bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex Differences in Spatial Learning and Memory in Valproic Acid Rat Model of Autism: Possible Beneficial Role of Exercise Interventions
Authors: Ghahremani Reza , Mohammadkhani Reihaneh , Salehi Iraj , Karimi Seyed Asaad , Zarei Mohammad
Published: April 2022

In the current study, we first tried to determine sex differences in spatial learning and memory in the valproic acid (VPA) rat model of autism. Second, the effects of interval training (IT) and continuous training (CT) exercises were examined in male and female offsprings. To induce autism-like animal model, the pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) at the embryonic day 12.5. IT and CT aerobic exercises were started at postnatal day 56. Then, on postnatal days 84–89, a Morris water maze (MWM) test was conducted on the separate groups of offsprings. Aerobic training was performed on a rodent treadmill with 0% slope for 8 weeks, 5 days/week, and 50 min/day. Unlike control animals, VPA-exposed female offspring had a better performance than VPA-exposed male offspring in MWM acquisition. In the case of MWM reference memory, we did not observe a sex difference between VPA-exposed male and VPA-exposed female offspring. Both IT and CT exercises in both control and VPA-exposed male rats significantly improved MWM acquisition. Moreover, both IT and CT exercises significantly improved MWM acquisition in control female rats. In addition, IT exercise (but not CT) significantly improved MWM acquisition in VPA-exposed female offsprings. Both IT and CT exercises in VPA-exposed that male and female offsprings improved the MWM reference memory. In conclusion, our observation demonstrated that prenatal exposure to VPA affects the spatial learning and memory in a sex dependent manner. We have shown that both IT and CT exercises are able to improve cognitive function in healthy and autistic rat offsprings.
Auricular Transcutaneous Vagus Nerve Stimulation Acutely Modulates Brain Connectivity in Mice
Authors: Brambilla-Pisoni Cecilia , Muñoz-Moreno Emma , Gallego-Amaro Ianire , Maldonado Rafael , Ivorra Antoni , Soria Guadalupe , Ozaita Andrés
Published: April 2022

Brain electrical stimulation techniques take advantage of the intrinsic plasticity of the nervous system, opening a wide range of therapeutic applications. Vagus nerve stimulation (VNS) is an approved adjuvant for drug-resistant epilepsy and depression. Its non-invasive form, auricular transcutaneous VNS (atVNS), is under investigation for applications, including cognitive improvement. We aimed to study the effects of atVNS on brain connectivity, under conditions that improved memory persistence in CD-1 male mice. Acute atVNS in the cymba conchae of the left ear was performed using a standard stimulation protocol under light isoflurane anesthesia, immediately or 3 h after the training/familiarization phase of the novel object-recognition memory test (NORT). Another cohort of mice was used for bilateral c-Fos analysis after atVNS administration. Spearman correlation of c-Fos density between each pair of the thirty brain regions analyzed allowed obtaining the network of significant functional connections in stimulated and non-stimulated control brains. NORT performance was enhanced when atVNS was delivered just after, but not 3 h after, the familiarization phase of the task. No alterations in c-Fos density were associated with electrostimulation, but a significant effect of atVNS was observed on c-Fos-based functional connectivity. atVNS induced a clear reorganization of the network, increasing the inter-hemisphere connections and the connectivity of locus coeruleus. Our results provide new insights into the effects of atVNS on memory performance and brain connectivity extending our knowledge of the biological mechanisms of bioelectronics in medicine.
Neural Control and Online Learning for Speed Adaptation of Unmanned Aerial Vehicles
Authors: Jaiton Vatsanai , Rothomphiwat Kongkiat , Ebeid Emad , Manoonpong Poramate
Published: April 2022

Unmanned aerial vehicles (UAVs) are involved in critical tasks such as inspection and exploration. Thus, they have to perform several intelligent functions. Various control approaches have been proposed to implement these functions. Most classical UAV control approaches, such as model predictive control, require a dynamic model to determine the optimal control parameters. Other control approaches use machine learning techniques that require multiple learning trials to obtain the proper control parameters. All these approaches are computationally expensive. Our goal is to develop an efficient control system for UAVs that does not require a dynamic model and allows them to learn control parameters online with only a few trials and inexpensive computations. To achieve this, we developed a neural control method with fast online learning. Neural control is based on a three-neuron network, whereas the online learning algorithm is derived from a neural correlation-based learning principle with predictive and reflexive sensory information. This neural control technique is used here for the speed adaptation of the UAV. The control technique relies on a simple input signal from a compact optical distance measurement sensor that can be converted into predictive and reflexive sensory information for the learning algorithm. Such speed adaptation is a fundamental function that can be used as part of other complex control functions, such as obstacle avoidance. The proposed technique was implemented on a real UAV system. Consequently, the UAV can quickly learn within 3–4 trials to proactively adapt its flying speed to brake at a safe distance from the obstacle or target in the horizontal and vertical planes. This speed adaptation is also robust against wind perturbation. We also demonstrated a combination of speed adaptation and obstacle avoidance for UAV navigations, which is an important intelligent function toward inspection and exploration.
Hyperdense Artery Sign and Clinical Outcomes After Endovascular Treatment in Acute Basilar Artery Occlusion
Authors: Hu Jinrong , He Wencheng , Zheng Bo , Huang Fang , Lv Kefeng , Liao Jiasheng , Chen Zhao , Jiang He , Wang Kuiyun , Wang Hongjun , Lei Yang , Liao Jiachuan , Sang Hongfei , Liu Shuai , Luo Weidong , Sun Ruidi , Yang Jie , Huang Jiacheng , Song Jiaxing , Li Fengli , Zi Wenjie , Long Chen , Yang Qingwu
Published: April 2022

Background

This study aimed to investigate the association between the hyperdense basilar artery sign (HBAS) on non-enhanced computed tomography (CT) and clinical outcomes in patients with acute basilar artery occlusion (BAO) who underwent endovascular treatment (EVT).

Methods

Eligible patients who underwent EVT due to acute BAO between January 2014 and May 2019 were divided into two groups based on HBAS. HBAS was assessed by two neuroradiologists using five grades on nonenhanced CT. The primary outcome was a favorable functional outcome (defined as a modified Rankin Scale [mRS] of 0–3) at 90 days. Secondary outcomes included successful recanalization and mortality within 90 days.

Results

Among 829 patients with BAO as assessed with CT angiography, magnetic resonance angiography, or digital subtraction angiography, 643 patients were treated with EVT. Of these, 51.32% (330/643) had HBAS. Patients with HBAS were older and had more severe neurological deficits and a higher frequency of atrial fibrillation than those without HBAS. There was no significant difference in favorable outcome (adjusted odds ratio [aOR]: 1.354, 95% confidence interval [CI]: 0.906–2.024; p = 0.14), successful recanalization (aOR: 0.926, 95% CI: 0.616-−1.393; p = 0.71), and mortality (aOR: 1.193, 95% CI: 0.839–1.695; p = 0.33) between patients with or without HBAS. Subgroup analysis showed that the HBAS predicted a favorable outcome in patients aged <60 years (aOR: 2.574, 95% CI: 1.234–5.368; p = 0.01) and patients with vertebral artery-V4 segment occlusion (aOR: 3.738, 95% CI: 1.212–11.530; p = 0.02). In patients with HBAS, the baseline National Institutes of Health Stroke Scale (NIHSS) score, posterior circulation–Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS), and stent retriever were associated with successful recanalization.

Conclusions

Our study did not find a significant association between HBAS and favorable outcomes and successful recanalization in patients with BAO who underwent EVT. Moreover, large prospective studies are warranted to further investigate this relationship.
Lack of Immunotherapy as the Only Predictor of Secondary Generalization in Very-Late-Onset Myasthenia Gravis With Pure Ocular Onset
Authors: Zhao Sijia , Yan Xu , Ding Jiaqi , Ren Kaixi , Sun Shuyu , Lu Jiarui , Zhang Chao , Zhang Kai , Li Zhuyi , Guo Jun
Published: April 2022

During the past two decades, an increasing number of patients with very-late-onset myasthenia gravis (v-LOMG) with an onset age of 65 years or older have been identified. However, few studies explore the predictors of secondary generalization in patients with v-LOMG with pure ocular onset. In this retrospective cohort study, 69 patients with v-LOMG were divided into ocular MG (OMG) and generalized MG (GMG), and the clinical characteristics and outcomes were compared. Cox regression analysis was performed to explore the predictors of generalization. The average onset age of the study population was 73.1 ± 4.2 years and the median disease duration was 48.0 months (interquartile range, 32.5–64.5 months). Serum acetylcholine receptor (AChR) antibody was detected in up to 86% of patients and concomitant diseases in approximately half of the patients. Male predominance was seen in OMG group while female predominance in GMG group (p = 0.043). Patients with OMG showed a lower positive rate of repetitive nerve stimulation (RNS) than those with GMG (p = 0.014), and favorable outcomes were obtained in more patients with OMG than those with GMG (p < 0.001). Of the 51 patients with pure ocular onset, 25 (49.0%) underwent secondary generalization. A higher probability of generalization was found in patients with positive RNS results and without immunotherapy (p = 0.018 and <0.001). Upon Cox regression analysis, immunotherapy was negatively associated with secondary generalization [HR (hazard ratio) 0.077, 95%CI [0.024–0.247], p < 0.001]. Altogether, compared to the patients with very-late-onset GMG, the counterparts with OMG exhibit a significantly higher female predominance and a lower positive rate of RNS tests, especially on facial and accessory nerves. Lack of immunotherapy is the only predictor of secondary generalization in those with pure ocular onset.
Human Umbilical Cord Mesenchymal Stem Cells to Treat Neuromyelitis Optica Spectrum Disorder (hUC–MSC–NMOSD): A Study Protocol for a Prospective, Multicenter, Randomized, Placebo-Controlled Clinical Trial
Authors: Yao Xiao-Ying , Xie Li , Cai Yu , Zhang Ying , Deng Ye , Gao Mei-Chun , Wang Yi-Shu , Xu Hui-Ming , Ding Jie , Wu Yi-Fan , Zhao Nan , Wang Ze , Song Ya-Ying , Wang Li-Ping , Xie Chong , Li Ze-Zhi , Wan Wen-Bin , Lin Yan , Jin Hai-Feng , Wang Kan , Qiu Hui-Ying , Zhuang Lei , Zhou Yan , Jin Yu-Yan , Ni Li-Ping , Yan Jia-Li , Guo Quan , Xue Jia-Hui , Qian Bi-Yun , Guan Yang-Tai
Published: April 2022

Background

Neuromyelitis Optica spectrum disorder (NMOSD) is severe relapsing and disabling autoimmune disease of the central nervous system. Its optimal first-line treatment to reduce relapse rate and ameliorate neurological disability remains unclear. We will conduct a prospective, multicenter, randomized, placebo-controlled clinical trial to study the safety and effectiveness of human umbilical cord mesenchymal stem cells (hUC–MSCs) in treating NMOSD.

Methods

The trial is planned to recruit 430 AQP4-IgG seropositive NMOSD patients. It consists of three consecutive stages. The first stage will be carried out in the leading center only and aims to evaluate the safety of hUC—MSCs. Patients will be treated with three different doses of hUC–MSCs: 1, 2, or 5 × 106 MSC/kg·weight for the low-, medium-, and high-dose group, respectively. The second and third stages will be carried out in six centers. The second stage aims to find the optimal dosage. Patients will be 1:1:1:1 randomized into the low-, medium-, high-dose group and the controlled group. The third stage aims to evaluate the effectiveness. Patients will be 1:1 randomized into the optimal dose and the controlled group. The primary endpoint is the first recurrent time and secondary endpoints are the recurrent times, EDSS scores, MRI lesion numbers, OSIS scores, Hauser walking index, and SF-36 scores. Endpoint events and side effects will be evaluated every 3 months for 2 years.

Discussion

Although hUC–MSC has shown promising treatment effects of NMOSD in preclinical studies, there is still a lack of well-designed clinical trials to evaluate the safety and effectiveness of hUC–MSC among NMOSD patients. As far as we know, this trial will be the first one to systematically demonstrate the clinical safety and efficacy of hUC–MSC in treating NMOSD and might be able to determine the optimal dose of hUC–MSC for NMOSD patients.

Trial registration

The study was registered with the Chinese Clinical Trial Registry (CHICTR.org.cn) on 2 March 2016 (registration No. ChiCTR-INR-16008037), and the revised trial protocol (Protocol version 1.2.1) was released on 16 March 2020.
Subclinical Atherosclerosis Could Increase the Risk of Hearing Impairment in Males: A Community-Based Cross-Sectional Survey of the Kailuan Study
Authors: Ruan Chunyu , Mao Xiang , Chen Shuohua , Wu Shouling , Wang Wei
Published: April 2022

Objective

The relationship between subclinical atherosclerosis and hearing impairment (HI) has not been widely considered. Brachial ankle pulse wave velocity (baPWV) is a good indicator of muscular artery elasticity and could be a feasible method to screen for subclinical atherosclerosis. Our study aimed to elucidate the relationship between baPWV and HI.

Methods

This cross-sectional study was based on the Kailuan cohort. All participants completed a standardized questionnaire and underwent physical examinations and laboratory assessments at recruitment. Since 2010, some participants received additional baPWV testing during follow-up visits, and some who were exposed to occupational hazards such as noise received a pure-tone average hearing threshold (PTA) test after 2014. Male subjects with a complete physical examination, baPWV, and PTA data were recruited for this study. HI was defined as PTA > 25 dB. Multivariate linear and multivariate logistic regression analyses were used to evaluate the relationship between baPWV and PTA or HI.

Results

Among 11,141 subjects, the age range was 18–65 years, with mean age of 43.3 ± 8.9 years, the average PTA was 20.54 ± 10.40 dB, and the detection rate of HI was 1,821/11,141 (16.3%). Subjects were divided into four subgroups according to baPWV quartile. As the baPWV quartile increased, age, systolic blood pressure, diastolic blood pressure, body mass index, total cholesterol, high-density-lipoprotein cholesterol, fasting blood glucose, PTA, and proportions of subjects reporting smoking, alcohol consumption, hypertension, and diabetes increased significantly (p < 0.05 for trend). The odds of HI were higher in the fourth quartile group [adjusted odds ratio (aOR): 1.33, 95% CI: 1.10–1.62] than in the first quartile group. For every 100 m/s increase in baPWV, the PTA increased by 13 dB (95% CI: 4–23). When we divided the subjects into young (5,478 subjects; age range 22–44 years; mean age 35.6 ± 5.5 years) or non-young subgroups (5,663 subjects; age range 45–65 years; mean age 50.7 ± 3.7 years) based on a cut-off age of 45 years, the aOR of the fourth quartile group increased to 2.65 (95% CI: 1.68–4.19), and the PTA increment increased to 18 dB (95% CI: 10–27) for every 100 m/s increase in baPWV in the young subgroup. However, this relationship became statistically insignificant in the non-young subgroup.

Conclusion

Our study revealed the quantitative relationship between baPWV and HI in the Kailuan cohort subjects, although the results are not universally consistent in different populations.
Greater Similarity Between L1 and L2’s Brain Network in Adults Than in Children
Authors: Cao Fan , Fan Yuyu , Yan Xin , Chen Wuying , Dodson-Garrett Maddie , Spray Gregory J. , Wang Zhao , Deng Yuan
Published: April 2022

It has been documented that processing L2 and L1 engages a very similar brain network in bilingual adults. However, it is not known whether this similarity is evident in bilingual children as well or it develops with learning from children to adults. In the current study, we compared brain activation in Chinese-English bilingual children and adults during L1 and L2 processing. We found greater similarity between L1 and L2 in adults than in children, supporting the convergence hypothesis which argues that when the proficiency of L2 increases, the L2’s brain network converges to the L1’s brain network. We also found greater differences between adults and children in the brain for L2 processing than L1 processing, even though there were comparable increase in proficiency from children to adults in L1 and L2. It suggests an elongated developmental course for L2. This study provides important insights about developmental changes in the bilingual brain.
Neuroevolution Guided Hybrid Spiking Neural Network Training
Authors: Lu Sen , Sengupta Abhronil
Published: April 2022

Neuromorphic computing algorithms based on Spiking Neural Networks (SNNs) are evolving to be a disruptive technology driving machine learning research. The overarching goal of this work is to develop a structured algorithmic framework for SNN training that optimizes unique SNN-specific properties like neuron spiking threshold using neuroevolution as a feedback strategy. We provide extensive results for this hybrid bio-inspired training strategy and show that such a feedback-based learning approach leads to explainable neuromorphic systems that adapt to the specific underlying application. Our analysis reveals 53.8, 28.8, and 28.2% latency improvement for the neuroevolution-based SNN training strategy on CIFAR-10, CIFAR-100, and ImageNet datasets, respectively in contrast to state-of-the-art conversion based approaches. The proposed algorithm can be easily extended to other application domains like image classification in presence of adversarial attacks where 43.2 and 27.9% latency improvements were observed on CIFAR-10 and CIFAR-100 datasets, respectively.
Activity in the Fronto-Parietal and Visual Cortex Is Modulated by Feature-Based Attentional Weighting
Authors: Lanssens Armien , Mantini Dante , de Beeck Hans Op , Gillebert Celine R.
Published: April 2022

In day-to-day dynamic activities where sensory input is abundant, stimulus representations in the visual cortex are modulated based on their attentional priority. Several studies have established the top-down role of a fronto-parietal dorsal attention network in selective attention. In the current study, we aimed to investigate whether activity of subregions of this network and the visual cortex is modulated by feature-based attentional weighting, and if so, whether their timecourses of activity are correlated. To this end, we analyzed fMRI data of 28 healthy subjects, who performed a feature-based go/no-go task. Participants had to attend to one or two colored streams of sinusoidal gratings and respond to each grating in the task-relevant stream(s) except to a single non-target grating. Univariate and multivariate fMRI results indicated that activity in bilateral fronto-parietal (frontal eye fields, intraparietal sulcus and superior parietal lobe) and visual (V1–V4, lateral occipital cortex and fusiform gyrus) regions was modulated by selecting one instead of attending to two gratings. Functional connectivity was not significantly different between fronto-parietal and visual regions when attending to one as opposed to two gratings. Our study demonstrates that activity in subregions of both the fronto-parietal and visual cortex is modified by feature-based attentional weighting.
Detection of Cross-Frequency Coupling Between Brain Areas: An Extension of Phase Linearity Measurement
Authors: Sorrentino Pierpaolo , Ambrosanio Michele , Rucco Rosaria , Cabral Joana , Gollo Leonardo L. , Breakspear Michael , Baselice Fabio
Published: April 2022

The current paper proposes a method to estimate phase to phase cross-frequency coupling between brain areas, applied to broadband signals, without any a priori hypothesis about the frequency of the synchronized components. N:m synchronization is the only form of cross-frequency synchronization that allows the exchange of information at the time resolution of the faster signal, hence likely to play a fundamental role in large-scale coordination of brain activity. The proposed method, named cross-frequency phase linearity measurement (CF-PLM), builds and expands upon the phase linearity measurement, an iso-frequency connectivity metrics previously published by our group. The main idea lies in using the shape of the interferometric spectrum of the two analyzed signals in order to estimate the strength of cross-frequency coupling. We first provide a theoretical explanation of the metrics. Then, we test the proposed metric on simulated data from coupled oscillators synchronized in iso- and cross-frequency (using both Rössler and Kuramoto oscillator models), and subsequently apply it on real data from brain activity. Results show that the method is useful to estimate n:m synchronization, based solely on the phase of the signals (independently of the amplitude), and no a-priori hypothesis is available about the expected frequencies.
A Comparison of Single- and Multi-Echo Processing of Functional MRI Data During Overt Autobiographical Recall
Authors: Gilmore Adrian W. , Agron Anna M. , González-Araya Estefanía I. , Gotts Stephen J. , Martin Alex
Published: April 2022

Recent years have seen an increase in the use of multi-echo fMRI designs by cognitive neuroscientists. Acquiring multiple echoes allows one to increase contrast-to-noise; reduce signal dropout and thermal noise; and identify nuisance signal components in BOLD data. At the same time, multi-echo acquisitions increase data processing complexity and may incur a cost to the temporal and spatial resolution of the acquired data. Here, we re-examine a multi-echo dataset previously analyzed using multi-echo independent components analysis (ME-ICA) and focused on hippocampal activity during the overtly spoken recall of recent and remote autobiographical memories. The goal of the present series of analyses was to determine if ME-ICA’s theoretical denoising benefits might lead to a practical difference in the overall conclusions reached. Compared to single-echo (SE) data, ME-ICA led to qualitatively different findings regarding hippocampal contributions to autobiographical recall: whereas the SE analysis largely failed to reveal hippocampal activity relative to an active baseline, ME-ICA results supported predictions of the Standard Model of Consolidation and a time limited hippocampal involvement. These data provide a practical example of the benefits multi-echo denoising in a naturalistic memory paradigm and demonstrate how they can be used to address long-standing theoretical questions.
EEG-TNet: An End-To-End Brain Computer Interface Framework for Mental Workload Estimation
Authors: Fan Chaojie , Hu Jin , Huang Shufang , Peng Yong , Kwong Sam
Published: April 2022

The mental workload (MWL) of different occupational groups' workers is the main and direct factor of unsafe behavior, which may cause serious accidents. One of the new and useful technologies to estimate MWL is the Brain computer interface (BCI) based on EEG signals, which is regarded as the gold standard of cognitive status. However, estimation systems involving handcrafted EEG features are time-consuming and unsuitable to apply in real-time. The purpose of this study was to propose an end-to-end BCI framework for MWL estimation. First, a new automated data preprocessing method was proposed to remove the artifact without human interference. Then a new neural network structure named EEG-TNet was designed to extract both the temporal and frequency information from the original EEG. Furthermore, two types of experiments and ablation studies were performed to prove the effectiveness of this model. In the subject-dependent experiment, the estimation accuracy of dual-task estimation (No task vs. TASK) and triple-task estimation (Lo vs. Mi vs. Hi) reached 99.82 and 99.21%, respectively. In contrast, the accuracy of different tasks reached 82.78 and 66.83% in subject-independent experiments. Additionally, the ablation studies proved that preprocessing method and network structure had significant contributions to estimation MWL. The proposed method is convenient without any human intervention and outperforms other related studies, which becomes an effective way to reduce human factor risks.
Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer
Authors: Datta Jharna , Willingham Natalie , Manouchehri Jasmine M. , Schnell Patrick , Sheth Mirisha , David Joel J. , Kassem Mahmoud , Wilson Tyler A. , Radomska Hanna S. , Coss Christopher C. , Bennett Chad E. , Ganju Ramesh K. , Sardesai Sagar D. , Lustberg Maryam , Ramaswamy Bhuvaneswari , Stover Daniel G. , Cherian Mathew A.
Published: April 2022

Background

Among women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer.

Methods

We measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERβ agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2-regulated genes.

Results

In this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples.

Conclusion

Our results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer.
Artificial Intelligence-Based Automated Treatment Planning of Postmastectomy Volumetric Modulated Arc Radiotherapy
Authors: Jiang Shengpeng , Xue Yi , Li Ming , Yang Chengwen , Zhang Daguang , Wang Qingxin , Wang Jing , Chen Jie , You Jinqiang , Yuan Zhiyong , Wang Xiaochun , Zhang Xiaodong , Wang Wei
Published: April 2022

As a useful tool, artificial intelligence has surpassed human beings in many fields. Artificial intelligence-based automated radiotherapy planning strategies have been proposed in lots of cancer sites and are the future of treatment planning. Postmastectomy radiotherapy (PMRT) decreases local recurrence probability and improves overall survival, and volumetric modulated arc therapy (VMAT) has gradually become the mainstream technique of radiotherapy. However, there are few customized effective automated treatment planning schemes for postmastectomy VMAT so far. This study investigated an artificial intelligence based automated planning using the MD Anderson Cancer Center AutoPlan (MDAP) system and Pinnacle treatment planning system (TPS), to effectively generate high-quality postmastectomy VMAT plans. In this study, 20 patients treated with PMRT were retrospectively investigated, including 10 left- and 10 right-sided postmastectomy patients. Chest wall and the supraclavicular, subclavicular, and internal mammary regions were delineated as target volume by radiation oncologists, and 50 Gy in 25 fractions was prescribed. Organs at risk including heart, spinal cord, left lung, right lung, and lungs were also contoured. All patients were planned with VMAT using 2 arcs. An optimization objective template was summarized based on the dose of clinical plans and requirements from oncologists. Several treatment planning parameters were investigated using an artificial intelligence algorithm, including collimation angle, jaw collimator mode, gantry spacing resolution (GSR), and number of start optimization times. The treatment planning parameters with the best performance or that were most preferred were applied to the automated treatment planning method. Dosimetric indexes of automated treatment plans (autoplans) and manual clinical plans were compared by the paired t-test. The jaw tracking mode, 2-degree GSR, and 3 rounds of optimization were selected in all the PMRT autoplans. Additionally, the 350- and 10-degree collimation angles were selected in the left- and right-sided PMRT autoplans, respectively. The uniformity index and conformity index of the planning target volume, mean heart dose, spinal cord D0.03cc, mean lung dose, and V5Gy and V20Gy of the lung of autoplans were significantly better compared with the manual clinical plans. An artificial intelligence-based automated treatment planning method for postmastectomy VMAT has been developed to ensure plan quality and improve clinical efficiency.
Case Report: Generalised Panniculitis as a Post-COVID-19 Presentation in Aicardi-Goutières Syndrome Treated With Ruxolitinib
Authors: Pararajasingam Abirami , Bradley Rachel E. , Evans Jennifer , Lowe Ashima , Goodwin Richard , Jolles Stephen
Published: April 2022

Aicardi-Goutières syndrome (AGS) is a rare hereditary early-onset encephalopathy. The syndrome was first described in 1984, and is characterised by upregulation of the type I interferon (IFN) pathway, which is involved in the host immune response against viral infections, including SARS-CoV-2. Whilst defects in type I IFN pathways have been described in association with severe coronavirus disease 2019 (COVID-19), less is known about the outcomes of upregulation. We describe an unusual case of generalised panniculitis as a post-COVID-19 phenomenon in a child with AGS. Our patient was initially managed with systemic steroid therapy, but due to relapse of symptoms on weaning, an alternative therapy was sought. In this case, a novel use of ruxolitinib, a JAK inhibitor, has resulted in lasting remission without complications. We discuss the probable protective role of IFN upregulation following COVID-19 infection in AGS and possible immunological mechanisms driving the panniculitis and therapeutic response in our case.
Pulmonary Function and Long-Term Respiratory Symptoms in Children and Adolescents After COVID-19
Authors: Knoke Leona , Schlegtendal Anne , Maier Christoph , Eitner Lynn , Lücke Thomas , Brinkmann Folke
Published: April 2022

Background

Persistent respiratory symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in adults are frequent, and there can be long-term impairment of pulmonary function. To date, only preliminary evidence is available on persistent respiratory sequelae of SARS-CoV-2 in children and adolescents. Our objective was to examine the long-term effects of symptomatic and asymptomatic SARS-CoV-2 infections on pulmonary function in this age group in a single-center, controlled, prospective study.

Methods

Participants with serological or polymerase chain reaction-based evidence of SARS-CoV-2 infection were recruited from a population-based study of seroconversion rates. Multiple-breath washout (MBW), body plethysmography, and diffusion capacity testing were performed for children and adolescents. Participants were interviewed about their symptoms during the acute phase of infection and long-lasting symptoms. Cases were compared with SARS-CoV-2 seronegative controls from the same population-based study with and without history of respiratory infection within 6 months prior to assessment. Primary endpoints were differences in pulmonary function, including diffusion capacity and MBW, between participants with and without evidence of SARS-CoV-2 infection. Secondary endpoints included correlation between lung function and long-lasting symptoms as well as disease severity.

Findings

In total, 73 seropositive children and adolescents (5–18 years) were recruited after an average of 2.6 months (range 0.4–6.0) following SARS-CoV-2 infection. Among 19 patients (27.1%) who complained of persistent or newly emerged symptoms since SARS-CoV-2, 8 (11.4%) reported respiratory symptoms. No significant differences were detected in frequency of abnormal pulmonary function when comparing cases with 45 controls, including 14 (31.1%) with a history of previous infection (SARS-CoV-2: 12, 16.4%; controls: 12, 27.7%; odds ratio 0.54, 95% confidence interval 0.22–1.34). Only two patients with persistent respiratory symptoms showed abnormal pulmonary function. Multivariate analysis revealed reduced forced vital capacity (p = 0.012) in patients with severe SARS-CoV-2 infection.

Interpretation

Pulmonary function is rarely impaired in children and adolescents after SARS-CoV-2 infection, except from those with severe infection, and did not differ between SARS-CoV-2 and other previous infections, suggesting that SARS-CoV-2 is not more likely to cause pulmonary sequelae than other infections. The discrepancy between persisting respiratory symptoms and normal pulmonary function suggests a different underlying pathology such as dysfunctional breathing.
The Outcome of Post-cardiotomy Extracorporeal Membrane Oxygenation in Neonates and Pediatric Patients: A Systematic Review and Meta-Analysis
Authors: Cho Hwa Jin , Choi Insu , Kwak Yujin , Kim Do Wan , Habimana Reverien , Jeong In-Seok
Published: April 2022

Objective

Post-cardiotomy extracorporeal membrane oxygenation (PC-ECMO) is a known rescue therapy for neonates and pediatric patients who failed to wean from cardiopulmonary bypass (CPB) or who deteriorate in intensive care unit (ICU) due to various reasons such as low cardiac output syndrome (LCOS), cardiac arrest and respiratory failure. We conducted a systematic review and meta-analysis to assess the survival in neonates and pediatric patients who require PC-ECMO and sought the difference in survivals by each indication for PC-ECMO.

Design

Systematic review and meta-analysis.

Setting

Multi-institutional analysis.

Participants

Neonates and pediatric patients who requires PC- ECMO.

Interventions

ECMO after open-heart surgery.

Results

Twenty-six studies were included in the analysis with a total of 186,648 patients and the proportion of the population who underwent PC-ECMO was 2.5% (2,683 patients). The overall pooled proportion of survival in this population was 43.3% [95% Confidence interval (CI): 41.3–45.3%; I2: 1%]. The survival by indications of PC-ECMO were 44.6% (95% CI: 42.6–46.6; I2: 0%) for CPB weaning failure, 47.3% (95% CI: 39.9–54.7%; I2: 5%) for LCOS, 37.6% (95% CI: 31.0–44.3%; I2: 32%) for cardiac arrest and 47.7% (95% CI: 32.5–63.1%; I2: 0%) for respiratory failure. Survival from PC-ECMO for single ventricle or biventricular physiology, was reported by 12 studies. The risk ratio (RR) was 0.74 for survival in patients with single ventricle physiology (95% CI: 0.63–0.86; I2: 40%, P < 0.001). Eight studies reported on the survival after PC-ECMO for genetic conditions. The RR was 0.93 for survival in patients with genetic condition (95% CI: 0.52–1.65; I2: 65%, P = 0.812).

Conclusions

PC-ECMO is an effective modality to support neonates and pediatric patients in case of failed CPB weaning and deterioration in ICU. Even though ECMO seems to improve survival, mortality and morbidity remain high, especially in neonates and pediatric patients with single ventricle physiology. Most genetic conditions alone should not be considered a contraindication to ECMO support, further studies are needed to determine which genetic abnormalities are associated with favorable outcome.
Multiple Organ Dysfunction Interactions in Critically Ill Children
Authors: Badke Colleen M. , Mayampurath Anoop , Sanchez-Pinto L. Nelson
Published: April 2022

Introduction

Multiple organ dysfunction (MOD) is a common pathway to morbidity and death in critically ill children. Defining organ dysfunction is challenging, as we lack a complete understanding of the complex pathobiology. Current pediatric organ dysfunction criteria assign the same diagnostic value—the same “weight”— to each organ system. While each organ dysfunction in isolation contributes to the outcome, there are likely complex interactions between multiple failing organs that are not simply additive.

Objective

Determine whether certain combinations of organ system dysfunctions have a significant interaction associated with higher risk of morbidity or mortality in critically ill children.

Methods

We conducted a retrospective observational cohort study of critically ill children at two large academic medical centers from 2010 and 2018. Patients were included in the study if they had at least two organ dysfunctions by day 3 of PICU admission based on the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) criteria. Mortality was described as absolute number of deaths and mortality rate. Combinations of two pediatric organ dysfunctions were analyzed with interaction terms as independent variables and mortality or persistent MOD as the dependent variable in logistic regression models.

Results

Overall, 7,897 patients met inclusion criteria and 446 patients (5.6%) died. The organ dysfunction interactions that were significantly associated with the highest absolute number of deaths were cardiovascular + endocrinologic, cardiovascular + neurologic, and cardiovascular + respiratory. Additionally, the interactions associated with the highest mortality rates were liver + cardiovascular, respiratory + hematologic, and respiratory + renal. Among patients with persistent MOD, the most common organ dysfunctions with significant interaction terms were neurologic + respiratory, hematologic + immunologic, and endocrinologic + respiratory. Further analysis using classification and regression trees (CART) demonstrated that the absence of respiratory and liver dysfunction was associated with the lowest likelihood of mortality.

Implications and Future Directions

Certain combinations of organ dysfunctions are associated with a higher risk of persistent MOD or death. Notably, the three most common organ dysfunction interactions were associated with 75% of the mortality in our cohort. Critically ill children with MOD presenting with these combinations of organ dysfunctions warrant further study.
Case Report: Prolonged Neutropenia in Premature Monoamniotic Twins With SARS-CoV-2 Infection Acquired by Vertical Transmission
Authors: Scholz Anna S. , Wallwiener Stephanie , Pöschl Johannes , Kuss Navina
Published: April 2022

Background

Vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a highly debated topic in the current pandemic situation. Early neonatal SARS-CoV-2 infection is rare and generally mild. Long-term data describing symptoms after COVID-19 in premature neonates is scarce.

Case Presentation

Two premature, monoamniotic neonates were born by cesarean section to a mother 5 days after onset of symptomatic COVID-19. On day three of life both neonates developed hyperthermia, respiratory distress, and hematological changes, of which neutropenia persisted for over 40 days. Nasopharyngeal swabs for SARS-CoV-2 turned positive four days after delivery although the neonates were strictly isolated. Both neonates showed nearly identical time courses of ct values.

Conclusion

Our case report revealed prolonged low absolute neutrophil counts in two preterm neonates with symptomatic SARS-CoV-2 infection that is reasonably assumed to have been transmitted vertically in utero. After preterm delivery to a SARS-CoV-2 positive mother, testing for SARS-CoV-2 infection in neonates is crucial. Both neutropenia and lymphopenia should alert physicians to test for SARS-CoV-2 infection and also to follow the case.
A Combined Human in Silico and CRISPR/Cas9-Mediated in Vivo Zebrafish Based Approach to Provide Phenotypic Data for Supporting Early Target Validation
Authors: Winter Matthew J. , Ono Yosuke , Ball Jonathan S. , Walentinsson Anna , Michaelsson Erik , Tochwin Anna , Scholpp Steffen , Tyler Charles R. , Rees Steve , Hetheridge Malcolm J , Bohlooly-Y Mohammad
Published: April 2022

The clinical heterogeneity of heart failure has challenged our understanding of the underlying genetic mechanisms of this disease. In this respect, large-scale patient DNA sequencing studies have become an invaluable strategy for identifying potential genetic contributing factors. The complex aetiology of heart failure, however, also means that in vivo models are vital to understand the links between genetic perturbations and functional impacts as part of the process for validating potential new drug targets. Traditional approaches (e.g., genetically-modified mice) are optimal for assessing small numbers of genes, but less practical when multiple genes are identified. The zebrafish, in contrast, offers great potential for higher throughput in vivo gene functional assessment to aid target prioritisation, by providing more confidence in target relevance and facilitating gene selection for definitive loss of function studies undertaken in mice. Here we used whole-exome sequencing and bioinformatics on human patient data to identify 3 genes (API5, HSPB7, and LMO2) suggestively associated with heart failure that were also predicted to play a broader role in disease aetiology. The role of these genes in cardiovascular system development and function was then further investigated using in vivo CRISPR/Cas9-mediated gene mutation analysis in zebrafish. We observed multiple impacts in F0 knockout zebrafish embryos (crispants) following effective somatic mutation, including changes in ventricle size, pericardial oedema, and chamber malformation. In the case of lmo2, there was also a significant impact on cardiovascular function as well as an expected reduction in erythropoiesis. The data generated from both the human in silico and zebrafish in vivo assessments undertaken supports further investigation of the potential roles of API5, HSPB7, and LMO2 in human cardiovascular disease. The data presented also supports the use of human in silico genetic variant analysis, in combination with zebrafish crispant phenotyping, as a powerful approach for assessing gene function as part of an integrated multi-level drug target validation strategy.
Integrated Network Pharmacology and Comprehensive Bioinformatics Identifying the Mechanisms and Molecular Targets of Yizhiqingxin Formula for Treatment of Comorbidity With Alzheimer’s Disease and Depression
Authors: Zhang Tingting , Wei Wei , Chang Surui , Liu Nanyang , Li Hao
Published: April 2022

Background: The Yizhiqinxin formula (YZQX) has been used to treat Alzheimer’s disease (AD) or major depression disorder (MDD). However, its specific underlying mechanisms and therapeutic targets remain unclear.

Methods: The ingredients and putative targets of YZQX were screened using the TCMSP and Drugbank databases. Next, the GEO database was used to retrieve relevant differentially expressed genes (DEGs) in AD or MDD and normal tissues. The PPI network was established, merged, and further screened to identify the main ingredients and core targets of YZQX against AD and MDD comorbidities. We performed enrichment analysis of core targets to identify biological processes and pathways. Finally, AutoDock software was used to validate the binding affinity between the crucial targets of direct action and their corresponding ingredients.

Results: A total of 43 ingredients were identified from YZQX, of which 43 were screened to yield 504 targets. By establishing the PPI network, 92 targets were regarded as targets of YZQX against AD and MDD comorbidities in the core network. Promising targets (HSP90AA1, ESR1, AKT1, VCAM1, EGFR, CDK1, MAPK1, CDK2, MYC, HSPB1, and HSPA5) and signaling pathways (PI3K-Akt signaling pathway, ubiquitin-mediated proteolysis, MAPK signaling pathway, etc.) were filtered and refined to elucidate the underlying mechanism of YZQX against AD and MDD comorbidities. Molecular docking confirmed the ingredients of YZQX (quercetin and kaempferol) could bind well to multiple crucial targets.

Conclusion: The ingredients of YZQX, such as quercetin and kaempferol, might treat AD and MDD comorbidities by acting on multiple targets and pathways.
Small Molecule Inhibitor Targeting CDT1/Geminin Protein Complex Promotes DNA Damage and Cell Death in Cancer Cells
Authors: Karantzelis Nikolaos , Petropoulos Michalis , De Marco Valeria , Egan David A. , Fish Alexander , Christodoulou Evangelos , Will David W. , Lewis Joe D. , Perrakis Anastassis , Lygerou Zoi , Taraviras Stavros
Published: April 2022

DNA replication initiation requires the loading of MCM2-7 complexes at the origins of replication during G1. Replication licensing renders chromatin competent for DNA replication and its tight regulation is essential to prevent aberrant DNA replication and genomic instability. CDT1 is a critical factor of licensing and its activity is controlled by redundant mechanisms, including Geminin, a protein inhibitor of CDT1. Aberrant CDT1 and Geminin expression have been shown to promote tumorigenesis in vivo and are also evident in multiple human tumors. In this study, we developed an in vitro AlphaScreen™ high-throughput screening (HTS) assay for the identification of small-molecule inhibitors targeting the CDT1/Geminin protein complex. Biochemical characterization of the most potent compound, AF615, provided evidence of specific, dose-dependent inhibition of Geminin binding to CDT1 both in-vitro and in cells. Moreover, compound AF615 induces DNA damage, inhibits DNA synthesis and reduces viability selectively in cancer cell lines, and this effect is CDT1-dependent. Taken together, our data suggest that AF615 may serve as a useful compound to elucidate the role of CDT1/Geminin protein complex in replication licensing and origin firing as well as a scaffold for further medicinal chemistry optimisation.