bluuebunny/crossref_metadata_2025 huggingface dataset:
T Cell Protein Tyrosine Phosphatase in Glucose Metabolism
Authors: Wang Ya-nan , Liu Shiyue , Jia Tingting , Feng Yao , Xu Xin , Zhang Dongjiao
Published: June 2021

T cell protein tyrosine phosphatase (TCPTP), a vital regulator in glucose metabolism, inflammatory responses, and tumor processes, is increasingly considered a promising target for disease treatments and illness control. This review discusses the structure, substrates and main biological functions of TCPTP, as well as its regulatory effect in glucose metabolism, as an attempt to be referenced for formulating treatment strategies of metabolic disorders. Given the complicated regulation functions in different tissues and organs of TCPTP, the development of drugs inhibiting TCPTP with a higher specificity and a better biocompatibility is recognized as a promising therapeutic strategy for diabetes or obesity. Besides, treatments targeting TCPTP in a specific tissue or organ are suggested to be considerably promising.
Machine Learning Uses Chemo-Transcriptomic Profiles to Stratify Antimalarial Compounds With Similar Mode of Action
Authors: van Heerden Ashleigh , van Wyk Roelof , Birkholtz Lyn-Marie
Published: June 2021

The rapid development of antimalarial resistance motivates the continued search for novel compounds with a mode of action (MoA) different to current antimalarials. Phenotypic screening has delivered thousands of promising hit compounds without prior knowledge of the compounds’ exact target or MoA. Whilst the latter is not initially required to progress a compound in a medicinal chemistry program, identifying the MoA early can accelerate hit prioritization, hit-to-lead optimization and preclinical combination studies in malaria research. The effects of drug treatment on a cell can be observed on systems level in changes in the transcriptome, proteome and metabolome. Machine learning (ML) algorithms are powerful tools able to deconvolute such complex chemically-induced transcriptional signatures to identify pathways on which a compound act and in this manner provide an indication of the MoA of a compound. In this study, we assessed different ML approaches for their ability to stratify antimalarial compounds based on varied chemically-induced transcriptional responses. We developed a rational gene selection approach that could identify predictive features for MoA to train and generate ML models. The best performing model could stratify compounds with similar MoA with a classification accuracy of 76.6 ± 6.4%. Moreover, only a limited set of 50 biomarkers was required to stratify compounds with similar MoA and define chemo-transcriptomic fingerprints for each compound. These fingerprints were unique for each compound and compounds with similar targets/MoA clustered together. The ML model was specific and sensitive enough to group new compounds into MoAs associated with their predicted target and was robust enough to be extended to also generate chemo-transcriptomic fingerprints for additional life cycle stages like immature gametocytes. This work therefore contributes a new strategy to rapidly, specifically and sensitively indicate the MoA of compounds based on chemo-transcriptomic fingerprints and holds promise to accelerate antimalarial drug discovery programs.
Cardiac Magnetic Resonance Predicting Outcomes Among Patients at Risk for Cardiac AL Amyloidosis
Authors: Agha Ali M. , Palaskas Nicolas , Patel Amit R. , DeCara Jeanne , Parwani Purvi , Iliescu Cezar , Durand Jean B. , Kim Peter , Hassan Saamir , Gladish Gregory , Lee Hans C. , Kaufman Gregory P. , Lopez-Mattei Juan C.
Published: June 2021

Introduction: Patients with systemic AL amyloidosis (AL) should be evaluated for cardiac amyloidosis (CA), as prognosis is strongly related to cardiac involvement. We assessed the characteristics of patients referred to cardiac magnetic resonance (CMR) with suspected CA from a cancer center and determine predictors of mortality/heart failure hospitalizations (HFH).

Methods: Forty-four consecutive patients referred for CMR with suspected CA were retrospectively included. Variables collected included cardiac biomarkers, in addition to echocardiographic and CMR variables. Survival analyses were performed to determine which variables were more predictive of mortality and HFH.

Results: Of the 44 patients included, 55% were females. 73% of patients were diagnosed with CA by CMR; 56% of them had an established diagnosis of AL. Patients with CA by CMR had higher native T1, higher extracellular volume (ECV) fraction, higher T2, less negative GLS by Echo, and higher troponin I and B-type natriuretic peptide (BNP). Kaplan-Meier survival analysis revealed that the following were predictive of mortality: an ECV ≥ 0.50 (p = 0.0098), CMR LVEF < 50% (p = 0.0010), T2/ECV ≤ 100 (p = 0.0001), and troponin I > 0.03 (p = 0.0025). In a stepwise conditional Cox logistic regression model, the only variable predictive of a composite of mortality and HFH was ECV (HR: 1.17, 95% CI = 1.02–1.34 p = 0.030).

Conclusion: ECV seems to be an important biomarker that could be a predictor of outcomes in cardiac AL amyloidosis. In combination, CMR and serum cardiac biomarkers might help to establish prognosis in patients with CA.
Performance and Signal Quality Analysis of Electrocardiogram Textile Electrodes for Smart Apparel Applications
Authors: Le Katherine , Servati Amir , Soltanian Saeid , Servati Peyman , Ko Frank
Published: June 2021

Electronic textile (e-textile) systems applied to biological signal monitoring are of great interest to the healthcare industry, given the potential to provide continuous and long-term monitoring of healthy individuals and patients. Most developments in e-textiles have focused on novel materials and systems without systematic considerations into how the hierarchical structure of fibrous assemblies may influence performance and compatibility of the materials during use. This study examines mechanisms underlying the stability and quality of textile-based electrocardiogram (ECG) electrodes used in a smart bra. Signal quality of the biometric data obtained affects feedback and user experience and may be influenced by characteristics and properties of the material. Under stationary and dynamic conditions, analysis of the raw ECG signal and heart rate, with respect to textile-electrode material properties have been performed. Currently, there is no standardized procedure to compare the ECG signal between electrode materials. In this study, several methods have been applied to compare differences between silver-based textile electrodes and silver/silver-chloride gel electrodes. The comparison methods serve to complement visual observations of the ECG signal acquired, as possible quantitative means to differentiate electrode materials and their performance. From the results obtained, signal quality, and heart rate (HR) detection were found to improve with increased skin contact, and textile structures with lower stretch and surface resistance, especially under dynamic/movement test conditions. It was found that the performance of the textile electrode materials compared exceeded ECG signal quality thresholds previously established for acceptable signal quality, specifically for the kurtosis (K > 5), and Pearson correlation coefficients (r ≥ 0.66) taken from average ECG waveforms calculated.
Common Variants in NUS1 and GP2 Genes Contributed to the Risk of Gestational Diabetes Mellitus
Authors: Zhang Tianxiao , Zhao Longrui , Wang Shujin , Liu Juan , Chang Ying , Ma Louyan , Feng Jia , Niu Yu
Published: June 2021

Background

Recently, NUS1 and GP2 genes were reported to be associated with the risk of type 2 diabetes (T2D) in a Japanese population. Given the sharing of pathogenic contribution from genetic factors between T2D and gestational diabetes mellitus (GDM), we conducted the study to systematically examine the relationship of NUS1 and GP2 genes with the susceptibility to GDM in Chinese Han population.

Methods

A total of 4,250 subjects comprised of 1,282 patients with GDM and 2,968 controls were recruited, and 20 tag single nucleotide polymorphisms (SNPs) (10 from NUS1 and 10 from GP2) were selected for genotyping. Association analyses were conducted for GDM and its related biomedical indexes including fasting glucose and HbA1c levels.

Results

Two SNPs, rs80196932 from NUS1 (P=2.93×10-5) and rs117267808 from GP2 (P=5.68×10-5), were identified to be significantly associated with the risk of GDM. Additionally, SNP rs80196932 was significantly associated with HbA1c level in both patients with GDM (P=0.0009) and controls (P=0.0003), while SNP rs117267808 was significantly associated with fasting glucose level in both patients with GDM (P=0.0008) and controls (P=0.0007). Serum levels of protein NUS1 and GP2 were measured for the study subjects, and significant differences were identified among groups with different genotypes of SNP rs80196932 and rs117267808, respectively.

Conclusions

Our findings indicate that NUS1 and GP2 genes contribute to the risk of GDM, which would help to offer the potential to improve our understanding of the etiology of GDM and, in turn, could facilitate the development of novel medicines and treatments for GDM.
Climate Change Impacts the Protective Effect of Forests: A Case Study in Switzerland
Authors: Moos Christine , Guisan Antoine , Randin Christophe F. , Lischke Heike
Published: June 2021

In steep terrain, forests play an important role as natural means of protection against natural hazards, such as rockfall. Due to climate warming, significant changes in the protection service of these forests have to be expected in future. Shifts of current to more drought adapted species may result in temporary or even irreversible losses in the reduction of rockfall risk provided by these forests. In this study, we assessed how the protective capacity against rockfall of a protection forest in the western part of the Valais in the Swiss Alps may change in future, by combining dynamic forest modelling with a quantitative risk analysis. Current and future forest development was modelled with the spatially explicit forest model TreeMig under a moderate (RCP4.5) and an extreme (RCP8.5) climate change scenario. The simulated forest scenarios were compared to ground-truth data from the current forest complex. We quantified the protective effect of the different forest scenarios based on the reduction of rockfall risk for people and infrastructure at the bottom of the slope. Rockfall risk was calculated on the basis of three-dimensional rockfall simulations. The forest simulations predicted a clear decrease in basal area of most of the currently occuring species (Fagus sylvatica, Picea abies, Larix decidua, and Abies alba) in future. The forest turned into a Quercus pubescens dominated forest, for both climate scenarios, mixed with Pinus sylvestris under RCP4.5. With climate warming, a clear increase in risk is expected for both climate change scenarios. In the long-term (>100 years), a stabilization of risk, or even a slight decline may be expected due to an increase in biomass of the trees. The results of this study further indicate that regular forest interventions may promote regeneration and thus accelerate the shift in species distribution. Future research should explore into more details the long-term effect of different adaptive forest management strategies on the protection service of forests under climate change.
Phosphorus Availability Alters the Effect of Tree Girdling on the Diversity of Phosphorus Solubilizing Soil Bacterial Communities in Temperate Beech Forests
Authors: Michas Antonios , Pastore Giovanni , Chiba Akane , Grafe Martin , Clausing Simon , Polle Andrea , Schloter Michael , Spohn Marie , Schulz Stefanie
Published: June 2021

Phosphorus (P) solubilization is an important process for P acquisition by plants and soil microbes in most temperate forests. The abundance of inorganic P solubilizing bacteria (PSB) is affected by the P concentration in the soil and the carbon input by plants. We used a girdling approach to investigate the interplay of root-derived C and initial P content on the community composition of gcd-harboring bacteria as an example of PSB, which produce gluconic acid. We hypothesized that gcd-harboring PSB communities from P-poor sites are more vulnerable to girdling, because of their lower diversity, and that a shift in gcd-harboring PSB communities by girdling is caused by a response of few, mostly oligotrophic, taxa. We used a high-throughput metabarcoding approach targeting the gcd gene, which codes for the quinoprotein glucose dehydrogenase, an enzyme involved in the solubilization of inorganic P. We compared the diversity of gcd-harboring PSB in the mineral topsoil from two temperate beech forests with contrasting P stocks, where girdling was applied and compared our data to the respective control plots with untreated young beech trees. At both sites, gcd-harboring PSB were dominated by Proteobacteria and Acidobacteria, however, with differences in relative abundance pattern on the higher phylogenetic levels. The P-poor site was characterized by a high relative abundance of Kaistia, whereas at the P-rich site, Dongia dominated the gcd-harboring bacterial communities. Girdling induced an increase in the relative abundance of Kaistia at the P-poor site, whereas other bacterial groups of the family Rhizobiaceae were reduced. At the P-rich site, major microbial responders differed between treatments and mostly Bradyrhizobium and Burkholderia were positively affected by girdling in contrast to uncultured Acidobacteria, where reduced relative abundance was found. Overall, these effects were consistent at different time points analyzed after the introduction of girdling. Our data demonstrate that plant-derived carbon influences community structure of gcd-harboring bacteria in temperate beech forest soils.
Mini-Review: Genetic Literacy and Engagement With Genetic Testing for Autism Spectrum Disorder
Authors: Little India D. , Gunter Chris
Published: June 2021

As genomic and personalized medicine is integrated into healthcare, the need for patients to understand and make decisions about their own genetic makeup increases. Genetic literacy, or one’s knowledge of genetic principles and their applications, measures an individual’s ability to apply genetic information to their own treatment. Increased genetic literacy can improve comprehension of genetic tests and therefore increase participation in testing to detect and treat genetic disorders. It can also help providers understand and explain genetic information to their patients. However, current research indicates that the population’s genetic literacy is generally low. Because many medical students, providers, and patients cannot adequately apply genetic information to their health, new and beneficial genetic technologies can be underused. More specifically, though genetic testing is recommended at the time of diagnosis for those affected by autism spectrum disorder (ASD), as few as 22% of families undergo genetic testing after diagnosis. While ASD, a neurodevelopmental condition characterized by impaired social communication and restricted interests, has both genetic and environmental risk, genetic testing can give clinicians useful information and help families avoid potentially painful and costly tests, even when many families do not receive a “positive” genetic result through microarrays or gene panels. Improving genetic literacy in populations affected by ASD can also improve attitudes toward genetic testing, thereby ensuring access to genetic health risk information. In this mini review, we discuss the current literature describing genetic literacy and genetic testing rates for ASD.
A Novel Computational Framework to Predict Disease-Related Copy Number Variations by Integrating Multiple Data Sources
Authors: Yuan Lin , Sun Tao , Zhao Jing , Shen Zhen
Published: June 2021

Copy number variation (CNV) may contribute to the development of complex diseases. However, due to the complex mechanism of path association and the lack of sufficient samples, understanding the relationship between CNV and cancer remains a major challenge. The unprecedented abundance of CNV, gene, and disease label data provides us with an opportunity to design a new machine learning framework to predict potential disease-related CNVs. In this paper, we developed a novel machine learning approach, namely, IHI-BMLLR (Integrating Heterogeneous Information sources with Biweight Mid-correlation and L1-regularized Logistic Regression under stability selection), to predict the CNV-disease path associations by using a data set containing CNV, disease state labels, and gene data. CNVs, genes, and diseases are connected through edges and then constitute a biological association network. To construct a biological network, we first used a self-adaptive biweight mid-correlation (BM) formula to calculate correlation coefficients between CNVs and genes. Then, we used logistic regression with L1 penalty (LLR) function to detect genes related to disease. We added stability selection strategy, which can effectively reduce false positives, when using self-adaptive BM and LLR. Finally, a weighted path search algorithm was applied to find topDpath associations and important CNVs. The experimental results on both simulation and prostate cancer data show that IHI-BMLLR is significantly better than two state-of-the-art CNV detection methods (i.e., CCRET and DPtest) under false-positive control. Furthermore, we applied IHI-BMLLR to prostate cancer data and found significant path associations. Three new cancer-related genes were discovered in the paths, and these genes need to be verified by biological research in the future.
Drug and Chemical Allergy: A Role for a Specific Naive T-Cell Repertoire?
Authors: Bechara Rami , Feray Alexia , Pallardy Marc
Published: June 2021

Allergic reactions to drugs and chemicals are mediated by an adaptive immune response involving specific T cells. During thymic selection, T cells that have not yet encountered their cognate antigen are considered naive T cells. Due to the artificial nature of drug/chemical-T-cell epitopes, it is not clear whether thymic selection of drug/chemical-specific T cells is a common phenomenon or remains limited to few donors or simply does not exist, suggesting T-cell receptor (TCR) cross-reactivity with other antigens. Selection of drug/chemical-specific T cells could be a relatively rare event accounting for the low occurrence of drug allergy. On the other hand, a large T-cell repertoire found in multiple donors would underline the potential of a drug/chemical to be recognized by many donors. Recent observations raise the hypothesis that not only the drug/chemical, but also parts of the haptenated protein or peptides may constitute the important structural determinants for antigen recognition by the TCR. These observations may also suggest that in the case of drug/chemical allergy, the T-cell repertoire results from particular properties of certain TCR to recognize hapten-modified peptides without need for previous thymic selection. The aim of this review is to address the existence and the role of a naive T-cell repertoire in drug and chemical allergy. Understanding this role has the potential to reveal efficient strategies not only for allergy diagnosis but also for prediction of the immunogenic potential of new chemicals.
Time Course and Clinical Relevance of Neurological Deterioration After Endovascular Recanalization Therapy for Anterior Circulation Large Vessel Occlusion Stroke
Authors: Li Zibao , Zhang Hongchuan , Han Jian , Chu Zhaohu , Zhao Shoucai , Yang Qian , Huang Xianjun , Zhou Zhiming
Published: June 2021

Neurological deterioration (ND) is a devastating complication for patients with ischemic stroke after endovascular recanalization therapy (EVT). We aimed to investigate the time course and clinical relevance of ND after EVT. Consecutive patients with acute ischemic stroke who underwent EVT for large arterial occlusions of the anterior cerebral circulation were enrolled. The National Institutes of Health Stroke Scale (NIHSS) scores were assessed before EVT, at the end of EVT, at 24 h (d1), on day 3 (d3), on day 15 (d15), at discharge and anytime when ND was indicated. ND was defined as an increase of ≥ 4 points in the NIHSS score and was divided into acute ND (AD, within 24 h), subacute ND (SD, d1–d3), and delayed ND (DD, d3–d15 or discharge). Using multivariable logistic regression analysis, we explored predictors and outcomes of ND at different time periods. As a result, of 343 patients, 129 (37.6%) experienced ND, including 90 (26.2%) with AD, 27 (7.9%) with SD and 12 (3.5%) with DD. Multivariable logistic regression analysis revealed that history of hypertension, cardioembolic stroke, lower Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and poor collaterals were significantly associated with an increased risk of AD; history of hypertension, lower ASPECTS, poor collaterals, and unsuccessful recanalization, with SD; and high admission NIHSS score, with DD. In addition, patients who experienced AD (OR = 10.22, P < 0.001), SD (OR = 15.89, P = 0.004), or DD (OR = 8.31, P = 0.015) were more likely to have poor outcomes. ND was a strong predictor of poor stroke outcomes. Management of related risk factors at different ND time periods might improve the prognosis of EVT.
Innovative Nanotechnology a Boon for Fight Against Pandemic COVID–19
Authors: Shehu Ibrahim Aminu , Auwal Nura Mustapha , Musa Muhammad Kabir , Mukhtar Abubakar , Yusuf Mashahudu Sha’arani , Yau Anees Ashir , Muhammad Murtala , Baba Dala Yusuf , Sani Salisu Abdullahi , Ahmad Mahmoud Seed , Islam Mojahidul
Published: June 2021

COVID – 19 is a contagious disease caused by severe acute respiratory syndrome (SARS-CoV2). The rate at which COVID – 19-virus spread from epidemic to pandemic within a short period is quite alarming. As of July 2020, the Dashboard of the World Health Organization (WHO) recorded over 15 million COVID – 19 cases across 213 countries, with mortality of over 620,000. The governments and healthcare agencies responsible for mitigating the virus's spread have adopted several strategies to end the pandemic. However, all hands were on deck to establish the standard treatment modalities of SARS-CoV-2 through inventing new drugs, vaccine candidates, or repurposing the existing medicines and robust diagnostic tools, in addition to other technological innovations. Therefore, nanotechnology’s employment would play a vital role in bringing multidisciplinary ways of developing affordable, reliable, and powerful tools for diagnosis, in addition to personal protection and effective medicines. Additionally, nanosensors' application would significantly aid the diagnoses of the COVID–19 even on asymptomatic patients, and thus would be an essential means for determining its prevalence. Likewise, nanoscale fibers can optimize personal equipment protection and allow their reusability for medical and economic benefits. Accordingly, the literature was intensively reviewed by searching for the combinations of the research keywords in the official scientific databases such as Science Direct, PubMed, and Google Scholar. Hence, this research highlighted the perspective contributions of nanotechnology in the war against the COVID-19 pandemic.
First-Pass Reperfusion by Mechanical Thrombectomy in Acute M1 Occlusion: The Size of Retriever Matters
Authors: Serna Candel Carmen , Aguilar Pérez Marta , Bäzner Hansjörg , Henkes Hans , Hellstern Victoria
Published: June 2021

Introduction: Single-pass complete reperfusion using stent retrievers has been shown to improve functional outcome in patients with large vessel occlusion strokes. The aim of this study was to investigate the optimal size of stent retrievers to achieve one-pass complete reperfusion by mechanical thrombectomy.

Methods: The study evaluated the results of aspiration-assisted mechanical thrombectomy of acute isolated occlusion of the middle cerebral artery in the M1 segment with a novel 5 × 40-mm stent retriever compared to the usual 4 × 20-mm device. Reperfusion status was quantified using the Thrombolysis In Cerebral Infarction (TICI) scale. We hypothesized that thrombectomy of M1 occlusions with 5 × 40-mm stent retriever yields higher rates of complete first-pass reperfusion (FP) (TICI ≥2c after one pass) and successful or modified FP (mFP) (TICI ≥2b after one pass) than thrombectomy with 4 × 20. We included isolated M1 occlusions treated with pRESET 5 × 40 (phenox) as first-choice device for thrombectomy and compared with M1 occlusions treated with pRESET 4 × 20. We excluded patients with additional occlusions or tandem stenosis or who received an intracranial stent or angioplasty as a part of the endovascular treatment.

Results: One hundred thirteen patients were included in the 4 × 20 group and 57 patients in the 5 × 40 group. The 5 × 40 group achieved higher FP compared to 4 × 20 group [61.4% (35 of 57 patients) vs. 40.7% (46 of 113), respectively; adjusted odds ratio (OR) and 95% confidence interval (95% CI) = 2.20 (1.08–4.48), p = 0.030] and a higher mFP [68.4%, 39 of 57 patients vs. 48.7%, 55 of 113; adjusted OR (95% CI) = 2.11 (1.04–4.28), p = 0.037]. Frequency of successful reperfusion (TICI ≥2b) was similar in both groups (100 vs. 97.3%), but frequency of complete reperfusion (TICI ≥2c) was higher in the 5 × 40 group [82.5 vs. 61.9%, adjusted OR (95% CI) = 2.47 (1.01–6.04), p = 0.047]. Number of passes to achieve reperfusion was lower in the 5 × 40 group than in the 4 × 20 group [1.6 ± 1.1 vs. 2 ± 1.4, p = 0.033; adjusted incidence rate ratio (95% CI) = 0.84 (0.69–1.03), p = 0.096]. Modified Rankin scale at 90 days was similar in 5 × 40 and 4 × 20 groups.

Conclusions: The size of stent retriever matters in acute M1 occlusions treated with aspiration-assisted mechanical thrombectomy. A longer stent retriever with a larger nominal diameter achieves a higher complete and successful FP and higher successful reperfusion compared to a shorter stent retriever.
Epidural Analgesia With or Without Oxytocin, but Not Oxytocin Alone, Administered During Birth Disturbs Infant Pre-feeding and Sucking Behaviors and Maternal Oxytocin Levels in Connection With a Breastfeed Two Days Later
Authors: Takahashi Yuki , Uvnäs-Moberg Kerstin , Nissen Eva , Lidfors Lena , Ransjö-Arvidson Anna-Berit , Jonas Wibke
Published: June 2021

AimsThis work aimed to study consequences of medical interventions in connection with birth on infant pre-feeding and feeding behaviors and on maternal oxytocin levels in connection with a breastfeed 2 days later.

Materials and MethodsMothers and their full-term newborns (n= 41) were videotaped during a breastfeed 2 days after birth. Duration and quality of rooting [Infant Breastfeeding Assessment Tool (IBFAT)] were assessed. Maternal blood samples were collected, oxytocin levels were analyzed, and mean oxytocin level and variance were calculated. Data on medical interventions during birth, number of breastfeedings, and infant weight loss since birth were recorded. Data were analyzed using logistic regression models.

ResultsThe duration of infant rooting was significantly shorter when the mother had received epidural analgesia. The shorter the duration of infant rooting, the more often infants had breastfed and the greater was the infant weight loss since birth. Mothers with epidural analgesiawithoxytocin had the lowest oxytocin mean levels in connection with a breastfeed. Oxytocin variance correlated positively with quality of rooting and correlated negatively with infant weight loss. In the control group alone, we found similar patterns of associations with oxytocin levels.

ConclusionEpidural analgesia and epidural analgesiawithoxytocin infusion in connection with birth negatively influenced infant rooting behavior and maternal mean oxytocin levels, respectively. Oxytocin infusion alone was without effect. The data also suggest that infants who suck well stimulate oxytocin release more efficiently, as expressed by a high oxytocin variance, leading to a better stimulation of milk production and consequently to a reduced infant weight loss 2 days after birth.
Age-Dependent Association Between Elevated Homocysteine and Cognitive Impairment in a Post-stroke Population: A Prospective Study
Authors: Zhou Shengnan , Chen Jiahao , Cheng Lin , Fan Kaili , Xu Minjie , Ren Wenwei , Chen Yunbin , Geng Dandan , Cheng Haoran , Luan Xiaoqian , Song Jiaying , Lin Gangqiang , Huang Guiqian , He Jincai
Published: June 2021

Background and Purpose: The results regarding the independent association between homocysteine (Hcy) levels and post-stroke cognitive impairment (PSCI) were inconsistent. The effect of age on this association has yet to be explored. This study aims to determine the relationship between Hcy levels, age, and cognitive impairment in a post-stroke population.

Methods: A total of 592 patients with acute ischemic stroke (AIS) completed follow-up. Serum Hcy levels were measured enzymatically by spectrophotometry within 24 h of admission. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE) 1 month after stroke, and the scores ≤ 24 were considered as cognitive impairment. Our study was dichotomized into two groups by a cut-off of 65 years. Multivariate logistic regression models were used to determine the association between baseline Hcy levels and cognitive impairment.

Results: According to the MMSE score, 317 (53.5%) patients had cognitive impairment. Patients with higher levels of Hcy were more prone to have cognitive impairment 1 month after stroke than patients with lower levels of Hcy (p < 0.001). The optimal cut-off points of Hcy level (μmol/L) were (T1) ≤ 8, (T2) 8–12, and (T3) ≥ 12. After adjusting for confounding factors, the multivariate regression analysis showed that the third Hcy tertile was independently associated with cognitive impairment [odds ratio (OR) = 2.057, 95% confidence interval (CI) = 1.133–3.735, p = 0.018). A stronger association [T2 (OR = 2.266, 95% CI = 1.042–4.926, p = 0.039); T3 (OR =3.583, 95% CI = 1.456–8.818, p = 0.005)] was found in the younger group. However, the independent association was not confirmed in the older group.

Conclusions: Elevated Hcy levels in the acute phase of ischemic stroke were independently associated with cognitive impairment in a post-stroke population. Furthermore, the association was age-dependent and more meaningful in a younger population aged below 65. So, Hcy levels in patients with stroke should be well-monitored, especially in younger patients.
Interventional Treatment for Cholangiocarcinoma
Authors: Li Hang , Chen Li , Zhu Guang-Yu , Yao Xijuan , Dong Rui , Guo Jin-He
Published: June 2021

Cholangiocarcinoma (CCA) is the second most common type of primary liver malignancy. The latest classification includes intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, with the latter one further categorized into perihilar and distal cholangiocarcinoma. Although surgical resection is the preferred treatment for CCA, less than half of the patients are actually eligible for radical surgical resection. Interventional treatment, such as intra-arterial therapies, ablation, and brachytherapy (iodine-125 seed implantation), has become an acceptable palliative treatment for patients with unresectable CCA. For these patients, interventional treatment is helpful for locoregional control, symptom relief, and improving quality of life. Herein, in a timely and topical manner, we will review these advances and highlight future directions of research in this article.
Combined Impacts of Genetic Variants of Long Non-Coding RNA MALAT1 and the Environmental Carcinogen on the Susceptibility to and Progression of Oral Squamous Cell Carcinoma
Authors: Ding Yi-Fang , Wen Yu-Ching , Chuang Chun-Yi , Lin Chiao-Wen , Yang Yi-Chieh , Liu Yu-Fan , Chang Wei-Min , Chang Lun-Ching , Yang Shun-Fa , Chien Ming-Hsien
Published: June 2021

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the oral cavity, and long non-coding (lnc)RNA of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was recently reported to play a crucial role in OSCC development and progression. However, potential effects of genetic variants of MALAT1 on the development of OSCC are still unclear. Herein, we performed a case-control study in 1350 patients with OSCC and 1199 healthy controls to evaluate the association between functional single-nucleotide polymorphisms (SNPs) of MALAT1 and OSCC susceptibility, as well as its clinicopathologic characteristics. A TaqMan allelic discrimination assay was used to genotype four tagging SNPs, viz., rs3200401 C>T, rs619586 A>G, rs1194338 C>A, and rs7927113 G>A, and results showed that the MALAT1 rs3200401 T allele had a lower risk of OSCC (adjusted odds ratio (AOR): 0.779, 95% confidence interval (CI): 0.632~0.960, p=0.019) and a higher risk of developing moderately (grade II)/poorly (grade III) differentiated OSCC (AOR: 1.508-fold, 95% CI: 1.049~2.169, p=0.027) under a dominant model. According to environmental carcinogen exposure, patients with a betel quid-chewing habit who carried the T allele of rs3200401 more easily developed high-grade (II/III) OSCC (AOR: 1.588, 95% CI: 1.055~2.390, p=0.027), and patients with the same genotype but who did not chew betel quid had a lower risk of developing lymph node metastasis (AOR: 0.437, 95% CI: 0.255~0.749, p=0.003). In addition to rs3200401, the rs619586 AG/GG genotype was associated with increased risks of developing advanced stages (III+IV) and larger tumor sizes (>T2) compared to the AA genotype, especially in the subgroup of betel quid chewers. Furthermore, analyses of clinical datasets revealed that the MALAT1 expression level was upregulated in OSCC compared to normal tissues, especially in the betel quid-chewing population. These results indicated involvement of MALAT1 SNPs rs3200401 and rs619586 in the development of OSCC and support the interaction between MALAT1 gene polymorphisms and the environmental carcinogen as a predisposing factor for OSCC progression.
The Utility of Gallbladder Absence on Ultrasound for Children With Biliary Atresia
Authors: Ho Andrea , Sacks Marla A. , Sapra Amita , Khan Faraz A.
Published: June 2021

Background: Biliary Atresia (BA) is congenital condition, where infant intra- and extrahepatic bile ducts become obliterated, leading to cholestasis, and cirrhosis if untreated. This study aims to assess the predictive measure of absent gallbladder on ultrasounds (US) performed in infants with cholestasis for diagnosing BA.

Method: After Institutional Review Board approval, retrospective chart reviews of 61 infants with cholestasis found 43 (70.5%) were diagnosed with BA. A pediatric radiologist provided interpretations of all ultrasounds in a blinded fashion. Statistical analysis was used to assess the utility of absence of gallbladder on US in predicting BA, confirmed intraoperatively.

Results: Absent gallbladder on US predicts absent gallbladder with 77% accuracy, 92% sensitivity, 73% specificity, PPV 43%, and NPV 97% (P < 0.001, Fisher exact test). To diagnose BA, absent gallbladder on US has 66% accuracy, 53% sensitivity, 94% specificity, 96% PPV, and 46% NPV (P < 0.001, Fisher exact test).

Conclusion: Sonographic gallbladder absence has high specificity and PPV, indicating utility for BA diagnosis; however, it is not useful for ruling out BA given its low sensitivity.
The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis
Authors: Abulfathi Ahmed A. , de Jager Veronique , van Brakel Elana , Reuter Helmuth , Gupte Nikhil , Vanker Naadira , Barnes Grace L. , Nuermberger Eric , Dorman Susan E. , Diacon Andreas H. , Dooley Kelly E. , Svensson Elin M.
Published: June 2021

Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.

Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5–1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise.

Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified.

Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.
Training Restricted Boltzmann Machines With a D-Wave Quantum Annealer
Authors: Dixit Vivek , Selvarajan Raja , Alam Muhammad A. , Humble Travis S. , Kais Sabre
Published: June 2021

Restricted Boltzmann Machine (RBM) is an energy-based, undirected graphical model. It is commonly used for unsupervised and supervised machine learning. Typically, RBM is trained using contrastive divergence (CD). However, training with CD is slow and does not estimate the exact gradient of the log-likelihood cost function. In this work, the model expectation of gradient learning for RBM has been calculated using a quantum annealer (D-Wave 2000Q), where obtaining samples is faster than Markov chain Monte Carlo (MCMC) used in CD. Training and classification results of RBM trained using quantum annealing are compared with the CD-based method. The performance of the two approaches is compared with respect to the classification accuracies, image reconstruction, and log-likelihood results. The classification accuracy results indicate comparable performances of the two methods. Image reconstruction and log-likelihood results show improved performance of the CD-based method. It is shown that the samples obtained from quantum annealer can be used to train an RBM on a 64-bit “bars and stripes” dataset with classification performance similar to an RBM trained with CD. Though training based on CD showed improved learning performance, training using a quantum annealer could be useful as it eliminates computationally expensive MCMC steps of CD.
How and to What Extent Immunological Responses to SARS-CoV-2 Shape Pulmonary Function in COVID-19 Patients
Authors: Laveneziana Pierantonio , Straus Christian , Meiners Silke
Published: June 2021

COVID-19 is a disease caused by a new coronavirus SARS-CoV-2, primarily impacting the respiratory system. COVID-19 can result in mild illness or serious disease leading to critical illness and requires admission to ICU due to respiratory failure. There is intense discussion around potential factors predisposing to and protecting from COVID-19. The immune response and the abnormal respiratory function with a focus on respiratory function testing in COVID-19 patients will be at the center of this Perspective article of the Frontiers in Physiology Series on “The Tribute of Physiology for the Understanding of COVID-19 Disease.” We will discuss current advances and provide future directions and present also our perspective in this field.
The Cough Reflex: The Janus of Respiratory Medicine
Authors: Sykes Dominic L. , Morice Alyn H.
Published: June 2021

In clinical practice, we commonly face adversity when encountering dysfunction of the cough reflex. Similar to ancient Roman deity Janus, it often presents with one of two opposing “faces”. Continual aberrant activation of the cough reflex, also known as chronic cough, can cause great detriment to quality of life and many of these patients are left misdiagnosed and undertreated. In contrast, loss of normal functioning of the cough reflex is the cause of a significant proportion of mortality in the elderly, primarily through the development of aspiration pneumonia. In this review we discuss both hyper- and hypo-activation of the cough reflex and how airway reflux and chronic aspiration may be involved in the aetiology and sequalae of both disease states. We detail the physiological and pharmacological mechanisms involved in cough, and how the recent development of P2X3 receptor antagonists may lead to the first pharmaceutical agent licensed for chronic cough. The treatment and prevention of loss of the cough reflex, which has been largely neglected, is also discussed as novel low-cost interventions could help prevent a number of hospital and domiciliary deaths from both acute and chronic aspiration.
Long-Term Profiles of Bullying Victims and Aggressors: A Retrospective Study
Authors: Valera-Pozo Mario , Flexas Albert , Servera Mateu , Aguilar-Mediavilla Eva , Adrover-Roig Daniel
Published: June 2021

Bullying is a widespread and worrying phenomenon, related to many different personal, behavioral, and social variables which can modulate it and its outcomes, also in the long term. These relationships are usually studied in children and adolescents, but less often in adults who have suffered or perpetrated bullying in the past. The present work explored the long-term characteristics of bullying victims and aggressors using a retrospective design. A sample of 138 adults of different ages completed an on-line protocol that included measures of bullying and victimization, substance use, sensitivity to reward and punishment, social skills, antisocial behavior, emotional regulation strategies, depression, anxiety, stress, self-esteem, and risk of suicide. The sample was divided into three groups (victims, aggressors, and controls) based on their responses to bullying-related questions. A set of Multiple Analyses of Variance with group as a fixed factor was carried out for each dependent variable. Victims and aggressors did not significantly differ in their self-reported substance consumption. Victims showed higher global depression, anxiety and stress in the past than aggressors (M = 34.66, SD = 11.74; aggressors: M = 19.70, SD = 16.53), higher emotional lack of control (M = 23.97, SD = 10.62; controls: M = 17.11, SD = 7.95) and rejection (M = 21.72, SD = 7.24; controls: M = 16.33, SD = 5.67), lower self-esteem (M = 27.72, SD = 6.70; controls: M = 31.60, SD = 6.60), and a larger frequency of suicidal thoughts (in the past) than controls. Aggressors showed higher sensitivity to reward (M = 12.03, SD = 3.66; controls: M = 8.42, SD = 3.92), larger communicational and relational skills (M = 22.10, SD = 7.20; controls: M = 17.96, SD = 7.16), and lower emotional sensitivity (M = 14.80, SD = 4.10; controls: M = 16.76, SD = 2.21). Accordingly, the logistic regression analysis identified sensitivity to reward and low psychological adjustment as the main predictors of the aggressor and victim profiles, respectively. The present results are discussed considering the extant literature on bullying and may help to improve prevention programs for this relevant social scourge.
The Relative Age Effect on Competition Performance of Spanish International Handball Players: A Longitudinal Study
Authors: de la Rubia Alfonso , Lorenzo Alberto , Bjørndal Christian Thue , Kelly Adam Leigh , García-Aliaga Abraham , Lorenzo-Calvo Jorge
Published: June 2021

Background: Competitive success is the ultimate objective of elite professional sport organisations. Relative age effects (RAE) impact athlete selection processes in the short and long-term performance. The aims of this study were: (i) examine the presence of RAE by gender, competitive level, and playing position, as well as evaluate the impact of RAE on individual (goals, percentage of effectiveness in shots, saves; percentage of effectiveness in saves, assists, turnovers, steals, blocked shots, penalties, minutes played, and minutes played per match) and collective competition performance (final team position); and (ii) analyse the impact of RAE on the evolutionary trends of individual performance in international competitions throughout 16 seasons in Spanish handball (2005–2020).

Methods: The sample included 631 Spanish handball players (male: n = 359; female: n = 272). A Chi-square goodness-of-fit test was used to assess whether a skewed birthdate distribution occurred. A one-way analysis of variance (ANOVA) of independent measures was used to examine the individual and collective statistical parameters by birth quartiles. A linear regression in a Hopkins sheet were performed to compare individual performance trends.

Results: The results revealed RAE in the male formative categories (p < 0.001), as well as the male and female senior categories (p < 0.05). By position, RAE especially affected the “centre-back” in the male formative (p < 0.01) and senior categories (p < 0.05). No significant relationship between RAE and individual performance was found in male formative categories, while an impact of RAE on the “minutes played” was detected in the female senior category (p < 0.05). With regard to collective performance, a higher number of relatively older handball players was observed in the best ranked teams in the male formative categories and in the quarter-final teams in the female formative categories (p < 0.05). Among the male players, relatively older players spent more minutes on the court than relatively younger players, although this advantage dissipated over time and did not lead to better performance. Among the female players, relatively younger players were found to perform better as the level of competitive handball increased.

Discussion: These findings are important for talent identification and development policies in sport federations and other elite sport institutions by demonstrating the many unintended consequences of selections to international competitions at the youth level.
Agomelatine, A Potential Multi-Target Treatment Alternative for Insomnia, Depression, and Osteoporosis in Postmenopausal Women: A Hypothetical Model
Authors: Yardimci Ahmet , Ozdede Mehmet Ridvan , Kelestimur Haluk
Published: June 2021

Insomnia, which is associated with menopausal depression, is a common symptom of menopause. Both symptoms have a common etiology, and can affect each other significantly. Pharmacological interventions, including hypnotics and antidepressants, and non-pharmacological therapies are generally administered in clinical practice for insomnia treatment. As another menopausal disorder, osteoporosis is described as a disease of low bone mineral density (BMD), affecting nearly 200 million women worldwide. Postmenopausal osteoporosis is common among middle-aged women. Since postmenopausal osteoporosis mainly results from low estrogen levels, menopausal hormone therapy (HT) is considered the first-line option for the prevention of osteoporosis during the menopausal period. However, almost no study has evaluated novel treatments for the combined prevention of insomnia, depression, and osteoporosis. Hence, it is necessary to develop new multi-target strategies for the treatment of these disorders to improve the quality of life during this vulnerable period. Melatonin is the major regulator of sleep, and it has been suggested to be safe and effective for bone loss therapy by MT-2 receptor activity. As a result, we hypothesize that agomelatine, an MT-1 and MT-2 receptor agonist and 5-HT2C receptor antagonist, holds promise in the combined treatment of insomnia, depression, and osteoporosis in middle-aged women during menopause.