bluuebunny/crossref_metadata_2025 huggingface dataset:
At the Intersection of Major and Minor Spliceosomes: Crosstalk Mechanisms and Their Impact on Gene Expression
Authors: Akinyi Maureen V. , Frilander Mikko J.
Published: July 2021

Many eukaryotic species contain two separate molecular machineries for removing non-coding intron sequences from pre-mRNA molecules. The majority of introns (more than 99.5% in humans) are recognized and excised by the major spliceosome, which utilizes relatively poorly conserved sequence elements at the 5′ and 3′ ends of the intron that are used for intron recognition and in subsequent catalysis. In contrast, the minor spliceosome targets a rare group of introns (approximately 0.5% in humans) with highly conserved sequences at the 5′ and 3′ ends of the intron. Minor introns coexist in the same genes with major introns and while the two intron types are spliced by separate spliceosomes, the two splicing machineries can interact with one another to shape mRNA processing events in genes containing minor introns. Here, we review known cooperative and competitive interactions between the two spliceosomes and discuss the mechanistic basis of the spliceosome crosstalk, its regulatory significance, and impact on spliceosome diseases.
Health and Gender Inequalities of the COVID-19 Pandemic: Adverse Impacts on Women's Health, Wealth and Social Welfare
Authors: Guerrina Roberta , Borisch Bettina , Callahan Leigh F. , Howick Jeremy , Reginster Jean-Yves , Mobasheri Ali
Published: July 2021

In this paper we discuss the nexus of health and gender inequalities associated with the COVID-19 pandemic and highlight its adverse impacts on women's health, welfare and social standing. The COVID-19 pandemic has exposed the link between socio-economic inequalities and health outcomes, especially in the area of rheumatic and musculoskeletal (RMDs) diseases. Women are more adversely affected by RMDs diseases compared to men. Epidemiological research carried out over several decades has demonstrated the presence of clear gender patterns in the manifestation of musculoskeletal diseases, including osteoarthritis (OA), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SS) and osteoporosis (OP). The public health measures that have been adopted to curb the spread of Sars-COV-2 are expected to have a particularly detrimental impact on women in the long term precisely because of the nexus between health outcomes and socio-economic structures. Moreover, the prioritization of urgent care will further compound this effect. COVID-19 has created a condition of ontological insecurity that is becoming increasingly manifested through various chronic diseases and associated comorbidities. RMDs and their impact on mobility and the ability of individuals to be independent, happy and mobile is a key public health challenge in the post-COVID-19 reality and a key part of the ongoing pandemic. There is an urgent need to engage with policymakers to publicize and prioritize this problem and develop viable solutions to address it.
Targeting Purinergic Receptor P2RX1 Modulates Intestinal Microbiota and Alleviates Inflammation in Colitis
Authors: Wang Xu , Yuan Xiao , Su Yuting , Hu Jing , Ji Qian , Fu Shengqiao , Li Rongkun , Hu Lipeng , Dai Chunhua
Published: July 2021

Inflammatory bowel disease (IBD) remains one of the most prevalent gastrointestinal diseases worldwide. Purinergic signaling has emerged as a promising therapeutic target of inflammation-associated diseases. However, little is known about the specific roles of purinergic receptors in IBD. In the present study, expression profile of purinergic receptors was screened in the public Gene Expression Omnibus (GEO) datasets, and we found that expression of P2RX1 was significantly upregulated in inflamed colon tissues. Then, purinergic receptor P2RX1 was genetically ablated in the background of C57BL/6 mice, and dextran sulfate sodium (DSS) was used to induce mice colitis. RNA sequencing results of colon tissues showed that genetic knockout of P2RX1 suppressed the inflammation responses in DSS-induced mice colitis. Flow cytometry indicated that neutrophil infiltration was inhibited in P2RX1 ablated mice. 16S ribosomal DNA sequencing revealed major differences of intestinal microbiota between WT and P2RX1 ablated mice. Functional metagenomics prediction indicated that the indole alkaloid biogenesis pathway was upregulated in P2RX1 gene ablated mice. Further studies revealed that microbiota metabolites (indole alkaloid)-involved aryl hydrocarbon receptor (AhR)/IL-22 axis was associated with the beneficial effects of P2RX1 ablation. Finally, we found that a specific P2RX1 inhibitor succeeded to improve the therapeutic efficiency of anti-TNF-α therapy in DSS-induced mice colitis. Therefore, our study suggests that targeting purinergic receptor P2RX1 may provide novel therapeutic strategy for IBD.
Dynamic Characteristic Analysis of Antibodies in Patients With COVID-19: A 13-Month Study
Authors: Shi Danrong , Weng Tianhao , Wu Jie , Dai Chunyan , Luo Rui , Chen Keda , Zhu Miaojin , Lu Xiangyun , Cheng Linfang , Chen Qiuqiang , Liu Fumin , Wu Zhigang , Wu Haibo , Jin Changzhong , Guo Miao , Chen Zhe , Wu Nanping , Yao Hangping , Zheng Min
Published: July 2021

There is a worldwide pandemic of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; yet our understanding remains limited on the characteristic of antibodies, especially for dynamic long-term tracking. Sequential serum samples were collected up to 416 days post onset of symptoms (POS) from 102 patients who were hospitalized with coronavirus disease 2019 (COVID-19). Immunoglobulin (Ig)G, IgM, and IgA levels targeting SARS-CoV-2 spike 1 receptor-binding domain (S1-RBD), spike 2 extracellular domain (S2-ECD), and nucleocapsid protein (N) were quantified as well as neutralizing activity. We were pleasantly surprised to find that the antibody remained detective and effective for more than a year POS. We also found the varied reactions of different antibodies as time passed: N-IgA rose most rapidly in the early stage of infection, while S2-IgG was present at a high level in the long time of observation. This study described the long traceable antibody response of the COVID-19 and offered hints about targets to screen for postinfectious immunity and for vaccination development of SARS-CoV-2.
A Glider Simulation Model Based on Optimized Support Vector Regression for Efficient Coordinated Observation
Authors: Yu Fangjie , Zhuang Zhiyuan , Yang Jie , Chen Ge
Published: July 2021

Multi-gliders have been widely deployed as an array in nowadays ocean observation for fine and long-term ocean research, especially in deep-sea exploration. However, the strong, variable ocean currents and the delayed information feedback of gliders are remaining huge challenges for the deployment of glider arrays which may cause that the observed data cannot meet the study needs and bring a prohibitive cost. In this paper, we develop a Glider Simulation Model (GSM) based on the support vector regression with the particle swarm optimization (PSO)-SVR algorithm to integrate the information feedback from gliders and ocean current data for rapid modeling to effectively predict the gliders’ trajectories. Based on the real-time predictive information of the trajectories, each glider can select future movement strategies. We utilize the in-suit datasets obtained by sea-wing gliders in ocean observation to train and test the simulation model. The results show that GSM has an effective and stable performance. The information obtained from the modeling approaches can be utilized for the optimization of the deployment of the glider arrays.
Mechanisms of Lateral Spreading in a Near-Field Buoyant River Plume Entering a Fjord
Authors: McPherson Rebecca A. , Stevens Craig L. , O'Callaghan Joanne M. , Lucas Andrew J. , Nash Jonathan D.
Published: July 2021

Observations collected from a fast-flowing buoyant river plume entering the head of Doubtful Sound, New Zealand, were analysed to examine the drivers of plume lateral spreading. The near-field plume is characterised by flow speeds of over 2 ms−1, and strong stratification (N2 > 0.1 s−2), resulting in enhanced shear which supports the elevated turbulence dissipation rates (ϵ > 10−3 W kg−1). Estimates of plume lateral spreading rates were derived from the trajectories of Lagrangian GPS surface drifters and from cross-plume hydrographic transects. Lateral spreading rates derived from the latter compared favourably with estimates derived from a control volume technique in a previous study. The lateral spreading of the plume was driven by a baroclinic pressure gradient toward the base of the plume. However, spreading rates were underestimated by the surface drifters. A convergence of near-surface flow from the barotropic pressure gradient concentrated the drifters within the plume core. The combination of enhanced internal turbulence stress and mixing at the base of the surface layer, and the presence of steep fjord sidewalls likely reduced the rate of lateral spreading relative to the theoretical spreading rate. The estimates of plume width from the observations provided evidence of scale-dependent dispersion which followed a 4/3 power law. Two theoretical models of dispersion, turbulence and shear flow dispersion, were examined to assess which was capable of representing the observed spreading. An analytical horizontal shear-flow dispersion model generated estimates of lateral dispersion that were consistent with the observed 4/3 law of dispersion. Therefore, horizontal shear dispersion appeared to be the dominant mechanism of dispersion, thus spreading, in the surface plume layer.
7Be/210Pbxs Ratio-Derived Age and Residence Time of Suspended Sediments in Galveston Bay
Authors: Schmidt Nicole , Dellapenna Timothy , Lin Peng
Published: July 2021

The winds associated with the passage of meteorological fronts cause waves that induce sediment remobilization/resuspension, especially within shallow estuaries such as Galveston Bay. The passage of cold fronts, collectively, on an annual to decadal basis, generate more sediment resuspension than most hurricanes and tropical storms. With a warming climate, the intensity of all meteorological events is shifting toward having greater impacts on these biologically productive environments. To better understand sediment resuspension within the bay, water samples were collected during frontal passages at two locations in Galveston Bay, including one location in the middle portion of the bay and another closer to the mouth of the bay. By collecting precipitation, water samples in both the middle and lower bay, and measuring the ratio of 7Be/210Pbxs in these samples; we quantified the residence times of total suspended sediment (TSS) in middle and lower Galveston Bay. Our results showed that suspended sediment age increased and percent of new suspended sediment decreased along the axis from the middle bay to the lower bay. This results from the initial introduction of newly labeled isotopes and suspended load coming from fluvial discharges which enter at the top of the bay and travel through the bay. The age of suspended sediment from the first sampling event was 70 ± 10 days, whereas the age in the second event was 16 ± 3 days greater. In the last sampling event, the age of suspended sediment event was 35 ± 7.4 days younger than the second, suggesting that the majority of suspended sediments was likely transported entirely out of the bay by the second cold front, prior to the final sampling event. This indicates that there are longer suspended sediment residence times when the water is trapped within the bay. Our estimated residence time of suspended sediments (51–105 days) suggest the particle-bound contaminants adsorb to suspended sediment may spend months suspended in the bay before exiting the bay or being accreted into the bay sediment column, increasing the exposure time of living organisms to various particle-bound contaminants.
Mechanical Strength of Graphene Reinforced Geopolymer Nanocomposites: A Review
Authors: Tay Chai Hua , Norkhairunnisa Mazlan
Published: July 2021

The emergence of high-strength graphene marks a new milestone in the material science field. With only a small percentage inclusion into the matrix system, this organic nanoparticle could tremendously improve the strength in vast arrays of composites. At the same time, there is a growing interest in using the low-cost, lightweight, and high early strength geopolymer as the new binder for concrete. Compared to the traditional Ordinary Portland Cement (OPC), geopolymer emits 80% less CO2 during its production while exerting similar strength. Thus, the geopolymer has the potential to commercialize as new and green concrete. Geopolymer is a mixture of aluminosilicate powders and alkaline solutions. When incorporated with nano-sized graphene, the material forms a composite known as Graphene Reinforced Geopolymer Nanocomposite (GRGN). The addition of graphene enhances the strength of geopolymer, which can further improve its competitiveness. However, this depends on several factors, including the types of graphene, the surface modification of graphene, and the concentration of alkaline solutions. Generally, the presence of graphene alters the porous structure of geopolymer into a substantially filled porous structure, thus increasing compressive strength and flexural strength. On the other hand, Graphene Oxide (GO) undergoes a chemical reduction in the alkaline solution, producing epoxy functional groups. The chemical treatment results in two conditions which are weak interaction between graphene and geopolymer matrix, and better graphene dispersibility in geopolymer matrix. This review also highlights the analytical modelling aspect of GRGN. The dissolution of Si(OH)4 and Al(OH)4- from the aluminosilicate source was consistent with experimental work and analytical modeling, while the dissolution of Si–OH on the surface-modified graphene indicated otherwise. Therefore, this paper will provide an insightful review of the GRGN mechanical properties.
Effect of Chinese Herbal Medicines on Hearing Loss Risk in Rheumatoid Arthritis Patients: Retrospective Claims Analysis
Authors: Li Hsin-Hua , Livneh Hanoch , Chen Wei-Jen , Fan Wen-Lin , Lu Ming-Chi , Guo How-Ran , Tsai Tzung-Yi
Published: July 2021

Objectives: Patients with rheumatoid arthritis (RA) are at a higher risk of extra-articular manifestations, especially hearing loss (HL). Although Chinese herbal medicines (CHM) are proven safe and effective treatments for inflammatory conditions, the effect of CHM use on HL in RA patients is unknown. This cohort study aims to determine the relationship between CHM use and the subsequent risk of HL among RA patients.

Methods: From health insurance claims data in Taiwan, a total of 6,905 persons aged 20–80 years with newly-diagnosed RA in 2000–2009 were identified. Of these, we recruited 2,765 CHM users and randomly selected 2,765 non-CHM users who matched with the users by the propensity score. Both cohorts were followed up until the end of 2012 to estimate the incidence of HL. Cox proportional hazards regression was used to estimate the adjusted hazard ratio (HR) for HL.

Results: The incidence of HL was lower in the CHM users than in the comparison cohort (8.06 vs. 10.54 per 1,000 person-years) (adjusted HR, 0.77; 95% CI, 0.63–0.94). Those who received CHM for more than 2 years had the greatest benefit against the onset of HL, with over 50% risk reduction. Prescriptions of Hai Piao Xiao, Yan Hu Suo, San-Qi, Huang Qin, Dang Shen, Jia-Wei-Xiao-Yao-San, Shu-Jing-Huo-Xue-Tang, and Dang-Gui-Nian-Tong-Tang were found to be associated with a reduced risk of HL.

Conclusions: Our findings suggest that adding CHM to conventional therapy may reduce the subsequent risk of HL in RA patients. Prospective randomized trials are recommended to further clarify whether the association revealed in this study supports such a causal relationship.
Network Analysis of Outpatients to Identify Predictive Symptoms and Combinations of Symptoms Associated With Positive/Negative SARS-CoV-2 Nasopharyngeal Swabs
Authors: Spechbach Hervé , Jacquerioz Frédérique , Prendki Virginie , Kaiser Laurent , Smit Mikaela , Calmy Alexandra , Chappuis François , Guessous Idris , Salamun Julien , Baggio Stéphanie
Published: July 2021

Background: Limited data exist on early predictive clinical symptoms or combinations of symptoms that could be included in the case definition of coronavirus disease 2019 (COVID-19), particularly for mild-to-moderate disease in an outpatient setting.

Methods: A cohort study of individuals presenting with clinical symptoms to one of the largest dedicated networks of COVID-19 test centers in Geneva, Switzerland, between March 2 and April 23, 2020. Individuals completed a symptom questionnaire, received a nurse-led check-up, and nasopharyngeal swabs were obtained. An analysis of clinical features predicting the positivity and negativity of the SARS-CoV-2 RT-PCR test was performed to determine the relationship between symptoms and their combinations.

Results: Of 3,248 patients included (mean age, 42.2 years; 1,504 [46.3%] male), 713 (22%) had a positive RT-PCR; 1,351 (41.6%) consulted within 3 days of symptom onset. The strongest predictor of a positive SARS-CoV-2 RT-PCR was anosmia, particularly in early disease, followed by fever, myalgia, and cough. Symptoms predictive of a negative test were breathing difficulties, abdominal symptoms, thoracic pain and runny nose. Three distinct networks of symptoms were identified, but did not occur together: respiratory symptoms; systemic symptoms related to fever; and other systemic symptoms related to anosmia.

Conclusions: Symptoms and networks of symptoms associated with a positive/negative SARS-CoV-2 RT-PCR are emerging and may help to guide targeted testing. Identification of early COVID-19-related symptoms alone or in combination can contribute to establish a clinical case definition and provide a basis for clinicians and public health authorities to distinguish it from other respiratory viruses early in the course of the disease, particularly in the outpatient setting.
Bilateral Diffuse Uveal Melanocytic Proliferation Secondary to Rectal Adenocarcinoma: A Case Report and Literature Review
Authors: Tong Nianting , Wang Liangyu , Wang Nan , Zhou Zhanyu
Published: July 2021

Background:Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic intraocular syndrome that causes progressive visual loss in patients, and is associated with an underlying malignancy. Recently, the incidence of BDUMP has increased with the prolonged life expectancy of oncology patients.

Case Presentation:We report a case of a 68-year-old man with significant visual loss in both eyes. The patient presented with a diffusely thickened choroid and ciliary body, extremely shallow anterior chamber, increased intraocular pressure, and cataract formation, accompanied by exudative retinal detachment in both eyes. He underwent a pars plana vitrectomy and choroidal biopsy, which revealed benign proliferation of melanocytes. A small amount of subretinal fluid persisted, and uveal thickness persisted in the early postoperative period. During the 1-year follow-up assessment, he underwent rectal tumor resection, and was pathologically diagnosed with rectal adenocarcinoma. Six months after the rectal tumor resection, the subretinal fluid was completely absorbed and the retina had reattached. The thickness of both the ciliary body and choroid had significantly decreased.

Conclusion:This case report describes a rare paraneoplastic intraocular syndrome, BDUMP, which was associated with rectal adenocarcinoma. Treatment for the primary malignancy gradually improved the visual symptoms and signs.
Apolipoprotein E Genotype, Meat, Fish, and Egg Intake in Relation to Mortality Among Older Adults: A Longitudinal Analysis in China
Authors: Jin Xurui , Xiong Shangzhi , Yuan Changzheng , Gong Enying , Zhang Xian , Yao Yao , Leng Yu , Niu Zhangming , Zeng Yi , Yan Lijing L.
Published: July 2021

Introduction: The interactions between apolipoprotein E (APOE) genotype and diet pattern changes were found significant in several trials, implying that APOE gene may modify the effect of animal protein-rich food on health outcomes. We aim to study the interaction of APOE genotype with the effect of meat, fish and egg intake on mortality.

Methods: This population-based study enrolled 8,506 older adults (mean age: 81.7 years, 52.3% female) from the Chinese Longitudinal Healthy Longevity Study. The intake frequency of meat, fish and egg was assessed by 3-point questions at baseline. Cox regression was conducted to calculate the hazard ratios for all-cause mortality of intake levels of meat, fish and egg. The analyses were stratified by APOE genotype and sex. The analyses were performed in 2020.

Results: In the multivariable-adjusted models, meat and fish intake was associated with all-cause mortality (high vs. low intake: meat: HR: 1.14, 95% CI: 1.01, 1.28; fish: HR: 0.83, 95% CI: 0.73, 0.95). APOE genotype have significant interactions with meat and fish intake (Ps < 0.05). Compared with low fish intake, high fish intake was associated with lower risk of mortality (HR: 0.74, 95% CI: 0.56–0.98) only among the APOE ε4 carriers. High meat intake was significantly associated with higher risks of mortality (HR: 1.13, 95% CI: 1.04–1.25) only among the APOE ε4 non-carriers. The interactive relationship was restricted among the male. No significant findings were observed between egg and mortality among carriers or non-carriers.

Conclusions: Among Chinese older adults, the significance of associations of mortality with reported meat or fish intake depended on APOE-E4 carriage status. If validated by other studies, our findings provide evidence for gene-based “precision” lifestyle recommendations.
Emergence and Clonal Spread of CTX-M-65-Producing Escherichia coli From Retail Meat in Portugal
Authors: Leão Célia , Clemente Lurdes , Moura Laura , Seyfarth Anne Mette , Hansen Inge M. , Hendriksen Rene S. , Amaro Ana
Published: July 2021

The emergence and dissemination of resistance to third- and fourth-generation cephalosporins among Enterobacteriaceae from different sources impose a global public health threat. Here, we characterized by whole-genome sequencing four Escherichia coli strains harboring the blaCTX–M–65 gene identified among 49 isolates from beef and pork collected at retail. The genomic content was determined using the Center for Genomic Epidemiology web tools. Additionally, the prediction and reconstruction of plasmids were conducted, the genetic platform of the blaCTX–M–65 genes was investigated, and phylogenetic analysis was carried out using 17 other genomes with the same sequence type and harboring the blaCTX–M–65 gene. All strains harbored blaCTX–M–65, blaOXA–1, and blaTEM–1B, and one also carried the blaSHV–12 gene. Other resistance genes, namely, qnrS2, aac(6′)-Ib-c, dfrA14, sul2, tetA, and mphA, were present in all the genomes; the mcr-1.1 gene was identified in the colistin-resistant strains. They belong to sequence type 2179, phylogenetic group B1, and serotype O9:H9 and carried plasmids IncI, IncFIC(FII), and IncFIB. All strains share an identical genetic environment with IS903 and ISEcp1 flanking the blaCTX–M–65 gene. It seems likely that the blaCTX–M–65 gene is located in the chromosome in all isolates based on deep in silico analysis. Our findings showed that the strains are clonally related and belong to two sub-lineages. This study reports the emergence of CTX-M-65-producing E. coli in Portugal in food products of animal origin. The chromosomal location of the blaCTX–M–65 gene may ensure a stable spread of resistance in the absence of selective pressure.
Estradiol Alters the Virulence Traits of Uropathogenic Escherichia coli
Authors: Engelsöy Ulrik , Svensson Maria A. , Demirel Isak
Published: July 2021

Uropathogenic Escherichia coli (UPEC) is the most common bacteria to cause urinary tract infection (UTI). Postmenopausal women have an increased risk of recurrent UTI. This is partly explained by estrogenic effects on host defenses against UTI. Current research is mostly focused on how UPEC affects host factors, but not so much is known about how host factors like hormones affect UPEC virulence. The aim of the present study was to investigate the impact of estradiol exposure on the virulence of UPEC. We found that a postmenopausal concentration of estradiol increased CFT073 growth and biofilm formation, but not the premenopausal concentrations. Real-time qPCR showed that estradiol altered the expression of genes associated with the iron acquisition system and metabolic pathways in CFT073. We also found that estradiol in a dose-dependent manner increased the expression of fimH and papC adhesins and increased colonization and invasion of bladder epithelial cells. The premenopausal concentration of estradiol also suppressed cytokine release from bladder epithelial cells. Additionally, we also showed using a Caenorhabditis elegans killing assay that estradiol increased the survival of CFT073-infected C. elegans worms. Taken together, our findings show that estradiol has the ability to alter the virulence traits of UPEC.
Viral UL8 Is Involved in the Antiviral Activity of Oleanolic Acid Against HSV-1 Infection
Authors: Shan Tianhao , Ye Ju , Jia Jiaoyan , Wang Zhaoyang , Jiang Yuzhou , Wang Yiliang , Wang Yifei , Zheng Kai , Ren Zhe
Published: July 2021

Herpes simplex virus type 1 (HSV-1) is highly prevalent in humans and can cause severe diseases, especially in immunocompromised adults and newborns, such as keratitis and herpes simplex encephalitis. At present, the clinical therapeutic drug against HSV-1 infection is acyclovir (ACV), and its extensive usage has led to the emergence of ACV-resistant strains. Therefore, it is urgent to explore novel therapeutic targets and anti-HSV-1 drugs. This study demonstrated that Oleanolic acid, a pentacyclic triterpenoid widely existing in natural product, had strong antiviral activity against both ACV-sensitive and -resistant HSV-1 strains in different cells. Mechanism studies showed that Oleanolic acid exerted its anti-HSV-1 activity in the immediate early stage of infection, which involved the dysregulation of viral UL8, a component of viral helicase-primase complex critical for viral replication. In addition, Oleanolic acid significantly ameliorated the skin lesions in an HSV-1 infection mediated zosteriform model. Together, our study suggested that Oleanolic acid could be a potential candidate for clinical therapy of HSV-1 infection-related diseases.
Assessment of Language Functions in Patients With Disorders of Consciousness Using an Alternative Communication Tool
Authors: Kujawa Katarzyna , Zurek Grzegorz , Kwiatkowska Agnieszka , Olejniczak Roman , Żurek Alina
Published: July 2021

This study aimed to describe the percentage of tasks involving language functions that were completed by patients diagnosed with disorders of consciousness, as observed during neurorehabilitation conducted for different periods of time using an alternative communication tool. The project involved six participants, who were observed for 1 month, 6 months, and 1 year. The patients were asked to solve tasks involving language functions with the use of an eye-controlled device. The language functions were evaluated on the basis of the average number of tasks performed by the patients, which was 70.45% for the whole subject group. It is not entirely clear what determined the changes in language functions during the research. It is crucial that patients performed the presented tasks even though their state of consciousness, as confirmed through medical documentation (unresponsive wakefulness syndrome), did not suggest the possibility of establishing any contact with them.
Long-Term Results of Neurological Outcome, Quality of Life, and Cosmetic Outcome After Cranioplastic Surgery: A Single Center Study of 202 Patients
Authors: Giese Henrik , Antritter Jennifer , Unterberg Andreas , Beynon Christopher
Published: July 2021

Objective: An increased interest in the surgical procedures of decompressive craniectomy (DC) and subsequent cranioplasty (CP) has emerged during the last decades with specific focus on mortality and complication rates. The aim of the present study was to evaluate long-term neurological and cosmetic outcomes as well as Quality of Life (QoL) after CP surgery.

Methods: We retrospectively reviewed the medical records of CP patients treated at our institution between 2004 and 2014 and performed a follow-up examination, with evaluation of neurological outcome using the modified Rankin Scale (mRS) and the Glasgow outcome scale (GOS), QoL (SF-36 and EQ-5D-3L). Furthermore, the cosmetic results after CP were analyzed.

Results: A total of 202 CP-patients were included in the present study. The main indications for DC and subsequent CP were space-occupying cerebral ischemia (32%), traumatic brain injury (TBI, 26%), intracerebral or subarachnoid hemorrhage (32%) and infection (10%). During a mean follow-up period of 91.9 months 46/42.6% of patients had a favorable neurological outcome (mRS ≤ 3/GOS ≥ 4). Patients with ischemia had a significant worse outcome (mRS 4.3 ± 1.5) compared with patients after TBI (3.1 ± 2.3) and infectious diseases requiring CP (2.4 ± 2.3). The QoL analysis showed that <1/3rd of patients (31.2%) had a good QoL (SF-36) with a mean EQ-5D-VAS of 59 ± 26. Statistical analysis confirmed a significant worse QoL of ischemia patients compared to other groups whereas multivariate regression analysis showed no other factors which may had an impact on the QoL. The majority (86.5%) of patients were satisfied with the cosmetic result after CP and regression analysis showed no significant factors associated with unfavorable outcomes.

Conclusion: Long-term outcome and QoL after CP were significantly influenced by the medical condition requiring DC. Early detection and evaluation of QoL after CP may improve the patient's outcome due to an immediate initiation of targeted therapies (e.g., occupational- or physiotherapy).
Unstable Gaze in Functional Dizziness: A Contribution to Understanding the Pathophysiology of Functional Disorders
Authors: Schröder Lena , von Werder Dina , Ramaioli Cecilia , Wachtler Thomas , Henningsen Peter , Glasauer Stefan , Lehnen Nadine
Published: July 2021

Objective: We are still lacking a pathophysiological mechanism for functional disorders explaining the emergence and manifestation of characteristic, severely impairing bodily symptoms like chest pain or dizziness. A recent hypothesis based on the predictive coding theory of brain function suggests that in functional disorders, internal expectations do not match the actual sensory body states, leading to perceptual dysregulation and symptom perception. To test this hypothesis, we investigated the account of internal expectations and sensory input on gaze stabilization, a physiologically relevant parameter of gaze shifts, in functional dizziness.

Methods: We assessed gaze stabilization in eight functional dizziness patients and 11 healthy controls during two distinct epochs of large gaze shifts: during a counter-rotation epoch (CR epoch), where the brain can use internal models, motor planning, and resulting internal expectations to achieve internally driven gaze stabilization; and during an oscillation epoch (OSC epoch), where, due to terminated motor planning, no movement expectations are present, and gaze is stabilized by sensory input alone.

Results: Gaze stabilization differed between functional patients and healthy controls only when internal movement expectations were involved [F(1,17) = 14.63, p = 0.001, and partial η2 = 0.463]: functional dizziness patients showed reduced gaze stabilization during the CR (p = 0.036) but not OSC epoch (p = 0.26).

Conclusion: While sensory-driven gaze stabilization is intact, there are marked, well-measurable deficits in internally-driven gaze stabilization in functional dizziness pointing at internal expectations that do not match actual body states. This experimental evidence supports the perceptual dysregulation hypothesis of functional disorders and is an important step toward understanding the underlying pathophysiology.
Parietal Lobe Reorganization and Widespread Functional Connectivity Integration in Upper-Limb Amputees: A rs-fMRI Study
Authors: Bao Bingbo , Wei Haifeng , Luo Pengbo , Zhu Hongyi , Hu Wencheng , Sun Yi , Shen Junjie , Zhu Tianhao , Lin Junqing , Huang Tengli , Li Jing , Wang Zhibin , Li Yuehua , Zheng Xianyou
Published: July 2021

The right parietal lobe plays an important role in body image, and disorders of body image emerge after lesions in the parietal lobe or with parietal lobe epilepsy. Body image disorder also often accompanies upper-limb amputation, in which the patient misperceives that their missing limb is still part of their body. Cortical reorganization is known to occur after upper-limb amputation, but it is not clear how widespread and to what degree functional connectivity (FC) is reorganized post-amputation, nor whether such changes might be related to misperceptions of body image. Twenty-four subjects who had a traumatically upper-limb amputees (ULAs) and 24 age-matched healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. Regions of interest (ROIs) in the right superior parietal gyrus (SPG_R) and right inferior parietal lobule (IPL_R) were defined using BrainNet Viewer. We calculated the amplitude of low-frequency fluctuations (ALFF) in ROIs and correlated the ROI mean amplitude of low-frequency fluctuations (mALFF) and mean scores on the phantom limb sensation (PLS) scale and beck depression index (BDI). We also calculated ROIs and whole-brain FC. Compared to the HC group, we observed significantly increased activation (mALFF) in ROIs of the ULA group. Moreover, correlation analyses revealed a significant positive correlation between ROI mALFF and scores on the PLS. There was a significant negative correlation between the SPG_R mALFF and BDI scores. Seed-based, whole-brain FC analysis revealed that FC in the ULA group significantly decreased in many brain regions across the entire brain. The right parietal lobe appears to be involved in some aspect of body awareness and depression in amputation patients. Upper-limb amputation results not only in reorganization in the local brain area formerly representing the missing limb, but also results in more widespread reorganization through FC changes in whole brain.
Increasing Serotonin to Reduce Parkinsonian Tremor
Authors: Caligiore Daniele , Montedori Francesco , Buscaglione Silvia , Capirchio Adriano
Published: July 2021

While current dopamine-based drugs seem to be effective for most Parkinson's disease (PD) motor dysfunctions, they produce variable responsiveness for resting tremor. This lack of consistency could be explained by considering recent evidence suggesting that PD resting tremor can be divided into different partially overlapping phenotypes based on the dopamine response. These phenotypes may be associated with different pathophysiological mechanisms produced by a cortical-subcortical network involving even non-dopaminergic areas traditionally not directly related to PD. In this study, we propose a bio-constrained computational model to study the neural mechanisms underlying a possible type of PD tremor: the one mainly involving the serotoninergic system. The simulations run with the model demonstrate that a physiological serotonin increase can partially recover dopamine levels at the early stages of the disease before the manifestation of overt tremor. This result suggests that monitoring serotonin concentration changes could be critical for early diagnosis. The simulations also show the effectiveness of a new pharmacological treatment for tremor that acts on serotonin to recover dopamine levels. This latter result has been validated by reproducing existing data collected with human patients.
A Portable Gluten Sensor for Celiac Disease Patients May Not Always Be Reliable Depending on the Food and the User
Authors: Marić Alena , Scherf Katharina Anne
Published: July 2021

A strict lifelong gluten-free (GF) diet is currently the only known effective treatment for celiac disease (CD), an inflammatory disorder of the small intestine with a worldwide prevalence of about 1%. CD patients need to avoid wheat, rye, and barley and consume GF foods containing <20 mg/kg of gluten. However, strict adherence to a GF diet tends to reduce the quality of life of CD patients compared to the general population and may lead to fear of inadvertent gluten consumption, especially when eating out. To help alleviate risk of gluten exposure, a portable gluten sensor was developed by Nima Labs that allows CD patients to test foods on site prior to consumption. With very limited independent information on the analytical performance of the Nima sensor available so far, our aim was to evaluate the reliability of the sensor using a variety of different foods with defined gluten content. All samples were tested with the sensor and analyzed by enzyme-linked immunosorbent assay as reference method. Of the 119 samples with gluten content ranging from 2 to 101,888 mg/kg tested in total, the sensor showed 80 positive (67.2%), 37 negative (31.1%) and 2 invalid results at the first of three consecutive measurements. The detection rate for samples containing ≥20 mg/kg of gluten was 90%. Samples containing 2 mg/kg of gluten or below consistently tested negative, but samples with a gluten content between 2 to 20 mg/kg of gluten may either test positive or negative. Overall, the performance of the sensor was acceptable in our study, but we observed systematic variation between different users that also appeared to depend on the sample being tested. This highlights the need to improve user education especially regarding the effect of sampling, testing limitations in case of partially hydrolyzed, fractionated or fermented gluten and training users on how to perform the test in a way that gluten will be reliably detected.
m(6)A Modification of lncRNA NEAT1 Regulates Chronic Myelocytic Leukemia Progression via miR-766-5p/CDKN1A Axis
Authors: Yao Fang-Yi , Zhao Cui , Zhong Fang-Min , Qin Ting-Yu , Wen Fang , Li Mei-Yong , Liu Jing , Huang Bo , Wang Xiao-Zhong
Published: July 2021

Background

Chronic myeloid leukemia (CML) is an acquired hematopoietic stem malignant disease originating from the myeloid system. Long non-coding RNAs (lncRNAs) have been widely explored in cancer tumorigenesis. However, their roles in CML remain largely unclear.

Methods

The peripheral blood mononuclear cells (PBMCs) and CML cell lines (K562, KCL22, MEG01, BV173) were collected for in vitro research. Real-time quantitative polymerase chain reaction was used to determine the mRNA expression levels. Cell viability and apoptosis were analyzed by cell counting kit 8 and flow cytometry assays. The targeting relationships were predicted using Starbase and TargetScan and ulteriorly verified by RNA pull-down and luciferase reporter assays. Western blotting assay was performed to assess the protein expressions. N6-methyladenosine (m6A) modification sites were predicted by SRAMP and confirmed by Methylated RNA immunoprecipitation (MeRIP) assay.

Results

LncRNA nuclear-enriched abundant transcript 1 (NEAT1) expression levels were decreased in the CML cell lines and PBMCs of CML patients. Moreover, METTL3-mediated m6A modification induced the aberrant expression of NEAT1 in CML. Overexpression of NEAT1 inhibited cell viability and promoted the apoptosis of CML cells. Additionally, miR-766-5p was upregulated in CML PBMCs and abrogated the effects of NEAT1 on cell viability and apoptosis of the CML cells. Further, CDKN1A was proved to be the target gene of miR-766-5p and was downregulated in the CML PBMCs. Knockdown of CDKN1A reversed the effects of NEAT1.

Conclusion

The current research elucidates a novel METTL3/NEAT1/miR-766-5p/CDKN1A axis which plays a critical role in the progression of CML.
Enteral Ca-Intake May Be Low and Affects Serum-PTH-Levels in Pre-school Children With Chronic Kidney Disease
Authors: Schmitz Lilith , Hoermann Pamela , Trutnau Birgit , Jankauskiene Augustina , Zaloszyc Ariane , Edefonti Alberto Carlo , Schmitt Claus Peter , Klaus Guenter
Published: July 2021

Treatment of chronic kidney disease (CKD) mineral bone disorder (MBD) is challenging in growing children due to the high amount of calcium needed for normal bone mineralization and the required dietary phosphate restriction, which often includes intake of calcium-rich products such as milk. Therefore, enteral calcium-intake (Ca-I) was calculated.

Patients: We looked at pediatric CKD-Patients aged 0–6 years.

Design: We used a retrospective analysis of Ca-I from dietary data collections. Ca-I below 60% or above 100% of the D-A-CH and the KDOQI reference values were considered as severe Ca deficiency or Ca overload, respectively.

Results: We had 41 children, median age 1.1 (range 0-5.8) years, body weight 7.3 (2.4–19.9) kg, and length 68 (48-105) cm at the time of first dietary data collection. Renal function was classified as CKD stage III in 20, IV in 28, V in 44, and VD in 142 dietary data collections. At the first dietary data collection, 5 children were in the CKD stage III, 10 in IV, 9 in V, and 17 were on dialysis. Only one child progressed to a higher CKD stage. In total, 234 dietary data collections were analyzed, and 65 follow-up collections were available from 33 children after a time interval of 26 (1–372) days. The median caloric intake was 120 (47–217)% of D-A-CH RDI. In 149 (63.6%) of the dietary data collections, enteral Ca-I was below the target (<100% of the D-A-CH and KDOQI RDI). Severe Ca-deficiency was found in 11 (26%) and 4 (12%) of the children at the first and second dietary data collection, respectively. In total, 11 children were on Ca-containing phosphate binders. In dietary data collection 1 and 2, there were seven children. From these, 4/7 and 4/7 patients had an enteral total Ca-I above the 100% D-A-CH-limit or above the KDOQI limit, respectively. Absolute dietary Ca-I and Ca-I normalized to body weight correlated negatively with PTH (r = −0.196, p < 0.005 and r = −0.13, p < 0.05).

Conclusion: Enteral Ca-I should repeatedly be monitored in CKD children because many may may otherwise be underexposed to enteral calcium and overexposed when calcium-containing phosphate binders are given. Our findings suggest a major impact of dietary calcium supply on bone health in pediatric CKD.
Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent
Authors: Kilpatrick Gavin J.
Published: July 2021

A program to identify novel intravenous sedatives with a short and predictable duration of action was initiated in the late 1990’s by Glaxo Wellcome. The program focussed on the identification of ester-based benzodiazepine derivatives that are rapidly broken down by esterases. Remimazolam was identified as one of the lead compounds. The project at Glaxo was shelved for strategic reasons at the late lead optimization stage. Via the GSK ventures initiative, the program was acquired by the small biotechnology company, TheraSci, and, through successive acquisitions, developed as the besylate salt at CeNeS and PAION. The development of remimazolam besylate has been slow by industry standards, primarily because of the resource limitations of these small companies. It has, however, recently been approved for anesthesia in Japan and South Korea, procedural sedation in the United States, China, and Europe, and for compassionate use in intensive care unit sedation in Belgium. A second development program of remimazolam was later initiated in China, using a slightly different salt form, remimazolam tosylate. This salt form of the compound has also recently been approved for procedural sedation in China. Remimazolam has the pharmacological profile of a classical benzodiazepine, such as midazolam, but is differentiated from other intravenous benzodiazepines by its rapid conversion to an inactive metabolite resulting in a short onset/offset profile. It is differentiated from other intravenous hypnotic agents, such as propofol, by its low liability for cardiovascular depression, respiratory depression, and injection pain. The benzodiazepine antagonist flumazenil can reverse the effects of remimazolam in case of adverse events and further shorten recovery times. The aim of this review is to provide an analysis of, and perspective on, published non-clinical and clinical information on 1) the pharmacology, metabolism, pharmacokinetics, and pharmacodynamic profile of remimazolam, 2) the profile of remimazolam compared with established agents, 3) gaps in the current understanding of remimazolam, 4) the compound’s discovery and development process and 5) likely future developments in the clinical use of remimazolam.
Pharmacoepidemiology of Drug Exposure in Intubated and Non-Intubated Preterm Infants With Severe Bronchopulmonary Dysplasia
Authors: Lewis T. , Truog W. , Nelin L. , Napolitano N. , McKinney R. L. ,   and on behalf of The BPD Collaborative
Published: July 2021

Background: Infants with severe bronchopulmonary dysplasia (BPD) are commonly treated with off-label drugs due to lack of approved therapies. To prioritize drugs for rigorous efficacy and safety testing, it is important to describe exposure patterns in this population.

Objective: Our objective was to compare rates of drug exposure between preterm infants with severe bronchopulmonary dysplasia based on respiratory support status at or beyond 36 weeks post-menstrual age.

Methods: A cross-sectional cohort study was performed on October 29, 2019. Preterm infants with severe BPD were eligible and details of respiratory support and drug therapy were recorded. Wilcoxon paired signed rank test was used to compare continuous variables between the invasive and non-invasive groups. Fisher’s exact test was used to compare binary variables by respiratory support status.

Results: 187 infants were eligible for the study at 16 sites. Diuretics were the drug class that most subjects were receiving on the day of study comprising 54% of the entire cohort, followed by inhaled steroids (47%) and short-acting bronchodilators (42%). Infants who were invasively ventilated (verses on non-invasive support) were significantly more likely to be receiving diuretics (p 0.013), short-acting bronchodilators (p < 0.01), long-acting bronchodilators (p < 0.01), systemic steroids (p < 0.01), systemic pulmonary hypertension drugs (p < 0.01), and inhaled nitric oxide (p < 0.01).

Conclusion: Infant with severe BPD, especially those who remain on invasive ventilation at 36 weeks, are routinely exposed to multiple drug classes despite insufficient pharmacokinetic, safety, and efficacy evaluations. This study helps prioritize sub-populations, drugs and drug classes for future study.