bluuebunny/crossref_metadata_2025 huggingface dataset:
The Predictive Value of Dynamic Intrinsic Local Metrics in Transient Ischemic Attack
Authors: Ma Huibin , Huang Guofeng , Li Mengting , Han Yu , Sun Jiawei , Zhan Linlin , Wang Qianqian , Jia Xize , Han Xiujie , Li Huayun , Song Yulin , Lv Yating
Published: February 2022

Background

Transient ischemic attack (TIA) is known as “small stroke.” However, the diagnosis of TIA is currently difficult due to the transient symptoms. Therefore, objective and reliable biomarkers are urgently needed in clinical practice.

Objective

The purpose of this study was to investigate whether dynamic alterations in resting-state local metrics could differentiate patients with TIA from healthy controls (HCs) using the support-vector machine (SVM) classification method.

Methods

By analyzing resting-state functional MRI (rs-fMRI) data from 48 patients with and 41 demographically matched HCs, we compared the group differences in three dynamic local metrics: dynamic amplitude of low-frequency fluctuation (d-ALFF), dynamic fractional amplitude of low-frequency fluctuation (d-fALFF), and dynamic regional homogeneity (d-ReHo). Furthermore, we selected the observed alterations in three dynamic local metrics as classification features to distinguish patients with TIA from HCs through SVM classifier.

Results

We found that TIA was associated with disruptions in dynamic local intrinsic brain activities. Compared with HCs, the patients with TIA exhibited increased d-fALFF, d-fALFF, and d-ReHo in vermis, right calcarine, right middle temporal gyrus, opercular part of right inferior frontal gyrus, left calcarine, left occipital, and left temporal and cerebellum. These alternations in the dynamic local metrics exhibited an accuracy of 80.90%, sensitivity of 77.08%, specificity of 85.37%, precision of 86.05%, and area under curve of 0.8501 for distinguishing the patients from HCs.

Conclusion

Our findings may provide important evidence for understanding the neuropathology underlying TIA and strong support for the hypothesis that these local metrics have potential value in clinical diagnosis.
The Relationship Between Vitamin D, Clinical Manifestations, and Functional Network Connectivity in Female Patients With Major Depressive Disorder
Authors: Zhu Dao-min , Zhao Wenming , Cui Shunshun , Jiang Ping , Zhang Yu , Zhang Cun , Zhu Jiajia , Yu Yongqiang
Published: February 2022

Evidence suggests the pivotal role of vitamin D in the pathophysiology of major depressive disorder (MDD) via its effects on the brain. Gender differences exist in both depression and vitamin D level. Our objective was to investigate the association between gender, vitamin D, clinical manifestations, and functional network connectivity in a large sample of MDD patients and healthy controls. Resting-state functional MRI data were collected from 122 patients and 119 controls, with independent component analysis adopted to examine large-scale inter- and intranetwork functional connectivity. Serum concentration of vitamin D (SCVD) and clinical manifestations were also assessed. MDD patients exhibited lower SCVD than controls in females but not males. Moreover, we identified a female-specific association between lower SCVD and poorer cognitive performance. Concurrently, MDD-related functional network connectivity changes were correlated with SCVD in females as well as depression and anxiety symptoms in female patients. Remarkably, MDD- and SCVD-related functional network connectivity alterations mediated the associations between SCVD and cognition in females. Aside from providing evidence for a female-specific neurobiological mechanism whereby low vitamin D might contribute to MDD and its associated clinical characteristics, our findings inform a novel conceptualization that adjuvant vitamin D supplementation therapy may yield clinical benefits in improving treatment outcomes in female patients with MDD.
Chronic Physical and Vicarious Psychosocial Stress Alter Fentanyl Consumption and Nucleus Accumbens Rho GTPases in Male and Female C57BL/6 Mice
Authors: Franco Daniela , Wulff Andreas B. , Lobo Mary Kay , Fox Megan E.
Published: February 2022

Chronic stress can increase the risk of developing a substance use disorder in vulnerable individuals. Numerous models have been developed to probe the underlying neurobiological mechanisms, however, most prior work has been restricted to male rodents, conducted only in rats, or introduces physical injury that can complicate opioid studies. Here we sought to establish how chronic psychosocial stress influences fentanyl consumption in male and female C57BL/6 mice. We used chronic social defeat stress (CSDS), or the modified vicarious chronic witness defeat stress (CWDS), and used social interaction to stratify mice as stress-susceptible or resilient. We then subjected mice to a 15 days fentanyl drinking paradigm in the home cage that consisted of alternating forced and choice periods with increasing fentanyl concentrations. Male mice susceptible to either CWDS or CSDS consumed more fentanyl relative to unstressed mice. CWDS-susceptible female mice did not differ from unstressed mice during the forced periods, but showed increased preference for fentanyl over time. We also found decreased expression of nucleus accumbens Rho GTPases in male, but not female mice following stress and fentanyl drinking. We also compare fentanyl drinking behavior in mice that had free access to plain water throughout. Our results indicate that stress-sensitized fentanyl consumption is dependent on both sex and behavioral outcomes to stress.
Variable Admittance Control of a Hand Exoskeleton for Virtual Reality-Based Rehabilitation Tasks
Authors: Topini Alberto , Sansom William , Secciani Nicola , Bartalucci Lorenzo , Ridolfi Alessandro , Allotta Benedetto
Published: February 2022

Robot-based rehabilitation is consolidated as a viable and efficient practice to speed up and improve the recovery of lost functions. Several studies highlight that patients are encouraged to undergo their therapies and feel more involved in the process when collaborating with a user-friendly robotic environment. Object manipulation is a crucial element of hand rehabilitation treatments; however, as a standalone process may result in being repetitive and unstimulating in the long run. In this view, robotic devices, like hand exoskeletons, do arise as an excellent tool to boost both therapy's outcome and patient participation, especially when paired with the advantages offered by interacting with virtual reality (VR). Indeed, virtual environments can simulate real-life manipulation tasks and real-time assign a score to the patient's performance, thus providing challenging exercises while promoting training with a reward-based system. Besides, they can be easily reconfigured to match the patient's needs by manipulating exercise intensity, e.g., Assistance-As-Needed (AAN) and the required tasks. Modern VR can also render interaction forces when paired to wearable devices to give the user some sort of proprioceptive force or tactile feedback. Motivated by these considerations, a Hand Exoskeleton System (HES) has been designed to be interfaced with a variable admittance control to achieve VR-based rehabilitation tasks. The exoskeleton assists the patient's movements according to force feedback and following a reference value calculated inside the VR. Whenever the patient grasps a virtual object, the HES provides the user with a force feedback sensation. In this paper, the virtual environment, developed within the Webots framework and rendering a HES digital-twin mapping and mimicking the actual HES motion, will be described in detail. Furthermore, the admittance control strategy, which continuously varies the control parameters to best render the force sensation and adapt to the user's motion intentions, will be investigated. The proposed approach has been tested on a single subject in the framework of a pilot study.
VIP-Expressing GABAergic Neurons: Disinhibitory vs. Inhibitory Motif and Its Role in Communication Across Neocortical Areas
Authors: Apicella Alfonso junior , Marchionni Ivan
Published: February 2022

GABAergic neurons play a crucial role in shaping cortical activity. Even though GABAergic neurons constitute a small fraction of cortical neurons, their peculiar morphology and functional properties make them an intriguing and challenging task to study. Here, we review the basic anatomical features, the circuit properties, and the possible role in the relevant behavioral task of a subclass of GABAergic neurons that express vasoactive intestinal polypeptide (VIP). These studies were performed using transgenic mice in which the VIP-expressing neurons can be recognized using fluorescent proteins and optogenetic manipulation to control (or regulate) their electrical activity. Cortical VIP-expressing neurons are more abundant in superficial cortical layers than other cortical layers, where they are mainly studied. Optogenetic and paired recordings performed in ex vivo cortical preparations show that VIP-expressing neurons mainly exert their inhibitory effect onto somatostatin-expressing (SOM) inhibitory neurons, leading to a disinhibitory effect onto excitatory pyramidal neurons. However, this subclass of GABAergic neurons also releases neurotransmitters onto other GABAergic and non-GABAergic neurons, suggesting other possible circuit roles than a disinhibitory effect. The heterogeneity of VIP-expressing neurons also suggests their involvement and recruitment during different functions via the inhibition/disinhibition of GABAergic and non-GABAergic neurons locally and distally, depending on the specific local circuit in which they are embedded, with potential effects on the behavioral states of the animal. Although VIP-expressing neurons represent only a tiny fraction of GABAergic inhibitory neurons in the cortex, these neurons’ selective activation/inactivation could produce a relevant behavioral effect in the animal. Regardless of the increasing finding and discoveries on this subclass of GABAergic neurons, there is still a lot of missing information, and more studies should be done to unveil their role at the circuit and behavior level in different cortical layers and across different neocortical areas.
Characterization of Hippocampal-Thalamic-Cortical Morphometric Reorganization in Temporal Lobe Epilepsy
Authors: Tung Hsin , Pan Szu-Yen , Lan Tsuo-Hung , Lin Yung-Yang , Peng Syu-Jyun
Published: February 2022

Introduction

Brain cortico-subcortical connectivity has been investigated in epilepsy using the functional MRI (MRI). Although structural images cannot demonstrate dynamic changes, they provide higher spatial resolution, which allows exploration of the organization of brain in greater detail.

Methods

We used high-resolution brain MRI to study the hippocampal-thalamic-cortical networks in temporal lobe epilepsy (TLE) using a volume-based morphometric method. We enrolled 22 right-TLE, 33 left-TLE, and 28 age/gender-matched controls retrospectively. FreeSurfer software was used for the thalamus segmentation.

Results

Among the 50 subfields, ipsilateral anterior, lateral, and parts of the intralaminar and medial nuclei, as well as the contralateral parts of lateral nuclei had significant volume loss in both TLE. The anteroventral nucleus was most vulnerable. Most thalamic subfields were susceptible to seizure burden, especially the left-TLE. SPM12 was used to conduct an analysis of the gray matter density (GMD) maps. Decreased extratemporal GMD occurred bilaterally. Both TLE demonstrated significant GMD loss over the ipsilateral inferior frontal gyrus, precentral gyrus, and medial orbital cortices.

Significance

Thalamic subfield atrophy was related to the ipsilateral inferior frontal GMD changes, which presented positively in left-TLE and negatively in right-TLE. These findings suggest prefrontal-thalamo-hippocampal network disruption in TLE.
Functional Network Changes After High-Frequency rTMS Over the Most Activated Speech-Related Area Combined With Speech Therapy in Chronic Stroke With Non-fluent Aphasia
Authors: Chang Won Kee , Park Jihong , Lee Ji-Young , Cho Sungmin , Lee Jongseung , Kim Won-Seok , Paik Nam-Jong
Published: February 2022

Objective

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) to the lesional hemisphere requires prudence in selecting the appropriate stimulation spot. Functional near-IR spectroscopy (fNIRS) can be used in both selecting the stimulation spot and assessing the changes of the brain network. This study aimed to evaluate the effect of HF-rTMS on the most activated spot identified with fNIRS and assess the changes of brain functional network in the patients with poststroke aphasia.

Methods

A total of five patients received HF-rTMS to the most activated area on the lesional hemisphere, followed by 30 min of speech therapy for 10 days. The Korean version of the Western aphasia battery (K-WAB) and fNIRS evaluation were done 1 day before the treatment, 1 day and 1 month after the last treatment session. Changes of K-WAB and paired cortical interaction and brain network analysis using graph theory were assessed.

Results

Aphasia quotient in K-WAB significantly increased after the treatment (P = 0.043). The correlation analysis of cortical interactions showed increased connectivity between language production and processing areas. Clustering coefficients of the left hemisphere were increased over a sparsity range between 0.45 and 0.58 (0.015 < p < 0.031), whereas the clustering coefficients of the right hemisphere, decreased over a sparsity range 0.15–0.87 (0.063 < p < 0.095). The global efficiency became lower over a network sparsity range between 0.47 and 0.75 (0.015 < p < 0.063).

Conclusion

Improvement of language function and changes of corticocortical interaction between language-related cortical areas were observed after HF-rTMS on the most activated area identified by fNIRS with combined speech therapy in the patients with poststroke aphasia.
Functional Independence and Disability Evaluation in Stroke Patients: Optimal Cutoff Scores for a Pictorial-Based Longshi Scale, Barthel Index, and Modified Rankin Scale
Authors: Liu Xiangxiang , Zhou Mingchao , Zhao Jingpu , Gao Yan , Wang Yao , Zhou Jing , Wan Li , Nie Guohui , Wang Yulong
Published: February 2022

Introduction

The modified Rankin Scale (mRS) and Barthel Index (BI) are widely used to measure functional outcomes worldwide. The Longshi Scale (LS), a novel pictorial-based instrument, was designed to improve the simplicity and convenience of measuring functional outcomes in the Chinese context. However, the disagreements in functional outcomes assessed by the mRS, BI, and LS are misleading, particularly in stroke patients. This study aimed to identify the optimal cutoff scores of LS and BI according to the mRS in Chinese stroke patients with different levels of functional disability.

Methods

The mRS, BI, and LS were applied to evaluate functional independence and disability in 7364 stroke patients in a multi-center cross-sectional study. Stroke patients were categorized into bedridden, domestic, and community groups in advance using the LS, indicating severe, moderate, and mild functional disability, respectively. The optimal cut-off scores of the LS and BI according to the mRS were identified via sensitivity, specificity, and Youden's index and stratified by different levels of functional disability determined by LS. We also plotted the receiver operator characteristic (ROC) curves of sensitivity and specificity and determined the area under the curve (AUC).

Results

In the bedridden group, LS and BI cutoff scores with the highest Youden's index were 5 and 10 for mRS 4, and the AUCs for the ROC curve were 0.848 and 0.863 for mRS 4. In the domestic group, LS and BI cutoff scores with the highest Youden's index were 5 and 65 for mRS 3, and the AUCs for the ROC curve were 0.796 and 0.826 for mRS 3. In the community group, LS cutoff scores with the highest sum of sensitivity and specificity were 9, 9, and 8 for mRS grades 0, 1, and 2, respectively, while the BI cutoff scores with the highest sum of sensitivity and specificity were 100, 100, and 95, respectively, while the AUCs for the ROC curve were 0.697 and 0.735 for mRS 2, 0.694 and 0.716 for mRS 1, and 0.628, and 0.660 for mRS 0.

Conclusions

The mRS is more precise to determine mild functional disability, whereas BI can provide more specific information on moderate and severe levels in stroke patients. Although LS was a less precise was to determine moderate and severe levels than BI, it is much simpler and more convenient to be applied to a large-scale population.
Episodic Memory Dysfunction and Effective Connectivity in Adult Patients With Newly Diagnosed Nonlesional Temporal Lobe Epilepsy
Authors: Bakhtiari Aftab , Bjørke Agnes Balint , Larsson Pål Gunnar , Olsen Ketil Berg , Nævra Marianne C. Johansen , Taubøll Erik , Heuser Kjell , Østby Ylva
Published: February 2022

Objective

Epilepsy is associated with both changes in brain connectivity and memory function, usually studied in the chronic patients. The aim of this study was to explore the presence of connectivity alterations measured by EEG in the parietofrontal network in patients with temporal lobe epilepsy (TLE), and to examine episodic memory, at the time point of diagnosis.

Methods

The parietofrontal network of newly diagnosed patients with TLE (N = 21) was assessed through electroencephalography (EEG) effective connectivity and compared with that of matched controls (N = 21). Furthermore, we assessed phenomenological aspects of episodic memory in both groups. Association between effective connectivity and episodic memory were assessed through correlation.

Results

Patients with TLE displayed decreased episodic (p ≤ 0.001, t = −5.18) memory scores compared with controls at the time point of diagnosis. The patients showed a decreased right parietofrontal connectivity (p = 0.03, F = 4.94) compared with controls, and significantly weaker connectivity in their right compared with their left hemisphere (p = 0.008, t = −2.93). There were no significant associations between effective connectivity and episodic memory scores.

Conclusions

We found changes in both memory function and connectivity at the time point of diagnosis, supporting the notion that TLE involves complex memory functions and brain networks beyond the seizure focus to strongly interconnected brain regions, already early in the disease course. Whether the observed connectivity changes can be interpreted as functionally important to the alterations in memory function, it remains speculative.
Ventriculoperitoneal Shunt Alone for Cerebrospinal Fluid Rhinorrhea With Neuroendocrine Alterations in Idiopathic Intracranial Hypertension: A Case Report and Literature Review
Authors: Peng Deqing , Yang Kaichuang , Wu Cheng , Gao Faliang , Sun Weijun , Lu Gang
Published: February 2022

Spontaneous skull base cerebrospinal fluid (CSF) leaks due to idiopathic intracranial hypertension (IIH) are a rare entity. Patients often present with CSF rhinorrhea, recurrent meningitis, chronic headache, and visual defects, while few patients have been reported to present with neuroendocrine alterations. Endonasal endoscopic repair is the first-line treatment for these leaks at present. However, the relatively high risk of recurrence remains the main cause of reoperation because of elevated intracranial pressure (ICP) after endoscopic surgery and absence of postoperative ICP management. A shunting procedure may stop CSF leakage or relieve symptoms in complex cases, and this is presently well-known as the last-line therapy for CSF liquorrhea. We describe a 29-year-old woman with spontaneous CSF rhinorrhea and neuroendocrine alterations due to IIH, and with no previous history of trauma, tumor, or nasal surgery. The bone defect in the skull base became implicated when the site of the leak was detected by cranial magnetic resonance imaging and computed tomography (CT). The patient was successfully managed via ventriculoperitoneal shunt (VPS) alone without endoscopic repair, and neuroendocrine alterations resolved after the shunting procedure.
Cingulo-Opercular and Frontoparietal Network Control of Effort and Fatigue in Mild Traumatic Brain Injury
Authors: Ramage Amy E. , Ray Kimberly L. , Franz Hannah M. , Tate David F. , Lewis Jeffrey D. , Robin Donald A.
Published: February 2022

Neural substrates of fatigue in traumatic brain injury (TBI) are not well understood despite the considerable burden of fatigue on return to productivity. Fatigue is associated with diminishing performance under conditions of high cognitive demand, sense of effort, or need for motivation, all of which are associated with cognitive control brain network integrity. We hypothesize that the pathophysiology of TBI results in damage to diffuse cognitive control networks, disrupting coordination of moment-to-moment monitoring, prediction, and regulation of behavior. We investigate the cingulo-opercular (CO) and frontoparietal (FP) networks, which are engaged to sustain attention for task and maintain performance. A total of 61 individuals with mild TBI and 42 orthopedic control subjects participated in functional MRI during performance of a constant effort task requiring altering the amount of effort (25, 50, or 75% of maximum effort) utilized to manually squeeze a pneumostatic bulb across six 30-s trials. Network-based statistics assessed within-network organization and fluctuation with task manipulations by group. Results demonstrate small group differences in network organization, but considerable group differences in the evolution of task-related modulation of connectivity. The mild TBI group demonstrated elevated CO connectivity throughout the task with little variation in effort level or time on task (TOT), while CO connectivity diminished over time in controls. Several interregional CO connections were predictive of fatigue in the TBI group. In contrast, FP connectivity fluctuated with task manipulations and predicted fatigue in the controls, but connectivity fluctuations were delayed in the mild traumatic brain injury (mTBI) group and did not relate to fatigue. Thus, the mTBI group’s hyper-connectivity of the CO irrespective of task demands, along with hypo-connectivity and delayed peak connectivity of the FP, may allow for attainment of task goals, but also contributes to fatigue. Findings are discussed in relation to performance monitoring of prediction error that relies on internal cues from sensorimotor feedback during task performance. Delay or inability to detect and respond to prediction errors in TBI, particularly evident in bilateral insula-temporal CO connectivity, corresponds to day-to-day fatigue and fatigue during task performance.
Fabrication and Assessment of Diosgenin Encapsulated Stearic Acid Solid Lipid Nanoparticles for Its Anticancer and Antidepressant Effects Using in vitro and in vivo Models
Authors: Khan Hina , Nazir Sadia , Farooq Rai Khalid , Khan Ishaq N. , Javed Aneela
Published: February 2022

Inflammatory cascade plays a pivotal role in the onset and progression of major depressive disorder (MDD) and glioblastoma multiforme (GBM). Therefore, questing natural compounds with anti-inflammatory activity such as diosgenin can act as a double-edged sword targeting cancer and cancer-induced inflammation simultaneously. The blood–brain barrier limits the therapeutic efficiency of the drugs against intracranial pathologies including depression and brain cancers. Encapsulating a drug molecule in lipid nanoparticles can overcome this obstacle. The current study has thus investigated the anticancer and antidepressant effect of Tween 80 (P80) coated stearic acid solid lipid nanoparticles (SLNPs) encapsulating the diosgenin. Physio-chemical characterizations of SLNPs were performed to assess their stability, monodispersity, and entrapment efficiency. In vitro cytotoxic analysis of naked and drug encapsulated SLNPs on U-87 cell line indicated diosgenin IC50 value to be 194.4 μM, while diosgenin encapsulation in nanoparticles slightly decreases the toxicity. Antidepressant effects of encapsulated and non-encapsulated diosgenin were comprehensively evaluated in the concanavalin-A–induced sickness behavior mouse model. Behavior test results indicate that diosgenin and diosgenin encapsulated nanoparticles significantly alleviated anxiety-like and depressive behavior. Diosgenin incorporated SLNPs also improved grooming behavior and social interaction as well as showed normal levels of neutrophils and leukocytes with no toxicity indication. In conclusion, diosgenin and diosgenin encapsulated solid lipid nanoparticles proved successful in decreasing in vitro cancer cell proliferation and improving sickness behavioral phenotype and thus merit further exploration.
Circulating MicroRNAs From Plasma Small Extracellular Vesicles as Potential Diagnostic Biomarkers in Pediatric Epilepsy and Drug-Resistant Epilepsy
Authors: Wang Yilong , Wang Yeping , Chen Yi , Hua Yi , Xu Lu , Zhu Mengying , Zhao Congying , Zhang Weiran , Sheng Guoxia , Liu Liu , Jiang Peifang , Yuan Zhefeng , Zhao Zhengyan , Gao Feng
Published: February 2022

Pediatric epilepsy is a neurological condition that causes repeated and unprovoked seizures and is more common in 1–5-year-old children. Drug resistance has been indicated as a key challenge in improving the clinical outcomes of patients with pediatric epilepsy. In the present study, we aimed to identify plasma small extracellular vesicles (sEVs) derived microRNAs (miRNAs) from the plasma samples of children for predicting the prognosis in patients with epilepsy and drug-resistant epilepsy. A total of 90 children clinically diagnosed with epilepsy [46 antiepileptic drug (AED)-responsive epilepsy and 44 drug-resistant epilepsy] and 37 healthy controls (HCs) were enrolled in this study. RNA sequencing was performed to identify plasma sEVs derived miRNAs isolated from the children’s plasma samples. Differentially expressed plasma sEVs derived miRNAs were identified using bioinformatics tools and were further validated by reverse transcription-polymerase chain reaction and receiver operator characteristic (ROC) curve analysis. In the present study, 6 miRNAs (hsa-miR-125b-5p, hsa-miR-150-3p, hsa-miR-199a-3p, hsa-miR-584-5p hsa-miR-199a-5p, and hsa-miR-342-5p) were selected for further validation. hsa-miR-584-5p, hsa-miR-342-5p, and hsa-miR-150-5p with area under curve (AUC) values of 0.846, 0.835, and 0.826, respectively, were identified as promising biomarkers of epilepsy. A logistic model combining three miRNAs (hsa-miR-584-5p, hsa-miR-342-5p, and hsa-miR-199a-3p) could achieve an AUC of 0.883 and a six miRNAs model (hsa-miR-342-5p, hsa-miR-584-5p, hsa-miR-150-5p, hsa-miR-125b-5p, hsa-miR-199a-3p, and hsa-miR-199a-5p) could attain an AUC of 0.888. The predicted probability of multiple miRNA panels was evaluated for differentiating between drug-resistant children and drug-responsive children. The AUC of a six-miRNA panel (hsa-miR-342-5p, hsa-miR-584-5p, hsa-miR-150-5p, hsa-miR-125b-5p, hsa-miR-199a-3p, and hsa-miR-199a-5p) reached 0.823. We identified and confirmed plasma sEVs derived miRNA biomarkers that could be considered as potential therapeutic targets for pediatric epilepsy and drug-resistant epilepsy.
Selective Enrichment of Munc13-2 in Presynaptic Active Zones of Hippocampal Pyramidal Cells That Innervate mGluR1α Expressing Interneurons
Authors: Holderith Noemi , Aldahabi Mohammad , Nusser Zoltan
Published: February 2022

Selective distribution of proteins in presynaptic active zones (AZs) is a prerequisite for generating postsynaptic target cell type-specific differences in presynaptic vesicle release probability (Pv) and short-term plasticity, a characteristic feature of cortical pyramidal cells (PCs). In the hippocampus of rodents, somatostatin and mGluR1α expressing interneurons (mGluR1α+ INs) receive small, facilitating excitatory postsynaptic currents (EPSCs) from PCs and express Elfn1 that trans-synaptically recruits mGluR7 into the presynaptic AZ of PC axons. Here we show that Elfn1 also has a role in the selective recruitment of Munc13-2, a synaptic vesicle priming and docking protein, to PC AZs that innervate mGluR1α+ INs. In Elfn1 knock-out mice, unitary EPSCs (uEPSCs) in mGluR1α+ INs have threefold larger amplitudes with less pronounced short-term facilitation, which might be the consequence of the loss of either mGluR7 or Munc13-2 or both. Conditional genetic deletion of Munc13-2 from CA1 PCs results in the loss of Munc13-2, but not mGluR7 from the AZs, and has no effect on the amplitude of uEPSCs and leaves the characteristic short-term facilitation intact at PC to mGluR1α+ IN connection. Our results demonstrate that Munc13-1 alone is capable of imposing low Pv at PC to mGluR1α+ IN synapses and Munc13-2 has yet an unknown role in this synapse.
Effect of Extrusion or Fermentation on Physicochemical and Digestive Properties of Barley Powder
Authors: Xiao Xiang , Li Jiaying , Xiong Hao , Tui Wenxuan , Zhu Ying , Zhang Jiayan
Published: February 2022

In this work, the effect of extrusion and fermentation on the physicochemical and digestive properties of barley powder was studied. The results showed that the contents of phenolics, β-glucan, protein, and lipid decreased after extrusion. The contents of nutrients (except lipid) increased after fermentation. Both extrusion and fermentation of barley can lead to the darkening of the color and effectively optimize the palatability by reducing the viscosity. In vitro digestion of starch showed that the content of as rapidly digestible starch increased after extrusion and fermentation. The contents of ferulic acid, 2-hydroxybenzoic acid, and caffeic acid decreased after extrusion, while the contents of chlorogenic acid, p-coumaric acid, and ferulic acid increased after fermentation. Basically, the content of all the phenolic showed an increasing trend after digestion. The antioxidant activity decreased after extrusion and increased after fermentation. Therefore, the nutritional composition and properties of barley powder were changed under the two processing methods.
Carbohydrate Mouth-Rinsing Improves Overtime Physical Performance in Male Ice Hockey Players During On-Ice Scrimmages
Authors: Nyman Danielle L. E. , Gamble Alexander S. D. , Bigg Jessica L. , Boyd Logan A. , Vanderheyden Alexander J. , Spriet Lawrence L.
Published: February 2022

Purpose

This randomized, double-blind, crossover study examined the effects of mouth-rinsing (MR) with a carbohydrate (CHO) vs. a placebo (PLA) solution on external and internal loads in hydrated ice hockey players during regulation and overtime (OT) periods of an on-ice scrimmage.

Methods

Twelve skilled male hockey players (22.6 [3.4] years, 178.9 [4.7] cm, 84.0 [6.5] kg) played three 20-min regulation periods and one 12-min OT period of small-sided 3-on-3 scrimmage. Skaters repeated 2 min shift and rest intervals. Participants mouth rinsed with 25 mL of CHO or PLA solution approximately every 10 min for a total of 7 rinses. A local positioning system (LPS) tracked external load variables including speed, distance, acceleration, and deceleration. Internal load was monitored with heart rate (HR) sensors and a rating of perceived exertion (RPE).

Results

During regulation play, both the conditions developed similar fatigue, with significantly decreased high-intensity distance, average speed and decelerations, and increased RPE, from period 1 to 2 and 3. In OT, CHO MR increased the distance skated at high-intensity (224 [77], 185 [66] m, p = 0.042), peak speed (24.6 [1.6], 23.7 [1.3] km·h−1, p = 0.016), number of sprints (1.9 [1.2], 1.2 [0.9], p = 0.011), and decreased distance skated at slow speed (300 [33], 336 [47], p = 0.034) vs. PLA MR. OT RPE was similar between the two conditions in spite of more work done in CHO MR.

Conclusions

CHO MR may be a valuable practice to protect against decrements in external load with increased playing time in ice hockey, and possibly allows athletes to perform more work relative to perceived levels of exertion.
Caffeine, Coffee, Tea and Risk of Rheumatoid Arthritis: Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies
Authors: Asoudeh Farzaneh , Dashti Fatemeh , Jayedi Ahmad , Hemmati Amirhossein , Fadel Abdulmannan , Mohammadi Hamed
Published: February 2022

Objective

Prospective cohort studies on coffee, tea and caffeine in relation to the risk of rheumatoid arthritis (RA) have shown conflicting results. The aim of this study was to conduct a dose–response meta-analysis of cohort studies on the association between dietary caffeine, different types of coffee and tea consumption and the risk of RA.

Methods

PubMed/Medline, Scopus and EMBASE were searched up to July 2021 to identify relevant studies that had considered different types of coffee (caffeinated or decaffeinated), tea or caffeine exposure with RA as the main, or one of the, outcome(s). Two authors independently screened 742 publications. Finally, five prospective cohort studies were included in our meta-analysis. Pooled relative risks (RRs) were calculated by using a fixed-effects model. We also performed linear and non-linear dose-response analyses to examine the dose-response relations.

Results

Comparing extreme categories, we found a positive, significant association between coffee (RR: 1.30; 95% CI: 1.04–1.62; I2 = 0%, n = 5) and decaffeinated coffee (RR: 1.89; 95% CI: 1.35–2.65; I2 = 38.1%, n =3) consumption and risk of RA. One additional cup of coffee consumed per day was associated with an increased risk of RA by 6% (95% CI: 1.02–1.10; I2 = 0%). This increase in the risk of RA for one cup/d of decaffeinated coffee was 11% (95% CI: 1.05–1.18; I2 = 38). No significant association was observed between caffeinated coffee, tea or caffeine intake and the risk of RA.

Conclusion

We found that a higher intake of coffee and decaffeinated coffee was associated with increased risk of RA. No significant association between caffeinated coffee, tea or caffeine intake and the risk of RA was observed.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=227665, identifier: CRD42021227665.
Tumor-Infiltrating Myeloid Cells Co-Express TREM1 and TREM2 and Elevated TREM-1 Associates With Disease Progression in Renal Cell Carcinoma
Authors: Ford Jill W. , Gonzalez-Cotto Marieli , MacFarlane Alexander W. , Peri Suraj , Howard O. M. Zack , Subleski Jeffrey J. , Ruth Karen J. , Haseebuddin Mohammed , Al-Saleem Tahseen , Yang Youfeng , Rayman Pat , Rini Brian , Linehan W. Marston , Finke James , Weiss Jonathan M. , Campbell Kerry S. , McVicar Daniel W.
Published: February 2022

Myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) contribute to cancer-related inflammation and tumor progression. While several myeloid molecules have been ascribed a regulatory function in these processes, the triggering receptors expressed on myeloid cells (TREMs) have emerged as potent modulators of the innate immune response. While various TREMs amplify inflammation, others dampen it and are emerging as important players in modulating tumor progression—for instance, soluble TREM-1 (sTREM-1), which is detected during inflammation, associates with disease progression, while TREM-2 expression is associated with tumor-promoting macrophages. We hypothesized that TREM-1 and TREM-2 might be co-expressed on tumor-infiltrating myeloid cells and that elevated sTREM-1 associates with disease outcomes, thus representing a possibility for mutual modulation in cancer. Using the 4T1 breast cancer model, we found TREM-1 and TREM-2 expression on MDSC and TAM and that sTREM-1 was elevated in tumor-bearing mice in multiple models and correlated with tumor volume. While TREM-1 engagement enhanced TNF, a TREM-2 ligand was detected on MDSC and TAM, suggesting that both TREM could be functional in the tumor setting. Similarly, we detected TREM-1 and Trem2 expression in myeloid cells in the RENCA model of renal cell carcinoma (RCC). We confirmed these findings in human disease by demonstrating the expression of TREM-1 on tumor-infiltrating myeloid cells from patients with RCC and finding that sTREM-1 was increased in patients with RCC. Finally, The Cancer Genome Atlas analysis shows that TREM1 expression in tumors correlates with poor outcomes in RCC. Taken together, our data suggest that manipulation of the TREM-1/TREM-2 balance in tumors may be a novel means to modulate tumor-infiltrating myeloid cell phenotype and function.
Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study
Authors: Tolaney Sara M. , Beeram Muralidhar , Beck J. Thaddeus , Conlin Alison , Dees E. Claire , Puhalla Shannon L. , Rexer Brent N. , Burris Howard A. , Jhaveri Komal , Helsten Teresa , Becerra Carlos , Kalinsky Kevin , Moore Kathleen N. , Manuel Allison M. , Lithio Andrew , Price Gregory L. , Chapman Sonya C. , Litchfield Lacey M. , Goetz Matthew P.
Published: February 2022

Background

Cyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.

Patients and Methods

Women ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0–1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1.

Results

Sixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease.

Conclusions

Abemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC.

Clinical Trial Registration

https://clinicaltrials.gov/, identifier NCT02057133
Optimal Initial Time Point of Local Radiotherapy for Unresectable Lung Adenocarcinoma: A Retrospective Analysis on Overall Arrangement of Local Radiotherapy in Advanced Lung Adenocarcinoma
Authors: Li Xinge , Wang Jie , Chang Xu , Gao Zhenhua , Teng Feifei , Meng Xue , Yu Jinming
Published: February 2022

Local radiotherapy (LRT) is reported to be of survival benefit for advanced non-small cell lung cancer (NSCLC) in accumulating evidence, but research on the optimal initial time point remains scarce. This IRB-approved retrospective analysis identified patients diagnosed with stage IIIb–IV unresectable lung adenocarcinoma who initiated front-line LRT at our institution between 2017 and 2020. The receiver operating characteristic (ROC) curve analyses were used to cut off the initial time of LRT (before and beyond 53 days). Patients were divided into two groups: one early to initiate radiotherapy group (≤53 days, EAR group) and one deferred radiotherapy group (>53 days, DEF group). The Kaplan–Meier method was used to estimate time-to-event endpoints; the Cox proportional hazard model was used to find out predictors of progression-free survival (PFS) and overall survival (OS). A total of 265 patients with a median age of 57 were enrolled. The median follow-up time was 26.4 months (ranging from 2.2 to 69.7 months). The mOS was 38.6 months and mPFS was 12.7 months. Age >60, bone and brain metastases, multisite metastases, and EGFR 19 mutation were independent predictors associated with OS. Early initiation of local radiotherapy within 53 days after diagnosis resulted in better PFS, but not in OS. A better OS was observed in patients with bone metastasis who underwent local radiotherapy initiated within 53 days.
Robot-Assisted Totally Intracorporeal Resection of Cutaneous Ureterostomy Tumor and Ileal Conduit Surgery: A Rare Case Report
Authors: Cai Lingkai , Zhuang Juntao , Cao Qiang , Yuan Baorui , Wu Qikai , Li Kai , Han Jie , Yu Hao , Lv JianCheng , Feng Dexiang , Liu Peikun , Yu Ruixi , Li Pengchao , Yang Xiao , Lu Qiang
Published: February 2022

Background

Radical cystectomy (RC) is the standard treatment for muscular invasive bladder cancer (MIBC) and some high-risk non-muscular invasive bladder cancer (NMIBC). Cutaneous ureterostomy is a common form of urinary diversion. However, after radical cystectomy, recurrence of upper urinary tract malignancies is possible. There is no relevant report on how to improve this situation’s management.

Case Presentation

This case is a 56-year-old male patient hospitalized due to the development of a new tumor in the ureteral cutaneous stoma following radical cystectomy for more than five years. A biopsy of the tumor revealed high-grade urothelial carcinoma. Computed tomography (CT) revealed that the local soft tissue around the cutaneous stoma was thickened, but no other lesions were visible. After evaluating the case, we chose robot-assisted completely intracorporeal resection of cutaneous ureterostomy tumor and ileal conduit surgery. The total time for the operation and the blood loss were 400 minutes and 150 ml, respectively. Following surgery, the patient got standard chemotherapy in combination with immunotherapy. Additionally, ten months following the surgery, the patient did not experience disease progression or complications.

Conclusion

The robot-assisted operation is safe and feasible for upper urinary tract tumor recurrence following radical cystectomy with cutaneous ureterostomy.
Enhancing Performance of Breast Ultrasound in Opportunistic Screening Women by a Deep Learning-Based System: A Multicenter Prospective Study
Authors: Zhao Chenyang , Xiao Mengsu , Ma Li , Ye Xinhua , Deng Jing , Cui Ligang , Guo Fajin , Wu Min , Luo Baoming , Chen Qin , Chen Wu , Guo Jun , Li Qian , Zhang Qing , Li Jianchu , Jiang Yuxin , Zhu Qingli
Published: February 2022

Purpose

To validate the feasibility of S-Detect, an ultrasound computer-aided diagnosis (CAD) system using deep learning, in enhancing the diagnostic performance of breast ultrasound (US) for patients with opportunistic screening-detected breast lesions.

Methods

Nine medical centers throughout China participated in this prospective study. Asymptomatic patients with US-detected breast masses were enrolled and received conventional US, S-Detect, and strain elastography subsequently. The final pathological results are referred to as the gold standard for classifying breast mass. The diagnostic performances of the three methods and the combination of S-Detect and elastography were evaluated and compared, including sensitivity, specificity, and area under the receiver operating characteristics (AUC) curve. We also compared the diagnostic performances of S-Detect among different study sites.

Results

A total of 757 patients were enrolled, including 460 benign and 297 malignant cases. S-Detect exhibited significantly higher AUC and specificity than conventional US (AUC, S-Detect 0.83 [0.80–0.85] vs. US 0.74 [0.70–0.77], p < 0.0001; specificity, S-Detect 74.35% [70.10%–78.28%] vs. US 54.13% [51.42%–60.29%], p < 0.0001), with no decrease in sensitivity. In comparison to that of S-Detect alone, the AUC value significantly was enhanced after combining elastography and S-Detect (0.87 [0.84–0.90]), without compromising specificity (73.93% [68.60%–78.78%]). Significant differences in the S-Detect’s performance were also observed across different study sites (AUC of S-Detect in Groups 1–4: 0.89 [0.84–0.93], 0.84 [0.77–0.89], 0.85 [0.76–0.92], 0.75 [0.69–0.80]; p [1 vs. 4] < 0.0001, p [2 vs. 4] = 0.0165, p [3 vs. 4] = 0.0157).

Conclusions

Compared with the conventional US, S-Detect presented higher overall accuracy and specificity. After S-Detect and strain elastography were combined, the performance could be further enhanced. The performances of S-Detect also varied among different centers.
Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells
Authors: Mesbahi Yashar , Trahair Toby N. , Lock Richard B. , Connerty Patrick
Published: February 2022

Despite intensive chemotherapy regimens, up to 60% of adults with acute myeloid leukaemia (AML) will relapse and eventually succumb to their disease. Recent studies suggest that leukaemic stem cells (LSCs) drive AML relapse by residing in the bone marrow niche and adapting their metabolic profile. Metabolic adaptation and LSC plasticity are novel hallmarks of leukemogenesis that provide important biological processes required for tumour initiation, progression and therapeutic responses. These findings highlight the importance of targeting metabolic pathways in leukaemia biology which might serve as the Achilles’ heel for the treatment of AML relapse. In this review, we highlight the metabolic differences between normal haematopoietic cells, bulk AML cells and LSCs. Specifically, we focus on four major metabolic pathways dysregulated in AML; (i) glycolysis; (ii) mitochondrial metabolism; (iii) amino acid metabolism; and (iv) lipid metabolism. We then outline established and emerging drug interventions that exploit metabolic dependencies of leukaemic cells in the treatment of AML. The metabolic signature of AML cells alters during different biological conditions such as chemotherapy and quiescence. Therefore, targeting the metabolic vulnerabilities of these cells might selectively eradicate them and improve the overall survival of patients with AML.