bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual-Task Gait as a Predictive Tool for Cognitive Impairment in Older Adults: A Systematic Review
Authors: Ramírez Felipe , Gutiérrez Myriam
Published: December 2021

The use of the dual-task model as a cognitive-motor interface has been extensively investigated in cross-sectional studies as a training task in cognitive impairment. However, few existing longitudinal studies prove the usefulness of this tool as a clinical marker of cognitive impairment in older people. What is the evidence in prospective studies about dual-task gait as a predictor of cognitive impairment in older adults? This study aims to review and discuss the current state of knowledge in prospective studies on the use of dual-task gait as a predictive tool for cognitive impairment in older adults. The methodology used was a systematic review, according to the PRISMA criteria for the search, summarize and report. A search in 3 databases (Pubmed, Web of Science, and Scopus) was carried out until April 2021. The search terms used were: “(gait OR walking) AND (cognitive decline) AND (dual-task) AND (follow-up OR longitudinal OR long-term OR prospective OR cohort OR predict).” We included prospective research articles with older people with cognitive evaluation at the beginning and the end of the follow-up and dual-task gait paradigm as initial evaluation associated with the presentation of cognitive impairment prediction using any dual-task gait parameters. After exclusion criteria, 12 studies were reviewed. The results indicate that eight studies consider dual-task gait parameters a useful cognitive-motor tool, finding that some of the evaluated parameters of dual-task gait significantly correlate with cognitive impairment over time. The most promising DT parameters associated with cognitive impairment prediction seem to be gait speed, speed cost, DT time, numbers of words during DT, among others. In sum, this study reviews the variety of dual-task gait parameters and their relevance as a simple tool for early cognitive impairment screening, opening a diagnostic window for the screening of cognitive impairment in older people.
Co-occurring Hearing Loss and Cognitive Decline in Older Adults: A Dual Group-Based Trajectory Modeling Approach
Authors: Tran Yvonne , Tang Diana , Lo Charles , McMahon Catherine , Mitchell Paul , Gopinath Bamini
Published: December 2021

Hearing loss and cognitive impairments are both highly prevalent neurological complications for older adults. While there is growing evidence to suggest that these two conditions are interrelated, little research has been conducted that directly examines the progression and developmental trajectories of these complications contemporaneously. The aim of the study is to identify the distinct trajectory profiles for hearing loss and cognitive function in an older population over a 10-year period. Through dual trajectory modeling, the interrelationship, co-occurring movements, and overlaps between these two complications were examined. We also investigated the influence of hearing aid ownership on cognitive function trajectories. We utilized longitudinal data from 1,445 participants in the Blue Mountains Hearing Study (aged 55+ years) involving repeated measures from a population-based survey with audiometric hearing assessments. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). The group-based trajectory modeling (GBTM) identified three trajectory profiles for both hearing loss and cognitive function in two older age groups (55–69 years and 70+ years). The outputs from the dual trajectories models showed the conditional probability for “no hearing loss” trajectories to be around 90% more likely to have “high-normal” cognitive function, demonstrating co-occurring overlap. In contrast, for “moderate to severe hearing loss” trajectories, the conditional probability drops to 65% and 79% for the 55–69 age group and 70+ age group respectively. There was also an increasing probability for “cognitive decline” conditional on the severity of hearing loss with 6.7%, 7.5%, and 8.7% for no hearing loss, mild hearing loss, and moderate to severe hearing loss trajectory groups. While we did not find any statistically significant difference in the influence of hearing aid use in the cognitive function trajectories, there was a consistent greater representation of non-hearing aid users in the trajectories with poorer cognitive function. This study found GBTM to identify trajectories that were in agreement with our current understanding of hearing loss and cognitive impairment in older adults. This study also adds to the existing evidence-base as dual trajectories demonstrated co-occurrence in developmental changes in these two common neurological complications for the older population.
Recollections on the Origins and Development of the Prosomeric Model
Authors: Puelles Luis
Published: December 2021

The prosomeric model was postulated jointly by L. Puelles and J. L. R. Rubenstein in 1993 and has been developed since by means of minor changes and a major update in 2012. This article explains the progressive academic and scientific antecedents leading LP to this collaboration and its subsequent developments. Other antecedents due to earlier neuroembryologists that also proposed neuromeric brain models since the late 19th century, as well as those who defended the alternative columnar model, are presented and explained. The circumstances that apparently caused the differential success of the neuromeric models in the recent neurobiological field are also explored.
Sensory Experience as a Regulator of Structural Plasticity in the Developing Whisker-to-Barrel System
Authors: Chen Chia-Chien , Brumberg Joshua C.
Published: December 2021

Cellular structures provide the physical foundation for the functionality of the nervous system, and their developmental trajectory can be influenced by the characteristics of the external environment that an organism interacts with. Historical and recent works have determined that sensory experiences, particularly during developmental critical periods, are crucial for information processing in the brain, which in turn profoundly influence neuronal and non-neuronal cortical structures that subsequently impact the animals’ behavioral and cognitive outputs. In this review, we focus on how altering sensory experience influences normal/healthy development of the central nervous system, particularly focusing on the cerebral cortex using the rodent whisker-to-barrel system as an illustrative model. A better understanding of structural plasticity, encompassing multiple aspects such as neuronal, glial, and extra-cellular domains, provides a more integrative view allowing for a deeper appreciation of how all aspects of the brain work together as a whole.
Migraine and Medical Ramifications: A Comprehensive Overview Based on Observational Study Meta-Analyses
Authors: Chen Weiwei , Qian Wenqi , Zhong Lixian , Jing Gongwei
Published: December 2021

Purpose: An umbrella review was conducted for comprehensively evaluating previous review-based literature together with meta-analysis of observational investigations probing correlations between migraine and medical end-point ramifications in patients. The breadth and validity of these associations were assessed.

Methods: Multiple online scientific repositories (including PubMed, Medline, Embase, and Web of Science) were investigated (inception-August 2021) for related meta-analyses focusing on links between migraine and all possible health/medical ramification end-points. A summary effect size and 95% CIs were determined for each identified study with such links. Heterogeneity and small-study influence traces were also evaluated. The AMSTAR 2 platform was employed for evaluating standards of methodology, together with objective criteria, for assessing the standards of datasets from each medical end-point scrutinized in this study.

Results: A total of 25 scientific reports comprising 10,237,230 participants for 49 meta-analyses of observational studies were selected. Among such 49 outcomes, 30 demonstrated statistical significance (P < 0.05). Significant associations were observed in multiple diseases, including cardiovascular/cerebrovascular, cerebral, pregnancy-related and metabolic disorders, other outcomes, and mortality.

Conclusion: The results showed that migraine increased the risk of 29 health outcomes, though lowered the risk of breast cancer. However, evidence quality was graded as high only for angina. The evidence quality of ischaemic stroke, stroke, MACCE, WMAs, and asthma was graded as moderate. All remaining 24 outcomes had an evidence grade of “weak.”
Determination of the Initial Abnormal Discharge Site in Temporal Lobe Epilepsy Through Combined EEG and Neuroimaging. What Is Next?
Authors: Rentería-Palomo Ana A. , Montes-Ochoa Jose L. , Martinez-Mayorga Adriana , Reyes-Vaca Jorge Guillermo , Rodríguez-Leyva Ildefonso
Published: December 2021

Objective: The objective of this study was to determine the relationship between atrophy of the hippocampus and severity of epilepsy in patients with temporal lobe epilepsy (TLE) as the first step to evaluate the possibility of surgery for epilepsy and analyze why patients cannot undergo epilepsy surgery.

Methods: Volumetric MRI of the hippocampus was performed in 51 consecutive patients (29 men; mean age 40) with TLE. TLE diagnosis, lateralization, and severity (mild, moderate, severe) of seizures were based on a comprehensive evaluation that included neurologic examination and EEG in all patients. Patients with evidence of a lesion other than hippocampal sclerosis were not included in the study. We assessed the relationship between hippocampal volumes and electrophysiological evidence of seizure severity.

Results: According to the affected side based on the EEG, a statistically significant difference (p < 0.001) in volume and a positive correlation between epilepsy and hippocampal atrophy were found.

Conclusion: Our results confirm that volume loss to the hippocampus in patients with TLE correlates with the severity of epilepsy based on the EEG. Therefore, surgical treatment is considered early when hippocampal atrophy is evident in patients with refractory TLE. However, in Latin American countries, it is a challenge to get a patient to undergo epilepsy surgery. Therefore, we try to analyze the sad situation in our hospital.
Identification of Carotid Artery Microstructure and Plaque Rupture Using C-Arm Cone-Beam CT: A Case Report
Authors: Dong Jia , Bai Xuesong , Dmytriw Adam A. , Xuan Lanlan , Wang Tao , Lu Xia , Feng Yao , Jiao Liqun
Published: December 2021

C-arm cone-beam computed tomography (CBCT) offers a high imaging resolution with a wide range of contrast to visualize vessels, soft tissue, and bone. We report the usefulness of CBCT in observing neovascularization, microcalcification, and plaque rupture. A 56-year-old man presented with vertigo and complain of an unsteady gait for 5 months. Catheter angiography demonstrated right severe carotid stenosis with irregular filling defect, which on high-resolution MRI showed vessel wall enhancement. The CBCT showed high density structures and linear contrast enhancement from the vascular lumen to the plaque, related to microstructure and plaque rupture. Carotid endarterectomy was performed, and histopathology confirmed that the high-density areas represented neovascularization and microcalcification, with linear enhancement representing plaque rupture. This is the first report showing that microcalcifications and plaque rupture can be identified by CBCT. Thus, CBCT can be used as a promising supplement to current imaging modalities to evaluate plaque components more accurately.
Case Report: Hemispherotomy in the First Days of Life to Treat Drug-Resistant Lesional Epilepsy
Authors: Makridis Konstantin L. , Prager Christine , Tietze Anna , Atalay Deniz A. , Triller Sebastian , Elger Christian E. , Thomale Ulrich-Wilhelm , Kaindl Angela M.
Published: December 2021

Background: Neonatal drug-resistant epilepsy is often caused by perinatal epileptogenic insults such as stroke, ischemia, hemorrhage, and/or genetic defects. Rapid seizure control is particularly important for cognitive development. Since early surgical intervention and thus a short duration of epilepsy should lead to an optimal developmental outcome, we present our experience with hemispherotomy in an infant at the corrected age of 1 week.

Methods: We report successful hemispherotomy for drug-resistant epilepsy in an infant with hemimegalencephaly at a corrected age of 1 week.

Results: The infant was diagnosed with drug-resistant lesional epilepsy due to hemimegalencephaly affecting the left hemisphere. Given congruent electroclinical findings, we performed a left vertical parasagittal transventricular hemispherotomy after critical interdisciplinary discussion. No complications occurred during the surgery. Intraoperatively; 118 ml of red blood cells (30 ml/kg) and 80 ml of plasma were transfused. The patient has been seizure-free since discharge without further neurological deficits.

Conclusion: We demonstrate that early epilepsy surgery is a safe procedure in very young infants if performed in a specialized center experienced with age-specific surgical conditions and perioperative management. The specific surgical difficulties should be weighed against the risk of life-long developmental drawbacks of ongoing detrimental epilepsy.
DR-IIXRN : Detection Algorithm of Diabetic Retinopathy Based on Deep Ensemble Learning and Attention Mechanism
Authors: Ai Zhuang , Huang Xuan , Fan Yuan , Feng Jing , Zeng Fanxin , Lu Yaping
Published: December 2021

Diabetic retinopathy (DR) is one of the common chronic complications of diabetes and the most common blinding eye disease. If not treated in time, it might lead to visual impairment and even blindness in severe cases. Therefore, this article proposes an algorithm for detecting diabetic retinopathy based on deep ensemble learning and attention mechanism. First, image samples were preprocessed and enhanced to obtain high quality image data. Second, in order to improve the adaptability and accuracy of the detection algorithm, we constructed a holistic detection model DR-IIXRN, which consists of Inception V3, InceptionResNet V2, Xception, ResNeXt101, and NASNetLarge. For each base classifier, we modified the network model using transfer learning, fine-tuning, and attention mechanisms to improve its ability to detect DR. Finally, a weighted voting algorithm was used to determine which category (normal, mild, moderate, severe, or proliferative DR) the images belonged to. We also tuned the trained network model on the hospital data, and the real test samples in the hospital also confirmed the advantages of the algorithm in the detection of the diabetic retina. Experiments show that compared with the traditional single network model detection algorithm, the auc, accuracy, and recall rate of the proposed method are improved to 95, 92, and 92%, respectively, which proves the adaptability and correctness of the proposed method.
Influence of Malnutrition According to the GLIM Criteria on the Clinical Outcomes of Hospitalized Patients With Cancer
Authors: Liu Chengyu , Lu Zhenhua , Li Zijian , Xu Jingyong , Cui Hongyuan , Zhu Mingwei
Published: December 2021

Background: Malnutrition is prevalent among patients with cancer. The Global Leadership Initiative on Malnutrition (GLIM) released new universal criteria for diagnosing malnutrition in 2019. The objectives of this study were to assess the prevalence of malnutrition in patients with cancer using the GLIM criteria, explore the correlation between the GLIM criteria, and clinical outcomes, and compare the GLIM criteria with subjective global assessment (SGA).

Methods: This retrospective analysis was conducted on 2,388 patients with cancer enrolled in a multicenter study. Nutritional risk was screened using the Nutritional Risk Screening-2002, and the nutritional status was assessed using SGA and GLIM criteria. Chi-square analysis and Wilcoxon rank sum test, stratified by age 65 years, were used to evaluate the effect of GLIM-defined malnutrition on clinical outcomes. Logistic regression analysis was used to analyze the nutritional status and complications, and the interrater reliability was measured using a kappa test.

Results: The prevalence of malnutrition defined by the GLIM criteria was 38.9% (929/2,388). GLIM-defined malnutrition was significantly associated with in-hospital mortality (P = 0.001) and length of hospital stays (P = 0.001). Multivariate logistic regression analysis showed GLIM-defined malnutrition significantly increased complications (odds ratio [OR] 1.716, 95% CI 1.227–2.400, P = 0.002). The GLIM criteria had a “moderate agreement” (kappa = 0.426) compared with the SGA.

Conclusions: The prevalence of malnutrition in hospitalized patients with cancer is high, and malnourishment in patients with cancer is associated with poorer clinical outcomes. The use of the GLIM criteria in assessing the nutritional status of inpatients with cancer is recommended and can be used as the basis for nutritional interventions.
A Novel Blood Index-Based Model to Predict Hepatitis B Virus-Associated Hepatocellular Carcinoma Recurrence After Curative Hepatectomy: Guidance on Adjuvant Transcatheter Arterial Chemoembolization Choice
Authors: Zou Yiping , Chen Zhihong , Lou Qi , Han Hongwei , Zhang Yuanpeng , Chen Zhenrong , Ma Zuyi , Shi Ning , Jin Haosheng
Published: December 2021

Background

Postoperative recurrence is a significant obstacle in hepatocellular carcinoma (HCC) treatment. This study aimed to construct a blood index-based model to predict hepatitis B virus-associated HCC (HBV-HCC) recurrence after curative hepatectomy.

Methods

A total of 370 patients who received initially curative hepatectomy for HBV-HCC were included in this study. A novel blood index signature (BIS) was identified and systematically analyzed for its recurrence predictive value. Following this, multivariate Cox regression analysis was performed to build a blood index-based nomogram.

Results

A BIS based on the aminotransferase-to-platelet ratio index and a systemic inflammatory response index was used to construct a nomogram. The model showed good clinical applicability and reliability. Notably, the patients in the high recurrence risk group tended to benefit from adjuvant transcatheter arterial chemoembolization (TACE).

Conclusion

A reliable model was constructed to predict the HBV-HCC recurrence after curative hepatectomy. This model can guide the surgeons in selecting patients with high recurrence risk patients who may benefit from adjuvant TACE.
HIF-1α Is a Rational Target for Future Ovarian Cancer Therapies
Authors: Wang Xin , Du Zhen-wu , Xu Tian-min , Wang Xiao-jun , Li Wei , Gao Jia-li , Li Jing , Zhu He
Published: December 2021

Ovarian cancer is the eighth most commonly diagnosed cancer among women worldwide. Even with the development of novel drugs, nearly one-half of the patients with ovarian cancer die within five years of diagnosis. These situations indicate the need for novel therapeutic agents for ovarian cancer. Increasing evidence has shown that hypoxia-inducible factor-1α(HIF-1α) plays an important role in promoting malignant cell chemoresistance, tumour metastasis, angiogenesis, immunosuppression and intercellular interactions. The unique microenvironment, crosstalk and/or interaction between cells and other characteristics of ovarian cancer can influence therapeutic efficiency or promote the disease progression. Inhibition of the expression or activity of HIF-1α can directly or indirectly enhance the therapeutic responsiveness of tumour cells. Therefore, it is reasonable to consider HIF-1α as a potential therapeutic target for ovarian cancer. In this paper, we summarize the latest research on the role of HIF-1α and molecules which can inhibit HIF-1α expression directly or indirectly in ovarian cancer, and drug clinical trials about the HIF-1α inhibitors in ovarian cancer or other solid malignant tumours.
Glycosylation Changes in Prostate Cancer Progression
Authors: Butler William , Huang Jiaoti
Published: December 2021

Prostate Cancer (PCa) is the most commonly diagnosed malignancy and second leading cause of cancer-related mortality in men. With the use of next generation sequencing and proteomic platforms, new biomarkers are constantly being developed to both improve diagnostic sensitivity and specificity and help stratify patients into different risk groups for optimal management. In recent years, it has become well accepted that altered glycosylation is a hallmark of cancer progression and that the glycan structures resulting from these mechanisms show tremendous promise as both diagnostic and prognostic biomarkers. In PCa, a wide range of structural alterations to glycans have been reported such as variations in sialylation and fucosylation, changes in branching, altered levels of Lewis and sialyl Lewis antigens, as well as the emergence of high mannose “cryptic” structures, which may be immunogenic and therapeutically relevant. Furthermore, aberrant expression of galectins, glycolipids, and proteoglycans have also been reported and associated with PCa cell survival and metastasis. In this review, we discuss the findings from various studies that have explored alteredN-andO-linked glycosylation in PCa tissue and body fluids. We further discuss changes inO-GlcNAcylation as well as altered expression of galectins and glycoconjugates and their effects on PCa progression. Finally, we emphasize the clinical utility and potential impact of exploiting glycans as both biomarkers and therapeutic targets to improve our ability to diagnose clinically relevant tumors as well as expand treatment options for patients with advanced disease.
The Potential Clinical Utility of Pressure-Based vs. Heat-Based Paradigms to Measure Conditioned Pain Modulation in Healthy Individuals and Those With Chronic Pain
Authors: El-Sayed Rima , Fauchon Camille , Kim Junseok A. , Firouzian Shahrzad , Osborne Natalie R. , Besik Ariana , Mills Emily P. , Bhatia Anuj , Davis Karen D.
Published: December 2021

Conditioned pain modulation (CPM) is a physiological measure thought to reflect an individual's endogenous pain modulation system. CPM varies across individuals and provides insight into chronic pain pathophysiology. There is growing evidence that CPM may help predict individual pain treatment outcome. However, paradigm variabilities and practical issues have impeded widespread clinical adoption of CPM assessment. This study aimed to compare two CPM paradigms in people with chronic pain and healthy individuals. A total of 30 individuals (12 chronic pain, 18 healthy) underwent two CPM paradigms. The heat CPM paradigm acquired pain intensity ratings evoked by a test stimulus (TS) applied before and during the conditioning stimulus (CS). The pressure CPM paradigm acquired continuous pain intensity ratings of a gradually increasing TS, before and during CS. Pain intensity was rated from 0 (no pain) to 100 (worst pain imaginable); Pain50 is the stimulus level for a response rated 50. Heat and pressure CPM were calculated as a change in TS pain intensity ratings at Pain50, where negative CPM scores indicate pain inhibition. We also determined CPM in the pressure paradigm as change in pressure pain detection threshold (PDT). We found that in healthy individuals the CPM effect was significantly more inhibitory using the pressure paradigm than the heat paradigm. The pressure CPM effect was also significantly more inhibitory when based on changes at Pain50 than at PDT. However, in individuals with chronic pain there was no significant difference in pressure CPM compared to heat or PDT CPM. There was no significant correlation between clinical pain measures (painDETECT and Brief Pain Inventory) and paradigm type (heat vs. pressure), although heat-based CPM and painDETECT scores showed a trend. Importantly, the pressure paradigm could be administered in less time than the heat paradigm. Thus, our study indicates that in healthy individuals, interpretation of CPM findings should consider potential modality-dependent effects. However, in individuals with chronic pain, either heat or pressure paradigms can similarly be used to assess CPM. Given the practical advantages of the pressure paradigm (e.g., short test time, ease of use), we propose this approach to be well-suited for clinical adoption.
Case Report: Traumatic Stress and Developmental Regression: An Unintended Consequence of Complex Cardiac Care
Authors: Dahl Claire M. , Kroupina Maria , Said Sameh M. , Somani Arif
Published: December 2021

This brief case report outlines a novel approach to supporting the development of a pediatric complex cardiac care patient. Patient X is a 19-month old patient who spent 5.5 months in hospital and underwent multiple surgeries including heart transplantation. This case report explores the impacts of his condition and care on his development and family functioning within the framework of an integrated care model. This case report is uniquely complimented by outpatient neurodevelopmental follow up, dyadic trauma-informed intervention and use of telemedicine allowing for a deeper understanding of the family adaptation that provide novel insight into long-term trajectory beyond discharge. Throughout care Patient X met criteria for both a traumatic stress disorder and global developmental delay. This case study highlights the threat complex care poses to neurodevelopment, pediatric mental health and family dynamics as well as opportunities for intervention.
T-Cell-Replete Versus ex vivo T-Cell-Depleted Haploidentical Haematopoietic Stem Cell Transplantation in Children With Acute Lymphoblastic Leukaemia and Other Haematological Malignancies
Authors: Kleinschmidt Katharina , Lv Meng , Yanir Asaf , Palma Julia , Lang Peter , Eyrich Matthias
Published: December 2021

Allogeneic haematopoietic stem cell transplantation (HSCT) represents a potentially curative option for children with high-risk or refractory/relapsed leukaemias. Traditional donor hierarchy favours a human leukocyte antigen (HLA)-matched sibling donor (MSD) over an HLA-matched unrelated donor (MUD), followed by alternative donors such as haploidentical donors or unrelated cord blood. However, haploidentical HSCT (hHSCT) may be entailed with significant advantages: besides a potentially increased graft-vs.-leukaemia effect, the immediate availability of a relative as well as the possibility of a second donation for additional cellular therapies may impact on outcome. The key question in hHSCT is how, and how deeply, to deplete donor T-cells. More T cells in the graft confer faster immune reconstitution with consecutively lower infection rates, however, greater numbers of T-cells might be associated with higher rates of graft-vs.-host disease (GvHD). Two different methods for reduction of alloreactivity have been established: in vivo T-cell suppression and ex vivo T-cell depletion (TCD). Ex vivo TCD of the graft uses either positive selection or negative depletion of graft cells before infusion. In contrast, T-cell-repleted grafts consisting of non-manipulated bone marrow or peripheral blood grafts require intense in vivo GvHD prophylaxis. There are two major T-cell replete protocols: one is based on post-transplantation cyclophosphamide (PTCy), while the other is based on anti-thymocyte globulin (ATG; Beijing protocol). Published data do not show an unequivocal benefit for one of these three platforms in terms of overall survival, non-relapse mortality or disease recurrence. In this review, we discuss the pros and cons of these three different approaches to hHSCT with an emphasis on the significance of the existing data for children with acute lymphoblastic leukaemia.
Respiratory Support of Infants With Congenital Diaphragmatic Hernia
Authors: Williams Emma , Greenough Anne
Published: December 2021

Optimisation of respiratory support of infants with congenital diaphragmatic hernia (CDH) is critical. Infants with CDH often have severe lung hypoplasia and abnormal development of their pulmonary vasculature, leading to ventilation perfusion mismatch. It is vital that lung protective ventilation strategies are employed during both initial stabilisation and post-surgical repair to avoid ventilator induced lung damage and oxygen toxicity to prevent further impairment to an already diminished gas-exchanging environment. There is a lack of robust evidence for the routine use of surfactant therapy during initial resuscitation of infants with CDH and thus administration cannot be recommended outside clinical trials. Additionally, inhaled nitric oxide has been shown to have no benefit in reducing the mortality rates of infants with CDH. Other therapeutic agents which beneficially act on pulmonary hypertension are currently being assessed in infants with CDH in randomised multicentre trials. The role of novel ventilatory modalities such as closed loop automated oxygen control, liquid ventilation and heliox therapy may offer promise for infants with CDH, but the benefits need to be determined in appropriately designed clinical trials.
Snake Venom Proteomics of Samar Cobra (Naja samarensis) from the Southern Philippines: Short Alpha-Neurotoxins as the Dominant Lethal Component Weakly Cross-Neutralized by the Philippine Cobra Antivenom
Authors: Palasuberniam Praneetha , Chan Yi Wei , Tan Kae Yi , Tan Choo Hock
Published: December 2021

The Samar Cobra, Naja samarensis, is endemic to the southern Philippines and is a WHO-listed Category 1 venomous snake species of medical importance. Envenomation caused by N. samarensis results in neurotoxicity, while there is no species-specific antivenom available for its treatment. The composition and neutralization of N. samarensis venom remain largely unknown to date. This study thus aimed to investigate the venom proteome of N. samarensis for a comprehensive profiling of the venom composition, and to examine the immunorecognition as well as neutralization of its toxins by a hetero-specific antivenom. Applying C18 reverse-phase high-performance liquid chromatography (RP-HPLC) and tandem mass spectrometry (LC-MS/MS), three-finger toxins (3FTx) were shown to dominate the venom proteome by 90.48% of total venom proteins. Other proteins in the venom comprised snake venom metalloproteinases, phospholipases A2, cysteine-rich secretory proteins, venom nerve growth factors, L-amino acid oxidases and vespryn, which were present at much lower abundances. Among all, short-chain alpha-neurotoxins (SαNTX) were the most highly expressed toxin within 3FTx family, constituting 65.87% of the total venom proteins. The SαNTX is the sole neurotoxic component of the venom and has an intravenous median lethal dose (LD50) of 0.18 μg/g in mice. The high abundance and low LD50 support the potent lethal activity of N. samarensis venom. The hetero-specific antivenom, Philippine Cobra Antivenom (PCAV, raised against Naja philippinensis) were immunoreactive toward the venom and its protein fractions, including the principal SαNTX. In efficacy study, PCAV was able to cross-neutralize the lethality of SαNTX albeit the effect was weak with a low potency of 0.20 mg/ml (defined as the amount of toxin completely neutralized per milliliter of the antivenom). With a volume of 5 ml, each vial of PCAV may cross-neutralize approximately 1 mg of the toxin in vivo. The findings support the potential para-specific use of PCAV in treating envenomation caused by N. samarensis while underscoring the need to improve the potency of its neutralization activity, especially against the highly lethal alpha-neurotoxins.
Cost-Effectiveness Analysis of Camrelizumab Plus Chemotherapy vs. Chemotherapy Alone as the First-Line Treatment in Patients With IIIB–IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Without EGFR and ALK Alteration from a Perspective of Health - Care System in China
Authors: Zhu Chen , Xing Xiao-xuan , Wu Bin , Liang Gang , Han Gang , Lin Cai-xia , Fang Hong-mei
Published: December 2021

Objective: The CAMEL clinical trial (412 patients were randomly assigned to either camrelizumab plus chemotherapy (n = 205) or chemotherapy alone (n = 207)) demonstrated that camrelizumab plus chemotherapy (CC) improved the overall survival time (OS) and progression-free survival time (PFS) of patients with metastatic nonsquamous non-small cell lung cancer (non-sq NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations (EGFRm and ALKm) vs. chemotherapy (C) alone. Our objective was to conduct a cost-effectiveness analysis of CC vs. C from a perspective of health - care system in China with a lifetime horizon to identify whether it will be cost-effective.

Materials and Methods: A partitioned survival model (PSM) was applied for patients with IIIB–IV non-sq NSCLC without EGFRm and ALKm. Transition parameters and proportions of three health states were derived from the CAMEL trial. The model was designed using a lifetime horizon, a 21-day cycle, and a 5% discount rate of costs and outcomes. It was deemed cost-effective in China if the incremental cost-effectiveness ratio (ICER) value is less than $32,457 per quality adjusted life-year (QALY). Deterministic and probabilistic sensitivity analyses were performed to verify the influence of parameter uncertainty on the results.

Results: In the base-case analysis, we found that the ICER of CC compared with C is $-7,382.72/QALY which meant that CC had lower costs and better outcomes. The results of the sensitivity analyses demonstrated that the result was robust for the ICERs never transcending the willingness-to-pay (WTP) threshold.

Conclusion: Camrelizumab plus chemotherapy is an obviously cost-effective therapeutic regime for patients of IIIB–IV non-sq NSCLC without EGFRm and ALKm in China at a $32,457 WTP threshold.
Mechanisms Underlying the Action of Ziziphi Spinosae Semen in the Treatment of Insomnia: A Study Involving Network Pharmacology and Experimental Validation
Authors: Bian Zhenhua , Zhang Wenming , Tang Jingyue , Fei Qianqian , Hu Minmin , Chen Xiaowei , Su Lianlin , Fei Chenghao , Ji De , Mao Chunqin , Tong Huangjin , Yuan Xiaohang , Lu Tulin
Published: December 2021

Purpose: This study aimed to investigate the potential mechanisms and related bioactive components of ZSS for the treatment of insomnia.

Method: The insomnia model of rat induced by PCPA was established. After oral administration of ZSS extract, the general morphological observation, pentobarbital sodium-induced sleep test and histopathological evaluation were carried out. Network pharmacology, assisted by UHPLC-Q-Exactive-MS/MS analysis, was developed to identify the targets of ZSS in the treatment of insomnia, as well as the corresponding signaling pathways. In addition, we validated the identified targets and pathways by RT-qPCR and immunohistochemical analysis.

Results: The pentobarbital sodium-induced sleep test, determination of 5-HT and GABA levles in hypothalamic tissues and HE staining showed that ZSS extract was an effective treatment for insomnia. Network pharmacology analysis identified a total of 19 candidate bioactive ingredients in ZSS extract, along with 433 potentially related targets. Next, we performed protein-protein interaction (PPI), MCODE clustering analysis, GO functional enrichment analysis, KEGG pathway enrichment analysis, and ingredient-target-pathway (I-T-P) sub-networks analysis. These methods allowed us to investigate the synergistic therapeutic effects of crucial pathways, including the serotonergic and GABAergic synapse pathways. Our analyses revealed that palmitic acid, coclaurine, jujuboside A, N-nornuciferine, caaverine, magnoflorine, jujuboside B, and betulinic acid, all played key roles in the regulation of these crucial pathways. Finally, we used the PCPA-induced insomnia in rats to validate the data generated by network pharmacology; these in vivo experiments clearly showed that pathways associated with the serotonergic and GABAergic system were activated in the rats model. Furthermore, ZSS treatment significantly suppressed high levels of HTR1A, GABRA1, and GABRG2 expression in the hypothalamus and reduced the expression levels of HTR2A.

Conclusion: Based on the combination of comprehensive network pharmacology and in vivo experiments, we successfully identified the potential pharmacological mechanisms underlying the action of ZSS in the treatment of insomnia. The results provide a theoretical basis for further development and utilization of ZSS, and also provide support for the development of innovative drugs for the treatment of insomnia.
Signaling Potential Therapeutic Herbal Medicine Prescription for Treating COVID-19 by Collaborative Filtering
Authors: Yang Fan , Zhang Qi , Yuan Zhongshang , Teng Saisai , Cui Lizhen , Xue Fuzhong , Wei Leyi
Published: December 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has aggressed in more than 200 countries and territories since Dec 2019, and 30 million cases of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 have been reported, including 950,000 deaths. Supportive treatment remains the mainstay of therapy for COVID-19. There are no small-molecule–specific antiviral drugs available to prevent and treat COVID-19 until recently. Herbal medicine can facilitate syndrome differentiation and treatment according to the clinical manifestations of patients and has demonstrated effectiveness in epidemic prevention and control. The National Health Commission (NHC) of China has recommended “three TCM prescriptions and three medicines,” as a group of six effective herbal formulas against COVID-19 in the released official file “Diagnosis and Treatment Protocol for COVID-19 Patients: Herbal Medicine for the Priority Treatment of COVID-19.” This study aimed to develop a collaborative filtering approach to signaling drug combinations that are similar to the six herbal formulas as potential therapeutic treatments for treating COVID-19. The results have been evaluated by herbal medicine experts’ domain knowledge.
Vitamin B6 Alleviates Lipopolysaccharide-induced Myocardial Injury by Ferroptosis and Apoptosis Regulation
Authors: Shan Meirong , Yu Xujie , Li Yajie , Fu Changning , Zhang Cheng
Published: December 2021

Vitamin B6 (VitB6) is a water-soluble vitamin and includes pyridoxine, pyridoxal, pyridoxamine, and their phosphorylated forms. In the current study, we demonstrated that VitB6 could improve lipopolysaccharide (LPS)–induced myocardial injury. We demonstrated that VitB6 can suppress LPS-induced oxidative stress and lipid peroxidation that lead to ferroptosis and apoptosis in vivo and in vitro. Moreover, we found that VitB6 can regulate the expression of iron regulatory proteins, maintaining intracellular iron homeostasis. To confirm that VitB6 could inhibit LPS-induced ferroptosis and apoptosis, we pretreated mice with ferrostatin-1 (Fer-1) and emricasan that efficiently mimicked VitB6 pharmacological effects. This improved the survival rate of mice challenged with a high LPS dose. In addition, VitB6 regulated the expression of LPS-induced apoptosis-related proteins and iron regulatory proteins. It mediated the expression of Nrf2, transcription factor NF-E2–related factor 2, which promoted the expression of antioxidant enzymes and restrained LPS-induced ferroptosis and apoptosis. Overall, our results indicated that VitB6 can be used on novel therapies to relieve LPS-induced myocardial injury.
New Potential of Roxatidine Acetate Hydrochloride on Atopic Dermatitis Mouse Model, Human Keratinocytes, and Human Skin Equivalent Model
Authors: Kang Yun-Mi , Lee Minho , An Hyo-Jin
Published: December 2021

Atopic dermatitis (AD) is a complex inflammatory skin disorder, characterized by a complicated pathophysiology and a wide range of clinical phenotypes. Roxatidine acetate chloride (RXA) is a precursor of Roxatidine and a histamine H2 receptor antagonist, used for the treatment of gastric ulcers. In this study, we aimed to examine whether RXA had anti-AD effects and determine the underlying molecular mechanism of RXA. The anti-AD effects were examined in Dermatophagoides farinae body (Dfb)-induced AD mouse model, tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated HaCaT keratinocytes, and human skin equivalent model using ELISA, histological analysis, immunohistochemistry, Western blot, and immunofluorescence. Results showed that RXA treatment significantly alleviated Dfb-induced AD skin symptoms and clinical severity in mice by decreasing the levels of immunoglobulin E, histamine, and inflammatory cytokines. RXA effectively inhibited the expression of adhesive molecules and recovered the filaggrin expression in Dfb-induced AD skin lesions and TNF-α/IFN-γ-stimulated HaCaT keratinocytes. Additionally, RXA significantly upregulated the expression of aryl hydrocarbon receptor and sirtuin1. The anti-AD effects of RXA were associated with suppressed nuclear factor kappa cascade. Overall, our results suggest that RXA may be a potential anti-AD candidate owing to its inhibitory effect against skin inflammation and protection of the skin barrier function in AD.
Anlotinib Alone or in Combination With Temozolomide in the Treatment of Recurrent High-Grade Glioma: A Retrospective Analysis
Authors: Yang Qunying , Guo Chengcheng , Lin Xiaoping , Luo Lili , He Zhenqiang , Lin Fuhua , Zhang Ji , Chen Yinsheng , Jiang Xiaobing , Ke Chao , Mou Yonggao
Published: December 2021

Background: Anlotinib is a multi-target anti-angiogenic agent. This retrospective study aimed to evaluate the efficacy and safety of anlotinib alone or in combination with temozolomide for the treatment of recurrent high-grade glioma.

Materials and Methods: The clinical data of patients with recurrent high-grade glioma treated with anlotinib alone or in combination with temozolomide in our cancer center were collected and analyzed. Treatment response was evaluated according to the response assessment for neuro-oncology criteria. Progression-free survival, progression-free survival at 6 months, overall survival, and overall survival at 12 months were evaluated by Kaplan–Meier method and compared by log-rank test.

Results: Between August 2019 and December 2020, 31 patients with recurrent high-grade glioma (21 of grade 4 and 10 of grade 3) were enrolled in this study. Seventeen patients received anlotinib alone and 14 received anlotinib plus temozolomide. All patients were heavily treated, the median lines of previous treatments were 2, and the median Karnofsky score was 60. At the data cutoff date, the median progression-free survival was 4.5 months and the progression-free survival at 6 months was 43.5%. The median overall survival was 7.7 months, and the overall survival at 12 months was 26.7%. The progression-free survival at 6 months and the overall survival at 12 months for 21 patients with grade 4 glioma was 40.2 and 27.9%, respectively. The tumor objective response rate was 41.9% in all patients and 33.3% in patients with grade 4 glioma. No grade 3 or worse treatment-related adverse events were recorded during the treatment.

Conclusion: Anlotinib alone or in combination with temozolomide showed encouraging efficacy and favorable tolerability in patients with recurrent high-grade glioma who had been heavily treated.
Synchronizability of Multi-Layer Dual-Center Coupled Star Networks
Authors: Zhu Jian , Huang Da , Yu Zhiyong , Pei Ping
Published: December 2021

In the research on complex networks, synchronizability is a significant measurement of network nature. Several research studies center around the synchronizability of single-layer complex networks and few studies on the synchronizability of multi-layer networks. Firstly, this paper calculates the Laplacian spectrum of multi-layer dual-center coupled star networks and multi-layer dual-center coupled star–ring networks according to the master stability function (MSF) and obtains important indicators reflecting the synchronizability of the above two network structures. Secondly, it discusses the relationships among synchronizability and various parameters, and numerical simulations are given to illustrate the effectiveness of the theoretical results. Finally, it is found that the two sorts of networks studied in this paper are of the same synchronizability, and compared with that of a single-center network structure, the synchronizability of two dual-center structures is relatively weaker.
A Briefing Survey on Advances of Coupled Networks With Various Patterns
Authors: Dong Gaogao , Duan Dongli , Xia Yongxiang
Published: December 2021

In real-world scenarios, networks do not exist in isolation but coupled together in different ways, including dependent, multi-support, and inter-connected patterns. And, when a coupled network suffers from structural instability or dynamic perturbations, the system with different coupling patterns shows rich phase transition behaviors. In this review, we present coupled network models with different coupling patterns developed from real scenarios in recent years for studying the system robustness. For the coupled networks with different coupling patterns, based on the network percolation theory, this paper mainly describes the influence of coupling patterns on network robustness. Moreover, for different coupling patterns, we here show readers the research background, research context, and the latest research results and applications. Furthermore, different approaches to improve system robustness with various coupling patterns and future possible research directions for coupled networks are explained and considered.
3D Printing Improve the Effectiveness of Fracture Teaching and Medical Learning: A Comprehensive Scientometric Assessment and Future Perspectives
Authors: Shi Jian , Fu Shenao , Cavagnaro María José , Xu Shaokang , Zhao Mingyi
Published: December 2021

Fractures of complex body parts are often serious and difficult to handle, and they have high technical and training requirements. However, the realistic situation is that there are few opportunities for the junior residents, trainee doctors, and especially medical students to contact enough clinical practice and see such fracture patients. Fortunately, with the rapid development and continuous progress of 3D printing and related technologies, this situation has gradually gotten better and better. In this research, we confirmed that 3D printing technology could improve the effectiveness of fracture teaching and medical learning from multiple dimensions. We comprehensively screened and assessed 223 papers from the Web of Science (WoS) Core Collection on October 3, 2021, with “((3D) AND ((printing) OR (printed)) AND (fracture)) AND ((education) OR (training) OR (teaching))” as the retrieval strategy. Additionally, we used the VOSviewer software to analyze the keywords and countries and the organizations of the publications, then a series of scientometric and visualized analyses were made based on the retrieval results. Afterward, multiple databases were retrieved according to our selection criteria, we selected eight studies for the extensive literature analysis. The extracted data contained information of authors, problems solved, participants, methods, assessments, results, and benefits/limitations. These intuitive and in-depth analyses further confirmed and appraised the advantages of 3D printing in complex fracture models more objectively. In conclusion, 3D printing could improve the effectiveness and extension of fracture teaching, as well as medical learning, by providing the powerful interaction with 3D effect, wakening students learning interest, and allowing the junior residents, trainee doctors to have as realistic a virtual practice experience as possible. Through this research, it is expected that more researchers could be attracted to conduct more comprehensive and thorough studies on the application of 3D printing for training and educational propose, to promote the development of 3D technology-based medical education practice and further deepen the reform of medical education and improve the quality of fracture education and learning.