bluuebunny/crossref_metadata_2025 huggingface dataset:
Bleeding Risk Profile in Patients on Oral Anticoagulation Undergoing Percutaneous Coronary Interventions: A Prospective 24 Months Cohort Study
Authors: Schukraft Sara , Huwyler Tibor , Ottiger-Mankaka Cindy , Lehmann Sonja , Cook Ezia , Doomun Daphné , Doomun Ianis , Goy Jean-Jacques , Stauffer Jean-Christophe , Togni Mario , Arroyo Diego , Puricel Serban , Cook Stéphane
Published: September 2021

Background: The Academic Research Consortium has identified a set of major and minor risk factors in order to standardize the definition of a high bleeding risk (ACR-HBR). Oral anticoagulation is a major criterion frequently observed.

Aims: The objective of this study is to quantify the risk of bleeding in patients on oral anticoagulation with at least one additional major ACR-HBR criteria in the Cardio-Fribourg Registry.

Methods: Between 2015 and 2017, consecutive patients undergoing percutaneous coronary intervention were prospectively included in the Cardio-Fribourg registry. The study population included patients with ongoing long-term oral anticoagulation (OAC) and planned to receive triple antithrombotic therapy. Patients were divided in two groups: patients on OAC with at least one additional major ACR-HBR criteria vs. patients on OAC without additional major ACR-HBR criteria. The primary endpoint was any bleeding during the 24-month follow-up. Secondary bleeding endpoint was defined as Bleeding Academic Research Classification (BARC) ≥3.

Results: Follow-up was completed in 142 patients at high bleeding risk on OAC, of which 33 (23%) had at least one additional major ACR-HBR criteria. The rate of the primary endpoint was 55% in patients on OAC with at least one additional ACR-HBR criteria compared with 14% in patients on OAC without additional ACR-HBR criteria (hazard ratio, 3.88; 95%CI, 1.85–8.14; p < 0.01). Patients with additional major ACR-HBR criteria also experienced significantly higher rates of BARC ≥ 3 bleedings (39% at 24 months).

Conclusion: The presence of at least one additional ACR-HBR criterion identifies patients on OAC who are at very high risk of bleeding after percutaneous coronary intervention.
Multi-Informant Assessment of Bullying in Austrian Schools
Authors: Paljakka Antonia , Schwab Susanne , Zurbriggen Carmen L. A.
Published: September 2021

This study explores the agreement of bullying reports from different perspectives. Nominations and (self and peer) ratings of 721 students (50.5% boys, 49.5% girls, aged 9–11), 46 teachers (91.3% female, 8.7% male;Mage= 40.28 years,SDage= 1.6, teaching experience between 2 and 36 years,Mexperience= 15.16,SDexperience= 1.68), 439 mothers, and 363 fathers were analyzed. Measures included a modified version of the Revised Olweus Bully/Victim questionnaire (OBVQ) as well as nomination items, with variables on physical and relational bullying and victimization, and frequency of experience. For descriptive analyses, group comparisons and correlations were performed and to test the dimensional structure of the modified Revised OBVQ we fitted a categorical confirmatory factor analysis (CCFA) for all four raters. To estimate the degree of agreement between the four raters, we applied a simple multitrait-multimethod (MTMM) analysis in a CCFA framework. Results indicated that teachers are more likely to recognize physical bullying than relational bullying. Significant gender effects were found, with more frequent nominations for boys and a larger gender effect for physical bullying. Overall, teachers reported the highest levels of bullying, and students reported significantly higher levels of victimization compared to the other raters. In terms of bullying, the MTMM model revealed a slightly higher agreement between students and parents than between students and teachers. The findings further indicate a tendency for lower agreement between student and adult reports than among adults’ reports. The notably high agreement between the ratings of mothers and fathers for both bullying and victimization supports the research strategy to include only one parent. Although bullying is assessed from various perspectives, the study does not provide prevalence estimates of bullying in Austria.
Transdisciplinary Approach for Bioinformatics Education in Southern Brazil
Authors: Dorn Marcio , Ligabue-Braun Rodrigo , Verli Hugo
Published: September 2021

The development and application of bioinformatics has been growing steadily, but its learning and training has been lagging. We have approached this problem through a bi-annual event, called EGB (Escola Gaúcha de Bioinformática), dedicated to undergraduate and graduate students (mainly from biology, biomedicine, chemistry, physics, and computer sciences), as well as professionals, to mingle and be presented to bioinformatics from sequence, structure, and computational standpoints simultaneously. The interactive environment provided by EGB allows for participants mingling, independently from their training background, fostering collaborative learning and experience exchange. Both lecturers and students are encouraged to collaborate and communicate, with no formal acknowledgement of “status differentiation”.
Forest Biosecurity Systems and Processes: An Indian Perspective
Authors: Gupta Kavita , Sankaran K. V.
Published: September 2021

Biological invasions continue unabated across the globe despite all efforts to manage the problem by implementing biosecurity regulations and associated management methods. In this context, this paper reviews the plant biosecurity legislation applicable to agriculture and forestry sectors in India to prevent/manage invasions, with the objective of identifying limitations in the legislation or lapses in implementing it and propose corrective measures. The legislation can be improved by: (1) revising and updating the Destructive Insects and Pests Act (1914) and Plant Quarantine Order 2003 and (2) establishing a National Sanitary and Phytosanitary Database Center to promote exchange of information. Establishing more plant quarantine stations with state-of-the-art facilities and a Biosecurity and Trade Unit may support implementation of legislation. Some of main gaps in information and research in biosecurity are identified. The plant biosecurity legislation, though meant to be common, mainly addresses the agriculture sector; its application in the forestry context is currently scarce. Hence, it is suggested that India may enact forest biosecurity scrupulously especially in the context of introducing the REDD + strategy and a Forest Certification Scheme. It is proposed that an integrated pest management (IPM) system involving e-pest surveillance, establishment of pest-free areas and use of biocontrol may help tackle emerging pest threats. The use of new technologies for remote sensing and detection and mapping of vegetation may help bio-surveillance, forecasting, and monitoring of pests. However, successful implementation of all management options demands formation of an exclusive national policy to manage invasive alien species and an action plan governed by a single agency. To realize the plant biosecurity goals, India may also strengthen regional cooperation to: (1) harmonize regulations for sanitary/phytosanitary and plant quarantine/biosafety measures and (2) use a common pest risk analysis (PRA) for unknown pests in the region. Capacity-building of officials to identify risky goods and verify conformity with Import Health Standards is raised. Also, raising awareness on biosecurity among all stakeholders and involving them in implementing the legislation would be helpful. The proposed National Agricultural Biosecurity System and the Agricultural Biosecurity Bill currently considered by the Indian Parliament is expected to address the inadequacies.
DNA Double Strand Break Repair Pathways in Response to Different Types of Ionizing Radiation
Authors: van de Kamp Gerarda , Heemskerk Tim , Kanaar Roland , Essers Jeroen
Published: September 2021

The superior dose distribution of particle radiation compared to photon radiation makes it a promising therapy for the treatment of tumors. However, the cellular responses to particle therapy and especially the DNA damage response (DDR) is not well characterized. Compared to photons, particles are thought to induce more closely spaced DNA lesions instead of isolated lesions. How this different spatial configuration of the DNA damage directs DNA repair pathway usage, is subject of current investigations. In this review, we describe recent insights into induction of DNA damage by particle radiation and how this shapes DNA end processing and subsequent DNA repair mechanisms. Additionally, we give an overview of promising DDR targets to improve particle therapy.
Enhanced Susceptibility of ADAP-Deficient Mice to Listeria monocytogenes Infection Is Associated With an Altered Phagocyte Phenotype and Function
Authors: Böning Martha A. L. , Parzmair Gerald P. , Jeron Andreas , Düsedau Henning P. , Kershaw Olivia , Xu Baolin , Relja Borna , Schlüter Dirk , Dunay Ildiko Rita , Reinhold Annegret , Schraven Burkhart , Bruder Dunja
Published: September 2021

The adhesion and degranulation-promoting adaptor protein (ADAP) serves as a multifunctional scaffold and is involved in the formation of immune signaling complexes. To date, only limited data exist regarding the role of ADAP in pathogen-specific immunity duringin vivoinfection, and its contribution in phagocyte-mediated antibacterial immunity remains elusive. Here, we show that mice lacking ADAP (ADAPko) are highly susceptible to the infection with the intracellular pathogenListeria monocytogenes(Lm) by showing enhanced immunopathology in infected tissues together with increased morbidity, mortality, and excessive infiltration of neutrophils and monocytes. Despite high phagocyte numbers in the spleen and liver, ADAPko mice only inefficiently controlled pathogen growth, hinting at a functional impairment of infection-primed phagocytes in the ADAP-deficient host. Flow cytometric analysis of hallmark pro-inflammatory mediators and unbiased whole genome transcriptional profiling of neutrophils and inflammatory monocytes uncovered broad molecular alterations in the inflammatory program in both phagocyte subsets following their activation in the ADAP-deficient host. Strikingly,ex vivophagocytosis assay revealed impaired phagocytic capacity of neutrophils derived fromLm-infected ADAPko mice. Together, our data suggest that an alternative priming of phagocytes in ADAP-deficient mice duringLminfection induces marked alterations in the inflammatory profile of neutrophils and inflammatory monocytes that contribute to enhanced immunopathology while limiting their capacity to eliminate the pathogen and to prevent the fatal outcome of the infection.
TR Locus Annotation and Characteristics of Rhinolophus ferrumequinum
Authors: Zhou Hao , Ma Long , Liu Longyu , Yao Xinsheng
Published: September 2021

T-cell antigen receptors (TRs) in vertebrates can be divided into αβ or γδ, encoded by TRA/D, TRG, or TRB loci. TRs play a central role in mammal cellular immunity, which occurs by rearrangement of V, D, J, and C genes in the loci. The bat is the only mammal with flying ability and is considered the main host of zoonotic viruses, an important public health concern. However, at present, little is known about the composition of bat TR genes. Based on the whole genome sequence of the greater horseshoe bat (Rhinolophus ferrumequinum) and referring to the TR/IG annotation rules formulated by the international ImMunoGeneTics information system (IMGT), we present a complete annotation of TRA/D, TRG, and TRB loci of R. ferrumequinum. A total of 128 V segments, three D segments, 85 J segments, and 6 C segments were annotated and compared with other known mammalian data. The characteristics of the TR locus and germline genes of R. ferrumequinum are analyzed.
A Prospective Survey of Skin Manifestations in Children With Inborn Errors of Immunity From a National Registry Over 17 Years
Authors: Al-Herz Waleed , Zainal Mohammad , Nanda Arti
Published: September 2021

Background and Objectives

Reports on skin manifestations in inborn errors of immunity (IEI) are based on retrospective analysis, small series, or isolated case reports. The present prospective study aimed to determine the spectrum of skin manifestations in children with IEI and their relevance to specific molecular defects.

Materials and Methods

The data were obtained from the Kuwait National Primary Immunodeficiency Disorders Registry during the period of 2004–2020.

Results

A total of 313 pediatric cases of IEI, 71% diagnosed at molecular level, were registered with a cumulative follow-up period of 29,734 months. Skin manifestations were seen in 40.3% of the patients, and they were among the presenting manifestations in 33%. Patients with skin manifestations were older at both onset and diagnosis ages of IEI symptoms, but this was statistically significant for the latter only. The diagnosis delay was significantly longer in patients with skin manifestations. There was a statistically significant association between having skin manifestations and IEI category, being more common in patients with complement deficiencies, combined immunodeficiencies, and diseases of immune dysregulation. There was no statistically significant association between having skin manifestations and both gender and survival. Skin infections were the most frequent manifestations followed by eczema and autoimmune associations. Among IEI with more than 10 cases, skin lesions were a consistent finding in dedicator of cytokinesis 8 (DOCK8) deficiency, hyper IgE syndrome, ataxia-telangiectasia, and recombination activation gene (RAG)1 deficiency.

Conclusions

Skin manifestations are common in IEI patients, and they had significant diagnosis delay and referral to specialists. Improvement of awareness about IEI is needed among pediatricians and dermatologists.
A Novel TLR4-Binding Domain of Peroxiredoxin From Entamoeba histolytica Triggers NLRP3 Inflammasome Activation in Macrophages
Authors: Li Xia , Feng Meng , Zhao Yanqing , Zhang Yuhan , Zhou Ruixue , Zhou Hang , Pang Zhen , Tachibana Hiroshi , Cheng Xunjia
Published: September 2021

Macrophages promote early host responses to infection by releasing pro-inflammatory cytokines, and they are crucial to combat amoebiasis, a disease affecting millions of people worldwide. Macrophages elicit pro-inflammatory responses following direct cell/cell interaction of Entamoeba histolytica, inducing NLRP3 inflammasome activation with high-output IL-1β/IL-18 secretion. Here, we found that trophozoites could upregulate peroxiredoxins (Prx) expression and abundantly secrete Prxs when encountering host cells. The C-terminal of Prx was identified as the key functional domain in promoting NLRP3 inflammasome activation, and a recombinant C-terminal domain could act directly on macrophage. The Prxs derived from E. histolytica triggered toll-like receptor 4-dependent activation of NLRP3 inflammasome in a cell/cell contact-independent manner. Through genetic, immunoblotting or pharmacological inhibition methods, NLRP3 inflammasome activation was induced through caspase-1-dependent canonical pathway. Our data suggest that E. histolytica Prxs had stable and durable cell/cell contact-independent effects on macrophages following abundantly secretion during invasion, and the C-terminal of Prx was responsible for activating NLRP3 inflammasome in macrophages. This new alternative pathway may represent a potential novel therapeutic approach for amoebiasis, a global threat to millions.
Idiopathic Bilateral Extraocular Myositis in a Subject With Poorly Controlled Type 2 Diabetes Mellitus: Case Report
Authors: Tatsumi Fuminori , Fushimi Yoshiro , Sanada Junpei , Shimoda Masashi , Kohara Kenji , Kimura Tomohiko , Obata Atsushi , Nakanishi Shuhei , Mune Tomoatsu , Kaku Kohei , Kaneto Hideaki
Published: September 2021

Background: Extraocular myositis is characterized by acute onset of orbital pain, extraocular muscle swelling, absence of thyroid disease, and effectiveness of steroid therapy. While oculomotor nerve paralysis is often observed in subjects with diabetes mellitus, extraocular muscle paralysis is very rare among various diabetic mononeuropathies. In addition, while most diabetic mononeuropathies are observed as sporadic and/or unilateral neuropathy, bilateral mononeuropathy is also very rare.

Case presentation: A 58-year-old male visited our institution due to diplopia. He was diagnosed as type 2 diabetes mellitus about 10 years before and treated with oral diabetes agents. To examine the cause of his symptom, he was hospitalized in our institution. Slight ptosis was observed, and failure of adduction was observed in the right eye. Glycemic control was poor; HbA1c was 9.3%. Liver, renal, and thyroid function were within normal range. Immunoglobulin (Ig) G was slightly high, but IgA, IgM, and IgG4 were within normal range. Various antibodies were all negative. Angiotensin-converting enzyme level was within normal range. There were no abnormalities in brain magnetic resonance imaging (MRI). After admission, to alleviate glucose toxicity, we started insulin therapy. On day 17, adduction failure of the left eye was observed in addition to the right eye. Vertical movement was also impaired in both eyes. Slight ptosis was observed in both eyes, and the right eye was completely close. In orbital MRI, some high signal was detected in both extraocular muscles. We performed steroid pulse therapy twice. About 4 months later, ptosis and vertical and horizontal movements in both eyes were almost completely recovered. Finally, we diagnosed him as idiopathic bilateral extraocular myositis.

Conclusions: We should bear in mind the possibility of idiopathic bilateral extraocular myositis especially in subjects with poor glycemic control, although its incident rate is extremely rare.
Long-Term Anatomical and Functional Survival of Boston Type 1 Keratoprosthesis in Congenital Aniridia
Authors: Dyer Ariann , De Faria Alix , Julio Gemma , Álvarez de Toledo Juan , Barraquer Rafael I. , de la Paz Maria Fideliz
Published: September 2021

Purpose: To analyze the long-term anatomical survival, functional survival, and complications of Boston type 1 keratoprosthesis (KPro) in the eyes with congenital aniridia-associated keratopathy (AAK).

Methods: A retrospective review of 12 eyes with congenital aniridia that underwent a Boston type 1 KPro surgery was conducted. A Kaplan–Meier analysis was performed. Anatomical and functional success criteria were KPro retention and a best corrected visual acuity (BCVA) ≤1.3 LogMAR (≥0.05 decimal) at the end of a follow-up period. Postoperative complications were recorded.

Results: The mean preoperative BCVA was 2.1 ± 0.9 (range: 3.8–1) LogMAR, and glaucoma was a comorbidity in all the cases. Five years after the surgery, the overall retention rate was 10/12 (83.3%), and 50% had functional success. Only three (25%) of the 12 cases did not achieve a BCVA ≤1.3 LogMAR. The cumulative probability of anatomical success was 92, 79, and 79% after 1, 5, and 10 years, respectively. The cumulative probability of functional success was 57 and 46% after 1 and 5 years, respectively. The mean anatomical and functional survival time was 10 ± 1.3 (95% IC = 7.5–12.3 years) and 3.8 ± 0.9 years (95% IC = 1.8–5.8 years), respectively. The most common postoperative complication was retroprosthetic membrane (RPM) formation in 8/16 cases (66%). The mean number of complications per case was 2.4 ± 1.8 (0–6).

Conclusions: The Boston type 1 KPro is a viable option for patients with AAK with good anatomical and functional long-term results. Glaucoma is an important preoperative condition that affects functional results. Retroprosthetic membrane formation seems to have a higher incidence in this condition.
Gut Microbiota Dysbiosis Influences Metabolic Homeostasis in Spodoptera frugiperda
Authors: Chen Yaqing , Zhou Huanchan , Lai Yushan , Chen Qi , Yu Xiao-Qiang , Wang Xiaoyun
Published: September 2021

Insect gut microbiota plays important roles in acquiring nutrition, preventing pathogens infection, modulating immune responses, and communicating with environment. Gut microbiota can be affected by external factors such as foods and antibiotics. Spodoptera frugiperda (Lepidoptera: Noctuidae) is an important destructive pest of grain crops worldwide. The function of gut microbiota in S. frugiperda remains to be investigated. In this study, we fed S. frugiperda larvae with artificial diet with antibiotic mixture (penicillin, gentamicin, rifampicin, and streptomycin) to perturb gut microbiota, and then examined the effect of gut microbiota dysbiosis on S. frugiperda gene expression by RNA sequencing. Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria were the most dominant phyla in S. frugiperda. We found that the composition and diversity of gut bacterial community were changed in S. frugiperda after antibiotics treatment. Firmicutes was decreased, and abundance of Enterococcus and Weissella genera was dramatically reduced. Transcriptome analysis showed that 1,394 differentially expressed transcripts (DETs) were found between the control and antibiotics-treated group. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that antibiotics-induced dysbiosis affected many biological processes, such as energy production, metabolism, and the autophagy–lysosome signal pathway. Our results indicated that dysbiosis of gut microbiota by antibiotics exposure affects energy and metabolic homeostasis in S. frugiperda, which help better understand the role of gut microbiota in insects.
The Costs and Benefits of Two Secondary Symbionts in a Whitefly Host Shape Their Differential Prevalence in the Field
Authors: Shan Hong-Wei , Liu Shu-Sheng
Published: September 2021

Insects commonly harbor maternally inherited intracellular symbionts in nature, and the microbial partners often exert influence on host reproduction and fitness to promote their prevalence. Here, we investigated composition of symbionts and their biological effects in the invasive Bemisia tabaci MED species of a whitefly complex. Our field surveys revealed that populations of the MED whitefly, in addition to the primary symbiont Portiera, mainly contain two secondary symbionts Hamiltonella, which is nearly fixed in the host populations, and Cardinium with infection frequencies ranging from 0 to 86%. We isolated and established Cardinium-positive and Cardinium-free whitefly lines with a similar nuclear genetic background from a field population, and compared performance of the two whitefly lines. The infection of Cardinium incurred significant fitness costs on the MED whitefly, including reduction of fecundity and egg viability as well as delay in development. We then selectively removed Hamiltonella from the Cardinium-free whitefly line and compared performance of two whitefly lines, one harboring both Portiera and Hamiltonella and the other harboring only Portiera. While depletion of Hamiltonella had little or only marginal effects on the fecundity, developmental rate, and offspring survival, the Hamiltonella-free whitefly line produced very few female offspring, often reducing the progeny female ratio from about 50% to less than 1%. Our findings indicate that the varying costs and benefits of the association between these two symbionts and the MED whitefly may play an important role in shaping their differential prevalence in the field.
Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women With Alzheimer’s Disease
Authors: Paranjpe Manish D. , Belonwu Stella , Wang Jason K. , Oskotsky Tomiko , Gupta Aarzu , Taubes Alice , Zalocusky Kelly A. , Paranjpe Ishan , Glicksberg Benjamin S. , Huang Yadong , Sirota Marina
Published: September 2021

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the United States. In spite of evidence of females having a greater lifetime risk of developing Alzheimer’s Disease (AD) and greater apolipoprotein E4-related (APOE ε4) AD risk compared to males, molecular signatures underlying these differences remain elusive.

Methods: We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls in seven independent datasets. Sex-specific gene expression patterns were investigated through use of gene-based, pathway-based and network-based approaches. The ability of a sex-specific AD gene expression signature to distinguish Alzheimer’s disease from healthy controls was assessed using a linear support vector machine model. Cell type deconvolution from whole blood gene expression data was performed to identify differentially regulated cells in males and females with AD.

Results: Strikingly gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. In females, network-based analysis revealed a coordinated program of gene expression involving several zinc finger nuclease genes related to Herpes simplex viral infection whose expression was modulated by the presence of the APOE ε4 allele. Interestingly, this gene expression program was missing in the brains of male AD patients. Cell type deconvolution identified an increase in neutrophils and naïve B cells and a decrease in M2 macrophages, memory B cells, and CD8+ T cells in AD samples compared to controls in females. Interestingly, among males with AD, no significant differences in immune cell proportions compared to controls were observed. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features produced an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males.

Conclusion: These results help identify sex and APOE ε4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.
Late-Life Depressive Symptomatology, Motoric Cognitive Risk Syndrome, and Incident Dementia: The “NuAge” Study Results
Authors: Beauchet Olivier , Sekhon Harmehr , Launay Cyrille P. , Gaudreau Pierrette , Morais José A. , Allali Gilles
Published: September 2021

Background: Late-life depressive symptomatology and motoric cognitive risk syndrome (MCR) have independently been associated with an increased risk for incident dementia. This study aimed to examine the association of late-life depressive symptomatology, MCR, and their combination on incident dementia in community-dwelling older adults living in Quebec (Canada).

Methods: The study was carried out in a subset of 1,098 community dwellers aged ≥65 years recruited in the “Nutrition as a determinant of successful aging: The Quebec longitudinal study” (NuAge), an observational prospective cohort study with 3 years follow-up. At baseline, MCR was defined by the association of subjective cognitive complaint with slow walking speed, and late-life depressive symptomatology with a 30-item Geriatric Depression Scale (GDS) score >5/30. Incident dementia, defined as a Modified Mini-Mental State score ≤79/100 test and Instrumental Activity Daily Living score <4/4, was assessed at each annual visit.

Results: The prevalence of late-life depressive symptomatology only was 31.1%, of MCR only 1.8%, and the combination of late-life depressive symptomatology and MCR 2.4%. The combination of late-life depressive symptomatology and MCR at baseline was associated with significant overall incident dementia (odds ratio (OR) = 2.31 with P ≤ 0.001) but not for MCR only (OR = 3.75 with P = 0.186) or late-life depressive symptomatology only (OR = 1.29 with P = 0.276).

Conclusions: The combination of late-life depressive symptomatology and MCR is associated with incident dementia in older community dwellers. The results suggested an interplay between late-life depressive symptomatology and MCR exposing them to an increased risk for dementia.
Human-Robot Interaction With Robust Prediction of Movement Intention Surpasses Manual Control
Authors: Veselic Sebastijan , Zito Claudio , Farina Dario
Published: September 2021

Physical human-robot interaction (pHRI) enables a user to interact with a physical robotic device to advance beyond the current capabilities of high-payload and high-precision industrial robots. This paradigm opens up novel applications where a the cognitive capability of a user is combined with the precision and strength of robots. Yet, current pHRI interfaces suffer from low take-up and a high cognitive burden for the user. We propose a novel framework that robustly and efficiently assists users by reacting proactively to their commands. The key insight is to include context- and user-awareness in the controller, improving decision-making on how to assist the user. Context-awareness is achieved by inferring the candidate objects to be grasped in a task or scene and automatically computing plans for reaching them. User-awareness is implemented by facilitating the motion toward the most likely object that the user wants to grasp, as well as dynamically recovering from incorrect predictions. Experimental results in a virtual environment of two degrees of freedom control show the capability of this approach to outperform manual control. By robustly predicting user intention, the proposed controller allows subjects to achieve superhuman performance in terms of accuracy and, thereby, usability.
Investigating Cortical Buffering Effects of Acute Moderate Intensity Exercise: A cTBS Study Targeting the Left Dorsolateral Prefrontal Cortex
Authors: Manocchio Felicia , Lowe Cassandra J.
Published: September 2021

Background: The beneficial effects of both single-session bouts of aerobic exercise and therapeutic exercise interventions on the cortical regions associated with top-down attentional control [i.e., prefrontal cortex (PFC)] have been well documented. However, it remains unclear whether aerobic exercise can be used to buffer against suppressive influences on the dorsolateral PFC (dlPFC).

Objective: The current study sought to determine whether a single session of moderate intensity aerobic exercise can offset the expected suppressive effects of continuous theta burst stimulation (cTBS) targeting the dorsolateral prefrontal cortex (dlPFC).

Methods: Twenty-two right-handed participants (aged 19–30) completed a 20-minute movement-only control session [10% heart rate reserve (HRR)] and moderate intensity (50% HRR) exercise in a counterbalanced order. Following each exercise session, participants received active cTBS to the left dlPFC. Changes in executive functions were quantified using a Flanker paradigm employed at baseline, post-exercise and post-cTBS time points. Additionally, EEG was used to measure changes in event-related potential components related to inhibitory control (i.e., N2) and attentional control (i.e., P3) during the flanker task.

Results: Behavioral results from the flanker task revealed a significant improvement in task performance following an acute bout of moderate intensity exercise. Furthermore, the effect of cTBS in both the movement-only control and moderate intensity conditions were non-significant. Similarly, EEG data from P3b and N2 ERP components revealed no changes to amplitude across time and condition. P3b latency data revealed a significant effect of time in both the moderate intensity and movement-only conditions, such that P3b latencies were significantly shorter across time points. Latency data within the N2 ERP component revealed no significant interactions or main effects.

Conclusion: The findings of the current study provide tentative support for the hypothesis that both moderate and light intensity exercise promote cortical buffering against the suppressive effects of cTBS targeting the dlPFC. However, in the absence of a no-movement control, a lack of expected suppressive effects of cTBS cannot be ruled out.
Cerebral Microbleeds May Be Less Detectable by Susceptibility Weighted Imaging MRI From 24 to 72 Hours After Traumatic Brain Injury
Authors: Környei Bálint S. , Szabó Viktor , Perlaki Gábor , Balogh Bendegúz , Szabó Steigerwald Dorottya K. , Nagy Szilvia A. , Tóth Luca , Büki András , Dóczi Tamás , Bogner Péter , Schwarcz Attila , Tóth Arnold
Published: September 2021

Purpose: A former rodent study showed that cerebral traumatic microbleeds (TMBs) may temporarily become invisible shortly after injury when detected by susceptibility weighted imaging (SWI). The present study aims to validate this phenomenon in human SWI.

Methods: In this retrospective study, 46 traumatic brain injury (TBI) patients in various forms of severity were included and willingly complied with our strict selection criteria. Clinical parameters potentially affecting TMB count, Rotterdam and Marshall CT score, Mayo Clinic Classification, contusion number, and total volume were registered. The precise time between trauma and MRI [5 h 19 min to 141 h 54 min, including SWI and fluid-attenuated inversion recovery (FLAIR)] was individually recorded; TMB and FLAIR lesion counts were assessed. Four groups were created based on elapsed time between the trauma and MRI: 0–24, 24–48, 48–72, and >72 h. Kruskal–Wallis, ANOVA, Chi-square, and Fisher’s exact tests were used to reveal differences among the groups within clinical and imaging parameters; statistical power was calculated retrospectively for each comparison.

Results: The Kruskal–Wallis ANOVA with Conover post hoc analysis showed significant (p = 0.01; 1−β > 0.9) median TMB number differences in the subacute period: 0–24 h = 4.00 (n = 11); 24–48 h = 1 (n = 14); 48–72 h = 1 (n = 11); and 72 h ≤ 7.5 (n = 10). Neither clinical parameters nor FLAIR lesions depicted significant differences among the groups.

Conclusion: Our results demonstrate that TMBs on SWI MRI may temporarily become less detectable at 24–72 h following TBI.
Computational Interspecies Translation Between Alzheimer’s Disease Mouse Models and Human Subjects Identifies Innate Immune Complement, TYROBP, and TAM Receptor Agonist Signatures, Distinct From Influences of Aging
Authors: Lee Meelim J. , Wang Chuangqi , Carroll Molly J. , Brubaker Douglas K. , Hyman Bradley T. , Lauffenburger Douglas A.
Published: September 2021

Mouse models are vital for preclinical research on Alzheimer’s disease (AD) pathobiology. Many traditional models are driven by autosomal dominant mutations identified from early onset AD genetics whereas late onset and sporadic forms of the disease are predominant among human patients. Alongside ongoing experimental efforts to improve fidelity of mouse model representation of late onset AD, a computational framework termed Translatable Components Regression (TransComp-R) offers a complementary approach to leverage human and mouse datasets concurrently to enhance translation capabilities. We employ TransComp-R to integratively analyze transcriptomic data from human postmortem and traditional amyloid mouse model hippocampi to identify pathway-level signatures present in human patient samples yet predictive of mouse model disease status. This method allows concomitant evaluation of datasets across different species beyond observational seeking of direct commonalities between the species. Additional linear modeling focuses on decoupling disease signatures from effects of aging. Our results elucidated mouse-to-human translatable signatures associated with disease: excitatory synapses, inflammatory cytokine signaling, and complement cascade- and TYROBP-based innate immune activity; these signatures all find validation in previous literature. Additionally, we identified agonists of the Tyro3 / Axl / MerTK (TAM) receptor family as significant contributors to the cross-species innate immune signature; the mechanistic roles of the TAM receptor family in AD merit further dedicated study. We have demonstrated that TransComp-R can enhance translational understanding of relationships between AD mouse model data and human data, thus aiding generation of biological hypotheses concerning AD progression and holding promise for improved preclinical evaluation of therapies.
Sodium Acetate Inhibit TGF-β1-Induced Activation of Hepatic Stellate Cells by Restoring AMPK or c-Jun Signaling
Authors: Li Weiwei , Deng Mingjuan , Gong Jiahui , Zhang Xiaoying , Ge Shaoyang , Zhao Liang
Published: September 2021

Short-chain fatty acids (SCFAs) are crucial gut microbial metabolites that play a major role in the occurrence and development of hepatic fibrosis (HF). However, the effect of SCFAs on hepatic stellate cells (HSCs), the major pro-fibrogenic cells, is yet undefined. In this study, the effects of three major SCFAs (acetate, propionate, and butyrate) were assessed on the activation of HSCs. LX2 cells were activated with TGF-β1 and treated with sodium acetate (NaA), sodium propionate (NaP), or sodium butyrate (NaB). SCFA treatment significantly reduced the protein levels of α-SMA and the phosphorylation of Smad2 and decreased the mRNA expression of Acta2/Col1a1/Fn in cells compared to the TGF-β1 treatment. Among the three SCFAs, NaA revealed the best efficacy at alleviating TGF-β1-induced LX2 cell activation. Additionally, acetate accumulated in the cells, and G protein-coupled receptor (GPR) 43 silencing did not have any impact on the inhibition of LX2 cell activation by NaA. These findings indicated that NaA enters into the cells to inhibit LX2 cell activation independent of GPR43. The results of phosphokinase array kit and Western blot indicated that NaA increased the AMP-activated protein kinase (AMPK) activation and reduced the phosphorylation of c-Jun in cultured LX2 cells, and siRNA-peroxisome proliferator-activated receptor (PPAR) -γ abolished the inhibitory effects of NaA against TGF-β1-induced LX2 cell activation. In conclusion, this study showed that NaA inhibited LX2 cell activation by activating the AMPK/PPARγ and blocking the c-Jun signaling pathways. Thus, SCFAs might represent a novel and viable approach for alleviating HF.
Immunotherapy and Targeting the Tumor Microenvironment: Current Place and New Insights in Primary Pulmonary NUT Carcinoma
Authors: Li Xiang , Shi Hui , Zhang Wei , Bai Chong , He Miaoxia , Ta Na , Huang Haidong , Ning Yunye , Fang Chen , Qin Hao , Dong Yuchao
Published: September 2021

Primary pulmonary nuclear protein of testis carcinoma is a rare and highly aggressive malignant tumor. It accounts for approximately 0.22% of primary thoracic tumors and is little known, so it is often misdiagnosed as pulmonary squamous cell carcinoma. No effective treatment has been formed yet, and the prognosis is extremely poor. This review aims to summarize the etiology, pathogenesis, diagnosis, treatment, and prognosis of primary pulmonary nuclear protein of testis carcinoma in order to better recognize it and discuss the current and innovative strategies to overcome it. With the increasing importance of cancer immunotherapy and tumor microenvironment, the review also discusses whether immunotherapy and targeting the tumor microenvironment can improve the prognosis of primary pulmonary nuclear protein of testis carcinoma and possible treatment strategies. We reviewed and summarized the clinicopathological features of all patients with primary pulmonary nuclear protein of testis carcinoma who received immunotherapy, including initial misdiagnosis, disease stage, immunohistochemical markers related to tumor neovascularization, and biomarkers related to immunotherapy, such as PD-L1 (programmed death-ligand 1) and TMB (tumor mutational burden). In the meanwhile, we summarized and analyzed the progression-free survival (PFS) and the overall survival (OS) of patients with primary pulmonary nuclear protein of testis carcinoma treated with PD-1 (programmed cell death protein 1)/PD-L1 inhibitors and explored potential population that may benefit from immunotherapy. To the best of our knowledge, this is the first review on the exploration of the tumor microenvironment and immunotherapy effectiveness in primary pulmonary nuclear protein of testis carcinoma.
Oncological Outcomes of Adjuvant Radiotherapy for Partial Ureterectomy in Distal Ureteral Urothelial Carcinoma Patients
Authors: Li Hong-zhen , Li Xiaoying , Gao Xian-shu , Qi Xin , Ma Ming-Wei , Qin Shangbin
Published: September 2021

Purpose

We retrospectively analyzed the oncological outcomes of T3 or G3 distal ureteral urothelial carcinoma (DUUC) underwent partial ureterectomy (PU) followed by adjuvant radiotherapy (ART).

Methods

From January 2008 to September 2019, clinical data from a total of 221 patients with pathologic T3 or G3 who underwent PU or RNU at our hospital were analyzed. 17 patients of them were treated with PU+ART, 72 with PU alone and 132 with radical nephroureterectomy (RNU). Clinicopathologic outcomes were evaluated. Survival was assessed using the Kaplan-Meier method. Cox regression addressed recurrence-free survival (RFS), metastasis-free survival (MFS), cancer specific survival (CSS) and overall survival (OS).

Results

Median age and follow-up time were 68 (IQR 62-76) years old and 43 (IQR 28-67) months, respectively. In univariate and multivariable analyses, no lymph node metastasis(LNM) and ART were independent prognostic factors of RFS (p=0.031 and 0.016, respectively). ART significantly improved 5-year RFS compared with the PU alone, (67.6%vs. 39.5%, HR: 2.431, 95%CI 1.210-4.883, p=0.039). There was no statistical difference in 5-year RFS between PU+ART and RNU groups (67.6%vs. 64.4%, HR=1.113, 95%CI 0.457-2.712, p=0.821). Compared with PU alone or RNU, PU+ART demonstrated no statistical difference in 5-year MFS (PU+ART 73.2%, PU 57.2%, RNU69.4%), CSS (70.7%, 55.1%, 76.6%, respectively), and OS (70.7%, 54.1%, 69.2%, respectively).

Conclusions

For distal ureteral urothelial carcinoma patients with T3 or G3, adjuvant radiotherapy could significantly improve recurrence-free survival compared with partial ureterectomy alone. There was no significant difference between survival outcomes of PU+ART and radical nephroureterectomy.
Novel Approaches Outside the Setting of Immunotherapy for the Treatment of Multiple Myeloma: The Case of Melflufen, Venetoclax, and Selinexor
Authors: Sgherza Nicola , Curci Paola , Rizzi Rita , Musto Pellegrino
Published: September 2021

Although the survival rate of patients with multiple myeloma has significantly improved in the last years thanks to the introduction of various classes of new drugs, such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, the vast majority of these subjects relapse with a more aggressive disease due to the acquisition of further genetic alterations that may cause resistance to current salvage therapies. The treatment of these often “triple” (or even more) refractory patients remains challenging, and alternative approaches are required to overcome the onset of that resistance. Immunotherapies with novel monoclonal, drug-conjugated, or bi-specific antibodies, as well as the use of chimeric antigen receptor T cells, have been recently developed and are currently investigated. However, other non-immunologic therapeutic regimens based on melfluflen, venetoclax, or selinexor, three molecules with new mechanisms of action, have also shown promising results in the setting of relapsed/refractory myeloma. Here we report the most recent literature data regarding these three drugs, focusing on their efficacy and safety in multiple myeloma.
Molecular Pathogenesis of Chronic Myelomonocytic Leukemia and Potential Molecular Targets for Treatment Approaches
Authors: Geissler Klaus
Published: September 2021

Numerous examples in oncology have shown that better understanding the pathophysiology of a malignancy may be followed by the development of targeted treatment concepts with higher efficacy and lower toxicity as compared to unspecific treatment. The pathophysiology of chronic myelomonocytic leukemia (CMML) is heterogenous and complex but applying different research technologies have yielded a better and more comprehensive understanding of this disease. At the moment treatment for CMML is largely restricted to the unspecific use of cytotoxic drugs and hypomethylating agents (HMA). Numerous potential molecular targets have been recently detected by preclinical research which may ultimately lead to treatment concepts that will provide meaningful benefits for certain subgroups of patients.
Efficacy of Sirolimus in Patients Requiring Tracheostomy for Life-Threatening Lymphatic Malformation of the Head and Neck: A Report From the European Reference Network
Authors: Holm Annegret , te Loo Maroeska , Schultze Kool Leo , Salminen Päivi , Celis Veronica , Baselga Eulalia , Duignan Sophie , Dvorakova Veronika , Irvine Alan D. , Boon Laurence M. , Vikkula Miikka , Ghaffarpour Nader , Niemeyer Charlotte M. , Rössler Jochen , Kapp Friedrich G.
Published: September 2021

Extensive lymphatic malformations (LMs) of the head and neck region may require tracheostomy to secure the airway. Treatment of these life-threatening LMs is usually multimodal and includes sclerotherapy and surgery, among others. Recently, systemic therapy with sirolimus has been introduced as an effective treatment for venous and lymphatic malformations; its efficacy and safety profile in patients with extensive LM requiring tracheostomy are, however, as yet not fully known. We performed a retrospective, multicenter review and identified 13 patients with an extensive LM of the head and neck region, who previously underwent placement of tracheostomy and subsequently received sirolimus treatment with the aim to improve the local respiratory situation and remove the tracheostomy. Under sirolimus therapy, tracheostomy could be reversed in 8/13 (62%) patients, a further 2/13 (15%) patients improved markedly, and removal of the tracheostomy was planned at the time of writing, while 3/13 (23%) patients showed insufficient or absent response to sirolimus, rendering tracheostomy reversal not feasible. The median duration of sirolimus treatment until removal of tracheostomy was 18 months (range, 8 months to 5.6 years). Adverse events of sirolimus therapy were common [10/13 (77%) patients], yet the majority of these were mild [9/10 (90%) patients] and only one severe adverse event was recorded, with ulceration and necrosis at a catheter insertion site. In conclusion, sirolimus can be considered an effective and safe salvage treatment in patients with extensive LM even after placement of a tracheostomy, as closure of the latter was possible in the majority of patients (62%) of our retrospective cohort. A better understanding of when to start sirolimus therapy, of the duration of treatment, and of factors allowing the prediction of treatment response will require further investigation.