bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: Hypoglycemia Due to a Novel Activating Glucokinase Variant in an Adult – a Molecular Approach
Authors: Koneshamoorthy Anojian , Seniveratne-Epa Dilan , Calder Genevieve , Sawyer Matthew , Kay Thomas W. H. , Farrell Stephen , Loudovaris Thomas , Mariana Lina , McCarthy Davis , Lyu Ruqian , Liu Xin , Thorn Peter , Tong Jason , Chin Lit Kim , Zacharin Margaret , Trainer Alison , Taylor Shelby , MacIsaac Richard J. , Sachithanandan Nirupa , Thomas Helen E. , Krishnamurthy Balasubramanian
Published: March 2022

We present a case of an obese 22-year-old man with activating GCK variant who had neonatal hypoglycemia, re-emerging with hypoglycemia later in life. We investigated him for asymptomatic hypoglycemia with a family history of hypoglycemia. Genetic testing yielded a novel GCK missense class 3 variant that was subsequently found in his mother, sister and nephew and reclassified as a class 4 likely pathogenic variant. Glucokinase enables phosphorylation of glucose, the rate-limiting step of glycolysis in the liver and pancreatic β cells. It plays a crucial role in the regulation of insulin secretion. Inactivating variants in GCK cause hyperglycemia and activating variants cause hypoglycemia. Spleen-preserving distal pancreatectomy revealed diffuse hyperplastic islets, nuclear pleomorphism and periductular islets. Glucose stimulated insulin secretion revealed increased insulin secretion in response to glucose. Cytoplasmic calcium, which triggers exocytosis of insulin-containing granules, revealed normal basal but increased glucose-stimulated level. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated INS and CKB genes and downregulated DLK1 and NPY genes in β-cells. Further studies are required to see if alteration in expression of these genes plays a role in the metabolic and histological phenotype associated with glucokinase pathogenic variant. There were more large islets in the patient’s pancreas than in control subjects but there was no difference in the proportion of β cells in the islets. His hypoglycemia was persistent after pancreatectomy, was refractory to diazoxide and improved with pasireotide. This case highlights the variable phenotype of GCK mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion.
Association of Age of Metabolic Syndrome Onset With Cardiovascular Diseases: The Kailuan Study
Authors: Huang Zegui , Wang Xianxuan , Ding Xiong , Cai Zefeng , Li Weijian , Chen Zekai , Fang Wei , Cai Zhiwei , Lan Yulong , Chen Guanzhi , Wu Weiqiang , Chen Zhichao , Wu Shouling , Chen Youren
Published: March 2022

Background

Metabolic syndrome (MetS) is associated with an increased risk of incident cardiovascular diseases (CVD), but the association between the new-onset MetS at different ages and the CVD risk remain unclear.

Methods

This was a prospective study comprising a total of 72,986 participants without MetS and CVD who participated in the Kailuan study baseline survey (July 2006 to October 2007). All participants received the biennial follow-up visit until December 31, 2019. In addition, 26,411 patients with new-onset MetS were identified from follow-up, and one control participant was randomly selected for each of them as a match for age ( ± 1 year) and sex. In the end, a total of 25,125 case-control pairs were involved. Moreover, the Cox proportional hazard model was established to calculate the hazard ratios (HR) for incident CVD across the onset age groups.

Results

According to the median follow-up for 8.47 years, 2,319 cases of incident CVD occurred. As MetS onset age increased, CVD hazards gradually decreased after adjusting for potential confounders. Compared with non-MetS controls, the HR and the 95% confidence interval (CI) for CVD were 1.84 (1.31–2.57) in the MetS onset age <45 years group, 1.67 (1.42–1.95) for the 45–54 years group, 1.36 (1.18–1.58) for the 55–64 years group, and 1.28 (1.10–1.50) for the ≥65 years group, respectively (p for interaction = 0.03).

Conclusions

The relative risks of CVD differed across MetS onset age groups, and the associations was more intense in the MetS onset group at a younger age.
Capacity Configuration Method of Hybrid Energy Storage Participating in AGC Based on Improved Meta-Model Optimization Algorithm
Authors: He Junqiang , Shi Changli , Wu Qingfeng , Zhang Wenjie , Gao Yunguang
Published: March 2022

To improve the performance and economy of the hybrid energy storage system (HESS) coordinating thermal generators to participate in automatic generation control (AGC), a HESS bi-layer capacity configuration model that considers the control strategy and net benefits of HESS is proposed. In addition, an improved mode-pursuing sampling (MPS) optimization algorithm based on meta-model is presented to improve the accuracy of model solving. In the lower layer, to improve the performance of HESS participating in AGC, a model predictive control (MPC) strategy is presented to distribute HESS power reasonably. Based on this, the upper layer develops a life-cycle net benefit model of HESS participating in AGC to improve its economy. The bi-layer model realizes iterative optimization of HESS capacity and operation through parameter transmission. Furthermore, to improve the solution accuracy of the bi-layer model, the convergence speed of the MPS algorithm is improved, so that the global search and local convergence speed can be taken into account. The case study results show that the bi-layer model can comprehensively consider the interaction between the economy and operating strategy of HESS. The proposed MPC strategy has better frequency regulation performance and the improved MPS algorithm has better solution performance.
How Digital Finance Affects the Continuous Technological Innovation of Chinese Energy Companies?
Authors: Guo Zhongkun , Peng Yulian , Chen Yajing
Published: March 2022

This paper discusses the impact of digital finance development on the continuous technological innovation and its mechanism in China’s energy companies. Analyzing the data of A-share listed energy companies in China’s Shanghai and Shenzhen stock markets from 2011 to 2018, using a fixed effects model, we find that digital finance development played a positive role in stimulating continuous technological innovation in Chinese energy companies. Moreover, we find that risk-taking plays a mediating effect, which is the development of digital finance encourages Chinese energy companies to carry out continuously innovative activities by increasing the level of corporate risk-taking. Finally, we find that in non-state-owned, small and highly externally funded energy companies, digital finance development shows a stronger effect in driving continuous technological innovation in Chinese energy companies through risk-taking. Our results highlight the role of risk-taking as an important mediator in the relationship between digital finance development and continuous technological innovation. It has enlightenment for China to make better use of digital finance to empower energy companies to continue to innovate.
Effects of Matrix Creep Properties on Effective Irradiation Swelling of U-10Mo/Zr Dispersion Nuclear Fuels
Authors: Li Yong , Zhang Jing , Jian Xiaobin , Yan Feng , Ding Shurong , Li Yuanming
Published: March 2022

A meso-mechanical model is established for the homogenized irradiation swelling of U-10Mo/Zr dispersion fuels, with an equivalent sphere chosen as the representative volume element (RVE). In the simulation, a mechanistic model for the fission gas swelling of U-10Mo particles and the creep model for Zr matrix with different values of the creep amplification factor are included. Based on the developed method, the results of effective irradiation swelling of U-10Mo/Zr dispersion fuels are obtained by finite element simulation. Additionally, the effects of matrix creep properties on the effective irradiation swelling are investigated. The numerical results indicate that 1) the Zr matrix has the function of restraining and compensating the irradiation swelling of fuel particles by the mechanical interactions between the fuel particles and the matrix; 2) with the increase in the creep amplification factor of the matrix, the effective irradiation swelling increases while the stresses in the fuel particles and the matrix decrease. The enhanced creep rate of the matrix is apt to result in less restraint of the effective irradiation swelling, but reduces the risk of radial crack initiation and propagation in the matrix; 3) based on the results of finite element simulation, a mathematic model for the effective irradiation swelling of U-10Mo/Zr dispersion fuels is fitted to correlate the effective irradiation swelling with different values of the matrix creep amplification factor under the considered irradiation conditions. The creep property of the matrix should be optimized because of its evident effects on the effective irradiation swelling and stresses of the U-10Mo/Zr dispersion fuels.
Comparative Study of Source Inversion Under Multiple Atmospheric Pollutant Emission Scenarios
Authors: Mao Shushuai , Lang Jianlei , Chen Tian , Cheng Shuiyuan , Hu Feng
Published: March 2022

Source inversion is an effective approach for estimating air pollutant source parameters (e.g., source emission or source strength [Q0], source horizontal location [x0, y0], and release height [z0]) in industrial activities or accidents. Air pollution events in the real world generally correspond to complex application scenarios arising from unknown source parameters (i.e., Q0, [Q0, z0], [Q0, x0, y0], and [Q0, x0, y0, z0]) and atmospheric dispersion conditions. However, the source inversion characteristic law of these complex practical scenarios and the interaction mechanism between source location prior information and source strength inversion have not been revealed. In this study, the source inversion performance (accuracy and robustness) under the aforementioned scenarios was evaluated based on the Prairie Grass field experiments. Results indicated that the estimation accuracy of source strength was worse with an increase in the number of unknown source parameters with absolute relative deviations of 34.4, 46.0, 80.1, and 83.6% for a single parameter and double, triple, and quadruple parameters, respectively. Source strength inversion performance was obviously affected by location parameters; robustness was markedly reduced when source height was unknown, whereas accuracy was obviously reduced when source horizontal locations were unknown. Impacts of atmospheric conditions on different source parameters were distinct. Extreme atmospheric conditions (stability A and F) can obviously reduce the estimation accuracy of source strength for single and double parameter inversion scenarios, whereas unstable conditions (stability A, B, and C) can reduce the estimation accuracy of source strength for triple and quadruple parameter scenarios. Source inversion accuracy and robustness were generally poor under extremely stable conditions. This study can fill the knowledge gap in characteristic laws of source inversion under complex application scenarios and the interaction relationship between different unknown source parameters. The results of the influence law of location prior information on source strength inversion have important guiding significance to further improve the inversion accuracy of source strength in practical environmental managements.
CRISPR/Cas-Based Gene Editing Strategies for DOCK8 Immunodeficiency Syndrome
Authors: Ravendran Sujan , Hernández Sabina Sánchez , König Saskia , Bak Rasmus O.
Published: March 2022

Defects in the DOCK8 gene causes combined immunodeficiency termed DOCK8 immunodeficiency syndrome (DIDS). DIDS previously belonged to the disease category of autosomal recessive hyper IgE syndrome (AR-HIES) but is now classified as a combined immunodeficiency (CID). This genetic disorder induces early onset of susceptibility to severe recurrent viral and bacterial infections, atopic diseases and malignancy resulting in high morbidity and mortality. This pathological state arises from impairment of actin polymerization and cytoskeletal rearrangement, which induces improper immune cell migration-, survival-, and effector functions. Owing to the severity of the disease, early allogenic hematopoietic stem cell transplantation is recommended even though it is associated with risk of unintended adverse effects, the need for compatible donors, and high expenses. So far, no alternative therapies have been developed, but the monogenic recessive nature of the disease suggests that gene therapy may be applied. The advent of the CRISPR/Cas gene editing system heralds a new era of possibilities in precision gene therapy, and positive results from clinical trials have already suggested that the tool may provide definitive cures for several genetic disorders. Here, we discuss the potential application of different CRISPR/Cas-mediated genetic therapies to correct the DOCK8 gene. Our findings encourage the pursuit of CRISPR/Cas-based gene editing approaches, which may constitute more precise, affordable, and low-risk definitive treatment options for DOCK8 deficiency.
Be a Mom: Patterns of Program Usage and Acceptability Among Women With Low-Risk and High-Risk for Postpartum Depression
Authors: Xavier Sandra , Monteiro Fabiana , Canavarro Maria Cristina , Fonseca Ana
Published: March 2022

Background

Be a Mom is a self-guided web-based intervention developed to prevent postpartum depression (PPD) symptoms and to promote maternal wellbeing, respectively among high and low-risk new mothers. This study aims to examine and compare (1) Be a Mom's patterns of usage and (2) Be a Mom's acceptability among women presenting high and low risk for PPD.

Methods

The sample was composed by 800 women who were randomized to Be a Mom [542 presenting high-risk (Postpartum Depression Predictors Inventory-Revised ≥ 5.5) and 258 presenting low-risk for PPD]. Data regarding patterns of usage were collected through the Be a Mom website. Acceptability data were collected through a brief questionnaire.

Results

27.9% of high-risk and 36.3% of low-risk women completed the program. A higher proportion of participants in the low-risk group completed Be a Mom [X(1)2 = 5.29, p = 0.021] and completed more modules [t(723) = −3.01, p = 0.003]. No significant differences were found between the groups in number of logins, minutes spent on the program, exercises completed and number of times audios were played. a higher proportion of women in the high-risk group considered that participating in Be a Mom was too demanding [X(1)2 = 8.21, p = 0.004].

Conclusions

Despite the low rates of completion, Be a Mom appears to be an acceptable option for both women with high-risk and low-risk for PPD. Lack of time seems to be the main reason for non-completion, so it is important to develop briefer versions of the program and introduce engagement strategies that may increase completion rate.
Neoadjuvant Immunotherapy for MSI-H/dMMR Locally Advanced Colorectal Cancer: New Strategies and Unveiled Opportunities
Authors: Zhang Xuan , Wu Tao , Cai Xinyi , Dong Jianhua , Xia Cuifeng , Zhou Yongchun , Ding Rong , Yang Renfang , Tan Jing , Zhang Lijuan , Zhang Ya , Wang Yuqin , Dong Chao , Li Yunfeng
Published: March 2022

Patients with locally advanced colorectal cancer (LACRC) have a high risk of recurrence and metastasis, although neoadjuvant therapy may provide some benefit. However, patients with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) LACRC receive little benefit from neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant chemotherapy (nCT). The 2015 KEYNOTE-016 trial identified MSI-H/dMMR as a biomarker indicative of immunotherapy efficacy, and pointed to the potential use of immune checkpoint inhibitors (ICIs). In 2017, the FDA approved two ICIs (pembrolizumab and nivolumab) for treatment of MSI-H/dMMR metastatic CRC (mCRC). In 2018, the CheckMate-142 trial demonstrated successful treatment of mCRC based on “double immunity” provided by nivolumab with ipilimumab, a regimen that may become a standard first-line treatment for MSI-H mCRC. In 2018, the FDA approved nivolumab alone or with ipilimumab for patients who progressed to MSI-H/dMMR mCRC after standard chemotherapy. The FDA then approved pembrolizumab alone as a first-line treatment for patients with MSI-H/dMMR CRC that was unresectable or metastatic. There is now interest in using these drugs in neoadjuvant immunotherapy (nIT) for patients with MSI-H/dMMR non-mCRC. In 2020, the NICHE trial marked the start of using nIT for CRC. This novel treatment of MSI-H/dMMR LACRC may change the approaches used for neoadjuvant therapy of other cancers. Our review of immunotherapy for CRC covers diagnosis and treatment, clinical prognostic characteristics, the mechanism of nIT, analysis of completed prospective and retrospective studies, and ongoing clinical trials, and the clinical practice of using nIT for MSI-H/dMMR LACRC. Our team also proposes a new organ-preservation strategy for patients with MSI-H/dMMR low LARC.
O-Linked β-N-Acetylglucosamine Modification: Linking Hypertension and the Immune System
Authors: dos Passos Junior Rinaldo Rodrigues , Bomfim Gisele Facholi , Giachini Fernanda R. , Tostes Rita C. , Lima Victor Vitorino
Published: March 2022

TheO-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of proteins dynamically regulates protein function, localization, stability, and interactions. This post-translational modification is intimately linked to cardiovascular disease, including hypertension. An increasing number of studies suggest that components of innate and adaptive immunity, active players in the pathophysiology of hypertension, are targets for O-GlcNAcylation. In this review, we highlight the potential roles of O-GlcNAcylation in the immune system and discuss how those immune targets of O-GlcNAcylation may contribute to arterial hypertension.
Multilocus Sequence Typing and Antifungal Susceptibility of Vaginal and Non-vaginal Candida glabrata Isolates From China
Authors: Chen Yisheng , Wu Yongqin , Lulou Kaiyi , Yao Dongting , Ying Chunmei
Published: March 2022

Candida glabrata is a common cause of Candida infections. In our present study, we investigated the antifungal susceptibility and molecular epidemiology of vaginal and non-vaginal C. glabrata isolates. Seventy-six vaginal C. glabrata strains isolated from patients with vulvovaginal candidiasis and 57 non-vaginal C. glabrata isolates were collected at two hospitals in Shanghai, China. Antifungal susceptibility was examined using a broth microdilution method. Multilocus sequence typing was used for genotyping. Overall, 28 (21.1%), 28 (21.1%), and 29 (21.8%) C. glabrata isolates were resistant to fluconazole, itraconazole, and voriconazole, respectively. Briefly, 18 (23.7%), 18 (23.7%), and 19 (25%) vaginal strains were resistant to fluconazole, itraconazole, and voriconazole. While the resistance to these antifungals were all 17.5% (10/57) in non-vaginal strains. All isolates retained susceptibility to amphotericin B, and only four non-vaginal isolates were caspofungin resistant. Genotyping identified 17 ST patterns. In non-vaginal samples, the same genotypes appear as in the vaginal samples, except for one genotype (ST-182), while in the vaginal samples more genotypes appear (ST8, ST19, ST45, ST55, ST66, ST80, ST138, and ST17). The most common genotype was ST7 (81 strains), followed by ST10 (14 strains) and ST15 (11 strains). The majority of resistant phenotype strains (25/30, 83.3%) correlated to the predominant genotype (ST7), and the rest belonged to ST3 (2/30, 6.7%), ST10 (1/30, 3.3%), ST19 (1/30, 3.3%), and ST45 (1/30, 3.3%). Our survey revealed cross-resistance in vaginal and non-vaginal C. glabrata isolates. Moreover, there is no genotype associated with the resistance phenotype.
Ultrafast and Cost-Effective Pathogen Identification and Resistance Gene Detection in a Clinical Setting Using Nanopore Flongle Sequencing
Authors: Avershina Ekaterina , Frye Stephan A. , Ali Jawad , Taxt Arne M. , Ahmad Rafi
Published: March 2022

Rapid bacterial identification and antimicrobial resistance gene (ARG) detection are crucial for fast optimization of antibiotic treatment, especially for septic patients where each hour of delayed antibiotic prescription might have lethal consequences. This work investigates whether the Oxford Nanopore Technology’s (ONT) Flongle sequencing platform is suitable for real-time sequencing directly from blood cultures to identify bacteria and detect resistance-encoding genes. For the analysis, we used pure bacterial cultures of four clinical isolates of Escherichia coli and Klebsiella pneumoniae and two blood samples spiked with either E. coli or K. pneumoniae that had been cultured overnight. We sequenced both the whole genome and plasmids isolated from these bacteria using two different sequencing kits. Generally, Flongle data allow rapid bacterial ID and resistome detection based on the first 1,000–3,000 generated sequences (10 min to 3 h from the sequencing start), albeit ARG variant identification did not always correspond to ONT MinION and Illumina sequencing-based data. Flongle data are sufficient for 99.9% genome coverage within at most 20,000 (clinical isolates) or 50,000 (positive blood cultures) sequences generated. The SQK-LSK110 Ligation kit resulted in higher genome coverage and more accurate bacterial identification than the SQK-RBK004 Rapid Barcode kit.
LC_Glucose-Inhibited Division Protein Is Required for Motility, Biofilm Formation, and Stress Response in Lysobacter capsici X2-3
Authors: Zhao Dan , Wang Hong , Li Zhiyuan , Han Shengnan , Han Chao , Liu Aixin
Published: March 2022

Glucose-inhibited division protein (GidA) plays a critical role in the growth, stress response, and virulence of bacteria. However, how gidA may affect plant growth-promoting bacteria (PGPB) is still not clear. Our study aimed to describe the regulatory function of the gidA gene in Lysobacter capsici, which produces a variety of lytic enzymes and novel antibiotics. Here, we generated an LC_GidA mutant, MT16, and an LC_GidA complemented strain, Com-16, by plasmid integration. The deletion of LC_GidA resulted in an attenuation of the bacterial growth rate, motility, and biofilm formation of L. capsici. Root colonization assays demonstrated that the LC_GidA mutant showed reduced colonization of wheat roots. In addition, disruption of LC_GidA showed a clear diminution of survival in the presence of high temperature, high salt, and different pH conditions. The downregulated expression of genes related to DNA replication, cell division, motility, and biofilm formation was further validated by real-time quantitative PCR (RT–qPCR). Together, understanding the regulatory function of GidA is helpful for improving the biocontrol of crop diseases and has strong potential for biological applications.
COVCOG 1: Factors Predicting Physical, Neurological and Cognitive Symptoms in Long COVID in a Community Sample. A First Publication From the COVID and Cognition Study
Authors: Guo Panyuan , Benito Ballesteros Alvaro , Yeung Sabine P. , Liu Ruby , Saha Arka , Curtis Lyn , Kaser Muzaffer , Haggard Mark P. , Cheke Lucy G.
Published: March 2022

Since its first emergence in December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has evolved into a global pandemic. Whilst often considered a respiratory disease, a large proportion of COVID-19 patients report neurological symptoms, and there is accumulating evidence for neural damage in some individuals, with recent studies suggesting loss of gray matter in multiple regions, particularly in the left hemisphere. There are a number of mechanisms by which COVID-19 infection may lead to neurological symptoms and structural and functional changes in the brain, and it is reasonable to expect that many of these may translate into cognitive problems. Indeed, cognitive problems are one of the most commonly reported symptoms in those experiencing “Long COVID”—the chronic illness following COVID-19 infection that affects between 10 and 25% of patients. The COVID and Cognition Study is a part cross-sectional, part longitudinal, study documenting and aiming to understand the cognitive problems in Long COVID. In this first paper from the study, we document the characteristics of our sample of 181 individuals who had experienced COVID-19 infection, and 185 who had not. We explore which factors may be predictive of ongoing symptoms and their severity, as well as conducting an in-depth analysis of symptom profiles. Finally, we explore which factors predict the presence and severity of cognitive symptoms, both throughout the ongoing illness and at the time of testing. The main finding from this first analysis is that that severity of initial illness is a significant predictor of the presence and severity of ongoing symptoms, and that some symptoms during the initial illness—particularly limb weakness—may be more common in those that have more severe ongoing symptoms. Symptom profiles can be well described in terms of 5 or 6 factors, reflecting the variety of this highly heterogenous condition experienced by the individual. Specifically, we found that neurological/psychiatric and fatigue/mixed symptoms during the initial illness, and that neurological, gastrointestinal, and cardiopulmonary/fatigue symptoms during the ongoing illness, predicted experience of cognitive symptoms.
Efficacy and Safety of IncobotulinumtoxinA in the Treatment of Lower Limb Spasticity in Japanese Subjects
Authors: Masakado Yoshihisa , Kagaya Hitoshi , Kondo Kunitsugu , Otaka Yohei , Dekundy Andrzej , Hanschmann Angelika , Geister Thorin L. , Kaji Ryuji
Published: March 2022

Objective

To confirm the efficacy and safety of incobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals GmbH; total dose 400 U) in Japanese subjects with lower limb (LL) poststroke spasticity using the Modified Ashworth Scale spasticity score for the plantar flexors (MAS-PF).

Methods

This phase III study (Japic clinical study database No. CTI-153030, 7 October 2015) included a double-blind, 12-week main period (MP) in which 208 subjects were randomized to receive one injection cycle of incobotulinumtoxinA 400 U (n = 104) or placebo (n = 104) in the pes equinus muscles, and an open-label extension (OLEX) that enrolled 202 subjects who received three injection cycles, 10–14 weeks in duration (the last cycle was fixed at 12 weeks). Changes in MAS-PF for incobotulinumtoxinA vs. placebo from baseline to Week 4 of the MP and to the end-of-cycle visits in the OLEX were evaluated.

Results

The area under the curve for the change in MAS-PF was statistically significantly greater with incobotulinumtoxinA vs. placebo in the MP (mean: −7.74 vs. −4.76; least squares mean: −8.40 vs. −5.81 [p = 0.0041]). In the OLEX, mean changes in MAS-PF from baseline to end-of-study showed continued improvement with repeated injections. No new safety concerns were observed with the incobotulinumtoxinA treatment. Its efficacy and safety were consistent regardless of the length of the injection cycle interval in the OLEX.

Conclusion

This study demonstrated that incobotulinumtoxinA (total dose 400 U) is an effective and a well-tolerated treatment for LL spasticity in Japanese subjects using flexible injection intervals of 10–14 weeks.
The Relationship Between Dysphagia and Pneumonia in Acute Stroke Patients: A Systematic Review and Meta-Analysis
Authors: Chang Min Cheol , Choo Yoo Jin , Seo Kyung Cheon , Yang Seoyon
Published: March 2022

Background

Dysphagia is a common complication after stroke and is associated with the development of pneumonia. This study aimed to summarize the relationship between dysphagia and pneumonia in post-stroke patients.

Materials and Methods

Articles published up to November 2021 were searched in the PubMed, Embase, Cochrane library, and Scopus databases. Studies that investigated the development of pneumonia in acute stroke patients with and without dysphagia were included. The methodological quality of individual studies was evaluated using the Risk Of Bias In Non-randomized Studies-of Interventions tool, and publication bias was evaluated using a funnel plot and Egger's test.

Results

Of 5,314 studies, five studies were included in the meta-analysis. The results revealed that the incidence of pneumonia was significantly higher in the dysphagia group than in the non-dysphagia group (OR 9.60; 95% CI 5.75–16.04; p < 0.0001; I2 = 78%). There was no significant difference in the mortality rate between the two groups (OR 5.64; 95% CI 0.83–38.18; p = 0.08; I2 = 99%).

Conclusion

Dysphagia is a significant risk factor for pneumonia after stroke. The early diagnosis and treatment of dysphagia in stroke patients are important to prevent stroke-associated pneumonia.
Association of Essential Tremor With Dementia and Affective Disorders: A Meta-Analysis
Authors: Shang Yajun , Chen Xinjie , Ai Mingda , Gao Xiaoran , Dai Shujuan , Zhao Mingjie , Yang Cen , Wang Liangfeng , Zhang Junyan , Zhong Lianmei , Bao Tianhao , Liu Xiaolei
Published: March 2022

Background

The dementia and affective disorders are common non-motor features in patients with essential tremor (ET). However, the relationship of ET with cognitive impairments and affective disorders remains controversial. This meta-analysis aimed to analyze the association of ET with dementia and affective disorders.

Methods

Original studies published from January 1999 to October 2019 were systematically searched from the database of Medline (OvidSP), EMBASE (OvidSP), and the Cochrane Central Register of Controlled Trials. Pooled standard mean difference (SMD, random effect model), odds ratios (ORs), relative risk (RR), and 95% CI were calculated.

Results

Compared with the Non-ET group, patients with ET had significantly lower Mini-Mental State Examination (MMSE) score (SMD, −1.16; 95% CI, −1.75 to −0.58; p = 0.0001) and had significantly higher depressive and anxiety symptoms scale score (SMD, 0.55; 95% CI, 0.22–0.87; p = 0.0009). The OR for dementia and affective disorders in individuals with ET compared with individuals without ET was 2.49 (95% CI, 2.17–2.85, p < 0.00001). While there was no significant difference in Montreal Cognitive Assessment (MoCA) score between ET and Non-ET groups (SMD, −0.52; 95% CI, −0.16 to 0.13; p = 0.23), there was a significant difference in the risk of mortality between ET and Non-ET groups (RR = 4.69, 95% CI, 2.18–10.07).

Conclusion

The non-motor symptoms should not be neglected among patients with ET. However, the causal relationship between ET and dementia, depression, and anxiety is unclear.
Impaired Glymphatic Transport Kinetics Following Induced Acute Ischemic Brain Edema in a Mouse pMCAO Model
Authors: Zhang Jianying , Zhao Hongchen , Xue Yang , Liu Yiqi , Fan Guohang , Wang He , Dong Qiang , Cao Wenjie
Published: March 2022

Background

Cerebral edema forms immediately after blood flow interruption in ischemic stroke, which largely increased the death and disability. The glymphatic (glial-lymphatic) pathway is a major regulator of the brain liquid dynamics and homeostasis. This study aimed to investigate the transport kinetics of the glymphatic system after the appearance of ischemic edema.

Methods

In this study, a coated filament was attached to the left middle cerebral artery (MCA) of mice to establish a mouse model of permanent middle cerebral artery occlusion with an intact blood-brain barrier (BBB). The glymphatic function was then quantified using contrast-enhanced MRI (11.7T) by employing an injection of gadobenate dimeglumine (BOPTA-Gd) into the cisterna magna of mice. We then evaluated the expression and polarization of aquaporin-4 (AQP4) as a proxy for the physiological state of the glymphatic system.

Results

Our results revealed a positive correlation between the signal intensity in T1-weighted images and the corresponding apparent diffusion coefficient (ADC) values in the cortex, striatum, and periventricular zone, suggesting that impaired glymphatic transport kinetics in these regions is correlated to the cytotoxic edema induced by the occlusion of MCA. Furthermore, the increased depolarization of AQP4 in the parenchyma perivascular space (PVS) was consistent with glymphatic failure following the induced early cerebral ischemic edema.

Conclusions

Glymphatic transport kinetics were suppressed between the onset of cytotoxic edema and the disruption of the BBB, which correlated with the diminishing ADC values that vary based on edema progression, and is associated with depolarization of AQP4 in the parenchyma PVSs.
Ammonia Scavenger Restores Liver and Muscle Injury in a Mouse Model of Non-alcoholic Steatohepatitis With Sarcopenic Obesity
Authors: Wang Zi-Xuan , Wang Meng-Yu , Yang Rui-Xu , Zhao Ze-Hua , Xin Feng-Zhi , Li Yu , Ren Tian-Yi , Fan Jian-Gao
Published: March 2022

Recent studies have revealed that sarcopenia is closely associated with obesity and non-alcoholic steatohepatitis (NASH). However, few attempted to explore the cause-and-effect relationship between sarcopenic obesity and NASH. In this study, we investigated muscular alterations in a rodent NASH model to elucidate their intrinsic relations and explore the potential therapeutic target. Forty-six 8-week-old and twenty 42-week-old male C57BL/6 mice (defined as young and middle-aged mice, respectively) were fed with a high-fat diet (HFD) for 12 or 20 weeks. A subset of young mice was subjected to ammonia lowering treatment by L-ornithine L-aspartate (LOLA). We examined body composition and muscle strength by nuclear magnetic resonance and grip strength meter, respectively. At the end of the 12th week, all HFD-fed mice developed typical steatohepatitis. Meanwhile, sarcopenia occurred in HFD-fed middle-aged mice, whereas young mice only demonstrated decreased grip strength. Until the end of week 20, young mice in the HFD group exhibited significant sarcopenia and obesity phenotypes, including decreased lean body mass and grip strength, and increased body fat mass and percentage body fat. Additionally, plasma ammonia level was markedly increased in HFD-fed mice of both ages at week 20. Plasma ammonia level was negatively associated with muscle strength and myofiber diameter in young mice. LOLA can significantly reduce plasma levels of ammonia, alanine aminotransaminase, aspartate aminotransaminase, and cholesterol in mice fed an HFD. Hepatic infiltration of inflammatory cells and collagen deposition area were significantly decreased in HFD group by LOLA treatment. Meanwhile, LOLA significantly increased lean body mass, grip strength, and average muscle fiber diameter of HFD-fed mice. These findings suggest that the occurrence of NASH precedes sarcopenia in HFD mice, and the steatohepatitis-related hyperammonemia might contribute to the pathogenesis of sarcopenia. LOLA might be an effective drug for both steatohepatitis and sarcopenic obesity.
Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer
Authors: Fan Yali , Wang Jiandong , Fang Ziwei , Pierce Stuart R. , West Lindsay , Staley Allison , Tucker Katherine , Yin Yajie , Sun Wenchuan , Kong Weimin , Prabhu Varun , Allen Joshua E. , Zhou Chunxiao , Bae-Jump Victoria L.
Published: March 2022

ONC201 is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP). The present study was to explore the anti-tumor potential effect of ONC201 in ovarian cancer cell lines and in a transgenic mouse model of high grade serous ovarian cancer under obese (high fat diet) and lean (low fat diet) conditions. ONC201 significantly suppressed cell proliferation, induced arrest in G1 phase, and increased cellular stress and apoptosis, accompanied by dual inhibition of the AKT/mTOR/S6 and MAPK pathways in OC cells. ONC201 also resulted in inhibition of adhesion and invasion via epithelial–mesenchymal transition and reduction of VEGF expression. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed the ONC201-induced oxidative stress response, and prevented ONC201-reduced VEGF and cell invasion by regulating epithelial–mesenchymal transition protein expression. Knockdown of ClpP in ovarian cancer cells reduced ONC201 mediated the anti-tumor activity and cellular stress. Diet-induced obesity accelerated ovarian tumor growth in the KpB mouse model. ONC201 significantly suppressed tumor growth, and decreased serum VEGF production in obese and lean mice, leading to a decrease in tumoral expression of Ki-67, VEGF and phosphorylation of p42/44 and S6 and an increase in ClpP and DRD5, as assessed by immunohistochemistry. These results suggest that ONC201 may be a promising therapeutic agent to be explored in future clinical trials in high-grade serous ovarian cancer.
Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor
Authors: Liu Na , Ling Rui , Tang Xiang , Yu Yunpeng , Zhou Yuepeng , Chen Deyu
Published: March 2022

Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Over 30 targeted inhibitors currently in preclinical and clinical trials have significant inhibitory effects on various tumors, including acute myelogenous leukemia (AML), diffuse large B cell lymphoma, prostate cancer, breast cancer and so on. However, resistance frequently occurs, revealing the limitations of BET inhibitor (BETi) therapy and the complexity of the BRD4 expression mechanism and action pathway. Current studies believe that when the internal and external environmental conditions of cells change, tumor cells can directly modify proteins by posttranslational modifications (PTMs) without changing the original DNA sequence to change their functions, and epigenetic modifications can also be activated to form new heritable phenotypes in response to various environmental stresses. In fact, research is constantly being supplemented with regards to that the regulatory role of BRD4 in tumors is closely related to PTMs. At present, the PTMs of BRD4 mainly include ubiquitination and phosphorylation; the former mainly regulates the stability of the BRD4 protein and mediates BETi resistance, while the latter is related to the biological functions of BRD4, such as transcriptional regulation, cofactor recruitment, chromatin binding and so on. At the same time, other PTMs, such as hydroxylation, acetylation and methylation, also play various roles in BRD4 regulation. The diversity, complexity and reversibility of posttranslational modifications affect the structure, stability and biological function of the BRD4 protein and participate in the occurrence and development of tumors by regulating the expression of tumor-related genes and even become the core and undeniable mechanism. Therefore, targeting BRD4-related modification sites or enzymes may be an effective strategy for cancer prevention and treatment. This review summarizes the role of different BRD4 modification types, elucidates the pathogenesis in the corresponding cancers, provides a theoretical reference for identifying new targets and effective combination therapy strategies, and discusses the opportunities, barriers, and limitations of PTM-based therapies for future cancer treatment.
Displacement of Native FXYD Protein From Na+/K+-ATPase With Novel FXYD Peptide Derivatives: Effects on Doxorubicin Cytotoxicity
Authors: Liu Chia-Chi , Kim Yeon Jae , Teh Rachel , Garcia Alvaro , Hamilton Elisha J. , Cornelius Flemming , Baxter Robert C. , Rasmussen Helge H.
Published: March 2022

The seven mammalian FXYD proteins associate closely with α/β heterodimers of Na+/K+-ATPase. Most of them protect the β1 subunit against glutathionylation, an oxidative modification that destabilizes the heterodimer and inhibits Na+/K+-ATPase activity. A specific cysteine (Cys) residue of FXYD proteins is critical for such protection. One of the FXYD proteins, FXYD3, confers treatment resistance when overexpressed in cancer cells. We developed two FXYD3 peptide derivatives. FXYD3-pep CKCK retained the Cys residue that can undergo glutathionylation and that is critical for protecting the β1 subunit against glutathionylation. FXYD3-pep SKSK had all Cys residues mutated to Serine (Ser). The chemotherapeutic doxorubicin induces oxidative stress, and suppression of FXYD3 with siRNA in pancreatic- and breast cancer cells that strongly express FXYD3 increased doxorubicin-induced cytotoxicity. Exposing cells to FXYD3-pep SKSK decreased co-immunoprecipitation of FXYD3 with the α1 Na+/K+-ATPase subunit. FXYD3-pep SKSK reproduced the increase in doxorubicin-induced cytotoxicity seen after FXYD3 siRNA transfection in pancreatic- and breast cancer cells that overexpressed FXYD3, while FXYD3-pep CKCK boosted the native protein’s protection against doxorubicin. Neither peptide affected doxorubicin’s cytotoxicity on cells with no or low FXYD3 expression. Fluorescently labeled FXYD3-pep SKSK was detected in a perinuclear distribution in the cells overexpressing FXYD3, and plasmalemmal Na+/K+-ATPase turnover could not be implicated in the increased sensitivity to doxorubicin that FXYD3-pep SKSK caused. FXYD peptide derivatives allow rapid elimination or amplification of native FXYD protein function. Here, their effects implicate the Cys residue that is critical for countering β1 subunit glutathionylation in the augmentation of cytotoxicity with siRNA-induced downregulation of FXYD3.
A Custom DNA-Based NGS Panel for the Molecular Characterization of Patients With Diffuse Gliomas: Diagnostic and Therapeutic Applications
Authors: Tirrò Elena , Massimino Michele , Broggi Giuseppe , Romano Chiara , Minasi Simone , Gianno Francesca , Antonelli Manila , Motta Gianmarco , Certo Francesco , Altieri Roberto , Manzella Livia , Caltabiano Rosario , Barbagallo Giuseppe Maria Vincenzo , Buttarelli Francesca Romana , Magro Gaetano , Giangaspero Felice , Vigneri Paolo
Published: March 2022

The management of patients with Central Nervous System (CNS) malignancies relies on the appropriate classification of these tumors. Recently, the World Health Organization (WHO) has published new criteria underlining the importance of an accurate molecular characterization of CNS malignancies, in order to integrate the information generated by histology. Next generation sequencing (NGS) allows single step sequencing of multiple genes, generating a comprehensive and specific mutational profile of the tumor tissue. We developed a custom NGS-based multi-gene panel (Glio-DNA panel) for the identification of the correct glioma oncotype and the detection of its essential molecular aberrations. Specifically, the Glio-DNA panel targets specific genetic and chromosomal alterations involving ATRX chromatin remodeler (ATRX), cyclin dependent kinase inhibitor 2A (CDKN2A), isocitrate dehydrogenase (NADP+) 1 (IDH1) and the telomerase reverse transcriptase (TERT) promoter while also recognizing the co-deletion of 1p/19q, loss of chromosome 10 and gain of chromosome 7. Furthermore, the Glio-DNA panel also evaluates the methylation level of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter that predicts temozolomide efficacy. As knowledge of the mutational landscape of each glioma is mandatory to define a personalized therapeutic strategy, the Glio-DNA panel also identifies alterations involving “druggable” or “actionable” genes. To test the specificity of our panel, we used two reference mutated DNAs verifying that NGS allele frequency measurement was highly accurate and sensitive. Subsequently, we performed a comparative analysis between conventional techniques - such as immunohistochemistry or fluorescence in situ hybridization - and NGS on 60 diffuse glioma samples that had been previously characterized. The comparison between conventional testing and NGS showed high concordance, suggesting that the Glio-DNA panel may replace multiple time-consuming tests. Finally, the identification of alterations involving different actionable genes matches glioma patients with potential targeted therapies available through clinical trials. In conclusion, our analysis demonstrates NGS efficacy in simultaneously detecting different genetic alterations useful for the diagnosis, prognosis and treatment of adult patients with diffuse glioma.
Giant Cell Arteritis: Updates and Controversies
Authors: Yu Erin , Chang Jessica R.
Published: March 2022

Giant cell arteritis (GCA) is a systemic granulomatous vasculitis affecting the medium and large-size arteries, and may present with a range of ophthalmic findings. This review will cover GCA epidemiology, pathophysiology, clinical presentation, diagnostic workup, and treatment.

Epidemiology and Pathophysiology

GCA is commonly found in elderly patients and individuals of Scandinavian descent. Recent publications suggest it may be more common in African Americans and Hispanics than previously thought. It is very rare in Asian and Middle-Eastern populations, and there is little data regarding African populations. Genetic studies have identified increased risk associated with HLA-DRB1*04. Rather than a response to a specific antigen such as varicella zoster virus, current immunology research suggests that GCA results from changes associated with the aging immune system.

Clinical presentation to Ophthalmology

Arteritic anterior ischemic optic neuropathy is the most common ophthalmic manifestation of GCA, but central or branch retinal artery occlusion, ophthalmic artery occlusion, cranial neuropathies causing diplopia, and more rarely anterior segment ischemia and anisocoria may also occur. Clinical testing including visual field testing, OCT, OCT-A, ICG and fluorescein angiography can be helpful in suggesting a diagnosis in addition to the clinical exam.

Diagnostic Workup

GCA is ultimately a clinical diagnosis, but it is usually supported with lab results, pathology, and/or imaging. Temporal artery biopsy (TAB) remains the gold standard diagnostic test although its sensitivity is debated and practice patterns still vary with respect to sample length and whether unilateral or simultaneous bilateral biopsies are performed. Some studies have reported higher sensitivity of ultrasounds over TAB, with added benefits of time efficiency and cost effectiveness, promoting the diagnostic use of ultrasounds. MRI and even PET CT protocols offer additional options for less invasive diagnostic testing.

Treatment

Vision-threatening GCA is treated acutely with emergent admission for intravenous methylprednisolone, and long-term high dose oral corticosteroids remain the standard of care, despite common and sometimes serious side effects. The use of steroid-sparing alternatives such as tocilizumab is becoming more common and additional agents are being investigated.