bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain Activation During Active Balancing and Its Behavioral Relevance in Younger and Older Adults: A Functional Near-Infrared Spectroscopy (fNIRS) Study
Authors: Lehmann Nico , Kuhn Yves-Alain , Keller Martin , Aye Norman , Herold Fabian , Draganski Bogdan , Taube Wolfgang , Taubert Marco
Published: March 2022

Age-related deterioration of balance control is widely regarded as an important phenomenon influencing quality of life and longevity, such that a more comprehensive understanding of the neural mechanisms underlying this process is warranted. Specifically, previous studies have reported that older adults typically show higher neural activity during balancing as compared to younger counterparts, but the implications of this finding on balance performance remain largely unclear. Using functional near-infrared spectroscopy (fNIRS), differences in the cortical control of balance between healthy younger (n = 27) and older (n = 35) adults were explored. More specifically, the association between cortical functional activity and balance performance across and within age groups was investigated. To this end, we measured hemodynamic responses (i.e., changes in oxygenated and deoxygenated hemoglobin) while participants balanced on an unstable device. As criterion variables for brain-behavior-correlations, we also assessed postural sway while standing on a free-swinging platform and while balancing on wobble boards with different levels of difficulty. We found that older compared to younger participants had higher activity in prefrontal and lower activity in postcentral regions. Subsequent robust regression analyses revealed that lower prefrontal brain activity was related to improved balance performance across age groups, indicating that higher activity of the prefrontal cortex during balancing reflects neural inefficiency. We also present evidence supporting that age serves as a moderator in the relationship between brain activity and balance, i.e., cortical hemodynamics generally appears to be a more important predictor of balance performance in the older than in the younger. Strikingly, we found that age differences in balance performance are mediated by balancing-induced activation of the superior frontal gyrus, thus suggesting that differential activation of this region reflects a mechanism involved in the aging process of the neural control of balance. Our study suggests that differences in functional brain activity between age groups are not a mere by-product of aging, but instead of direct behavioral relevance for balance performance. Potential implications of these findings in terms of early detection of fall-prone individuals and intervention strategies targeting balance and healthy aging are discussed.
Intraneural Topography of Rat Sciatic Axons: Implications for Polyethylene Glycol Fusion Peripheral Nerve Repair
Authors: Hibbard Emily A. , Sengelaub Dale R.
Published: March 2022

Peripheral nerve injuries are the most common type of nerve trauma. We have been working with a novel repair technique using a plasmalemmal fusogen, polyethylene glycol (PEG), to re-fuse the membranes of severed axons. PEG-fusion repair allows for immediate re-innervation of distal targets, prevents axonal degeneration, and improves behavioral recovery. PEG-fusion of severed axons is non-specific, and we have previously reported that following injury and PEG-fusion misconnections between spinal motoneurons and their distal targets were present. Surprisingly, appropriately paired proximal and distal motor axons were observed in all PEG-fused animals. We hypothesized that a topographic organization of axons contributing to the sciatic nerve could explain the incidence of appropriate connections. We traced the course of specific axon populations contributing to the sciatic nerve in young adult male and female rats. Following intraneural injection of Fast Blue into the tibial branch, labeled axons were confined to a discrete location throughout the course of the nerve. Following intramuscular injection of cholera toxin-conjugated horseradish peroxidase into the anterior tibialis, labeled axons were confined to a smaller but still discrete location throughout the nerve. In both cases, the relative locations of labeled axons were consistent bilaterally within animals, as well as across animals and sexes. Thus, the relatively consistent location of specific axon populations could allow for realignment of appropriate populations of axons, and enhanced behavioral recovery seen in PEG-fused animals. Knowing the organization of axons within the sciatic nerve promotes accurate territory realignment during repair, therefore aiding in recovery outcomes.
Multisystem Mitochondrial Disease Associated With a Mare m.10000G>A Mitochondrial tRNAGly (MT-TG) Variant
Authors: Yang Haiyan , Zhang Victor Wei , Ai Liang , Gan Siyi , Wu Liwen
Published: March 2022

Background

Mitochondrial diseases are clinically heterogeneous, can occur at any age, and can manifest with a wide range of clinical symptoms. They can involve any organ or tissue, characteristically involve multiple systems, typically affecting organs that are highly dependent on aerobic metabolism, and making a definitive molecular diagnosis of a mitochondrial disorder is challenging.

Methods

Clinical data of the proband and his family members were gathered in a retrospective study. Whole-exome sequencing and full-length sequencing of the mitochondrial genome that were performed on peripheral blood, urine, and oral mucosa cells were applied for genetic analysis.

Results

In this study, we reported a childhood-onset mitochondrial phenotype in a 13-year-old patient. Analysis of the next-generation sequencing data of the nuclear genome and the full-length sequencing of the mitochondrial genome revealed the rare m.10000G>A variant in MT-TG that was present at variable heteroplasmy levels across tissue types: 32.7% in the blood, 56.15% in urinary epithelial cells, and 27.3% in oral mucosa cells. No variant was found in the peripheral blood of his mother and sister. No pathogenic mutation of nDNA was found.

Conclusion

Our results added evidence that the de novo m.10000G>A variation in the highly conserved sequence of MT-TG appears to suggest a childhood-onset mitochondrial phenotype in the 13-year-old patient, thus broadening the genotypic interpretation of mitochondrial DNA-related diseases.
Bilaterally Reduced Rolandic Beta Band Activity in Minor Stroke Patients
Authors: Kulasingham Joshua P. , Brodbeck Christian , Khan Sheena , Marsh Elisabeth B. , Simon Jonathan Z.
Published: March 2022

Stroke patients with hemiparesis display decreased beta band (13–25 Hz) rolandic activity, correlating to impaired motor function. However, clinically, patients without significant weakness, with small lesions far from sensorimotor cortex, exhibit bilateral decreased motor dexterity and slowed reaction times. We investigate whether these minor stroke patients also display abnormal beta band activity. Magnetoencephalographic (MEG) data were collected from nine minor stroke patients (NIHSS < 4) without significant hemiparesis, at ~1 and ~6 months postinfarct, and eight age-similar controls. Rolandic relative beta power during matching tasks and resting state, and Beta Event Related (De)Synchronization (ERD/ERS) during button press responses were analyzed. Regardless of lesion location, patients had significantly reduced relative beta power and ERS compared to controls. Abnormalities persisted over visits, and were present in both ipsi- and contra-lesional hemispheres, consistent with bilateral impairments in motor dexterity and speed. Minor stroke patients without severe weakness display reduced rolandic beta band activity in both hemispheres, which may be linked to bilaterally impaired dexterity and processing speed, implicating global connectivity dysfunction affecting sensorimotor cortex independent of lesion location. Findings not only illustrate global network disruption after minor stroke, but suggest rolandic beta band activity may be a potential biomarker and treatment target, even for minor stroke patients with small lesions far from sensorimotor areas.
Dynamical Network Models From EEG and MEG for Epilepsy Surgery—A Quantitative Approach
Authors: Cao Miao , Vogrin Simon J. , Peterson Andre D. H. , Woods William , Cook Mark J. , Plummer Chris
Published: March 2022

There is an urgent need for more informative quantitative techniques that non-invasively and objectively assess strategies for epilepsy surgery. Invasive intracranial electroencephalography (iEEG) remains the clinical gold standard to investigate the nature of the epileptogenic zone (EZ) before surgical resection. However, there are major limitations of iEEG, such as the limited spatial sampling and the degree of subjectivity inherent in the analysis and clinical interpretation of iEEG data. Recent advances in network analysis and dynamical network modeling provide a novel aspect toward a more objective assessment of the EZ. The advantage of such approaches is that they are data-driven and require less or no human input. Multiple studies have demonstrated success using these approaches when applied to iEEG data in characterizing the EZ and predicting surgical outcomes. However, the limitations of iEEG recordings equally apply to these studies—limited spatial sampling and the implicit assumption that iEEG electrodes, whether strip, grid, depth or stereo EEG (sEEG) arrays, are placed in the correct location. Therefore, it is of interest to clinicians and scientists to see whether the same analysis and modeling techniques can be applied to whole-brain, non-invasive neuroimaging data (from MRI-based techniques) and neurophysiological data (from MEG and scalp EEG recordings), thus removing the limitation of spatial sampling, while safely and objectively characterizing the EZ. This review aims to summarize current state of the art non-invasive methods that inform epilepsy surgery using network analysis and dynamical network models. We also present perspectives on future directions and clinical applications of these promising approaches.
Nonlinear Association of Glycosylated Hemoglobin With Single Intracranial Aneurysm Rupture in Patients With Diabetes Mellitus: A Cross-Sectional Study
Authors: Su Shi-Xing , Wang Xue-Tao , Li Xi-Feng , Duan Chuan-Zhi , Bi Yi-Ming , Zhang Xin
Published: March 2022

Background

The published literature linking diabetes mellitus (DM) to intracranial aneurysm (IA) ruptured has been controversial and limited by methodology. Thus, this study was performed to examine whether hyperglycemia control status is independently associated with single IA rupture in patients with DM.

Methods

We conducted a cross-sectional study on two Chinese hospitals between January 2010 and November 2017. Medical records of 223 patients with single IA and DM were reviewed and analyzed. We used glycosylated hemoglobin (GHB) as the independent variable of interest, and the outcome variable was ruptured status of IA. Covariates included data on demographics, morphological parameters, lifestyle habits, clinical features, and comorbidities.

Results

Multivariable adjusted binary logistic regression and sensitivity analyses indicated that GHB was not associated with IA rupture (odds ratio OR, = 1.07, 95% CI 0.84–1.35). A nonlinear association between GHB and IA rupture was observed, whose inflection points were 5.5 and 8.9. The OR values (95% confidence intervals) were 0.38 (0.16–0.9) at the range of 1.88–5.5% of GHB, 1.6 (1.03, 2.5) at the range of 5.5–8.9%, and 0.56 (0.06–5.34) at the range of 8.9–10.1, respectively.

Conclusion

The independent correlation between GHB and risk of IA rupture presented is nonlinear. The good glycemic control in single IA patients with DM can reduce the risk of IA rupture, and vice versa.
A Cell Cycle-Related 13-mRNA Signature to Predict Prognosis in Hepatocellular Carcinoma
Authors: Zhou Yang , Lei Dengliang , Hu Gangli , Luo Fang
Published: March 2022

We aimed to propose a cell cycle-related multi/mRNA signature (CCS) for prognosis prediction and uncover new tumor-driver genes for hepatocellular carcinoma (HCC). Cell cycle-related gene sets and HCC samples with mRNA-Seq data were retrieved from public sources. The genes differentially expressed in HCCs relative to normal peritumoral tissues were extracted through statistical analysis. The CCS was constructed by Cox regression analyses. Predictive capacity and clinical practicality of the signature were evaluated and validated. The expression of the function-unknown genes in the CCS was determined by RT-qPCR. Candidate gene TICRR was selected for subsequent validation through functional experiments. A cell cycle-related 13-mRNA signature was generated from the exploratory cohort [The Cancer Genome Atlas (TCGA), n = 371)]. HCC cases were classified as high- vs. low-risk groups per overall survival (OS) [hazard ratio (HR) = 2.699]. Significantly, the CCS exhibited great predictive value for prognosis in three independent cohorts, particularly in GSE76427 cohort [area under the curve (AUC) = 0.835/0.822/0.808/0.821/0.826 at 1/2/3/4/5 years]. The nomogram constructed by integrating clinicopathological features with the CCS indicated high accuracy and practicability. Significant enrichment of tumorigenesis-associated pathways was observed in the high-risk patients by Gene Set Enrichment Analysis (GSEA). RT-qPCR revealed that TICRR was overexpressed in HCC samples. Increased TICRR expression implied poor prognosis in HCC patients. Furthermore, depletion of TICRR in HCC cells decreased cell proliferation and the G1/S transition. In conclusion, the established 13-CCS had efficacy in prognostic prediction of HCC patients. Additionally, TICRR was demonstrated as a tumor-driver gene for this deadly disease.
Transcatheter Arterial Chemoembolization in Combination With High-Intensity Focused Ultrasound for Intermediate and Advanced Hepatocellular Carcinoma: A Meta-Analysis
Authors: Wang Yun-Bing , Ma Rong , Wang Zhi-Biao , Shi Qiu-Ling , Zhang Lian , Chen Wen-Zhi , Gong Jian-Ping , Bai Jin
Published: March 2022

Background

The study was conducted to explore whether high-intensity focused ultrasound (HIFU) can improve the effect of transcatheter arterial chemoembolization (TACE) in intermediate and advanced hepatocellular carcinoma (HCC).

Methods

PubMed, Embase, Cochrane Library, Web of Science, Wanfang Data, CQVIP, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical (CBM) databases were searched for randomized controlled trials (RCTs) comparing the effect of TACE in combination with HIFU group (group A) to TACE alone group (group B) in treating intermediate and advanced HCC. The primary outcomes were overall survival (OS) rate and tumor response rate. The odds ratio (OR) and 95% confidence interval (CI) for each study were calculated and then pooled with fixed effects model or random effects model. Sensitivity analyses and subgroup analyses were conducted. A publication bias was also evaluated.

Results

After literature selection, eleven RCTs involving 803 patients were included in this meta-analysis. This meta-analysis revealed that group A was associated with an increased 6-month OS rate (OR = 0.20), 12-month OS rate (OR = 0.23), 24-month OS rate (OR = 0.32), and overall response rate (WHO criterion, OR = 0.22; RECIST criterion, OR = 0.30). Furthermore, subgroup analyses showed no bias in the result. Given the limited number of studies that reported major complications, no additional meta-analysis of complication was conducted. Despite no special treatment, any complication following HIFU treatment was found to subside within 3-7 days.

Conclusion

TACE in combination with HIFU is associated with increased OS and tumor response in intermediate and advanced HCC. Current evidence supports the use of HIFU after TACE treatment in intermediate and advanced HCC.
Chemoradiotherapy Versus Chemotherapy Alone for Advanced Esophageal Squamous Cell Carcinoma: The Role of Definitive Radiotherapy for Primary Tumor in the Metastatic Setting
Authors: Li Li-Qing , Fu Qing-Guo , Zhao Wei-Dong , Wang Yu-Dan , Meng Wan-Wan , Su Ting-Shi
Published: March 2022

Introduction

The role of definitive radiotherapy in advanced esophageal squamous cell carcinoma (ESCC), especially in the metastatic setting, remains unclear. Therefore, we aimed to investigate the efficacy of chemoradiotherapy (CRT) versus chemotherapy (CT) alone in these selected patients.

Methods

We retrospectively evaluated 194 newly diagnosed advanced ESCC who underwent definitive CRT or CT alone, including 97 patients with locally advanced and 97 patients with distant metastatic disease. Cumulative overall survival (OS) and progression-free survival (PFS) were evaluated with a log-rank test. Propensity score matching was used to simulate random allocation. In addition, we performed subgroup analysis in the locally advanced and metastatic disease.

Results

After matching, 63 well-paired patients were selected. The adjusted median OS (12.5 vs. 7.6 months, p = 0.002) and PFS (9.0 vs. 4.8 months, p = 0.0025) in the CRT group were superior to that in the CT-alone group. Further subgroup analysis revealed that CRT conferred survival benefits to both locally advanced and metastatic cohorts. For patients with distant metastasis, median OS (12.9 vs. 9.3 months, p = 0.029) and PFS (9.9 vs. 4.0 months, p =0.0032) in the CRT group were superior to that in the CT-alone group. In a multivariate Cox regression analysis of the entire cohort, additional definitive radiotherapy was independently associated with better OS (p = 0.041) and PFS (p = 0.007).

Conclusions

In both locally advanced and metastatic ESCC, additional definitive-dose radiotherapy was associated with improved clinical outcomes. Therefore, more consideration should be given to its application in the metastatic setting.
Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53
Authors: Butz Henriett , Lövey József , Szentkereszty Márton , Bozsik Anikó , Tóth Erika , Patócs Attila
Published: March 2022

Since the introduction of next-generation sequencing, the frequency of germline pathogenic TP53 variants and the number of cases with unusual clinical presentations have been increasing. This has led to the expansion of the classical Li–Fraumeni syndrome concept to a wider cancer predisposition syndrome designated as the Li–Fraumeni spectrum. Here, we present a case with a malignant, metastatic perivascular epithelioid cell tumor (PEComa) of the thigh muscle and a sinonasal carcinoma harboring a novel TP53 germline splice mutation (NM_000546.5:c.97-2A>C). The classical presentation of LFS in the long-since deceased mother and the presence of a germline TP53 variant in the proband suggested a possible familial TP53-related condition. Complex pathological, molecular, and clinical genetic analyses (whole exome sequencing of germline variants, multigene panel sequencing of tumor DNA, Sanger validation, an in vitro functional test on splicing effect, 3D protein modeling, p53 immunohistochemistry, and pedigree analysis) were performed. The in vitro characterization of the splice mutation supported the pathogenic effect that resulted in exon skipping. A locus-specific loss of heterozygosity in the PEComa but not in the sinonasal carcinoma was identified, suggesting the causative role of the splice mutation in the PEComa pathogenesis, because we excluded known pathogenetic pathways characteristic to PEComas (TSC1/2, TFE3, RAD51B). However, the second hit affecting TP53 in the molecular pathogenesis of the sinonasal carcinoma was not identified. Although PEComa has been reported previously in two patients with Li–Fraumeni syndrome, to the best of our knowledge, this is the first report suggesting a relationship between the aberrant TP53 variant and PEComa.
Integrated Network Pharmacology and Experimental Verification to Explore the Molecular Mechanism of Hedysarum Multijugum Maxim–Curcumae Rhizoma Herb Pair for Treating Non-Small Cell Lung Cancer
Authors: Hu Shaopu , Ge Mengxue , Zhang Shuixiu , Jiang Min , Hu Kaiwen , Gao Lei
Published: March 2022

Background

Hedysarum Multijugum Maxim–Curcumae Rhizoma (HMMCR), a well-known herb pair in traditional Chinese medicine (TCM), has been widely used for the treatment of various cancers. However, the active components of HMMCR and the underlying mechanism of HMMCR for non-small-cell lung carcinoma (NSCLC) remain unclear.

Methods

Active ingredients of HMMCR were detected by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). On this basis, potential targets of HMMCR were obtained from SwissTargetPrediction database. NSCLC-related targets were collected from four public databases (GeneCards, OMIM, TTD, and PharmGkb). The drug ingredients–disease targets network was visualized. The hub targets between HMMCR and NSCLC were further analyzed by protein–protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Subsequently, the results predicted by network pharmacology were further validated via in vitro experiments.

Results

A total of 181 compounds were identified from the aqueous extract of HMMCR. Through network analysis, a compound–target network including 153 active ingredients of HMMCR and 756 HMMCR-NSCLC co-targets was conducted; 6 crucial compounds and 62 hub targets were further identified. The results of KEGG enrichment analysis showed that PI3K/Akt signaling pathway may be the critical pathway of HMMCR in the treatment of NSCLC. The in vitro experiments indicated that HMMCR inhibits the proliferation and migration of NSCLC cells via inactivation of the PI3K/Akt signaling pathway, consistent with the results predicted by network pharmacology.

Conclusion

Integrating LC-ESI-MS/MS, network pharmacology approach, and in vitro experiments, this study shows that HMMCR has vital therapeutic effect on NSCLC through multi-compound, multi-target, and multi-pathway, which provides a rationale for using HMMCR for the treatment of NSCLC.
Risk Stratification and Distribution of Hepatocellular Carcinomas in CEUS and CT/MRI LI-RADS: A Meta-Analysis
Authors: Zhou Yan , Qin Zhengyi , Ding Jianmin , Zhao Lin , Chen Ying , Wang Fengmei , Jing Xiang
Published: March 2022

Background

CEUS LI-RADS and CT/MRI LI-RADS have been used in clinical practice for several years. However, there is a lack of evidence-based study to compare the proportion of hepatocellular carcinomas (HCCs) in each category and the distribution of HCCs of these two categorization systems.

Purpose

The purpose of this study was to compare the proportion of HCCs between corresponding CEUS LI-RADS and CT/MRI LI-RADS categories and the distribution of HCCs and non-HCC malignancies in each category.

Methods

We searched PubMed, Embase, and Cochrane Central databases from January 2014 to December 2021. The proportion of HCCs and non-HCC malignancies and the corresponding sensitivity, specificity, accuracy, diagnostic odds ratio (DOR), and area under the curve (AUC) of the LR-5 and LR-M categories were determined using a random-effect model.

Results

A total of 43 studies were included. The proportion of HCCs in CEUS LR-5 was 96%, and that in CECT/MRI LR-5 was 95% (p > 0.05). The proportion of non-HCC malignancy in CEUS LR-M was lower than that of CT/MRI LR-M (35% vs. 58%, p = 0.01). The sensitivity, specificity, and accuracy of CEUS LR-5 for HCCs were 73%, 92%, and 78%, respectively, and of CT/MRI LR-5 for HCCs, 69%, 92%, and 76%, respectively.

Conclusion

With the upshift of the LI-RADS category, the proportion of HCCs increased. CEUS LR-3 has a lower risk of HCCs than CT/MRI LR-3. CEUS LR-5 and CT/MRI LR-5 have a similar diagnostic performance for HCCs. CEUS LR-M has a higher proportion of HCCs and a lower proportion of non-HCC malignancies compared with CT/MRI LR-M.
Comparison of Effectiveness of Two Different Doses of Propranolol on Kaposiform Hemangioendothelioma
Authors: Wei Li , Li Li , Xu Zigang , Zhang Bin , Han Xiaofeng , Wang Chen , Liu Yuanxiang , Xiu Bingyu , Qiu Lei , Sun Yujuan , Ma Lin
Published: March 2022

Objective

To compare the clinical efficacy and safety of two different doses of propranolol in the treatment of cutaneous kaposiform hemangioendothelioma (KHE).

Methods

The cohort of this prospective case–control study comprised 11 children with KHE treated from October 2015 to August 2018 in our institution. All participants were clinically and pathologically diagnosed as having cutaneous KHE. The children were allocated to two groups: six children in Group A (low-dose group) received oral propranolol 1.5 mg/kg/d, whereas five in Group B (high-dose group) received oral propranolol 2 mg/kg/d. The children were checked and photographed before and after treatment. Changes in the tumors were tracked by clinical and ultrasound examination. Follow-up visits to monitor for adverse reactions occurred regularly.

Results

Grade I, Grade II, and Grade IV improvements in tumors were each noted in one child in Group A (three improved in total) and Grade III in two and Grade IV in another two children in Group B (four improved in total). Oral propranolol was effective in 50 and 80% of children in Groups A and B, respectively; this difference is statistically significant (P < 0.01). Minor adverse reactions occurred in eight of the 11 children.

Conclusions

Propranolol treatment is effective against cutaneous KHE. There were no serious adverse reactions, and the treatment was safe in the long term. A dose of 2 mg/kg/d was more effective than 1.5 mg/kg/d in the treatment of KHE and did not increase the rate of adverse reactions. Children with KHE should be treated with propranolol 2 mg/kg/d orally.
Increased Risk for Thromboembolism After Fontan Surgery: Considerations for Thromboprophylaxis
Authors: Van Den Helm Suelyn , Sparks Christopher Noel , Ignjatovic Vera , Monagle Paul , Attard Chantal
Published: March 2022

The Fontan circulation introduces an increased risk of thromboembolism which is associated with substantial mortality and morbidity. Adverse outcomes of thromboembolic complications post-Fontan surgery vary in both nature and severity, ranging from local tissue infarction and pulmonary embolism to Fontan failure and ischemic stroke. Furthermore, recent studies have identified that subclinical stroke is common yet underdiagnosed in Fontan patients. Fontan patients are commonly treated with antiplatelet agents and/or anticoagulants as primary thromboprophylaxis. Optimal thromboprophylaxis management in the Fontan population is still unclear, and clinical consensus remains elusive despite the growing literature on the subject. This perspective will describe the nature of thromboembolism post-Fontan surgery and provide evidence for the use of both current and emerging thromboprophylaxis options for children and adults living with Fontan circulation.
Application of Intra-articular Corticosteroid Injection in Juvenile Idiopathic Arthritis
Authors: Li Sha , Zhang Wei , Lin Yan
Published: March 2022

Juvenile idiopathic arthritis (JIA) is one of the common rheumatic diseases in pediatrics. Persistent synovitis and joint pain cause reduced range of motion, deformity and gait interruption, which are important reasons for children's disability and a decline in their quality of life. Rheumatology experts have explored good treatment strategies, among which intra-articular corticosteroid injections (IACIs) targeting joints can greatly reduce these systemic adverse reactions while still obtaining local anti-inflammatory effects. Local inhibition of synovitis by the use of steroid hormones in a joint cavity can avoid or reduce adverse reactions of systemic therapy, prevent or treat leg length variance and joint contracture, solve Baker's cyst, improve tenosynovitis, promote physical therapy and rehabilitation, make gait change smoothly, relieve pain, and restore joint function. Given the importance of IACIs in treating JIA, this paper reviewed the case selection, drug injection, dose selection, current anesthesia and injection techniques, the efficacy, recurrence, and influencing factors of IACIs, the management of physiotherapy intervention post-injection, the application of ultrasound guidance and the safety and complications of IACIs in children with JIA. This study aims to guide the use of IACIs for the best approach throughout the review.
Liver Involvement in Acute Respiratory Infections in Children and Adolescents – Results of a Non-interventional Study
Authors: Kamin Wolfgang , Adams Ortwin , Kardos Peter , Matthys Heinrich , Meister Norbert , Strassburg Christian P.
Published: March 2022

Background

In children and adults with acute respiratory tract infections (ARTI), elevations of serum liver enzyme activities are frequently observed in clinical practice. However, epidemiological data particularly in the pediatric population are very limited. The aim of this study was to assess the incidence of hepatic involvement, to identify the viruses and to analyze risk factors in children and adolescents with ARTI in a real-world setting.

Methods

We report on a prospective, multicenter, non-interventional study with 1,010 consecutive patients aged 1–17 years with ARTI who consulted a physician within 5 days after onset of symptoms. Laboratory blood tests and PCR virus detection in nasopharyngeal lavage were performed at first presentation and after 3–7 days. Patients with elevated activities of serum liver enzymes (ASAT, ALAT, and γ-GT) were determined in local laboratories and values were normalized by dividing by the individual upper limit of the normal range (ULN). The resulting index (<1 means below ULN, >1 means above ULN) allowed to compare results from laboratories with different reference ranges.

Results

Laboratory test results of 987 patients were available at first visit. 11.1% (95% CI: 9.2–13.3%) exhibited an elevation of ASAT, ALAT, and/or γ-GT activities. Virus DNA or RNA was identified in nasopharyngeal lavages of 63% of the patients. 12.2% of patients with positive PCR and 9.7% of those with negative PCR (p = 0.25) had elevated serum liver enzyme activities. The highest rates were observed in patients with a positive result for influenza B virus (24.4%) followed by human metapneumovirus (14.6%), and human coronavirus (others than SARS-CoV-2) (13.6%). The rate of children and adolescents with ARTI and elevation of serum liver enzyme activities correlated with the virus species and with overweight of the patients but did not differ in patients with or without previous medication intake.

Conclusion

Elevated enzyme activities are present in about 10% of children and adolescents with ARTI. In our cohort, these elevations were mild to moderate; probably resulting from an inflammation process with hepatic involvement.
Qingda Granule Attenuates Angiotensin II-Induced Renal Apoptosis and Activation of the p53 Pathway
Authors: Long Linzi , Zhang Xiuli , Wen Ying , Li Jiapeng , Wei Lihui , Cheng Ying , Liu Huixin , Chu Jianfeng , Fang Yi , Xie Qiurong , Shen Aling , Peng Jun
Published: March 2022

Background: Qingda granules (QDG) exhibit antihypertension and multiple-target-organ protection. However, the therapeutic potential of QDG on hypertensive renal injury remains unknown. Therefore, the main objective of the current study is to explore the effects and underlying mechanisms of QDG treatment on renal injury in angiotensin (Ang) II-infused mice.

Methods and results: Mice were infused with Ang II (500 ng/kg/min) or saline for 4 weeks with subcutaneously implanted osmotic pumps. After infusion, mice in the Ang II + QDG group were intragastrically administrated with QDG daily (1.145 g/kg/day), whereas the control group and Ang II group were intragastrically administrated with the same amount of double-distilled water. Blood pressure of the mice monitored using the CODA™ noninvasive blood pressure system revealed that QDG treatment significantly attenuated elevated blood pressure. Moreover, hematoxylin–eosin staining indicated that QDG treatment ameliorated Ang II-induced renal morphological changes, including glomerular sclerosis and atrophy, epithelial cell atrophy, and tubular dilatation. RNA-sequencing (RNA-seq) identified 662 differentially expressed transcripts (DETs) in renal tissues of Ang II-infused mice, which were reversed after QDG treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis based on DETs in both comparisons of Ang II vs. Control and Ang II + QDG vs. Ang II identified multiple enriched pathways, including apoptosis and p53 pathways. Consistently, terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining and Annexin V staining revealed that QDG treatment significantly attenuated Ang II-induced cell apoptosis in renal tissues and cultured renal tubular epithelial cell lines (NRK-52E). Furthermore, western blot analysis indicated that Ang II infusion significantly upregulated the protein expression of p53, BCL2-associated X (BAX), cle-caspase-9, and cle-caspase-3, while downregulating the protein expression of BCL-2 in renal tissues, which were attenuated after QDG treatment.

Conclusion: Collectively, QDG treatment significantly attenuated hypertensive renal injury, partially by attenuating renal apoptosis and suppressing p53 pathways, which might be the underlying mechanisms.
Translational Pharmacokinetic–Pharmacodynamic Modeling of NaV1.7 Inhibitor MK-2075 to Inform Human Efficacious Dose
Authors: Ballard Jeanine E. , Pall Parul S. , Vardigan Joshua , Zhao Fuqiang , Holahan Marie A. , Zhou Xiaoping , Jochnowitz Nina , Kraus Richard L. , Klein Rebecca M. , Henze Darrell A. , Houghton Andrea K. , Burgey Christopher S. , Gibson Christopher , Struyk Arie
Published: March 2022

MK-2075 is a small-molecule selective inhibitor of the NaV1.7 channel investigated for the treatment of postoperative pain. A translational strategy was developed for MK-2075 to quantitatively interrelate drug exposure, target modulation, and the desired pharmacological response in preclinical animal models for the purpose of human translation. Analgesics used as a standard of care in postoperative pain were evaluated in preclinical animal models of nociceptive behavior (mouse tail flick latency and rhesus thermode heat withdrawal) to determine the magnitude of pharmacodynamic (PD) response at plasma concentrations associated with efficacy in the clinic. MK-2075 was evaluated in those same animal models to determine the concentration of MK-2075 required to achieve the desired level of response. Translation of MK-2075 efficacious concentrations in preclinical animal models to a clinical PKPD target in humans was achieved by accounting for species differences in plasma protein binding and in vitro potency against the NaV1.7 channel. Estimates of human pharmacokinetic (PK) parameters were obtained from allometric scaling of a PK model from preclinical species and used to predict the dose required to achieve the clinical exposure. MK-2075 exposure–response in a preclinical target modulation assay (rhesus olfaction) was characterized using a computational PKPD model which included a biophase compartment to account for the observed hysteresis. Translation of this model to humans was accomplished by correcting for species differences in PK NaV1.7 potency, and plasma protein binding while assuming that the kinetics of distribution to the target site is the same between humans and rhesus monkeys. This enabled prediction of the level of target modulation anticipated to be achieved over the dosing interval at the projected clinical efficacious human dose. Integration of these efforts into the early development plan informed clinical study design and decision criteria.
Asthma Therapies on Pulmonary Tuberculosis Pneumonia in Predominant Bronchiectasis–Asthma Combination
Authors: Yeh Jun-Jun , Lin Hui-Chuan , Yang Yu-Cih , Hsu Chung-Y. , Kao Chia-Hung
Published: March 2022

Background: It is sometimes difficult to distinguish between asthma and bronchiectasis as their symptoms overlap, and these two diseases are associated with pulmonary tuberculosis (PTB) or pneumonia.

Objective: The purpose of this study is to determine the effects of bronchodilator drugs, steroids, antidepressants drugs, and antianxiety drugs on the risks of PTB or pneumonia in patients with bronchiectasis–asthma combination or bronchiectasis–asthma–chronic obstructive pulmonary disease combination—BCAS cohort.

Methods: After propensity score matching, we retrospectively studied patients with BCAS (N = 620) and without BCAS (N = 2,314) through an analysis. The cumulative incidence of PTB or pneumonia was analyzed through Cox proportional regression. After adjustment for sex, age, comorbidities, and medications [including long-acting beta2 agonist/muscarinic antagonists (LABAs/LAMAs), short-acting beta2 agonist/muscarinic antagonists (SABAs/SAMAs), leukotriene receptor antagonist, montelukast, steroids (inhaled corticosteroids, ICSs; oral steroids, OSs), anti-depressants (fluoxetine), and anti-anxiety drugs (benzodiazepines, BZDs)], we calculated the adjusted hazard ratios (aHR) and their 95% confidence intervals (95% CI) for these risks. Similar to OSs, ICSs are associated with an increased risk of PTB or pneumonia, lumping these two as steroids (ICSs/OSs).

Results: For the aHR (95% CI), with non-LABAs/non-OSs as the reference 1, the use of LABAs [0.70 (0.52–0.94)]/OSs [0.35 (0.29–0.44)] was associated with a lower risk of PTB or pneumonia. However, the current use of LABAs [2.39 (1.31–4.34)]/SABAs [1.61 (1.31–1.96)], steroids [ICSs 3.23 (1.96–5.29)]/OSs 1.76 (1.45–2.14)], and BZDs [alprazolam 1.73 (1.08–2.75)/fludiazepam 7.48 (1.93–28.9)] was associated with these risks. The current use of LAMAs [0.52 (0.14–1.84)]/SAMAs [1.45 (0.99–2.11)] was not associated with these risks.

Conclusion: The current use of LAMAs/SAMAs is relatively safe with respect to PTB or pneumonia risks, but LABAs/SABAs, steroids, and BZDs could be used after evaluation of the benefit for the BCAS cohort. However, we must take the possible protopathic bias into account.
Prescription Appropriateness of Drugs for Peptic Ulcer and Gastro-Esophageal Reflux Disease: Baseline Assessment in the LAPTOP-PPI Cluster Randomized Trial
Authors: Ardoino Ilaria , Casula Manuela , Molari Giulia , Mucherino Sara , Orlando Valentina , Menditto Enrica , Franchi Carlotta
Published: March 2022

Background: Drugs for peptic ulcer and gastro-esophageal reflux disease (GERD) are among the most widely prescribed, frequently without appropriate indications. This represents an important issue, as it leads to risk of adverse events for patients and unnecessary costs for National Health Service.

Aim: To assess the prescription appropriateness of drugs for GERD, in the frame of the “Evaluation of the effectiveness of a Low-cost informative intervention to improve the Appropriate PrescripTiOn of Proton PumP Inhibitors in older people in primary care: a cluster-randomized controlled study” (LAPTOP-PPI) (Clinicaltrial.gov: NCT04637750).

Methods: The appropriateness of drug prescription was assessed on data collected in administrative databases, by integrating information on concomitant medications, outpatient medical and laboratory procedures and hospital discharge diagnoses, according to the reimbursement criteria provided by the Italian Medicine Agency. We analyzed data of community-dwelling people aged 65 years and over, living in the areas of Bergamo (Northern Italy) and Caserta (Southern Italy), from July 1 to 31 December 2019.

Results: Among 380,218 patients, 175,342 (46.1%) received at least one prescription of drugs for GERD. All in all, we found that only 41.2% of patients received appropriate prescriptions.

Conclusion: Given the potential risk of adverse drug reactions, especially in older people, educational interventions should be prompted for physicians, in order to improve the quality of prescription of drugs for GERD and, in turn, avoid unfavorable health outcomes and unnecessary costs.
Absorption, Metabolism, and Excretion of ACT-1004-1239, a First-In-Class CXCR7 Antagonist: In Vitro, Preclinical, and Clinical Data
Authors: Huynh Christine , Seeland Swen , Segrestaa Jerome , Gnerre Carmela , Hogeback Jens , Meyer zu Schwabedissen Henriette E. , Dingemanse Jasper , Sidharta Patricia N.
Published: March 2022

ACT-1004-1239 is a potent, selective, first-in-class CXCR7 antagonist, which shows a favorable preclinical and clinical profile. Here we report the metabolites and the metabolic pathways of ACT-1004-1239 identified using results fromin vitroandin vivostudies. Two complementaryin vitrostudies (incubation with human liver microsomes in the absence/presence of cytochrome P450- [CYP] specific chemical inhibitors and incubation with recombinant CYPs) were conducted to identify CYPs involved in ACT-1004-1239 metabolism. For thein vivoinvestigations, a microtracer approach was integrated in the first-in-human study to assess mass balance and absorption, distribution, metabolism, and excretion (ADME) characteristics of ACT-1004-1239. Six healthy male subjects received orally 100 mg non-radioactive ACT-1004-1239 together with 1 μCi14C-ACT-1004-1239. Plasma, urine, and feces samples were collected up to 240 h post-dose and14C-drug-related material was measured with accelerator mass spectrometry. This technique was also used to construct radiochromatograms of pooled human samples. Metabolite structure elucidation of human-relevant metabolites was performed using high performance liquid chromatography coupled with high resolution mass spectrometry and facilitated by the use of rat samples. CYP3A4 was identified as the major CYP catalyzing the formation of M1in vitro. In humans, the cumulative recovery from urine and feces was 84.1% of the dose with the majority being eliminated via the feces (69.6%) and the rest via the urine (14.5%). In human plasma, two major circulating metabolites were identified, i.e., M1 and M23. EliminationviaM1 was the only elimination pathway that contributed to ≥25% of ACT-1004-1239 elimination. M1 was identified as a secondary amine metabolite following oxidative N-dealkylation of the parent. M23 was identified as a difluorophenyl isoxazole carboxylic acid metabolite following central amide bond hydrolysis of the parent. Other metabolites observed in humans were A1, A2, and A3. Metabolite A1 was identified as an analog of M1 after oxidative defluorination, whereas both, A2 and A3, were identified as a reduced analog of M1 and parent, respectively, after addition of two hydrogen atoms at the isoxazole ring. In conclusion, CYP3A4 contributes to a relevant extent to ACT-1004-1239 disposition and two major circulating metabolites were observed in humans.

Clinical Trial Registration:(https://clinicaltrials.gov/ct2/show/NCT03869320) ClinicalTrials.gov Identifier NCT03869320.
Canagliflozin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Inhibiting NF-κB Signaling and Upregulating Bif-1
Authors: Niu Yaoyun , Zhang Yuehui , Zhang Wanqiu , Lu Jinghua , Chen Yang , Hao Wenhui , Zhou Jin , Wang Lijun , Xie Weidong
Published: March 2022

NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is an important component of the innate immune system that mediates the secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. However, current studies have shown that the abnormal activation of the NLRP3 inflammasome is associated with inflammatory diseases such as atherosclerosis, diabetes, and pneumonia. In this study, we found that canagliflozin (CAN) transcriptionally inhibited NLRP3 inflammasome-related proteins by inhibiting the transduction of the nuclear factor κB signal. Autophagy is largely involved in the post-translational modifications of the NLRP3 inflammasome and is an important regulator of NLRP3 inflammasome assembly and activation. Bax-interacting factor 1 (Bif-1) plays an important role in autophagosome formation during early-stage autophagy. Our results are the first to indicate that CAN, a hypoglycemic drug, can inhibit the activation of NLRP3 inflammasome and inflammation by upregulating Bif-1 and autophagy in a non-hypoglycemic manner. This study provides new information regarding the treatment of patients with pneumonia, particularly those with concurrent diabetes.
Pulmonary Inflammatory Response in Lethal COVID-19 Reveals Potential Therapeutic Targets and Drugs in Phases III/IV Clinical Trials
Authors: López-Cortés Andrés , Guerrero Santiago , Ortiz-Prado Esteban , Yumiceba Verónica , Vera-Guapi Antonella , León Cáceres Ángela , Simbaña-Rivera Katherine , Gómez-Jaramillo Ana María , Echeverría-Garcés Gabriela , García-Cárdenas Jennyfer M. , Guevara-Ramírez Patricia , Cabrera-Andrade Alejandro , Puig San Andrés Lourdes , Cevallos-Robalino Doménica , Bautista Jhommara , Armendáriz-Castillo Isaac , Pérez-Villa Andy , Abad-Sojos Andrea , Ramos-Medina María José , León-Sosa Ariana , Abarca Estefanía , Pérez-Meza Álvaro A. , Nieto-Jaramillo Karol , Jácome Andrea V. , Morillo Andrea , Arias-Erazo Fernanda , Fuenmayor-González Luis , Quiñones Luis Abel , Kyriakidis Nikolaos C.
Published: March 2022

Background: It is imperative to identify drugs that allow treating symptoms of severe COVID-19. Respiratory failure is the main cause of death in severe COVID-19 patients, and the host inflammatory response at the lungs remains poorly understood.

Methods: Therefore, we retrieved data from post-mortem lungs from COVID-19 patients and performed in-depth in silico analyses of single-nucleus RNA sequencing data, inflammatory protein interactome network, and shortest pathways to physiological phenotypes to reveal potential therapeutic targets and drugs in advanced-stage COVID-19 clinical trials.

Results: Herein, we analyzed transcriptomics data of 719 inflammatory response genes across 19 cell types (116,313 nuclei) from lung autopsies. The functional enrichment analysis of the 233 significantly expressed genes showed that the most relevant biological annotations were inflammatory response, innate immune response, cytokine production, interferon production, macrophage activation, blood coagulation, NLRP3 inflammasome complex, and the TLR, JAK-STAT, NF-κB, TNF, oncostatin M signaling pathways. Subsequently, we identified 34 essential inflammatory proteins with both high-confidence protein interactions and shortest pathways to inflammation, cell death, glycolysis, and angiogenesis.

Conclusion: We propose three small molecules (baricitinib, eritoran, and montelukast) that can be considered for treating severe COVID-19 symptoms after being thoroughly evaluated in COVID-19 clinical trials.
Challenges in the Development of Drug Delivery Systems Based on Small Extracellular Vesicles for Therapy of Brain Diseases
Authors: Loch-Neckel Gecioni , Matos Ana Teresa , Vaz Ana Rita , Brites Dora
Published: March 2022

Small extracellular vesicles (sEVs) have ∼30–200 nm diameter size and may act as carriers of different cargoes, depending on the cell of origin or on the physiological/pathological condition. As endogenous nanovesicles, sEVs are important in intercellular communication and have many of the desirable features of an ideal drug delivery system. sEVs are naturally biocompatible, with superior targeting capability, safety profile, nanometric size, and can be loaded with both lipophilic and hydrophilic agents. Because of their biochemical and physical properties, sEVs are considered a promising strategy over other delivery vehicles in the central nervous system (CNS) since they freely cross the blood-brain barrier and they can be directed to specific nerve cells, potentiating a more precise targeting of their cargo. In addition, sEVs remain stable in the peripheral circulation, making them attractive nanocarrier systems to promote neuroregeneration. This review focuses on the recent progress in methods for manufacturing, isolating, and engineering sEVs that can be used as a therapeutic strategy to overcome neurodegeneration associated with pathologies of the CNS, with particular emphasis on Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis diseases, as well as on brain tumors.