bluuebunny/crossref_metadata_2025 huggingface dataset:
Autonomic Symptoms in Older Adults Are Common and Associated With Health-Related Quality of Life
Authors: Renno-Busch Sarah , Hildesheim Hanna , van Uem Janet M. T. , Sünkel Ulrike , Röben Benjamin , Brockmann Kathrin , Mychajliw Christian , Eschweiler Gerhard W. , Berg Daniela , Maetzler Walter
Published: November 2021

Background:Autonomic symptoms are common in older adults, and a large body of literature focusing on age-related diseases shows that autonomic symptoms in these diseases constrain Health-Related Quality of Life (HRQoL). To our best knowledge, the association between autonomic symptoms in older adults, independent of specific diseases, and HRQoL has not yet been assessed.

Aim:To assess the frequency and the effect of autonomic symptoms in general, as well as orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor symptoms, on HRQoL in older adults.

Methods:Cross-sectional data of the fourth visit of the Tübinger evaluation of Risk factors for Early detection of Neurodegeneration (TREND) study were included. Autonomic symptoms, as assessed with the Composite Autonomic Symptom Score 31 (COMPASS 31), were quantified and compared with HRQoL, as assessed with the EuroQol five-level version (EQ-5D-5L). Statistical analyses included Spearman's rank correlation and multiple linear regression analysis.

Results:The analysis included 928 participants with a median of 68 years; 47% were women. Of those, 85% reported at least one autonomic symptom. Gastrointestinal and secretomotor symptoms were most common. The COMPASS 31 total score and all subdomains were significantly associated with reduced HRQoL. Among the subdomains, the strongest correlations with HRQoL were found for gastrointestinal and bladder symptoms. Overall, autonomic symptoms alone explained 20% of the variance of HRQoL; when depressive mood was added, the model explained 32%.

Conclusion:Autonomic symptoms are associated with HRQoL and depressive symptoms in older adults.
A High-Tryptophan Diet Reduces Seizure-Induced Respiratory Arrest and Alters the Gut Microbiota in DBA/1 Mice
Authors: Yue Qiang , Cai Mingfei , Xiao Bo , Zhan Qiong , Zeng Chang
Published: November 2021

Background and Aims: Central 5-hydroxytryptamine (5-HT) defects are responsible for the occurrence of sudden unexpected death in epilepsy (SUDEP). The DBA/1 mouse is an animal model of SUDEP since the mouse exhibits audiogenic seizure-induced respiratory arrest (S-IRA). The synthesis of central 5-HT is closely related to the gut microbiota. Moreover, emerging studies suggest a possible role for the microbiota in mitigating seizure likelihood. Based on this, we aimed to explore the effect of a high-tryptophan diet (HTD) on SUDEP as well as the synthesis and metabolism of central 5-HT. Furthermore, we investigated the involvement of the gut microbiota in this process.

Methods: All DBA/1 mice were subjected to acoustic stimulation to induce seizures. Only those mice that exhibited S-IRA were randomly assigned to the normal diet (ND) group (n = 39) or HTD group (n = 53). After 1 month of dietary intervention, (1) S-IRA rates were evaluated, (2) the concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the plasma and brain were determined by ultra-high-pressure liquid chromatography, and (3) the fecal flora biodiversity and species composition were analyzed by 16S rDNA microbiota profiling.

Results: The S-IRA rate in DBA/1 mice was significantly reduced in the HTD group compared with that in the control group. HTD increased the levels of 5-HT and 5-HIAA in both the telencephalon and midbrain. HTD significantly elevated the species richness and diversity of the gut microbiota. Moreover, there was a significant difference in the gut microbiota composition between the two groups, and the intestinal flora was dominated by Proteobacteria and Actinobacteria after HTD.

Conclusions: HTD is efficient in lowering S-IRA rates and elevating the central 5-HT level in DBA/1 mice. The gut microbiota was altered after HTD intervention. The significant increase in Proteobacteria and Actinobacteria may be related to the SUDEP-protective effect of HTD. Our findings shed light on a candidate choice of dietary prevention for SUDEP.
Deep Learning Recurrent Neural Network for Concussion Classification in Adolescents Using Raw Electroencephalography Signals: Toward a Minimal Number of Sensors
Authors: Thanjavur Karun , Hristopulos Dionissios T. , Babul Arif , Yi Kwang Moo , Virji-Babul Naznin
Published: November 2021

Artificial neural networks (ANNs) are showing increasing promise as decision support tools in medicine and particularly in neuroscience and neuroimaging. Recently, there has been increasing work on using neural networks to classify individuals with concussion using electroencephalography (EEG) data. However, to date the need for research grade equipment has limited the applications to clinical environments. We recently developed a deep learning long short-term memory (LSTM) based recurrent neural network to classify concussion using raw, resting state data using 64 EEG channels and achieved high accuracy in classifying concussion. Here, we report on our efforts to develop a clinically practical system using a minimal subset of EEG sensors. EEG data from 23 athletes who had suffered a sport-related concussion and 35 non-concussed, control athletes were used for this study. We tested and ranked each of the original 64 channels based on its contribution toward the concussion classification performed by the original LSTM network. The top scoring channels were used to train and test a network with the same architecture as the previously trained network. We found that with only six of the top scoring channels the classifier identified concussions with an accuracy of 94%. These results show that it is possible to classify concussion using raw, resting state data from a small number of EEG sensors, constituting a first step toward developing portable, easy to use EEG systems that can be used in a clinical setting.
Do We Swallow the Waste From Our Brain?
Authors: Leaston Joshua , Kulkarni Praveen , Gharagouzloo Codi , Qiao Ju , Bens Nicole , Ferris Craig F.
Published: November 2021

Ferumoxytol, an iron oxide nanoparticle, was infused into the lateral cerebroventricle of awake rats to follow its movement and clearance from the brain using magnetic resonance imaging. Within minutes the contrast agent could be observed accumulating in the subarachnoid space, nasal cavity, nasal pharynx, and soft palate at the back of the throat. In a subsequent study fluorescent quantum dots were infused into the brain of rats and within 15 min could be observed in the esophagus using microscopy. These imaging studies clearly show that these large nanoparticle tracers (∼20 nm in diameter) leave the brain through the nasal cavity and end up in the gut. There are numerous studies going back decades reporting the clearance of tracers put directly into the brain. While these studies show the slow accumulation of trace in the blood and lymphatics, they report only accounting for less than 50% of what was originally put in the brain.
Proteomic Identification of an Endogenous Synaptic SUMOylome in the Developing Rat Brain
Authors: Pronot Marie , Kieffer Félicie , Gay Anne-Sophie , Debayle Delphine , Forquet Raphaël , Poupon Gwénola , Schorova Lenka , Martin Stéphane , Gwizdek Carole
Published: November 2021

Synapses are highly specialized structures that interconnect neurons to form functional networks dedicated to neuronal communication. During brain development, synapses undergo activity-dependent rearrangements leading to both structural and functional changes. Many molecular processes are involved in this regulation, including post-translational modifications by the Small Ubiquitin-like MOdifier SUMO. To get a wider view of the panel of endogenous synaptic SUMO-modified proteins in the mammalian brain, we combined subcellular fractionation of rat brains at the post-natal day 14 with denaturing immunoprecipitation using SUMO2/3 antibodies and tandem mass spectrometry analysis. Our screening identified 803 candidate SUMO2/3 targets, which represents about 18% of the synaptic proteome. Our dataset includes neurotransmitter receptors, transporters, adhesion molecules, scaffolding proteins as well as vesicular trafficking and cytoskeleton-associated proteins, defining SUMO2/3 as a central regulator of the synaptic organization and function.
Light Sheet Illumination for 3D Single-Molecule Super-Resolution Imaging of Neuronal Synapses
Authors: Gagliano Gabriella , Nelson Tyler , Saliba Nahima , Vargas-Hernández Sofía , Gustavsson Anna-Karin
Published: November 2021

The function of the neuronal synapse depends on the dynamics and interactions of individual molecules at the nanoscale. With the development of single-molecule super-resolution microscopy over the last decades, researchers now have a powerful and versatile imaging tool for mapping the molecular mechanisms behind the biological function. However, imaging of thicker samples, such as mammalian cells and tissue, in all three dimensions is still challenging due to increased fluorescence background and imaging volumes. The combination of single-molecule imaging with light sheet illumination is an emerging approach that allows for imaging of biological samples with reduced fluorescence background, photobleaching, and photodamage. In this review, we first present a brief overview of light sheet illumination and previous super-resolution techniques used for imaging of neurons and synapses. We then provide an in-depth technical review of the fundamental concepts and the current state of the art in the fields of three-dimensional single-molecule tracking and super-resolution imaging with light sheet illumination. We review how light sheet illumination can improve single-molecule tracking and super-resolution imaging in individual neurons and synapses, and we discuss emerging perspectives and new innovations that have the potential to enable and improve single-molecule imaging in brain tissue.
Application of Electroencephalography-Based Machine Learning in Emotion Recognition: A Review
Authors: Cai Jing , Xiao Ruolan , Cui Wenjie , Zhang Shang , Liu Guangda
Published: November 2021

Emotion recognition has become increasingly prominent in the medical field and human-computer interaction. When people’s emotions change under external stimuli, various physiological signals of the human body will fluctuate. Electroencephalography (EEG) is closely related to brain activity, making it possible to judge the subject’s emotional changes through EEG signals. Meanwhile, machine learning algorithms, which are good at digging out data features from a statistical perspective and making judgments, have developed by leaps and bounds. Therefore, using machine learning to extract feature vectors related to emotional states from EEG signals and constructing a classifier to separate emotions into discrete states to realize emotion recognition has a broad development prospect. This paper introduces the acquisition, preprocessing, feature extraction, and classification of EEG signals in sequence following the progress of EEG-based machine learning algorithms for emotion recognition. And it may help beginners who will use EEG-based machine learning algorithms for emotion recognition to understand the development status of this field. The journals we selected are all retrieved from the Web of Science retrieval platform. And the publication dates of most of the selected articles are concentrated in 2016–2021.
Protective Effects of Shrimp Peptide on Dextran Sulfate Sodium-Induced Colitis in Mice
Authors: Xiang Xingwei , Jiang Qihong , Shao Wan , Li Jinhong , Zhou Yufang , Chen Lin , Deng Shanggui , Zheng Bin , Chen Yufeng
Published: November 2021

Inflammatory bowel disease, an intestinal relapsing inflammatory disease, not only impairs gastrointestinal function but also increases the chances of developing colon cancer. Currently, the effects of shrimp peptide (SP) in mice model of ulcerative colitis (UC) are still unclear. In particular, it is uncertain whether SP affects the gut flora with UC mice. In this study, we investigated the anti-inflammatory effects of SP on a dextran sulfate sodium (DSS)-induced mouse model of UC. Firstly, the molecular weight of SP was mainly distributed in the range of 180–1,000 Da (61.95% proportion), and the amino acid composition showed that SP contained 17 amino acids, of which, the essential amino acids accounted for 54.50%. In vivo, oral SP significantly attenuated the severity of colitis, such as diarrhea, weight loss, and rectal bleeding. Furthermore, treatment with SP remarkably ameliorated intestinal barrier integrity, thus lowering the levels of the inflammatory cytokines and ameliorating antioxidant indices and intestinal injury indicators in the serum and colon. Lastly, the cecal contents were used to sequence and analyze the 16S rRNA genes of bacteria. Results suggested that treatment with SP could restore the balance of intestinal flora in modeled mice by regulating the abundance of pathogenic and beneficial bacteria. Furthermore, SP could significantly improve intestinal flora dysfunction in mice with UC. In summary, our findings show that SP has a prophylactic and therapeutic effect in UC in vivo, thereby highlighting its broad medicinal applications.
Dairy Consumption, Lactase Persistence, and Mortality Risk in a Cohort From Southern Sweden
Authors: Sonestedt Emily , Borné Yan , Wirfält Elisabet , Ericson Ulrika
Published: November 2021

Background: Whether high dairy consumption is related to longevity is still unclear, and additional studies of prospective cohorts with high-quality dietary data from populations with wide consumption ranges are needed.

Objective: To examine the association between dairy consumption and mortality in a Swedish cohort.

Design: Among 26,190 participants (62% females, 45–73 years old) without diabetes and cardiovascular disease from the population-based Malmö Diet and Cancer cohort, 7,156 individuals died during a mean follow-up time of 19 years. Data on intake of dairy (non-fermented milk, fermented milk, cheese, cream and butter) were collected from 7 day food records and food questionnaires. A genetic marker (rs4988235) associated with lactase persistence was detected among 22,234 individuals born in Sweden.

Results: Higher intakes up to 1,000 g/day of non-fermented milk were associated with only marginal higher mortality rates after adjusting for potential confounders. However, intakes above 1,000 g/day (1.5% of the population) were associated with 34% (95% CI: 14, 59%, p-trend=0.002) higher mortality compared to that with < 200 g/day. Fermented milk and cheese intake were inversely associated with mortality. Cream showed a protective association only among men. Butter was not associated with mortality. CT/TT genotype carriers (i.e., individuals with lactase persistence) had a 27% higher reported consumption of non-fermented milk, and non-significant higher mortality risk (HR = 1.08; 95% CI = 0.96, 1.23; p = 0.20) than CC genotype carriers.

Conclusions: Higher mortality rates were mainly observed among participants consuming more than 1,000 g of non-fermented milk per day. In contrast, fermented milk and cheese were associated with lower mortality. Because dairy products differ in composition, it is important to examine them separately in their relation to health and disease. The use of a genetic variant as an objective marker of lactose-containing milk intake should be examined in relation to mortality in a larger population.
The Impact of Mismatch Repair Status on Prognosis of Patients With Gastric Cancer: A Multicenter Analysis
Authors: Guan Wen-Long , Ma Yue , Cui Yue-Hong , Liu Tian-Shu , Zhang Yan-Qiao , Zhou Zhi-Wei , Xu Jian-Ying , Yang Li-Qiong , Li Jia-Yu , Sun Yu-Ting , Xu Rui-Hua , Wang Feng-Hua , Qiu Miao-Zhen
Published: November 2021

Background

The clinical role of deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) in gastric cancer (GC) is still controversial. We aimed to analyze the relationship between dMMR/MSI-H and clinicopathological features along with survival.

Methods

Patients who were diagnosed with GC at the three big cancer centers in China from 2015 to 2020 were evaluated retrospectively. MMR/MSI status was assessed using immunohistochemistry/PCR. Clinical and pathological data were collected from the medical record system.

Results

A total of 196 patients with dMMR/MSI-H status were enrolled for analysis. The prevalence of MSI-H/dMMR in GC was 6.6%. Another 694 proficient MMR (pMMR) GC patients were enrolled for comparison. Compared with pMMR patients, dMMR/MSI-H patients were associated with older age, female predominance, distal location in the stomach, earlier TNM stage, intestinal subtype, better differentiation, and more negative HER2 status. The median overall survival (OS) of the dMMR/MSI-H group was better than that of the pMMR/microsatellite stability (MSS) group (not reached vs. 53.9 months, p = 0.014). Adjuvant chemotherapy had no impact in both disease-free survival (DFS) and OS of dMMR/MSI-H patients (p = 0.135 and 0.818, respectively). dMMR/MSI-H patients had poorer response and progression-free survival (PFS) of first-line chemotherapy, though they were statistically significant (p = 0.361 and 0.124, respectively).

Conclusions

dMMR/MSI-H GC patients have specific clinicopathological characteristics and better prognosis than pMMR patients.
Case Report: Malignant Primary Sellar Paraganglioma With Unusual Genetic and Imaging Features
Authors: Stojanoski Stefan , Boldt Henning Bünsow , Kozic Dusko , Patócs Attila , Korbonits Márta , Medic-Stojanoska Milica , Casar-Borota Olivera
Published: November 2021

Background

Paraganglioma occurs rarely in the sellar/parasellar region. Here, we report a patient with malignant paraganglioma with primary sellar location with unusual genetic and imaging features.

Case Presentation

A 31-year-old male presented with mild hypertension, headache, nausea, and vomiting. A sellar/parasellar tumor mass was revealed by magnetic resonance imaging (MRI), while an endocrine work-up found partial hypopituitarism, suggesting that it was a non-functioning pituitary tumor. Antihypertensive therapy and hormone replacement were initiated. Tumor reduction was achieved with transsphenoidal neurosurgery. However, histological diagnosis was not possible due to extensive tissue necrosis. After 4 years of stable disease, the residual tumor showed re-growth requiring gamma knife radiosurgery. Four years after the radiosurgery, MRI showed a significant tumor progression leading to a second neurosurgery. This time, pathological and immunohistochemical findings revealed paraganglioma. Plasma levels of metanephrine and normetanephrine were normal. A gene sequencing panel performed on DNA extracted from blood excluded germline mutations in 17 susceptibility genes. The patient developed new tumor masses in the neck, and the third surgery was performed. Immunohistochemistry demonstrated lack of ATRX (alpha thalassemia/mental retardation syndrome X-linked) protein in tumor cells, indicating an ATRX gene mutation. Molecular genetic analysis performed on tumor DNA revealed a combination of ATRX and TP53 gene abnormalities; this was not previously reported in paraganglioma. MRI and 68Ga-DOTANOC PET/CT revealed the full extent of the disease. Therapy with somatostatin LAR and 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) was initiated.

Conclusion

Although rare, paraganglioma should be considered in the differential diagnosis of sellar/parasellar tumor lesions, even in the absence of typical imaging features. ATRX gene mutation in paraganglioma is an early predictor of malignant behavior and a potential novel therapeutic marker when pharmacological therapy targeting mutated ATRX becomes available.
High-LET Carbon and Iron Ions Elicit a Prolonged and Amplified p53 Signaling and Inflammatory Response Compared to low-LET X-Rays in Human Peripheral Blood Mononuclear Cells
Authors: Macaeva Ellina , Tabury Kevin , Michaux Arlette , Janssen Ann , Averbeck Nicole , Moreels Marjan , De Vos Winnok H. , Baatout Sarah , Quintens Roel
Published: November 2021

Understanding the differences in biological response to photon and particle radiation is important for optimal exploitation of particle therapy for cancer patients, as well as for the adequate application of radiation protection measures for astronauts. To address this need, we compared the transcriptional profiles of isolated peripheral blood mononuclear cells 8 h after exposure to 1 Gy of X-rays, carbon ions or iron ions with those of non-irradiated cells using microarray technology. All genes that were found differentially expressed in response to either radiation type were up-regulated and predominantly controlled by p53. Quantitative PCR of selected genes revealed a significantly higher up-regulation 24 h after exposure to heavy ions as compared to X-rays, indicating their prolonged activation. This coincided with increased residual DNA damage as evidenced by quantitative γH2AX foci analysis. Furthermore, despite the converging p53 signature between radiation types, specific gene sets related to the immune response were significantly enriched in up-regulated genes following irradiation with heavy ions. In addition, irradiation, and in particular exposure to carbon ions, promoted transcript variation. Differences in basal and iron ion exposure-induced expression of DNA repair genes allowed the identification of a donor with distinct DNA repair profile. This suggests that gene signatures may serve as a sensitive indicator of individual DNA damage repair capacity. In conclusion, we have shown that photon and particle irradiation induce similar transcriptional pathways, albeit with variable amplitude and timing, but also elicit radiation type-specific responses that may have implications for cancer progression and treatment
A Multivariate Diagnostic Model Based on Urinary EpCAM-CD9-Positive Extracellular Vesicles for Prostate Cancer Diagnosis
Authors: Dai Yibei , Wang Yiyun , Cao Ying , Yu Pan , Zhang Lingyu , Liu Zhenping , Ping Ying , Wang Danhua , Zhang Gong , Sang Yiwen , Wang Xuchu , Tao Zhihua
Published: November 2021

Introduction

Prostate cancer (PCa) is one of the most frequently diagnosed cancers and the leading cause of cancer death in males worldwide. Although prostate-specific antigen (PSA) screening has considerably improved the detection of PCa, it has also led to a dramatic increase in overdiagnosing indolent disease due to its low specificity. This study aimed to develop and validate a multivariate diagnostic model based on the urinary epithelial cell adhesion molecule (EpCAM)-CD9–positive extracellular vesicles (EVs) (uEVEpCAM-CD9) to improve the diagnosis of PCa.

Methods

We investigated the performance of uEVEpCAM-CD9 from urine samples of 193 participants (112 PCa patients, 55 benign prostatic hyperplasia patients, and 26 healthy donors) to diagnose PCa using our laboratory-developed chemiluminescent immunoassay. We applied machine learning to training sets and subsequently evaluated the multivariate diagnostic model based on uEVEpCAM-CD9 in validation sets.

Results

Results showed that uEVEpCAM-CD9 was able to distinguish PCa from controls, and a significant decrease of uEVEpCAM-CD9 was observed after prostatectomy. We further used a training set (N = 116) and constructed an exclusive multivariate diagnostic model based on uEVEpCAM-CD9, PSA, and other clinical parameters, which showed an enhanced diagnostic sensitivity and specificity and performed excellently to diagnose PCa [area under the curve (AUC) = 0.952, P < 0.0001]. When applied to a validation test (N = 77), the model achieved an AUC of 0.947 (P < 0.0001). Moreover, this diagnostic model also exhibited a superior diagnostic performance (AUC = 0.917, P < 0.0001) over PSA (AUC = 0.712, P = 0.0018) at the PSA gray zone.

Conclusions

The multivariate model based on uEVEpCAM-CD9 achieved a notable diagnostic performance to diagnose PCa. In the future, this model may potentially be used to better select patients for prostate transrectal ultrasound (TRUS) biopsy.
The Correlation Between Bronchopulmonary Dysplasia and Platelet Metabolism in Preterm Infants
Authors: Yan Longli , Ren Zhuxiao , Wang Jianlan , Xia Xin , Yang Liling , Miao Jiayu , Xu Fang , Gao Weiwei , Yang Jie
Published: November 2021

Background: Platelets play an important role in the formation of pulmonary blood vessels, and thrombocytopenia is common in patients with pulmonary diseases. However, a few studies have reported on the role of platelets in bronchopulmonary dysplasia.

Objective: The objective of the study was to explore the relationship between platelet metabolism and bronchopulmonary dysplasia in premature infants.

Methods: A prospective case-control study was performed in a cohort of premature infants (born with a gestational age <32 weeks and a birth weight <1,500 g) from June 1, 2017 to June 1, 2018. Subjects were stratified into two groups according to the diagnostic of bronchopulmonary dysplasia: with bronchopulmonary dysplasia (BPD group) and without bronchopulmonary dysplasia (control group). Platelet count, circulating megakaryocyte count (MK), platelet-activating markers (CD62P and CD63), and thrombopoietin (TPO) were recorded and compared in two groups 28 days after birth; then serial thrombopoietin levels and concomitant platelet counts were measured in infants with BPD.

Results: A total of 252 premature infants were included in this study. Forty-eight premature infants developed BPD, 48 premature infants without BPD in the control group who were matched against the study infants for gestational age, birth weight, and admission diagnosis at the age of postnatal day 28. Compared with the controls, infants with BPD had significantly lower peripheral platelet count [BPD vs. controls: 180.3 (24.2) × 109/L vs. 345.6 (28.5) × 109/L, p = 0.001]. Circulating MK count in the BPD group was significantly more abundant than that in the control group [BPD vs. controls: 30.7 (4.5)/ml vs. 13.3 (2.6)/ml, p = 0.025]. The level of CD62p, CD63, and TPO in BPD group was significantly higher than the control group [29.7 (3.1%) vs. 14.5 (2.5%), 15.4 (2.0%) vs. 5.8 (1.7%), 301.4 (25.9) pg/ml vs. 120.4 (14.2) pg/ml, all p < 0.05]. Furthermore, the concentration of TPO was negatively correlated with platelet count in BPD group with thrombocytopenia.

Conclusions: Our findings suggest that platelet metabolism is involved in the development of BPD in preterm infants. The possible mechanism might be through increased platelet activation and promoted TPO production by feedback.
Case Report: Propranolol Therapy for Infantile Tremor Syndrome in a Child With Vitamin B12 Deficiency
Authors: Cyr Amélie , Frehlick Ryan , Stammers David , Crone Megan
Published: November 2021

Vitamin B12 deficiency in childhood presents with a wide variety of symptoms including anemia, failure to thrive and developmental delays. It is a diagnostic consideration in children who are exclusively breastfed or have minimal solid intake, especially if their mother is vegetarian or has underlying vitamin B12 deficiency. Infantile tremor syndrome (ITS) has been associated with vitamin B12 deficiency. ITS presents with neurological symptoms such as developmental delays and tremors. The tremors seen in ITS can be profound and interfere with daily functioning. Different therapies have been tried for those tremors without much evidence or information regarding their efficacy and dosing regimens. We present the case of a 13-month-old girl with vitamin B12 deficiency who developed ITS with significant tremors after initiation of vitamin B12 therapy. She was treated with propranolol which resulted in significant improvement in her tremors. This case highlights the efficacy and safety of propranolol for the treatment of ITS in the context of vitamin B12 deficiency.
Association of Age and Sex With Multi-Modal Cerebral Physiology in Adult Moderate/Severe Traumatic Brain Injury: A Narrative Overview and Future Avenues for Personalized Approaches
Authors: Batson C. , Gomez A. , Sainbhi A. S. , Froese L. , Zeiler F. A.
Published: November 2021

The impact of age and biological sex on outcome in moderate/severe traumatic brain injury (TBI) has been documented in large cohort studies, with advanced age and male sex linked to worse long-term outcomes. However, the association between age/biological sex and high-frequency continuous multi-modal monitoring (MMM) cerebral physiology is unclear, with only sparing reference made in guidelines and major literature in moderate/severe TBI. In this narrative review, we summarize some of the largest studies associating various high-frequency MMM parameters with age and biological sex in moderate/severe TBI. To start, we present this by highlighting the representative available literature on high-frequency data from Intracranial Pressure (ICP), Cerebral Perfusion Pressure (CPP), Extracellular Brain Tissue Oxygenation (PbtO2), Regional Cerebral Oxygen Saturations (rSO2), Cerebral Blood Flow (CBF), Cerebral Blood Flow Velocity (CBFV), Cerebrovascular Reactivity (CVR), Cerebral Compensatory Reserve, common Cerebral Microdialysis (CMD) Analytes and their correlation to age and sex in moderate/severe TBI cohorts. Then we present current knowledge gaps in the literature, discuss biological implications of age and sex on cerebrovascular monitoring in TBI and some future avenues for bedside research into the cerebrovascular physiome after TBI.
Anticholesterolemic Activity of Three Vegetal Extracts (Artichoke, Caigua, and Fenugreek) and Their Unique Blend
Authors: Frigerio Jessica , Tedesco Erik , Benetti Federico , Insolia Violetta , Nicotra Giovanna , Mezzasalma Valerio , Pagliari Stefania , Labra Massimo , Campone Luca
Published: November 2021

Hepatic-related diseases, in particular hyperlipidemia and hypercholesterolemia, are a thorn on the side of the national health institutes around the globe. Indeed, liver lipid and cholesterol dysregulation could lead to atherosclerotic plaque formation and cardiovascular diseases. Currently, statin administration and monacolin K consumption are the main therapies proposed to counter this alarming connection, but relevant side effects are known. To overcome this issue, safe nutraceutical formulations and/or vegetal extracts, endowed with anticholesterolemic activity, could be instrumental in hypercholesterolemia prevention and treatment. In the present work, the anticholesterolemic efficacy of three vegetal extracts used in traditional medicine (artichoke, caigua, and fenugreek), their unique blend (ACFB), and the monacolin K-containing red yeast extract (RYR), was investigated with an in vitro approach based on hepatic cell line HepG2. The impact on cholesterol of the three extracts, their blend, and RYR were investigated by determining hepatocyte total and free cholesterol and bile acids biosynthesis. According to our results, the anticholesterolemic activity of the vegetal extracts was confirmed, and a novel choleretic activity of caigua extract was evidenced. ACFB showed to be safer than RYR while showing a similar effect on total and free cholesterol and bile acids synthesis compared to it. The anticholesterolemic activity of the blend was obtained with lower vegetal extract concentrations compared with the single vegetal extract, potentially indicating an additive effect between the extracts. In conclusion, the vegetal extracts and their blend, ACFB, are safe and are endowed with anticholesterolemic activity, potentially providing complementary therapies to the statin-based ones for hyperlipidemia and hypercholesterolemia-related complications.
Pulsatile Bi-Directional Aerosol Flow Affects Aerosol Delivery to the Intranasal Olfactory Region: A Patient-Specific Computational Study
Authors: Farnoud Ali , Tofighian Hesam , Baumann Ingo , Martin Andrew R. , Rashidi Mohammad M. , Menden Micheal P. , Schmid Otmar
Published: November 2021

The nasal olfactory region is a potential route for non-invasive delivery of drugs directly from the nasal epithelium to the brain, bypassing the often impermeable blood-brain barrier. However, efficient aerosol delivery to the olfactory region is challenging due to its location in the nose. Here we explore aerosol delivery with bi-directional pulsatile flow conditions for targeted drug delivery to the olfactory region using a computational fluid dynamics (CFD) model on the patient-specific nasal geometry. Aerosols with aerodynamic diameter of 1 µm, which is large enough for delivery of large enough drug doses and yet potentially small enough for non-inertial aerosol deposition due to, e.g., particle diffusion and flow oscillations, is inhaled for 1.98 s through one nostril and exhaled through the other one. The bi-directional aerosol delivery with steady flow rate of 4 L/min results in deposition efficiencies (DEs) of 50.9 and 0.48% in the nasal cavity and olfactory region, respectively. Pulsatile flow with average flow rate of 4 L/min (frequency: 45 Hz) reduces these values to 34.4 and 0.12%, respectively, and it mitigates the non-uniformity of right-left deposition in both the cavity (from 1.77- to 1.33-fold) and the olfactory region (from 624- to 53.2-fold). The average drug dose deposited in the nasal cavity and the olfactory epithelium region is very similar in the right nasal cavity independent of pulsation conditions (inhalation side). In contrast, the local aerosol dose in the olfactory region of the left side is at least 100-fold lower than that in the nasal cavity independent of pulsation condition. Hence, while pulsatile flow reduces the right-left (inhalation-exhalation) imbalance, it is not able to overcome it. However, the inhalation side (even with pulsation) allows for relatively high olfactory epithelium drug doses per area reaching the same level as in the total nasal cavity. Due to the relatively low drug deposition in olfactory region on the exhalation side, this allows either very efficient targeting of the inhalation side, or uniform drug delivery by performing bidirectional flow first from the one and then from the other side of the nose.
Case Report: Persistent Pulmonary Hypertension of the Newborn and Narrowing of the Ductus Arteriosus After Topical Use of Non-Steroidal Anti-Inflammatory During Pregnancy
Authors: Le Duc Kévin , Gilliot Sixtine , Baudelet Jean Benoit , Mur Sébastien , Boukhris Mohamed Riadh , Domanski Olivia , Odou Pascal , Storme Laurent
Published: November 2021

Background: The use of non-steroidal anti-inflammatory drugs (NSAIDs) during the third trimester of pregnancy can cause premature constriction of the ductus arteriosus. This report describes a case of in utero narrowing of the ductus arteriosus (DA) diagnosed postnatally in a baby with Persistent Pulmonary Hypertension of the Newborn (PPHN), after maternal use of Diclofenac-Epolamine 140 mg patch during the second and third trimester.

Case Presentation: A fetal ultrasounds revealed an enlarged hypertrophic right ventricle at 32 weeks of gestation. Detailed questioning of the mother highlighted that topical Diclofenac (FLECTOR®) had been used at 26 and at 31 weeks of gestation. An echocardiography performed 8 h postnatally showed supra-systemic pulmonary hypertension, a restrictive ductus arteriosus and a dilated right ventricle. The newborn was treated by inhaled nitric oxide and oral Sildenafil and was discharged from hospital on day 24. He had a complete normalization of his pulmonary vascular resistance on day 48.

Conclusion: This case illustrates the potential fetal and neonatal complications associated with maternal topical Diclofenac medication during pregnancy resulting in antenatal closure of the DA.
Clinical Validation of a Volumetric Absorptive Micro-Sampling Device for Pharmacokinetic Studies With Tranexamic Acid
Authors: Grassin-Delyle Stanislas , Lamy Elodie , Semeraro Michaela , Runge Iléana , Treluyer Jean-Marc , Mansukhani Raoul , Arribas Monica , Roberts Ian , Shakur-Still Haleema
Published: November 2021

We assessed the accuracy of tranexamic acid (TXA) concentrations measured in capillary whole blood using volumetric absorptive micro-sampling (VAMS) devices. Paired venous and VAMS capillary blood samples were collected from 15 healthy volunteers participating in a pharmacokinetic study of alternative routes (oral, IM and IV) of administering TXA. To assess accuracy across a range of concentrations, blood was drawn at different times after TXA administration. We measured TXA concentrations in plasma, whole blood from samples collected by venepuncture and whole blood from venous and capillary samples collected using VAMS devices. TXA was measured using a validated high sensitivity liquid chromatography - mass spectrometry method. We used Bland-Altman plots to describe the agreement between the TXA concentrations obtained with the different methods. In the 42 matched samples, the mean plasma TXA concentration was 14.0 mg/L (range 2.6–36.5 mg/L) whereas the corresponding whole blood TXA concentration was 7.7 mg/L (range 1.6–17.5 mg/L). When comparing TXA concentrations in VAMS samples of venous and capillary whole blood, the average bias was 0.07 mg/L (lower and upper 95% limits of agreement: −2.1 and 2.2 mg/L respectively). When comparing TXA concentrations in venous whole blood and VAMS capillary whole blood, the average bias was 0.7 mg/L (limits of agreement: −2.7 and 4.0 mg/L). Volumetric absorptive micro-sampling devices are sufficiently accurate for use in pharmacokinetic studies of tranexamic acid treatment in the range of plasma concentrations relevant for the assessment of fibrinolysis inhibition.
Recent Advances in Pharmacological Intervention of Osteoarthritis: A Biological Aspect
Authors: Deng Jinxia , Zong Zhixian , Su Zhanpeng , Chen Haicong , Huang Jianping , Niu Yanru , Zhong Huan , Wei Bo
Published: November 2021

Osteoarthritis (OA) is a degenerative joint disease in the musculoskeletal system with a relatively high incidence and disability rate in the elderly. It is characterized by the degradation of articular cartilage, inflammation of the synovial membrane, and abnormal structure in the periarticular and subchondral bones. Although progress has been made in uncovering the molecular mechanism, the etiology of OA is still complicated and unclear. Nevertheless, there is no treatment method that can effectively prevent or reverse the deterioration of cartilage and bone structure. In recent years, in the field of pharmacology, research focus has shifted to disease prevention and early treatment rather than disease modification in OA. Biologic agents become more and more attractive as their direct or indirect intervention effects on the initiation or development of OA. In this review, we will discuss a wide spectrum of biologic agents ranging from DNA, noncoding RNA, exosome, platelet-rich plasma (PRP), to protein. We searched for key words such as OA, DNA, gene, RNA, exosome, PRP, protein, and so on. From the pharmacological aspect, stem cell therapy is a very special technique, which is not included in this review. The literatures ranging from January 2016 to August 2021 were included and summarized. In this review, we aim to help readers have a complete and precise understanding of the current pharmacological research progress in the intervention of OA from the biological aspect and provide an indication for the future translational studies.
Bias, Precision and Timeliness of Historical (Background) Rate Comparison Methods for Vaccine Safety Monitoring: An Empirical Multi-Database Analysis
Authors: Li Xintong , Lai Lana YH , Ostropolets Anna , Arshad Faaizah , Tan Eng Hooi , Casajust Paula , Alshammari Thamir M. , Duarte-Salles Talita , Minty Evan P. , Areia Carlos , Pratt Nicole , Ryan Patrick B. , Hripcsak George , Suchard Marc A. , Schuemie Martijn J. , Prieto-Alhambra Daniel
Published: November 2021

Using real-world data and past vaccination data, we conducted a large-scale experiment to quantify bias, precision and timeliness of different study designs to estimate historical background (expected) compared to post-vaccination (observed) rates of safety events for several vaccines. We used negative (not causally related) and positive control outcomes. The latter were synthetically generated true safety signals with incident rate ratios ranging from 1.5 to 4. Observed vs. expected analysis using within-database historical background rates is a sensitive but unspecific method for the identification of potential vaccine safety signals. Despite good discrimination, most analyses showed a tendency to overestimate risks, with 20%-100% type 1 error, but low (0% to 20%) type 2 error in the large databases included in our study. Efforts to improve the comparability of background and post-vaccine rates, including age-sex adjustment and anchoring background rates around a visit, reduced type 1 error and improved precision but residual systematic error persisted. Additionally, empirical calibration dramatically reduced type 1 to nominal but came at the cost of increasing type 2 error.
Network Pharmacology-Based Analysis of Pogostemon cablin (Blanco) Benth Beneficial Effects to Alleviate Nonalcoholic Fatty Liver Disease in Mice
Authors: Cui Yizhe , Wang Qiuju , Chang Renxu , Aboragah Ahmad , Loor Juan J. , Xu Chuang
Published: November 2021

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is associated with high morbidity and mortality. Pogostemon cablin (Blanco) Benth/Huo Xiang (HX) is a perennial herb with unique anti-oxidant and anti-inflammatory properties, and thus, can positively affect liver function. In this study, we used network pharmacology to predict the potential mechanism of HX on NAFLD. Pharmacological experiments were used to verify the effect of HX on the functions of NAFLD. Network pharmacology identified nine components that interacted with 82 NAFLD-related targets, revealing four target genes: TNF, IL6, TP53, and AKT1. HX prevents the development and progression of NAFLD through different pathways and targets with quercetin-regulated lipid metabolism, anti-inflammatory, and anti-oxidant pathways playing an essential role in the treatment of NAFLD. Compared with feeding HFD, HX significantly attenuated lipid accumulation in vivo with mice and also in vitro with mouse liver cells. A high dose of HX decreased hepatocyte lipid accumulation and the abundance of SREBF1 and FASN. Validation experiments revealed that HX inhibited the activation of NF-κB/IκB signaling and decreased the release and levels of pro-inflammatory factors (TNF-α and IL-6). These data suggest that HX can attenuate abnormal lipid metabolic responses and enhance antioxidant mechanisms. Thus, the pharmacological effects from plants used in traditional Chinese medicine are achievde through a multi-level response.
Empirical and Theoretical Analysis of Particle Diffusion in Mucus
Authors: Cobarrubia Antonio , Tall Jarod , Crispin-Smith Austin , Luque Antoni
Published: November 2021

Mucus is a complex fluid that coats multiple organs in animals. Various physicochemical properties can alter the diffusion of microscopic particles in mucus, impacting drug delivery, virus infection, and disease development. The simultaneous effect of these physicochemical properties in particle diffusion, however, remains elusive. Here, we analyzed 106 published experiments to identify the most dominant factors controlling particle diffusion in mucus. The effective diffusion—defined using a one-second sampling time window across experiments—spanned seven orders of magnitude, from 10–5to 102 μm2/s. Univariate and multivariate statistical analyses identified the anomalous exponent (the logarithmic slope of the mean-squared displacement) as the strongest predictor of effective diffusion, revealing an exponential relationship that explained 89%of the variance. A theoretical scaling analysis revealed that a stronger correlation of the anomalous exponent over the generalized diffusion constant occurs for sampling times two orders of magnitude larger than the characteristic molecular (or local) displacement time. This result predicts that at these timescales, the molecular properties controlling the anomalous exponent, like particle–mucus unbinding times or the particle to mesh size ratio, would be the most relevant physicochemical factors involved in passive microrheology of particles in mucus. Our findings contrast with the fact that only one-third of the studies measured the anomalous exponent, and most experiments did not report the associated molecular properties predicted to dominate the motion of particles in mucus. The theoretical foundation of our work can be extrapolated to other systems, providing a guide to identify dominant molecular mechanisms regulating the mobility of particles in mucus and other polymeric fluids.
Construction of Optical Topological Cavities Using Photonic Crystals
Authors: Yuan Meng , Xu Tao , Hang Zhi Hong
Published: November 2021

A novel design of the Fabry–Pérot optical cavity is proposed, utilizing both the topological interface state structures and photonic bandgap materials with a controllable reflection phase. A one-to-one correspondence between the traditional Fabry–Pérot cavity and optical topological cavity is found, while the tunable reflection phase of the photonic crystal mirrors provides an extra degree of freedom on cavity mode selection. The relationship between the Zak phase and photonic bandgap provides theoretical guidance to the manipulation of the reflection phase of photonic crystals. The dispersions of interface states with different topology origins are explored. Linear interfacial dispersion emerging in photonic crystals with the valley–spin Hall effect leads to an extra n = 0 cavity mode compared to the Zak phase–induced deterministic interface states with quadratic dispersion. The frequency of the n = 0 cavity mode is not affected by the cavity length, whose quality factor can also be tuned by the thickness of the photonic crystal mirrors. With the recent help of topology photonics in the tuning reflection phase and dispersion relationship, we hope our results can provide more intriguing ideas to construct topological optical devices.
Identifying Influential SLD Authoritative Name Servers on the Internet
Authors: Xu Haiyan , Zhang Zhaoxin , Han Bing , Yan Jianen
Published: November 2021

DNS plays an important role on the Internet. The addressing of most applications depends on the proper operation of DNS. The root servers and the top-level domain servers are relied upon by many domains on the Internet, and their security affects the whole Internet. As a result, more attention has been paid to the security of servers at these two levels. However, the security of second-level domains and their servers also needs to be brought to the forefront. This paper focuses on showing the complex resolving dependencies and identifying influential name servers for second-level domains. We start by detecting domain name resolution paths and building up a name dependency graph. Then we construct domain name resolution networks of different numbers and sizes, which are connected by a certain number of domain name resolution graphs. On this basis, the network is analyzed from the perspective of complex network analysis, and a multi-indicators node importance evaluation method based on partial order is proposed to identify the influential name servers of the network. Once these name servers are not properly configured and fail or are compromised by DDoS attacks, it will cause resolution failure for a wide range of domain names.