bluuebunny/crossref_metadata_2025 huggingface dataset:
The LeVe CPAP System for Oxygen-Efficient CPAP Respiratory Support: Development and Pilot Evaluation
Authors: Culmer Pete , Davis Birch W. , Waters I. , Keeling A. , Osnes C. , Jones D. , de Boer G. , Hetherington R. , Ashton S. , Latham M. , Beacon T. , Royston T. , Miller R. , Littlejohns A. , Parmar J. , Lawton Tom , Murdoch S. , Brettle D. , Musasizi R. , Nampiina G. , Namulema E. , Kapur N.
Published: August 2021

Background: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a significant demand on healthcare providers (HCPs) to provide respiratory support for patients with moderate to severe symptoms. Continuous Positive Airway Pressure (CPAP) non-invasive ventilation can help patients with moderate symptoms to avoid the need for invasive ventilation in intensive care. However, existing CPAP systems can be complex (and thus expensive) or require high levels of oxygen, limiting their use in resource-stretched environments.

Technical Development + Testing: The LeVe (“Light”) CPAP system was developed using principles of frugal innovation to produce a solution of low complexity and high resource efficiency. The LeVe system exploits the air flow dynamics of electric fan blowers which are inherently suited to delivery of positive pressure at appropriate flow rates for CPAP. Laboratory evaluation demonstrated that performance of the LeVe system was equivalent to other commercially available systems used to deliver CPAP, achieving a 10 cm H2O target pressure within 2.4% RMS error and 50–70% FiO2 dependent with 10 L/min oxygen from a commercial concentrator.

Pilot Evaluation: The LeVe CPAP system was tested to evaluate safety and acceptability in a group of ten healthy volunteers at Mengo Hospital in Kampala, Uganda. The study demonstrated that the system can be used safely without inducing hypoxia or hypercapnia and that its use was well-tolerated by users, with no adverse events reported.

Conclusions: To provide respiratory support for the high patient numbers associated with the COVID-19 pandemic, healthcare providers require resource efficient solutions. We have shown that this can be achieved through frugal engineering of a CPAP ventilation system, in a system which is safe for use and well-tolerated in healthy volunteers. This approach may also benefit other respiratory conditions which often go unaddressed in Low and Middle Income Countries (LMICs) for want of context-appropriate technology designed for the limited oxygen resources available.
Genomic Characterization of ESBL- and Carbapenemase-Positive Enterobacteriaceae Co-harboring mcr-9 in Japan
Authors: Nakamura Akihiro , Nakamura Tatsuya , Niki Makoto , Kuchibiro Tomokazu , Nishi Isao , Komatsu Masaru
Published: August 2021

Worldwide spread of Enterobacteriaceae resistant to colistin, a polypeptide antibacterial drug for last-resort treatment of carbapenemase-producing Enterobacteriaceae (CPE) infections, is concerning. This study aimed to elucidate colistin MICs and molecular characteristics of mcr-1 to mcr-9 of ESBL-producing Escherichia coli (ESBL-Ec) and CPE in Japan and clarify the genomic structure of strains harboring mcr genes (especially mcr-9). This study included 168 ESBL-Ec and 126 CPE strains isolated at Japanese medical facilities. Colistin susceptibility testing and multiplex PCR targeting mcr-1 to mcr-9 were performed for all strains with S1-nuclease pulsed-field gel electrophoresis, Southern blot hybridization, and whole-genome sequencing (WGS) with hybrid assembly performed for mcr gene-carrying strains. Two CPE strains showed a MIC ≥ 4 μg/ml in colistin susceptibility testing, with no known resistance mechanism detected. However, PCR conducted on all target strains detected three mcr-9-carrying strains showing colistin susceptibility. The blaCTX–M–62-positive E. coli THUN648 strain simultaneously carried blaCTX–M–62 and mcr-9 on a 275-kbp plasmid. Besides, blaIMP–6 + blaCTX–M–2-positive Klebsiella pneumoniae THUN262 and blaGES–24-positive Enterobacter kobei THUN627 had mcr-9 encoded on the chromosome. Only THUN627 encoded qseB/C, which is suggested to be a regulatory gene for mcr-9, downstream of mcr-9. However, this strain showed no increased expression of these genes in mRNA quantitative analysis under colistin exposure. Colistin MICs of ESBL-Ec and CPE in Japan were all below 2 μg/ml, which is below the epidemiological cutoff (ECOFF) value (https://eucast.org/) or clinical breakpoint (CB) (CLSI M100-S30) reported for colistin, indicating neither “microbiological” nor “clinical” resistance. Several colistin-susceptible Enterobacteriaceae carrying silent mcr-9 encoded on plasmids and chromosomes have already spread worldwide along with other antimicrobial resistance genes. However, the mechanism of colistin resistance by mcr-9 remains unclear.
Antimicrobial Compounds in the Volatilome of Social Spider Communities
Authors: Lammers Alexander , Zweers Hans , Sandfeld Tobias , Bilde Trine , Garbeva Paolina , Schramm Andreas , Lalk Michael
Published: August 2021

Social arthropods such as termites, ants, and bees are among others the most successful animal groups on earth. However, social arthropods face an elevated risk of infections due to the dense colony structure, which facilitates pathogen transmission. An interesting hypothesis is that social arthropods are protected by chemical compounds produced by the arthropods themselves, microbial symbionts, or plants they associate with. Stegodyphus dumicola is an African social spider species, inhabiting communal silk nests. Because of the complex three-dimensional structure of the spider nest antimicrobial volatile organic compounds (VOCs) are a promising protection against pathogens, because of their ability to diffuse through air-filled pores. We analyzed the volatilomes of S. dumicola, their nests, and capture webs in three locations in Namibia and assessed their antimicrobial potential. Volatilomes were collected using polydimethylsiloxane (PDMS) tubes and analyzed using GC/Q-TOF. We showed the presence of 199 VOCs and tentatively identified 53 VOCs. More than 40% of the tentatively identified VOCs are known for their antimicrobial activity. Here, six VOCs were confirmed by analyzing pure compounds namely acetophenone, 1,3-benzothiazole, 1-decanal, 2-decanone, 1-tetradecene, and docosane and for five of these compounds the antimicrobial activity were proven. The nest and web volatilomes had many VOCs in common, whereas the spider volatilomes were more differentiated. Clear differences were identified between the volatilomes from the different sampling sites which is likely justified by differences in the microbiomes of the spiders and nests, the plants, and the different climatic conditions. The results indicate the potential relevance of the volatilomes for the ecological success of S. dumicola.
Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer’s Disease
Authors: Wan Lily , Ai Jia-Qi , Yang Chen , Jiang Juan , Zhang Qi-Lei , Luo Zhao-Hui , Huang Rou-Jie , Tu Tian , Pan Aihua , Tu Ewen , Manavis Jim , Xiao Bo , Yan Xiao-Xin
Published: August 2021

Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of SHANK3 are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer’s disease (AD)-type β-amyloid (Aβ) and Tau pathogenesis. In general, Shank3 immunoreactivity (IR) exhibited largely a neuropil pattern with differential laminar/regional distribution across brain regions. In youth and adults, subsets of pyramidal/multipolar neurons in the cerebrum, striatum, and thalamus showed moderate IR, while some large-sized neurons in the brainstem and the granule cells in the cerebellar cortex exhibited light IR. In double immunofluorescence, Shank3 IR occurred at the sublemmal regions in neuronal somata and large dendrites, apposing to synaptophysin-labeled presynaptic terminals. In aged cases, immunolabeled neuronal somata were reduced, with disrupted neuropil labeling seen in the molecular layer of the dentate gyrus in AD cases. In immunoblot, levels of Shank3 protein were positively correlated with that of the postsynaptic density protein 95 (PSD95) among different brain regions. Levels of Shank3, PSD95, and synaptophysin immunoblotted in the prefrontal, precentral, and cerebellar cortical lysates were reduced in the aged and AD relative to youth and adult groups. Taken together, the differential Shank3 expression among brain structures/regions indicates the varied local density of the excitatory synapses. The enriched Shank3 expression in the forebrain subregions appears inconsistent with a role of this protein in the modulation of high cognitive functions. The decline of its expression in aged and AD brains may relate to the degeneration of excitatory synapses.
Quantifying the Brain Predictivity of Artificial Neural Networks With Nonlinear Response Mapping
Authors: Anand Aditi , Sen Sanchari , Roy Kaushik
Published: August 2021

Quantifying the similarity between artificial neural networks (ANNs) and their biological counterparts is an important step toward building more brain-like artificial intelligence systems. Recent efforts in this direction use neural predictivity, or the ability to predict the responses of a biological brain given the information in an ANN (such as its internal activations), when both are presented with the same stimulus. We propose a new approach to quantifying neural predictivity by explicitly mapping the activations of an ANN to brain responses with a non-linear function, and measuring the error between the predicted and actual brain responses. Further, we propose to use a neural network to approximate this mapping function by training it on a set of neural recordings. The proposed method was implemented within the TensorFlow framework and evaluated on a suite of 8 state-of-the-art image recognition ANNs. Our experiments suggest that the use of a non-linear mapping function leads to higher neural predictivity. Our findings also reaffirm the observation that the latest advances in classification performance of image recognition ANNs are not matched by improvements in their neural predictivity. Finally, we examine the impact of pruning, a widely used ANN optimization, on neural predictivity, and demonstrate that network sparsity leads to higher neural predictivity.
The Impact of Homocysteine on the Risk of Hormone-Related Cancers: A Mendelian Randomization Study
Authors: He Qian , Yang Ze , Sun Yandi , Qu Zihao , Jia Xueyao , Li Jingjia , Lin Yindan , Luo Yan
Published: August 2021

Background: Aberrant homocysteine level is associated with metabolic disorders and DNA damage, which may be involved in the carcinogenesis of hormone-related cancers, but clinical results of observational studies are controversial. In this study, we investigated the causal relationships between plasma homocysteine and breast cancer (BRCA), prostate cancer (PrCa), and renal cell carcinoma (RCC) using Mendelian randomization (MR) analyses.

Design and Methods: To investigate the putative causal associations between homocysteine and the aforementioned three types of cancers, a two-sample MR study was employed for the study. The primary strategy for summary data analyses was the inverse-variance-weighted (IVW) approach. In our study, the single-nucleotide polymorphisms (SNPs) excluded confounding factors through Linkage Disequilibrium (LD). Phenoscanner tests were the instrumental variants (IVs), homocysteine was the exposure, and BRCA, PrCa, and RCC were the outcomes. Single-nucleotide polymorphisms associated with homocysteine were extracted from a large genome-wide association study (GWAS) meta-analysis of European participants (n = 44,147). Summary Statistics of BRCA were obtained from the latest and largest GWAS meta-analysis comprising of 82 studies from Breast Cancer Association Consortium (BCAC) studies, including women of European ancestry (133,384 cases and 113,789 controls); we obtained summary-level data from the GWAS meta-analysis of PrCa comprising 79,148 cases and 61,106 controls of European ancestry, and the dataset of RCC was a sex-specific GWAS meta-analysis comprising of two kidney cancer genome-wide scans for men (3,227 cases and 4,916 controls) and women (1,992 cases and 3,095 controls) of European ancestry. The MR-Egger and weight median analyses were applied for the pleiotropy test.

Results: The results showed null associations between plasma homocysteine levels and overall BRCA (effect = 0.97, 95% CI: 0.90–1.06, P = 0.543), overall PrCa (effect = 1.01, 95% CI: 0.93–1.11, P = 0.774), RCC in men (effect = 0.99, 95% CI: 0.73–1.34, P = 0.929), and RCC in women (effect = 0.89, 95% CI: 0.61–1.31, P = 0.563).

Conclusions: We found no putative causal associations between homocysteine and risk of BRCA, PrCa, and RCC.
Detection of Oesophageal Fistula by Radionuclide Salivagram SPECT/CT
Authors: Wang Yingwei , Wang Chao , Liu Lin , Huang Xinwen , Guo Zhaoyou , Zeng Wei , Sun Rui , Chen Yue
Published: August 2021

Purpose

Videofluoroscopic swallowing study (VFSS) is currently the most widely used clinical examination method for diagnosis of oesophageal fistula, but it has many limitations. Therefore, we evaluated radionuclide salivagram single-photon emission computed tomography (SPECT/CT) as a new method of oesophageal fistula diagnosis.

Methods

We retrospectively evaluated the data of 11 patients (10 men and 1 woman, aged 41 to 70 years, with an average age of 58.6 years) who had clinically suspected oesophageal fistula from January 2019 to October 2020. They underwent radionuclide salivagram SPECT/CT and VFSS examinations, and we analysed and compared the results of the two examinations.

Results

A total of 11 patients were included in this study. Ten underwent both salivagram and VFSS examinations. One patient was unable to swallow the contrast agent; therefore, only salivagram was performed, and we excluded this patient from the VFSS analysis. A total of 11 patients underwent salivagram examinations, of which 6 were positive and 5 were negative. A total of 10 patients were tested by VFSS, of which 6 results were positive and 4 were negative.

Conclusion

Radionuclide salivagram SPECT/CT and VFSS are complementary, which can greatly improve the clinical diagnosis and prognosis of oesophageal fistula. When the patient cannot perform the VFSS, or the clinical symptoms are inconsistent with the VFSS imaging findings, the salivagram is an ideal test method.
Radioimmunotherapy for Brain Metastases: The Potential for Inflammation as a Target of Choice
Authors: Corroyer-Dulmont Aurélien , Jaudet Cyril , Frelin Anne-Marie , Fantin Jade , Weyts Kathleen , Vallis Katherine A. , Falzone Nadia , Sibson Nicola R. , Chérel Michel , Kraeber-Bodéré Françoise , Batalla Alain , Bardet Stéphane , Bernaudin Myriam , Valable Samuel
Published: August 2021

Brain metastases (BM) are frequently detected during the follow-up of patients with malignant tumors, particularly in those with advanced disease. Despite a major progress in systemic anti-cancer treatments, the average overall survival of these patients remains limited (6 months from diagnosis). Also, cognitive decline is regularly reported especially in patients treated with whole brain external beam radiotherapy (WBRT), due to the absorbed radiation dose in healthy brain tissue. New targeted therapies, for an earlier and/or more specific treatment of the tumor and its microenvironment, are needed. Radioimmunotherapy (RIT), a combination of a radionuclide to a specific antibody, appears to be a promising tool. Inflammation, which is involved in multiple steps, including the early phase, of BM development is attractive as a relevant target for RIT. This review will focus on the (1) early biomarkers of inflammation in BM pertinent for RIT, (2) state of the art studies on RIT for BM, and (3) the importance of dosimetry to RIT in BM. These two last points will be addressed in comparison to the conventional EBRT treatment, particularly with respect to the balance between tumor control and healthy tissue complications. Finally, because new diagnostic imaging techniques show a potential for the detection of BM at an early stage of the disease, we focus particularly on this therapeutic window.
Single-Cell RNA Sequencing Reveals the Migration of Osteoclasts in Giant Cell Tumor of Bone
Authors: Feng Wenyu , He Mingwei , Jiang Xiaohong , Liu Huijiang , Xie Tianyu , Qin Zhaojie , Huang Qian , Liao Shijie , Lin Chengsen , He Juliang , Xu Jiake , Ma Jie , Liu Yun , Wei Qingjun
Published: August 2021

Giant cell tumor of bone (GCTB) is benign tumor that can cause significant osteolysis and bone destruction at the epiphysis of long bones. Osteoclasts are thought to be highly associated with osteolysis in GCTB. However, the migration of osteoclasts in GCTB remains unclear. A deeper understanding of the complex tumor microenvironment is required in order to delineate the migration of osteoclasts in GCTB. In this study, samples were isolated from one patient diagnosed with GCTB. Single-cell RNA sequencing (scRNA-seq) was used to detect the heterogeneity of GCTB. Multiplex immunofluorescence staining was used to evaluate the cell subtypes identified by scRNA-seq. A total of 8,033 cells were obtained from one patient diagnosed with GCTB, which were divided into eight major cell types as depicted by a single-cell transcriptional map. The osteoclasts were divided into three subsets, and their differentiation trajectory and migration status were further analyzed. Osteoclast migration may be regulated via a series of genes associated with cell migration. Furthermore, four signaling pathways (RANKL, PARs, CD137 and SMEA3 signaling pathway) were found to be highly associated with osteoclast migration. This comprehensive single-cell transcriptome analysis of GCTB identified a series of genes associated with cell migration as well as four major signaling pathways that were highly related to the migration of osteoclasts in GCTB. Our findings broaden the understanding of GCTB bionetworks and provides a theoretical basis for anti-osteolysis therapy against GCTB in the future.
A Propensity-Matched Analysis of Survival of Clinically Diagnosed Early-Stage Lung Cancer and Biopsy-Proven Early-Stage Non-Small Cell Lung Cancer Following Stereotactic Ablative Radiotherapy
Authors: Zhang Ran , Guo Yanling , Yan Yujie , Liu Yuanjun , Zhu Yaoyao , Kang Jingjing , Li Fangjuan , Sun Xiaojiang , Xing Ligang , Xu Yaping
Published: August 2021

Purpose

Stereotactic body radiotherapy (SBRT) has been increasingly regarded as a reasonable option for early-stage lung cancer patients without pretreatment pathologic results, but the efficacy and safety in a Chinese population remains unclear. The aim of this study was to compare survival outcomes and toxicities between patients with clinically diagnosed early-stage lung cancer or biopsy-proven early-stage non-small cell lung cancer and to demonstrate the rationality of this treatment.

Material and Methods

From May 2012 to December 2018, 56 patients with clinically diagnosed early-stage lung cancer and 60 patients with early-stage biopsy-proven were selected into non-pathological group and pathological group, respectively. Propensity score matching (PSM) was performed to reduce patient selection bias. Survival analysis with log-rank test was used to assess the differences of treatment outcomes, which included local control (LC), progression-free survival (PFS), and overall survival (OS).

Results

The median age was 76 (range 47–93) years, and the median follow-up time was 58.3 (range 4.3–95.1) months in the cohort without pathologic results. The median age was 74 (range 57–88) years, and the median follow-up time was 56.3 (range 2.6–94) months in the cohort with pathologic results. 45 matched-pair were analyzed. The 5-year LC, PFS, and OS rates in matched-pair patients with or without pathologic biopsy were 85.5% and 89.8%, 40.6% and 70.9%, and 63.2% and 76.1%, respectively. On Kaplan-Meier survival analysis after PSM analysis, there was no significant difference between patients with pathologic results versus patients with no pathologic results in terms of LC (P= 0.498) and OS (P=0.141). Of the matched-pair patients treated with SBRT, only 1 patient experienced grade 3 or above radiation pneumonitis.

Conclusion

For early-stage lung cancer patients with medically inoperable or not suitable for invasive diagnosis, SBRT may be a good local treatment.
Germline BAP1 Mutation in a Family With Multi-Generational Meningioma With Rhabdoid Features: A Case Series and Literature Review
Authors: Prasad Rahul N. , Gardner Ulysses G. , Yaney Alexander , Prevedello Daniel M. , Koboldt Daniel C. , Thomas Diana L. , Mardis Elaine R. , Palmer Joshua D.
Published: August 2021

Meningioma is the most common primary brain tumor, and recurrence risk increases with increasing WHO Grade from I to III. Rhabdoid meningiomas are a subset of WHO Grade III tumors with rhabdoid cells, a high proliferation index, and other malignant features that follow an aggressive clinical course. Some meningiomas with rhabdoid features either only focally or without other malignant features are classified as lower grade yet still recur early. Recently, inactivating mutations in the tumor suppressor gene BAP1 have been associated with poorer prognosis in rhabdoid meningioma and meningioma with rhabdoid features, and germline mutations have been linked to a hereditary tumor predisposition syndrome (TPDS) predisposing patients primarily to melanoma and mesothelioma. We present the first report of a familial BAP1 inactivating mutation identified after multiple generations of a family presented with meningiomas with rhabdoid features instead of with previously described BAP1 loss-associated malignancies. A 24-year-old female presented with a Grade II meningioma with rhabdoid and papillary features treated with subtotal resection, adjuvant external beam radiation therapy, and salvage gamma knife radiosurgery six years later. Around that time, her mother presented with a meningioma with rhabdoid and papillary features managed with resection and adjuvant radiation therapy. Germline testing was positive for a pathogenic BAP1 mutation in both patients. Sequencing of both tumors demonstrated biallelic BAP1 inactivation via the combination of germline BAP1 mutation and either loss of heterozygosity or somatic mutation. No additional mutations implicated in oncogenesis were noted from either patient’s germline or tumor sequencing, suggesting that the inactivation of BAP1 was responsible for pathogenesis. These cases demonstrate the importance of routine BAP1 tumor testing in meningioma with rhabdoid features regardless of grade, germline testing for patients with BAP1 inactivated tumors, and tailored cancer screening in this population.
Early Breast Cancers During Pregnancy Treated With Breast-Conserving Surgery in the First Trimester of Gestation: A Feasibility Study
Authors: Blundo Concetta , Giroda Massimo , Fusco Nicola , Sajjadi Elham , Venetis Konstantinos , Leonardi M. Cristina , Vicini Elisa , Despini Luca , Rossi Claudia F. , Runza Letterio , Sfondrini Maria S. , Piciotti Roberto , Di Loreto Eugenia , Scarfone Giovanna , Guerini-Rocco Elena , Viale Giuseppe , Veronesi Paolo , Buonomo Barbara , Peccatori Fedro A. , Galimberti Viviana E.
Published: August 2021

Breast cancer is the most common malignancy occurring during gestation. In early-stage breast cancer during pregnancy (PrBC), breast-conserving surgery (BCS) with delayed RT is a rational alternative to mastectomy, for long considered the standard-of-care. Regrettably, no specific guidelines on the surgical management of these patients are available. In this study, we investigated the feasibility and safety of BCS during the first trimester of pregnancy in women with early-stage PrBC. All patients with a diagnosis of PrBC during the first trimester of pregnancy jointly managed in two PrBC-specialized Centers were included in this study. All patients underwent BCS followed by adjuvant radiotherapy to the ipsilateral breast after delivery. Histopathological features and biomarkers were first profiled on pre-surgical biopsies. The primary outcome was the isolated local recurrence (ILR). Among 168 PrBC patients, 67 (39.9%) were diagnosed during the first trimester of gestation. Of these, 30 patients (age range, 23-43 years; median=36 years; gestational age, 2-12 weeks; median=7 weeks; median follow-up time=6.5 years) met the inclusion criteria. The patients that were subjected to radical surgery (n=14) served as controls. None of the patients experienced perioperative surgical complications. No ILR were observed within three months (n=30), 1 year (n=27), and 5 years (n=18) after surgery. Among the study group, 4 (12.3%) patients experienced ILR or new carcinomas after 6-13 years, the same number (n=4) had metastatic dissemination after 3-7 years. These patients are still alive and disease-free after 14-17 years of follow-up. The rate of recurrences and metastasis in the controls were not significantly different. The findings provide evidence that BCS in the first trimester PrBC is feasible and reasonably safe for both the mother and the baby.
Serum and Urinary Osteocalcin in Healthy 7- to 19-Year-Old Finnish Children and Adolescents
Authors: Paldánius Päivi M. , Ivaska Kaisa K. , Mäkitie Outi , Viljakainen Heli
Published: August 2021

Children and adolescents have high bone turnover marker (BTM) levels due to high growth velocity and rapid bone turnover. Pediatric normative values for BTMs reflecting bone formation and resorption are vital for timely assessment of healthy bone turnover, investigating skeletal diseases, or monitoring treatment outcomes. Optimally, clinically feasible measurement protocols for BTMs would be validated and measurable in both urine and serum. We aimed to (a) establish sex- and age-specific reference intervals for urinary and serum total and carboxylated osteocalcin (OC) in 7- to 19-year-old healthy Finnish children and adolescents (n= 172), (b) validate these against standardized serum and urinary BTMs, and (c) assess the impact of anthropometry, pubertal status, and body composition on the OC values. All OC values in addition to other BTMs increased with puberty and correlated with pubertal growth, which occurred and declined earlier in girls than in boys. The mean serum total and carboxylated OC and urinary OC values and percentiles for sex-specific age categories and pubertal stages were established. Correlation between serum and urinary OC was weak, especially in younger boys, but improved with increasing age. The independent determinants for OC varied, the urinary OC being the most robust while age, height, weight, and plasma parathyroid hormone (PTH) influenced serum total and carboxylated OC values. Body composition parameters had no influence on any of the OC values. In children and adolescents, circulating and urinary OC reflect more accurately growth status than bone mineral density (BMD) or body composition. Thus, validity of OC, similar to other BTMs, as a single marker of bone turnover, remains limited. Yet, serum and urinary OC similarly to other BTMs provide a valuable supplementary tool when assessing longitudinal changes in bone health with repeat measurements, in combination with other clinically relevant parameters.
Mexiletine Treatment for Neonatal LQT3 Syndrome: Case Report and Literature Review
Authors: Bagkaki Alena , Tsoutsinos Alexandros , Hatzidaki Eleftheria , Tzatzarakis Manolis , Parthenakis Fragiskos , Germanakis Ioannis
Published: August 2021

Background: Early diagnosis of long QT type 3 (LQT3) syndrome during the neonatal period is of paramount clinical importance. LQT3 syndrome results in increased mortality and a mutation-specific response to treatment compared to other more common types of LQT syndrome. Mexiletine, a sodium channel blocker, demonstrates a mutation-specific QTc shortening effect in LQT3 syndrome patients.

Case Presentation: A neonate manifested marked QTc prolongation after birth. An electrocardiogram (ECG) recording was performed due to positive family history of genetically confirmed LQT3 syndrome (SCN5A gene missense mutation Tyr1795Cys), and an association with sudden cardiac death was found in family members. The mexiletine QTc normalizing effect (QTc shortening from 537 to 443 ms), practical issues related to oral mexiletine treatment of our young patient, along with a literature review regarding identification and mexiletine treatment in infants with LQT3 syndrome are presented.

Conclusions: Mexiletine could be considered in the treatment of high-risk LQT3 patients already in the neonatal period in addition to b-blocker therapy. Availability of standardized commercial mexiletine pediatric formulas, serum mexiletine level analyses, and future prospective studies are needed to evaluate the potential beneficial effect of early mexiletine treatment on the incidence of future acute cardiac events in these high-risk LQT syndrome patients.
Role of Hemoperfusion With CytoSorb Associated With Continuous Kidney Replacement Therapy on Renal Outcome in Critically III Children With Septic Shock
Authors: Bottari Gabriella , Lorenzetti Giulia , Severini Flavia , Cappoli Andrea , Cecchetti Corrado , Guzzo Isabella
Published: August 2021

Introduction: Sepsis-associated acute kidney injury (SA-AKI) represents a relevant cause of mortality and morbidity in critically ill children. Since with the “inflammatory theory” the authors have been witnessed an important role of inflammatory mediators in the pathophysiology and in the prognosis of SA-AKI, making the need of adjunctive therapies in association with kidney replacement therapies mandatory. Hemoperfusion with CytoSorb is a safe and well-tolerated therapy in septic shock: the very high surface area of the absorber means it is able to efficiently remove cytokines and other medium size molecules involved in cytokine storm, thus playing a synergistic effect with Continuous Kidney Replacement Therapy (CKRT).

Materials and Methods: We retrospectively analyzed data from a cohort of eight critically ill children treated from January 2018 to March 2020 describing the impact of CKRT plus hemoperfusion with CytoSorb on renal outcome in critically ill children with septic shock.

Results: We evidenced a significant reduction in interleukin (IL)-6 an IL-10 after hemoperfusion with CytoSorb in our pediatric population. Furthermore, we were able to show a significant improvement of creatinine and blood urea nitrogen (BUN) after blood purification and at pediatric intensive care units (PICU) discharge. We have observed a median of 2.5 CKRT days after stop of hemoperfusion (Q1 0.25; Q3 18.75). None of our patients required CKRT 30 days after PICU discharge (PICU-D). None of them developed CKD.

Conclusion: Hemoperfusion with CytoSorb is a valuable therapeutic option in combination with CKRT in SA-AKI. More studies are warranted to confirm our results and in particular to define the role of this adjuvant therapy as a preemptive strategy to protect renal function in pediatric septic shock.
A Polysaccharide From the Whole Plant of Plantago asiatica L. Enhances the Antitumor Activity of Dendritic Cell-Based Immunotherapy Against Breast Cancer
Authors: Gao Jiafeng , Zhang Yi-Nan , Cui Jingwen , Zhang Jiatong , Ming Yuexiang , Hao Zhihui , Xu Huihao , Cheng Nan , Zhang Di , Jin Yipeng , Lin Degui , Lin Jiahao
Published: August 2021

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) that mediate T-cell immune responses. Breast cancer is one of the most commonly diagnosed diseases and its mortality rate is higher than any other cancer in both humans and canines. Plantain polysaccharide (PLP), extracted from the whole plant of Plantago asiatica L., could promote the maturation of DCs. In this research, we found that PLP could upregulate the maturation of DCs both in vitro and in vivo. PLP-activated DCs could stimulate lymphocytes’ proliferation and differentiate naive T cells into cytotoxic T cells. Tumor antigen-specific lymphocyte responses were enhanced by PLP and CIPp canine breast tumor cells lysate-pulsed DCs, and PLP and CIPp-cell-lysate jointly stimulated DCs cocultured with lymphocytes having the great cytotoxicity on CIPp cells. In the 4T1 murine breast tumor model, PLP could control the size of breast tumors and improve immunity by recruiting DCs, macrophages, and CD4+ and CD8+ T cells in the tumor microenvironment. These results indicated that PLP could achieve immunotherapeutic effects and improve immunity in the breast tumor model.
Optimized Dosing Regimens of Meropenem in Septic Children Receiving Extracorporeal Life Support
Authors: Wang Yixue , Chen Weiming , Huang Yidie , Wang Guangfei , Li Zhiping , Yan Gangfeng , Chen Chao , Lu Guoping
Published: August 2021

Objectives: To develop a population pharmacokinetic model of meropenem in children with sepsis receiving extracorporeal life support (ECLS) and optimize the dosage regimen based on investigating the probability of target attainment (PTA).

Methods: The children with sepsis were prospectively enrolled in a pediatric intensive care unit from January 2018 to December 2019. The concentration-time data were fitted using nonlinear mixed effect model approach by NONMEM program. The stochastic simulation considering various scenarios based on proposed population pharmacokinetics model were conducted, and the PTAs were calculated to optimize the dosage regimens.

Results: A total of 25 children with sepsis were enrolled, of whom13 received ECMO, 9 received CRRT, and 4 received ECMO combined with CRRT. 12 children received a two-step 3-h infusion and 13 children received 1-h infusion. Bodyweight and creatinine clearance had significant impacts on the PK parameters. ECMO intervention was not related to the PK properties. If 100%T > MIC was chosen as target, children receiving 40 mg/kg q8h over a 3 h-infusion only reached the PTA up to 77.4%. If bacteria with MIC 2 mg/L were to be treated with meropenem and the PTA target was 50%T > MIC, a dose of 40 mg/kg q8h for 1 h infusion would be necessary.

Conclusions: The PK properties of meropenem in septic children receiving extracorporeal life support were best described. We recommended the opitimized dosing regimens for septic children receiving ECLS depending on the PTA of PK target 50%T > MIC and 100%T > MIC, for children with sepsis during ECLS with different body weight, estimated creatinine clearance (eCRCL) and MIC of bacteria.
Assessment of Cardiovascular Functioning Among Regular Kratom (Mitragyna speciosa Korth) Users: A Case Series
Authors: Leong Bin Abdullah Mohammad Farris Iman , Singh Darshan
Published: August 2021

Multiorgan toxicities have been extensively reported in kratom (Mitragyna speciosa Korth) users in Western countries but not in Southeast Asia. Existing literature argued that this discrepancy may be due to underreporting of kratom-related toxicity cases in Southeast Asia. Hence, this case series filled the research gap by clinically assessing the cardiovascular functioning and serum mitragynine level of regular kratom users in its traditional settings in Malaysia. Nine regular kratom users without history of polysubstance use were recruited from the same community via snowball sampling and were subjected to electrocardiogram (ECG) and echocardiogram assessments. Serum mitragynine analysis was also performed by solid-phase extraction and liquid chromatography-tandem mass spectrometry. The mean serum mitragynine level was 10.3 mg/L (SD = 6.9) and ranged from 2.5 mg/L to 22.4 mg/L. Those who consumed an average daily quantity of four or more glasses of brewed kratom juice (p = 0.045) and those who had prolonged QTc intervals (p = 0.017) had significantly higher serum mitragynine level. Echocardiographic findings of all the respondents were normal except one reported left ventricular hypertrophy and another had trivial tricuspid regurgitation with pulmonary artery systolic pressure (PASP) of 10 + 5 mmHg. Regular kratom use without concomitant use of other illicit substances may not provoke any risk of cardiovascular impairment or toxicity except for prolonged QTc interval, which appeared to be dose dependent. However, as this study was limited by a small sample size, future studies with larger sample size are warranted to confirm our findings.
Naringin Exerts Therapeutic Effects on Mice Colitis: A Study Based on Transcriptomics Combined With Functional Experiments
Authors: Dong Jianyi , Chen Yuanyuan , Yang Fang , Zhang Weidong , Wei Kun , Xiong Yongjian , Wang Liang , Zhou Zijuan , Li Changyi , Wang Jingyu , Chen Dapeng
Published: August 2021

Naringin has been shown to exert protective effects in an animal model of ulcerative colitis, but detailed mechanisms remain unclear. This study aimed to investigate function and signaling mechanisms underlying naringin-induced therapeutic effects on colitis. Two mouse models were established to mimic human Inflammatory bowel disease (IBD) by treating drinking water with dextran sodium sulphate or intra-colonic administration of 2, 4, 6-trinitrobenzene sulfonic acid. Transcriptomics combined with functional experiments were used to investigate underlying mechanisms. Colitis symptoms, including weight loss and high disease activity index were significantly reversed by naringin. The inflammatory response, oxidative reactions, and epithelial cell apoptosis that occur with colitis were also alleviated by naringin. After naringin treatment, transcriptomics results identified 753 differentially expressed mRNAs that were enriched in signaling pathways, including the neuroactive ligand-receptor interaction, calcium signaling, and peroxisome proliferator-activated receptor (PPAR) signaling. The naringin-induced alleviation of colitis was significantly inhibited by the PPAR-γ inhibitor BADGE. In IEC-6 and RAW264.7 cells incubated with lipopolysaccharide (LPS), NF-κB-p65, a downstream protein of PPAR-γ, was significantly increased. Naringin suppressed LPS-induced high expression of NF-κB-p65, which was inhibited by small interfering RNA targeting PPAR-γ. Our study clarifies detailed mechanisms underlying naringin-induced therapeutic effects on mice colitis, and PPAR-γ was found to be the main target of naringin by functional experiments both in vivo and in vitro. Our study supplies new scientific information for the use of naringin in colitis treatment.
Research on the Failure Evolution Process of Rock Mass Base on the Acoustic Emission Parameters
Authors: Liu Xiaohui , Zhao Xiaoping , Zhang Shishu , Congyan Ran , Zhao Rui
Published: August 2021

Fracture mechanics behavior and acoustic emission (AE) characteristics of fractured rock mass are related to underground engineering safety construction, disaster prediction, and early warning. In this study, the failure evolution characteristics of intact and fracture (e.g., single fracture, parallel fractures, cross fractures, and mixed fractures) coal were studied and contrasted with each other on the basis of the distribution of max amplitude of AE. The study revealed some meaningful results, where the value of b (i.e., the distribution characteristic of max amplitude of AE) could represent the failure evolution process of intact and fractured coal. The maximum amplitude distribution of AE events was characterized by Gaussian normal distribution, and the probability of the maximum amplitude of AE events corresponding to 35∼50 dB was the largest. In the stress range of 60∼80%, AE events and maximum amplitude increased rapidly, and the corresponding b value decreased. The energy of AE events showed a downward trend after reaching the maximum value at about 80% stress level. Under the same stress level, the more complex the fracture was, the larger the b value of coal–rock mass was, and the stronger the inhibition effect on the fracture expansion caused by the internal fracture distribution was. Due to the anisotropy of coal–rock mass with a single crack, the distribution of the b value was more discrete, while the anisotropy of coal–rock mass with mixed crack decreased, and the dispersion of the b value decreased. The deformation of cracked coal mainly caused by the adjustment of cracks during the initial loading b value experienced a trend of decreasing first, then increasing, and then decreasing in the loading process. When the load reached 0.8 times of the peak strength, the b value had a secondary decreasing trend, indicating the macroscopic failure of the sample, which could be used as a precursor criterion for the complete failure of coal–rock mass.
Development of 18F-Labeled Resazurin Derivatives for the Detection of Tumor Metabolic Activity Using Cerenkov Imaging
Authors: Arroyo Alejandro D. , Guzman Andrea E. , Kachur Alexander V. , Popov Anatoliy V. , Delikatny E. James
Published: August 2021

This paper describes functional fluorinated bioactivatable molecules to study cancer metabolism using Cerenkov imaging. Resazurin (RA), or Alamar Blue, is a commonly used viability dye and redox sensor. Under reductive conditions or by the action of NADH dehydrogenases, RA is reduced into resorufin (RAred), a highly fluorescent molecule. Cold- and radiolabeled monofluorinated resazurin (MFRA) and difluorinated resazurin (DFRA) were synthesized using electrophilic fluorination. The fluorescence of the reduced probes allowed for the detection of Cerenkov Radiation Energy Transfer (CRET). Cerenkov imaging of MFRAred showed a 4-fold increase in signal at 640 nm relative to MFRA, demonstrating the ability to differentiate between oxidized and reduced species via optical imaging. CRET allows the measurement of signal at longer wavelengths closer to the near infrared (NIR) window, ideal for in vivo imaging. MFRA reduction showed different rates in two breast cancer cell lines: MDA-MB-231, a triple-negative breast cancer, and 4175-Luc+, an aggressive MDA-MB-231 variant, isolated from murine lung metastases. 4175-Luc + cells showed a more rapid reduction of RA and MFRAox than MDA-MB-231 cells. Intratumoral injections of 18F-FDG/MFRA showed a faster reduction of the probe in 4175-Luc + tumors than in MDA-MB-231, suggesting that the metabolic feature observed in the cells is maintained in the tumors. MFRA is a promising probe to determine tumor energy imbalance, reductive environments and assess metastatic potential of tumors. Furthermore, the use of 18F-labeled probes allows for dual modality PET/Cerenkov imaging for probe localization and biodistribution while assessing probe reduction simultaneously.
Increased Mobility of the Atrial Septum in Aortic Root Dilation: An Observational Study on Transesophageal Echocardiography
Authors: Heidemann Altair , Dall'Oglio Lorença , Bertoldi Eduardo Gehling , Foppa Murilo
Published: August 2021

Background: There is a growing interest in the relationship between atrial septal anatomy and cardioembolic stroke. Anecdotal reports suggest that the enlargement of the aortic root could interfere with atrial septal mobility (ASM). We sought to investigate the association between ASM and aortic root dilation.

Methods and Findings: From all consecutive clinically requested transesophageal echocardiogram (TEE) studies performed during the study period in a single institution, we were able to review and evaluate the ASM and anteroposterior length, aortic root diameter, and the prevalence of atrial septal aneurysm (ASA) and of patent foramen ovale (PFO) in 336 studies. Additional variables, such as left ventricular ejection fraction, left atrial diameter, diastolic dysfunction, age, sex, weight, height, previous stroke, atrial fibrillation, and TEE indication, were extracted from patient medical records and echocardiographic clinical reports. In 336 patients, we found a mean ASM of 3.4 mm, ranging from 0 to 21 mm; 15% had ASA and 14% had PFO. There was a 1.0 mm increase in ASM for every 10-mm increase in aortic root diameter adjusted for age, sex, weight, height, ejection fraction, and left atrial size (B = 0.1; P = 0.04). Aortic diameter was not associated with a smaller septal length (B = 0.03; P = 0.7).

Conclusion: An increased motion of the atrial septum can occur in association with aortic dilation. These findings deserve attention for the relevance of aortic root anatomy in future studies involving atrial septal characteristics and embolic stroke risk.
Cytokinin Regulation of Source-Sink Relationships in Plant-Pathogen Interactions
Authors: McIntyre Kathryn E. , Bush Daniel R. , Argueso Cristiana T.
Published: August 2021

Cytokinins are plant hormones known for their role in mediating plant growth. First discovered for their ability to promote cell division, this class of hormones is now associated with many other cellular and physiological functions. One of these functions is the regulation of source-sink relationships, a tightly controlled process that is essential for proper plant growth and development. As discovered more recently, cytokinins are also important for the interaction of plants with pathogens, beneficial microbes and insects. Here, we review the importance of cytokinins in source-sink relationships in plants, with relation to both carbohydrates and amino acids, and highlight a possible function for this regulation in the context of plant biotic interactions.
A Study of Disposition, Engagement, Efficacy, and Vitality of Teachers in Designing Science, Technology, Engineering, and Mathematics Education
Authors: Lin Pei-Yi , Chai Ching Sing , Jong Morris Siu-Yung
Published: August 2021

This study proposes and tests a theoretical model of how perceptions of disposition, engagement, and efficacy of teachers for science, technology, engineering, and mathematics (STEM) e-learning can predict their sense of vitality when they designed STEM education. Upon the proposition, we developed and validated an instrument for examining the relationships between these variables. The participants were 122 secondary teachers of STEM education from Hong Kong. The instrument included four design aspects as follows: (i) disposition, (ii) lesson design engagement, (iii) efficacy for designing STEM e-learning, and (iv) vitality of teachers after attending a series of STEM professional development activities. To analyze the relationships among the variables, partial least squares structural equation modeling was employed. The disposition of teachers predicted lesson design engagement and both of these factors, in turn, predicted efficacy for designing STEM e-learning. In other words, if teachers have a high proposition toward designing learning activities, their engagement in the lesson design process may enhance their capacities in designing and implementing such activities. Also, the disposition of teachers and lesson design engagement predicted their vitality, revealing that well-suited STEM teachers should not only be able to design a STEM curriculum but also have a positive perception of STEM education.
Effects of Attribute Affirmation and Achievement Goals on High School Students' Motivation
Authors: Liu Cheng-Hong , Huang Po-Sheng , Yin Xian-Rui , Chiu Fa-Chung
Published: August 2021

Researchers have suggested that receiving attribute affirmation (AA) may increase the motivation of students to confront a challenge. However, we posited that to determine whether AA increases the motivation of students to confront a challenging task, we must consider dispositional achievement goals of the students. The participants were 171 junior-high-school students, randomly assigned to an AA or no affirmation condition. The results showed that AA enhanced the tendency to confront a challenging task for students who endorsed low mastery-approach goals (MAGs) and low performance-approach goals (PAGs) simultaneously (b = 0.5, p = 0.015). The effect was mainly mediated by the increasing state performance-approach goals (SPAGs) in confronting the task (indirect effect = 0.21, 95% CI = 0.04–0.49); however, being attribute-affirmed decreased the tendency to confront the challenging task for students adopting a dominant PAG orientation (b = −0.76, p = 0.049). In addition, for students adopting a dominant MAG orientation or adopting high MAGs and high PAGs simultaneously, no difference was noted in the tendency to confront the task between participants in the control and attribute-affirmed conditions.