bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: An Adult Patient With Deficiency of Adenosine Deaminase 2 Resembled Unilateral Frosted Branch Angiitis
Authors: Xu Yufeng , Shan Yi , Hu Yin , Cao Jing , Wang Yijie , Lou Lixia , Ye Panpan
Published: April 2021

Purpose: Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive systemic autoinflammatory disorder. We describe a rare case of an adult patient with DADA2 who presented with unilateral frosted branch angiitis (FBA) combined with branch retinal vein occlusion and panuveitis.

Method: This paper is a clinical case report.

Results: A 31-year-old male patient complained of blurred vision in his right eye for 2 days. His fundus examination showed FBA combined with branch retinal vein occlusion and panuveitis. He had a medical history of intermittent and recurrent fever, skin rash and aphthous ulcer for 5 years, and lacunar infarction for 1 month. Laboratory examinations showed hypogammaglobulinemia and mild prolonged activated partial thromboplastin time (APTT). Brain magnetic resonance imaging (MRI) revealed old lacunar infarction in the right basal ganglia and the lateral ventricle and fresh lacunar infarction in the right pons, respectively. The perivascular sheathing of FBA and macular edema were resolved after steroid administration and treatment of intravitreal anti-VEGF injection. During the period of follow-up, the patient subsequently suffered from recurrence of strokes, abnormality of coagulation function, sudden hearing loss of the left ear, and diplopia. His gene sequencing results demonstrated several deletion mutations in ADA2, and the diagnosis of DADA2 was eventually confirmed.

Conclusions: FBA represents a very rare ocular feature of DADA2 and may in some cases be the presenting manifestation. Therefore, ophthalmologists need to be aware of this rare autoinflammatory disease.
De novo Portal Vein Thrombosis in Non-Cirrhotic Non-Alcoholic Fatty Liver Disease: A 9-Year Prospective Cohort Study
Authors: Abdel-Razik Ahmed , Mousa Nasser , Shabana Walaa , Yassen Ahmed H. , Abdelsalam Mostafa , Wahba Mohamed M. , Helmy Eman Mohamed , Tawfik Ahmed M. , Zalata Khaled , Hasan Ahmad S. , Elhelaly Rania , Elzehery Rasha , Fathy Aya Ahmed , El-Wakeel Niveen , Eldars Waleed
Published: April 2021

Background and Aims: Approximately 30–40% of portal vein thrombosis (PVT) remains of unknown origin. The association between non-alcoholic fatty liver disease (NAFLD) and PVT is a matter of debate. This study aimed to investigate the association between PVT and NAFLD.

Methods: We included 94 out of 105 consecutive NAFLD patients in this prospective cohort study in addition to 94 from the healthy control group. We evaluated biochemical, clinical, immunological, and histopathological parameters; waist circumference (WC); leptin; adiponectin; and leptin/adiponectin ratio (LAR) for all participants at baseline and every 3 years thereafter. We described the characteristics of participants at baseline and showed individual WC, LAR, and PVT characteristics. Potential parameters to predict PVT development within 9 years were determined.

Results: PVT developed in eight (8.5%) patients, mainly in the portal trunk. Univariate analysis showed three PVT-associated factors: diabetes mellitus (P = 0.013), WC (P < 0.001), and LAR (P = 0.002). After adjusting multiple confounding variables, the multivariate model showed that the only significant variables were WC and LAR. By applying the receiver operating characteristic curve, WC had 98.8% specificity, 87.5% sensitivity, and 0.894 area under the curve (AUC) for prediction of PVT (P < 0.001) at cutoff values of > 105 cm. In comparison, LAR had 60.5% specificity, 87.5% sensitivity, and 0.805 AUC for PVT prediction (P < 0.001) at cutoff values of >7.5.

Conclusions: This study suggests that increased central obesity and LAR were independently associated with PVT development in non-cirrhotic NAFLD patients, and they should be considered risk factors that may participate in PVT multifactorial pathogenesis.
Adolescent and Young Adult ME/CFS After Confirmed or Probable COVID-19
Authors: Petracek Lindsay S. , Suskauer Stacy J. , Vickers Rebecca F. , Patel Neel R. , Violand Richard L. , Swope Renee L. , Rowe Peter C.
Published: April 2021

Introduction: Fatigue is a common acute symptom following SARS-CoV-2 infection (COVID-19). The presence of persistent fatigue and impaired daily physical and cognitive function has led to speculation that like SARS-CoV-1 infection, COVID-19 will be followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Methods and Results: We describe three adolescent and young adult patients who had confirmed or probable COVID-19 infections early on during the pandemic and were referred for evaluation to the Chronic Fatigue Clinic at the Johns Hopkins Children's Center. All patients reported orthostatic intolerance symptoms within the first 2 weeks of illness, and 10-min passive standing tests were consistent with postural tachycardia syndrome. After 6 months of illness, all three patients met criteria for ME/CFS. Clinical features of interest included strong histories of allergies in all three patients, two of whom had elevations in plasma histamine. Each demonstrated limitations in symptom-free range of motion of the limbs and spine and two presented with pathological Hoffman reflexes. These comorbid features have been reported in adolescents and young adults with ME/CFS.

Conclusion: ME/CFS can be triggered by COVID-19 in adolescents and young adults. Further work is needed to determine the pathogenesis of ME/CFS after COVID-19 and optimal methods of treating these patients. Our preliminary study calls attention to several comorbid features that deserve further attention as potential targets for intervention. These include neuromuscular limitations that could be treated with manual forms of therapy, orthostatic intolerance and POTS for which there are multiple medications and non-pharmacologic therapies, treatable allergic and mast cell phenomena, and neurologic abnormalities that may require specific treatment. Larger studies will need to ascertain the prevalence of these abnormalities.
Biocompatibility in Ternary Fermentations With Lachancea thermotolerans, Other Non-Saccharomyces and Saccharomyces cerevisiae to Control pH and Improve the Sensory Profile of Wines From Warm Areas
Authors: Vaquero Cristian , Loira Iris , Heras José María , Carrau Francisco , González Carmen , Morata Antonio
Published: April 2021

Global warming is causing serious problems, especially, in warm regions, where musts with excess sugars and high pH produce wines with decreased freshness and unstable evolution. This study aimed to determine biocompatibility between yeast species, the capacity for microbiological acidification, and the aromatic profile produced in ternary fermentations in whichLachancea thermotoleranshas been co-inoculated withHanseniaspora vineae,Torulaspora delbrueckii, orMetschnikowia pulcherrima, and the fermentation process is subsequently completed with sequential inoculation ofSaccharomyces cerevisiae. For this purpose, different cell culture media and instruments were used such as infrared spectroscopy, enzymatic autoanalyzer, chromatograph coupled with a flame ionization detector, spectrophotometric analysis, among others. The behavior of these yeasts was evaluated alone and in co-inoculation, always finishing the fermentation with sequential inoculation ofS. cerevisiae, at a stable temperature of 16°C and with a low level of sulfites (25 mg/L) in white must. Significant results were obtained in terms of biocompatibility using population counts (CFU/ml) in differential plating media that permitted monitoring. Quantification of the five species was studied. Concerning acidification byL. thermotoleransin co-inoculations, we showed some metabolic interactions, such as the inhibition of acidification whenH. vineae/L. thermotoleranswere used, generating just over 0.13 g/L of lactic acid and, conversely, a synergistic effect whenM. pulcherrima/L. thermotoleranswere used, achieving 3.2 g/L of lactic acid and a reduction in pH of up to 0.33. A diminution in alcohol content higher than 0.6% v/v was observed in co-inoculation with theL. thermotolerans/M. pulcherrimayeasts, with total sugar consumption and very slow completion of fermentation in the inoculations withH. vineaeandT. delbrueckii. The aromatic composition of the wines obtained was analyzed and a sensory evaluation conducted, and it was found that bothL. thermotoleransand co-inoculations retained more aromatic esters over time and had a lower evolution toward the yellow tones typical of oxidation and that the best sensory evaluation was that of the Lt + Mp co-inoculation.Lachancea thermotoleransand co-inoculations produced wines with low levels of volatile acidity (<0.4 g/L). This work shows that good consortia strategies with binary and ternary fermentations of yeast strains can be a powerful bio-tool for producing more complex wines.
Inhibitory Activity of Natural Synergetic Antimicrobial Consortia Against Salmonella enterica on Broiler Chicken Carcasses
Authors: Zhang Liya , Ben Said Laila , Diarra Moussa Sory , Fliss Ismail
Published: April 2021

The currently most utilized antimicrobial agent in poultry processing facilities is peracetic acid, a chemical increasingly recognized as hazardous to human health. We evaluated the efficacy of mixtures of natural antimicrobial compounds, namely reuterin, microcin J25, and lactic acid, for reducing the viability of Salmonella enterica and total aerobes on broiler chicken carcasses. The compounds were compared singly and in combination with water and 0.1% peracetic acid. The minimum inhibitory concentrations of reuterin, lactic acid, and microcin J25 against S. enterica serovar Enteritidis were respectively 2 mM, 0.31%, and 0.03 μM. In vitro, the combinations of reuterin + lactic acid and reuterin + microcin J25 were synergic, making these compounds effective at four times lower concentrations than those used alone. Salmonella viable counts fell to zero within 10 min of contact with reuterin + lactic acid at 10 times the concentrations used in combination, compared to 18 h in the case of reuterin + microcin J25. Sprayed onto chilled chicken carcasses, this reuterin + lactic acid mixture reduced Salmonella spp. counts by 2.02 Log CFU/g, whereas reuterin + microcin J25 and peracetic acid reduced them by respectively 0.83 and 1.13 Log CFU/g. The synergy of reuterin with lactic acid or microcin J25 as inhibitors of bacterial growth was significant. Applied as post-chill spray, these mixtures could contribute to food safety by decreasing Salmonella counts on chicken carcasses.
Characteristics of the Microbial Community in the Production of Chinese Rice-Flavor Baijiu and Comparisons With the Microflora of Other Flavors of Baijiu
Authors: Hu Yuanliang , Lei Xinyi , Zhang Xiaomin , Guan Tongwei , Wang Luyao , Zhang Zongjie , Yu Xiang , Tu Junming , Peng Nan , Liang Yunxiang , Zhao Shumiao
Published: April 2021

Rice-flavor baijiu is one of the four basic flavor types of Chinese baijiu. Microbial composition plays a key role in the classification of baijiu flavor types and the formation of flavor substances. In this study, we used high-throughput sequencing technology to study the changes of microbial community in the production of rice-flavor baijiu, and compared the microbial community characteristics during production of rice-, light-, and strong-flavor baijiu. The results showed that the species diversity of bacteria was much higher than that of fungi during the brewing of rice-flavor baijiu. The bacterial diversity index first increased and then decreased, while the diversity of fungi showed an increasing trend. A variety of major microorganisms came from the environment and raw rice materials; the core bacteria were Lactobacillus, Weissella, Pediococcus, Lactococcus, Acetobacter, etc., among which Lactobacillus was dominant (62.88–99.23%). The core fungi were Saccharomyces (7.06–83.50%) and Rhizopus (15.21–90.89%). Temperature and total acid content were the main physicochemical factors affecting the microbial composition. Non-metric multidimensional scaling analysis showed that during the fermentation of rice-, light-, and strong-flavor baijiu, their microbial communities formed their own distinct systems, with considerable differences among different flavor types. Compared with the other two flavor types of baijiu, in the brewing process of rice-flavor baijiu, microbial species were fewer and dominant microorganisms were prominent, which may be the main reason for the small variety of flavor substances in rice-flavor baijiu. This study provides a theoretical basis for the production of rice-flavor baijiu, and lays a foundation for studying the link between baijiu flavor formation and microorganisms.
Weighted Gene Co-expression Network Analysis Identifies CALD1 as a Biomarker Related to M2 Macrophages Infiltration in Stage III and IV Mismatch Repair-Proficient Colorectal Carcinoma
Authors: Zheng Hang , Bai Yuge , Wang Jingui , Chen Shanwen , Zhang Junling , Zhu Jing , Liu Yucun , Wang Xin
Published: April 2021

Immunotherapy has achieved efficacy for advanced colorectal cancer (CRC) patients with a mismatch-repair-deficient (dMMR) subtype. However, little immunotherapy efficacy was observed in patients with the mismatch repair-proficient (pMMR) subtype, and hence, identifying new immune therapeutic targets is imperative for those patients. In this study, transcriptome data of stage III/IV CRC patients were retrieved from the Gene Expression Omnibus database. The CIBERSORT algorithm was used to quantify immune cellular compositions, and the results revealed that M2 macrophage fractions were higher in pMMR patients as compared with those with the dMMR subtype; moreover, pMMR patients with higher M2 macrophage fractions experienced shorter overall survival (OS). Subsequently, weighted gene co-expression network analysis and protein–protein interaction network analysis identified six hub genes related to M2 macrophage infiltrations in pMMR CRC patients: CALD1, COL6A1, COL1A2, TIMP3, DCN, and SPARC. Univariate and multivariate Cox regression analyses then determined CALD1 as the independent prognostic biomarker for OS. CALD1 was upregulated specifically the in CMS4 CRC subtype, and single-sample Gene Set Enrichment Analysis (ssGSEA) revealed that CALD1 was significantly correlated with angiogenesis and TGF-β signaling gene sets enrichment scores in stage III/IV pMMR CRC samples. The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm and correlation analysis revealed that CALD1 was significantly associated with multiple immune and stromal components in a tumor microenvironment. In addition, GSEA demonstrated that high expression of CALD1 was significantly correlated with antigen processing and presentation, chemokine signaling, leukocyte transendothelial migration, vascular smooth muscle contraction, cytokine–cytokine receptor interaction, cell adhesion molecules, focal adhesion, MAPK, and TGF-beta signaling pathways. Furthermore, the proliferation, invasion, and migration abilities of cancer cells were suppressed after reducing CALD1 expression in CRC cell lines. Taken together, multiple bioinformatics analyses and cell-level assays demonstrated that CALD1 could serve as a prognostic biomarker and a prospective therapeutic target for stage III/IV pMMR CRCs.
The Emerging Role of RNA Modifications in DNA Double-Strand Break Repair
Authors: Jimeno Sonia , Balestra Fernando R. , Huertas Pablo
Published: April 2021

The correct repair of DNA double-strand breaks is essential for maintaining the stability of the genome, thus ensuring the survival and fitness of any living organism. Indeed, the repair of these lesions is a complicated affair, in which several pathways compete for the DNA ends in a complex balance. Thus, the fine-tuning of the DNA double-strand break repair pathway choice relies on the different regulatory layers that respond to environmental cues. Among those different tiers of regulation, RNA modifications have just emerged as a promising field.
Quantitative Assessment of Changes in Hemodynamics After Obliteration of Large Intracranial Carotid Aneurysms Using Computational Fluid Dynamics
Authors: Liu Yongsheng , Jiang Guinan , Wang Feng , An Xiangbo
Published: April 2021

Background: It was speculated that the alteration of the geometry of the artery might lead to hemodynamic changes of distal arteries. This study was to investigate the hemodynamic changes of distal arterial trees, and to identify the factors accounting for hyperperfusion after the obliteration of large intracranial aneurysms.

Methods: We retrospectively reviewed data of 12 patients with intracranial carotid aneurysms. Parametric models with intracranial carotid aneurysm were created. Patient-specific geometries were generated by three-dimensional rotational angiography. To mimic the arterial geometries after complete obliteration of the aneurysms, the aneurysms were virtually removed. The Navier–Stokes equations were solved using ANSYS CFX 14. The average wall shear stress, pressure and flow velocity were measured.

Results: Pressure ratio values were significantly higher in A1 segments, M1 segments, and M2 + M3 segments after obliteration of the aneurysms (p = 0.048 in A1 segments, p = 0.017 in M1 segments, p = 0.001 in M2 + M3 segments). Velocity ratio values were significantly higher in M1 segments and M2 + M3 segments after obliteration of the aneurysms (p = 0.047 in M1 segments, p = 0.046 in M2 + M3 segments). The percentage of pressure ratio increase after obliteration of aneurysms was significantly correlated with aneurysmal angle (r = 0.739, p = 0.006 for M2 + M3).

Conclusions: The pressure and flow velocity of distal arterial trees became higher after obliteration of aneurysms. The angle between the aneurysm and the parent artery was the factor accounting for pressure increase after treatment.
Effects of Vestibular Rehabilitation on Physical Activity and Subjective Dizziness in Patients With Chronic Peripheral Vestibular Disorders: A Six-Month Randomized Trial
Authors: Shiozaki Tomoyuki , Ito Taeko , Wada Yoshiro , Yamanaka Toshiaki , Kitahara Tadashi
Published: April 2021

Introduction:The present study aimed to determine whether supervised vestibular rehabilitation therapy (VRT) by physical therapists (PTs) affects subjective dizziness in patients with chronic vestibular disorders, and whether supervised VRT-induced changes in subjective dizziness are related to the changes in physical activity levels in daily life.

Methods:Patients (n= 47) with chronic peripheral vestibular disorders were randomly divided into the VRT group (n= 25) and control group (n= 22). Patients in the VRT group received weekly supervised visits from PTs for a period of 6 months. Every other month, both groups were advised by neuro-otologists to increase the amount of activity in their daily life. All patients wore an accelerometer device, which recorded their physical activity for seven successive days before the end of the intervention. Patients also completed the dizziness and unsteadiness questionnaires before and after the intervention.

Results:Subjective dizziness decreased significantly regardless of whether supervised VRT was administered; however, dizziness evoked by social activity and head and body movements improved more significantly in the VRT group than in the control group. In the VRT group, there was a significant negative correlation between the increase in sedentary behavior and improvement in subjective dizziness, and a significant positive correlation between the increase in light physical activity and improvement in subjective dizziness at the second month of intervention. The VRT group showed a significantly higher rate of increase in light physical activity than the control group, after 6 months of intervention.

Conclusion:Supervised VRT could be highly effective in treating subjective dizziness in patients with chronic peripheral vestibular disorders. We believe frequent (weekly) and medium-term (6 months) PT-guided interventions may be highly effective in enhancing physical activity in daily life, and may subsequently improve subjective dizziness in these patients.

Trial registration:This clinical study was registered with University hospital Medical Information Network (identification number: 000028832).https://www.umin.ac.jp/
Nosological Differences in the Nature of Punctate White Matter Lesions in Preterm Infants
Authors: Malova Mariya , Morelli Elena , Cardiello Valentina , Tortora Domenico , Severino Mariasavina , Calevo Maria Grazia , Parodi Alessandro , De Angelis Laura Costanza , Minghetti Diego , Rossi Andrea , Ramenghi Luca Antonio
Published: April 2021

Background: The pathogenesis of punctuate white matter lesions (PWMLs), a mild form of white matter damage observed in preterm infants, is still a matter of debate. Susceptibility-weighted imaging (SWI) allows to differentiate PWMLs based on the presence (SWI+) or absence (SWI–) of hemosiderin, but little is known about the significance of this distinction. This retrospective study aimed to compare neuroradiological and clinical characteristics of SWI+ and SWI– PWMLs.

Materials and Methods: MR images of all VLBW infants scanned consecutively at term-equivalent age between April 2012 and May 2018 were retrospectively reviewed, and infants with PWMLs defined as small areas of high T1 and/or low T2 signal in the periventricular white matter were selected and included in the study. Each lesion was analyzed separately and characterized by localization, organization pattern, and distance from the lateral ventricle. Clinical data were retrieved from the department database.

Results: A total of 517 PWMLs were registered in 81 patients, with 93 lesions (18%) visible on SWI (SWI+), revealing the presence of hemosiderin deposits. On univariate analysis, compared to SWI- PWML, SWI+ lesions were closer to the ventricle wall, more frequently organized in linear pattern and associated with lower birth weight, lower gestational age, lower admission temperature, need for intubation, bronchopulmonary dysplasia, retinopathy of prematurity, and presence of GMH-IVH. On multivariate analysis, closer distance to the ventricle wall on axial scan and lower birth weight were associated with visibility of PMWLs on SWI (p = 0.003 and p = 0.0001, respectively).

Conclusions: Our results suggest a nosological difference between SWI+ and SWI– PWMLs. Other prospective studies are warranted to corroborate these observations.
Contribution of Audiogram Classification in Evaluating Vestibular Dysfunction in Sudden Sensorineural Hearing Loss With Vertigo
Authors: Jiang Zhuang , Zhang Jiajia , Wang Ying , Huang Xuan , Yao Qingxiu , Feng Yanmei , Huang Shujian , Wang Hui , Yin Shankai
Published: April 2021

Object: We aimed to identify the relationship between vertigo symptoms and the involvement of vestibular dysfunction in sudden sensorineural hearing loss (SSNHL) and the contribution of audiogram classification.

Methods: A total of 50 patients with unilateral SSNHL were retrospectively divided into the vertigo group and non-vertigo group depending on the presence of vertigo. The involved vestibular end organs (VEOs) were verified by a battery of vestibular function tests including video head impulse test (vHIT), cervical vestibular-evoked myogenic potential (cVEMP), and ocular VEMP (oVEMP). The correlations of audiogram configurations, initial pure-tone average (PTA), number of involved VEOs, prognosis (complete recovery rate), and vestibular functions were analyzed between the two groups. Additionally, the vestibular functions in a subgroup of profound SSNHL patients were further compared within groups with or without vertigo.

Results: Significant differences in the initial audiogram configurations (p = 0.033) and the abnormal rates of the posterior semicircular canal (PSC) (p = 0.035) and oVEMP (p = 0.046) were found between the two groups. The number of involved VEOs was related to the initial PTA in the vertigo group (p = 0.002, r = 0.541) and non-vertigo group (p = 0.042, r = 0.446). The prognosis was related to the abnormal rate of cVEMP and the number of involved VEOs in both vertigo group (p = 0.008, r = 0.482; p = 0.039, r = 0.385, respectively) and non-vertigo group (p = 0.016, r = 0.520; p = 0.022, r = 0.495, respectively), and it was especially related to the audiogram configurations in the vertigo group (p < 0.001, r = 0.692). However, after classification by audiogram configurations, there was no statistical difference in the abnormal rates of all vestibular function tests or the number of involved VEOs between the profound SSNHL patients with or without vertigo.

Conclusion: The relationship between the involvement of vestibular dysfunction and vertigo symptoms in patients with SSNHL was significantly different before and after audiogram classification. When evaluating the vestibular dysfunction in SSNHL patients, more attention should be paid to the audiogram configuration.
A Set of Eight Key Questions Helps to Classify Common Vestibular Disorders—Results From the DizzyReg Patient Registry
Authors: Strobl Ralf , Grözinger Michael , Zwergal Andreas , Huppert Doreen , Filippopulos Filipp , Grill Eva
Published: April 2021

Precise history taking is the key to develop a first assumption on the diagnosis of vestibular disorders. Particularly in the primary care setting, algorithms are needed, which are based on a small number of questions and variables only to guide appropriate diagnostic decisions. The aim of this study is to identify a set of such key variables that can be used for preliminary classification of the most common vestibular disorders. A four-step approach was implemented to achieve this aim: (1) we conducted an online expert survey to collect variables that are meaningful for medical history taking, (2) we used qualitative content analysis to structure these variables, (3) we identified matching variables of the patient registry of the German Center for Vertigo and Balance Disorders, and (4) we used classification trees to build a classification model based on these identified variables and to analyze if and how these variables contribute to the classification of common vestibular disorders. We included a total of 1,066 patients with seven common vestibular disorders (mean age of 51.1 years, SD = 15.3, 56% female). Functional dizziness was the most frequent diagnosis (32.5%), followed by vestibular migraine (20.2%) and Menière's disease (13.3%). Using classification trees, we identified eight key variables which can differentiate the seven vestibular disorders with an accuracy of almost 50%. The key questions comprised attack duration, rotational vertigo, hearing problems, turning in bed as a trigger, doing sport or heavy household chores as a trigger, age, having problems with walking in the dark, and vomiting. The presented algorithm showed a high-face validity and can be helpful for taking initial medical history in patients with vertigo and dizziness. Further research is required to evaluate if the identified algorithm can be applied in the primary care setting and to evaluate its external validity.
Vestibular Function in Children and Adults Before and After Unilateral or Sequential Bilateral Cochlear Implantation
Authors: Guan Ruirui , Wang Yanqi , Wu Sasa , Zhang Bo , Sun Jingwu , Guo Xiaotao , Sun Jiaqiang
Published: April 2021

Background: Cochlear implantation (CI) helps patients with severe or profound sensorineural hearing loss (SNHL) restore hearing and speech abilities. However, some patients exhibit abnormal vestibular functions with symptoms such as dizziness or balance disorders, after CI. Whether age at CI and CI approach (unilateral or sequential bilateral) affect vestibular functions in users with cochlear implants remains unclear.

Objectives: To investigate the vestibular functions in children and adults before and after unilateral or sequential bilateral CI.

Materials and Methods: Thirty-seven patients with severe or profound SNHL who were candidates for a first- or second-side CI were divided into three groups: first-side CI-implanted adults (≥18 years), first-side CI-implanted children (6–17 years), and second-side CI-implanted children (6–17 years). All cases were implanted with the round window approach to minimize damage to the intra-cochlear structures. The caloric test, vestibular evoked myogenic potential (VEMP) test, video head impulse test (vHIT), Dizziness Handicap Inventory (DHI), Pediatric Vestibular Symptom Questionnaire (PVSQ), and audiometric tests were performed before and 1 month after CI.

Results: The abnormal rates of caloric test and VEMP test after CI in the first-side CI-implanted adults and children significantly increased compared with those before CI. The pre-implantation VEMP test showed significantly higher abnormal rates between first- and second-side CI-implanted children. No other significant differences of abnormal rates between first- and second-side CI-implanted children or between first-side CI-implanted adults and children were found. In second-side CI-implanted children, PVSQ scores significantly increased at day 3 post-implantation but decreased at day 30.

Conclusion: CI has a negative effect on the results of caloric and VEMP tests, but not on vHIT, indicating that the otolith and low-frequency semicircular canal (SCC) are more vulnerable to damage from CI. The alterations of vestibular functions resulting from CI surgery may be independent of age at CI and CI approach (unilateral or sequential bilateral). Long-term impacts on the vestibular function from CI surgery, as well as the chronic electrical stimulation to the cochlea, are still to be investigated.
Neuroimmune Interactions and Rhythmic Regulation of Innate Lymphoid Cells
Authors: Jacquelot Nicolas , Belz Gabrielle T. , Seillet Cyril
Published: April 2021

The Earth’s rotation around its axis, is one of the parameters that never changed since life emerged. Therefore, most of the organisms from the cyanobacteria to humans have conserved natural oscillations to regulate their physiology. These daily oscillations define the circadian rhythms that set the biological clock for almost all physiological processes of an organism. They allow the organisms to anticipate and respond behaviorally and physiologically to changes imposed by the day/night cycle. As other physiological systems, the immune system is also regulated by circadian rhythms and while diurnal variation in host immune responses to lethal infection have been observed for many decades, the underlying mechanisms that affect immune function and health have only just started to emerge. These oscillations are generated by the central clock in our brain, but neuroendocrine signals allow the synchronization of the clocks in peripheral tissues. In this review, we discuss how the neuroimmune interactions create a rhythmic activity of the innate lymphoid cells. We highlight how the disruption of these rhythmic regulations of immune cells can disturb homeostasis and lead to the development of chronic inflammation in murine models.
Prognostic Role of Blood Markers in Primary Central Nervous System Lymphoma Patients Treated With High-Dose Methotrexate-Based Therapy
Authors: Luo Qian , Yang Chunli , Fu Chunxi , Wu Wanchun , Wei Yi , Zou Liqun
Published: April 2021

Purpose: Primary central nervous system lymphoma (PCNSL) is a rare type of extra-nodal non-Hodgkin lymphoma, but the prognostic value of blood parameters indicating systemic inflammation and nutritional status remains unknown. We aim to explore the prognostic role of blood parameters in PCNSL.

Methods: All PCNSL patients diagnosed at West China Hospital between February 2011 and February 2020 were retrospectively screened. For patients who were initially treated with high-dose methotrexate (HD-MTX)-based therapy, clinical data were collected. Survival analyses were performed using the Kaplan–Meier method and multivariable Cox proportional regression. The accuracies of different multivariate models were assessed by Harrell's C statistical analysis (C-index).

Results: Sixty patients were included. Median overall survival (OS) was 4.8 ± 3.7 years, and median progression-free survival (PFS) was 1.9 ± 1.3 years. In the multivariate analysis, hemoglobin (Hb) (HR 3.940, p = 0.013), neutrophil–lymphocyte ratio (NLR) (HR 10.548, p = 0.034), and total bilirubin (TBIL) (HR 3.429, p = 0.004) had independent prognostic values for PFS, while lymphocyte–monocyte ratio (LMR) (HR 6.195, p = 0.039), systemic immune-inflammation index (SII) (HR 5.144, p = 0.012), and TBIL (HR 3.892, p = 0.009) were independently related to OS. The C-index of the Memorial Sloan-Kettering Cancer Center (MSKCC) score increased from 0.57 to 0.72 when SII and TBIL were combined.

Conclusions: Our study indicated that pretreatment Hb, NLR, SII, LMR, and TBIL were convenient prognostic factors in PCNSL. Adding SII and TBIL to the MSKCC score can better predict the survival of PCNSL based on HD-MTX regimens.
Brain Metastases from Esophageal Squamous Cell Carcinoma: Clinical Characteristics and Prognosis
Authors: Xiao Linlin , Mowery Yvonne M. , Czito Brian G. , Wu Yajing , Gao Guangbin , Zhai Chang , Wang Jianing , Wang Jun
Published: April 2021

Purpose

Due to the low incidence of intracranial disease among patients with esophageal cancer (EC), optimal management for these patients has not been established. The aim of this real-world study is to describe the clinical characteristics, treatment approaches, and outcomes for esophageal squamous cell carcinoma (ESCC) patients with brain metastases in order to provide a reference for treatment and associated outcomes of these patients.

Methods

Patients with ESCC treated at the Fourth Hospital of Hebei Medical University between January 1, 2009 and May 31,2020 were identified in an institutional tumor registry. Patients with brain metastases were included for further analysis and categorized by treatment received. Survival was evaluated by the Kaplan-Meier method and Cox proportional hazards models.

Results

Among 19,225 patients with ESCC, 66 (0.34%) were diagnosed with brain metastases. Five patients were treated with surgery, 40 patients were treated with radiotherapy, 10 with systemic therapy alone, and 15 with supportive care alone. The median follow-up time was 7.3 months (95% CI 7.4-11.4). At last follow-up, 59 patients are deceased and 7 patients are alive. Median overall survival (OS) from time of brain metastases diagnosis was 7.6 months (95% CI 5.3-9.9) for all cases. For patients who received locoregional treatment, median OS was 10.9 months (95% CI 7.4-14.3), and survival rates at 6 and 12 months were 75.6% and 37.2%, respectively. For patients without locoregional treatment, median OS was 3.0 months (95% CI 2.5-3.5), and survival rates at 6 and 12 months were 32% and 24%, respectively. OS was significantly improved for patients who received locoregional treatment compared to those treated with systematic treatment alone or supportive care (HR: 2.761, 95% CI 1.509-5.053, P=0.001). The median OS of patients with graded prognostic assessment (GPA) score 0-2 was 6.4 months, compared to median OS of 12.3 months for patients with GPA >2 (HR: 0.507, 95% CI 0.283-0.911).

Conclusion

Brain metastases are rare in patients with ESCC. GPA score maybe a useful prognostic tool for ESCC patients with brain metastases. Receipt of locoregional treatment including brain surgery and radiotherapy was associated with improved survival.
Young-Onset Carcinogenesis – The Potential Impact of Perinatal and Early Life Metabolic Influences on the Epigenome
Authors: Barreto Savio George , Pandol Stephen J.
Published: April 2021

The last decade has witnessed a significant rise in cancers in young adults. This spectrum of solid organ cancers occurring in individuals under the age of 40 years (some reports extending the age-group to <50 years) in whom aetiology of cancer cannot be traced back to pre-existing familial cancer syndromes, is referred to as termed young-, or early- onset cancers. The underlying causes for young-onset carcinogenesis have remained speculative. We recently proposed a hypothesis to explain the causation of this entity. We propose that the risk for young-onset cancer begins in the perinatal period as a result of the exposure of the foetus to stressors, including maternal malnutrition, smoking or alcohol, with the consequent epigenomic events triggered to help the foetus cope/adapt. Exposure to the same stressors, early in the life of that individual, facilitates a re-activation of these ‘responses designed to be protective’ but ultimately resulting in a loss of regulation at a metabolic and/or genetic level culminating in the evolution of the neoplastic process. In this manuscript, we will provide a rationale for this hypothesis and present evidence to further support it by clarifying the pathways involved, including elucidating a role for Acetyl-CoA and its effect on the epigenome. We present strategies and experimental models that can be used to test the hypothesis. We believe that a concerted effort by experts in different, but complementary fields, such as epidemiology, genetics, and epigenetics united towards the common goal of deciphering the underlying cause for young-onset cancers is the urgent need. Such efforts might serve to prove, or disprove, the presented hypothesis. However, the more important aim is to develop strategies to reverse the disturbing trend of the rise in young-onset cancers.
Epigenetic Regulation of Epithelial to Mesenchymal Transition in the Cancer Metastatic Cascade: Implications for Cancer Therapy
Authors: Liu Qiu-Luo , Luo Maochao , Huang Canhua , Chen Hai-Ning , Zhou Zong-Guang
Published: April 2021

Metastasis is the end stage of cancer progression and the direct cause of most cancer-related deaths. The spreading of cancer cells from the primary site to distant organs is a multistep process known as the metastatic cascade, including local invasion, intravasation, survival in the circulation, extravasation, and colonization. Each of these steps is driven by the acquisition of genetic and/or epigenetic alterations within cancer cells, leading to subsequent transformation of metastatic cells. Epithelial–mesenchymal transition (EMT), a cellular process mediating the conversion of cell from epithelial to mesenchymal phenotype, and its reverse transformation, termed mesenchymal–epithelial transition (MET), together endow metastatic cells with traits needed to generate overt metastases in different scenarios. The dynamic shift between these two phenotypes and their transitional state, termed partial EMT, emphasizes the plasticity of EMT. Recent advances attributed this plasticity to epigenetic regulation, which has implications for the therapeutic targeting of cancer metastasis. In this review, we will discuss the association between epigenetic events and the multifaceted nature of EMT, which may provide insights into the steps of the cancer metastatic cascade.
Establishment and Verification of a Predictive Model for Node Pathological Complete Response After Neoadjuvant Chemotherapy for Initial Node Positive Early Breast Cancer
Authors: Zhu Jiujun , Jiao Dechuang , Yan Min , Chen Xiuchun , Wang Chengzheng , Lu Zhenduo , Li Lianfang , Sun Xianfu , Qin Li , Guo Xuhui , Zhang Chongjian , Qiao Jianghua , Li Jianbin , Fan Zhimin , Wang Haibo , Zhang Jianguo , Yin Yongmei , Fu Peifen , Geng Cuizhi , Jin Feng , Jiang Zefei , Cui Shude , Liu Zhenzhen
Published: April 2021

Objective

Axillary node status after neoadjuvant chemotherapy (NCT) in early breast cancer patients influences the axillary surgical staging procedure. This study was conducted for the identification of the likelihood of patients being node pathological complete response (pCR) post NCT. We aimed to recognize patients most likely to benefit from sentinel lymph node biopsy (SLNB) following NCT and to reduce the risk of missed detection of positive lymph nodes through the construction and validation of a clinical preoperative scoring prediction model.

Methods

The existing data (from March 2010 to December 2018) of the Chinese Society of Clinical Oncology Breast Cancer Database (CSCO-BC) was used to evaluate the independent related factors of node pCR after NCT by Binary Logistic Regression analysis. A predictive model was established according to the score of considerable factors to identify ypN0. Model performance was confirmed in a cohort of NCT patients treated between January 2019 and December 2019 in Henan Cancer Hospital, and model discrimination was evaluated via assessing the area under the receiver operating characteristic (ROC) curve (AUC).

Results

Multivariate regression analysis showed that the node stage before chemotherapy, the expression level of Ki-67, biologic subtype, and breast pCR were all independent related factors of ypN0 after chemotherapy. According to the transformation and summation of odds ratio (OR) values of each variable, the scoring system model was constructed with a total score of 1–5. The AUC for the ROC curves was 0.715 and 0.770 for the training and the validation set accordingly.

Conclusions

A model was established and verified for predicting ypN0 after chemotherapy in newly diagnosed cN+ patients and the model had good accuracy and efficacy. The underlined effective model can suggest axillary surgical planning, and reduce the risk of missing positive lymph nodes by SLNB after NCT. It has great value for identifying initial cN+ patients who are more appropriate for SLNB post-chemotherapy.
Hippo Pathway Core Genes Based Prognostic Signature and Immune Infiltration Patterns in Lung Squamous Cell Carcinoma
Authors: Gu Chang , Chen Jiafei , Dang Xuening , Chen Chunji , Huang Zhenyu , Shen Weidong , Shi Xin , Dai Chenyang , Chen Chang
Published: April 2021

Background

We investigated the prognostic effects and their patterns of immune infiltration of hippo pathway core genes in lung squamous cell carcinoma, in order to find some clues for underlying mechanisms of LUSC tumorigenesis and help developing new therapeutic methods.

Methods

The mutational data, transcriptome data and corresponding clinical medical information of LUSC patients were extracted from The Cancer Genome Atlas (TCGA) database. Differential expression genes (DEGs) and Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were explored. Survival analysis for the hippo core genes and the prognostic model were performed. Immune infiltration was estimated by CIBERSORT algorithm and some immune checkpoints-related genes were further investigated.

Results

Overall, 551 LUSC samples were included in our study, consisting of 502 LUSC tumor samples and 49 adjacent normal samples, respectively. There were 1910 up-regulated DEGs and 2253 down-regulated DEGs were finally identified. The top five mutational hippo pathway core genes were LATS1 (4%), WWC1 (2%), TAOK1 (2%), TAOK3 (2%), and TAOK2 (2%), respectively. the mutation of LATS2 was highly associated with co-mutational NF2 (P <0.05) and TAOK1 (P <0.05). In survival analyses, we found only WWC1 (log-rank p = 0.046, HR = 1.32, 95% CI = 1–1.73) and LATS2 (log-rank p = 0.013, HR = 1.41, 95%CI = 1.08–1.86) had significant prognostic roles. After getting the three subgroups according to the subtyping results, we demonstrated that T cell gamma delta (p = 5.78e-6), B cell memory (p = 4.61e-4) and T cell CD4+ memory resting (p = 2.65e-5) had significant differences among the three groups. SIGLEC15 (P <0.01) and CD274 (P <0.05) also had statistical differences among the three subgroups.

Conclusions

Our study verified the prognostic roles of WWC1 and LATS2 in LUSC patients. Immune checkpoints-related genes SIGLEC15 and CD274 had statistical differences among the three subgroups, which may provide new perceptions on the molecular mechanisms in LUSC and maybe helpful for precisely selecting specific LUSC patients with potential immunotherapy benefits.
Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus
Authors: Liao Panli , Xiang Tianchao , Li Hongxia , Fang Ye , Fang Xiaoyan , Zhang Zhiqing , Cao Qi , Zhai Yihui , Chen Jing , Xu Linan , Liu Jialu , Tang Xiaoshan , Liu Xiaorong , Wang Xiaowen , Luan Jiangwei , Shen Qian , Chen Lizhi , Jiang Xiaoyun , Ma Duan , Xu Hong , Rao Jia
Published: April 2021

Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. We utilized a multicenter strategy to investigate the genotype and phenotype in a cohort of Chinese children clinically diagnosed with NDI from 2014 to 2019. Ten boys from nine families were identified with mutations in AVPR2 or AQP2 along with dehydration, polyuria–polydipsia, and severe hypernatremia. Genetic screening confirmed the diagnosis of seven additional relatives with partial or subclinical NDI. Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane region of AVPR2 and an enrichment of diagnostic mutations in the C-terminal region of AQP2. The pathogenic variants are significantly more likely to be located inside the domain compared with population variants. Through the structural analysis and in silico prediction, the eight mutations identified in this study were presumed to be disease-causing. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment for hypernatremia dehydration in neonates should not use isotonic saline as a rehydration fluid. Genetic analysis presumably confirmed the diagnosis of NDI in each patient in our study. We outlined methods for the early identification of NDI through phenotype and genotype, and outlined optimized treatment strategies.
miRNAs and Leukotrienes in Respiratory Syncytial Virus Infection
Authors: Liu Zhi , Fan Panpan , Chen Ming , Xu Yueshi , Zhao Dongchi
Published: April 2021

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate posttranscription by binding to 3′-untranslated regions of target mRNAs. Recent functional studies have elucidated mechanisms that miRNAs regulate leukotriene synthesis by perturbing arachidonic acid metabolism. Both microarrays and high-throughput sequencing revealed distinct differential expression of miRNAs in children with respiratory syncytial virus (RSV) infection compared with healthy controls. Abnormal miRNA expression may contribute to higher leukotriene levels, which is associated with airway hyperreactivity. Targeting miRNAs may benefit to restore the homeostasis of inflammatory reaction and provide new strategies to alleviate airway hyperreactivity induced by RSV. In this article, we provide an overview of the current knowledge about miRNAs modulating leukotrienes through regulation of arachidonic acid metabolism with a special focus on miRNAs aberrantly expressed in children with RSV infection.