bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensory-thresholded switch of neural firing states in a computational model of the ventromedial hypothalamus
Authors: Rahy Ryan , Asari Hiroki , Gross Cornelius T.
Published: September 2022

The mouse ventromedial hypothalamus (VMH) is both necessary and sufficient for defensive responses to predator and social threats. Defensive behaviors typically involve cautious approach toward potentially threatening stimuli aimed at obtaining information about the risk involved, followed by sudden avoidance and flight behavior to escape harm. In vivo neural recording studies in mice have identified two major populations of VMH neurons that either increase their firing activity as the animal approaches the threat (called Assessment+ cells) or increase their activity as the animal flees the threat (called Flight+ cells). Interestingly, Assessment+ and Flight+ cells abruptly decrease and increase their firing activity, respectively, at the decision point for flight, creating an escape-related “switch” in functional state. This suggests that the activity of the two cell types in VMH is coordinated and could result from local circuit interactions. Here, we used computational modeling to test if a local inhibitory feedback circuit could give rise to key features of the neural activity seen in VMH during the approach-to-flight transition. Starting from a simple dual-population inhibitory feedback circuit receiving repeated trains of monotonically increasing sensory input to mimic approach to threat, we tested the requirement for balanced sensory input, balanced feedback, short-term synaptic plasticity, rebound excitation, and inhibitory feedback exclusivity to reproduce an abrupt, sensory-thresholded reciprocal firing change that resembles Assessment+ and Flight+ cell activity seen in vivo. Our work demonstrates that a relatively simple local circuit architecture is sufficient for the emergence of firing patterns similar to those seen in vivo and suggests that a reiterative process of experimental and computational work may be a fruitful avenue for better understanding the functional organization of mammalian instinctive behaviors at the circuit level.
Anomalous cerebral morphology of pregnant women with cleft fetuses
Authors: Li Zhen , Li Chunlin , Liang Yuting , Wang Keyang , Wang Li , Zhang Xu , Wu Qingqing
Published: September 2022

Objective

Pregnancy leads to long-lasting changes in brain structure for healthy women; however, little is known regarding alterations in the cortical features of pregnant women with malformed fetuses. Isolated clefts of the lip and/or palate (ICL/P) are the most common congenital anomaly in the craniofacial region, which is highly gene-associated. We speculated that pregnant women carrying fetuses with ICL/P may have associated risk genes and specific brain changes during pregnancy.

Methods

In this study, we investigated T1-weighted brain magnetic resonance imaging data from 48 pregnant women: 24 women carrying fetuses with ICL/P (ICL/P group) and 24 women carrying normal fetuses (normal controls), then explored intergroup differences in gray matter volume (GMV), cortical thickness (CT) and cortical complexity (gyrification).

Results

Compared with controls, the ICL/P group had decreased total intracranial volume (TIV) than normal controls; besides, they exhibited increased GMV in the left cuneus, decreased GMV in the right superior temporal gyrus; increased CT in the left precuneus and left superior parietal gyrus, decreased CT involving parsopercularis, fusiform, middle temporal in the left hemisphere and supramarginal, precentral gyrus (PreCG) in the right hemisphere; increased gyrification in the left insula and PreCG, the left middle temporal, and the right supratemporal gyrus.

Conclusion

Pregnant women with ICL/P fetuses had brain morphology changes involving language, auditory, vision, and sensory cortex, which may be their special brain changes compared to normal pregnant women. This study may provide clues for the early detection of fetuses with ICL/P, and be vital for preconception and prenatal counseling with non-invasive methods.
On the reliability of deep learning-based classification for Alzheimer’s disease: Multi-cohorts, multi-vendors, multi-protocols, and head-to-head validation
Authors: Song Yeong-Hun , Yi Jun-Young , Noh Young , Jang Hyemin , Seo Sang Won , Na Duk L. , Seong Joon-Kyung
Published: September 2022

Structural changes in the brain due to Alzheimer’s disease dementia (ADD) can be observed through brain T1-weighted magnetic resonance imaging (MRI) images. Many ADD diagnostic studies using brain MRI images have been conducted with machine-learning and deep-learning models. Although reliability is a key in clinical application and applicability of low-resolution MRI (LRMRI) is a key to broad clinical application, both are not sufficiently studied in the deep-learning area. In this study, we developed a 2-dimensional convolutional neural network-based classification model by adopting several methods, such as using instance normalization layer, Mixup, and sharpness aware minimization. To train the model, MRI images from 2,765 cognitively normal individuals and 1,192 patients with ADD from the Samsung medical center cohort were exploited. To assess the reliability of our classification model, we designed external validation in multiple scenarios: (1) multi-cohort validation using four additional cohort datasets including more than 30 different centers in multiple countries, (2) multi-vendor validation using three different MRI vendor subgroups, (3) LRMRI image validation, and finally, (4) head-to-head validation using ten pairs of MRI images from ten individual subjects scanned in two different centers. For multi-cohort validation, we used the MRI images from 739 subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort, 125 subjects from the Dementia Platform of Korea cohort, 234 subjects from the Premier cohort, and 139 subjects from the Gachon University Gil Medical Center. We further assessed classification performance across different vendors and protocols for each dataset. We achieved a mean AUC and classification accuracy of 0.9868 and 0.9482 in 5-fold cross-validation. In external validation, we obtained a comparable AUC of 0.9396 and classification accuracy of 0.8757 to other cross-validation studies in the ADNI cohorts. Furthermore, we observed the possibility of broad clinical application through LRMRI image validation by achieving a mean AUC and classification accuracy of 0.9404 and 0.8765 at cross-validation and AUC and classification accuracy of 0.8749 and 0.8281 at the ADNI cohort external validation.
A spinal manipulative therapy altered brain activity in patients with lumbar disc herniation: A resting-state functional magnetic resonance imaging study
Authors: Wen Ya , Chen Xiao-Min , Jin Xin , Ling Dong-Ya , Chen Shao , Huang Qin , Kong Ning , Chai Jin-Er , Wang Qing , Xu Mao-Sheng , Du Hong-Gen
Published: September 2022

Purpose

Lumbar disc herniation (LDH) is one of the leading causes of low-back pain and results in a series of clinical symptoms, including pain, reflex loss, and muscle weakness. Spinal manipulative therapy (SMT) can relieve pain and promote internal and external stabilization of the lumbar spine. In this study, we investigated whether the brain alterations of LDH patients with SMT were frequency-dependent based on the calculation of Amplitude of Low-Frequency Fluctuations (ALFF) and fractional ALFF (fALFF). Further, we established a cohort of LDH patients to evaluate the contribution of SMT treatments to brain functional reorganization.

Methods

A total of 55 participants, including 27 LDH patients and 28 health controls (HCs), were collected. All LDH patients underwent two fMRI scans (before SMT and after the sixth SMT session). To represent LDH-related brain oscillatory activities, we calculated the ALFF and fALFF in the conventional band (0.01–0.08 Hz), the slow-4 band (0.027–0.073 Hz), and the slow-5 band (0.01–0.027 Hz). Moreover, we extracted ALFF and fALFF values in clusters with significant differences to evaluate the SMT effect.

Results

Compared with HCs, the LDH patients before SMT (LDH-pre) exhibited increased fALFF in right lingual gyri in the conventional band, and showed increased fALFF in left Cerebelum_Crus1 in the slow-4 band. We further examined the abnormal brain activities changes before and after the SMT intervention. The ALFF and fALFF values of LDH-pre group were higher than those of the HCs and LDH-pos groups. After SMT, the increased ALFF and fALFF values were suppressed for patients in conventional band and slow-4 band.

Conclusion

The present study characterized the altered regional patterns in spontaneous neural activity in patients with LDH. Meanwhile, SMT is an effective treatment of LDH, and we supposed that it might have been involved in modulating dysfunctional brain regions which are important for the processing of pain. The findings of the current study may provide new insights to understand pathological mechanism of LDH.
Interest of the BLAST paradigm and salivary markers for the evaluation of sleepiness in drivers
Authors: Thieux Marine , Guyon Aurore , Herbillon Vania , Merle Lydie , Lachaux Jean-Philippe , Plancoulaine Sabine , Seugnet Laurent , Franco Patricia
Published: September 2022

Objectives

Sleepiness is associated with decreased cognitive abilities and remains one of the main causes of fatal road accidents. The tools currently available to assess sleepiness, such as questionnaires, are subject to intra- and inter-individual variability, while multiple sleep latency tests are only feasible in few sleep laboratories. The main objective of this study was to explore new potential markers (neurocognitive, biological) to objectively assess sleepiness in drivers.

Methods

A total of 186 drivers (median age 44 years, range 20–74 years, 73% men, 14% obese) were included during a break at a highway service area, in the morning, while on the road for vacation. Questionnaires on sleepiness and sleep characteristics (habitual and on the night before travel), the Bron-Lyon Attention Stability Test (BLAST), and two salivary samples (α-amylase and oxalate) were collected. Associations between measures of sleepiness [Epworth Sleepiness Scale (ESS), and Stanford Sleepiness Scale (SSS)], sleep characteristics, neurocognitive, and biological markers were tested using regression models adjusted for confounding factors.

Results

The night before travel, 83% of the drivers reduced their sleep time and 30% slept 5 h or less. The higher the number of miles to be traveled, the higher the decrease, and the shorter the sleep time. The night before travel, 18 and 24% of the drivers complained of poor sleep quality and difficulty falling asleep. The sleep characteristics on the night before travel were associated with the habitual sleep characteristics. At the time of the test, 47% of the drivers scored pathologically on the SSS. Poor sleep quality and difficulty falling asleep the night before travel were associated with increased sleepiness as assessed by the SSS and decreased attentional ability as assessed by the BLAST. No association between salivary markers and acute sleepiness was observed.

Conclusions

The sleep characteristics of the night before travel were associated with sleepiness and attentional performance. The SSS and the BLAST could be used by individual drivers in a self-evaluation context. Biological markers showed a high variability and limited association with sleep parameters across subjects, emphasizing the need for within-subject designs to assess their usefulness.
A neglected neurodegenerative disease: Adult-onset globoid cell leukodystrophy
Authors: Wu Guode , Li Zhenhua , Li Jing , Li Xin , Wang Manxia , Zhang Jing , Liu Guangyao , Zhang Pengfei
Published: September 2022

Globoid cell leukodystrophy (GLD), or Krabbe disease (KD) is a rare neurodegenerative disease, and adult-onset GLD is more even neglected by clinicians. This review provides detailed discussions of the serum enzymes, genes, clinical manifestations, neuroimaging features, and therapies of GLD, with particular emphasis on the characteristics of adult-onset GLD, in an attempt to provide clinicians with in-depth insights into this disease.
The influence of in vitro gastrointestinal digestion and fecal fermentation on the flowers of Juglans regia: Changes in the active compounds and bioactivities
Authors: Jin Ximeng , Ru Yuerong , Zhang Xuechun , Kan Huan , Xiang Ping , He Xuemei , Sun Jian , He Xiahong , Wang Zhengxing
Published: September 2022

The objective of the research was to investigate the digestion and fecal fermentation characteristics of the flowers of Juglans regia (FJR), by using in vitro simulated digestion model (oral, gastric, and intestine) as well as colonic fermentation. As a result, the contents of most active substances and functional activities of FJR were decreased as the digestion proceeded, and showed a trend of first increasing and then decreasing in the fecal fermentation phase. In the oral digestion phase, the total phenolic and total flavonoid contents were released most with the values of 11.43 and 9.41 μg/mg, respectively. While in the gastric digestion phase, the antioxidant abilities, α-glucosidase and α-amylase inhibitory abilities were the weakest. By using high-performance liquid chromatography, 13 phenolic acids and 3 flavonoids were detected. Of these, the highest number of identified compounds were found in the undigested and the oral digestion stages, which were mainly salicylic acid, epicatechin, 3,5-dihydroxybenoic acid, vanillic acid, and protocatechuic acid. However, great losses were observed during the gastric and intestinal digestion stages, only epicatechin, salicylic acid, and protocatechuic acid were found. Surprisingly, fecal fermentation released more abundant phenolic substances compared to gastric and intestinal digestion. Additionally, FJR reduced the pH values in the colonic fermentation system, significantly promoted the production of short-chain fatty acids, and regulated the microbe community structure by improving the community richness of beneficial microbiota. This indicated that FJR had the benefit to improve the microorganismal environment in the intestine. Further Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that FJR could suppress the metabolic pathways related to diseases, such as infectious diseases, metabolic diseases and neurodegenerative diseases. In conclusion, although the bioactivities of FJR decreased significantly after in vitro gastrointestinal digestion and fecal fermentation, it still maintained certain antioxidant and hypoglycemic ability in vitro. This study described the detailed changes in the active compounds and bioactivities of FJR during in vitro gastrointestinal digestion and fecal fermentation, and its effects on microbiota composition and SCFAs levels in feces. Our results revealed the potential health benefits of FJR, and could provide a reference for its further research and development.
Vitamin D supplementation positively affects anthropometric indices: Evidence obtained from an umbrella meta-analysis
Authors: Musazadeh Vali , Zarezadeh Meysam , Ghalichi Faezeh , Kalajahi Fateme Hamedi , Ghoreishi Zohreh
Published: September 2022

Despite the growing evidence from meta-analyses on vitamin D’s anti-obesity properties, their results are controversial. The current umbrella review was performed to assess the available evidence and provide a conclusive explanation in this regard. The international databases PubMed, Scopus, Embase, Web of Science and Google Scholar were systematically searched till March, 2022. A random-effects model was used to run the meta-analysis. All meta-analyses that examined the effect of vitamin D supplementation on BW, BMI, WC, and fat mass were included. Findings of 14 meta-analyses revealed that vitamin D supplementation reduced body mass index (BMI) (ES: −0.11 kg/m2; 95% CI: −0.18, −0.05, p?0.001; I2 = 61.0%, p < 0.001), and waist circumference (WC) (ES = −0.79 cm; 95% CI: −1.20, −0.37; p < 0.001; I2 = 46.5%, p = 0.096) in comparison to control group. However, the effects of vitamin D on body weight (ES = −0.16 kg, 95% CI: −0.36, 0.04; p = 0.125; I2 = 57.0%, p = 0.017), and fat mass (ES: 0.02, 95% CI: −0.20, 0.24, p = 0.868; I2 = 0.0%, p = 0.531) were not considerable. Vitamin D supplementation significantly improved levels of obesity indices such as BMI, and WC.
Dietary brewer’s spent yeast enhances growth, hematological parameters, and innate immune responses at reducing fishmeal concentration in the diet of climbing perch, Anabas testudineus fingerlings
Authors: Gokulakrishnan M. , Kumar Rajesh , Pillai Bindu R. , Nanda S. , Bhuyan S. K. , Kumari Rakhi , Debbarma Jackson , Ferosekhan S. , Siddaiah G. M. , Sundaray Jitendra Kumar
Published: September 2022

A 60-day feeding trial was conducted to optimally reduce the fishmeal level in climbing perch (Anabas testudineus) fingerling diet using a dietary brewer’s spent yeast biomass (BSY) based diet. In this study, five isonitrogenous (35% CP) and isocaloric (19.15 MJ/Kg) feeds were prepared by replacing 0 (BSY0), 25% (BSY25), 50% (BSY50), 75% (BSY75) and 100% (BSY100) of fishmeal protein using BSY protein. A total of 225 numbers of uniform-sized climbing perch fingerlings (3.29 ± 0.09 g) were randomly stocked in the 15 rectangular FRP (Fiber-reinforced plastic) tanks (150 L capacity). The experimental fish were fed twice daily at 4% BW for the first fortnight and later reduced to 3% BW based on satiation. At the end of the feeding trial, the weight gain (WG) of fish increased with the increasing BSY incorporation rates corresponding to fishmeal content and peaked at 77.88%, and beyond that, WG decreased. Food conversion ratios decreased as dietary BSY levels increased and peaked at 76.28%. All other growth and feed utilization parameters followed a similar trend of weight gain. Hepatosomatic index (HSI) and viscerosomatic index (VSI), A:G ratio, serum catalase activity, and monocytes were unaffected and the total serum protein, albumin, globulin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), respiratory burst activity, lysozyme levels, myeloperoxidase activity, hemoglobulin, red blood cells, white blood cells, neutrophils, eosinophils, lymphocytes, and gut protease activities were increased significantly (P < 0.05) with the increasing replacement levels and peaked between 25 and 75%. The serum SOD activity and total platelets were decreased, whereas the serum uric acid and gut amylase activities were increased significantly to the increasing levels of FM replacement in the diets (P < 0.05). Among treatments, the BSY100 resulted in an overall poor growth response combined with relatively reduced values in nearly all biochemical parameters. The whole-body composition was nearly unaffected. The integrated biomarker response of various biochemical indicators from the different treatments has shown that the 50% fishmeal protein can be optimally replaced by BSY, which would cause an 18% reduction in the Economic conversion ratio (ECR) and −270.28 gCO2e– reduction in carbon footprint value per kg of climbing perch fingerlings production.
Meso-Rex bypass shunt vs. transposition shunt for cavernous transformation of portal vein in children
Authors: Lv Yong , Pu Lihui , Song Jiulin , Yang Jian , Zou Guoyou , Yang Jiayin , Xiang Bo , Jin Shuguang
Published: September 2022

Background

Cavernous transformation of the portal vein (CTPV) causes portal hypertension in children. Among Meso-Rex treatments, it is unclear whether the Meso-Rex bypass shunt (MRB) or the Meso-Rex transposition shunt (MRT) offers lower postoperative morbidity. Our objective was to evaluate postoperative outcomes, comparing MRB and MRT for children with CTPV.

Methods

A retrospective study was conducted on children undergoing Meso-Rex for CTPV from January 2010 to December 2020. The primary outcome was shunt complications, including shunt stenosis and thrombus. The secondary outcome was re-operation.

Results

Of the 43 patients included, 21 underwent MRT and 22 underwent MRB. MRT was associated with a higher rate of shunt complications when compared to MRB (23.8 vs. 9.1%, p = 0.191). The patients exhibited a higher rate of re-operation under the MRT than under the MRB (19 vs. 4.5%, p = 0.138). The operative time in the MRT group was significantly shorter than in the MRB group. Compared to MRT, the reduction in the length and thickness of the spleen was significantly greater in the MRB group. The increases in platelets were significantly higher in the MRB group than in the MRT group. The postoperative shunt velocity of MRB was notably faster than MRT. There was no significant difference in postoperative portal pressure between the two groups (p > 0.05).

Conclusion

Both MRB and MRT result in acceptable postoperative outcomes, but MRT is associated with higher post-shunt complications, which often increase the re-operation rate. This study suggests that MRB may offer advantages for children with CTPV.
Plasma lacosamide monitoring in children with epilepsy: Focus on reference therapeutic range and influencing factors
Authors: Li Yue , Guo Hong-Li , Zhang Yuan-Yuan , Dong Na , Hu Ya-Hui , chen Jing , Lu Xiao-Peng , Chen Feng
Published: September 2022

Background

Lacosamide (LCM) is a newer anti-seizure medication (ASM) that was approved in China in 2018, but its real-world clinical data and plasma concentrations in Chinese children with epilepsy are very limited. Of note, the reference range for routine LCM therapeutic drug monitoring is still unknown. The purpose of this study was to investigate the efficacy and safety of LCM as a monotherapy or an adjunctive treatment with other ASMs and to evaluate the potential factors affecting its efficacy and variable LCM plasma concentrations in Chinese children with epilepsy.

Methods

Children with epilepsy (<18 years) with routine plasma LCM monitoring from March 2019 to December 2021 at the Department of Pharmacy, Children's Hospital of Nanjing Medical University were retrospectively collected. Clinical data were obtained from the hospital information system.

Results

76 pediatric patients (52 males) were finally enrolled. Mean age was 7.9 years (1.3–17.3 years) with a mean dose of LCM 6.3 mg/kg/day (2.0–11.3 mg/kg/day). The TDM data as a whole showed that the median plasma trough concentration (C0) was 3.42 μg/mL (1.25–8.31 μg/mL). A 6-month LCM add-on therapy produced 70% of patients achieving ≥50% seizure frequency reductions, and the number was 81% for the one-year follow-up findings. Interestingly, more patients who took LCM monotherapy achieved seizure freedom over the same periods of follow-up observations. Under maintenance dosages, approximately 92.1% of the C0 values were 2.0–7.0 μg/mL. The plasma-C0-to-daily dose (C0/Dose) ratio was significantly associated with age and body weight (BW). The C0/Dose ratio in patients aged 1– ≤ 6 and 6– ≤ 12 years was significantly higher by 81% and 29% than those aged 12– ≤ 18 years, respectively. The C0/Dose ratio in patients with a BW of ≥40 kg was 1.7-fold lower than in patients with a BW of ≤ 20 kg. In addition, complex LCM-ASMs interactions were observed. Oxcarbazepine significantly decreased the C0/Dose ratio of LCM by 28%.

Conclusion

This retrospective study confirmed the effectiveness and tolerability of the LCM treatment used alone or with other ASMs in children with focal epilepsy. Children with higher BW and older age have lower C0/Dose ratio. Complex drug interactions between LCM and other concomitant ASMs were revealed. Notably, based on the data in our hands, the reference range, i.e., 2.0–7.0 μg/mL, for routine LCM monitoring may be feasible. The real-world evidence of this study supports LCM as a promising option in children with focal epilepsy.
Combination of paeoniflorin and liquiritin alleviates neuropathic pain by lipid metabolism and calcium signaling coordination
Authors: Chen Yan-Yan , Feng Li-Mei , Xu Ding-Qiao , Yue Shi-Jun , Fu Rui-Jia , Zhang Mei-Mei , Tang Yu-Ping
Published: September 2022

Neuropathic pain (NP) affects 7%–10% of the general population and is still hard to cure. Here, we validated the therapeutic effect and demonstrated the mechanism of paeoniflorin and liquiritin combination (PL) on NP from the perspective of integrated lipidomics and transcriptomics for the first time. SwissTargetPrediction indicated that PL mainly targets lipid metabolism. Notably, lipidomics revealed that imbalanced lipid levels in the NP model could be reprogrammed to normal levels by PL treatment. RNA-sequencing showed that PL treatment could also rebalance the lipid metabolism in an indirect manner. Pathway analysis highly enriched the calcium signaling pathway among the most significant categories. Altogether, these findings suggested that PL can not only balance the lipid metabolism in direct and indirect manners but also reverse the dysfunctional activation of the calcium signaling pathway, thereby alleviating NP. This helps to better understand the mechanisms of NP and provides a new important potential therapeutic option for NP.
Emerging trends and hot spots of NLRP3 inflammasome in neurological diseases: A bibliometric analysis
Authors: Yu Xiaoyan , Yu Chuan , He Wenfang
Published: September 2022

Background: NLRP3 inflammasome has been of great interest in the field of neurological diseases. To visualize the research hotspots and evolutionary trends in this area, we collected the relevant articles in the Web of Science Core Collection database from 2010 to 2022 and analyzed them using CiteSpace software.

Methods: We performed a systematic search of the literature within the Web of Science Core Collection database using the strategy described below: TS = NLRP3 inflammasome AND TS = neurological diseases OR TS = neurological disorder OR TS = brain disorder OR TS = brain injury OR TS = central nervous system disease OR TS = CNS disease OR TS = central nervous system disorder OR TS = CNS disorder AND Language = English from 2010 to 2022. The type of literature was limited to articles and reviews. The data were processed using CiteSpace software (version 5.8. R3).

Results: A total of 1,217 literature from 67 countries/regions and 337 research institutions was retrieved. Publications in this area have increased rapidly since 2013. China presents the highest number of published articles, but the United States has a higher centrality and h-index. The top five most published institutions and authors are from China, Zhejiang University and Li Y ranking first, respectively. Of the ten most cited articles, Prof. Heneka MT and colleagues accounted for three of them. In terms of the co-occurrence keyword diagram, the five most frequent keywords are “nlrp3 inflammasome”, “activation”, “oxidative stress”, “expression”, and “alzheimers disease”.

Conclusion: The research of NLRP3 inflammasome in neurological disorders is overall developing well. Chinese scholars contributed the most significant number of articles, while researchers from developed countries presented more influential papers. The importance of NLRP3 inflammasome in neurological diseases is widely appreciated, and the mechanism is under study. Moreover, NLRP3 inflammasome is emerging as a promising therapeutic target in treating neurological disorders. However, despite decades of research, our understanding of NLRP3 inflammasome in central nervous system diseases is still lacking. More and more profound research is needed in the future.
Differential effects of ketoconazole, fluconazole, and itraconazole on the pharmacokinetics of pyrotinib in vitro and in vivo
Authors: Wang Li , Wu Fan , Xu Jia , Wang Yu , Fei Weidong , Jiang Hui , Geng Peiwu , Zhou Quan , Wang Shuanghu , Zheng Yongquan , Deng Huadong
Published: September 2022

It has been reported that drug-drug interactions (DDIs) can affect the pharmacokinetics and pharmacodynamics of various oral drugs. To better understand the effects of azole antifungal drugs (ketoconazole, fluconazole, and itraconazole) on pyrotinib’s pharmacokinetics, DDIs between pyrotinib and three azoles were studied with Sprague-Dawley (SD) rat liver microsomes in vitro. Additionally, in vivo pyrotinib metabolic experiment was also performed. Twenty-four male SD rats were randomly divided into four groups: the ketoconazole (40 mg/kg), fluconazole (40 mg/kg), itraconazole (40 mg/kg), and the control group. UPLC-MS/MS was used for the determination of Pyrotinib’s plasma concentration in rats. In vitro experiments showed that IC50 values of ketoconazole, fluconazole and itraconazole were 0.06, 11.55, and 0.27 μM, respectively, indicating that these drugs might reduce the clearance rate of pyrotinib at different degrees. In rat studies, coadministration of pyrotinib with ketoconazole or fluconazole could dramatically increase the Cmax and AUC(0-t) values and decrease the clearance rate of pyrotinib, especially for ketoconazole. However, coadministration with itraconazole had no impact on the pharmacokinetic characters of pyrotinib. These data indicated that ketoconazole and fluconazole could significantly decrease the metabolism of pyrotinib both in vitro and in vivo. More attentions should be paid when pyrotinib is combined with azole antifungal drugs in clinic although further investigation is still required in future.
Trends in the utilization of psychotropic medications in China from 2018 to 2021
Authors: Zhang Xinyan , Hu Xiaowen , Zhao Yuxuan , Lu Christine Y. , Nie Xiaoyan , Shi Luwen
Published: September 2022

Background: Monitoring psychotropic medicine consumption trends can provide information on the extent of pharmacological interventions for mental disorders and availability of psychotropic medicines.

Objectives: This study aimed to illustrate the trends in psychotropic drug utilization in China’s hospitals.

Methods: We retrospectively analyzed the aggregated monthly psychotropic procurement records of 1009 hospitals from 31 provinces in China from January 2018 to September 2021. Total psychotropic medicine consumption included the sales of antipsychotics, antidepressants, anxiolytics, mood stabilizers, and sedatives or hypnotics. Information, including generic name, procurement amount, dosage form, strength, purchase time, and geographical data, was collected. Population-weighted psychotropic utilization was expressed in defined daily dose per 1000 inhabitants per day (DDD/1000/day).

Results: Psychotropic medicine sales increased from 4.5 DDD/1000/day in Q1 2018 to 6.4 DDD/1000/day in Q3 2021; total utilization in China’s hospitals increased by 42.2%. The use of each class of psychotropics showed a gradually increasing trend. Antidepressants were the most consumed psychotropics, accounting for 48.4% of the total psychotropic utilization (3.1/6.4 DDD/1000/day), followed by sedatives or hypnotics (31.3%; 2.0/6.4 DDD/1000/day) and antipsychotics (15.6%; 1.0/6.7 DDD/1000/day). Among all sub-classes of psychotropics, a most significant growth in DDD per 1000 inhabitants per day was seen for selective serotonin reuptake inhibitors (1.2–1.9 DDD/1000/day), whereas the consumption of typical antipsychotics (from 0.1 to 0.09 DDD/1000/day) and tricyclic antidepressants (from 0.05 to 0.03 DDD/1000/day) decreased during the study period. Psychotropic utilization substantially increased between Q1 2018 and Q3 2021 in regions with different economic levels. In Q3 2021, total psychotropic utilization in secondary and tertiary hospitals was 9.4 DDD/1000/day and 6.0 DDD/1000/day, respectively. Sedatives or hypnotics in secondary hospitals accounted for the largest proportion of utilized psychotropics (43.6%; 4.1/9.4 DDD/1000/day), whereas antidepressants were the most commonly used psychotropic in tertiary hospitals (50.0%, 3.0/6.0 DDD/1000/day).

Conclusion: This study showed that despite increases in psychotropic medication use, the consumption of medicines is still much lower than in other countries and regions internationally. With reference to the estimated prevalence of corresponding mental disorders, our study illustrates that a large treatment gap for mental health problems exists in China. In addition, the wide use of psychotropics with weak clinical evidence raises serious concerns regarding rational use. Greater efforts are needed to increase the availability of psychotropic medicines and to facilitate proper psychotropic use.
Thiosemicarbazones and selected tyrosine kinase inhibitors synergize in pediatric solid tumors: NDRG1 upregulation and impaired prosurvival signaling in neuroblastoma cells
Authors: Krchniakova Maria , Paukovcekova Silvia , Chlapek Petr , Neradil Jakub , Skoda Jan , Veselska Renata
Published: September 2022

Tyrosine kinase inhibitors (TKIs) are frequently used in combined therapy to enhance treatment efficacy and overcome drug resistance. The present study analyzed the effects of three inhibitors, sunitinib, gefitinib, and lapatinib, combined with iron-chelating agents, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) or di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). Simultaneous administration of the drugs consistently resulted in synergistic and/or additive activities against the cell lines derived from the most frequent types of pediatric solid tumors. The results of a detailed analysis of cell signaling in the neuroblastoma cell lines revealed that TKIs inhibited the phosphorylation of the corresponding receptor tyrosine kinases, and thiosemicarbazones downregulated the expression of epidermal growth factor receptor, platelet-derived growth factor receptor, and insulin-like growth factor-1 receptor, leading to a strong induction of apoptosis. Marked upregulation of the metastasis suppressor N-myc downstream regulated gene-1 (NDRG1), which is known to be activated and upregulated by thiosemicarbazones in adult cancers, was also detected in thiosemicarbazone-treated neuroblastoma cells. Importantly, these effects were more pronounced in the cells treated with drug combinations, especially with the combinations of lapatinib with thiosemicarbazones. Therefore, these results provide a rationale for novel strategies combining iron-chelating agents with TKIs in therapy of pediatric solid tumors.
Grounding Human Machine Interdependence Through Dependence and Trust Networks: Basic Elements for Extended Sociality
Authors: Falcone Rino , Castelfranchi Cristiano
Published: September 2022

In this paper, we investigate the primitives of collaboration, useful also for conflicting and neutral interactions, in a world populated by both artificial and human agents. We analyze in particular the dependence network of a set of agents. And we enrich the connections of this network with the beliefs that agents have regarding the trustworthiness of their interlocutors. Thanks to a structural theory of what kind of beliefs are involved, it is possible not only to answer important questions about the power of agents in a network, but also to understand the dynamical aspects of relational capital. In practice, we are able to define the basic elements of an extended sociality (including human and artificial agents). In future research, we will address autonomy.
Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges
Authors: Itani Maha M. , Jarrah Hala , Maaliki Dina , Radwan Zeina , Farhat Rima , Itani Hana A.
Published: September 2022

We have previously shown that effector memory (TEM) cells accumulate in the bone marrow (BM) and the kidney in response to l-NAME/high salt challenge. It is not well understood if measures to block the exodus of that effector memory cells prevent redistribution of these cells and protect from hypertension-induced renal damage. We hypothesized that that effector memory cells that accumulate in the bone marrow respond to repeated salt challenges and can be reactivated and circulate to the kidney. Thus, to determine if mobilization of bone marrow that effector memory cells and secondary lymphoid organs contribute to the hypertensive response to delayed salt challenges, we employed fingolimod (FTY720), an S1PR1 functional antagonist by downregulating S1PR, which inhibits the egress of that effector memory cells used effectively in the treatment of multiple sclerosis and cardiovascular diseases. We exposed wild-type mice to the l-NAME for 2 weeks, followed by a wash-out period, a high salt diet feeding for 4 weeks, a wash-out period, and then a second high salt challenge with or without fingolimod. A striking finding is that that effector memory cell egress was dramatically attenuated from the bone marrow of mice treated with fingolimod with an associated reduction of renal that effector memory cells. Mice receiving fingolimod were protected from hypertension. We found that wild-type mice that received fingolimod during the second high salt challenge had a marked decrease in the renal damage markers. CD3+ T cell infiltration was significantly attenuated in the fingolimod-treated mice. To further examine the redistribution of bone marrow that effector memory cells in response to repeated hypertensive stimuli, we harvested the bone marrow from CD45.2 mice following the repeated high salt protocol with or without fingolimod; that effector memory cells were sorted and adoptively transferred (AT) to CD45.1 naïve recipients. Adoptively transferred that effector memory cells from mice treated with fingolimod failed to home to the bone marrow and traffic to the kidney in response to a high salt diet. We conclude that memory T cell mobilization contributes to the predisposition to hypertension and end-organ damage for prolonged periods following an initial episode of hypertension. Blocking the exodus of reactivated that effector memory cells from the bone marrow protects the kidney from hypertension-induced end-organ damage.
Iron and zinc micronutrients and soil inoculation of Trichoderma harzianum enhance wheat grain quality and yield
Authors: Ali Iftikhar , Khan Ajab , Ali Ahmad , Ullah Zahid , Dai Dong-Qin , Khan Naveed , Khan Asif , Al-Tawaha Abdel Rahman , Sher Hassan
Published: September 2022

Malnutrition is mainly caused by iron and zinc micronutrient deficiencies affecting about half of the world's population across the globe. Biofortification of staple crops is the right approach to overcome malnutrition and enhance nutrient contents in the daily food of humans. This study aimed to evaluate the role of foliar application of iron and zinc in Trichoderma harzianum treated soil on various growth characteristics, quality, and yield of wheat varieties. Plants were examined in the absence/presence of T. harzianum, and iron and zinc micronutrients in both optimal and high-stress conditions. Although the symbiotic association of T. harzianum and common wheat is utilized as an effective approach for wheat improvement because of the dynamic growth promoting the ability of the fungus, this association was found tremendously effective in the presence of foliar feeding of micronutrients for the enhancement of various growth parameters and quality of wheat. The utilization of this approach positively increased various growth parameters including spike length, grain mass, biomass, harvest index, and photosynthetic pigments. The beneficial role of T. harzianum in combination with zinc and iron in stimulating plant growth and its positive impact on the intensities of high molecular weight glutenin subunits (HMW-GS) alleles make it an interesting approach for application in eco-friendly agricultural systems. Further, this study suggests a possible alternative way that does not merely enhances the wheat yield but also its quality through proper biofortification of iron and zinc to fulfill the daily needs of micronutrients in staple food.
A tough woman around tender men: Dilma Rousseff, gendered double bind, and misogynistic backlash
Authors: Jalalzai Farida , Kreft Brianna , Martinez-Port Lizbet , dos Santos Pedro A. G. , Smith Brigid M.
Published: September 2022

Dilma Rousseff's presidency ended in controversial form. The first woman elected to the position in Brazil, Rousseff's 2016 impeachment was seen as a coup by her supporters and as a necessary step for democracy by her detractors. With the Brazilian economy facing its worst recession in history and the Car Wash corruption scandal ravaging the political class, critics continually raised questions about Rousseff's leadership style and abilities. This article analyzes how this criticism in part can be attributed to gendered subjective understandings of preferred leadership traits. Using a thematic analysis of interviews with political actors in five different Brazilian states conducted in 2017 and 2018, we demonstrate that gender stereotypes and sexism fueled criticisms about women's political leadership. While Rousseff's presidency was riddled with problems, the president's leadership style and abilities were scrutinized in distinct gendered ways, indicating a gendered double bind and a backlash against women in politics.
Fear of COVID-19 and secondary trauma: Moderating role of self-efficacy
Authors: Li Yaling , Abbas Qamar , Manthar Shahjehan , Hameed Aftab , Asad Zainab
Published: September 2022

COVID-19 has affected millions of people around the globe. People's mental health, especially those of nurses, has been primarily affected by the fear of this virus. More focus has been paid to vaccination and treatment of the virus, but less attestation has been given to addressing the mental health of people affected by the virus. Empirical studies show that different external factors are not easily manageable and controllable by the individual. This study preliminarily explores the connection between fear of COVID-19 and secondary traumatic stress in nurses. Further, it examines the moderating effects of occupational self-efficacy on the relationship between fear of COVID-19 and secondary traumatic stress. Data for the study was collected from the nurses of six large hospitals in Karachi, Pakistan. The final analysis was performed on 243 samples. Studies on COVID-19 suggest that increased occupational self-efficacy decreases fear and its impact. This study offers insights for managers to develop stress management programs and provide proper training and counseling sessions to the nurses to motivate them emotionally. Theoretically, this study broadens the understanding of the theory of emotions by using the pandemic as a stressor. Future studies may explore different roles of occupational self-efficacy and study its influential role in managing different kinds of emotions explained by the theory of emotions. Managers at the workplace could design different self-efficacy training for nurses to increase their self-motivation to fight different types of stress they face at the workplace.
Power and variety-seeking: A compensatory perspective
Authors: Wang Jin , Jin Fei
Published: September 2022

In the current research, we show that low-power state promotes variety-seeking. We argue that this effect occurs because consumers in low-power state desire control and variety-seeking as a way to restore sense of control. The effect of power on variety-seeking is reduced when consumer knowledge in a certain consumption domain is high (vs. low) because knowledge is an alternative way to retain sense of control. Three experiments provide systematic evidence for this effect across different product categories. These findings contribute to the literature on how variety-seeking can be used as a way to compensate and enhance our understanding of power and consumer knowledge.
The impact of teacher attitude and teaching approaches on student demotivation: Disappointment as a mediator
Authors: Tang Yeyao , Hu Jifan
Published: September 2022

Student demotivation with English as a medium of instruction has attracted increased attention of scholars, particularly in those countries where it is taught as a second or foreign language. While there is a consensus that proficiency in English brings several benefits, it is found that students are demotivated to learn in English. As a result, many studies have tried to investigate the factors that reduce the motivation to learn in English. Drawing on disappointment theory, this study aims to investigate why and how the discouraging attitude of a teacher and discouraging teaching approaches create negative emotions (i.e., disappointment with English as a medium of instruction), which in turn demotivates Chinese students with English as a medium of instruction. This study has adopted a cross-sectional research design. The data were collected through a self-administered questionnaire survey from Chinese students (n = 428) studying in different universities in China. The hypothesized relationships were tested through PLS-based SEM by using Warp-PLS 7.0 software. The findings show that teachers' discouraging attitudes and discouraging teaching approaches are important determinants of student demotivation with English as a medium of instruction. The results also confirm that student disappointment is an important underlying mechanism in the relationship between exogenous and endogenous variables. This study contributes to the literature on student demotivation with English as a medium of instruction by superficially identifying teacher-related factors in China, which were previously overlooked. The implications of this study are that the university administration should monitor the attitude of the teachers toward English, as well as their teaching approaches, in order to curb any potential threat to student motivation. The administration should train the teachers on how to show a positive attitude and follow encouraging teaching approaches. In this way, students' disappointment with the English language and teaching methodology can also be overcome, which will ultimately increase their motivation with English as a medium of instruction in universities.
Mental health and adaptive functioning among school-aged children living with HIV in Zambia
Authors: Kalungwana Lisa , Malcolm-Smith Susan , Schrieff Leigh
Published: September 2022

Background

The number of children living with HIV (CLWHIV) has been increasing, reflected by lower mortality. However, this change is coupled with higher rates of morbidity, where CLWHIV face considerable challenges, including neurocognitive delays and mental health and behavioral functioning challenges. Despite Sub-Sahara accounting for the highest number of CLWHIV, there is still limited research on the effects of HIV on child mental health and adaptive functioning.

Method

Mental health and adaptive functioning were assessed in 120 children. The sample included 62 CLWHIV and 58 demographically-matched HIV-uninfected children aged 6–12 years. Mental health was assessed using the Connors, while adaptive functioning was assessed using the Vineland Adaptive Behavioral Scale (VABS).

Results

Scores obtained were within average ranges for mental health (T-score 40–59) and adaptive functioning standard scores (70–115). However, CLWHIV had significantly higher mental health problems than uninfected children in executive functioning and aggressiveness (p < 0.05). CLWHIV had lower adaptive functioning scores on the VABS Communication domain although these differences were not significant. In the Daily Living Skills domain, CLWHIV had significantly higher scores than the HIV-uninfected children (p < 0.05). There were no significant differences in the Socialization subdomain. Furthermore, CLWHIV had significantly higher scores on the Maladaptive Behavior scales of the VABS' internalizing and externalizing subdomains.

Conclusion

Challenges to mental health and adaptive functioning are still pervasive among CLWHIV. These findings support the need to develop support mechanisms for CLWHIV to help address mental health and adaptive functioning problems, especially as they progress into adolescence.