bluuebunny/crossref_metadata_2025 huggingface dataset:
Recurrent Anti-AMPA Receptor Limbic Encephalitis: A Case Report and Literature Review
Authors: Fang Yuanyuan , Pan Dengji , Huang Hao
Published: December 2021

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis is a relatively rare anti-neuronal surface antigen autoimmune encephalitis (LE). We described a case of a 47-year-old Chinese man having anti-AMPA receptor limbic encephalitis initially presented with cognitive decline, undetectable antibodies, and normal imaging findings in magnetic resonance image (MRI) and then developed into typical autoimmune limbic encephalitis a few months later with a course of multiple relapses. In addition, we found progressive brain atrophy in our case, which was a rare presentation of LE. This report also summarized the characteristics of nine reported cases of anti-AMPA receptor limbic encephalitis with relapse up to date. This case highlighted that autoimmune limbic encephalitis is an important differential diagnosis for patients with typical symptoms even when the MRI and antibodies are normal, and more attention should be paid to the relapse of anti-AMPA receptor encephalitis.
Long-Term Follow-Up of Single-Fiber Multiple Low-Intensity Energy Laser Ablation Technique of Benign Thyroid Nodules
Authors: Squarcia Mattia , Mora Mireia , Aranda Gloria , Carrero Enrique , Martínez Daniel , Jerez Ramona , Valero Ricard , Berenguer Joan , Halperin Irene , Hanzu Felicia A.
Published: December 2021

Aim

The short-term and long-term efficacy of different thermal percutaneous ablation techniques remains a topical issue. Our group implemented percutaneous laser ablation (LA), a moving-shot technique to increase efficiency and reduce costs and variability of LA by applying multiple lower-intensity energy illuminations (MLIEI) covering the nodular volume (V) through changes in position of a single laser fiber within the thyroid nodule. The aim of the present study was to evaluate the efficacy of the single-fiber LA-MLIEI during a 5-year follow-up and to identify possible predictors of the final outcome.

Methods

Prospective study: Thirty outpatients (23 women and seven men) with benign symptomatic thyroid nodules were assigned to single-fiber LA-MLIEI, between 2012 and 2015. A single LA session was performed under real-time ultrasound (US) guidance using a 1,064-nm continuous-wave laser at 3 W. A 400-µm optical fiber was inserted through a 21-gauge needle, and 3–10 illuminations were performed per nodule, administering between 400 and 850 J/illumination. The total administered energy was calculated on the initial V of the nodule and the estimated ablation area. US evaluation was performed after LA-MLIEI at 1 week and 1, 3, 6, and 12 months and after that annually up to 5 years. Clinical symptoms, laboratory thyroid function during follow-up, and acute and chronic complications of treatment were registered.

Results

On follow-up, 67% (n: 20) were responders to single-fiber LA-MLIEI, while 33% (n: 10) were non-responders. The responder group initiated V reduction (ΔV) at 1 month, with remission of symptoms, and presented a 50% ΔV at 3 months of treatment; the maximum response was achieved at 24 months and remained stable until the end of the study. The non-responder group presented a ΔV of less than 50% at 12 months; though a tendency to >50% ΔV was observed at 24–36 months, there was subsequent regrowth, and 40% of this group required surgery. ΔV was positively correlated with the total administered energy/V (J/V) and inversely with nodule V. No severe adverse effects were observed. Thyroid function remained normal in all patients. Remission of symptoms occurred rapidly after 1 month.

Conclusions

LA with multiple fractional discharges employing a single fiber in a unique session is a safe and inexpensive technique that allows rapid reduction of thyroid nodules, with a stable response up to 5 years, similarly to what has been reported with the conventional LA. Total nodule volume appears as a predictive factor of the reduction.
Accuracy of Various Forms of Contrast-Enhanced MRI for Diagnosing Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis
Authors: Zhao Chun , Dai Hongyan , Shao Juwei , He Qian , Su Wei , Wang Peng , Tang Qiuyue , Zeng Junren , Xu Song , Zhao Juanjuan , Xiang Shutian
Published: December 2021

Background

Contrast-enhanced MRI can be used to identify patients with hepatocellular carcinoma (HCC). However, studies around the world have found differing diagnostic accuracies for the technique. Hence, we designed this meta-analysis to assess the accuracy of contrast-enhanced MRI for HCC diagnosis.

Methods

We conducted a systematic search for all studies reporting the diagnostic accuracy of contrast-enhanced MRI for HCC in the databases of MEDLINE, EMBASE, Cochrane Library, Web of Science, SCOPUS, ScienceDirect, and Google Scholar from inception until January 2021. We used the “Midas” package from the STATA software to perform the meta-analysis.

Results

Our study was based on 21 publications with 5,361 patients. The pooled HCC diagnosis sensitivity and specificity were 75% (95% CI, 70%–80%) and 90% (95% CI, 88%–92%), respectively, for gadoxetic acid-enhanced MRI; and they were 70% (95% CI, 57%–81%) and 94% (95% CI, 85%–97%), respectively, for MRI with extracellular contrast agents (ECA-MRI). We found significant heterogeneity with a significant chi-square test and an I2 statistic >75%. We also found significant publication bias as per Deeks’ test results and funnel plot.

Conclusion

We found that both types of contrast-enhanced MRI are accurate diagnostic and surveillance tools for HCC and offer high sensitivity and specificity. Further studies on different ethnic populations are required to strengthen our findings.
Indocyanine Green to Assess Vascularity of Ileal Conduit Anastomosis During Pelvic Exenteration for Recurrent/Persistent Gynecological Cancer: A Pilot Study
Authors: Bizzarri Nicolò , Foschi Nazario , Loverro Matteo , Tortorella Lucia , Santullo Francesco , Rosati Andrea , Gueli Alletti Salvatore , Costantini Barbara , Gallotta Valerio , Ferrandina Gabriella , Fagotti Anna , Fanfani Francesco , Ercoli Alfredo , Chiantera Vito , Scambia Giovanni , Vizzielli Giuseppe
Published: December 2021

Introduction

Pelvic exenteration performed for recurrent/persistent gynecological malignancies has been associated with urological short- and long-term morbidity due to altered vascularization of tissues for previous radiotherapy. The aims of the present study were to describe the use of intravenous indocyanine green (ICG) to assess vascularity of urinary diversion (UD) after pelvic exenteration for gynecologic cancers, to evaluate the feasibility and safety of this technique, and to assess the postoperative complications.

Methods

Prospective, observational, single-center, pilot study including consecutive patients undergoing anterior or total pelvic exenteration due to persistent/recurrent gynecologic cancers between August 2020 and March 2021 at Fondazione Policlinico Gemelli IRCCS, Rome, Italy. All patients underwent intravenous injection of 3–6 ml of ICG (1.25 mg/ml) once the UD was completed. A near-infrared camera was used to evaluate ICG perfusion of anastomoses (ileum–ileum, right and left ureter with small bowel, and colostomy or colorectal sides of anastomosis) a few seconds after ICG injection.

Results

Fifteen patients were included in the study. No patient reported adverse reactions to ICG injection. Only 3/15 patients (20.0%) had an optimal ICG perfusion in all anastomoses. The remaining 12 (80.0%) patients had at least one ICG deficit; the most common ICG deficit was on the left ureter: 3 (20.0%) vs. 1 (6.7%) patient had no ICG perfusion on the left vs. right ureter, respectively (p = 0.598). 8/15 (53.3%) and 6/15 (40.0%) patients experienced grade ≥3 30-day early and late postoperative complications, respectively. Of these, two patients had early and one had late postoperative complications directly related to poor perfusion of anastomosis (UD leak, ileum–ileum leak, and benign ureteric stricture); all these cases had a suboptimal intraoperative ICG perfusion.

Conclusion

The use of ICG to intraoperatively assess the anastomosis perfusion at time of pelvic exenteration for gynecologic malignancy is a feasible and safe technique. The different vascularization of anastomotic stumps may be related to anatomical sites and to previous radiation treatment. This approach could be in support of selecting patients at higher risk of complications who may need personalized follow-up.
Prognostic and Clinicopathological Significance of the Systemic Immune-Inflammation Index in Patients With Renal Cell Carcinoma: A Meta-Analysis
Authors: Jin Mingyu , Yuan Shaoying , Yuan Yiming , Yi Luqi
Published: December 2021

Background

The systemic immune-inflammation index (SII) is a hematological parameter based on neutrophil, platelet, and lymphocyte counts. Studies that have investigated the prognostic value of SII in patients with renal cell carcinoma (RCC) have reported controversial results. In this study, we systematically investigated the prognostic value of SII in patients with RCC.

Methods

We systematically searched English articles in the PubMed, Embase, Web of Science, and Cochrane Library databases up to October 2021. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were used to obtain pooled results.

Results

The meta-analysis included 10 studies that enrolled 3,180 patients. A high SII was associated with poor overall survival (HR 1.75, 95% CI 1.33–2.30, p<0.001) in patients with RCC. However, a high SII was not shown to be a significant prognostic factor for progression-free survival/disease-free survival (HR 1.22, 95% CI 0.84–1.76, p=0.293) or poor cancer-specific survival (HR 1.46, 95% CI 0.68–3.12, p=0.332) in patients with RCC. A high SII was correlated with male sex (OR 1.51, 95% CI 1.11–2.04, p=0.008), Fuhrman grade G3–G4 (OR 1.80, 95% CI 1.08–3.00, p=0.024), and poor risk based on the International Metastatic Renal Cell Carcinoma Database Consortium criteria (OR 19.12, 95% CI 9.13–40.06, p<0.001).

Conclusion

A high SII was independently associated with poor survival outcomes in patients with RCC. Additionally, an elevated SII indicated more aggressive disease. The SII may serve as a useful cost-effective prognostic indicator in patients with RCC.
Building Radiomics Models Based on Triple-Phase CT Images Combining Clinical Features for Discriminating the Risk Rating in Gastrointestinal Stromal Tumors
Authors: Shao Meihua , Niu Zhongfeng , He Linyang , Fang Zhaoxing , He Jie , Xie Zongyu , Cheng Guohua , Wang Jian
Published: December 2021

We aimed to build radiomics models based on triple-phase CT images combining clinical features to predict the risk rating of gastrointestinal stromal tumors (GISTs). A total of 231 patients with pathologically diagnosed GISTs from July 2012 to July 2020 were categorized into a training data set (82 patients with high risk, 80 patients with low risk) and a validation data set (35 patients with high risk, 34 patients with low risk) with a ratio of 7:3. Four diagnostic models were constructed by assessing 20 clinical characteristics and 18 radiomic features that were extracted from a lesion mask based on triple-phase CT images. The receiver operating characteristic (ROC) curves were applied to calculate the diagnostic performance of these models, and ROC curves of these models were compared using Delong test in different data sets. The results of ROC analyses showed that areas under ROC curves (AUC) of model 4 [Clinic + CT value of unenhanced (CTU) + CT value of arterial phase (CTA) + value of venous phase (CTV)], model 1 (Clinic + CTU), model 2 (Clinic + CTA), and model 3 (Clinic + CTV) were 0.925, 0.894, 0.909, and 0.914 in the training set and 0.897, 0.866, 0,892, and 0.892 in the validation set, respectively. Model 4, model 1, model 2, and model 3 yielded an accuracy of 88.3%, 85.8%, 86.4%, and 84.6%, a sensitivity of 85.4%, 84.2%, 76.8%, and 78.0%, and a specificity of 91.2%, 87.5%, 96.2%, and 91.2% in the training set and an accuracy of 88.4%, 84.1%, 82.6%, and 82.6%, a sensitivity of 88.6%, 77.1%, 74.3%, and 85.7%, and a specificity of 88.2%, 91.2%, 91.2%, and 79.4% in the validation set, respectively. There was a significant difference between model 4 and model 1 in discriminating the risk rating in gastrointestinal stromal tumors in the training data set (Delong test, p < 0.05). The radiomic models based on clinical features and triple-phase CT images manifested excellent accuracy for the discrimination of risk rating of GISTs.
Predictive Performance of Serum S100B Versus LDH in Melanoma Patients: A Systematic Review and Meta-Analysis
Authors: Janka Eszter Anna , Várvölgyi Tünde , Sipos Zoltán , Soós Alexandra , Hegyi Péter , Kiss Szabolcs , Dembrovszky Fanni , Csupor Dezső , Kéringer Patrik , Pécsi Dániel , Solymár Margit , Emri Gabriella
Published: December 2021

Background

Currently, no consensus on the use of blood tests for monitoring disease recurrence in patients with resected melanoma exists. The only meta-analysis conducted in 2008 found that elevated serum S100B levels were associated with significantly worse survival in melanoma patients. Serum LDH is an established prognostic factor in patients with advanced melanoma.

Objective

To compare the discriminative and prognostic ability of serum S100B with that of serum LDH in patients with melanoma.

Methods

This systematic review and meta-analysis were reported in accordance with the PRISMA Statement. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42019137138).

Results

A quantitative analysis of data from 6 eligible studies included 1,033 patients with cutaneous melanoma. The discriminative ability of serum S100B at identifying disease relapse [pooled Area Under the ROC (AUROC) 78.64 (95% CI 70.28; 87.01)] was significantly greater than the discriminative ability of serum LDH [AUROC 64.41 (95% CI 56.05; 7278)] (p=0.013). Ten eligible studies with 1,987 patients were included in the risk of death analysis. The prognostic performance of serum S100B [pooled estimate of adjusted hazard ratio (HR) 1.78 (95% CI 1.38; 2.29)] was independent but not superior to that of serum LDH [HR 1.60 (95% CI 1.36; 2.29)].

Limitations

A relatively small number of articles were eligible and there was considerable heterogeneity across the included studies.

Conclusions

Serum biomarkers may provide relevant information on melanoma patient status and should be further researched. Serum S100B is a valid marker for diagnosis of melanoma recurrence.

Systematic Review Registration

The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42019137138).
SENP2 Reduces Hepatocellular Carcinoma Stemness and Improves Sorafenib Sensitivity Through Inactivating the AKT/GSK3β/CTNNB1 Pathway
Authors: Tang Xiaohui , Liu Bohao , Zhang Chen , Tang Wenbin , Liang Shitian , Xiao Yadan , Deng Ruoyu , Li Zhuan
Published: December 2021

Background

Small ubiquitin-like modifier specific peptidase 2 (SENP2) suppresses the progression and chemoresistance of several cancers, while few studies report its role in hepatocellular carcinoma (HCC). This study aimed to evaluate the effect of SENP2 on stemness, sorafenib sensitivity, and downstream pathway in HCC, with validation of its molecular mechanisms by compensation experiment.

Methods

SENP2 was regulated by plasmid transfection; meanwhile, in a compensation experiment, protein kinase B (AKT) was activated by SC79 treatment and β-catenin (CTNNB1) was overexpressed by plasmid transfection. After modification, sorafenib sensitivity was detected by cell counting kit-8 assay; stemness was evaluated by CD133+ cell proportion and sphere formation assay.

Results

SENP2 was decreased in HCC cell lines (including Hep3B, Li7, and Huh7) compared with normal human liver epithelial cell lines, which was further reduced in HCC stem cells than in normal HCC cells. Subsequently, SENP2 overexpression inhibited CD133+ cell proportion, decreased sphere formation ability, promoted sorafenib sensitivity, suppressed AKT and glycogen synthase kinase-3β (GSK3β) phosphorylation, and reduced CTNNB1 expression in Huh7 and Hep3B cells, while SENP2 knockdown showed the reverse effects. The following compensation experiment revealed that activating AKT or overexpressing CTNNB1 promoted CD133+ cell proportion and sphere formation ability but suppressed sorafenib sensitivity in Huh7 and Hep3B cells. Moreover, activating AKT or overexpressing CTNNB1 attenuated the effect of SENP2 overexpression on stemness and sorafenib sensitivity in Huh7 and Hep3B cells.

Conclusion

SENP2 suppresses HCC stemness and increases sorafenib sensitivity through inactivating the AKT/GSK3β/CTNNB1 signaling pathway.
KDM6 Demethylases and Their Roles in Human Cancers
Authors: Hua Chunyan , Chen Jiaqing , Li Shuting , Zhou Jianan , Fu Jiahong , Sun Weijian , Wang Wenqian
Published: December 2021

Cancer therapy is moving beyond traditional chemotherapy to include epigenetic approaches. KDM6 demethylases are dynamic regulation of gene expression by histone demethylation in response to diverse stimuli, and thus their dysregulation has been observed in various cancers. In this review, we first briefly introduce structural features of KDM6 subfamily, and then discuss the regulation of KDM6, which involves the coordinated control between cellular metabolism (intrinsic regulators) and tumor microenvironment (extrinsic stimuli). We further describe the aberrant functions of KDM6 in human cancers, acting as either a tumor suppressor or an oncoprotein in a context-dependent manner. Finally, we propose potential therapy of KDM6 enzymes based on their structural features, epigenetics, and immunomodulatory mechanisms, providing novel insights for prevention and treatment of cancers.
Biomedical Applications of Non-Small Cell Lung Cancer Spheroids
Authors: Rozenberg Julian M. , Filkov Gleb I. , Trofimenko Alexander V. , Karpulevich Evgeny A. , Parshin Vladimir D. , Royuk Valery V. , Sekacheva Marina I. , Durymanov Mikhail O.
Published: December 2021

Lung malignancies accounted for 11% of cancers worldwide in 2020 and remained the leading cause of cancer deaths. About 80% of lung cancers belong to non-small cell lung cancer (NSCLC), which is characterized by extremely high clonal and morphological heterogeneity of tumors and development of multidrug resistance. The improvement of current therapeutic strategies includes several directions. First, increasing knowledge in cancer biology results in better understanding of the mechanisms underlying malignant transformation, alterations in signal transduction, and crosstalk between cancer cells and the tumor microenvironment, including immune cells. In turn, it leads to the discovery of important molecular targets in cancer development, which might be affected pharmaceutically. The second direction focuses on the screening of novel drug candidates, synthetic or from natural sources. Finally, “personalization” of a therapeutic strategy enables maximal damage to the tumor of a patient. The personalization of treatment can be based on the drug screening performed using patient-derived tumor xenografts or in vitro patient-derived cell models. 3D multicellular cancer spheroids, generated from cancer cell lines or tumor-isolated cells, seem to be a helpful tool for the improvement of current NSCLC therapies. Spheroids are used as a tumor-mimicking in vitro model for screening of novel drugs, analysis of intercellular interactions, and oncogenic cell signaling. Moreover, several studies with tumor-derived spheroids suggest this model for the choice of “personalized” therapy. Here we aim to give an overview of the different applications of NSCLC spheroids and discuss the potential contribution of the spheroid model to the development of anticancer strategies.
Combined Stereotactic Body Radiotherapy and Immunotherapy Versus Transarterial Chemoembolization in Locally Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis
Authors: Chiang Chi-Leung , Chiu Keith Wan-Hang , Lee Francis Ann-Shing , Kong Feng-Ming Spring , Chan Albert Chi-Yan
Published: December 2021

Immunotherapy has achieved modest clinical activity in HCC patients. Propensity score matching analysis was conducted to compare the efficacy and safety of combined stereotactic SBRT-IO versus TACE in patients with locally advanced HCC in a tertiary center of Hong Kong. Patients with locally advanced HCC who were medically inoperable for, refractory to, or refused to curative surgical interventions were eligible. The primary outcome was PFS; the secondary outcomes were OS, ORR as per mRECIST version 1.1, and TRAEs. Matching pair analysis was performed to compare the clinical outcomes. A total of 226 patients were eligible. Approximately 16 patients in the SBRT-IO group were matched with 48 patients treated with TACE. The median tumor size was 10 cm (range: 2.9–19.6 cm) and 20.3% of the patients had portal vein invasion. The 12- and 24-month PFS were significantly better in the SBRT-IO group (93.3% vs 16.7% and 77.8% vs 2.1%, respectively, p <0.001); the 12- and 24-month OS were also better in the SBRT-IO arm (93.8% vs 31.3% and 80.4% vs 8.3%, respectively, p <0.001). The ORR was 87.5% (CR: 50%, PR: 37.5%) in SBRT-IO arm compared to 16.7% (CR: 2.4%, PR: 14.3%) in those receiving TACE alone (p <0.001). There were fewer ≥grade 3 TRAE (60.4% vs 18.8%, p = 0.004) and treatment discontinuations (25% vs 12.5%, p = 0.295) due to adverse events in the SBRT-IO arm. SBRT-IO had significant superior survival and less treatment toxicity than TACE in patients with locally advanced HCC. Our results provide rationale for studying this combination therapy in prospective randomized trials.
Dexmedetomidine Use in Infants Undergoing Cooling Due to Neonatal Encephalopathy (DICE Trial): A Randomized Controlled Trial: Background, Aims and Study Protocol
Authors: Baserga Mariana , DuPont Tara L. , Ostrander Betsy , Minton Stephen , Sheffield Mark , Balch Alfred H. , Bahr Timothy M. , Watt Kevin M.
Published: December 2021

Background: Neonatal hypoxia-ischemia encephalopathy (HIE) is the leading cause of neonatal death and poor neurodevelopmental outcomes worldwide. Therapeutic hypothermia (TH), while beneficial, still leaves many HIE treated infants with lifelong disabilities. Furthermore, infants undergoing TH often require treatment for pain and agitation which may lead to further brain injury. For instance, morphine use in animal models has been shown to induce neuronal apoptosis. Dexmedetomidine is a potent α2-adrenergic receptor agonist that may be a better alternative to morphine for newborns with HIE treated with TH. Dexmedetomidine provides sedation, analgesia, and prevents shivering but does not suppress ventilation. Importantly, there is increasing evidence that dexmedetomidine has neuroprotective properties. Even though there are limited data on pharmacokinetics (PK), safety and efficacy of dexmedetomidine in infants with HIE, it has been increasingly administered in many centers.

Objectives: To review the current approach to treatment of pain, sedation and shivering in infants with HIE undergoing TH, and to describe a new phase II safety and pharmacokinetics randomized controlled trial that proposes the use of dexmedetomidine vs. morphine in this population.

Methods: This article presents an overview of the current management of pain and sedation in critically ill infants diagnosed with HIE and undergoing TH for 72 h. The article describes the design and methodology of a randomized, controlled, unmasked multicenter trial of dexmedetomidine vs. morphine administration enrolling 50 (25 per arm) neonates ≥36 weeks of gestation with moderate or severe HIE undergoing TH and that require pain/sedation treatment.

Results and Conclusions: Dexmedetomidine may be a better alternative to morphine for the treatment of pain and sedation in newborns with HIE treated with TH. There is increasing evidence that dexmedetomidine has neuroprotective properties in several preclinical studies of injury models including ischemia-reperfusion, inflammation, and traumatic brain injury as well as adult clinical trials of brain trauma. The Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal Encephalopathy (DICE) trial will evaluate whether administration of dexmedetomidine vs. morphine is safe, establish dexmedetomidine optimal dosing by collecting opportunistic PK data, and obtain preliminary neurodevelopmental data to inform a large Phase III efficacy trial with long term neurodevelopment impairment as the primary outcome.
Management of Upper Airway Infantile Hemangiomas: Experience of One Italian Multidisciplinary Center
Authors: Corbeddu Marialuisa , Meucci Duino , Diociaiuti Andrea , Giancristoforo Simona , Rotunno Roberta , Gonfiantini Michaela Veronika , Trozzi Marilena , Bottero Sergio , El Hachem May
Published: December 2021

Airway infantile hemangiomas (IHs) can represent a life-threatening condition since the first months of life. They may be isolated or associated to cutaneous IHs, and/or part of PHACES syndrome. Diagnosis, staging, and indication to treatment are not standardized yet despite the presence in the literature of previous case series and reviews. The diagnosis might be misleading, especially in the absence of cutaneous lesions. Airway endoscopy is the gold standard both for diagnosis and follow-up since it allows evaluation of precise localization and entity of obstruction and/or stricture. Proliferation of IH in the infant airways manifests frequently with stridor and treatment is required as soon as possible to prevent further complications. The first line of therapy is oral propranolol, but duration of treatment is not yet well-defined. All considered, we report the experience of our multidisciplinary center from 2009 to date, on 36 patients affected by airway IHs, and successfully treated with oral propranolol. Thus, the authors propose their experience for the management of airway IHs, specifically early diagnosis, when to perform endoscopy, how to interpret its findings, and when to stop the treatment.
Preschool Confusion Assessment Method for the Intensive Care Unit–Spanish (psCAM-ICU-S): Cross-Cultural Adaptation and Validation in Colombia
Authors: Pinzón-Casas Edwar , Soto-Trujillo Maira , Camargo-Agón Laura , Henao-Castaño Ángela , Gualdrón Nathalie , Bonilla-González Carolina
Published: December 2021

Objective: The goal of the present study was to perform a cross-cultural adaptation and clinical validation of the Preschool Confusion Assessment Method for the Intensive Care Unit–Spanish (psCAM-ICU-S) for its clinical use in the Colombian Population.

Methods: We designed a Cross-cultural adaptation study followed by a cross-sectional validation study at a Single-center Pediatric Intensive Care Unit (PICU) at a University Hospital in Bogotá, Colombia. The study population was children aged from 6 months to 5 years and 11 months who had been treated in the PICU with a Richmond sedation-agitation scale score of−3 or higher. A three-phase study was carried out. The first phase comprised the application of psychometric tests on the tool. In the second phase, the psCAM-ICU-S was applied to the target population. Patients were evaluated by a nurse and a pediatric intensivist using the psCAM-ICU-S; additionally, a child psychiatrist evaluated each patient using the DSM-V criteria; the psychiatrist evaluation was chosen as the gold standard for the diagnosis of delirium. In the third phase, an evaluation of the tool's effectiveness was carried out by using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios. Interrater agreement was also assessed by using the Fleiss' kappa.

Results: Psychometric tests established the instrument's reliability and consistency as well as the clarity of its items. A total of 31 patients were evaluated. On average, the instrument presented a sensitivity of 93.3%, specificity of 94.8%, PPV 78%, NPV 99%, a positive likelihood ratio of 19.93, and a negative ratio of 0.07. The prevalence of delirium was 16.1% by the child psychiatrist and 25.8% using de psCAM-ICU-S. We confirmed high Interrater agreement, Kappa index (0.672–0.902).

Conclusions: The psCAM-ICU-S was a valid and reliable instrument for the diagnosis of delirium in critically ill pediatric patients.
Analysis of the Risk Factors in Prognosis of Kawasaki Disease With Coronary Artery Lesions
Authors: Hu Jinling , Ren Weidong
Published: December 2021

Abstract: Kawasaki disease (KD) is one of the most common forms of systemic vasculitis in children. Pathological features include extensive inflammation of small and medium blood vessels throughout the body. The primary complication of KD is coronary artery lesions (CALs). A total of 640 children with KD were admitted to the Department of Pediatric Cardiology at Shengjing Hospital of China Medical University from January 2017 to December 2019. These patients comprised 52 coronary artery aneurysm (CAA) cases and 47 coronary artery dilation (CAD) cases. Echocardiography was performed during the acute KD phase and then at 1, 3, 6, 12, and 24 months after KD onset. Patients were divided into a poor prognosis group (n = 30) and a normal group (n = 69) based on CALs prognosis. Differences in laboratory data, clinical manifestations and coronary artery damage rates were compared between the two groups. Univariate analysis was performed on these data, and an ROC curve was used to analyze the efficacy of each risk factor. Univariate analysis revealed that age (months), number of coronary arteries involved (NACI), IgM, IgA and brain natriuretic peptide (ProBNP) levels were higher in the poor prognosis group compared with the normal group, procalcitonin (PCT) levels in the poor prognosis group were lower than in the normal group (P < 0.05).

Conclusion: Age ≥ 18 months, IgM ≥ 1.07g/L, IgA ≥ 0.728g/L and NCAI ≥ 3 were poor prognostic factors of KD children with CALs. These parameters can be used as a reference indicator of early prediction where combined detection might improve the accuracy and sensitivity of prediction. Follow-up should be maintained to monitor changes in the coronary artery by echocardiography.
Population Pharmacokinetic Model Development of Tacrolimus in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplantation
Authors: Brooks Jordan T. , Keizer Ron J. , Long-Boyle Janel R. , Kharbanda Sandhya , Dvorak Christopher C. , Friend Brian D.
Published: December 2021

Background: With a notably narrow therapeutic window and wide intra- and interindividual pharmacokinetic (PK) variability, initial weight-based dosing along with routine therapeutic drug monitoring of tacrolimus are employed to optimize its clinical utilization. Both supratherapeutic and subtherapeutic tacrolimus concentrations can result in poor outcomes, thus tacrolimus PK variability is particularly important to consider in the pediatric population given the differences in absorption, distribution, metabolism, and excretion among children of various sizes and at different stages of development. The primary goals of the current study were to develop a population PK (PopPK) model for tacrolimus IV continuous infusion in the pediatric and young adult hematopoietic cell transplant (HCT) population and implement the PopPK model in a clinically available Bayesian forecasting tool.

Methods: A retrospective chart review was conducted of 111 pediatric and young adult patients who received IV tacrolimus by continuous infusion early in the post-transplant period during HCT from February 2016 to July 2020 at our institution. PopPK model building was performed in NONMEM. The PopPK model building process included identifying structural and random effects models that best fit the data and then identifying which patient-specific covariates (if any) further improved model fit.

Results: A total of 1,648 tacrolimus plasma steady-state trough concentrations were included in the PopPK modeling process. A 2-compartment structural model best fit the data. Allometrically-scaled weight was a covariate that improved estimation of both clearance and volume of distribution. Overall, model predictions only showed moderate bias, with minor under-prediction at lower concentrations and minor over-prediction at higher predicted concentrations. The model was implemented in a Bayesian dosing tool and made available at the point-of-care.

Discussion: Novel therapeutic drug monitoring strategies for tacrolimus within the pediatric and young adult HCT population are necessary to reduce toxicity and improve efficacy in clinical practice. The model developed presents clinical utility in optimizing the use of tacrolimus by enabling model-guided, individualized dosing of IV, continuous tacrolimus via a Bayesian forecasting platform.
In Silico Prediction and Bioactivity Evaluation of Chemical Ingredients Against Influenza A Virus From Isatis tinctoria L
Authors: Cai Chuipu , Xu Lvjie , Fang Junfeng , Dai Zhao , Wu Qihui , Liu Xiaoyi , Wang Qi , Fang Jiansong , Liu Ai-Lin , Du Guan-Hua
Published: December 2021

Influenza A virus (IAV) is one of the major causes of seasonal endemic diseases and unpredictable periodic pandemics. Due to the high mutation rate and drug resistance, it poses a persistent threat and challenge to public health.Isatis tinctoriaL. (Banlangen, BLG), a traditional herbal medicine widely used in Asian countries, has been reported to possess strong efficacy on respiratory viruses, including IAV. However, its effective anti-IAV components and the mechanism of actions (MOAs) are not yet fully elucidated. In this study, we first summarized the chemical components and corresponding contents in BLG according to current available chemical analysis literature. We then presented a network-basedin silicoframework for identifying potential drug candidates against IAV from BLG. A total of 269 components in BLG were initially screened by drug-likeness and ADME (absorption, distribution, metabolism, and excretion) evaluation. Thereafter, network predictive models were builtviathe integration of compound–target networks and influenza virus–host proteins. We highlighted 23 compounds that possessed high potential as anti-influenza virus agents. Through experimental evaluation, six compounds, namely, eupatorin, dinatin, linarin, tryptanthrin, indirubin, and acacetin, exhibited good inhibitory activity against wild-type H1N1 and H3N2. Particularly, they also exerted significant effects on drug-resistant strains. Finally, we explored the anti-IAV MOAs of BLG and showcased the potential biological pathways by systems pharmacology analysis. In conclusion, this work provides important information on BLG regarding its use in the development of anti-IAV drugs, and the network-based prediction framework proposed here also offers a powerfulful strategy for thein silicoidentification of novel drug candidates from complex components of herbal medicine.
Valeriana jatamansi Jones ex Roxb. Against Post-Traumatic Stress Disorder, Network Pharmacological Analysis, and In Vivo Evaluation
Authors: Yang Xue , Guo Jian-You , Jiang Ya-Ni , Liu Meng-Meng , Li Qiu-Yu , Li Jia-Yuan , Wei Xiao-Jia , Wan Guo-Hui , Shi Jin-Li
Published: December 2021

Zhi zhu xiang (ZZX) is the root and rhizome of Valeriana jatamansi Jones ex Roxb. Recent studies have shown that ZZX can exert antianxiety, antidepressant, and sedative effects. Because post-traumatic stress disorder (PTSD) is similar to depression and anxiety in terms of its etiology, pathogenesis, and clinical manifestations, it is possible that ZZX may also be useful for the prevention and treatment of PTSD. In this study, a mouse model of PTSD was established and used to study the pharmacological action of a 95% ethanol extract of ZZX on PTSD via a series of classic behavioral tests. We found that a 95% ethanol extract of ZZX was indeed effective for relieving the symptoms of PTSD in mice. Moreover, network pharmacology analysis was used to predict the potential active ingredients, targets, and possible pathways of ZZX in the treatment of PTSD. The neurotransmitter system, the hypothalamic–pituitary–adrenal (HPA) axis, and the endocannabinoid (eCB) system were identified to be the most likely pathways for anti-PTSD action in ZZX. Due to the lack of a falsification mechanism in network pharmacology, in vivo tests were carried out in mice, and the expression levels of neurotransmitters, hormones, and genes of key targets were detected by enzyme-linked immunosorbent assay and real-time PCR to further verify this inference. Analysis showed that the levels of norepinephrine, 5-hydroxytryptamine, and glutamic acid were increased in the hippocampus, prefrontal cortex, and amygdala of PTSD mice, while the levels of dopamine and γ-aminobutyric acid were decreased in these brain regions; furthermore, ZZX could restore the expression of these factors, at least to a certain extent. The levels of adrenocorticotropic hormone, corticosterone, and corticotropin-releasing hormone were increased in these different brain regions and the serum of PTSD mice; these effects could be reversed by ZZX to a certain extent. The expression levels of cannabinoid receptor 1 and diacylglycerol lipase α mRNA were decreased in PTSD mice, while the levels of fatty acid amide hydrolase and monoacylglycerol lipase mRNA were increased; these effects were restored by ZZX to a certain extent. In conclusion, our findings suggest that ZZX may provide new therapeutic pathways for treating PTSD by the regulation of neurotransmitters, the HPA, and expression levels of eCB-related genes in the brain.
Effects of Puerarin on the Prevention and Treatment of Cardiovascular Diseases
Authors: Zhou Yan-Xi , Zhang Hong , Peng Cheng
Published: December 2021

Puerarin, an isoflavone glycoside derived from Pueraria lobata (Willd.) Ohwi, has been identified as a pharmacologically active component with diverse benefits. A large number of experimental and clinical studies have demonstrated that puerarin is widely used in the treatment of a variety of diseases. Among them, cardiovascular diseases (CVDs) are the leading cause of death in the world, and therefore remain one of the most prominent global public health concerns. In this review, we systematically analyze the preclinical investigations of puerarin in CVDs, such as atherosclerosis, cardiac hypertrophy, heart failure, diabetic cardiovascular complications, myocardial infarction, stroke and hypertension. In addition, the potential molecular targets of puerarin are also discussed. Furthermore, we summarize the clinical trails of puerarin in the treatment of CVDs. Finally, the therapeutic effects of puerarin derivatives and its drug delivery systems are overviewed.
Screening for Activity Against AMPA Receptors Among Anticonvulsants—Focus on Phenytoin
Authors: Dron M. Y. , Zhigulin A. S. , Tikhonov D. B. , Barygin O. I.
Published: December 2021

The interest in AMPA receptors as a target for epilepsy treatment increased substantially after the approval of perampanel, a negative AMPA receptor allosteric antagonist, for the treatment of partial-onset seizures and generalized tonic-clonic seizures. Here we performed a screening for activity against native calcium-permeable AMPA receptors (CP-AMPARs) and calcium-impermeable AMPA receptors (CI-AMPARs) among different anticonvulsants using the whole-cell patch-clamp method on isolated Wistar rat brain neurons. Lamotrigine, topiramate, levetiracetam, felbamate, carbamazepine, tiagabin, vigabatrin, zonisamide, and gabapentin in 100-µM concentration were practically inactive against both major subtypes of AMPARs, while phenytoin reversibly inhibited them with IC50 of 30 ± 4 μM and 250 ± 60 µM for CI-AMPARs and CP-AMPARs, respectively. The action of phenytoin on CI-AMPARs was attenuated in experiments with high agonist concentrations, in the presence of cyclothiazide and at pH 9.0. Features of phenytoin action matched those of the CI-AMPARs pore blocker pentobarbital, being different from classical competitive inhibitors, negative allosteric inhibitors, and CP-AMPARs selective channel blockers. Close 3D similarity between phenytoin and pentobarbital also suggests a common binding site in the pore and mechanism of inhibition. The main target for phenytoin in the brain, which is believed to underlie its anticonvulsant properties, are voltage-gated sodium channels. Here we have shown for the first time that phenytoin inhibits CI-AMPARs with similar potency. Thus, AMPAR inhibition by phenytoin may contribute to its anticonvulsant properties as well as its side effects.
Computational Modelling of Glucose Uptake by SGLT1 and Apical GLUT2 in the Enterocyte
Authors: Afshar Nima , Safaei Soroush , Nickerson David P. , Hunter Peter J. , Suresh Vinod
Published: December 2021

It has been suggested that glucose absorption in the small intestine depends on both constitutively expressed SGLT1 and translocated GLUT2 in the brush border membrane, especially in the presence of high levels of luminal glucose. Here, we present a computational model of non-isotonic glucose uptake by small intestinal epithelial cells. The model incorporates apical uptake via SGLT1 and GLUT2, basolateral efflux into the blood via GLUT2, and cellular volume changes in response to non-isotonic conditions. The dependence of glucose absorption on luminal glucose, blood flow rate, and inlet blood glucose concentration is studied. Uptake via apical GLUT2 is found to be sensitive to all these factors. Under a range of conditions, the maximum apical GLUT2 flux is about half of the SGLT1 flux and is achieved at high luminal glucose (> 50 mM), high blood flow rates, and low inlet blood concentrations. In contrast, SGLT1 flux is less sensitive to these factors. When luminal glucose concentration is less than 10 mM, apical GLUT2 serves as an efflux pathway for glucose to move from the blood to the lumen. The model results indicate that translocation of GLUT2 from the basolateral to the apical membrane increases glucose uptake into the cell; however, the reduction of efflux capacity results in a decrease in net absorption. Recruitment of GLUT2 from a cytosolic pool elicits a 10–20% increase in absorption for luminal glucose levels in the a 20–100 mM range. Increased SGLT1 activity also leads to a roughly 20% increase in absorption. A concomitant increase in blood supply results in a larger increase in absorption. Increases in apical glucose transporter activity help to minimise cell volume changes by reducing the osmotic gradient between the cell and the lumen.
Micro-CT Study of Mongolian Gerbil Humeral Bone After Prolonged Spaceflight Based on a New Algorithm for Delimitation of Long-Bone Regions
Authors: Krivonosov Yuri S. , Gulimova Victoria I. , Buzmakov Alexey V. , Zolotov Denis A. , Cedola Alessia , Bukreeva Inna , Asadchikov Victor E. , Saveliev Sergey V.
Published: December 2021

The Mongolian gerbil displays unique physiological and anatomical features that make this species an attractive object for biological experiments in space. However, until recently, the Mongolian gerbil has remained a novel, mostly unstudied animal model in investigating bone loss in weightlessness (G0). After 12 days of orbital Foton-M3 mission, the humerus of Mongolian gerbils has been studied here via micro-computed tomography (micro-CT) to quantify bone morphometric parameters. The samples from the flight group, delayed synchronous ground-control group, and basal control group were investigated, and main morphometric parameters were reported in the article. The accurate selection of a region of interest is an essential step for a correct assessment of bone parameters. We proposed a new, easy and efficient method for delimiting the bone’s basic regions in the humerus. It is based on quantitative estimation of X-ray attenuation in the cortical bone as a function of humerus bone length. The micro-CT analysis of the basic bone regions revealed a difference in bone morphometric parameters between the flight and control gerbils. The most significant bone loss was observed in the cortical part of the proximal humeral zone in the flight group. No statistically significant changes of volume fraction in the cancellous tissue of proximal and distal epiphyses and metaphyses were observed. A statistically significant increase in both cancellous bone volume and bone X-ray attenuation in the flight group was detected in the proximal part of the diaphyses. We assume that enhanced calcium deposition in the diaphyseal cancellous tissue occurred due to a bone response to G0 conditions.
Vascular Stiffness in Aging and Disease
Authors: Vatner Stephen F. , Zhang Jie , Vyzas Christina , Mishra Kalee , Graham Robert M. , Vatner Dorothy E.
Published: December 2021

The goal of this review is to provide further understanding of increased vascular stiffness with aging, and how it contributes to the adverse effects of major human diseases. Differences in stiffness down the aortic tree are discussed, a topic requiring further research, because most prior work only examined one location in the aorta. It is also important to understand the divergent effects of increased aortic stiffness between males and females, principally due to the protective role of female sex hormones prior to menopause. Another goal is to review human and non-human primate data and contrast them with data in rodents. This is particularly important for understanding sex differences in vascular stiffness with aging as well as the changes in vascular stiffness before and after menopause in females, as this is controversial. This area of research necessitates studies in humans and non-human primates, since rodents do not go through menopause. The most important mechanism studied as a cause of age-related increases in vascular stiffness is an alteration in the vascular extracellular matrix resulting from an increase in collagen and decrease in elastin. However, there are other mechanisms mediating increased vascular stiffness, such as collagen and elastin disarray, calcium deposition, endothelial dysfunction, and the number of vascular smooth muscle cells (VSMCs). Populations with increased longevity, who live in areas called “Blue Zones,” are also discussed as they provide additional insights into mechanisms that protect against age-related increases in vascular stiffness. Such increases in vascular stiffness are important in mediating the adverse effects of major cardiovascular diseases, including atherosclerosis, hypertension and diabetes, but require further research into their mechanisms and treatment.
Lifespan Analysis of Dystrophic mdx Fast-Twitch Muscle Morphology and Its Impact on Contractile Function
Authors: Kiriaev Leonit , Kueh Sindy , Morley John W. , North Kathryn N. , Houweling Peter J. , Head Stewart I.
Published: December 2021

Duchenne muscular dystrophy is caused by the absence of the protein dystrophin from skeletal muscle and is characterized by progressive cycles of necrosis/regeneration. Using the dystrophin deficient mdx mouse model, we studied the morphological and contractile chronology of dystrophic skeletal muscle pathology in fast-twitch Extensor Digitorum Longus muscles from animals 4–22 months of age containing 100% regenerated muscle fibers. Catastrophically, the older age groups lost ∼80% of their maximum force after one eccentric contraction (EC) of 20% strain with the greatest loss of ∼92% recorded in senescent 22-month-old mdx mice. In old age groups, there was minimal force recovery ∼24% after 120 min, correlated with a dramatic increase in the number and complexity of branched fibers. This data supports our two-phase model where a “tipping point” is reached when branched fibers rupture irrevocably on EC. These findings have important implications for pre-clinical drug studies and genetic rescue strategies.