bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of a Harmonized Enzyme-Linked-Lectin-Assay (ELLA-NI) Based Neuraminidase Inhibition Assay Standard Operating Procedure (SOP) for Quantification of N1 Influenza Antibodies and the Use of a Calibrator to Improve the Reproducibility of the ELLA-NI With Reverse Genetics Viral and Recombinant Neuraminidase Antigens: A FLUCOP Collaborative Study
Authors: Bernard Marie-Clotilde , Waldock Joanna , Commandeur Sylvie , Strauß Lea , Trombetta Claudia Maria , Marchi Serena , Zhou Fan , van de Witte Serge , van Amsterdam Peter , Ho Sammy , Hoschler Katja , Lugovtsev Vladimir , Weir Jerry P. , Montomoli Emanuele , Cox Rebecca J. , Engelhardt Othmar G. , Friel Damien , Wagner Ralf , Ollinger Thierry , Germain Sophie , Sediri-Schön Hanna
Published: June 2022

Current vaccination strategies against influenza focus on generating an antibody response against the viral haemagglutination surface protein, however there is increasing interest in neuraminidase (NA) as a target for vaccine development. A critical tool for development of vaccines that target NA or include an NA component is available validated serology assays for quantifying anti-NA antibodies. Additionally serology assays have a critical role in defining correlates of protection in vaccine development and licensure. Standardisation of these assays is important for consistent and accurate results. In this study we first validated a harmonized enzyme-linked lectin assay (ELLA)- Neuraminidase Inhibition (NI) SOP for N1 influenza antigen and demonstrated the assay was precise, linear, specific and robust within classical acceptance criteria for neutralization assays for vaccine testing. Secondly we tested this SOP with NA from influenza B viruses and showed the assay performed consistently with both influenza A and B antigens. Third, we demonstrated that recombinant NA (rNA) could be used as a source of antigen in ELLA-NI. In addition to validating a harmonized SOP we finally demonstrated a clear improvement in inter-laboratory agreement across several studies by using a calibrator. Importantly we showed that the use of a calibrator significantly improved agreement when using different sources of antigen in ELLA-NI, namely reverse genetics viruses and recombinant NA. We provide a freely available and detailed harmonized SOP for ELLA-NI. Our results add to the growing body of evidence in support of developing biological standards for influenza serology.
Human Testicular Germ Cells, a Reservoir for Zika Virus, Lack Antiviral Response Upon Zika or Poly(I:C) Exposure
Authors: Kuassivi Ohiniba Nadège , Abiven Hervé , Satie Anne-Pascale , Cartron Matéo , Mahé Dominique , Aubry Florence , Mathieu Romain , Rebours Valérie , Le Tortorec Anna , Dejucq-Rainsford Nathalie
Published: June 2022

Zika virus (ZIKV) is an emerging teratogenic arbovirus that persists in semen and is sexually transmitted. We previously demonstrated that ZIKV infects the human testis and persists in testicular germ cells (TGCs) for several months after patients’ recovery. To decipher the mechanisms underlying prolonged ZIKV replication in TGCs, we compared the innate immune response of human testis explants and isolated TGCs to ZIKV and to Poly(I:C), a viral RNA analog. Our results demonstrate the weak innate responses of human testis to both ZIKV and Poly(I:C) as compared with other tissues or species. TGCs failed to up-regulate antiviral effectors and type I IFN upon ZIKV or Poly(I:C) stimulation, which might be due to a tight control of PRR signaling, as evidenced by the absence of activation of the downstream effector IRF3 and elevated expression of repressors. Importantly, exogenous IFNβ boosted the innate immunity of TGCs and inhibited ZIKV replication in the testis ex vivo, raising hopes for the prevention of ZIKV infection and persistence in this organ.
Z-RNA and the Flipside of the SARS Nsp13 Helicase: Is There a Role for Flipons in Coronavirus-Induced Pathology?
Authors: Herbert Alan , Poptsova Maria
Published: June 2022

We present evidence suggesting that the severe acute respiratory syndrome (SARS) coronavirus non-structural protein 13 (Nsp13) modulates the Z-RNA dependent regulated cell death pathways . We show that Z-prone sequences [called flipons] exist in coronavirus and provide a signature (Z-sig) that enables identification of the animal viruses from which the human pathogens arose. We also identify a potential RIP Homology Interaction Motif (RHIM) in the helicase Nsp13 that resembles those present in proteins that initiate Z-RNA-dependent cell death through interactions with the Z-RNA sensor protein ZBP1. These two observations allow us to suggest a model in which Nsp13 down regulates Z-RNA activated innate immunity by two distinct mechanisms. The first involves a novel ATP-independent Z-flipon helicase (flipase) activity in Nsp13 that differs from that of canonical A-RNA helicases. This flipase prevents formation of Z-RNAs that would otherwise activate cell death pathways. The second mechanism likely inhibits the interactions between ZBP1 and the Receptor Interacting Proteins Kinases RIPK1 and RIPK3 by targeting their RHIM domains. Together the described Nsp13 RHIM and flipase activities have the potential to alter the host response to coronaviruses and impact the design of drugs targeting the Nsp13 protein. The Z-sig and RHIM domains may provide a way of identifying previously uncharacterized viruses that are potentially pathogenic for humans.
Metabolic Syndrome in Psoriasis Is Associated With Upregulation of CXCL16 on Monocytes and a Dysbalance in Innate Lymphoid Cells
Authors: Schielke Lisa , Zimmermann Nick , Hobelsberger Sarah , Steininger Julian , Strunk Anne , Blau Kristin , Hernandez Jessica , Künzel Stephan , Ziegenbalg Robert , Rösing Sarah , Beissert Stefan , Abraham Susanne , Günther Claudia
Published: June 2022

Psoriasis is frequently associated with the metabolic syndrome and occurs more often in obese individuals. In order to understand innate immune mechanisms mediating this inflammatory pattern we investigated expression of the chemokine and lipid scavenger receptor CXCL16 in patients with psoriasis and associated comorbidities. CXCL16 expression was enhanced on all monocyte subsets in psoriatic patients compared with healthy controls and positively correlated with psoriasis activity and severity index, body mass index and the risk for cardiovascular disease indicated by PROCAM score. The intensity of CXCL16 expression on monocytes further correlated with their capability to phagocytose oxidized LDL indicating the possibility to transform into foam cells in atherosclerotic plaques. Patients with psoriasis and atherosclerosis or obesity displayed elevated numbers of innate lymphoid cells in blood with specific increase of the IFN-γ or IL-17 producing ILC1 and ILC3 subpopulations. The expression of the CXCL16 receptor, CXCR6, was increased in ILCs and co-expressed with CCR6 but not CCR7 indicating their migratory potential to psoriatic skin or adipose tissue that is characterized by strong CXCL16 and CCL20 expression. This hypothesis was supported by the finding that the percentage of CXCR6 expressing ILCs was alleviated in blood of psoriatic patients. Together these data link a strong expression of CXCL16 to metabolic syndrome in psoriasis and indicate a possible link to ILC activation and tissue distribution in obese psoriatic patients. These data contribute to the understanding of the complex interaction of innate immunity and metabolic state in psoriasis.
Vγ2 x PD-L1, a Bispecific Antibody Targeting Both the Vγ2 TCR and PD-L1, Improves the Anti-Tumor Response of Vγ2Vδ2 T Cell
Authors: Yang Rui , He Qing , Zhou Hui , Gong Cheng , Wang Xing , Song Xingpan , Luo Fang , Lei Yang , Ni Qian , Wang Zili , Xu Shasha , Xue Yan , Zhang Man , Wen Haimei , Fang Lijuan , Zeng Liang , Yan Yongxiang , Shi Jian , Zhang Jing , Yi Jizu , Zhou Pengfei
Published: June 2022

The potent cytotoxic property of Vγ2Vδ2 T cells makes them attractive for adoptive T cell transfer therapy. The transfusing of the expanded Vγ2Vδ2 T cells into cancer patients shows well-tolerated, but the clinical response rates are required to be improved, implying that there is still an unmet efficacy with low toxicity for this novel anti-tumor therapy. In this study, we test the anti-tumor efficacy of a Y-body-based bispecific antibody (bsAb) Vγ2 x PD-L1 that preferentially redirects Vγ2Vδ2 T cells to combat PD-L1 positive tumor cells. With nanomolar affinity levels to Vγ2Vδ2 T cells and PD-L1+ tumor cells, Vγ2 x PD-L1 bridges a Vγ2Vδ2 T cell with a SKOV3 tumor cell to form a cell-to-cell conjugation. In a PD-L1-dependent manner, the bsAb elicits effective activation (CD25+CD69+), IFNγ releasing, degranulation (CD107a+), and cytokine production (IFNγ+ and TNFα+) of expanded Vγ2Vδ2 T cells. The activations of the Vγ2Vδ2 T cells eliminate PD-L1-expressing human cancer cell lines, including H1975, SKOV3, A375, H1299, and H2228 cells, but not PD-L1 negative cells including HEK-293 (293) cells and healthy PBMCs. Finally, we show that combining Vγ2 x PD-L1 with adoptively transferring Vγ2Vδ2 T cells inhibits the growth of existing tumor xenografts and increases the number of Vγ2Vδ2 T cells into the tumor bed. Vγ2 x PD-L1 represents a promising reagent for increasing the efficacy of adoptively transferred Vγ2Vδ2 T cells in the treatment of PD-L1 positive malignant tumors.
Viral Circular RNAs and Their Possible Roles in Virus-Host Interaction
Authors: Zhang Xing , Liang Zi , Wang Chonglong , Shen Zeen , Sun Sufei , Gong Chengliang , Hu Xiaolong
Published: June 2022

Circular RNAs (circRNAs) as novel regulatory molecules have been recognized in diverse species, including viruses. The virus-derived circRNAs play various roles in the host biological process and the life cycle of the viruses. This review summarized the circRNAs from the DNA and RNA viruses and discussed the biogenesis of viral and host circRNAs, the potential roles of viral circRNAs, and their future perspective. This review will elaborate on new insights gained on viruses encoded circRNAs during virus infection.
Changes in the Blood Viscosity in Patients With SARS-CoV-2 Infection
Authors: Al-kuraishy Hayder M. , Al-Gareeb Ali I. , Al-Hamash Sadiq M. , Cavalu Simona , El-Bouseary Maisra M. , Sonbol Fatma I. , Batiha Gaber El-Saber
Published: June 2022

Coronavirus disease 2019 (COVID-19) is caused by a novel virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2-induced hyperinflammation together with alteration of plasma proteins, erythrocyte deformability, and platelet activation, may affect blood viscosity. Thus, this review aimed to study the link between SARS-CoV-2 infection and alteration of blood viscosity in COVID-19 patients. In order to review findings related to hyperviscosity in COVID-19, we suggested a protocol for narrative review of related published COVID-19 articles. Hyperviscosity syndrome is developed in different hematological disorders including multiple myeloma, sickle cell anemia, Waldenstorm macroglobulinemia, polycythemia, and leukemia. In COVID-19, SARS-CoV-2 may affect erythrocyte morphology via binding of membrane cluster of differentiation 147 (CD147) receptors, and B and 3 proteins on the erythrocyte membrane. Variations in erythrocyte fragility and deformability with endothelial dysfunction and oxidative stress in SARS-CoV-2 infection may cause hyperviscosity syndrome in COVID-19. Of interest, hyperviscosity syndrome in COVID-19 may cause poor tissue perfusion, peripheral vascular resistance, and thrombosis. Most of the COVID-19 patients with a blood viscosity more than 3.5 cp may develop coagulation disorders. Of interest, hyperviscosity syndrome is more commonly developed in vaccine recipients who had formerly received the COVID-19 vaccine due to higher underlying immunoglobulin concentrations, and only infrequently in those who have not received the COVID-19 vaccine. Taken together, these observations are untimely too early to give a final connotation between COVID-19 vaccination and the risk for development of hyperviscosity syndrome, consequently prospective and retrospective studies are necessary in this regard.
Uterine Cavity Parameters Evaluated by Hysteroscopy can Predict the Live Birth Rate For Intrauterine Adhesion Patients
Authors: Zhao Xingping , Sun Dan , Zhang Aiqian , Huang Huan , Zhu Xiuting , Yi Shuijing , Xu Dabao
Published: June 2022

We aim to establish an objective and accurate prediction model by evaluating the uterine cavity and correlate these key factors with the live birth rate after hysteroscopic adhesiolysis (HA). A total of 457 intrauterine adhesions (IUA) patients were retrospectively enrolled in this study. The participants underwent HA and second-look hysteroscopy at the Third Xiangya Hospital of Central South University. Pregnancy outcomes, including spontaneous live births and no live births (miscarriages and infertility), were followed. Clinical parameters, containing the number of visible uterine horns and tubal ostia, the length of the uterine cavity, among others, were measured and analyzed to determine the dominant variables in an attempt to establish the live birth rate, prediction models. Women in the no live birth group were older than that in the live birth group (P = 0.0002, OR = 0.895, 95% CI: 0.844–0.949) and were more likely to be 2 gravidity (P = 0.0136, OR = 2.558, 95% CI: 1.213–5.394). Uterine cavity length in pre-HA hysteroscopy was longer in the live birth group (P = 0.0018, OR = 1.735, 95% CI: 1.227–2.453), and adhesion scores in pre-HA hysteroscopy were more frequently above 6 (P = 0.0252, OR = 0.286, 95% CI: 0.096–0.856) in the no live birth group. During the second-look, hysteroscopy, visible bilateral fallopian tube ostia were more frequently observed in the live birth group (P = 0.0339, OR = 11.76, 95% CI: 1.207–114.611), and adhesion scores were 4–6 (P < 0.0001, OR = 0.032, 95% CI: 0.007–0.146) and above 6 (P < 0.0001, OR = 0.012, 95% CI: 0.002–0.073) in the no live birth group. The areas under the curves (AUCs) of the pre-HA and second-look hysteroscopy prediction models were 0.7552 and 0.8484, respectively. We established an objective and accurate method for evaluating the uterine cavity by hysteroscopy, and second-look hysteroscopy is more valuable than the fist hysteroscopy in predicting the live birth rate following HA. Visible bilateral fallopian tube ostia or adhesion scores were <4 in the second-look hysteroscopy might predict live birth after surgery.
Clinical Characteristics and Risk Factors for Evisceration in Trauma-Dominant Orbital Cellulitis: A 10-Year Review
Authors: Jiang Zhaoxin , Zhongliu Xueying , Ding Xiaohu , Yang Yao , Duan Fang , Lin Xiaofeng
Published: June 2022

Purpose

To analyze the clinical characteristics of trauma-dominant orbital cellulitis (OC) and evaluate the risk factors associated with evisceration.

Methods

This retrospective study included inpatients diagnosed with orbital cellulitis at the Zhongshan Ophthalmic Center between January 2010 and December 2020. The demographic features, etiology, clinical characteristics, microbiological isolates, and risk factors associated with evisceration were analyzed.

Results

Among 148 consecutive subjects (n = 148, 148 eyes), the mean age was 42.07 ± 20.35 years and 70.27% were male. Penetrating globe injuries were the most common (52.03%). No light perception (NLP) was recorded in 50% of patients on admission. Endophthalmitis was observed in 103 cases (69.59%), intraocular foreign bodies (IOFB) were detected in 43 cases (29.05%), and total corneal melting was observed in 31 cases (20.95%). Sixty patients (40.54%) underwent evisceration. Logistic regression analysis showed that total corneal dissolution [odds ratio (OR) = 83.019, P = 0.000], IOFB (OR = 3.402, P = 0.016), and NLP (OR = 0.185, P = 0.001) were risk factors for evisceration. Microorganism detection showed that Pseudomonas aeruginosa and Bacillus cereus were the leading pathogens.

Conclusion

Among hospitalized trauma-dominant OC patients, middle-aged men were the major subjects and penetrating globe injury was the major cause. Significant complications such as complete visual loss and evisceration were unavoidable in many patients with OC in the current study. NLP, IOFB, and total corneal melting were the risk factors for evisceration.
Biofilm Formation and Antimicrobial Susceptibility of E. coli Associated With Colibacillosis Outbreaks in Broiler Chickens From Saskatchewan
Authors: Sivaranjani Murugesan , McCarthy Madeline C. , Sniatynski Michelle K. , Wu Linzhi , Dillon Jo-Anne R. , Rubin Joseph E. , White Aaron P.
Published: June 2022

The global poultry industry has grown to the extent that the number of chickens now well exceeds the number of humans on Earth. Escherichia coli infections in poultry cause significant morbidity and economic losses for producers each year. We obtained 94 E. coli isolates from 12 colibacillosis outbreaks on Saskatchewan farms and screened them for antimicrobial resistance and biofilm formation. Fifty-six isolates were from broilers with confirmed colibacillosis, and 38 isolates were from healthy broilers in the same flocks (cecal E. coli). Resistance to penicillins, tetracyclines, and aminoglycosides was common in isolates from all 12 outbreaks, while cephalosporin resistance varied by outbreak. Most E. coli were able to form biofilms in at least one of three growth media (1/2 TSB, M63, and BHI broth). There was an overall trend that disease-causing E. coli had more antibiotic resistance and were more likely to form biofilms in nutrient-rich media (BHI) as compared to cecal strains. However, on an individual strain basis, there was no correlation between antimicrobial resistance and biofilm formation. The 21 strongest biofilm forming strains consisted of both disease-causing and cecal isolates that were either drug resistant or susceptible. Draft whole genome sequencing indicated that many known antimicrobial resistance genes were present on plasmids, with disease-causing E. coli having more plasmids on average than their cecal counterparts. We tested four common disinfectants for their ability to kill 12 of the best biofilm forming strains. All disinfectants killed single cells effectively, but biofilm cells were more resistant, although the difference was less pronounced for the disinfectants that have multiple modes of action. Our results indicate that there is significant diversity and complexity in E. coli poultry isolates, with different lifestyle pressures affecting disease-causing and cecal isolates.
In vivo Trial of Bifidobacterium longum Revealed the Complex Network Correlations Between Gut Microbiota and Health Promotional Effects
Authors: Kim You-Tae , Kim Chul-Hong , Kwon Joon-Gi , Cho Jae Hyoung , Shin Young-Sup , Kim Hyeun Bum , Lee Ju-Hoon
Published: June 2022

Complete genome sequence analysis ofBifidobacterium longumsubsp.longumBCBL-583 isolated from a Korean female fecal sample showed no virulence factor or antibiotic resistance gene, suggesting human safety. In addition, this strain has oxygen and heat tolerance genes for food processing, and cholesterol reduction and mucin adhesion-related genes were also found. Forin vivoevaluations, a high fat diet (HFD) mouse model was used, showing that BCBL-583 administration to the model (HFD-583) reduced the total cholesterol and LDL-cholesterol in the blood and decreased pro-inflammatory cytokines but increased anti-inflammatory cytokines, substantiating its cholesterol reduction and anti-inflammation activities. Subsequent microbiome analysis of the fecal samples from the HFD mouse model revealed that BCBL-583 administration changed the composition of gut microbiota. After 9 weeks feeding of bifidobacteria, Firmicutes, Actinobacteria, and Bacteroidetes increased, but Proteobacteria maintained in the HFD mouse models. Further comparative species-level compositional analysis revealed the inhibitions of cholesterol reduction-relatedEubacterium coprostanoligenesand obesity-relatedLactococcusby the supplementation ofB. longumBCBL-583, suggesting its possible cholesterol reduction and anti-obesity activities. The correlation analysis of HFD-583 between the gut microbiota compositional change and cholesterol/immune response showed that Verrucomicrobia, Firmicutes, Actinobacteria, and Bacteroidetes may play an important role in cholesterol reduction and anti-inflammation. However, correlation analysis of Proteobacteria showed the reverse correlation in HFD-583. Interestingly, the correlation analysis ofB. longumATCC 15707 administration to HFD model showed similar patterns of cholesterol but different in immune response patterns. Therefore, this correlation analysis suggests that the microbial composition and inflammatory cytokine/total-cholesterol may be closely related in the administration of BCBL-583 in the HFD mice group. Consequently, BCBL-583 could be a good probiotic strain for gut health promotion through gut microbiota modulation.
Comparison of Conventional Logistic Regression and Machine Learning Methods for Predicting Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Multicentric Observational Cohort Study
Authors: Hu Ping , Li Yuntao , Liu Yangfan , Guo Geng , Gao Xu , Su Zhongzhou , Wang Long , Deng Gang , Yang Shuang , Qi Yangzhi , Xu Yang , Ye Liguo , Sun Qian , Nie Xiaohu , Sun Yanqi , Li Mingchang , Zhang Hongbo , Chen Qianxue
Published: June 2022

Background

Timely and accurate prediction of delayed cerebral ischemia is critical for improving the prognosis of patients with aneurysmal subarachnoid hemorrhage. Machine learning (ML) algorithms are increasingly regarded as having a higher prediction power than conventional logistic regression (LR). This study aims to construct LR and ML models and compare their prediction power on delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH).

Methods

This was a multicenter, retrospective, observational cohort study that enrolled patients with aneurysmal subarachnoid hemorrhage from five hospitals in China. A total of 404 aSAH patients were prospectively enrolled. We randomly divided the patients into training (N = 303) and validation cohorts (N = 101) according to a ratio of 75–25%. One LR and six popular ML algorithms were used to construct models. The area under the receiver operating characteristic curve (AUC), accuracy, balanced accuracy, confusion matrix, sensitivity, specificity, calibration curve, and Hosmer–Lemeshow test were used to assess and compare the model performance. Finally, we calculated each feature of importance.

Results

A total of 112 (27.7%) patients developed DCI. Our results showed that conventional LR with an AUC value of 0.824 (95%CI: 0.73–0.91) in the validation cohort outperformed k-nearest neighbor, decision tree, support vector machine, and extreme gradient boosting model with the AUCs of 0.792 (95%CI: 0.68–0.9, P = 0.46), 0.675 (95%CI: 0.56–0.79, P < 0.01), 0.677 (95%CI: 0.57–0.77, P < 0.01), and 0.78 (95%CI: 0.68–0.87, P = 0.50). However, random forest (RF) and artificial neural network model with the same AUC (0.858, 95%CI: 0.78–0.93, P = 0.26) were better than the LR. The accuracy and the balanced accuracy of the RF were 20.8% and 11% higher than the latter, and the RF also showed good calibration in the validation cohort (Hosmer-Lemeshow: P = 0.203). We found that the CT value of subarachnoid hemorrhage, WBC count, neutrophil count, CT value of cerebral edema, and monocyte count were the five most important features for DCI prediction in the RF model. We then developed an online prediction tool (https://dynamic-nomogram.shinyapps.io/DynNomapp-DCI/) based on important features to calculate DCI risk precisely.

Conclusions

In this multicenter study, we found that several ML methods, particularly RF, outperformed conventional LR. Furthermore, an online prediction tool based on the RF model was developed to identify patients at high risk for DCI after SAH and facilitate timely interventions.

Clinical Trial Registration

http://www.chictr.org.cn, Unique identifier: ChiCTR2100044448.
The Impact of COVID-19 Confinement on Tinnitus and Hearing Loss in Older Adults: Data From the LOST in Lombardia Study
Authors: Jarach Carlotta Micaela , Lugo Alessandra , Stival Chiara , Bosetti Cristina , Amerio Andrea , Cavalieri d'Oro Luca , Iacoviello Licia , Odone Anna , Stuckler David , Zucchi Alberto , van den Brandt Piet , Garavello Werner , Cederroth Christopher R. , Schlee Winfried , Gallus Silvano ,   The LOST in Lombardia Study Investigators
Published: June 2022

Background

Although a direct relationship between tinnitus or hearing difficulties and COVID-19 has been suggested, current literature provides inconsistent results, and no research has been undertaken in older adults.

Methods

In November 2020, we conducted the LOST in Lombardia survey, a telephone-based cross-sectional study on a sample of 4,400 individuals representative of the general population aged ≥65 years from Lombardy region, Northern Italy. Individuals with diagnosed tinnitus and/or hearing loss were asked whether their conditions had improved or deteriorated in 2020 compared to 2019.

Results

Overall, 8.1% of older adults reported a diagnosis of tinnitus and 10.5% of hearing loss. In 2020 compared to 2019, among individuals with tinnitus, those with increasing severity (5.0%) were similar to those decreasing it (5.3%). Among individuals with hearing loss, more people reported an increase (13.6%) than a decrease (3.2%) in their disease severity. No individual with a diagnosis in 2020 of tinnitus (n = 6) or hearing loss (n = 13) had COVID-19. The incidence of tinnitus was lower in 2020 (rate: 14.8 per 10,000 person-years) than in previous years (rate in 1990–2019: 36.0 per 10,000 person-years; p = 0.026). There was no change in the incidence of hearing loss (p = 0.134).

Conclusions

In this large representative sample of older adults, on average neither COVID-19 confinement nor SARS-CoV-2 infection appeared to increase the severity or incidence of tinnitus. The increased severity of hearing difficulties may totally or partially be explained by physiologic deterioration of the condition, or by a misperception due to the use of face-masks.
Multisite Harmonization of Structural DTI Networks in Children: An A-CAP Study
Authors: Onicas Adrian I. , Ware Ashley L. , Harris Ashley D. , Beauchamp Miriam H. , Beaulieu Christian , Craig William , Doan Quynh , Freedman Stephen B. , Goodyear Bradley G. , Zemek Roger , Yeates Keith Owen , Lebel Catherine
Published: June 2022

The analysis of large, multisite neuroimaging datasets provides a promising means for robust characterization of brain networks that can reduce false positives and improve reproducibility. However, the use of different MRI scanners introduces variability to the data. Managing those sources of variability is increasingly important for the generation of accurate group-level inferences. ComBat is one of the most promising tools for multisite (multiscanner) harmonization of structural neuroimaging data, but no study has examined its application to graph theory metrics derived from the structural brain connectome. The present work evaluates the use of ComBat for multisite harmonization in the context of structural network analysis of diffusion-weighted scans from the Advancing Concussion Assessment in Pediatrics (A-CAP) study. Scans were acquired on six different scanners from 484 children aged 8.00–16.99 years [Mean = 12.37 ± 2.34 years; 289 (59.7%) Male] ~10 days following mild traumatic brain injury (n = 313) or orthopedic injury (n = 171). Whole brain deterministic diffusion tensor tractography was conducted and used to construct a 90 x 90 weighted (average fractional anisotropy) adjacency matrix for each scan. ComBat harmonization was applied separately at one of two different stages during data processing, either on the (i) weighted adjacency matrices (matrix harmonization) or (ii) global network metrics derived using unharmonized weighted adjacency matrices (parameter harmonization). Global network metrics based on unharmonized adjacency matrices and each harmonization approach were derived. Robust scanner effects were found for unharmonized metrics. Some scanner effects remained significant for matrix harmonized metrics, but effect sizes were less robust. Parameter harmonized metrics did not differ by scanner. Intraclass correlations (ICC) indicated good to excellent within-scanner consistency between metrics calculated before and after both harmonization approaches. Age correlated with unharmonized network metrics, but was more strongly correlated with network metrics based on both harmonization approaches. Parameter harmonization successfully controlled for scanner variability while preserving network topology and connectivity weights, indicating that harmonization of global network parameters based on unharmonized adjacency matrices may provide optimal results. The current work supports the use of ComBat for removing multiscanner effects on global network topology.
SPTBN5, Encoding the βV-Spectrin Protein, Leads to a Syndrome of Intellectual Disability, Developmental Delay, and Seizures
Authors: Khan Amjad , Bruno Lucia Pia , Alomar Fadhel , Umair Muhammad , Pinto Anna Maria , Khan Abid Ali , Khan Alamzeb , Saima  , Fabbiani Alessandra , Zguro Kristina , Furini Simone , Mencarelli Maria Antonietta , Renieri Alessandra , Resciniti Sara , Peña-Guerra Karla A. , Guzmán-Vega Francisco J. , Arold Stefan T. , Ariani Francesca , Khan Shahid Niaz
Published: June 2022

Whole exome sequencing has provided significant opportunities to discover novel candidate genes for intellectual disability and autism spectrum disorders. Variants in the spectrin genes SPTAN1, SPTBN1, SPTBN2, and SPTBN4 have been associated with neurological disorders; however, SPTBN5 gene-variants have not been associated with any human disorder. This is the first report that associates SPTBN5 gene variants (ENSG00000137877: c.266A>C; p.His89Pro, c.9784G>A; p.Glu3262Lys, c.933C>G; p.Tyr311Ter, and c.8809A>T; p.Asn2937Tyr) causing neurodevelopmental phenotypes in four different families. The SPTBN5-associated clinical traits in our patients include intellectual disability (mild to severe), aggressive tendencies, accompanied by variable features such as craniofacial and physical dysmorphisms, autistic behavior, and gastroesophageal reflux. We also provide a review of the existing literature related to other spectrin genes, which highlights clinical features partially overlapping with SPTBN5.
The Voltage-Gated Calcium Channel EGL-19 Acts on Glia to Drive Olfactory Adaptation
Authors: Chen Du , Cheng Hankui , Liu Siyan , Al-Sheikh Umar , Fan Yuedan , Duan Duo , Zou Wenjuan , Zhu Linhui , Kang Lijun
Published: June 2022

Calcium channelopathies have been strongly linked to cardiovascular, muscular, neurological and psychiatric disorders. The voltage-gated calcium channels (VGCC) are vital transducers of membrane potential changes to facilitate the dynamics of calcium ions and release of neurotransmitter. Whether these channels function in the glial cell to mediate calcium variations and regulate behavioral outputs, is poorly understood. Our results showed that odorant and mechanical stimuli evoked robust calcium increases in the amphid sheath (AMsh) glia from C. elegans, which were largely dependent on the L-Type VGCC EGL-19. Moreover, EGL-19 modulates the morphologies of both ASH sensory neurons and AMsh glia. Tissue-specific knock-down of EGL-19 in AMsh glia regulated sensory adaptability of ASH neurons and promoted olfactory adaptation. Our results reveal a novel role of glial L-Type VGCC EGL-19 on olfaction, lead to improved understanding of the functions of VGCCs in sensory transduction.
Multi-Omic Analyses Reveal Bifidogenic Effect and Metabolomic Shifts in Healthy Human Cohort Supplemented With a Prebiotic Dietary Fiber Blend
Authors: Kang Jea Woo , Tang Xinyu , Walton Charles J. , Brown Mark J. , Brewer Rachel A. , Maddela Rolando L. , Zheng Jack Jingyuan , Agus Joanne K. , Zivkovic Angela M.
Published: June 2022

Dietary fiber, a nutrient derived mainly from whole grains, vegetables, fruits, and legumes, is known to confer a number of health benefits, yet most Americans consume less than half of the daily recommended amount. Convenience and affordability are key factors determining the ability of individuals to incorporate fiber-rich foods into their diet, and many Americans struggle to access, afford, and prepare foods rich in fiber. The objective of this clinical study was to test the changes in microbial community composition, human metabolomics, and general health markers of a convenient, easy to use prebiotic supplement in generally healthy young participants consuming a diet low in fiber. Twenty healthy adults participated in this randomized, placebo-controlled, double-blind, crossover study which was registered at clinicaltrials.gov as NCT03785860. During the study participants consumed 12 g of a prebiotic fiber supplement and 12 g of placebo daily as a powder mixed with water as part of their habitual diet in randomized order for 4 weeks, with a 4-week washout between treatment arms. Fecal microbial DNA was extracted and sequenced by shallow shotgun sequencing on an Illumina NovaSeq. Plasma metabolites were detected using liquid chromatography–mass spectrometry with untargeted analysis. The phylum Actinobacteria, genusBifidobacterium, and severalBifidobacteriumspecies (B. bifidum, B. adolescentis, B. breve, B. catenulatum, andB. longum)significantly increased after prebiotic supplementation when compared to the placebo. The abundance of genes associated with the utilization of the prebiotic fiber ingredients (sacA, xfp, xpk) and the production of acetate (poxB, ackA) significantly changed with prebiotic supplementation. Additionally, the abundance of genes associated with the prebiotic utilization (xfp, xpk), acetate production (ackA), and choline to betaine oxidation (gbsB) were significantly correlated with changes in the abundance of the genusBifidobacteriumin the prebiotic group. Plasma concentrations of the bacterially produced metabolite indolepropionate significantly increased. The results of this study demonstrate that an easy to consume, low dose (12 g) of a prebiotic powder taken daily increases the abundance of beneficial bifidobacteria and the production of health-promoting bacteria-derived metabolites in healthy individuals with a habitual low-fiber diet.

Clinical Trial Registration

www.clinicaltrials.gov/, identifier: NCT03785860
Advancement of Protein- and Polysaccharide-Based Biopolymers for Anthocyanin Encapsulation
Authors: Song Jiahui , Yu Yue , Chen Minghuang , Ren Zhongyang , Chen Lin , Fu Caili , Ma Zheng feei , Li Zhanming
Published: June 2022

Although evidence shows that anthocyanins present promising health benefits, their poor stability still limits their applications in the food industry. Increasing the stability of anthocyanins is necessary to promote their absorption and metabolism and improve their health benefits. Numerous encapsulation approaches have been developed for the targeted release of anthocyanins to retain their bioactivities and ameliorate their unsatisfactory stability. Generally, choosing suitable edible encapsulation materials based on biopolymers is important in achieving the expected goals. This paper presented an ambitious task of summarizing the current understanding and challenges of biopolymer-based anthocyanin encapsulation in detail. The food-grade edible microencapsulation materials, especially for proteins and polysaccharides, should be employed to improve the stability of anthocyanins for effective application in the food industry. The influence factors involved in anthocyanin stability were systematically reviewed and highlighted. Food-grade proteins, especially whey protein, caseinate, gelatin, and soy protein, are attractive in the food industry for encapsulation owing to the improvement of stability and their health benefits. Polysaccharides, such as starch, pectin, chitosan, cellulose, mucilages, and their derivatives, are used as encapsulation materials because of their satisfactory biocompatibility and biodegradability. Moreover, the challenges and perspectives for the application of anthocyanins in food products were presented based on current knowledge. The proposed perspective can provide new insights into the amelioration of anthocyanin bioavailability by edible biopolymer encapsulation.
NTF2 Upregulation in HNSCC: a Predictive Marker and Potential Therapeutic Target Associated With Immune Infiltration
Authors: Xuan Guangxu , Zhang Xin , Zhang Min , Yu Minghang , Zhou Yujie , He Xiaosong , Hu Xiaopeng , Wang Xi , Liu Liangfa
Published: June 2022

Background

Head and neck squamous cell carcinoma (HNSCC) is a type of malignant tumor with an increasing incidence worldwide and a meager 5-year survival rate. It is known that nuclear transporter factor 2 (NTF2) transports related proteins into the nucleus physiologically. However, the role of NTF2 in HNSCC remains unclear.

Methods

In this study, RNA-Seq data of HNSCC samples with corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) database. In addition, other expression profiling data were downloaded from the Gene Expression Omnibus (GEO) database. The differential expressions of NTF2, along with the overall survival (OS) rates were identified and analyzed. Then, the clinical features and expression levels of NTF2 were utilized to develop a prognostic model. The study also utilized the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods to determine the related pathways of NTF2. Furthermore, the Tumor Immune Estimation Resource (TIMER) database was referenced to discover the immune correlation of NTF2. In this research investigation, RT-qPCR, western blotting, Cell Counting Kit-8 (CCK-8) assay, wound-healing assay, and immunohistochemical (IHC) staining methods were adopted to perform experimental verifications.

Results

This study’s results confirmed that the NTF2 expressions were significantly increased in HNSCC tissue when compared with normal tissue. In addition, the high expression levels of NTF2 were found to be associated with poor prognoses, which was confirmed via the IHC validations of HNSCC samples with survival data. The results of functional enrichment analysis showed that the NTF2 was associated with epithelial cell growth, skin differentiation, keratosis, and estrogen metabolism. Furthermore, the expressions of NTF2 were determined to be negatively involved with immune infiltrations and correlated with immune checkpoint blockade (ICB) responses following various ICB therapy strategies. The results of the CCK-8 assay and wound-healing assay confirmed the NTF2’s promoting effects on the proliferation and migration of tumor cells.

Conclusions

This study defined a novel prognostic model associated with the expressions of NTF2, which was shown to be independently related to the OS of HNSCC. It was concluded in this study that NTF2 might be a potential diagnostic and prognostic biomarker for HNSCC.
The Histopathological Types and Distribution Characteristics of Gastric Mixed Tumors
Authors: Zhu Fang-Heng , Wang Yang-Kun , Zhou Jun-Ling , Meng Nian-Long , Wang Yue , Jiang Bo , Wang Su-Nan
Published: June 2022

Objective

The present study aimed to investigate the histopathological types and distribution characteristics of gastric mixed tumors.

Methods

Detailed histological observations, together with related immunohistochemical and genetic tests, were analyzed on 960 surgically resected samples in 6 hospitals with gastric mixed tumors from May 2017 to May 2021 in this retrospective study.

Results

Epithelial-derived tumors accounted for 80.10% (769/960) of the gastric mixed tumor samples studied, and tumors of different tissue origins accounting for 10.83% (104/960), mesenchymal-derived tumors accounting for 6.25% (60/960), neuroendocrine tumors accounting for 2.40% (23/960), and lymphoma accounting for 0.42% (4/960). The histological types of gastric mixed tumors identified as most commonly were epithelial originated, followed by mixed tumors of different tissue originated, then mixed neuroendocrine, lymphoma, and mesenchymal originated in sequence. The histological number of gastric mixed tumors was ≤ 3 in 83.23% (799/960) of cases and > 4 in 16.77% (161/960) of cases. The mixed histological patterns of gastric mixed tumors were divided into three types: those with tumor cells interspersed with each other, those with incomplete fibrous tissue separation, and those without fibrous tissue separation. The gene target characteristics of gastric mixed tumors were the existence of multi-gene mutation, including human epidermalgrowth factor receptor-2 (HER2) gene amplification, key result areas (K-ras) and platelet-derived growth factor receptor alpha (PDGFRA).

Conclusion

Gastric mixed tumors should be adequately sampled, each piece of tissue should be involved in the morphological proportional division of the tumor, and any independent histological component should be written into the pathological examination report.
Treatment Patterns for Patients With Unresected Stage III NSCLC: Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database
Authors: Shang Shijie , Wang Ruiyang , Wang Fei , Wu Meng , Chen Dawei , Yu Jinming
Published: June 2022

Background

Recently, immunotherapy (IO) has shown striking survival improvement in unresectable stage III non-small cell lung cancer (NSCLC). However, the role of chemo-radiotherapy (CRT) for improvement in outcomes should not be disregarded. This study aimed to compare the treatment patterns and illustrate the impact of radiotherapy on the cancer-specific survival (CSS) and overall survival (OS) of patients with unresected locally advanced stage III NSCLC.

Methods

We retrospectively analyzed the data of patients with stage III NSCLC patients who did not undergo surgery from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database between 2001 and 2016, and three continuous years were regarded as one unit. Using the Kaplan-Meier method, we identified the CSS and OS. Then, a linear regression model was graphed to analyze the correlation between median survival of CSS or OS and calendar years in the radiotherapy alone, chemotherapy alone, and CRT groups.

Results

A total of 20986 patients were included in this study. In the overall cohort, CSS and OS improved consistently. To explore the reason for the improved survival, patients were divided into three different cohorts: radiotherapy alone, chemotherapy alone, and CRT. From 2001 to 2015, the median CSS improved persistently, 7, 8, 8, 9, and 11 months in the radiotherapy alone group and 12, 13, 15, 17, 19 months in the CRT group, but improvement in outcomes was less consistent in the chemotherapy alone group (10, 9, 11, 12, 12 months). To better visualize the correlation between CSS and calendar year, linear regression was performed, yielding r2 = 0.8032, P = 0.0395 for the radiotherapy alone group; r2 = 0.7206, P = 0.0689 for the chemotherapy alone group; and r2 = 0.9878, P = 0.0006 for the CRT group. Similar findings were observed in the OS data. In addition to this, we also analyzed different pathological types and also obtained the same results.

Conclusions

The survival of patients with unresectable stage III NSCLC has improved substantially, and the most pronounced and consistent improvements were observed in the CRT group. In addition to IO, radiotherapy played an essential role in the treatment of unresectable stage III NSCLC in the past years and should be considered in the design of clinical trials.
Homologous Recombination Deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small Cell Lung and Prostate Cancers, and the Mechanisms of Resistance to PARP Inhibitors
Authors: Mekonnen Negesse , Yang Hobin , Shin Young Kee
Published: June 2022

Homologous recombination (HR) is a highly conserved DNA repair mechanism that protects cells from exogenous and endogenous DNA damage. Breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) play an important role in the HR repair pathway by interacting with other DNA repair proteins such as Fanconi anemia (FA) proteins, ATM, RAD51, PALB2, MRE11A, RAD50, and NBN. These pathways are frequently aberrant in cancer, leading to the accumulation of DNA damage and genomic instability known as homologous recombination deficiency (HRD). HRD can be caused by chromosomal and subchromosomal aberrations, as well as by epigenetic inactivation of tumor suppressor gene promoters. Deficiency in one or more HR genes increases the risk of many malignancies. Another conserved mechanism involved in the repair of DNA single-strand breaks (SSBs) is base excision repair, in which poly (ADP-ribose) polymerase (PARP) enzymes play an important role. PARP inhibitors (PARPIs) convert SSBs to more cytotoxic double-strand breaks, which are repaired in HR-proficient cells, but remain unrepaired in HRD. The blockade of both HR and base excision repair pathways is the basis of PARPI therapy. The use of PARPIs can be expanded to sporadic cancers displaying the “BRCAness” phenotype. Although PARPIs are effective in many cancers, their efficacy is limited by the development of resistance. In this review, we summarize the prevalence of HRD due to mutation, loss of heterozygosity, and promoter hypermethylation of 35 DNA repair genes in ovarian, breast, colorectal, pancreatic, non-small cell lung cancer, and prostate cancer. The underlying mechanisms and strategies to overcome PARPI resistance are also discussed.
Trends in Incidence, Mortality, and Survival of Penile Cancer in the United States: A Population-Based Study
Authors: Deng Xinxi , Liu Yang , Zhan Xiangpeng , Chen Tao , Jiang Ming , Jiang Xinhao , Chen Luyao , Fu Bin
Published: June 2022

Purpose

The aim of this study is to investigate the trends in incidence and mortality, and explore any change in survival of penile cancer in the United States.

Methods

We obtained data from the Surveillance, Epidemiology, and End Results (SEER) database (2000–2018) utilizing the SEER Stat software. The joinpoint regression was used to analyze the secular trend of incidence and incidence-based mortality (IBM) stratified by age, race, and summary stage. The 5-year relative survival rate was also calculated.

Result

The age-adjusted rates of penile cancer patients were 0.38 (0.37–0.39) and 0.21 (0.2–0.21) for overall incidence and IBM, respectively. The 5-year relative survival rates were 67.7%, 66.99%, and 65.67% for the calendar periods of 2000–2004, 2005–2009, and 2010–2014, respectively. No significant changes in incidence by era were observed from 2000 to 2018 [annual percentage change (APC) = 0.5%, p = 0.064]. The IBM rate of penile cancer showed an initial significant increase from 2000 to 2002 (APC = 78.6%, 95% CI, −1.7–224.6) followed by a deceleration rate of 4.6% (95% CI, 3.9–5.3) during 2002 to 2018. No significant improvement in 5-year relative survival was observed. The trends by age, race, and summary stage in incidence and IBM were significantly different.

Conclusion

This study, using population-level data from the SEER database, showed an increasing trend in IBM and no significant improvement in the 5-year relative survival rate. Meanwhile, the incidence of penile cancer exhibited a relatively stable trend during the study period. These results might be due to the lack of significant progress in the treatment and management of penile cancer patients in the United States in recent decades. More efforts, like increasing awareness among the general population and doctors, and centralized management, might be needed in the future to improve the survival of this rare disease.