bluuebunny/crossref_metadata_2025 huggingface dataset:
Exopolysaccharide Produced by Pediococcus pentosaceus E8: Structure, Bio-Activities, and Its Potential Application
Authors: Jiang Guangyang , He Juan , Gan Longzhan , Li Xiaoguang , Xu Zhe , Yang Li , Li Ran , Tian Yongqiang
Published: June 2022

The novel exopolysaccharide EPS-E8, secreted by Pediococcus pentosaceus E8, was obtained by anion-exchange and gel filtration chromatography. Structural analyses identified EPS-E8 as a heteropolysaccharide containing mannose, glucose, and galactose. Its major backbone consists of →2)-α-D-Manp-(1→2,6)-α-D-Glcp-(1→6)-α-D-Manp-(1→, and its molecular weight is 5.02 × 104 g/mol. Using atomic force microscopy and scanning electron microscopy, many spherical and irregular reticular-like shapes were observed in the microstructure of EPS-E8. EPS-E8 has outstanding thermal stability (305.7°C). Both the zeta potential absolute value and average particle diameter increased gradually with increasing concentration. Moreover, at a concentration of 10 mg/ml, the antioxidant capacities of, 1-Diphenyl-2-picrylhydrazyl (DPPH), ABTS and hydroxyl radical were 50.62 ± 0.5%, 52.17 ± 1.4%, and 58.91 ± 0.7%, respectively. EPS-E8 possesses excellent emulsifying properties against several food-grade oils, and its activity is retained under various conditions (temperature, pH, and ionic strength). Finally, we found that EPS-E8 as a polysaccharide-based coating could reduce the weight loss and malondialdehyde (MDA) content of strawberry, as well as preserving the vitamin C and soluble solid content during storage at 20°C. Together, the results support the potential application of EPS-E8 as an emulsifier, and a polysaccharide-based coating in fruit preservation.
Non-Coding RNAs: New Dawn for Diabetes Mellitus Induced Erectile Dysfunction
Authors: Xu Wenchao , Jiang Hongyang , Liu Jihong , Li Hao
Published: June 2022

Erectile dysfunction (ED) is a common sexual dysfunction in males, with multifactorial alterations which consist of psychological and organic. Diabetes mellitus (DM) induced erectile dysfunction (DMED) is a disconcerting and critical complication of DM, and remarkably different from non-diabetic ED. The response rate of phosphodiesterase type 5 inhibitor (PDE5i), a milestone for ED therapy, is far from satisfactory in DMED. Unfortunately, the contributing mechanisms of DMED remains vague. Hence, It is urgent to seek for novel prospective biomarkers or targets of DMED. Numerous studies have proved that non-coding RNAs (ncRNAs) play essential roles in the pathogenesis process of DM, which comprise of long non-coding RNAs (lncRNAs) and small non-coding RNAs (sncRNAs) like microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs) and circular RNAs (circRNAs). However, the implications of ncRNAs in DMED are still understudied. This review highlights the pathophysiology of DMED, summarizes identified mechanisms of ncRNAs associated with DMED and covers the topic of perspectives for ncRNAs in DMED.
Enlarged Perivascular Spaces in the Basal Ganglia Independently Related to Gait Disturbances in Older People With Cerebral Small Vessel Diseases
Authors: Yang Shuna , Li Xuanting , Hu Wenli , Qin Wei , Yang Lei
Published: June 2022

Background and Objective

Gait disturbances are common in older people and are associated with adverse consequences, e.g., falls and institutionalization. Enlarged perivascular spaces in the basal ganglia (BG-EPVS) are considered an magnetic resonance imaging (MRI) marker of cerebral small vessel diseases (CSVD). However, the consequences of BG-EPVS are largely unknown. Previous studies showed that other CSVD markers were related to gait disturbances. However, the relation between BG-EPVS and gait performance is unclear. Therefore, we aimed to explore the relation between BG-EPVS and gait performance in elderly individuals.

Methods

We recruited older people with CSVD in the Neurology Department of our hospital from December 1, 2020 to October 31, 2021. Participants with BG-EPVS > 20 on the unilateral side of the basal ganglia slice containing the maximum number were classified into the BG-EPVS group (n = 78), and the rest were classified into the control group (n = 164). Quantitative gait parameters and gait variability were provided by the Intelligent Device for Energy Expenditure and Activity (IDEEA; MiniSun, United States) gait analysis system. Semiquantitative gait assessment was measured with the Tinetti test. Point-biserial correlation and multivariate linear regression analysis were performed to investigate the association between BG-EPVS and gait performance.

Results

The BG-EPVS group had a slower gait speed and cadence, shorter stride length, longer stance phase percentage, smaller pre-swing angle and footfall, and lower Tinetti gait test and balance test scores compared with those in the control group (P < 0.05). There were no statistical differences in stride length variability and stride time variability between the two groups (P > 0.05). A correlation analysis showed that BG-EPVS were negatively related to gait speed, cadence, stride length, pre-swing angle, and footfall (γrange = −0.497 to −0.237, P < 0.001) and positively related to stance phase percentage (γ = 0.269, P < 0.001). BG-EPVS was negatively related to the score of the Tinetti gait test (γ = −0.449, P < 0.001) and the balance test (γ = −0.489, P < 0.001). The multiple linear regression analysis indicated that BG-EPVS was an independent risk factor for gait disturbances and poor balance after adjusting for confounders, including other CSVD markers.

Conclusion

Large numbers of BG-EPVS were independently related to gait disturbances in older people with CSVD. This finding provides information about the consequences of BG-EPVS and risk factors for gait disturbances.
Neuroprotective and Neurotoxic Effects of Glial-Derived Exosomes
Authors: Oyarce Karina , Cepeda María Yamila , Lagos Raúl , Garrido Camila , Vega-Letter Ana María , Garcia-Robles María , Luz-Crawford Patricia , Elizondo-Vega Roberto
Published: June 2022

Exosomes derived from glial cells such as astrocytes, microglia, and oligodendrocytes can modulate cell communication in the brain and exert protective or neurotoxic effects on neurons, depending on the environmental context upon their release. Their isolation, characterization, and analysis under different conditions in vitro, in animal models and samples derived from patients has allowed to define the participation of other molecular mechanisms behind neuroinflammation and neurodegeneration spreading, and to propose their use as a potential diagnostic tool. Moreover, the discovery of specific molecular cargos, such as cytokines, membrane-bound and soluble proteins (neurotrophic factors, growth factors, misfolded proteins), miRNA and long-non-coding RNA, that are enriched in glial-derived exosomes with neuroprotective or damaging effects, or their inhibitors can now be tested as therapeutic tools. In this review we summarize the state of the art on how exosomes secretion by glia can affect neurons and other glia from the central nervous system in the context of neurodegeneration and neuroinflammation, but also, on how specific stress stimuli and pathological conditions can change the levels of exosome secretion and their properties.
Contributing Factors and Induced Outcomes of Psychological Stress Response in Stroke Survivors: A Systematic Review
Authors: Zhang Song , Yuan Yuan , Zhuang Wenwen , Xiong Tianqing , Xu Yijun , Zhang Jingwen , Tao Chunhua , Liang Jingyan , Wang Yingge
Published: June 2022

Background

Remarkable evidence indicates that psychological stress is significantly associated with stroke. However, a uniform recommendation to identify and alleviate poststroke psychological stress responses and improve postmorbid outcomes is not currently available. Thus, this systematic review aimed to summarize the types of poststroke psychological stress, measurement tools, contributing factors, and outcomes.

Methods

This systematic review was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A literature search was conducted in PubMed, Web of Science, Embase, CNKI, WanFangData, and CQVIP from database inception to November 2021. Cross-sectional and longitudinal studies were included in this research. Quality assessment was performed based on the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.

Results

Eighteen quantitative, peer-reviewed studies were included for analysis. Selected articles mainly investigated perceived stress and posttraumatic stress disorder after stroke. We classified the contributing factors into four categories: sociodemographic factors, clinical disease factors, psychological factors, and behavioral and lifestyle factors. The postmorbid outcomes were divided into three categories: clinical disease outcomes, psychological outcomes, and behavioral and quality of life outcomes.

Conclusions

Compared to common patients, stroke survivors with the following characteristics suffered an increased psychological stress response: younger age, the presence of caregivers, depression, unsuitable coping strategies, etc. Meanwhile, lower quality of life, worse drug compliance, worse functional independence, and more severe mental disorders were significantly associated with increased psychological stress symptoms. Further studies are required to provide more trustworthy and meaningful references for mitigating the damage caused by psychological stress after stroke.
Neurological Involvement in COVID-19 Among Non-Hospitalized Adolescents and Young Adults
Authors: Havdal Lise Beier , Berven Lise Lund , Selvakumar Joel , Stiansen-Sonerud Tonje , Leegaard Truls Michael , Tjade Trygve , Zetterberg Henrik , Blennow Kaj , Wyller Vegard Bruun Bratholm
Published: June 2022

Introduction

Coronavirus disease 2019 (COVID-19) is prevalent among young people, and neurological involvement has been reported. We investigated neurological symptoms, cognitive test results, and biomarkers of brain injury, as well as associations between these variables in non-hospitalized adolescents and young adults with COVID-19.

Methods

This study reports baseline findings from an ongoing observational cohort study of COVID-19 cases and non-COVID controls aged 12–25 years (Clinical Trials ID: NCT04686734). Symptoms were charted using a standardized questionnaire. Cognitive performance was evaluated by applying tests of working memory, verbal learning, delayed recall, and recognition. The brain injury biomarkers, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp), were assayed in serum samples using ultrasensitive immunoassays.

Results

A total of 405 COVID-19 cases and 111 non-COVID cases were prospectively included. Serum Nfl and GFAp concentrations were significantly elevated in COVID-19 cases as compared with non-COVID controls (p = 0.050 and p = 0.014, respectively). The COVID-19 cases reported more fatigue (p < 0.001) and post-exertional malaise (PEM) (p = 0.001) compared to non-COVID-19 controls. Cognitive test performance and clinical neurological examination did not differ across the two groups. Within the COVID-19 group, there were no associations between symptoms, cognitive test results, and NfL or GFAp levels. However, fatigue and PEM were strongly associated with older age and female sex.

Conclusions

Non-hospitalized adolescents and young adults with COVID-19 reported more fatigue and PEM and had slightly elevated levels of brain injury markers, but showed normal cognitive performance. No associations were found between symptoms, brain injury markers, and cognitive test results, but fatigue and PEM were strongly related to female sex and older age.
Functional Connectivity of the Chemosenses: A Review
Authors: Farruggia Michael C. , Pellegrino Robert , Scheinost Dustin
Published: June 2022

Functional connectivity approaches have long been used in cognitive neuroscience to establish pathways of communication between and among brain regions. However, the use of these analyses to better understand how the brain processes chemosensory information remains nascent. In this review, we conduct a literature search of all functional connectivity papers of olfaction, gustation, and chemesthesis, with 103 articles discovered in total. These publications largely use approaches of seed-based functional connectivity and psychophysiological interactions, as well as effective connectivity approaches such as Granger Causality, Dynamic Causal Modeling, and Structural Equation Modeling. Regardless of modality, studies largely focus on elucidating neural correlates of stimulus qualities such as identity, pleasantness, and intensity, with task-based paradigms most frequently implemented. We call for further “model free” or data-driven approaches in predictive modeling to craft brain-behavior relationships that are free from a priori hypotheses and not solely based on potentially irreproducible literature. Moreover, we note a relative dearth of resting-state literature, which could be used to better understand chemosensory networks with less influence from motion artifacts induced via gustatory or olfactory paradigms. Finally, we note a lack of genomics data, which could clarify individual and heritable differences in chemosensory perception.
Causal Relationship of Genetically Predicted Serum Micronutrients Levels With Sarcopenia: A Mendelian Randomization Study
Authors: Sha Tingting , Li Wei , He Hongyi , Wu Jing , Wang Yilun , Li Hui
Published: June 2022

Objectives

Previous observational studies have suggested associations between concentrations of several circulating micronutrients and sarcopenia. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. Therefore, we aimed to examine the causal effects of the levels of genetically predicted serum micronutrients on sarcopenia.

Methods

Single nucleotide polymorphisms (SNPs) were chosen from large-scale genome-wide association studies of participants only with European descent and were used as genetic instruments for the levels of 10 serum micronutrients (calcium, magnesium, selenium, copper, iron, zinc, Vitamin A, Vitamin B12, Vitamin D, and Vitamin E). Sarcopenia was defined by referencing to the 2019 definition given by the European Working Group on Sarcopenia in Older People (EWGSOP). A two-sample Mendelian randomization (MR) analysis was carried out to examine the associations between the levels of genetically predicted serum micronutrients and the risk of sarcopenia. Then, sensitivity analyses (including weighted median, MR-Egger and leave-one-out sensitivity analyses) were performed to evaluate the robustness of study findings. The estimates were presented as odds ratio (OR) with their 95% confidence intervals (CIs) per one standard deviation (SD) increase in the exposures.

Results

A total of 378,635 UK Biobank participants, including 572 participants who were identified with sarcopenia, were included in this study. The iron status was shown to have a clear effect on the risk of sarcopenia based on MR analyses. The per one SD increment in the genetically-determined serum iron level corresponded to a 53% increase in the risk of sarcopenia (OR = 1.53, 95% CI: 1.31–1.78, P = 0.001). The exclusion of SNPs of the circulating iron level (i.e., rs1799945 SNP, rs1800562 SNP or rs855791 SNP) did not attenuate the magnitude of the signal in MR analysis. There was little evidence supporting the associations between other remaining micronutrients and sarcopenia.

Conclusions

An increased risk of sarcopenia was observed with a genetically higher concentration of iron, suggesting that iron may play a role in the occurrence or development of sarcopenia.
PPP2CA Is a Novel Therapeutic Target in Neuroblastoma Cells That Can Be Activated by the SET Inhibitor OP449
Authors: Galiger Celimene , Dahlhaus Meike , Vitek Michael Peter , Debatin Klaus-Michael , Beltinger Christian
Published: June 2022

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and has a poor prognosis in high-risk cases, requiring novel therapies. Pathways that depend on phospho-signaling maintain the aggressiveness of NB. Protein phosphatase 2 (PP2A) with its catalytic subunit PPP2CA is a major phosphatase in cancer cells, including NB. We show that reduction of PPP2CA by knock-down decreased growth of NB cells and that complete ablation of PPP2CA by knock-out was not tolerated. Thus, NB cells are addicted to PPP2CA, an addiction augmented by MYCN activation. SET, a crucial endogenous inhibitor of PP2A, was overexpressed in poor-prognosis NB. The SET inhibitor OP449 effectively decreased the viability of NB cells, independent of their molecular alterations and in line with a tumor suppressor function of PPP2CA. The contrasting concentration-dependent functions of PPP2CA as an essential survival gene at low expression levels and a tumor suppressor at high levels are reminiscent of other genes showing this so-called Goldilocks phenomenon. PP2A reactivated by OP449 decreased activating phosphorylation of serine/threonine residues in the AKT pathway. Conversely, induced activation of AKT led to partial rescue of OP449-mediated viability inhibition. Dasatinib, a kinase inhibitor used in relapsed/refractory NB, and OP449 synergized, decreasing activating AKT phosphorylations. In summary, concomitantly reactivating phosphatases and inhibiting kinases with a combination of OP449 and dasatinib are promising novel therapeutic approaches to NB.
Dosing Pattern and Early Cumulative Dose of Liposomal Irinotecan in Metastatic Pancreatic Cancer: A Real-World Multicenter Study
Authors: Su Yung-Yeh , Chiang Nai-Jung , Li Chung-Pin , Yen Chia-Jui , Yang Shih-Hung , Chou Wen-Chi , Chen Jen-Shi , Chiu Tai-Jan , Chen Yen-Yang , Chuang Shih-Chang , Bai Li-Yuan , Chiu Chang-Fang , Peng Cheng-Ming , Chan De-Chuan , Chiu Sz-Chi , Yang Yi-Hsin , Shan Yan-Shen , Chen Li‐Tzong
Published: June 2022

Introduction

This multicenter, real-world cohort study aimed to evaluate the effectiveness of early cumulative dose administration and dosing pattern of liposomal irinotecan plus fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (mPDAC).

Material and Methods

The electronic medical records of mPDAC patients treated with nal-IRI+5-FU/LV in nine participating centers were manually reviewed. To accommodate to the NAPOLI-1 study population, only patients with an Eastern Cooperative Oncology Group Performance Score of 0–1 were included. The survival impact of the relative 6-week cumulative dose and dosing pattern (standard vs. reduced starting dose, with and without further dose modification) were investigated.

Results

Of the 473 included patients, their median overall survival (mOS) was 6.8 [95% CI, 6.2–7.7] months. The mOS of patients who received a relative 6-week cumulative dose of >80%, 60%–80%, and <60% were 7.9, 8.2, and 4.3 months, respectively (p<0.0001). Their survival impact remained significant after covariate adjustment using Cox regression. The mOS was 8.0–8.2 months in patients with a standard starting dose with and without early dose modification, and 9.3 and 6.7 months in those who had a reduced starting dose with and without escalation in the subsequent treatment, respectively. The incidence of grade 3–4 neutropenia and diarrhea was 23.3% and 2.7%, respectively.

Conclusion

Our results support the use of nal-IRI+5-FU/LV in gemcitabine-refractory mPDAC and suggest that a lower starting dose followed by a re-escalation strategy could achieve clinical outcomes comparable to those with standard starting doses in real-world practice.
ALDH1A1 in Cancers: Bidirectional Function, Drug Resistance, and Regulatory Mechanism
Authors: Yue Hanxun , Hu Zenan , Hu Rui , Guo Zeying , Zheng Ya , Wang Yuping , Zhou Yongning
Published: June 2022

Aldehyde dehydrogenases 1 family member A1(ALDH1A1) gene codes a cytoplasmic enzyme and shows vital physiological and pathophysiological functions in many areas. ALDH1A1 plays important roles in various diseases, especially in cancers. We reviewed and summarized representative correlative studies and found that ALDH1A1 could induce cancers via the maintenance of cancer stem cell properties, modification of metabolism, promotion of DNA repair. ALDH1A1 expression is regulated by several epigenetic processes. ALDH1A1 also acted as a tumor suppressor in certain cancers. The detoxification of ALDH1A1 often causes chemotherapy failure. Currently, ALDH1A1-targeted therapy is widely used in cancer treatment, but the mechanism by which ALDH1A1 regulates cancer development is not fully understood. This review will provide insight into the status of ALDH1A1 research and new viewpoint for cancer therapy.
Nanomaterial Technology and Soft Tissue Sarcomas
Authors: Zhou Changkai , Chen Xue , Huang Ying , Zhang Qi , Zhu Shu , Fu Wei
Published: June 2022

Soft tissue sarcomas (STSs) are relatively rare heterogeneous solid tumors of the mesenchymal origin. They account for approximately 1% of all malignant tumors in adults and have more than 70 histological subtypes. Consequently, the rarity and heterogeneity of STSs make their diagnosis and treatment very challenging. Nanotechnology has attracted increasing attention from researchers due to the unique physicochemical and biological properties of nanomaterials with potential medical applications as nanoprobes, drug delivery systems, photosensitizers, radioenhancers, antitumor agents, and their combinations for cancer diagnosis and treatment. This review discusses the progress made in the use of nanotechnology for the diagnosis and treatment of STSs and highlights future prospects of the STS multimodality therapy.
Temporal Summation in Fibromyalgia Patients: Comparing Phasic and Tonic Paradigms
Authors: Castelo-Branco Luis , Cardenas-Rojas Alejandra , Rebello-Sanchez Ingrid , Pacheco-Barrios Kevin , de Melo Paulo S. , Gonzalez-Mego Paola , Marduy Anna , Vasquez-Avila Karen , Costa Cortez Pablo , Parente Joao , Teixeira Paulo E. P. , Rosa Gleysson , McInnis Kelly , Caumo Wolnei , Fregni Felipe
Published: June 2022

Introduction

Fibromyalgia (FM) is associated with dysfunctional pain modulation mechanisms, including central sensitization. Experimental pain measurements, such as temporal summation (TS), could serve as markers of central sensitization and have been previously studied in these patients, with conflicting results. Our objective in this study was to explore the relationships between two different protocols of TS (phasic and tonic) and test the associations between these measures and other clinical variables.

Materials and Methods

In this cross-sectional analysis of a randomized clinical trial, patients were instructed to determine their pain-60 test temperature, then received one train of 15 repetitive heat stimuli and rated their pain after the 1st and 15th stimuli: TSPS-phasic was calculated as the difference between those. We also administered a tonic heat test stimulus at the same temperature continuously for 30 s and asked them to rate their pain levels after 10 s and 30 s, calculating TSPS-tonic as the difference between them. We also collected baseline demographic data and behavioral questionnaires assessing pain, depression, fatigue, anxiety, sleepiness, and quality of life. We performed univariable analyses of the relationship between TSPS-phasic and TSPS-tonic, and between each of those measures and the demographic and clinical variables collected at baseline. We then built multivariable linear regression models to find predictors for TSPS-phasic and TSPS-tonic, while including potential confounders and avoiding collinearity.

Results

Fifty-two FM patients were analyzed. 28.85% developed summation during the TSPS-phasic protocol while 21.15% developed summation during the TSPS-tonic protocol. There were no variables associated TSPS phasic or tonic in the univariable analyses and both measures were not correlated. On the multivariate model for the TSPS-phasic protocol, we found a weak association with pain variables. BPI-pain subscale was associated with more temporal summation in the phasic protocol (ß = 0.38, p = 0.029), while VAS for pain was associated with less summation in the TSPS-tonic protocol (ß = −0.5, p = 0.009).

Conclusion

Our results suggest that, using heat stimuli with pain-60 temperatures, a TSPS-phasic protocol and a TSPS-tonic protocol are not correlated and could index different neural responses in FM subjects. Further studies with larger sample sizes would be needed to elucidate whether such responses could help differentiating subjects with FM into specific phenotypes.
Continuous Renal Replacement Therapy in Pediatric Patients With Acute Kidney Injury After Liver Transplantation
Authors: Sun Yan , Gao Sinan , Wang Xingqiang , Yu Lixin , Xu Min , Gao Wei , Sun Chao , Wang Bing
Published: June 2022

Objective

This study aimed to explore the clinical application of continuous renal replacement therapy (CRRT) in pediatric patients with acute kidney injury (AKI) after liver transplantation.

Methods

Pediatric patients who underwent liver transplantation were retrospectively investigated. Those who developed AKI within 1 year after the surgery were included and divided into a CRRT group and a non-CRRT group. The perioperative conditions and postoperative complications of the two groups were compared along with the prognoses of the groups to analyze the high-risk factors of the postoperative CRRT.

Results

189 (36.91%) patients developed AKI within 1 year after the liver transplantation surgery. There were 18 patients in the CRRT group and 171 in the non-CRRT group. The differences in the preoperative conditions were not statistically significant between the two groups. Compared with the non-CRRT group, patients in the CRRT group had significantly longer transplantation times, higher volumes of intraoperative hemorrhage, and increased incidence of postoperative unscheduled surgery, postoperative primary nonfunction of the transplanted liver, secondary liver transplantation, hepatic artery occlusion, and intestinal fistula (P < 0.05). Moreover, the proportion of patients in AKI stage 3 is higher in the CRRT group (83.33%) than that in the non-CRRT group (11.11%), P < 0.001. The median time to initiate CRRT was 10 days postoperatively, the median number of CRRT treatments per patient was 2 times, the average duration of each CRRT treatment was 10.1 h, and the average rate of the decrease in blood creatinine per treatment was 25.6%. Results of multivariate logistic regression analysis showed that AKI stage 3 [OR=40.000, 95%CI (10.598, 150.969), P = 0.016], postoperative unscheduled surgery [OR=6.269, 95%CI (3.051, 26.379), P = 0.007], and hepatic artery occlusion [OR = 17.682, 95%CI (1.707, 40.843), P = 0.001] were recognized as risk factors for postoperative AKI with CRRT therapy. The one- and two-year survival rates were 72.22% and 72.22% in the CRRT group, respectively; and 97.08% and 96.49% in the non-CRRT group, accordingly. There were statistically significant differences in the one- and two-year survival rates between the two groups (P < 0.001).

Conclusion

The incidence of AKI after liver transplantation in pediatric patients was high. Patients with AKI stage 3, hepatic artery occlusion, and underwent unscheduled surgery postoperatively were with a high likelihood of receiving CRRT, which was related to a lower one- and two-year survival rates. CRRT effectively improved the one- and two-year survival rates.
First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy
Authors: Xie Zhiying , Sun Chengyue , Liu Chang , Chu Xujun , Gang Qiang , Yu Meng , Zheng Yiming , Meng Lingchao , Li Fan , Xia Dongliang , Wang Li , Li Ying , Deng Jianwen , Lv He , Wang Zhaoxia , Zhang Wei , Yuan Yun
Published: June 2022

Background

The precise genetic diagnosis of a sarcoglycanopathy or dystrophinopathy is sometimes extremely challenging, as pathogenic non-coding variants and/or complex structural variants do exist in DMD or sarcoglycan genes. This study aimed to determine the genetic diagnosis of three patients from two unrelated families with a suspected sarcoglycanopathy or dystrophinopathy based on their clinical, radiological, and pathological features, for whom routine genomic detection approaches failed to yield a definite genetic diagnosis.

Methods

Muscle-derived reverse transcription-polymerase chain reaction analysis and/or TA cloning of DMD, SGCA, SGCB, SGCD, and SGCG mRNA were performed to identify aberrant transcripts. Genomic Sanger sequencing around the aberrant transcripts was performed to detect possible splice-altering variants. Bioinformatic and segregation studies of the detected genomic variants were performed in both families.

Results

In patients F1-II1 and F1-II2, we identified two novel pathogenic compound heterozygous variants in SGCB. One is a deep intronic splice-altering variant (DISV), c.243 + 1558C > T in intron 2 causing the activation of an 87-base pair (bp) pseudoexon, and the other one is a non-canonical splicing site variant, c.243 + 6T > A leading to the partial intron inclusion of 10-bp sequence. A novel DISV, c.243 + 1576C > G causing a 106-bp pseudoexon activation, and a nonsense variant in SGCB were identified in compound heterozygous state in patient F2-II1. Unexpectedly, the predicted nonsense variant, c.334C > T in exon 3, created a new donor splice site in exon 3 that was stronger than the natural one, resulting in a 97-bp deletion of exon 3 (r.333_429del).

Conclusion

This is the first identification of rare exonic and DISVs in the SGCB gene.
Progress of Pathogenesis in Pediatric Multifocal Atrial Tachycardia
Authors: Chen Huaiyang , Ma Yingxu , Wang Yefeng , Luo Haiyan , Xiao Zhenghui , Chen Zhi , Liu Qiming , Xiao Yunbin
Published: June 2022

Multifocal atrial tachycardia (MAT) is defined as irregular P-P, R-R, and P-R intervals, isoelectric baseline between P waves, and ventricular rate over 100 beats/min. Although the prognosis of pediatric MAT in most patients is favorable, adverse outcomes of MAT have been reported, such as cardiogenic death (3%), respiratory failure (6%), or persistent arrhythmia (7%), due to delayed diagnosis and poorly controlled MAT. Previous studies demonstrated that pediatric MAT is associated with multiple enhanced automatic lesions located in the atrium or abnormal automaticity of a single lesion located in the pulmonary veins via multiple pathways to trigger electrical activity. Recent studies indicated that pediatric MAT is associated with the formation of a re-entry loop, abnormal automaticity, and triggering activity. The occurrence of pediatric MAT is affected by gestational disease, congenital heart disease, post-cardiac surgery, pulmonary hypertension, and infectious diseases, which promote MAT via inflammation, redistribution of the autonomic nervous system, and abnormal ion channels. However, the pathogenesis of MAT needs to be explored. This review is aimed to summarize and analyze the pathogenesis in pediatric MAT.
Prevention of Radiodermatitis With Topical Chinese Herbal Medicine: A Systematic Review and Meta-Analysis
Authors: Yu Hui-Bo , Han Bao-Jin , Cao Hui-Juan
Published: June 2022

Objectives: Topical Chinese herbal medicine (TCHM) is widely used to prevent radiodermatitis in patients who receive radiation therapy in China. However, evidence regarding its efficacy remains limited. The purpose of the review is to evaluate the effects of TCHM in preventing radiodermatitis.

Methods: The protocol of this review was registered in PROSPERO (CRD42020220620). Relevant clinical trials were identified (from January 1, 2010, to April 24, 2022) through 11 electronic databases, including PubMed, SpringerLink, Proquest, the Cochrane Central Register of Controlled Trials, Scopus, the ProQuest Dissertation & Theses Global, PsycINFO, Applied Social Sciences Index and Abstracts, the Chinese National Knowledge Infrastructure Databases, Wangfang Data Knowledge Service Platform, and the Chongqing VIP Chinese Science and Technology Periodical Database. The quality of the included trials was assessed through a risk of bias assessment using Version 2 of the Cochrane risk-of-bias tool (RoB 2.0). We included RCTs that compared TCHM single used or as adjunctive treatment with routine drugs, conventional therapy, or placebo for cancer patients who are about to start radiation therapy and do not possess any type of dermatitis or skin lesions at that time. Primary outcomes of interest were the incidence of radiodermatitis and the grade of radiodermatitis according to the RTOG (Radiation Therapy Oncology Group). Secondary outcomes included the recovery time of skin and mucosa, the occurrence time of radiodermatitis, the radiation dose, quality of life, and adverse events. Data were summarized using risk ratio (RR) calculations and 95% confidence intervals (CI) for binary outcomes or mean difference (MD) with 95% CI for continuous outcomes. Certainty of the evidence was assessed according to the GRADE criteria.

Results: In this review, 38 randomized controlled trials (RCTs) were included. Risk of bias assessment through RoB 2.0 showed that two studies were rated as low risk, two studies were rated as high risk, and the rest were rated as having some concerns. Compared with routine drugs, TCHM may have an advantage in reducing RTOG grading (RR = 0.46, 95%CI 0.35–0.60), decreasing the recovery time of radiodermatitis (MD = −2.35, 95%CI 3.58 to −1.12 days), delaying the occurrence of radiodermatitis (MD = 2.36, 95%CI 1.74–2.98), and improving the quality of life of patients (RR = 1.46, 95%CI 1.03–2.06). Compared with conventional therapy, TCHM may also have an advantage in decreasing the grade of RTOG (RR = 0.28, 95%CI 0.21–0.38).

Conclusion: Current low evidence revealed that TCHM may have better efficacy in the prevention of radiodermatitis; however, more high-quality RCTs are still warranted to testify this conclusion.

Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020220620), identifier (PROSPERO 2020 CRD42020220620).
A Prescribing Cascade of Proton Pump Inhibitors Following Anticholinergic Medications in Older Adults With Dementia
Authors: Trenaman Shanna C. , Harding Austin , Bowles Susan K. , Kirkland Susan A. , Andrew Melissa K.
Published: June 2022

Introduction: Prescribing cascade refers to use of a medication to treat a drug-related adverse event. Prescribing cascades increase medication use, cost, and risk of adverse events.

Objective: Our objective was to use administrative health data to identify whether use of medications from the anticholinergic cognitive burden scale was associated with proton pump inhibitor (PPI) prescribing consistent with a prescribing cascade in older adults with dementia.

Method: The cohort was comprised of Nova Scotia Seniors’ Pharmacare beneficiaries identified to have dementia and medication dispensation data recorded between 1 April 2010, or cohort entry and 31 March 2015. Anticholinergic medications from the anticholinergic cognitive burden scale (ACB) were abstracted. A look back period of 365 days identified if a PPI had been dispensed preceding anticholinergic dispensation. PPI initiation within 30, 60, 90, or 180 days of the anticholinergic medication was assessed. Demographic description of those dispensed anticholinergic medications or PPIs were reported. Risk factors for the prescribing cascade were investigated with logistic regression and Cox proportional hazards modelling including a sex-stratified analysis.

Results: We identified 28,952 Nova Scotia Seniors’ Pharmacare beneficiaries with dementia and prescription dispensation data. Anticholinergic medications were frequently dispensed with 63.4% of the cohort dispensed at least one prescription for an anticholinergic medication. The prescribing cascade defined as up to 180-days between anticholinergic medication inititation and PPI dispensation, occurred in 1,845 Nova Scotia Seniors’ Pharmacare beneficiaries with dementia (incidence 6.4%). Multivariate regression showed those experiencing the prescribing cascade after initiating any anticholinergic were younger (OR 0.98, 95%CI [0.97–0.98]), less likely to live in an urban location (OR 0.82, 95%CI [0.74–0.91]), or to be men (OR 0.74, 95%CI [0.67–0.82]). Cox regression demonstrated an increased risk of starting a PPI within 180 days when initiating any medication from the ACB (HR 1.38, 95%CI [1.29–1.58]).

Discussion: Regression modelling suggested that anticholinergic medications increased the risk of PPI dispensation consistent with a prescribing cascade in the cohort. The identification of the prescribing cascade in this population of older Nova Scotia Seniors’ Pharmacare Program beneficiaries with dementia using administrative health data highlights how routinely collected health data can be used to identify prescribing cascades.
Reverse Triggering: An Introduction to Diagnosis, Management, and Pharmacologic Implications
Authors: Murray Brian , Sikora Andrea , Mock Jason R. , Devlin Thomas , Keats Kelli , Powell Rebecca , Bice Thomas
Published: June 2022

Reverse triggering is an underdiagnosed form of patient-ventilator asynchrony in which a passive ventilator-delivered breath triggers a neural response resulting in involuntary patient effort and diaphragmatic contraction. Reverse triggering may significantly impact patient outcomes, and the unique physiology underscores critical potential implications for drug-device-patient interactions. The purpose of this review is to summarize what is known of reverse triggering and its pharmacotherapeutic consequences, with a particular focus on describing reported cases, physiology, historical context, epidemiology, and management. The PubMed database was searched for publications that reported patients presenting with reverse triggering. The current body of evidence suggests that deep sedation may predispose patients to episodes of reverse triggering; as such, providers may consider decreasing sedation or modifying ventilator settings in patients exhibiting ventilator asynchrony as an initial measure. Increased clinician awareness and research focus are necessary to understand appropriate management of reverse triggering and its association with patient outcomes.
Genetic Polymorphisms in CYP2C19 Cause Changes in Plasma Levels and Adverse Reactions to Anlotinib in Chinese Patients With Lung Cancer
Authors: Tan Tingfei , Han Gongwei , Cheng Ziwei , Jiang Jiemei , Zhang Li , Xia Zitong , Wang Xinmeng , Xia Quan
Published: June 2022

Background: Anlotinib is a small molecular multi-targeting tyrosine kinase inhibitor. Growing evidence indicates that treatment efficacy, and toxicity varies considerably between individuals. Therefore, this study aimed to investigate the relationship between cytochrome P450 (CYP450) gene polymorphisms, drug concentrations, and their adverse reactions in anlotinib-treated patients with lung cancer.

Methods: We enrolled 139 patients with lung cancer, treated with anlotinib. Twenty loci in the following five genes of the CYP450 family were genotyped: CYP450 family 3 subfamily A member 5 (CYP3A5), 3 subfamily A member 4 (CYP3A4), 2 subfamily C member 9 (CYP2C9), 2 subfamily C member 19 (CYP2C19), and 1 subfamily A member 2 (CYP1A2). Data on adverse reactions were collected from patients, and plasma anlotinib concentrations were measured.

Results: There were significant variances in plasma trough concentration (3.95–52.88 ng/ml) and peak plasma concentration (11.53–42.8 ng/ml) following administration of 8 mg anlotinib. Additionally, there were significant differences in the plasma trough concentration (5.65–81.89 ng/ml) and peak plasma concentration (18.01–107.18 ng/ml) following administration of 12 mg anlotinib. Furthermore, for CYP2C19-rs3814637, the peak plasma concentrations of mutant allele T carriers (TT+CT) were significantly higher than those of wildtypes (CC). For CYP2C19-rs11568732, the peak plasma concentrations of the mutant allele G carriers (GT+GG) were significantly higher than those of the wild-type (TT). More importantly, the incidence rates of hypertension and hemoptysis (peripheral lung cancer) with TT+CT in rs3814637 and GT+GG in rs11568732 were significantly higher than those with CC and TT.

Conclusions: The plasma trough and peak concentrations varied significantly for both 8 and 12 mg of anlotinib. Single-nucleotide polymorphisms in CYP2C19 are significantly associated with hypertension, hemoptysis, and anlotinib peak concentrations. Polymorphisms in CYP450 may explain inter-individual differences in anlotinib-related adverse reactions.
RE-Place: A Unique Project Collecting Expertise on New Approach Methodologies
Authors: Van Mulders Mieke , Liodo Missigba Nancy , Mertens Birgit , Rogiers Vera
Published: June 2022

By applying “New Approach Methodologies (NAMs)” based on innovative technologies such as computer modeling, high throughput testing, omics, and sophisticated cell cultures, the use of experimental animals in the life sciences can be reduced or sometimes even completely avoided. Stimulating NAMs may benefit from a bottom-up approach, i.e., local initiatives mapping the available NAMs and promoting their use. An example of such an initiative in Belgium is the RE-Place project, which collects the available NAMs in one central database, and links this knowledge with the names of experts and research centers. To this extent, a template was created to collect the information of interest in a fast and consistent manner. Based on this template, a web-based application was developed to facilitate the entry of information, which was evaluated in a pilot study by experts in the field of NAMs. After integration of their feedback, a revised version of the RE-Place online tool was launched to the public. Aspects such as user-friendliness, quality of submitted information, protection of personal data and Intellectual Property (IP) rights were all considered in the development process. Hurdles like incentives for collaboration were also taken into account. Information submitted with the online tool is directly integrated in the RE-Place open access database. By consulting the database, scientists from various disciplines can easily identify the different types of NAMs and the experts using them in Belgium. As such, the RE-Place database contributes to building trust in the use of NAMs and stimulating their use and regulatory uptake.
Theoretical Investigation on C11H8 Bicyclic Carbene and Allene Isomers
Authors: Roy Tarun , Satpati Sayon , Thimmakondu Venkatesan S. , Ghosal Subhas
Published: June 2022

Recent studies postulate that the presence of polycyclic aromatic hydrocarbons (PAHs) in the interstellar medium (ISM) could have been formed through resonance-stabilized arylcarbene intermediates. However, identifying most of these reactive intermediates is very challenging experimentally due to their metastability and other experimental constrains. Thus, computational studies that cover the thermodynamic versus kinetic stability of various possible structures would be beneficial for successfully identifying new molecules either in the laboratory and/or in the ISM. In this paper, more than four hundred C11H8 carbene isomers have been theoretically investigated employing density functional theory (DFT). Hybrid density functionals B3LYP and ωB97XD with 6-311 + G (d,p) basis set have been used for singlet electronic states, whereas, triplet spin states were optimized at the same level using an unrestricted Hartree-Fock wavefunction. Although the skeletal structures of C11H8 can be categorized into monocyclic, bicyclic, tricyclic, tetracyclic and acyclic isomers, bicyclic carbenes have shown better stability due to the presence of resonance stabilized azulenyl/naphthyl rings. In this category, some isomers (1-, 2-, 5- and 6-azulenylcarbenes and 1- and 2-naphthylcarbenes) have also been detected recently in the laboratory and simple aromatic carbenes such as cyclopropenylidene and its homologues are detected in the ISM. Thus, we have systematically investigated the energetic and spectroscopic properties of resonance stabilized 5-, 6-, 7- and 8-membered ring containing bicyclic isomers of C11H8 and the fingerprint regions of the infrared spectrum for each class of these bicyclic compounds.
Regulation of Cardiac Contractility by the Alpha 2 Subunit of the Na+/K+-ATPase
Authors: Skogestad Jonas , Aronsen Jan Magnus
Published: June 2022

Cytosolic Na + concentrations regulate cardiac excitation-contraction coupling and contractility. Inhibition of the Na+/K+-ATPase (NKA) activity increases cardiac contractility by increasing cytosolic Ca2+ levels, as increased cytosolic Na+ levels are coupled to less Ca2+ extrusion and/or increased Ca2+ influx from the Na+/Ca2+-exchanger. NKA consists of one α subunit and one β subunit, with α1 and α2 being the main α isoforms in cardiomyocytes. Substantial evidence suggests that NKAα2 is the primary regulator of cardiac contractility despite being outnumbered by NKAα1 in cardiomyocytes. This review will mainly focus on differential regulation and subcellular localization of the NKAα1 and NKAα2 isoforms, and their relation to the proposed concept of subcellular gradients of Na+ in cardiomyocytes. We will also discuss the potential roles of NKAα2 in mediating cardiac hypertrophy and ventricular arrhythmias.
Discordant Spirometry and Impulse Oscillometry Assessments in the Diagnosis of Small Airway Dysfunction
Authors: Lu Lifei , Peng Jieqi , Zhao Ningning , Wu Fan , Tian Heshen , Yang Huajing , Deng Zhishan , Wang Zihui , Xiao Shan , Wen Xiang , Zheng Youlan , Dai Cuiqiong , Wu Xiaohui , Zhou Kunning , Ran Pixin , Zhou Yumin
Published: June 2022

Background and objective: Spirometry is commonly used to assess small airway dysfunction (SAD). Impulse oscillometry (IOS) can complement spirometry. However, discordant spirometry and IOS in the diagnosis of SAD were not uncommon. We examined the association between spirometry and IOS within a large cohort of subjects to identify variables that may explain discordant spirometry and IOS findings.

Methods: 1,836 subjects from the ECOPD cohort underwent questionnaires, symptom scores, spirometry, and IOS, and 1,318 subjects were examined by CT. We assessed SAD with R5-R20 > the upper limit of normal (ULN) by IOS and two of the three spirometry indexes (maximal mid-expiratory flow (MMEF), forced expiratory flow (FEF)50%, and FEF75%) < 65% predicted. Multivariate regression analysis was used to analyze factors associated with SAD diagnosed by only spirometry but not IOS (spirometry-only SAD) and only IOS but not spirometry (IOS-only SAD), and line regression was used to assess CT imaging differences.

Results: There was a slight agreement between spirometry and IOS in the diagnosis of SAD (kappa 0.322, p < 0.001). Smoking status, phlegm, drug treatment, and family history of respiratory disease were factors leading to spirometry-only SAD. Spirometry-only SAD had more severe emphysema and gas-trapping than IOS-only SAD in abnormal lung function. However, in normal lung function subjects, there was no statistical difference in emphysema and gas-trapping between discordant groups. The number of IOS-only SAD was nearly twice than that of spirometry.

Conclusion: IOS may be more sensitive than spirometry in the diagnosis of SAD in normal lung function subjects. But in patients with abnormal lung function, spirometry may be more sensitive than IOS to detect SAD patients with clinical symptoms and CT lesions.