bluuebunny/crossref_metadata_2025 huggingface dataset:
Feeding Hotspots and Distribution of Fin and Humpback Whales in the Norwegian Sea From 2013 to 2018
Authors: Løviknes Sunniva , Jensen Knut H. , Krafft Bjørn A. , Anthonypillai Valantine , Nøttestad Leif
Published: February 2021

Fin whales (Balaenoptera physalus) and humpback whales (Megaptera novaeangliae) are commonly found in the Norwegian Sea during the summer months. Records from around 1995 to 2004 show that their distribution patterns were mainly associated with those of macro-zooplankton. More recent studies conducted from 2009 to 2012 demonstrate marked shifts, with fin whale distribution related to pelagic fish distribution, decreasing densities of humpbacks, and increased densities of toothed whales. During the same period, historically large abundances of pelagic planktivorous fish in the Norwegian Sea were reported. The goals of this study were to examine the summer distribution of fin and humpback whales from 2013 to 2018 and to assess the potential association between distribution and environmental impact factors. Results suggest a pronounced northerly shift in distribution for both species, a feeding hotspot for fin whales at the shelf area between Svalbard and Norway, and one near Bear Island for humpback whales. Fin whale distribution was associated with that of blue whiting (Micromesistius poutassou) and capelin (Mallotus villosus), whereas humpback whale distribution was associated with that of euphausiids (Meganyctiphanes norvegica, Thysanoessa longicaudata, andThysanoessa inermis), capelin, and herring (Clupea harengus). However, a significant negative spatial correlation was found between whale occurrence and the widely expanding population of northeast Atlantic mackerel (Scomber scombrus). The results of this study suggest that the prey composition of fin and humpback whales in recent years contain a large proportion of fish. The apparent northerly shift in the distribution of these whale species is largely determined by the availability of prey, but it likely is also impacted by direct or indirect interspecific interactions, especially with killer whales (Orcinus orca). Such large-scale pronounced changes in distribution seem to confirm a high degree of plasticity in fin and humpback whale feeding in the Norwegian Sea.
The Relationship of Acupuncture Use to the Endometriosis Risk in Females With Rheumatoid Arthritis: Real-World Evidence From Population-Based Health Claims
Authors: Chen Wei-Jen , Livneh Hanoch , Hsu Chien-Hui , Hu Ying-To , Lai Ning-Sheng , Guo How-Ran , Tsai Tzung-Yi
Published: February 2021

Objectives: Women affected by rheumatoid arthritis (RA) have a higher risk of endometriosis, an estrogen-dependent, chronic inflammatory disease. Though acupuncture has long been a safe and effective therapy for treating inflammatory conditions, it is unclear whether it could prevent the onset of endometriosis. This study aims to determine the effect of acupuncture on the subsequent risk of endometriosis in female RA patients.

Methods: Between 1998 and 2010, female subjects with RA were recruited from a nationwide database (5,736 patients; age ≥20 years). Enrolled patients included 2,407 acupuncture users and 2,407 nonusers randomly selected using propensity scores. The occurrence of endometriosis was recorded through the end of 2012. Cox proportional hazards regression was used to estimate the adjusted hazard ratio (HR) associated with acupuncture use.

Results: During the follow-up period, 35 acupuncture users and 94 non-users developed endometriosis, with incidence rates of 2.36 and 4.91 per 1,000 person-years, respectively. Acupuncture use was associated with a 55% lower endometriosis risk (adjusted HR, 0.45; 95% confidence interval, 0.31–0.65). Those who received high intensity acupuncture (≥15 packages) had the greatest benefit.

Conclusions: Findings suggest that adding acupuncture to conventional therapy may decrease the subsequent endometriosis risk in female RA patients. Prospective randomized trials are recommended to further clarify whether the association revealed in this study supports a causal link.
Sequential Exposure to Antenatal Microbial Triggers Attenuates Alveolar Growth and Pulmonary Vascular Development and Impacts Pulmonary Epithelial Stem/Progenitor Cells
Authors: Widowski Helene , Reynaert Niki L. , Ophelders Daan R. M. G. , Hütten Matthias C. , Nikkels Peter G. J. , Severens-Rijvers Carmen A. H. , Cleutjens Jack P. M. , Kemp Matthew W. , Newnham John P. , Saito Masatoshi , Usuda Haruo , Payne Matthew S. , Jobe Alan H. , Kramer Boris W. , Delhaas Tammo , Wolfs Tim G. A. M.
Published: February 2021

Perinatal inflammatory stress is strongly associated with adverse pulmonary outcomes after preterm birth. Antenatal infections are an essential perinatal stress factor and contribute to preterm delivery, induction of lung inflammation and injury, pre-disposing preterm infants to bronchopulmonary dysplasia. Considering the polymicrobial nature of antenatal infection, which was reported to result in diverse effects and outcomes in preterm lungs, the aim was to examine the consequences of sequential inflammatory stimuli on endogenous epithelial stem/progenitor cells and vascular maturation, which are crucial drivers of lung development. Therefore, a translational ovine model of antenatal infection/inflammation with consecutive exposures to chronic and acute stimuli was used. Ovine fetuses were exposed intra-amniotically to Ureaplasma parvum 42 days (chronic stimulus) and/or to lipopolysaccharide 2 or 7 days (acute stimulus) prior to preterm delivery at 125 days of gestation. Pulmonary inflammation, endogenous epithelial stem cell populations, vascular modulators and morphology were investigated in preterm lungs. Pre-exposure to UP attenuated neutrophil infiltration in 7d LPS-exposed lungs and prevented reduction of SOX-9 expression and increased SP-B expression, which could indicate protective responses induced by re-exposure. Sequential exposures did not markedly impact stem/progenitors of the proximal airways (P63+ basal cells) compared to single exposure to LPS. In contrast, the alveolar size was increased solely in the UP+7d LPS group. In line, the most pronounced reduction of AEC2 and proliferating cells (Ki67+) was detected in these sequentially UP + 7d LPS-exposed lambs. A similar sensitization effect of UP pre-exposure was reflected by the vessel density and expression of vascular markers VEGFR-2 and Ang-1 that were significantly reduced after UP exposure prior to 2d LPS, when compared to UP and LPS exposure alone. Strikingly, while morphological changes of alveoli and vessels were seen after sequential microbial exposure, improved lung function was observed in UP, 7d LPS, and UP+7d LPS-exposed lambs. In conclusion, although sequential exposures did not markedly further impact epithelial stem/progenitor cell populations, re-exposure to an inflammatory stimulus resulted in disturbed alveolarization and abnormal pulmonary vascular development. Whether these negative effects on lung development can be rescued by the potentially protective responses observed, should be examined at later time points.
Novel Multiparametric Nomogram for Overall Survival Prediction in Complicated Intra-Abdominal Infection: A Multicenter Study in China
Authors: Huang Sisi , Chen Limin , Liu Jiao , Zhang Sheng , Zhang Lidi , Wen Zhenliang , Chen Yizhu , Chen Dechang
Published: February 2021

Background: Complicated intra-abdominal infections (cIAIs) in the abdominal cavity or within an abdominal organ are numerous and frequent dangerous entities in the treatment of critically ill patients. Early clinical evaluation is necessary.

Methods: This retrospective multicenter study included patients from 10 intensive care units (ICUs). Risk factors for the overall survival (OS) of patients with cIAI were selected using least absolute shrinkage and selection operator regression, and a nomogram was constructed subsequently. Calibration curve and receiver operating characteristic (ROC) curve were used to evaluate the calibration and discriminative ability.

Results: In total, 544 patients diagnosed with cIAI were enrolled and divided into the study (n = 276) and validation (n = 268) sets. Sex, acute gastrointestinal injury, acute kidney injury, rare bacterium infection, Charlson score, and APACHE II score were identified as independent risk factors and were constructed for the nomogram. The nomogram showed marked calibration capability with a concordance index (C-index) of 0.909 and 0.831 in the study and validation set, respectively. Compared with the common clinical prognostic scoring system, the nomogram achieved the highest discrimination ability with an area under the curve (AUC) value of 0.91 and 0.83 in the study set and validation set, respectively.

Conclusions: Our newly constructed nomogram provides a useful tool for risk stratification and prognosis evaluation of cIAI.
Case Report: Identification of SARS-CoV-2 in Cerebrospinal Fluid by Ultrahigh-Depth Sequencing in a Patient With Coronavirus Disease 2019 and Neurological Dysfunction
Authors: Xiang Pan , Xu Xinmin , Lu Xin , Gao Lili , Wang Huizhu , Li Zhenpeng , Xiong Haofeng , Li Ruihong , Xiong Yanwen , Pu Lin , Qin Tian , Jin Fangfang , Ren Hongyu , Li Chuansheng , Yang Jing , Zhang Ming , Gong Jie , Chen Xiaoping , Zheng Han , Tan Jianbo , Sun Yao , Zhao Fei , Hou Xuexin , Liu Yufeng , Guo Hebing , Hao Jingjing , Kan Biao , Zhou Haijian , Wang Yajie , Liu Jingyuan
Published: February 2021

We reported that the complete genome sequence of SARS-Coronavirus-2 (SARS-CoV-2) was obtained from a cerebrospinal fluid (CSF) sample by ultrahigh-depth sequencing. Fourteen days after onset, seizures, maxillofacial convulsions, intractable hiccups and a significant increase in intracranial pressure developed in an adult coronavirus disease 2019 patient. The complete genome sequence of SARS-CoV-2 obtained from the cerebrospinal fluid indicates that SARS-CoV-2 can invade the central nervous system. In future, along with nervous system assessment, the pathogen genome detection and other indicators are needed for studying possible nervous system infection of SARS-CoV-2.
Current Challenges in the Management of Infective Endocarditis
Authors: Cuervo Guillermo , Escrihuela-Vidal Francesc , Gudiol Carlota , Carratalà Jordi
Published: February 2021

Infective endocarditis is a relatively rare, but deadly cause of sepsis, with an overall mortality ranging from 20 to 25% in most series. Although the classic clinical classification into syndromes of acute or subacute endocarditis have not completely lost their usefulness, current clinical forms have changed according to the profound epidemiological changes observed in developed countries. In this review, we aim to address the changing epidemiology of endocarditis, several recent advances in the understanding of the pathophysiology of endocarditis and endocarditis-triggered sepsis, new useful diagnostic tools as well as current concepts in the medical and surgical management of this disease. Given its complexity, the management of infective endocarditis requires the close collaboration of multidisciplinary endocarditis teams that must decide on the diagnostic approach; the appropriate initial treatment in the critical phase; the detection of patients needing surgery and the timing of this intervention; and finally the accurate selection of patients for out-of-hospital treatment, either at home hospitalization or with oral antibiotic treatment.
Colistin Resistance Among Multiple Sequence Types of Klebsiella pneumoniae Is Associated With Diverse Resistance Mechanisms: A Report From India
Authors: Azam Mudsser , Gaind Rajni , Yadav Gulshan , Sharma Amit , Upmanyu Kirti , Jain Manisha , Singh Ruchi
Published: February 2021

Background: The resistance to colistin and carbapenems in Klebsiella pneumoniae infections have been associated with increased morbidity and mortality worldwide. A retrospective observational study was conducted to determine the prevalence and molecular events contributing to colistin resistance.

Methods: Clinical samples were screened for colistin resistance and underlying mechanisms were studied by PCR-based amplification and sequence analysis of genes of two-component regulatory system (phoPQ and pmrAB), regulatory transmembrane protein-coding mgrB, and mobilized colistin resistance genes (mcr-1-8). Gene expression of pmrC and pmrK was analyzed by qRT-PCR, and the genetic relationship was assessed by MLST. The putative effect of amino-acid substitutions was predicted by a combination of bioinformatics tools.

Results: Of 335 Klebsiella spp. screened, 11 (3.2%) were identified as colistin-resistant (MIC range, 8 to >128 μg/ml). K. pneumoniae isolates belonged to clonal complex-11 (CC11) with sequence types (STs): 14, 16, 43, 54, 147 and 395, whereby four isolates conferred three novel STs (3986, 3987 and 3988) profiles. Sequence analysis revealed non-synonymous potentially deleterious mutations in phoP (T151A), phoQ (del87–90, del263–264, L30Q, and A351D), pmrA (G53S), pmrB (D150V, T157P, L237R, G250C, A252G, R315P, and Q331H), and mgrB (C28G) genes. The mgrB gene in three strains was disrupted by insertion sequences encoding IS1-like and IS5/IS1182 family-like transposase genes. All 11 isolates showed an elevation in the transcription level of pmrC gene. Mobilized colistin-resistance (mcr) genes were not detected. All but one of the colistin-resistant isolates was also resistant to carbapenems; β-lactamase genes blaNDM-1-like, blaOXA-48-like, and blaCTX-M-like were detected in eight, five, and nine isolates, respectively.

Conclusion: All the studied colistin- and carbapenem-resistant K. pneumoniae isolates were genetically distinct, and various mechanisms of colistin resistance were detected, indicating its spontaneous emergence in this bacterial species.
Antifungal and Antibiofilm Activities of B-Type Oligomeric Procyanidins From Commiphora leptophloeos Used Alone or in Combination With Fluconazole Against Candida spp.
Authors: Dantas-Medeiros Renato , Zanatta Ana Caroline , de Souza Luanda Bárbara Ferreira Canário , Fernandes Júlia Morais , Amorim-Carmo Bruno , Torres-Rêgo Manoela , Fernandes-Pedrosa Matheus de Freitas , Vilegas Wagner , Araújo Thiago Antǒnio de Sousa , Michel Sylvie , Grougnet Raphaël , Chaves Guilherme Maranhão , Zucolotto Silvana Maria
Published: February 2021

Commiphora leptophloeos (Burseraceae) is a medicinal plant native to Brazil which is popularly used for treating oral and vaginal infections. There has been no scientific evidence pointing to its efficacy in the treatment of these infections. Thus, this study sought to investigate the cytotoxic, antifungal, and antibiofilm activity of C. leptophloeos against Candida spp. and to isolate, identify, and quantify the content of B-type oligomeric procyanidins (BDP) in the extract of C. leptophloeos stem bark. The extract and the n-butanol fraction were obtained by maceration and liquid-liquid partition, respectively. Phytochemical analysis performed by HPLC-PDA/ELSD and FIA-ESI-IT-MS/MS allowed the identification and quantification of BDP in the samples. The application of centrifugal partition chromatography helped isolate BDP, which was identified by 1H NMR and MS analyses. Candida spp. reference strains and clinical isolates (including fluconazole-resistant strains) derived from the blood cultures of candidemic patients and the vaginal secretion of patients with vulvovaginal candidiasis were used for evaluating the antifungal and antibiofilm effects. Minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) were determined by the microdilution technique, and biofilm inhibition was evaluated through crystal violet and XTT assays. The combined action of BDP with fluconazole was determined by the checkerboard method. The extract, the n-butanol fraction, and the BDP exhibited antifungal activity with MIC values ranging from 312.5 to 2500 μg/mL and were found to significantly reduce the biofilm formed in all the Candida strains investigated. BDP showed a fungicidal potential against strains of Candida spp. (especially against fluconazole-resistant strains), with MIC and MFC values ranging from 156.2 to 2500 μg/mL. In addition, the combined application of BDP and fluconazole produced synergistic antifungal effects against resistant Candida spp. (FICI = 0.31–1.5). The cytotoxic properties of the samples evaluated in human erythrocytes through hemolytic test did not show hemolytic activity under active concentrations. The findings of the study show that C. leptophloeos has antifungal and antibiofilm potential but does not cause toxicity in human erythrocytes. Finally, BDP, which was isolated for the first time in C. leptophloeos, was found to exhibit antifungal effect against Candida spp. either when applied alone or in combination with fluconazole.
Review: Lessons Learned From Clinical Trials Using Antimicrobial Peptides (AMPs)
Authors: Dijksteel Gabrielle S. , Ulrich Magda M. W. , Middelkoop Esther , Boekema Bouke K. H. L.
Published: February 2021

Antimicrobial peptides (AMPs) or host defense peptides protect the host against various pathogens such as yeast, fungi, viruses and bacteria. AMPs also display immunomodulatory properties ranging from the modulation of inflammatory responses to the promotion of wound healing. More interestingly, AMPs cause cell disruption through non-specific interactions with the membrane surface of pathogens. This is most likely responsible for the low or limited emergence of bacterial resistance against many AMPs. Despite the increasing number of antibiotic-resistant bacteria and the potency of novel AMPs to combat such pathogens, only a few AMPs are in clinical use. Therefore, the current review describes (i) the potential of AMPs as alternatives to antibiotics, (ii) the challenges toward clinical implementation of AMPs and (iii) strategies to improve the success rate of AMPs in clinical trials, emphasizing the lessons we could learn from these trials.
High Throughput Sequencing for the Detection and Characterization of RNA Viruses
Authors: Fitzpatrick Amy H. , Rupnik Agnieszka , O'Shea Helen , Crispie Fiona , Keaveney Sinéad , Cotter Paul
Published: February 2021

This review aims to assess and recommend approaches for targeted and agnostic High Throughput Sequencing of RNA viruses in a variety of sample matrices. HTS also referred to as deep sequencing, next generation sequencing and third generation sequencing; has much to offer to the field of environmental virology as its increased sequencing depth circumvents issues with cloning environmental isolates for Sanger sequencing. That said however, it is important to consider the challenges and biases that method choice can impart to sequencing results. Here, methodology choices from RNA extraction, reverse transcription to library preparation are compared based on their impact on the detection or characterization of RNA viruses.
Supplemental Xylooligosaccharide Modulates Intestinal Mucosal Barrier and Cecal Microbiota in Laying Hens Fed Oxidized Fish Oil
Authors: Zhou Jian-min , Zhang Hai-jun , Wu Shu-geng , Qiu Kai , Fu Yu , Qi Guang-hai , Wang Jing
Published: February 2021

Our previous study indicated that dietary xylooligosaccharide (XOS) supplementation improved feed efficiency, ileal morphology, and nutrient digestibility in laying hens. The objective of this study was to evaluate the mitigative effects of XOS on intestinal mucosal barrier impairment and microbiota dysbiosis induced by oxidized fish oil (OFO) in laying hens. A total of 384 Hy-Line Brown layers at 50 weeks of age were randomly divided into four dietary treatments, including the diets supplemented with 20 g/kg of fresh fish oil (FFO group) or 20 g/kg of oxidized fish oil (OFO group), and the OFO diets with XOS addition at 200 mg/kg (OFO/XOS200 group) or 400 mg/kg (OFO/XOS400 group). Each treatment had eight replicates with 12 birds each. The OFO treatment decreased (P < 0.05) the production performance of birds from 7 to 12 weeks of the experiment, reduced (P < 0.05) ileal mucosal secretory immunoglobulin A (sIgA) content, and increased (P < 0.05) serum endotoxin concentration, as well as downregulated (P < 0.05) mRNA expression of claudin-1 (CLDN1) and claudin-5 (CLDN5) in the ileal mucosa at the end of the experiment. Dietary XOS addition (400 mg/kg) recovered (P < 0.05) these changes and further improved (P < 0.05) ileal villus height (VH) and the villus height-to-crypt depth ratio (VCR). In addition, OFO treatment altered cecal microbial composition of layers, and these alterations were probably involved in OFO-induced ileal mucosal impairment as causes or consequences. Supplemental XOS remodeled cecal microbiota of layers fed the OFO diet, characterized by an elevation in microbial richness and changes in microbial composition, including increases in Firmicutes, Ruminococcaceae, Verrucomicrobia (Akkermansia), Paraprevotella, Prevotella_9, and Oscillospira, along with a decrease in Erysipelatoclostridium. The increased abundance of Verrucomicrobia (Akkermansia) had positive correlations with the improved ileal VH and ileal mucosal expression of CLDN1. The abundance of Erysipelatoclostridium decreased by XOS addition was negatively associated with ileal VH, VCR, ileal mucosal sIgA content, and the relative expression of zonula occludens-2, CLDN1, and CLDN5. Collectively, supplemental XOS alleviated OFO-induced intestinal mucosal barrier dysfunction and performance impairment in laying hens, which could be at least partially attributed to the modulation of gut microbiota.
Statistical and Machine Learning Techniques in Human Microbiome Studies: Contemporary Challenges and Solutions
Authors: Moreno-Indias Isabel , Lahti Leo , Nedyalkova Miroslava , Elbere Ilze , Roshchupkin Gennady , Adilovic Muhamed , Aydemir Onder , Bakir-Gungor Burcu , Santa Pau Enrique Carrillo-de , D’Elia Domenica , Desai Mahesh S. , Falquet Laurent , Gundogdu Aycan , Hron Karel , Klammsteiner Thomas , Lopes Marta B. , Marcos-Zambrano Laura Judith , Marques Cláudia , Mason Michael , May Patrick , Pašić Lejla , Pio Gianvito , Pongor Sándor , Promponas Vasilis J. , Przymus Piotr , Saez-Rodriguez Julio , Sampri Alexia , Shigdel Rajesh , Stres Blaz , Suharoschi Ramona , Truu Jaak , Truică Ciprian-Octavian , Vilne Baiba , Vlachakis Dimitrios , Yilmaz Ercument , Zeller Georg , Zomer Aldert L. , Gómez-Cabrero David , Claesson Marcus J.
Published: February 2021

The human microbiome has emerged as a central research topic in human biology and biomedicine. Current microbiome studies generate high-throughput omics data across different body sites, populations, and life stages. Many of the challenges in microbiome research are similar to other high-throughput studies, the quantitative analyses need to address the heterogeneity of data, specific statistical properties, and the remarkable variation in microbiome composition across individuals and body sites. This has led to a broad spectrum of statistical and machine learning challenges that range from study design, data processing, and standardization to analysis, modeling, cross-study comparison, prediction, data science ecosystems, and reproducible reporting. Nevertheless, although many statistics and machine learning approaches and tools have been developed, new techniques are needed to deal with emerging applications and the vast heterogeneity of microbiome data. We review and discuss emerging applications of statistical and machine learning techniques in human microbiome studies and introduce the COST Action CA18131 “ML4Microbiome” that brings together microbiome researchers and machine learning experts to address current challenges such as standardization of analysis pipelines for reproducibility of data analysis results, benchmarking, improvement, or development of existing and new tools and ontologies.
Machine Learning Profiling of Alzheimer's Disease Patients Based on Current Cerebrospinal Fluid Markers and Iron Content in Biofluids
Authors: Ficiarà Eleonora , Boschi Silvia , Ansari Shoeb , D'Agata Federico , Abollino Ornella , Caroppo Paola , Di Fede Giuseppe , Indaco Antonio , Rainero Innocenzo , Guiot Caterina
Published: February 2021

Alzheimer's disease (AD) is the most common form of dementia, characterized by a complex etiology that makes therapeutic strategies still not effective. A true understanding of key pathological mechanisms and new biomarkers are needed, to identify alternative disease-modifying therapies counteracting the disease progression. Iron is an essential element for brain metabolism and its imbalance is implicated in neurodegeneration, due to its potential neurotoxic effect. However, the role of iron in different stages of dementia is not clearly established. This study aimed to investigate the potential impact of iron both in cerebrospinal fluid (CSF) and in serum to improve early diagnosis and the related therapeutic possibility. In addition to standard clinical method to detect iron in serum, a precise quantification of total iron in CSF was performed using graphite-furnace atomic absorption spectrometry in patients affected by AD, mild cognitive impairment, frontotemporal dementia, and non-demented neurological controls. The application of machine learning techniques, such as clustering analysis and multiclassification algorithms, showed a new potential stratification of patients exploiting iron-related data. The results support the involvement of iron dysregulation and its potential interaction with biomarkers (Tau protein and Amyloid-beta) in the pathophysiology and progression of dementia.
Miniaturized DNA Sequencers for Personal Use: Unreachable Dreams or Achievable Goals
Authors: Huo Wenxing , Ling Wei , Wang Zilun , Li Ya , Zhou Mingxing , Ren Miaoning , Li Xueting , Li Jiameng , Xia Zhiqiang , Liu Xinyu , Huang Xian
Published: February 2021

The appearance of next generation sequencing technology that features short read length with high measurement throughput and low cost has revolutionized the field of life science, medicine, and even computer science. The subsequent development of the third-generation sequencing technologies represented by nanopore and zero-mode waveguide techniques offers even higher speed and long read length with promising applications in portable and rapid genomic tests in field. Especially under the current circumstances, issues such as public health emergencies and global pandemics impose soaring demand on quick identification of origins and species of analytes through DNA sequences. In addition, future development of disease diagnosis, treatment, and tracking techniques may also require frequent DNA testing. As a result, DNA sequencers with miniaturized size and highly integrated components for personal and portable use to tackle increasing needs for disease prevention, personal medicine, and biohazard protection may become future trends. Just like many other biological and medical analytical systems that were originally bulky in sizes, collaborative work from various subjects in engineering and science eventually leads to the miniaturization of these systems. DNA sequencers that involve nanoprobes, detectors, microfluidics, microelectronics, and circuits as well as complex functional materials and structures are extremely complicated but may be miniaturized with technical advancement. This paper reviews the state-of-the-art technology in developing essential components in DNA sequencers and analyzes the feasibility to achieve miniaturized DNA sequencers for personal use. Future perspectives on the opportunities and associated challenges for compact DNA sequencers are also identified.
Diagnostic Performance of MRI Volumetry in Epilepsy Patients With Hippocampal Sclerosis Supported Through a Random Forest Automatic Classification Algorithm
Authors: Princich Juan Pablo , Donnelly-Kehoe Patricio Andres , Deleglise Alvaro , Vallejo-Azar Mariana Nahir , Pascariello Guido Orlando , Seoane Pablo , Veron Do Santos Jose Gabriel , Collavini Santiago , Nasimbera Alejandro Hugo , Kochen Silvia
Published: February 2021

Introduction: Several methods offer free volumetry services for MR data that adequately quantify volume differences in the hippocampus and its subregions. These methods are frequently used to assist in clinical diagnosis of suspected hippocampal sclerosis in temporal lobe epilepsy. A strong association between severity of histopathological anomalies and hippocampal volumes was reported using MR volumetry with a higher diagnostic yield than visual examination alone. Interpretation of volumetry results is challenging due to inherent methodological differences and to the reported variability of hippocampal volume. Furthermore, normal morphometric differences are recognized in diverse populations that may need consideration. To address this concern, we highlighted procedural discrepancies including atlas definition and computation of total intracranial volume that may impact volumetry results. We aimed to quantify diagnostic performance and to propose reference values for hippocampal volume from two well-established techniques: FreeSurfer v.06 and volBrain-HIPS.

Methods: Volumetry measures were calculated using clinical T1 MRI from a local population of 61 healthy controls and 57 epilepsy patients with confirmed unilateral hippocampal sclerosis. We further validated the results by a state-of-the-art machine learning classification algorithm (Random Forest) computing accuracy and feature relevance to distinguish between patients and controls. This validation process was performed using the FreeSurfer dataset alone, considering morphometric values not only from the hippocampus but also from additional non-hippocampal brain regions that could be potentially relevant for group classification. Mean reference values and 95% confidence intervals were calculated for left and right hippocampi along with hippocampal asymmetry degree to test diagnostic accuracy.

Results: Both methods showed excellent classification performance (AUC:> 0.914) with noticeable differences in absolute (cm3) and normalized volumes. Hippocampal asymmetry was the most accurate discriminator from all estimates (AUC:1~0.97). Similar results were achieved in the validation test with an automatic classifier (AUC:>0.960), disclosing hippocampal structures as the most relevant features for group differentiation among other brain regions.

Conclusion: We calculated reference volumetry values from two commonly used methods to accurately identify patients with temporal epilepsy and hippocampal sclerosis. Validation with an automatic classifier confirmed the principal role of the hippocampus and its subregions for diagnosis.
Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON)—An International Network on Care and Research for Patients With Neurodegeneration With Brain Iron Accumulation (NBIA)
Authors: Karin Ivan , Büchner Boriana , Gauzy Florence , Klucken Angelika , Klopstock Thomas
Published: February 2021

In order to improve clinical care, coordinate research activities and raise awareness for the ultra-orphan Neurodegeneration with Brain Iron Accumulation (NBIA) disorders, a group of NBIA clinicians and researchers, industry partners and patient advocacies from six European countries, Canada and the US joined forces in 2010 to set-up the collaborative initiative TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration). As a research project, TIRCON received funding in the 7th Framework Programme (FP7) of the European Union (EU) from 2011 to 2015. After successful and timely completion of the initial FP7 project, funding and donations from industry and patient organizations have sustained the further development of TIRCON's dedicated clinical research infrastructure and its governance architecture, as well as the ongoing efforts undertaken in the NBIA community to establish a network of care. From the beginning, the University Hospital of the Ludwig-Maximilians-University in Munich, Germany has been coordinating the TIRCON initiative. It consists of 8 work packages, of which the first double-blind, placebo-controlled, randomized, multi-site clinical trial in NBIA (deferiprone in PKAN, completed) and a global patient registry and biobank, currently comprising baseline and follow-up data of > 400 NBIA patients have gained particular importance. Here we describe TIRCON's history with all the challenges and achievements in diagnosing and treating NBIA. Today, TIRCON lays the ground for future clinical care and research. In these times, it may also serve as a good example of well-directed governmental funding and fruitful international scientific collaboration.
Neuromorphic Analog Implementation of Neural Engineering Framework-Inspired Spiking Neuron for High-Dimensional Representation
Authors: Hazan Avi , Ezra Tsur Elishai
Published: February 2021

Brain-inspired hardware designs realize neural principles in electronics to provide high-performing, energy-efficient frameworks for artificial intelligence. The Neural Engineering Framework (NEF) brings forth a theoretical framework for representing high-dimensional mathematical constructs with spiking neurons to implement functional large-scale neural networks. Here, we present OZ, a programable analog implementation of NEF-inspired spiking neurons. OZ neurons can be dynamically programmed to feature varying high-dimensional response curves with positive and negative encoders for a neuromorphic distributed representation of normalized input data. Our hardware design demonstrates full correspondence with NEF across firing rates, encoding vectors, and intercepts. OZ neurons can be independently configured in real-time to allow efficient spanning of a representation space, thus using fewer neurons and therefore less power for neuromorphic data representation.
Scheduling and Rescheduling Operations Using Decision Support Systems: Insights From Emotional Influences on Decision-Making
Authors: Mailliez Mélody , Battaïa Olga , Roy Raphaëlle N.
Published: February 2021

For many years, manufacturers have focused on improving their productivity. Production scheduling operations are critical for this objective. However, in modern manufacturing systems, the original schedule must be regularly updated as it takes places in a dynamic and uncertain environment. The modern manufacturing environment is therefore very stressful for the managers in charge of the production process because they have to cope with many disruptions and uncertainties. To help them in their decision-making process, several decision support systems (DSSs) have been developed. A recent and enormous challenge is the implementation of DSSs to efficiently manage the aforementioned issues. Nowadays, these DSSs are assumed to reduce the users' stress and workload because they automatically (re)schedule the production by applying algorithms. However, to the best of our knowledge, the reciprocal influence of users' mental state (i.e., cognitive and affective states) and the use of these DSSs have received limited attention in the literature. Particularly, the influence of users' unrelated emotions has received even less attention. However, these influences are of particular interest because they can account for explaining the efficiency of DSSs, especially in modulating DSS feedback processing. As a result, we assumed that investigating the reciprocal influences of DSSs and users' mental states could provide useful avenues of investigation. The intention of this article is then to provide recommendations for future research on scheduling and rescheduling operations by suggesting the investigation of users' mental state and encouraging to conduct such research within the neuroergonomic approach.
Comparative Efficacy and Safety of PARP Inhibitors as Maintenance Therapy in Platinum Sensitive Recurrent Ovarian Cancer: A Network Meta-Analysis
Authors: Xu Yangchun , Ding Lei , Tian Yuan , Bi Miaomiao , Han Ning , Wang Ling
Published: February 2021

This meta-analysis investigated the comparative efficacy and safety of PARP inhibitor monotherapy as maintenance treatment in platinum sensitive recurrent ovarian cancer (ROC). Electronic databases were systematically searched for relevant RCTs. The primary endpoint was PFS. The results were stratified based on three categories: BRCA mutated patients, HRD patients, and overall population. The secondary outcome were discontinuations due to adverse events and grade 3 or 4 adverse events in maintenance phase. Five eligible RCTs were included in the network meta-analysis. For patients with BRCA mutated ovarian cancer, olaparib-throughout (HR = 0.21 with 95% CrI: 0.081–0.55), rucaparib (HR = 0.23 with 95% CrI: 0.16–0.34), olaparib (HR = 0.27 with 95% CrI: 0.20–0.35), and niraparib (HR = 0.26 with 95% CrI: 0.17–0.41) were all highly effective in comparison with placebo at improving PFS. For HRD patients, both rucaparib (HR = 0.32 with 95% CrI: 0.24–0.42) and niraparib (HR = 0.38 with 95% CrI: 0.24–0.60) were all highly effective in comparison with placebo at improving PFS. For the overall population, olaparib-throughout (HR = 0.51 with 95% CrI: 0.34–0.76), rucaparib (HR = 0.37 with 95% CrI: 0.30–0.45), olaparib (HR = 0.35 with 95% CrI: 0.25–0.49), and niraparib (HR = 0.38 with 95% CrI: 0.30–0.48) were all highly effective in comparison with placebo at improving PFS. Regarding grade 3 or 4 adverse events, the incidence of grade 3 or 4 toxicity reactions to rucaparib and niraparib were significantly higher than in the olaparib group. In terms of discontinuations due to adverse events, the treatment discontinuations were not significantly different between the three drugs. In summary, all the included maintenance treatment regimens are effective regardless of BRCA mutational status, and no statistically significant differences between rucaparib, niraparib and Olaparib in terms of PFS. In terms of safety profile, the three drugs present manageable adverse events. Clinicians should consider potential adverse events related to each of these interventions in clinical practice, and the adverse events are generally manageable.
EZH2-TROAP Pathway Promotes Prostate Cancer Progression Via TWIST Signals
Authors: Jin Lu , Zhou Yibin , Chen Guangqiang , Dai Guangcheng , Fu Kai , Yang Dongrong , Zhu Jin
Published: February 2021

Trophinin-associated protein (TROAP) has been shown to be overexpressed and promotes tumor progression in some tumors. We performed this study to assess the biological and clinical significance of TROAP in prostate cancer. We downloaded TROAP mRNA expression data from TCGA and GEO databases. We analyzed expressions of TROAP and other genes in prostate cancer tumors at different stages and assessed Gleason scores. We used Celigo image, Transwell, and rescue assays, and flow cytometry detection to assess growth, apoptosis, proliferation, migration, and invasion of the prostate cancer cells. We identified and validated up- and down-stream genes in the TROAP pathway. The mRNA data suggested that TROAP expression was markedly upregulated in prostate cancer compared with its expression in normal tissues, especially in cancers with high stages and Gleason scores. Moreover, a high TROAP expression was associated with poor patient survival. Results of our in vitro assay showed that TROAP knockdown inhibited DU145 and PC3 cell proliferation and viability via cell apoptosis and S phase cycle arrest. The Transwell assay showed that TROAP knockdown inhibited cell migration and invasion, probably through MMP-9 and E-Cadherin modulation. Overexpression of TWIST partially abrogated the inhibitory effects of TROAP knockdown on prostate cancer cells. Our integrative mechanism dissection revealed that TROAP is in a pathway downstream of EZH2 and that it activates the TWIST/c-Myc pathway to regulate prostate cancer progression. In all, we identified TROAP as a driver of prostate cancer development and progression, providing a novel target for prostate cancer treatments.
Enhanced Angiogenesis in Salivary Duct Carcinoma Ex-Pleomorphic Adenoma
Authors: Suzuki Takayoshi , Kano Satoshi , Suzuki Masanobu , Yasukawa Shinichiro , Mizumachi Takatsugu , Tsushima Nayuta , Hatanaka Kanako C. , Hatanaka Yutaka , Matsuno Yoshihiro , Homma Akihiro
Published: February 2021

Salivary duct carcinoma (SDC) is morphologically similar to breast cancer, with HER2-overexpression reported. With regard to the pattern of disease onset, SDC can arise from de novo or carcinoma ex-pleomorphic adenoma (Ca-ex-PA). Recently, multiple molecular profiles of SDC as well as breast cancer have been reported, with significant differences in HER2 expression between Ca-ex-PA and de novo. We assessed the differences in gene expression between onset classifications. We conducted immunohistochemical analysis and HER2-DISH for 23 patients and classified SDCs into three subtypes as follows: “HER2-positive” (HER2+/any AR), “Luminal-AR” (HER2-/AR+), and “Basal-like” (HER2-/AR-). We assessed the expression levels of 84 functional genes for 19 patients by using a qRT-PCR array. Ten cases were classified as HER2-positive, seven cases as Luminal-AR, and six cases as Basal-like. The gene expression pattern was generally consistent with the corresponding immunostaining classification. The expression levels of VEGFA, ERBB2(HER2), IGF1R, RB1, and XBP1 were higher, while those of SLIT2 and PTEN were lower in Ca-ex-PA than in de novo. The functions of those genes were concentrated in angiogenesis and AKT/PI3K signaling pathway (Fisher’s test: p-value = 0.025 and 0.004, respectively). Multiple machine learning methods, OPLS-DA, LASSO, and RandomForest, also show that VEGFA can be a candidate for the characteristic differences between Ca-ex-PA and de novo. In conclusion, the AKT/PI3K signaling pathway leading to angiogenesis was hyper-activated in all SDCs, particularly in those classified into the Ca-ex-PAs. VEGFA was over-expressed significantly in the Ca-ex-PA, which can be a crucial factor in the malignant conversion to SDC.
Identification and Validation of a Prognostic Gene Signature for Diffuse Large B-Cell Lymphoma Based on Tumor Microenvironment-Related Genes
Authors: Pan Tao , He Yizi , Chen Huan , Pei Junfei , Li Yajun , Zeng Ruolan , Xia Jiliang , Zuo Yilang , Qin Liping , Chen Siwei , Xiao Ling , Zhou Hui
Published: February 2021

Diffuse large B-cell lymphoma (DLBCL) is an extremely heterogeneous tumor entity, which makes prognostic prediction challenging. The tumor microenvironment (TME) has a crucial role in fostering and restraining tumor development. Consequently, we performed a systematic investigation of the TME and genetic factors associated with DLBCL to identify prognostic biomarkers for DLBCL. Data for a total of 1,084 DLBCL patients from the Gene Expression Omnibus database were included in this study, and patients were divided into a training group, an internal validation group, and two external validation groups. We calculated the abundance of immune–stromal components of DLBCL and found that they were related to tumor prognosis and progression. Then, differentially expressed genes were obtained based on immune and stromal scores, and prognostic TME‐related genes were further identified using a protein–protein interaction network and univariate Cox regression analysis. These genes were analyzed by the least absolute shrinkage and selection operator Cox regression model to establish a seven-gene signature, comprising TIMP2, QKI, LCP2, LAMP2, ITGAM, CSF3R, and AAK1. The signature was shown to have critical prognostic value in the training and validation sets and was also confirmed to be an independent prognostic factor. Subgroup analysis also indicated the robust prognostic ability of the signature. A nomogram integrating the seven-gene signature and components of the International Prognostic Index was shown to have value for prognostic prediction. Gene set enrichment analysis between risk groups demonstrated that immune-related pathways were enriched in the low-risk group. In conclusion, a novel and reliable TME relevant gene signature was proposed and shown to be capable of predicting the survival of DLBCL patients at high risk of poor survival.
The Efficacy and Safety of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease
Authors: Tang Hui , Zhou Jianfeng , Bai Chunmei
Published: February 2021

Immune checkpoint inhibitor (ICI) is a revolutionary breakthrough in the field of cancer treatment. Because of dysregulated activation of the immune system, patients with autoimmune disease (AID) are usually excluded from ICI clinical trials. Due to a large number of cancer patients with preexisting AID, the safety and efficacy of ICIs in these patients deserve more attention. This review summarizes and analyzes the data regarding ICI therapy in cancer patients with preexisting AID from 17 published studies. Available data suggests that the efficacy of ICIs in AID patients is comparable to that in the general population, and the incidence of immune-related adverse events (irAEs) is higher but still manageable. It is recommended to administer ICIs with close monitoring of irAEs in patients with a possibly high benefit-risk ratio after a multidisciplinary discussion based on the patient’s AID category and severity, the patient’s tumor type and prognosis, alternative treatment options, and the patient’s intention. Besides, the prevention and management of irAEs in AID patients have been discussed.
IPEX Syndrome: Improved Knowledge of Immune Pathogenesis Empowers Diagnosis
Authors: Barzaghi Federica , Passerini Laura
Published: February 2021

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic autoimmune disease with variable clinical manifestations, ranging from early-onset severe autoimmunity, including enteropathy, eczema, and type 1 diabetes, to late-onset or atypical symptoms. Despite the clinical heterogeneity, the unifying feature of IPEX is mutation of the FOXP3 gene, which encodes a transcription factor essential for maintenance of thymus-derived regulatory T cells (Tregs). In IPEX patients, Tregs can be present, although unstable and impaired in function, unable to inhibit proliferation and cytokine production of effector T (Teff) cells. Mutated FOXP3 can also disrupt other compartments: FOXP3-deficient Teff cells proliferate more than the wild-type counterpart, display altered T-cell-receptor signaling response, a reduced T-naïve compartment and a skew toward a Th2 profile. Due to FOXP3 mutations, the frequency of autoreactive B cells is increased and the IgA and IgE production is altered, together with early emergence of tissue-specific autoantibodies. Recently, the awareness of the wide clinical spectrum of IPEX improved the diagnostic tools. In cases presenting with enteropathy, histological evaluation is helpful, although there are no pathognomonic signs of disease. On the other hand, the study of FOXP3 expression and in vitro Treg function, as well as the detection of specific circulating autoantibodies, is recommended to narrow the differential diagnosis. Nowadays, Sanger sequencing should be limited to cases presenting with the classical triad of symptoms; otherwise, next-generation sequencing is recommended, given the cost-effectiveness and the advantage of excluding IPEX-like syndromes. The latter approach could be time spearing in children with severe phenotypes and candidate to advanced therapies.