bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal Characteristics of Debris Flow Surges
Authors: Zhang Jun , Li Yong , Guo Xiaojun , Yang Taiqiang , Liu Daochuan , Yu Bin
Published: May 2021

Debris flow is one of the most destructive geomorphological events in mountainous watersheds, which usually appears in the form of successive surge waves as observed all over the world. In particular, debris flows in the Jiangjia Gully in southwest China have displayed a great variety of surge phenomena; each debris flow event contains tens or hundreds of separate surges originating from different sources. Therefore, the surge sequence of an event must encode the information of debris flow developing. The unmanned aerial vehicle photos provide an overview of debris flow sources, showing the different potentials of the debris flow and surge sequences present various patterns responding to the rainfall events. Then the variety of rainfalls and material sources determine the diversity of surge sequence. Using time series analysis to the surge discharge sequences, we calculate the Hurst exponent, the autocorrelation function, and the power spectrum exponent and find that all the sequences commonly share the property of long-term memory and these parameters are correlated in an exponential form, with values depending on rainfall patterns. Moreover, all events show a gross trend of discharge decay, despite the local rainfall process, which implies the intrinsic nature of the surge sequence as a systematic behavior of watershed. It is expected that these findings are heuristic for establishing mechanisms of debris flow initiation and evolution in a watershed.
Human Pluripotent Stem Cells Go Diabetic: A Glimpse on Monogenic Variants
Authors: Heller Sandra , Melzer Michael Karl , Azoitei Ninel , Julier Cécile , Kleger Alexander
Published: May 2021

Diabetes, as one of the major diseases in industrial countries, affects over 350 million people worldwide. Type 1 (T1D) and type 2 diabetes (T2D) are the most common forms with both types having invariable genetic influence. It is accepted that a subset of all diabetes patients, generally estimated to account for 1–2% of all diabetic cases, is attributed to mutations in single genes. As only a subset of these genes has been identified and fully characterized, there is a dramatic need to understand the pathophysiological impact of genetic determinants on β-cell function and pancreatic development but also on cell replacement therapies. Pluripotent stem cells differentiated along the pancreatic lineage provide a valuable research platform to study such genes. This review summarizes current perspectives in applying this platform to study monogenic diabetes variants.
Microbial Communities of the Drinking Water With Gradient Radon Concentration Are Primarily Contributed by Radon and Heavy Metal Content
Authors: Nayak Tilak , De Debjit , Karmakar Parimal , Deb Argha , Dhal Paltu Kumar
Published: May 2021

Radon and heavy metal (HM) contamination in drinking water and their impact on health have been reported earlier. However, relatively little is known about the microbial community in drinking water with gradients of radon and the drivers of microbial community patterns in such water. With this view, we first examine microbial dynamics of drinking water in the permissible level of 93 ± 2 Bq/l as control, 510 ± 1.5 6 Bq/l and 576 ± 2 Bq/l as medium, and 728 ± 3 Bq/l as high radon-containing tube wells from Dumka and Godda districts, which comes under a major fault of the eastern fringes of India. Attempts have also been made to predict the impact of the radon contamination gradient and other water environmental parameters on community structure. The measured physicochemical character revealed strong clustering by the sampling site with respect to its radon and HM content. The radon-contaminated sites represent HM-rich nutrient-limited sites compared to the control. Radon (Rn), HM (Pb, Cu, and As), and total suspended solids (TSSs) were the most determinant variable among the parameters and influenced the microbial community composition of that region. The microbial diversity of those sites was lower, and this measured diversity decreased gradually on the sites with an increased gradient of radon contamination. The dominant microbial families in the contaminated sites were Moraxellaceae, Chitinophagaceae, unclassified Candidatus Azambacteria, unclassified Candidatus Moranbacteria, unclassified Candidatus Collierbacteria, and Gammaproteobacterial members, which are reported to abundantly inhabit radiation and chemolithotrophic environments and pose better radionuclide protective mechanisms, while the bacterial members dominant in the control site were Comamonadaceae, Rhodocyclaceae, Nitrospirales Incertae Sedis, cvE6, unclassified Woesearchaeota (DHVEG-6), and Holophagaceae, which are reported to be abundant in natural soil and drinking water, and labile in harsh environments. Relative sequence abundance of Comamonadaceae was decreasing on the sites with an increasing radon gradient, while the opposite trend was observed for Chitinophagaceae. The distribution of such microbial assemblages is linked to radon and heavy metal, highlighting that taxa with distinct environmental preferences underlie apparent clustering by sites; thus, we can utilize them for biostimulation-based in situ bioremediation purposes.
Therapeutic Opportunities of Interleukin-33 in the Central Nervous System
Authors: Sun Yun , Wen Yankai , Wang Luxi , Wen Liang , You Wendong , Wei Shuang , Mao Lin , Wang Hao , Chen Zuobing , Yang Xiaofeng
Published: May 2021

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is involved in various diseases. IL-33 exerts its effects via its heterodimeric receptor complex, which comprises suppression of tumorigenicity 2 (ST2) and the IL-1 receptor accessory protein (IL-1RAP). Increasing evidence has demonstrated that IL-33/ST2 signaling plays diverse but crucial roles in the homeostasis of the central nervous system (CNS) and the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infection, trauma, and ischemic stroke. In the current review, we focus on the functional roles and cellular signaling mechanisms of IL-33 in the CNS and evaluate the potential for diagnostic and therapeutic applications.
Amelioration of Beta Interferon Inhibition by NS4B Contributes to Attenuating Tembusu Virus Virulence in Ducks
Authors: Zhang Wei , Zeng Miao , Jiang Bowen , Lu Tong , Guo Jiaqi , Hu Tao , Wang Mingshu , Jia Renyong , Zhu Dekang , Liu Mafeng , Zhao Xinxin , Yang Qiao , Wu Ying , Zhang Shaqiu , Ou Xumin , Liu Yunya , Zhang Ling , Yu Yanling , Pan Leichang , Cheng Anchun , Chen Shun
Published: May 2021

Our previous studies reported that duck Tembusu virus nonstructural protein 2A (NS2A) is a major inhibitor of the IFNβ signaling pathway through competitively binding to STING with TBK1, leading to a reduction in TBK1 phosphorylation. Duck TMUV NS2B3 could cleave and bind STING to subvert the IFNβ signaling pathway. Here, we found that overexpression of duck TMUV NS4B could compete with TBK1 in binding to STING, reducing TBK1 phosphorylation and inhibiting the IFNβ signaling pathway by using the Dual-Glo® Luciferase Assay System and the NanoBiT protein-protein interaction (PPI) assay. We further identified the E2, M3, G4, W5, K10 and D34 residues in NS4B that were important for its interaction with STING and its inhibition of IFNβ induction, which were subsequently introduced into a duck TMUV replicon and an infectious cDNA clone. We found that the NS4B M3A mutant enhanced RNA replication and exhibited significantly higher titer levels than WT at 48-72 hpi but significantly decreased mortality (80%) in duck embryos compared to WT (100%); the NS4B G4A and R36A mutants slightly reduced RNA replication but exhibited the same titer levels as WT. However, the NS4B R36A mutant did not attenuate the virulence in duck embryos, whereas the G4A mutant significantly decreased the mortality (70%) of duck embryos. In addition, the NS4B W5A mutant did not affect viral replication, whereas the D34A mutant slightly reduced RNA replication, and both mutants exhibited significantly lower titer levels than the WT and significantly decreased mortality (90% and 70%, respectively) in duck embryos. Hence, our findings provide new insight into the development of attenuated flaviviruses by targeting the disabling viral strategies used to evade the innate defense mechanisms.
Transmigration of Neutrophils From Patients With Familial Mediterranean Fever Causes Increased Cell Activation
Authors: Martirosyan Anush , Poghosyan David , Ghonyan Susanna , Mkrtchyan Nune , Amaryan Gayane , Manukyan Gayane
Published: May 2021

Familial Mediterranean fever (FMF) is caused by pyrin-encoding MEFV gene mutations and characterized by the self-limiting periods of intense inflammation, which are mainly mediated by a massive influx of polymorphonuclear neutrophils (PMNs) into the inflamed sites. Perturbation of actin polymerization by different pathogens was shown to activate the pyrin inflammasome. Our aim was to test whether cytoskeletal dynamics in the absence of pathogens may cause abnormal activation of PMNs from FMF patients. We also aimed to characterize immunophenotypes of circulating neutrophils and their functional activity. Circulating PMNs displayed heterogeneity in terms of cell size, granularity and immunophenotypes. Particularly, PMNs from the patients in acute flares (FMF-A) exhibited a characteristic of aged/activated cells (small cell size and granularity, up-regulated CXCR4), while PMNs form the patients in remission period (FMF-R) displayed mixed fresh/aged cell characteristics (normal cell size and granularity, up-regulated CD11b, CD49d, CXCR4, and CD62L). The findings may suggest that sterile tissue-infiltrated PMNs undergo reverse migration back to bone marrow and may explain why these PMNs do not cause immune-mediated tissue damage. A multidirectional expression of FcγRs on neutrophils during acute flares was also noteworthy: up-regulation of FcγRI and down-regulation of FcγRII/FcγRIII. We also observed spontaneous and fMPL-induced activation of PMNs from the patients after transmigration through inserts as seen by the increased expression of CD11b and intracellular expression of IL-1β. Our study suggests heightened sensitivity of mutated pyrin inflammasome towards cytoskeletal modifications in the absence of pathogens.
Radiation-Induced Immunity and Toxicities: The Versatility of the cGAS-STING Pathway
Authors: Constanzo Julie , Faget Julien , Ursino Chiara , Badie Christophe , Pouget Jean-Pierre
Published: May 2021

In the past decade, radiation therapy (RT) entered the era of personalized medicine, following the striking improvements in radiation delivery and treatment planning optimization, and in the understanding of the cancer response, including the immunological response. The next challenge is to identify the optimal radiation regimen(s) to induce a clinically relevant anti-tumor immunity response. Organs at risks and the tumor microenvironment (e.g. endothelial cells, macrophages and fibroblasts) often limit the radiation regimen effects due to adverse toxicities. Here, we reviewed how RT can modulate the immune response involved in the tumor control and side effects associated with inflammatory processes. Moreover, we discussed the versatile roles of tumor microenvironment components during RT, how the innate immune sensing of RT-induced genotoxicity, through the cGAS-STING pathway, might link the anti-tumor immune response, radiation-induced necrosis and radiation-induced fibrosis, and how a better understanding of the switch between favorable and deleterious events might help to define innovative approaches to increase RT benefits in patients with cancer.
The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment
Authors: Liu Yishan , Liu Hao , Li Zitao , Fan Hualin , Yan Xiumin , Liu Xiao , Xuan Jianyan , Feng Du , Wei Xiangcai
Published: May 2021

Background

Hormones and immune imbalance are critical factors in polycystic ovary syndrome (PCOS). The alternation of immune microenvironment of oocytes may play a significant role in infertility of PCOS patients.

Objective

This study explores the role of follicular fluid microenvironment change in inflammatory pathways activation of granulosa cells (GCs) in PCOS women infertility.

Methods

We enrolled 27 PCOS patients and 30 controls aged 22 to 38 years who underwent IVF and collected their luteinized granulosa cells (LGCs). Meanwhile, a granulosa-like tumor cell line (KGN) as a cell-model assisted this study. Key inflammatory markers in human ovarian GCs and follicular fluid were detected by RT-qPCR, Western blotting, or ELISA. The KGN cells were treated with follicle supernatant mixed with normal medium to simulate the microenvironment of GCs in PCOS patients, and the inflammation indicators were observed. The assembly of NLRP3 inflammasomes was detected by immunofluorescence techniques. Dihydroethidium assay and EdU proliferation assay were used to detect ROS and cell proliferation by flow cytometry.

Results

Compared with normal controls (n = 19), IL-1β (P = 0.0005) and IL-18 (P = 0.021) in the follicular fluid of PCOS patients (n = 20) were significantly increased. The NF-κB pathway was activated, and NLRP3 inflammasome was formatted in ovarian GCs of PCOS patients. We also found that inflammation of KGN cells was activated with LPS irritation or stimulated by follicular fluid from PCOS patients. Finally, we found that intracellular inflammation process damaged mitochondrial structure and function, which induced oxidative stress, affected cellular metabolism, and impaired cell proliferation.

Conclusion

Inflammatory microenvironment alteration in the follicular fluid of PCOS patients leads to activated inflammatory pathway in GCs, serving as a crucial factor that causes adverse symptoms in patients. This study provides a novel mechanism in the inflammatory process of PCOS.
The Influence of Clamping, Structure Geometry, and Material on Seismic Metamaterial Performance
Authors: Varma T. Venkatesh , Ungureanu Bogdan , Sarkar Saikat , Craster Richard , Guenneau Sébastien , Brûlé Stéphane
Published: May 2021

Diverting and controlling the impact of elastic vibrations upon an infrastructure is a major challenge for seismic hazard mitigation and for the reduction of machine noise and vehicle vibration in the urban environment. Seismic metamaterials (SMs), with their inherent ability to manipulate wave propagation, provide a key route for overcoming the technological hurdles involved in this challenge. Engineering the structure of the SM serves as a basis to tune and enhance its functionality, and inspired by split rings, swiss-rolls, notch-shaped, and labyrinthine designs of elementary cells in electromagnetic and mechanical metamaterials, we investigate altering the structure geometries of SMs with the aim of creating large bandgaps in a subwavelength regime. Interestingly, clamping an SM to the bedrock creates a zero frequency stopband, but further effects can be observed in the higher frequency regime due to their specific geometry. We show that square stiff inclusions perform better in comparison to circular ones while keeping the same filling fraction. En route to enhancing the bandgap, we have also studied the performance of SMs with different constituent materials; we find that steel columns, as inclusions, show large bandgaps, however, the columns are too large for steel to be a feasible material in practical or financial terms. Non-reinforced concrete would be preferable for industry level scaling up of the technology because, concrete is cost-effective, easy to cast directly at the construction site and easy to provide arbitrary geometry of the structure. As a part of this study, we show that concrete columns can also be designed to exhibit bandgaps if we cast them within a soft soil coating surrounding the protected area for various civil structures like a bridge, building, oil pipelines, etc. Although our motivation is for ground vibration, and we use the frequencies, lengthscales, and material properties relevant for that application, it is notable that we use the equations of linear elasticity, and our investigation is more broadly relevant in solid mechanics.
Challenging Methicillin Resistance Detection in Bone and Joint Infections: Focus on the MRSA/SA SSTI® Strategy
Authors: Titécat Marie , Loïez Caroline , Demaeght François , Leclerc Jean-Thomas , Martin Théo , Dezèque Hervé , Migaud Henri , Senneville Eric
Published: May 2021

The genus Staphylococcus is the main causative agent of bone and joint infections (BJI) in which outcomes are impacted by both effective surgical and appropriate antimicrobial management. In this context, methicillin resistance (MR) detection is a microbiological challenge to optimize the anti-staphylococcal drug coverage and to secure the surgical procedure. During the last decade, molecular tools have been developed to rapidly detect bacterial-resistant strains in clinical samples. The GeneXpert MRSA/SA SSTI® assay (Cepheid, Sunnyvale, CA, USA) is a real-time PCR method aimed at detecting methicillin-resistant Staphylococcus aureus (MRSA) in skin and soft tissues infections. In the literature, this test has been reported to be diverted from its original purpose to be evaluated in surgical samples. Within the current review, we update the GeneXpert MRSA/SA SSTI® assay performance in staphylococcal species determination (i.e., S. aureus vs. coagulase-negative species) together with MR genotype detection, when performed in osteoarticular infections.
Case Report: Viral Pneumonia Could Prompt the Advancement of Immune-Mediated Liver Disease
Authors: Li Qian , Wang Jun , Zhou Xueshi , Lu Hongzhou , Lu Mengji , Huang Lihua
Published: May 2021

Background: The impact of the influenza A (H1N1) and SARS-CoV-2 virus on the development of autoimmune hepatitis has not been described previously.

Methods: In this case series, we evaluated the dynamic changes in liver function of three patients with autoimmune hepatitis who presented with viral infection (two with the H1N1 and one with the SARS-CoV-2 virus) during the recent COVID-19 outbreak.

Result: Patient 1 was a 68-year-old woman with a history of hepatitis of unknown origin before being infected with the H1N1 virus. Autoimmune hepatitis with an exacerbation of liver injury was diagnosed during the infection. Patient 2 was a 48-year-old woman with pre-existing autoimmune hepatitis. Despite being on immunosuppressant therapy (using glucocorticoids), liver injury recurred with elevated total bilirubin and gamma-glutamyl transferase levels post H1N1 infection. Patient 3 was a 61-year-old woman with probable autoimmune hepatitis. Liver injury recurred with a flare in alanine transaminase/aspartate transaminase levels post SARS-CoV-2 infection, in spite of the patient being on liver protection therapy (using ursodeoxycholic acid).

Conclusion: The case series raises the possibility that COVID-19 or influenza induced pneumonia triggers the progression of autoimmune hepatitis.
Infection by Diverse HIV-1 Subtypes Leads to Different Elevations in HERV-K Transcriptional Levels in Human T Cell Lines
Authors: Li Xi , Guo Yaolin , Li Hanping , Huang Xiaofeng , Pei Zhichao , Wang Xiaolin , Liu Yongjian , Jia Lei , Li Tianyi , Bao Zuoyi , Wang Xiaorui , Han Leilei , Han Jingwan , Li Jingyun , Li Lin
Published: May 2021

Human endogenous retroviruses (HERVs) make up ~8% of the human genome, and for millions of years, they have been subject to strict biological regulation. Many HERVs do not participate in normal physiological activities in the body. However, in some pathological conditions, they can be abnormally activated. For example, HIV infection can cause abnormal activation of HERVs, and under different infection conditions, HERV expression may be different. We observed significant differences in HERV-K transcription levels among HIV-1 subtype-infected individuals. The transcriptional levels in the HERV-K gag region were significantly increased in HIV-1 B subtype-infected patients, while the transcriptional levels in the HERV-K pol region were significantly increased in CRF01_AE and CRF07_BC subtype-infected patients. In vitro, the transcriptional levels of HEVR-K were increased 5-fold and 15-fold in MT2 cells transfected with two different HIV-1 strains (B and CRF01_AE, respectively). However, there was no significant difference in transcriptional levels among regions of HERV-K. When MT2 cells were infected with different subtypes of HIV-1 Tat proteins (B, CRF01_AE), which is constructed by lentiviruses, and the transcription levels of HERV-K were increased 4-fold and 2-fold, respectively. Thus, different subtypes of HIV-1 have different effects on HERV-K transcription levels, which may be caused by many factors, not only Tat protein.
Mitomycin C Inhibits Esophageal Fibrosis by Regulating Cell Apoptosis and Autophagy via lncRNA-ATB and miR-200b
Authors: Zhang Yin , Wang Qinge , Xu Yuping , Sun Jing , Ding Yanbo , Wang Li , Chen Bingfang , Sun Kewen , Chen Jianping
Published: May 2021

Benign esophageal strictures (BESs) frequently results from esophageal fibrosis. The transformation of fibroblasts into fibrocyte is an important cause of fibrosis. The treatment of fibrosis is challenging. Some previous studies have indicated the antifibrotic effect of mitomycin C (MMC). However, the mechanism of action of MMC and its optimal dose for treatment remains unclear. In the present study, the role of MMC in fighting fibrosis and its mechanism was investigated. Human esophageal fibroblast cells (HEFs)were treated without or with MMC, at 2, 5, 10 μg/ml, combining with mimic lncRNA-ATB, miR-200b inhibitor, rapamycin (RAPA), and 3-Methyladenine (3-MA). The cell viability, and cell apoptosis were evaluated. In addition, expression of apoptosis related proteins (caspase8 and caspase3), autophagy related proteins (LC3II and ATG5) and fibrosis related proteins (α-SMA collagen-1 and TGF-β) were also evaluated. Furthermore, autophagosome was observed by transmission electron microscope. Results showed that the expression of lncRNA-ATB was down-regulated and miR-200b was up-regulated after treated with MMC. And MMC induced cell apoptosis and inhibited cell autophagy. On the other hand, RAPA, mimic lncRNA-ATB and miR-200b inhibitor reduced fibrogenic effect of MMC on HEFs. Collectively, this study suggests that MMC inhibited esophageal fibrosis by regulating cell apoptosis and autophagy via downregulating lncRNA-ATB and upregulating miR-200b.
Circulating Neurofilament Light Predicts Cognitive Decline in Patients With Post-stroke Subjective Cognitive Impairment
Authors: Wang Jian-Hong , Huang Jie , Guo Fu-Qiang , Wang Fang , Yang Shu , Yu Neng-Wei , Zheng Bo , Wang Jian
Published: May 2021

Background

Subjective cognitive impairment (SCI) is common after acute ischemic stroke and adversely affects the quality of life. SCI is associated with an increased risk of developing mild cognitive impairment and dementia. Identifying biomarkers which could predict long-term cognitive outcomes of post-stroke SCI is of importance for early intervention. This study aims to investigate the association between circulating neurofilament light (NfL) and long-term cognitive function in patients with post-stroke SCI.

Methods

This longitudinal study recruited 304 patients with post-stroke SCI, and serum NfL levels were determined at baseline. These patients were followed up for 12 months for the observation of cognitive change. Cognitive performances were assessed by a Chinese version of the Telephone Interview of Cognitive Status-40 (TICS-40) scale.

Results

The patients were divided into a progression group (as determined by decreased TICS-40 scores) and a stable group (as determined by increased or unchanged TICS-40 scores). The progression group had significantly higher serum NfL levels than the stable group at baseline. Serum NfL levels were predictive for longitudinal cognitive decline during follow-up.

Conclusion

These findings imply that circulating NfL could predict the long-term cognitive change of patients with post-stroke SCI.
Reproducing Human Arm Strategy and Its Contribution to Balance Recovery Through Model Predictive Control
Authors: Shen Keli , Chemori Ahmed , Hayashibe Mitsuhiro
Published: May 2021

The study of human balance recovery strategies is important for human balance rehabilitation and humanoid robot balance control. To date, many efforts have been made to improve balance during quiet standing and walking motions. Arm usage (arm strategy) has been proposed to control the balance during walking motion in the literature. However, limited research exists on the contributions of the arm strategy for balance recovery during quiet standing along with ankle and hip strategy. Therefore, in this study, we built a simplified model with arms and proposed a controller based on nonlinear model predictive control to achieve human-like balance control. Three arm states of the model, namely, active arms, passive arms, and fixed arms, were considered to discuss the contributions of arm usage to human balance recovery during quiet standing. Furthermore, various indexes such as root mean square deviation of joint angles and recovery energy consumption were verified to reveal the mechanism behind arm strategy employment. In this study, we demonstrate to computationally reproduce human-like balance recovery with and without arm rotation during quiet standing while applying different magnitudes of perturbing forces on the upper body. In addition, the conducted human balance experiments are presented as supplementary information in this paper to demonstrate the concept on a typical example of arm strategy.
Transitions of Care Coordination Intervention Identifies Barriers to Discharge in Hospitalized Stroke Patients
Authors: Zimmerman William Denney , Grenier Rachel E. , Palka Sydney V. , Monacci Kelsey J. , Lantzy Amanda K. , Leutbecker Jacqueline A. , Geng Xue , Denny Mary Carter
Published: May 2021

Background: Prolonged hospital lengths of stay increase costs, delay rehabilitation, and expose acute ischemic stroke patients to hospital-acquired infections. We designed and implemented a nurse-driven transitions of care coordinator (TOCC) program to facilitate the transition of care from the acute care hospital setting to rehabilitation centers and home.

Methods: This was a single-blinded, prospective, randomized pilot study of 40 participants to evaluate the feasibility of implementing a TOCC program led by a stroke nurse navigator in hospitalized acute ischemic stroke patients. The intervention consisted of a stroke nurse navigator completing eight specific tasks, including meeting with stroke patients and their families, facilitating communication between team members at multi-disciplinary rounds, assisting with referrals to rehabilitation facilities, providing stroke education, and arranging stroke clinic follow-up appointments, which were confirmed to be completed by independent study personnel. The primary outcome was to assess the feasibility of the program. The secondary outcomes included comparing hospital length of stay (LOS) and patient satisfaction between the TOCC and usual care groups. We also explored the association between patient-level variables and LOS.

Results: The TOCC program was feasible with all pre-specified components completed in 84.2% (95% CI: 60.4–96.6%) and was not significantly different from the assumed completion rate of 75% (p = 0.438). There was no significant difference in median LOS between the two groups [TOCC 5.95 days (4.02, 9.57) vs. usual care 4.01 days (2.00, 10.45), false discovery rate (FDR)-adjusted p = 0.138]. There was a trend toward higher patient median satisfaction in the TOCC group [TOCC 35.00 (33.00, 35.00) vs. usual care 30 (26.00, 35.00), FDR-adjusted p = 0.1] as assessed by a questionnaire at 30 days after discharge. The TOCC study allowed us to identify patient variables (gender, insurance, stroke severity, and discharge disposition) that were significantly associated with longer hospital LOS.

Conclusion: A TOCC program is feasible and can serve as a guide for future allocation of resources to facilitate transitions of care and avoid prolonged hospital stays.
Implementation and Rationale for a Unified Clinical and Imaging Protocol for Evaluation and Treatment of Moyamoya Angiopathy: A Single Institutional Experience
Authors: Larson Anthony S. , Lehman Vance T. , Savastano Luis E. , Lanzino Giuseppe , Campeau Norbert G. , Welker Kirk M. , Klaas James P.
Published: May 2021

Moyamoya disease (MMD) is a complex and incompletely-understood cerebrovascular pathological entity that requires thorough clinical and imaging evaluation. Moyamoya is rare, thereby making the establishment of an effective, thorough and interdisciplinary patient evaluation protocol challenging, even within specialized referral centers. Nevertheless, implementation of such a protocol is crucial in order to provide the best possible evaluation and treatment for MMD patients. Here, we describe our institution's implementation of, rationale for, and experience with a comprehensive multidisciplinary collaboration and evaluation strategy for adult patients with moyamoya. This evaluation course consists of, first of all, a thorough clinical and laboratory evaluation with a vascular neurologist. This is followed by a comprehensive imaging assessment which evaluates angiographic and parenchymal features, in addition to cerebrovascular functionality. Finally, appropriate referrals are made to consulting services as indicated, which includes vascular neurosurgery. These steps are described in detail herein.
An Audit and Comparison of pH, Measured Concentration, and Particulate Matter in Mannitol and Hypertonic Saline Solutions
Authors: Carr Christopher J. , Scoville Jonathan , Ruble James , Condie Chad , Davis Gary , Floyd Candace L. , Kelly Logan , Monson Ken , Reichert Ethan , Sarigul Buse , Hawryluk Gregory W. J.
Published: May 2021

Background: The preferred hyperosmolar therapy remains controversial. Differences in physical properties such as pH and osmolality may be important considerations in hyperosmolar agent selection. We aimed to characterize important physical properties of commercially available hyperosmolar solutions.

Methods: We measured pH and concentration in 37 commonly-used hyperosmolar solutions, including 20 and 25% mannitol and 3, 5, 14.6, and 23.4% hypertonic saline. pH was determined digitally and with litmus paper. Concentration was determined by freezing point and vapor pressure osmometry. Salinity/specific gravity was measured with portable refractometry. Particulate matter was analyzed with filtration and light microscopy and with dynamic light scattering nephelometry.

Results: pH of all solutions was below physiological range (measured range 4.13–6.80); there was no correlation between pH and solution concentration (R2 = 0.005, p = 0.60). Mannitol (mean 5.65, sd 0.94) was less acidic than hypertonic saline (5.16, 0.60). 14/59 (24%) pH measurements and 85/111 concentration measurements were outside manufacturer standards. All 36/36 mannitol concentration measurements were outside standards vs. 48/72 (67%) hypertonic saline (p < 0.0001). All solutions examined on light microscopy contained crystalline and/or non-crystalline particulate matter up to several hundred microns in diameter. From nephelometry, particulate matter was detected in 20/22 (91%) solutions.

Conclusion: We present a novel characterization of mannitol and hypertonic saline. Further research should be undertaken, including research examining development of acidosis following hyperosmolar therapy, the relevance of our findings for dose-response, and the clinical relevance of particulate matter in solution.
A Probabilistic Atlas of the Pineal Gland in the Standard Space
Authors: Razavi Foroogh , Raminfard Samira , Kalantar Hormozi Hadis , Sisakhti Minoo , Batouli Seyed Amir Hossein
Published: May 2021

Pineal gland (PG) is a structure located in the midline of the brain, and is considered as a main part of the epithalamus. There are numerous reports on the facilitatory role of this area for brain function; hormone secretion and its role in sleep cycle are the major reports. However, reports are rarely available on the direct role of this structure in brain cognition and in information processing. A suggestion for the limited number of such studies is the lack of a standard atlas for the PG; none of the available MRI templates and atlases has provided parcellations for this structure. In this study, we used the three-dimensional (3D) T1-weighted MRI data of 152 healthy young volunteers, and provided a probabilistic map of the PG in the standard Montreal Neurologic Institute (MNI) space. The methods included collecting the data using a 64-channel head coil on a 3-Tesla Prisma MRI Scanner, manual delineation of the PG by two experts, and robust template and atlas construction algorithms. This atlas is freely accessible, and we hope importing this atlas in the well-known neuroimaging software packages would help to identify other probable roles of the PG in brain function. It could also be used to study pineal cysts, for volumetric analyses, and to test any associations between the cognitive abilities of the human and the structure of the PG.
Different Impact of Heart Rate Variability in the Deep Cerebral and Central Hemodynamics at Rest: An in silico Investigation
Authors: Scarsoglio Stefania , Ridolfi Luca
Published: May 2021

Background: Heart rate variability (HRV), defined as the variability between consecutive heartbeats, is a surrogate measure of cardiac vagal tone. It is widely accepted that a decreased HRV is associated to several risk factors and cardiovascular diseases. However, a possible association between HRV and altered cerebral hemodynamics is still debated, suffering from HRV short-term measures and the paucity of high-resolution deep cerebral data. We propose a computational approach to evaluate the deep cerebral and central hemodynamics subject to physiological alterations of HRV in an ideal young healthy patient at rest.

Methods: The cardiovascular-cerebral model is composed by electrical components able to reproduce the response of the different cardiovascular regions and their features. The model was validated over more than thirty studies and recently exploited to understand the hemodynamic mechanisms between cardiac arrythmia and cognitive deficit. Three configurations (baseline, increased HRV, and decreased HRV) are built based on the standard deviation (SDNN) of RR beats. For each configuration, 5,000 RR beats are simulated to investigate the occurrence of extreme values, alteration of the regular hemodynamics pattern, and variation of mean perfusion/pressure levels.

Results: In the cerebral circulation, our results show that HRV has overall a stronger impact on pressure than flow rate mean values but similarly alters pressure and flow rate in terms of extreme events. By comparing reduced and increased HRV, this latter induces a higher probability of altered mean and extreme values, and is therefore more detrimental at distal cerebral level. On the contrary, at central level a decreased HRV induces a higher cardiac effort without improving the mechano-contractile performance, thus overall reducing the heart efficiency.

Conclusions: Present results suggest that: (i) the increase of HRV per se does not seem to be sufficient to trigger a better cerebral hemodynamic response; (ii) by accounting for both central and cerebral circulations, the optimal HRV configuration is found at baseline. Given the relation inversely linking HRV and HR, the presence of this optimal condition can contribute to explain why the mean HR of the general population settles around the baseline value (70 bpm).
Tumor Control Probability Modeling for Radiation Therapy of Keratinocyte Carcinoma
Authors: Prior Phillip , Awan Musaddiq J. , Wilson J Frank , Li X. Allen
Published: May 2021

Skin cancer patients may be treated definitively using radiation therapy (RT) with electrons, kilovoltage, or megavoltage photons depending on tumor stage and invasiveness. This study modeled tumor control probability (TCP) based on the pooled clinical outcome data of RT for primary basal and cutaneous squamous cell carcinomas (BCC and cSCC, respectively). Four TCP models were developed and found to be potentially useful in developing optimal treatment schemes based on recommended ASTRO 2020 Skin Consensus Guidelines for primary, keratinocyte carcinomas (i.e. BCC and cSCC).

Background

Radiotherapy (RT) with electrons or photon beams is an excellent primary treatment option for keratinocyte carcinoma (KC), particularly for non-surgical candidates. Our objective is to model tumor control probability (TCP) based on the pooled clinical data of primary basal and cutaneous squamous cell carcinomas (BCC and cSCC, respectively) in order to optimize treatment schemes.

Methods

Published reports citing crude estimates of tumor control for primary KCs of the head by tumor size (diameter: ≤2 cm and >2 cm) were considered in our study. A TCP model based on a sigmoidal function of biological effective dose (BED) was proposed. Three-parameter TCP models were generated for BCCs ≤2 cm, BCCs >2cm, cSCCs ≤2 cm, and cSCCs >2 cm. Equivalent fractionation schemes were estimated based on the TCP model and appropriate parameters.

Results

TCP model parameters for both BCC and cSCC for tumor sizes ≤2 cm and >2cm were obtained. For BCC, the model parameters were found to be TD50 = 56.62 ± 6.18 × 10-3 Gy, k = 0.14 ± 2.31 × 10−2 Gy−1 and L = 0.97 ± 4.99 × 10−3 and TD50 = 55.78 ± 0.19 Gy, k = 1.53 ± 0.20 Gy−1 and L = 0.94 ± 3.72 × 10−3 for tumor sizes of ≤2 cm and >2 cm, respectively. For SCC the model parameters were found to be TD50 = 56.81 ± 19.40 × 104 Gy, k = 0.13 ± 7.92 × 104 Gy−1 and L = 0.96 ± 1.31 × 10-2 and TD50 = 58.44 ± 0.30 Gy, k = 2.30 ± 0.43 Gy−1 and L = 0.91± 1.22 × 10−2 for tumors ≤2cm and >2 cm, respectively. The TCP model with the derived parameters predicts that radiation regimens with higher doses, such as increasing the number of fractions and/or dose per fraction, lead to higher TCP, especially for KCs >2 cm in size.

Conclusion

Four TCP models for primary KCs were developed based on pooled clinical data that may be used to further test the recommended kV and MV x-ray and electron RT regimens from the 2020 ASTRO guidelines. Increasing both number of fractions and dose per fraction may have clinically significant effects on tumor control for tumors >2 cm in size for both BCC and cSCC.
Complement C1q (C1qA, C1qB, and C1qC) May Be a Potential Prognostic Factor and an Index of Tumor Microenvironment Remodeling in Osteosarcoma
Authors: Chen Long-hao , Liu Jin-Fu , Lu Yan- , He Xin-yu , Zhang Chi- , Zhou Hong-hai
Published: May 2021

The tumor microenvironment (TME) has important effects on the tumorigenesis and development of osteosarcoma (OS). However, the dynamic mechanism regulating TME immune and matrix components remains unclear. In this study, we collected quantitative data on the gene expression of 88 OS samples from The Cancer Genome Atlas (TCGA) database and downloaded relevant clinical cases of OS from the TARGET database. The proportions of tumor-infiltrating immune cells (TICs) and the numbers of immune and matrix components were determined by CIBERSORT and ESTIMATE calculation methods. Protein-protein interaction (PPI) network construction and Cox regression analysis were conducted to analyze differentially expressed genes (DEGs). The complement components C1qA, C1qB and C1qC were then determined to be predictive factors through univariate Cox analysis and PPI cross analysis. Further analysis found that the levels of C1qA, C1qB and C1qC expression were positively linked to OS patient survival time and negatively correlated with the clinicopathological feature percent necrosis at definitive surgery. The results of gene set enrichment analysis (GSEA) demonstrated that genes related to immune functions were significantly enriched in the high C1qA, C1qB and C1qC expression groups. Proportion analysis of TICs by CIBERSORT showed that the levels of C1qA, C1qB and C1qC expression were positively related to M1 and M2 macrophages and CD8+ cells and negatively correlated with M0 macrophages. These results further support the influence of the levels of C1qA, C1qB and C1qC expression on the immune activity of the TME. Therefore, C1qA, C1qB and C1qC may be potential indicators of remodeling in the OS TME, which is helpful to predict the prognosis of patients with OS and provide new ideas for immunotherapy for OS.
An Approach to Accelerate Healing and Shorten the Hospital Stay of Patients With Anastomotic Leakage After Esophagectomy: An Explorative Study of Systematic Endoscopic Intervention
Authors: Zhong LeQi , Zhong JiuDi , Tan ZiHui , Wei YiTong , Su XiaoDong , Wen ZheSheng , Rong TieHua , Hu Yi , Luo KongJia
Published: May 2021

Objective

To explore the comprehensive role of systemic endoscopic intervention in healing esophageal anastomotic leak.

Methods

In total, 3919 consecutive patients with esophageal cancer who underwent esophagectomy and immediate esophageal reconstruction were screened. In total, 203 patients (5.10%) diagnosed with anastomotic leakage were included. The participants were divided into three groups according to differences in diagnosis and treatment procedures. Ninety-four patients received conventional management, 87 patients received endoscopic diagnosis only, and the remaining 22 patients received systematic endoscopic intervention. The primary endpoint was overall healing of the leak after oncologic esophageal surgery. The secondary endpoints were the time from surgery to recovery and the occurrence of adverse events.

Results

173 (85.2%; 95% CI, 80.3-90.1%) of the 203 patients were successfully healed, with a mean healing time of 66.04 ± 3.59 days (median: 51 days; range: 13-368 days), and the overall healing rates differed significantly among the three groups according to the stratified log-rank test (P<0.001). The median healing time of leakage was 37 days (95% CI: 33.32-40.68 days) in the endoscopic intervention group, 51 days (95% CI: 44.86-57.14 days) in the endoscopic diagnostic group, and 67 days (95% CI: 56.27-77.73 days) in the conventional group. The overall survival rate was 78.7% (95% CI: 70.3 to 87.2%) in the conventional management group, 89.7% (95% CI: 83.1 to 96.2%) in the endoscopic diagnostic group and 95.5% (95% CI: 86.0 to 100%) in the systematic endoscopic intervention group. Landmark analysis indicated that the speed of wound healing in the endoscopic intervention group was 2-4 times faster at any period than that in the conservative group. There were 20 (21.28%) deaths among the 94 patients in the conventional group, 9 (10.34%) deaths among the 87 patients in the endoscopic diagnostic group and 1 (4.55%) death among the 22 patients in the endoscopic intervention group; this difference was statistically significant (Fisher exact test, P < 0.05).

Conclusion

Tailored endoscopic treatment for postoperative esophageal anastomotic leakage based on endoscopic diagnosis is feasible and effective. Systematic endoscopic intervention shortened the treatment period and reduced mortality and should therefore be considered in the management of this disease.
Potential Impact of ALKBH5 and YTHDF1 on Tumor Immunity in Colon Adenocarcinoma
Authors: Yan Guanyu , An Yue , Xu Boyang , Wang Ningning , Sun Xuren , Sun Mingjun
Published: May 2021

Background

ALKBH5 and YTHDF1 are regarded as the eraser and reader, respectively, in N6-methyladenosine (m6A) modification. Recently, immune contexture has been drawing increasing attention in terms of the progression and treatment of cancers. This study aimed to determine the relationship between ALKBH5/YTHDF1 and immunological characteristics of colon adenocarcinoma (COAD).

Methods

Expression of ALKBH5 and YTHDF1 was investigated across TCGA and GEO validated in our study. Patients with COAD were divided into two clusters using consensus clustering based on the expression of ALKBH5 and YTHDF1. We then compared their clinical characteristics and performed gene set enrichment analysis (GSEA) to identify the functional differences. Immune infiltration analyses were conducted using ESTIMATE, CIBERSORT, and ssGSEA. In addition, we evaluated the expression of the targets of immune checkpoint inhibitors (ICIs) and calculated the tumor mutation burden (TMB) of the tumor samples. Weighted gene co-expression network analysis (WGCNA) was used to identify the genes related to both ALKBH5/YTHDF1 expression and immunity. GSE39582 was utilized for external validation of immunological features between the two clusters.

Results

Cluster 2 had high expression of ALKBH5 and lesser so of YTHDF1, whereas Cluster 1 had just the reverse. Cluster 1 had a higher N stage and pathological stage than Cluster 2. The latter had stronger immune infiltration, higher expression of targets of ICIs, more TMB, and a larger proportion of deficiency in mismatch repair-microsatellite instability-high (dMMR-MSI-H) status than Cluster 1. Moreover, WGCNA revealed 14 genes, including PD1 and LAG3, related to both the expression of ALKBH5/YTHDF1 and immune scores.

Conclusions

ALKBH5 and YTHDF1 influence immune contexture and can potentially transform cold tumors into hot tumors in patients with COAD.
miR-1258 Attenuates Tumorigenesis Through Targeting E2F1 to Inhibit PCNA and MMP2 Transcription in Glioblastoma
Authors: Qin Hongkun , Gui Yanping , Ma Rong , Zhang Heng , Guo Yabing , Ye Yuting , Li Jia , Zhao Li , Wang Yajing
Published: May 2021

MicroRNAs are a group of endogenous small non-coding RNAs commonly dysregulated in tumorigenesis, including glioblastoma (GBM), the most malignant brain tumor with rapid proliferation, diffuse invasion, and therapeutic resistance. Accumulating evidence has manifested that miR-1258 exerts an inhibitory role in many human cancers. However, the expression pattern of miR-1258 and its potential function in GBM tumorigenesis remain unclear. In this study, we reported that miR-1258 expression decreased with the ascending pathological grade of glioma, which indicated an unfavorable prognosis of patients. Functional assays revealed an inhibitory effect of miR-1258 on malignant proliferation, therapeutic resistance, migration, and invasion of GBM in vitro. Moreover, xenograft models also suggested a repression effect of miR-1258 on gliomagenesis. Mechanistically, miR-1258 directly targeted E2F1 in 3’-untranslated regions and attenuated E2F1-mediated downstream gene PCNA and MMP2 transcriptions. Furthermore, restoration of E2F1 expression in GBM cells effectively rescued the tumor-suppressive effect of miR-1258. Our studies illustrated that miR-1258 functioned as a tumor suppressor in GBM by directly targeting E2F1, subsequently inhibiting PCNA and MMP2 transcriptions, which contributed to new potential targets for GBM therapy and other E2F1-driven cancers.