bluuebunny/crossref_metadata_2025 huggingface dataset:
Wild-type cutoff for Apramycin against Escherichia coli
Authors: Yang Yuqi , Xiao Tianshi , Li Jiarui , Cheng Ping , Li Fulei , Yu Hongxiao , Liu Ruimeng , Muhammad Ishfaq , Zhang Xiuying
Published: August 2020

Background

Apramycin is used exclusively for the treatment of Escherichia coli (E.coli) infections in swine around the world since the early 1980s. Recently, many research papers have demonstrated that apramycin has significant in vitro activity against multidrug-resistant E.coli isolated in hospitals. Therefore, ensuring the proper use of apramycin in veterinary clinics is of great significance of public health. The objectives of this study were to develop a wild-type cutoff for apramycin against E.coli using a statistical method recommended by Clinical and Laboratory Standards Institute (CLSI) and to investigate the prevalence of resistance genes that confer resistance to apramycin in E. coli.

Results

Apramycin susceptibility testing of 1230 E.coli clinical isolates from swine were determinded by broth microdilution testing according to the CLSI document M07-A9. A total number of 310 E.coli strains from different minimum inhibitory concentration (MIC) subsets (0.5–256 μg/mL) were selected for the detection of resistance genes (aac(3)-IV; npmA; apmA) in E. coli by PCR. The percentage of E. coli isolates at each MIC (0.5, 1, 2, 4, 8, 16, 32, 64, 128, and 256 μg/mL) was 0.08, 0.08, 0.16, 2.93, 31.14, 38.86, 12.85, 2.03, 1.46, and 10.41%. The MIC50 and MIC90 were 16 and 64 μg/mL. All the 310 E.coli isolates were negative for npmA and apmA gene, and only the aac(3)-IV gene was detected in this study.

Conclusions

The wild-type cutoff for apramycin against E.coli was defined as 32 μg/mL. The prevelance of aac(3)-IV gene mainly concentrated in these MIC subsets ‘MIC ≥ 64 μg/ mL’, which indicates that the wild-type cutoff established in our study is reliable. The wild-type cutoff offers interpretion criteria of apramycin susceptibility testing of E.coli.
Circ_0000140 restrains the proliferation, metastasis and glycolysis metabolism of oral squamous cell carcinoma through upregulating CDC73 via sponging miR-182-5p
Authors: Guo Jia , Su Yuanyuan , Zhang Meng
Published: August 2020

Background

Oral squamous cell carcinoma (OSCC) is a more common cancer in the world. Emerging evidence suggests that circular RNAs (circRNAs) participate in the progression of OSCC. However, the role of circ_0000140 in OSCC is still unknown.

Methods

The expression of circ_0000140 and microRNA-182-5p (miR-182-5p) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Also, cell proliferation, migration and invasion were measured by colony formation and transwell assays, respectively. Western blot (WB) analysis was used to test the levels of proliferation, metastasis and glycolysis metabolism-related proteins as well as cell division cycle 73 (CDC73) protein. Further, the extracellular acidification rate (ECAR) of cells was detected by the Seahorse XF Extracellular Flux Analyzer. The lactate acid level of cells was tested by Lactate Assay Kit. Moreover, dual-luciferase reporter was used to verify the interaction between miR-182-3p and circ_0000140 or CDC73, and RNA immunoprecipitation (RIP) assay was employed to further confirm the relationship between miR-182-3p and circ_0000140. In addition, mice xenograft models were built to measure the effect of circ_0000140 on OSCC tumor growth in vivo.

Results

Circ_0000140 was lowly expressed in OSCC, and its overexpression hindered proliferation, migration, invasion and glycolysis metabolism in OSCC cells. MiR-182-5p could be sponged by circ_0000140, and its mimic could invert the suppression of circ_0000140 overexpression on OSCC progression. CDC73 could be targeted by miR-182-3p, and its silencing could reverse the inhibition of miR-182-3p inhibitor on OSCC progression. Further, overexpressed circ_0000140 reduced the OSCC tumor growth in vivo.

Conclusions

Circ_0000140 might play an anti-cancer role in OSCC, which provided a novel target for clinical therapy of OSCC.
Comprehensive analysis of key genes associated with ceRNA networks in nasopharyngeal carcinoma based on bioinformatics analysis
Authors: Xu Yuanji , Huang Xinyi , Ye Wangzhong , Zhang Yangfan , Li Changkun , Bai Penggang , Lin Zhizhong , Chen Chuanben
Published: August 2020

Background

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with high morbidity rates in the east and southeast Asia. The molecular mechanisms of NPC remain largely unknown. We explored the pathogenesis, potential biomarkers, and prognostic indicators of NPC.

Methods

We analyzed mRNAs, long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) in the whole transcriptome sequencing dataset of our hospital (five normal tissues vs. five NPC tissues) and six microarray datasets (62 normal tissues vs. 334 NPC tissues) downloaded from the Gene Expression Omnibus (GSE12452, GSE13597, GSE95166, GSE126683, and GSE70970, GSE43039). Differential expression analyses, gene ontology (GO) enrichment, kyoto encyclopedia of genes and genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were conducted. The lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks were constructed using the miRanda and TargetScan database, and a protein–protein interaction (PPI) network of differentially expressed genes (DEGs) was built using Search Tool for the Retrieval of Interacting Genes (STRING) software. Hub genes were identified using Molecular Complex Detection (MCODE), NetworkAnalyzer, and CytoHubba.

Results

We identified 61 mRNAs, 14miRNAs, and 10 lncRNAs as shared DEGs related to NPC in seven datasets. Changes in NPC were enriched in the chromosomal region, sister chromatid segregation, and nuclear chromosome segregation. GSEA indicated that the mitogen-activated protein kinase (MAPK) pathway, phosphatidylinositol-3 OH kinase/protein kinase B (PI3K-Akt) pathway, apoptotic pathway, and tumor necrosis factor (TNF) were involved in the initiation and development of NPC. Finally, 20 hub genes were screened out via the PPI network.

Conclusions

Several DEGs and their biological processes, pathways, and interrelations were found in our current study by bioinformatics analyses. Our findings may offer insights into the biological mechanisms underlying NPC and identify potential therapeutic targets for NPC.
Dietary patterns of Chinese women of childbearing age during pregnancy and their relationship to the neonatal birth weight
Authors: Yan Hui , Dang Shaonong , Zhang Yaodong , Luo Shuying
Published: August 2020

Objective

To examine the type of maternal dietary patterns during pregnancy and the distribution characteristics of children’s birth weight and the association between dietary patterns and neonatal birth weight in China.

Methods

Data were derived from a cross-sectional program named “The prevalence and risk factors of birth defects in Shaanxi Province” in July to November in 2013. A stratified multistage random sampling method was used to select women and their children. The mother’s diet during pregnancy was investigated using semi-quantitative food frequency questionnaire (FFQ) to collect the frequency and amount of food consumption, and the newborn birth weight as well as related social demographic information was collected at the same time. In our study, 0–1 year old children and their mothers with complete dietary survey data were selected as research objects. The main dietary patterns were identified according to factor analysis, and latent class analysis (LCA) was used to investigate the social demographic factors affecting dietary patterns. The logistic regression model was used to assess the association between birth weight and maternal dietary patterns during pregnancy by establishing three adjusting models and the data were stratified for further analysis by urban-rural and regions.

Results

A total of 15,980 participants were involved in this study. Four dietary patterns were identified: “vegetarian pattern”, “balance pattern”, “traditional pattern” and “processing pattern”. Compared with moderate tertile, women in the highest tertile of adherence to vegetarian pattern increased the risk of low birth weight in offspring in rural areas (OR = 1.61, 95%CI:1.06–2.93) and middle region (OR = 1.75, 95%CI:1.18–2.62), and the traditional pattern had greater odds of lower birth weight in the middle region (OR = 1.55, 95%CI:1.05–3.75). The processing pattern was found a protective factor for the occurrence of low birth weight in rural areas (OR = 0.98, 95%CI:0.43–0.99) but was a risk factor for low birth weight in the southern region (OR = 8.83, 95%CI:1.22–15.16). The balance pattern was a protective factor for the occurrence of low birth weight in the northern region(OR = 0.35, 95%CI:0.14–0.83).

Conclusion

The vegetarian and traditional pattern may be positively related to a higher risk of low birth weight while the balanced pattern may keep birth weight of offspring within the appropriate range. Health education of balanced diet and individual nutrition guidance during pregnancy should be strengthened, to make the dietary structure during pregnancy are more reasonable, reduce the occurrence of adverse birth weight of newborns.
Pressure based MRI-compatible muscle fascicle length and joint angle estimation
Authors: Song Hyungeun , Israel Erica , Srinivasan Shriya , Herr Hugh
Published: August 2020

Background

Functional magnetic resonance imaging (fMRI) provides critical information about the neurophysiology of the central nervous systems (CNS), posing clinical significance for the understanding of neuropathologies and advancement of rehabilitation. Typical fMRI study designs include subjects performing designed motor tasks within specific time frames, in which fMRI data are then analyzed by assuming that observed functional brain activations correspond to the designed tasks. Therefore, developing MRI-compatible sensors that enable real-time monitoring of subjects’ task performances would allow for highly accurate fMRI studies. While several MRI-compatible sensors have been developed, none have demonstrated the ability to measure individual muscle fascicle length during fMRI, which could help uncover the complexities of the peripheral and central nervous systems. Furthermore, previous MRI-compatible sensors have been focused on biologically intact populations, limiting accessibility to populations such as those who have undergone amputation.

Methods

We propose a lightweight, low-cost, skin impedance-insensitive pressure-based muscular motion sensor (pMMS) that provides reliable estimates of muscle fascicle length and joint angle. The muscular motions are captured through measured pressure changes in an air pocket wrapped around the muscle of interest, corresponding to its muscular motion. The muscle fascicle length and joint angle are then estimated from the measured pressure changes based on the proposed muscle-skin-sensor interaction dynamics. Furthermore, we explore an integration method of multiple pMMS systems to expand the sensor capacity of estimating muscle fascicle length and joint angle. Ultrasound imaging paired with joint encoder measurements are utilized to assess pMMS estimation accuracy of muscle fascicle length in the tibialis anterior (TA) and ankle joint angle, respectively, of five biologically intact subjects.

Results

We found that a single pMMS sufficiently provides robust and accurate estimations of TA muscle fascicle length and ankle joint angle during dorsiflexion at various speeds and amplitudes. Further, differential pressure readings from two pMMSs, in which each pMMS were proximally and distally placed, were able to mitigate errors due to perturbations, expanding pMMS capacity for muscle fascicle length and ankle joint angle estimation during the full range of plantar flexion and dorsiflexion.

Conclusions

Our results from this study demonstrate the feasibility of the pMMS system to further be incorporated in fMRI settings for real-time monitoring of subjects’ task performances, allowing sophisticated fMRI study designs.
A face-to-face comparison of claudin-5 transduced human brain endothelial (hCMEC/D3) cells with porcine brain endothelial cells as blood–brain barrier models for drug transport studies
Authors: Gericke Birthe , Römermann Kerstin , Noack Andreas , Noack Sandra , Kronenberg Jessica , Blasig Ingolf Ernst , Löscher Wolfgang
Published: August 2020

Background

Predictive in vitro models of the human blood–brain barrier (BBB) are essential in early drug discovery and development. Among available immortalized human brain capillary endothelial cell lines (BCECs), the hCMEC/D3 cell line has become the most widely used in vitro BBB model. However, monolayers of hCMEC/D3 cells form only moderately restrictive barriers, most likely because the major tight junction protein, claudin-5, is markedly downregulated. Thus, hCMEC/D3 monolayers cannot be used for vectorial drug transport experiments, which is a major disadvantage of this model.

Methods

Here we transduced hCMEC/D3 cells with a claudin-5 plasmid and compared the characteristics of these cells with those of hCMEC/D3 wildtype cells and primary cultured porcine BCECs.

Results

The claudin-5 transduced hCMEC/D3 exhibited expression levels (and junctional localization) of claudin-5 similar to those of primary cultured porcine BCECs. The transduced cells exhibited increased TEER values (211 Ω cm2) and reduced paracellular mannitol permeability (8.06%/h), indicating improved BBB properties; however, the barrier properties of porcine BCECs (TEER 1650 Ω cm2; mannitol permeability 3.95%/h) were not reached. Hence, vectorial transport of a selective P-glycoprotein substrate (N-desmethyl-loperamide) was not observed in claudin-5 transduced hCMEC/D3 (or wildtype) cells, whereas such drug transport occurred in porcine BCECs.

Conclusions

The claudin-5 transduced hCMEC/D3 cells provide a tool to studying the contribution of claudin-5 to barrier tightness and how this can be further enhanced by additional transfections or other manipulations of this widely used in vitro model of the BBB.
Non-destructive identification of single hard seed via multispectral imaging analysis in six legume species
Authors: Hu Xiaowen , Yang Lingjie , Zhang Zuxin
Published: August 2020

Background

Physical dormancy (hard seed) occurs in most species of Leguminosae family and has great consequences not only for ecological adaptation but also for agricultural practice of these species. A rapid, nondestructive and on-site screening method to detect hard seed within species is fundamental important for maintaining seed vigor and germplasm storage as well as understanding seed adaptation to various environment. In this study, the potential of multispectral imaging with object-wise multivariate image analysis was evaluated as a way to identify hard and soft seeds in Acacia seyal, Galega orientulis, Glycyrrhiza glabra, Medicago sativa, Melilotus officinalis, and Thermopsis lanceolata. Principal component analysis (PCA), linear discrimination analysis (LDA), and support vector machines (SVM) methods were applied to classify hard and soft seeds according to their morphological features and spectral traits.

Results

The performance of discrimination model via multispectral imaging analysis was varied with species. For M. officinalis, M. sativa, and G. orientulis, an excellent classification could be achieved in an independent validation data set. LDA model had the best calibration and validation abilities with the accuracy up to 90% for M. sativa. SVM got excellent seed discrimination results with classification accuracy of 91.67% and 87.5% for M. officinalis and G. orientulis, respectively. However, both LDA and SVM model failed to discriminate hard and soft seeds in A. seyal, G. glabra, and T. lanceolate.

Conclusions

Multispectral imaging together with multivariate analysis could be a promising technique to identify single hard seed in some legume species with high efficiency. More legume species with physical dormancy need to be studied in future research to extend the use of multispectral imaging techniques.
Leaf to panicle ratio (LPR): a new physiological trait indicative of source and sink relation in japonica rice based on deep learning
Authors: Yang Zongfeng , Gao Shang , Xiao Feng , Li Ganghua , Ding Yangfeng , Guo Qinghua , Paul Matthew J. , Liu Zhenghui
Published: August 2020

Background

Identification and characterization of new traits with sound physiological foundation is essential for crop breeding and production management. Deep learning has been widely used in image data analysis to explore spatial and temporal information on crop growth and development, thus strengthening the power of identification of physiological traits. Taking the advantage of deep learning, this study aims to develop a novel trait of canopy structure that integrate source and sink in japonica rice.

Results

We applied a deep learning approach to accurately segment leaf and panicle, and subsequently developed the procedure of GvCrop to calculate the leaf to panicle ratio (LPR) of rice canopy during grain filling stage. Images of training dataset were captured in the field experiments, with large variations in camera shooting angle, the elevation and the azimuth angles of the sun, rice genotype, and plant phenological stages. Accurately labeled by manually annotating the panicle and leaf regions, the resulting dataset were used to train FPN-Mask (Feature Pyramid Network Mask) models, consisting of a backbone network and a task-specific sub-network. The model with the highest accuracy was then selected to check the variations in LPR among 192 rice germplasms and among agronomical practices. Despite the challenging field conditions, FPN-Mask models achieved a high detection accuracy, with Pixel Accuracy being 0.99 for panicles and 0.98 for leaves. The calculated LPR displayed large spatial and temporal variations as well as genotypic differences. In addition, it was responsive to agronomical practices such as nitrogen fertilization and spraying of plant growth regulators.

Conclusion

Deep learning technique can achieve high accuracy in simultaneous detection of panicle and leaf data from complex rice field images. The proposed FPN-Mask model is applicable to detect and quantify crop performance under field conditions. The newly identified trait of LPR should provide a high throughput protocol for breeders to select superior rice cultivars as well as for agronomists to precisely manage field crops that have a good balance of source and sink.
Why ‘understanding’ of research may not be necessary for ethical emergency research
Authors: Kaye Dan Kabonge
Published: August 2020

Background

Randomized controlled trials (RCTs) are central to generating knowledge about effectiveness of interventions as well as risk, protective and prognostic factors related to diseases in emergency newborn care. Whether prospective participants understand the purpose of research, and what they perceive as the influence of the context on their understanding of the informed consent process for RCTs in emergency obstetric and newborn care are not well documented.

Methods

Conceptual review.

Discussion

Research is necessary to identify how the illnesses may be prevented, to explore the causes, and to investigate what medications could be used to manage such illness. Voluntary informed consent requires that prospective participants understand the disclose information about the research, and use this to make autonomous informed decision about participation, in line with their preferences and values. Yet the emergency context affects how information may be disclosed to prospective research participants, how much participants may comprehend, and how participants may express their voluntary decision to participate, all of which pose a threat to the validity of the informed consent. I challenge the claim that the ‘understanding’ of research is always necessary for ethical informed consent for research during emergency care. I argue for reconceptualization of the value of understanding, through recognition of other values that may be equally important. I then present a reflective perspective that frames moral reflection about autonomy, beneficence and justice in research in emergency research.

Conclusion

While participant ‘understanding’ of research is important, it is neither necessary nor sufficient for a valid informed consent, and may compete with other values with which it needs to be considered.
Dynamic hip screws versus cannulated screws for femoral neck fractures: a systematic review and meta-analysis
Authors: Li Lang , Zhao Xue , Yang Xiaodong , Tang Xueyang , Liu Ming
Published: August 2020

Objective

Dynamic hip screw (DHS) and cannulated screws (CS) are widely used for femoral neck fractures. However, there is no definite result as to which surgical method bring less complications. We performed this study to compare the complication (mortality, non-union, avascular necrosis (AVN), and revision) of DHS and CS for the treatment of femoral neck fractures patients.

Methods

We searched Pubmed, Ovid, Cochrane Central Register of Controlled Trials, and other relevant studies related the comparison of DHS versus CS for femoral neck fractures from inception to Jan 7, 2020. The quality of the included randomized controlled trials (RCTs) and retrospective studies were assessed using the Cochrane Collaboration tool and Newcastle-Ottawa (NOS), respectively. The meta-analysis was performed by the RevMan 5.2 software.

Results

Nine RCTs and seven retrospective cohort studies were included for meta-analysis. CS was found to be superior to DHS with respect to AVN rate (OR 1.47; 95% CI 1.08–1.99; p = 0.01, I2 = 0%). There were no significant between-group differences with respect to mortality, non-union, and revision (p > 0.05).

Conclusion

DHS and CS have similar complication including mortality, revision rate, and non-union, but CS has superior to DHS on ANV. However, further studies are required to provide more robust evidence owing to some limitations.
The design of an “H” joystick for closed reduction and its application in segmental and comminuted femoral shaft fractures: an innovative technique
Authors: Jia Zhaofeng , Wang Shijin , Xiao Tinghui , Jiang Wei , Zhou Tianjian , Liu Qisong , Li Guangheng , Hu Xinjia
Published: August 2020

Background

Closed reduction and locked intramedullary nailing has become a common surgical method in the treatment of femoral shaft fractures. Overlap and rotation displacements can usually be corrected through the use of an orthopedic traction table. However, lateral displacement and angulation persist.

Methods

In this paper, we describe a joystick that can be used in the closed reduction of a fracture. It can correct lateral displacement and angulation, and has the advantage of multi-direction reduction. The device described in this paper includes two parallel horizontal joysticks, one vertical main joystick and four assistant rods. Moreover, there are many specific spacing holes in the two parallel horizontal joysticks and a groove structure in the vertical main joystick. When the main “H” joystick is pressed, it can adjust lateral displacements and angulation because of the lever principle. The distance between parallel horizontal joysticks and assistant rods can be adjusted to the fracture position and body mass index of different patients.

Results

The study participants consisted of 11 males and 5 females with a mean age of 31.0 years. All participants had good closed reduction and achieved bony union without any complications such as infection, nerve injury, non-union, malunion, and limb length discrepancy. By using an “H” joystick, closed femoral shaft fracture reduction and locked intramedullary nailing becomes simpler and faster.

Conclusion

Based on the use of this instrument, we can easily and conveniently obtain the correct reduction situation, which leads to better surgical results. This device can be applied in the reduction of clinical femoral fractures and gradually extended to the reduction of other fractures.
Impingement-free hip range of motion after osteochondroplasty and relative neck lengthening in adults with healed Perthes disease
Authors: Elmarghany Mohammed , Abd El-Ghaffar Tarek M. , Elgeushy Ahmed , Hasanin Yehia , Elzahed Ehab , Abulsoud Mohamed I. , Moawad Mohamed
Published: August 2020

Objective

Our main objective is to assess the efficiency of the osteochondroplasty with relative neck lengthening in adults with healed Perthes clinically (through assessment of impingement-free hip ROM, functional scores) and radiographically.

Patients and methods

This was a prospective case series study included 30 hips of 30 patients who underwent osteochondroplasty and RNL due to symptomatic healed LCPD. This study included 16 males (53.3%) and 14 females (46.7%). The age of patients ranged from 19 to 40 years with mean age 26.4 years at the date of surgery (SD 6.4).

Results

Median time of follow-up was 27.7 months after surgery (range 12–60 months). Two patients (6.6%) developed avascular necrosis (AVN) and needing total hip replacement; none of our patients developed nerve injury, detachment of the trochanteric fragment, and wound infection needing treatment. Preoperative Stulberg classes II and III improved more than preoperative Stulberg classes IV and V, although not statistically significant (P = 0.1104, n = 30). The mean HHS and WOMAC score values for each patient were higher in the Stulberg II and III groups compared to the Stulberg IV and V groups

Conclusion

Head and neck osteochondroplasty performed through the surgical dislocation approach, combined with RFNL, relieved pain and restored function in most of the patients with reasonable complications.

Level of evidence

IV
Flavonoids from Aurantii Fructus Immaturus and Aurantii Fructus: promising phytomedicines for the treatment of liver diseases
Authors: Wu Jianzhi , Huang Guangrui , Li Yajing , Li Xiaojiaoyang
Published: August 2020

Background

Liver diseases and related complications are major sources of morbidity and mortality, which places a huge financial burden on patients and lead to nonnegligible social problems. Therefore, the discovery of novel therapeutic drugs for the treatment of liver diseases is urgently required.Aurantii Fructus Immaturus(AFI) andAurantii Fructus(AF) are frequently used herbal medicines in traditional Chinese medicine (TCM) formulas for the treatment of diverse ailments. A variety of bioactive ingredients have been isolated and identified from AFI and AF, including alkaloids, flavonoids, coumarins and volatile oils.

Main body

Emerging evidence suggests that flavonoids, especially hesperidin (HD), naringenin (NIN), nobiletin (NOB), naringin (NRG), tangeretin (TN), hesperetin (HT) and eriodictyol (ED) are major representative bioactive ingredients that alleviate diseases through multi-targeting mechanisms, including anti-oxidative stress, anti-cytotoxicity, anti-inflammation, anti-fibrosis and anti-tumor mechanisms. In the current review, we summarize the recent progress in the research of hepatoprotective effects of HD, NIN, NOB, NRG, TN, HT and ED and highlight the potential underlying molecular mechanisms. We also point out the limitations of the current studies and shed light on further in-depth pharmacological and pharmacokinetic studies of these bioactive flavonoids.

Conclusion

This review outlines the recent advances in the literature and highlights the potential of these flavonoids isolated from AFI and AF as therapeutic agents for the treatment of liver diseases. Further pharmacological studies will accelerate the development of natural products in AFI and AF and their derivatives as medicines with tantalizing prospects in the clinical application.
Fabry disease screening in high-risk populations in Japan: a nationwide study
Authors: Yoshida Shinichiro , Kido Jun , Sawada Takaaki , Momosaki Ken , Sugawara Keishin , Matsumoto Shirou , Endo Fumio , Nakamura Kimitoshi
Published: August 2020

Background

Fabry disease (FD) is a X-linked inherited disorder caused by mutations in the GLA gene, which results in the deficiency of α-galactosidase A (α-Gal A). This leads to the progressive accumulation of metabolites, which can cause multisystemic dysfunction. A recent screening study among neonates reported an increase in the incidence of FD, and numerous FD patients remain undiagnosed or even misdiagnosed. Therefore, this study aimed to identify patients with FD by performing high-risk screening in 18,135 individuals, enrolled from October 2006 to March 2019, with renal, cardiac, or neurological manifestations from all prefectures in Japan. A total of 601 hospitals participated in this study.

Results

Low α-Gal A activity was detected in 846 individuals, with 224 of them diagnosed with FD by GLA sequencing. Cases with a family history of FD (n = 64) were also subjected to sequencing, without α-Gal A assay, as per individual request, and 12 of them were diagnosed with a variant of FD. A total of 236 patients with FD (97 males and 139 females) were identified from among 18,199 participants. A total of 101 GLA variants, including 26 novel variants, were detected in the 236 patients with FD from 143 families, with 39 amenable variants (39%) and 79 of the 236 patients (33%) suitable for migalastat treatment.

Conclusions

From among 18,199 participants, 101 GLA variants, including 26 novel variants, were identified in the 236 patients with FD from 143 families. Migalastat was identified as a suitable treatment option in 33% of the patients with FD and 39% of the GLA variants were detected as amenable. Therefore, the simple screening protocol using dried blood spots that was performed in this study could be useful for early diagnosis and selection of appropriate treatments for FD in high-risk and underdiagnosed patients with various renal, cardiac, or neurological manifestations.
A Germany-wide survey study on the patient journey of patients with hereditary angioedema
Authors: Magerl Markus , Gothe Holger , Krupka Simon , Lachmann Anja , Ohlmeier Christoph
Published: August 2020

Background

Hereditary angioedema (HAE) is a rare genetic disease and characterized by clinical features such as paroxysmal, recurrent angioedema of the skin, the gastrointestinal tract, and the upper airways. Swelling of the skin occurs primarily in the face, extremities and genitals. Gastrointestinal attacks are accompanied by painful abdominal cramps, vomiting and diarrhea. Due to the low prevalence and the fact that HAE patients often present with rather unspecific symptoms such as abdominal cramps, the final diagnosis is often made after a long delay. The aim of this German-wide survey was to characterize the period between occurrence of first symptoms and final diagnosis regarding self-perceived health, symptom burden and false diagnoses for patients with HAE.

Results

Overall, 81 patients with HAE were included and participated in the telephone-based survey. Of those, the majority reported their current health status as “good” (47.5%) or “very good” (13.8%), which was observed to be a clear improvement compared to the year before final diagnosis (“good” (16.3%), “very good” (11.3%)). Edema in the extremities (85.2%) and in the gastrointestinal tract (81.5%) were the most currently reported symptoms and occurred earlier than other reported symptoms (mean age at onset 18.1 and 17.8 years, respectively). Misdiagnoses were observed in 50.6% of participating HAE patients with appendicitis and allergy being the most frequently reported misdiagnoses (40.0 and 30.0% of those with misdiagnosis, respectively). Patients with misdiagnosis often received mistreatment (80.0%) with pharmaceuticals and surgical interventions as the most frequently carried out mistreatments (65.6 and 56.3% of those with mistreatment, respectively). The mean observed diagnostic delay was 18.1 years (median 15.0 years). The diagnostic delay was higher in older patients and index patients.

Conclusions

This study showed that self-perceived status of health for patients is much better once the final correct diagnosis has been made and specific treatment was available. Further challenge in the future will still be to increase awareness for HAE especially in settings which are normally approached by patients at occurrence of first symptoms to assure early referral to specialists and therefore increase the likelihood of receiving an early diagnosis.
Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant
Authors: Safka Brozkova Dana , Varga Lukas , Uhrova Meszarosova Anna , Slobodova Zuzana , Skopkova Martina , Soltysova Andrea , Ficek Andrej , Jencik Jan , Lastuvkova Jana , Gasperikova Daniela , Seeman Pavel
Published: August 2020

Background

The Roma are a European ethnic minority threatened by several recessive diseases.

Variants inMANBAcause a rare lysosomal storage disorder named beta-mannosidosis whose clinical manifestation includes deafness and mental retardation. Since 1986, only 23 patients with beta-mannosidosis and biallelicMANBAvariants have been described worldwide.

Results

We now report on further 10 beta-mannosidosis patients of Roma origin from eight families in the Czech and Slovak Republics with hearing loss, mental retardation and homozygous pathogenic variants inMANBA.

MANBAvariant c.2158-2A>G screening among 345 anonymized normal hearing controls from Roma populations revealed a carrier/heterozygote frequency of 3.77%. This is about 925 times higher than the frequency of this variant in the gnomAD public database and classifies the c.2158-2A>G variant as a prevalent, ethnic-specific variant causing hearing loss and mental retardation in a homozygous state. The frequency of heterozygotes/carriers is similar to another pathogenic variant c.71G>A (p.W24*) inGJB2, regarded as the most frequent variant causing deafness in Roma populations.

Conlcusion

Beta-mannosidosis, due to a homozygous c.2158-2A>GMANBAvariant, is an important and previously unknown cause of hearing loss and mental retardation among Central European Roma.
Neonatal supraventricular tachycardia and necrotizing enterocolitis: case report and literature review
Authors: Mecarini Federico , Comitini Federica , Bardanzellu Flaminia , Neroni Paola , Fanos Vassilios
Published: August 2020

Background

Necrotizing enterocolitis (NEC) and supraventricular tachycardia (SVT) are serious emergencies in the neonatal period. Although these conditions are recognized as distinct pathologies, literature reports suggest that recurrent episodes of SVT may predispose patients to NEC via disturbances in mesenteric blood flow and a decrease in tissue perfusion.

Case presentation

We present a case of a preterm infant affected by recurrent episodes of SVT who developed the initial stage of NEC on the 17th day of life. Moreover, a detailed description of all the cases described in the literature is reported.

Materials and methods

An integrative review of the updated literature in the Medline database and PubMed and scientific books and articles was conducted. The research from October 2019 to December 2019 was searched for with MeSH and free terms (necrotizing enterocolitis, supraventricular tachycardia) and was linked by Boolean operators.

Conclusions

SVT can be considered a risk factor for the development of NEC. Therefore, clinicians should have a high level of suspicion for NEC in infants affected by SVT. This article is the first structured literature review analysing the association between SVT and NEC.
A case report of glucose transporter 1 deficiency syndrome with growth hormone deficiency diagnosed before starting ketogenic diet
Authors: Tornese Gianluca , Patti Giuseppa , Pellegrin Maria Chiara , Costa Paola , Faletra Flavio , Faleschini Elena , Barbi Egidio
Published: August 2020

Background

Growth failure and growth hormone deficiency (GHD) have been reported as one accessory feature of GLUT1 deficiency syndrome (GLUT1DS), considered so far as a long-term adverse effects of ketogenic diet which is used to treat this condition.

Case presentation

We report the case of a 10-year-old Caucasian boy referred for short stature (height − 2.56 SDS) and delayed growth (growth velocity − 4.33 SDS) who was diagnosed with GHD and started treatment with recombinant human growth hormone (rhGH). Because of his history of seizures with infantile onset, deceleration of head growth with microcephaly, ataxia, and moderate intellectual disability, a lumbar puncture was performed, which revealed a low CSF glucose concentration with a very low CSF-to-blood glucose ratio (< 0.4), and genetic tests detected a SLC2A1 gene exon 1 deletion confirming a diagnosis of GLUT1DS. Ketogenic diet was started. After 5.5 years of rhGH treatment his height was normalized (− 1.15 SDS). No side effects were reported during treatment, particularly on glycemic metabolism.

Conclusions

This is the first case of GHD in a Caucasian boy with GLUT1DS diagnosed before starting ketogenic diet, with a good response to rhGH treatment and absence of side effects. We speculate that GHD may represent a poorly recognized clinical feature of GLUT1DS rather than a complication due to ketogenic diet. Under-diagnosis may derive from the fact that growth failure is usually ascribed to ketogenic diet and therefore not further investigated. Pediatric neurologists need to be alerted to the possible presence of GHD in patients with GLUT1DS with slow growth, while pediatric endocrinologist need to refer GHD patients with additional features (motor and cognitive developmental delay, seizures with infantile onset, deceleration of head growth with acquired microcephaly, movement disorder with ataxia, dystonia, and spasticity) that may suggest GLUT1DS.
Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma
Authors: Sa Jason K. , Chang Nakho , Lee Hye Won , Cho Hee Jin , Ceccarelli Michele , Cerulo Luigi , Yin Jinlong , Kim Sung Soo , Caruso Francesca P. , Lee Mijeong , Kim Donggeon , Oh Young Taek , Lee Yeri , Her Nam-Gu , Min Byeongkwi , Kim Hye-Jin , Jeong Da Eun , Kim Hye-Mi , Kim Hyunho , Chung Seok , Woo Hyun Goo , Lee Jeongwu , Kong Doo-Sik , Seol Ho Jun , Lee Jung-Il , Kim Jinho , Park Woong-Yang , Wang Qianghu , Sulman Erik P. , Heimberger Amy B. , Lim Michael , Park Jong Bae , Iavarone Antonio , Verhaak Roel G. W. , Nam Do-Hyun
Published: August 2020

Background

Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages.

Results

We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCOhigh TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCOhigh TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments.

Conclusions

Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.
Improved reference genome of the arboviral vector Aedes albopictus
Authors: Palatini Umberto , Masri Reem A. , Cosme Luciano V. , Koren Sergey , Thibaud-Nissen Françoise , Biedler James K. , Krsticevic Flavia , Johnston J. Spencer , Halbach Rebecca , Crawford Jacob E. , Antoshechkin Igor , Failloux Anna-Bella , Pischedda Elisa , Marconcini Michele , Ghurye Jay , Rhie Arang , Sharma Atashi , Karagodin Dmitry A. , Jenrette Jeremy , Gamez Stephanie , Miesen Pascal , Masterson Patrick , Caccone Adalgisa , Sharakhova Maria V. , Tu Zhijian , Papathanos Philippos A. , Van Rij Ronald P. , Akbari Omar S. , Powell Jeffrey , Phillippy Adam M. , Bonizzoni Mariangela
Published: August 2020

Background

The Asian tiger mosquito Aedes albopictus is globally expanding and has become the main vector for human arboviruses in Europe. With limited antiviral drugs and vaccines available, vector control is the primary approach to prevent mosquito-borne diseases. A reliable and accurate DNA sequence of the Ae. albopictus genome is essential to develop new approaches that involve genetic manipulation of mosquitoes.

Results

We use long-read sequencing methods and modern scaffolding techniques (PacBio, 10X, and Hi-C) to produce AalbF2, a dramatically improved assembly of the Ae. albopictus genome. AalbF2 reveals widespread viral insertions, novel microRNAs and piRNA clusters, the sex-determining locus, and new immunity genes, and enables genome-wide studies of geographically diverse Ae. albopictus populations and analyses of the developmental and stage-dependent network of expression data. Additionally, we build the first physical map for this species with 75% of the assembled genome anchored to the chromosomes.

Conclusion

The AalbF2 genome assembly represents the most up-to-date collective knowledge of the Ae. albopictus genome. These resources represent a foundation to improve understanding of the adaptation potential and the epidemiological relevance of this species and foster the development of innovative control measures.
Intravenous iron isomaltoside versus oral iron supplementation for treatment of iron deficiency in pregnancy: protocol for a randomised, comparative, open-label trial
Authors: Markova Veronika , Hansen Rebecka , Thomsen Lars Lykke , Pinborg Anja , Moos Torben , Holm Charlotte
Published: August 2020

Background

Iron deficiency is common in pregnancy. If left untreated, iron deficiency can lead to iron deficiency anaemia, which is a condition related to maternal and neonatal morbidity. The prevalence of iron deficiency increases through the trimesters, which means that women with iron deficiency in the beginning of pregnancy also have a great risk of developing iron deficiency anaemia during pregnancy. Standard treatment is oral iron in individualised intensified doses based on screening values in 1st trimester.

Maternal symptoms of iron deficiency and iron deficiency anaemia include fatigue, reduced physical performance, and restless legs syndrome (RLS). Severe anaemia may cause dizziness, dyspnea, palpitation, orthostatism, and syncope, and it decreases the woman’s ability to cope with blood loss during delivery. The anaemia may also compromise contractility in the uterine musculature increasing the risk for prolonged labour, caesarean section, and postpartum haemorrhage. Foetal iron deficiency may cause low birthweight and adversely affect foetal and early childhood brain development with long-term deficits.

Methods

In this randomised comparative, open-label, single-centre, phase IV trial, 200 pregnant women between 14 and 21 weeks of gestation who have iron deficiency after 4 weeks of standard treatment will be randomised 1:1 to either a single 1000 mg dose of intravenously administered ferric derisomaltose/iron isomaltoside 1000 or a fixed dose of 100 mg oral ferrous fumarate containing 60 mg ascorbic acid.

The primary endpoint is to prevent iron deficiency anaemia defined by a low level of haemoglobin throughout the trial. Other endpoints include other haematological indices of iron deficiency and anaemia, clinical outcomes by questionnaires, and collection of adverse events. Explorative endpoints by medical record follow-up include complications up to 7 days after delivery.

Discussion

This trial will provide evidence on how to prevent iron deficiency anaemia. The trial population represents a clinical reality where pregnant women often have sustained iron deficiency despite an increased oral iron dose. Thus, this evidence can be used to consider the optimal 2nd line of treatment in iron-deficient pregnant women.

Trial registration

European Union Drug Regulating Authorities Clinical Trials Database 2017-000776-29. Registered on 3 May 2017.

ClinicalTrials.gov NCT03188445. Registered on 15 June 2017.
“Protocol for a phase 2, randomized, double-blind, placebo-controlled, safety and efficacy study of dutogliptin in combination with filgrastim in early recovery post-myocardial infarction”: study protocol for a randomized controlled trial
Authors: von Lewinski Dirk , Selvanayagam Joseph B. , Schatz Richard A. , Jilma Bernd , Kubica Jacek , Povsic Thomas J. , Nix Darrell , Henauer Stephan , Wallner Markus ,   on behalf of the REC-DUT-002 study group
Published: August 2020

Background

Regenerative therapies offer new approaches to improve cardiac function after acute ST-elevation myocardial infarction (STEMI). Previous trials using bone marrow cells, selected stem cell populations, or cardiac stem cell progenitors require invasive procedures and had so far inconclusive results. A less invasive approach utilizes granulocyte-colony stimulating factor (G-CSF) to mobilize stem cells to circulating blood and induce neovascularization and differentiation into endothelial cells and cardiomyocytes. Stromal cell-derived factor 1 alpha (SDF-1α) is an important chemokine for initiating stem cell migration and homing to ischemic myocardium. SDF-1α concentrations can be increased by inhibition of CD26/DPP4. Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model.

Methods

We test the safety and tolerability and efficacy of dutogliptin in combination with filgrastim (G-CSF) in patients with STEMI (EF < 45%) following percutaneous coronary intervention (PCI). Preliminary efficacy will be analyzed using cardiac magnetic resonance imaging (cMRI) to detect > 3.8% improvement in left ventricular ejection fraction (LV-EF) compared to placebo. One hundred forty subjects will be randomized to filgrastim plus dutogliptin or matching placebos.

Discussion

The REC-DUT-002 trial is the first to evaluate dutogliptin in combination with G-CSF in patients with STEMI. Results will lay the foundation for an appropriately powered cardiovascular outcome trial to test the efficacy of this combined pharmacological strategy.

Trial registration

EudraCT no.: 2018-000916-75. Registered on 7 June 2018. IND number: 123717