosis factor‐α and the ERK pathway was blocked using a selective molecule‐based inhibitor U0126. Gene expression of catabolic and anabolic markers, proinflammatory, and NPCs markers was investigated. The enzymatic activity of matrix metalloproteinases (MMP)2/MMP9 was determined by gelatin zymography and nitrite production was assessed by Griess reaction. The NPC metabolic activity and viability were assessed using resazurin sodium‐salt and live/dead assays, and subsequently, the specificity of U0126 on ERK1/2 signaling was determined. The catabolic enzyme MMP3 (p = 0.0001) and proinflammatory cytokine interleukin 6 (p = 0.036) were downregulated by U0126 in NPCs under inflammatory conditions. A significant increase of the cytokeratin 19 (p = 0.0031) was observed, suggesting a partial and possible recovery of the NP phenotype. U0126 does not seem to have an effect on prostaglandin production, aggrecanases, or other anabolic genes. We confirmed that U0126 selectively blocks the ERK phosphorylation and only affects the cell metabolic activity without the reduction of viable cells. Inhibition of ERK signaling downregulates important metalloproteinases and proinflammatory cytokines, and upregulates some NP markers, suggesting its potential to treat IVD degeneration.
Mending the Model for End‐Stage Liver Disease: An in‐depth review of the past, present, and future portopulmonary hypertension Model for End‐Stage Liver Disease exception
Authors: DuBrock Hilary M. , del Valle Kathryn T. , Krowka Michael J.
Published: February 2022

Patients with portopulmonary hypertension (POPH) have an increased cardiovascular and overall mortality risk when undergoing liver transplantation (LT). However, such risk is not captured in their Model for End‐Stage Liver Disease (MELD) laboratory score. POPH MELD exception criteria were established in 2006 with the aim of prioritizing these patients for LT prior to pulmonary hypertension (PH) progression and eventual right heart failure. The original criteria emphasized a posttreatment, pre‐LT mean pulmonary arterial pressure (mPAP) of <35 mm Hg and pulmonary vascular resistance (PVR) <400 dynes‐s‐cm−5 or <5 Wood units (WU). Since 2006, there have been important advances in the treatment of POPH with pulmonary arterial hypertension (PAH)–targeted therapies and newer evidence regarding LT outcomes and risk factors for perioperative mortality. Specifically, PVR rather than mPAP has been shown to be more strongly associated with outcomes, including mortality. In addition, among treated patients with POPH, mPAP may be persistently elevated related to an elevated cardiac output or other factors that do not necessarily reflect POPH disease severity. Thus, in February 2021, the Organ Procurement and Transplantation Network approved proposed modifications to POPH MELD exception criteria, now allowing either of the following posttreatment, pre‐LT hemodynamic profiles: mPAP less than 35 mm Hg and posttreatment PVR less than 400 dynes‐s‐cm−5 (or less than 5 WU) or mPAP greater than or equal to 35 mm Hg and less than 45 mm Hg and posttreatment PVR less than 240 dynes‐s‐cm−5 (or less than 3 WU). This article reviews the history of the POPH MELD exception criteria, describes the recent modifications to the exception criteria and the evidence supporting them, and highlights unanswered questions and areas for future research.
Elucidating the Size‐Dependency of In Vitro Digested Polystyrene Microplastics on Human Intestinal Cells Health and Function
Authors: Ma Yiyuan , Koh Jie Yan Cheryl , Lim Hong Kit , Shi Pujiang , Tay Chor Yong
Published: February 2022

The prevalence of microplastics (MPs) contamination in a broad spectrum of potable water sources has raised significant environmental and public health concerns. While evidence of ingested MPs bioaccumulation in the gastrointestinal tract (GIT) of aquatic and terrestrial organisms is mounting, the understanding of the effects of MPs on human gastrointestinal health remains scant. Herein, the potential deleterious biological effects of pristine and in vitro digested polystyrene (PS) MPs of varying sizes (i.e., 0.1, 1, and 10 µm) are systematically examined over a wide concentration range of 25–400 µg mL−1 on two human intestinal cell lines, namely Caco‐2 and NCM 460. Specifically, significant internalization of 0.1 and 1 µm PS ‐MPs have been observed in both cell types 24 h postexposure. However, multiparametric dose and time‐dependent analysis encompassing cell viability, reactive oxygen species (ROS), and nutrient absorption/metabolism measurement revealed no significant adversarial outcomes. Interestingly, it is found that the 0.1 µm PS‐MPs can perturb redox homeostasis in NCM460 but not in Caco‐2 cells. Based on the in vitro experimental boundaries and findings, it is concluded that ingested PS‐MPs pose little acute cytotoxic harm to human gastrointestinal health.
Rationally Driven Drug Nonradiative Decay via a Label‐Free Polyprodrug Strategy to Renew Tumor Cascade Photothermal‐Chemotherapy
Authors: Zhang Wenjia , Lyu Xiaoming , Zhang Li , Wang Wenhui , Shen Qi , Lu Siyu , Lu Ligong , Zhan Meixiao , Hu Xianglong
Published: February 2022

Drugs are frequently used for only chemotherapy that ignores their photophysical properties that potentially endow them with other therapeutic potency. Additionally, current photothermal‐chemotherapy replies on the codelivery of drugs and photothermal agents, but their spatiotemporal delivery and precise release is unsatisfactory. Herein, label‐free doxorubicin (DOX) polyprodrug nanoparticles (DPNs) are formulated from disulfide bonds‐tethered DOX polyprodrug amphiphiles (PDMA‐b‐PDOXM). Benefiting from boosted nonradiative decay of high‐density DOX, significant fluorescence quenching and photothermal effects are observed for DPNs without common photothermal agents. Upon cellular uptake and laser irradiation, the heat can promote lysosomal escape of DPNs into reductive cytosol, whereupon free DOX is released to activate chemotherapy and fluorescence, achieving rational cascade photothermal‐chemotherapy. The current label‐free polyprodrug strategy can make full use of drugs; it provides an alternative insight to extend the therapeutic domain of drugs.
Stochastic Resonance of a Confined Flexible Polymer
Authors: Nagarajan Karthik , Chen Shing Bor
Published: February 2022

The dynamics of a flexible polymer confined in two connected rectangular cavities with a small structureless hole in between subject to an oscillatory force has been studied via overdamped Brownian dynamics simulations. The system exhibits a stochastic resonance (SR) phenomenon which arises from both geometric and entropic effects. SR only occurs when the amplitude and frequency of the external force are greater and smaller than the critical values respectively. Another important factor is the lateral dimension of the cavities, which affects the chain's timely access to the hole at a given thermal noise via lateral diffusion before the direction reversal of the periodic force. The entropic effect associated with the polymer conformation emerges when the pore width is sufficiently small relative to the chain size. SR may take place at smaller thermal noise for longer chains due to the bead connectivity that assists the chain migration through the hole.
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

Background

Hereditary 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.

Methods

Clinical 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.

Results

We 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.

Conclusions

Our 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.
Output‐based event‐triggered control of networked systems subject to bilateral packet dropouts
Authors: Li Chengchao , Wu Chunyu , Abozinadah E. , Alassafi Madini O. , Xu Ning
Published: February 2022

In this paper, an output‐based event‐triggered control problem of discrete‐time networked control systems (NCSs) subject to bilateral packet dropouts is investigated. In view of stochastic sequences of packet dropouts in the measurement channels (from sensors to controller) and the control channels (from controller to actuators), the NCS is converted into a closed‐loop stochastic parameter system. In the aid of a Lyapunov functional based on stochastic variables, the sufficient conditions on design of a dynamic output feedback control law and bilateral event‐triggering conditions are derived to guarantee the exponentially mean‐square stability for NCSs. Furthermore, an improved iterative algorithm is given to obtain the output‐based control law and event‐triggering parameters from a set of nonconvex inequalities. Finally, a numerical example and the corresponding simulation results are given to illustrate the validity and applicability of the developed techniques.
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

Scope

Osteoporosis 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 Results

OVX 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.

Conclusion

Calcium 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

Scope: 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

Scope

High‐fat‐diet (HFD) is an important factor in obesity. Extracellular matrix (ECM) regulates white adipose tissue (WAT), but its mechanism is unknown.

Methods and Results

This 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.

Conclusion

HFD‐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

Purpose

With 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 time

Methods

To 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.

Results

DDE 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).

Conclusions

The 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

Purpose

To 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.

Methods

We 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.

Results

The 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.

Conclusion

Various 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

SARS‐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

Despite 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

Objective

Chromosomal 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.

Methods

Retrospective 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.

Results

2372 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).

Conclusions

Acceptance 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

SARS‐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

International 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

In 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

Pulmonary 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.
Brain activation measurement for motion gain decision of surgical endoscope manipulation
Authors: Miura Satoshi , Kaneko Taisei , Kawamura Kazuya , Kobayashi Yo , Fujie Masakatsu G.
Published: February 2022

Background

Robotic surgery improves minimally invasive interventions. However, it is challenging to determine the best gain settings for control of the endoscope. Providing the surgeon with the ability to manipulate the endoscope at an appropriate speed will likely improve the surgery by reducing the surgeon's stress. In this study, we validated the feasibility of a gain‐tuning method in which the operator's brain activity is measured and used to evaluate stress levels.

Methods

We developed an endoscope‐manipulation simulator and used functional near‐infrared spectroscopy to measure the prefrontal cortical activity, while participants controlled the simulator at different gain values.

Results

The brain activation levels in the prefrontal cortex exhibited significant differences under different viewpoint motion gain conditions.

Conclusions

The stress‐related brain activity was significantly reduced at specific gains, indicating that the brain activity evaluation would be useful to determine the parameters related to the operator's feelings.
Systematic review of the efficacy, effectiveness and safety of recombinant haemagglutinin seasonal influenza vaccines for the prevention of laboratory‐confirmed influenza in individuals ≥18 years of age
Authors: O Murchu Eamon , Comber Laura , Jordan Karen , Hawkshaw Sarah , Marshall Liam , O’Neill Michelle , Ryan Máirín , Teljeur Conor , Carnahan Annasara , Pérez Jaime Jesús , Robertson Anna Hayman , Johansen Kari , Jonge Jorgen de , Krause Tyra , Nicolay Nathalie , Nohynek Hanna , Pavlopoulou Ioanna , Pebody Richard , Penttinen Pasi , Soler‐Soneira Marta , Wichmann Ole , Harrington Patricia
Published: February 2022

The most effective means of preventing seasonal influenza is through vaccination. In this systematic review, we investigated the efficacy, effectiveness and safety of recombinant haemagglutinin (HA) seasonal influenza vaccines to prevent laboratory‐confirmed influenza. A systematic literature search was conducted in electronic databases and grey literature sources up to 7 February 2020. Randomised controlled trials and non‐randomised studies of interventions were eligible for inclusion. The search returned 28,846 records, of which 10 studies on recombinant HA influenza vaccine met our inclusion criteria. One study found that the quadrivalent recombinant HA influenza vaccine had higher relative vaccine efficacy (rVE) in preventing laboratory‐confirmed influenza during the 2014–15 season compared with traditional quadrivalent vaccination in adults aged ≥50 years (rVE = 30%, 95% CI 10%–47%, moderate‐certainty evidence). In a subgroup analysis, higher rVE was reported for influenza A (rVE = 36%, 95% CI 14% to 53%), but not for B (non‐significant). Another study reported higher efficacy for the trivalent recombinant HA vaccine compared with placebo (VE = 45%, 95% CI 19–63, 1 RCT, low‐certainty evidence) in adults aged 18–55 years. With the exception of a higher rate of chills (RR = 1.33, 95% CI 1.03–1.72), the safety profile of recombinant HA vaccines was comparable to that of traditional influenza vaccines. The evidence base for the efficacy and effectiveness of recombinant HA influenza vaccines is limited at present, although one study found that the quadrivalent recombinant HA influenza vaccine had higher rVE compared with traditional quadrivalent vaccination in adults aged ≥50 years.
Leaders' sustainability competences and small and medium‐sized enterprises outcomes: The role of social entrepreneurial orientation
Authors: Álvarez‐García José , Hormiga‐Pérez Esther , Sarango‐Lalangui Paul O. , del Río‐Rama María de la Cruz
Published: February 2022

The market for socially conscious products and services has grown exponentially in the last years. Consequently, adding social value is among the great challenges that companies have to face nowadays. In view of this, companies need leaders with a set of specific skills that prepares them to act and compete in this new environment. This is especially true for small and medium‐sized enterprises (SMEs), which are even more dependent on their leaders' competences. The aim of this article is to analyse the influence of leaders' sustainability competences on the social entrepreneurial orientation of SMEs of the tourism sector, as well as the influence of this strategy on the firm's performance. The methodology used to validate the measurement scales is exploratory and confirmatory factor analysis and the structural equation modelling technique is applied to analyse the causal relationships proposed in the model. The results show that sustainability competences positively affect social entrepreneurial orientation; specifically, the social risk‐taking and proactivity competence has a positive influence on the economic and social performance of SMEs, and in particular, on their green innovation performance. These results highlight the key role that leaders' competences have in SMEs' social orientation and thus, the importance of training in competences for sustainable development.