bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimation of Minimum Biofilm Eradication Concentration (MBEC) on In Vivo Biofilm on Orthopedic Implants in a Rodent Femoral Infection Model
Authors: Okae Yu , Nishitani Kohei , Sakamoto Akio , Kawai Toshiyuki , Tomizawa Takuya , Saito Motoo , Kuroda Yutaka , Matsuda Shuichi 
Published: July 2022

The formation of a biofilm on the implant surface is a major cause of intractable implant-associated infection. To investigate the antibiotic concentration needed to eradicate the bacteria inside a biofilm, the minimum biofilm eradication concentration (MBEC) has been used, mostly against in vitro biofilms on plastic surfaces. To produce a more clinically relevant environment, an MBEC assay against biofilms on stainless-steel implants formed in a rat femoral infection model was developed. The rats were implanted with stainless steel screws contaminated by two Staphylococcus aureus strains (UAMS-1, methicillin-sensitive Staphylococcus aureus; USA300LAC, methicillin-resistant Staphylococcus aureus) and euthanized on days 3 and 14. Implants were harvested, washed, and incubated with various concentrations (64–4096 μg/mL) of gentamicin (GM), vancomycin (VA), or cefazolin (CZ) with or without an accompanying systemic treatment dose of VA (20 μg/mL) or rifampicin (RF) (1.5 μg/mL) for 24 h. The implant was vortexed and sonicated, the biofilm was removed, and the implant was re-incubated to determine bacterial recovery. MBEC on the removed biofilm and implant was defined as in vivo MBEC and in vivo implant MBEC, respectively, and the concentrations of 100% and 60% eradication were defined as MBEC100 and MBEC60, respectively. As for in vivo MBEC, MBEC100 of GM was 256–1024 μg/mL, but that of VA and CZ ranged from 2048–4096 μg/mL. Surprisingly, the in vivo implant MBEC was much higher, ranging from 2048 μg/mL to more than 4096 μg/mL. The addition of RF, not VA, as a secondary antibiotic was effective, and MBEC60 on day 3 USA300LAC biofilm was reduced from 1024 μg/mL with GM alone to 128 μg/mL in combination with RF and the MBEC60 on day 14 USA300LAC biofilm was reduced from 2048 μg/mL in GM alone to 256 μg/mL in combination with RF. In conclusion, a novel MBEC assay for in vivo biofilms on orthopedic implants was developed. GM was the most effective against both methicillin-sensitive and methicillin-resistant Staphylococcus aureus, in in vivo biofilms, and the addition of a systemic concentration of RF reduced MBEC of GM. Early initiation of treatment is desired because the required concentration of antibiotics increases with biofilm maturation.
A Sticky Situation: Variable Agreement Between Platelet Function Tests Used to Assess Anti-platelet Therapy Response
Authors: Nakahara Hirotomo , Sarker Tania , Dean Christina L. , Skukalek Susana L. , Sniecinski Roman M. , Cawley C. Michael , Guarner Jeannette , Duncan Alexander , Maier Cheryl L. 
Published: July 2022

BackgroundPlatelet function testing to monitor antiplatelet therapy is important for reducing thromboembolic complications, yet variability across testing methods remains challenging. Here we evaluated the agreement of four different testing platforms used to monitor antiplatelet effects of aspirin (ASA) or P2Y12 inhibitors (P2Y12-I).MethodsBlood and urine specimens from 20 patients receiving dual antiplatelet therapy were analyzed by light transmission aggregometry (LTA), whole blood aggregometry (WBA), VerifyNow PRUTest and AspirinWorks. Result interpretation based on pre-defined cutoff values was used to calculate raw agreement indices, and Pearson's correlation coefficient determined using individual units of measure.ResultsAgreement between LTA and WBA for P2Y12-I-response was 60% (r = 0.65, high-dose ADP; r = 0.75, low-dose ADP). VerifyNow agreed with LTA in 75% (r = 0.86, high-dose ADP; r = 0.75, low-dose ADP) and WBA in 55% (r = 0.57) of cases. Agreement between LTA and WBA for ASA-response was 45% (r = 0.09, high-dose collagen WBA; r = 0.19, low-dose collagen WBA). AspirinWorks agreed with LTA in 60% (r = 0.32) and WBA in 35% (r = 0.02, high-dose collagen WBA; r = 0.08, low-dose collagen WBA) of cases.ConclusionsOverall agreement varied from 35 to 75%. LTA and VerifyNow demonstrated the highest agreement for P2Y12-I-response, followed by moderate agreement between LTA and WBA. LTA and AspirinWorks showed moderate agreement for aspirin response, while WBA showed the weakest agreement with both LTA and AspirinWorks. The results from this study support the continued use of LTA for monitoring dual antiplatelet therapy, with VerifyNow as an appropriate alternative for P2Y12-I-response. Integration of results obtained from these varied testing platforms with patient outcomes remains paramount for future studies.
NADPH-Oxidase Derived Hydrogen Peroxide and Irs2b Facilitate Re-oxygenation-Induced Catch-Up Growth in Zebrafish Embryo
Authors: Zasu Ayaka , Hishima Futa , Thauvin Marion , Yoneyama Yosuke , Kitani Yoichiro , Hakuno Fumihiko , Volovitch Michel , Takahashi Shin-Ichiro , Vriz Sophie , Rampon Christine , Kamei Hiroyasu 
Published: July 2022

Oxygen deprivation induces multiple changes at the cellular and organismal levels, and its re-supply also brings another special physiological status. We have investigated the effects of hypoxia/re-oxygenation on embryonic growth using the zebrafish model: hypoxia slows embryonic growth, but re-oxygenation induces growth spurt or catch-up growth. The mitogen-activated kinase (MAPK)-pathway downstream insulin-like growth factor (IGF/Igf) has been revealed to positively regulate the re-oxygenation-induced catch-up growth, and the role of reactive oxygen species generated by environmental oxygen fluctuation is potentially involved in the phenomenon. Here, we report the role of NADPH-oxidase (Nox)-dependent hydrogen peroxide (H2O2) production in the MAPK-activation and catch-up growth. The inhibition of Nox significantly blunted catch-up growth and MAPK-activity. Amongst two zebrafish insulin receptor substrate 2 genes (irs2a and irs2b), the loss of irs2b, but not its paralog irs2a, resulted in blunted MAPK-activation and catch-up growth. Furthermore, irs2b forcedly expressed in mammalian cells allowed IGF-MAPK augmentation in the presence of H2O2, and the irs2b deficiency completely abolished the somatotropic action of Nox in re-oxygenation condition. These results indicate that redox signaling alters IGF/Igf signaling to facilitate hypoxia/re-oxygenation-induced embryonic growth compensation.
Impact of Forest Canopy Closure on Snow Processes in the Changbai Mountains, Northeast China
Authors: Gao Yuan , Shen Lidu , Cai Rongrong , Wang Anzhi , Yuan Fenghui , Wu Jiabing , Guan Dexin , Yao Huaxia 
Published: July 2022

Forest canopy closure affects snow processes by changing the redistribution of snowfall, snow interception, accumulation, sublimation, and melt. However, how the forest closure impacts snow processes at different periods has not been well explored. We conducted 3-year measurements of snow density and depth and carried out snow process calculations (i.e., interception, sublimation, and snowmelt) from 2018 to 2021 in four mixed forests with different canopy closures and an open site in the Changbai Mountains, northeast China. We found that the snow density of the five study sites varied greatly (0.14–0.45 g/cm3). The snow depth (SD) at four mixed forests sites was smaller than that of the nearby open site. The SD decreased as the forest canopy closure increased. Additionally, the forest interception effect increased with the canopy closure and decreased as the snowfall intensity increased. The total interception efficiency of the four mixed forests in normal snow years changed from 34% to 73% and increased with forest canopy closure. The averaged sublimation rate (Ss) and snowmelt rate (Sr) of the four mixed forests varied during different periods of snow process. The Ss was 0.1–0.4 mm/day during the accumulation period and 0.2–1.0 mm/day during the ablation period, and the Sr was 1.5–10.5 mm/day during the ablation period. There was a good correlation between Ss, or Sr, and canopy closure, but interannual variation was observed in the correlation. The mean values of the effect of the four mixed forests on understory SWE (snow water equivalent) over the 3 years ranged from −45% to −65%. Moreover, the impact effect was correlated with the forest canopy closure and enhanced with the canopy closure. This study provided more scientific information for studies of snow cover response to forest management.
Impact of a Low-Permeability Layer on the Pumping Efficiency Under Threats of Saltwater Up-Coning
Authors: Wu Zhenyu , Tang Maozhu , Daly Edoardo , Lu Chunhui 
Published: July 2022

Previous studies on saltwater up-coning are mostly based on the assumption of a homogeneous aquifer and neglect the effect of heterogeneity. A numerical study was carried out to explore the impact of a low-permeability (k) layer on the pumping efficiency under threats of saltwater up-coning. It is found that the presence of the low-k layer could impede up-coning of saltwater, thereby improving significantly pumping efficiency, as expected. For the cases adopted, when the permeability of the 2 m thick low-k layer is three orders of magnitude less than that of the corresponding homogeneous aquifer, the pumping duration (i.e., the time before the salinity of pumped water reaches 2%) can be up to about 10 times longer than that of the homogeneous aquifer case. Additionally, a sound linear relationship could be developed between the normalized pumping duration of the layered case (E) (defined as the difference of the pumping duration between layered and homogeneous cases relative to the pumping duration in the homogeneous case) and the permeability of the homogeneous aquifer relative to that of the low-k layer (β). However, a short low-k layer may lead to the failure of this linear relationship. Moreover, a thicker low-k layer leads to a larger E when all other conditions are unchanged. When varying the location of the low-k layer, the large E occurs for the low-k layer located below and near the well bottom. The results obtained in the current study offer significant implications for preventing saltwater up-coning and improving the pumping efficiency through natural and artificial barriers.
Novel Variant Expands the Clinical Spectrum of CUX2-Associated Developmental and Epileptic Encephalopathies
Authors: Zhang Feng , Li Fuwei , Chen Fujian , Huang Jinrong , Luo Qiong , Du Xilong , Zhou Jiapeng , Gu Weiyue , Xu Kaishou 
Published: July 2022

Developmental and epileptic encephalopathies (DEE) caused by heterozygous deleterious variants in Cut Like Homeobox2 (CUX2) is rare. To the best of our knowledge the only variant associated with a phenotype in this gene is the de novo missense variant c.1768G &gt; A, p.Glu590Lys; however, further additional research is needed to characterize the relationship between disease and variants in this gene. In this study, we reported a patient from a non-consanguineous Chinese family presenting with epilepsy, developmental delay, and speech delay. Additionally, the patient responded well to levetiracetam, and at his last follow-up (5.5 years old), he had discontinued antiepileptic drug treatment and remained seizure-free for 6 months. To identify possible causative variants, trio-whole exome sequencing was performed. We identified a novel de novo missense CUX2 c.2834C &gt; T, p. Thr945Met variant in the patient. Based on clinical and genetics information associated with the bioinformatics analyses, we hypothesized that this variant was the cause of the reported phenotype. AlphaFold and SWISS-MODEL homology modeling servers were used to predict the three-dimensional (3D) structure of CUX2 protein. Predictions based on the 3D-structure modeling indicated that the p.Thr945Met substitution was likely to alter the DNA-binding specificities and affect protein function. On the basis of clinical characteristics and genetic analysis, we presented one case diagnosed with DEE67. Our finding expanded the clinical and molecular spectrum of CUX2 variants.
BTC as a Novel Biomarker Contributing to EMT via the PI3K-AKT Pathway in OSCC
Authors: Shen Ting , Yang Tianru , Yao Mianfeng , Zheng Ziran , He Mi , Shao Mengying , Li Jiang , Fang Changyun 
Published: July 2022

Purpose: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of the head and neck, while metastasis is the main cause of OSCC-related death. There is an urgent need to explore novel prognostic biomarkers and identify biological targets related to metastasis in OSCC treatment.Methods: Analysis of differential expression was performed using datasets in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Immunohistochemistry (IHC) was conducted to assess the expression of betacellulin (BTC) in OSCC. SCC4 and CAL27 cells were used for in vitro experiments, in which CCK-8, transwell assays, and wounding healing assays were performed to verify the biological functions of BTC. The role of BTC in EMT was analyzed by EMT score and Western blot.Results: Through the analysis of the mRNA expression profile data from TCGA database in OSCC, we found that only low expression of BTC was significantly correlated with a poor prognosis in OSCC patients. The results of IHC assays and TCGA databases showed that the expression level of BTC was related to the tumor stage, histological grade, and metastasis status. In vitro analysis showed that overexpression of BTC significantly suppressed the proliferation and migration of OSCC cells. Furthermore, we confirmed that BTC could affect EMT through the PI3K-AKT signaling pathway.Conclusion: The overexpression of BTC suppresses the proliferation, migration, and EMT of OSCC cells via the PI3K-AKT pathways, leading to a better prognosis in OSCC. BTC may be used as a novel molecular marker to assess the prognosis of OSCC patients.
Elucidation of the Application of Blood Test Biomarkers to Predict Immune-Related Adverse Events in Atezolizumab-Treated NSCLC Patients Using Machine Learning Methods
Authors: Zhou Jian-Guo , Wong Ada Hang-Heng , Wang Haitao , Tan Fangya , Chen Xiaofei , Jin Su-Han , He Si-Si , Shen Gang , Wang Yun-Jia , Frey Benjamin , Fietkau Rainer , Hecht Markus , Ma Hu , Gaipl Udo S. 
Published: July 2022

BackgroundDevelopment of severe immune-related adverse events (irAEs) is a major predicament to stop treatment with immune checkpoint inhibitors, even though tumor progression is suppressed. However, no effective early phase biomarker has been established to predict irAE until now.MethodThis study retrospectively used the data of four international, multi-center clinical trials to investigate the application of blood test biomarkers to predict irAEs in atezolizumab-treated advanced non-small cell lung cancer (NSCLC) patients. Seven machine learning methods were exploited to dissect the importance score of 21 blood test biomarkers after 1,000 simulations by the training cohort consisting of 80%, 70%, and 60% of the combined cohort with 1,320 eligible patients.ResultsXGBoost and LASSO exhibited the best performance in this study with relatively higher consistency between the training and test cohorts. The best area under the curve (AUC) was obtained by a 10-biomarker panel using the XGBoost method for the 8:2 training:test cohort ratio (training cohort AUC = 0.692, test cohort AUC = 0.681). This panel could be further narrowed down to a three-biomarker panel consisting of C-reactive protein (CRP), platelet-to-lymphocyte ratio (PLR), and thyroid-stimulating hormone (TSH) with a small median AUC difference using the XGBoost method [for the 8:2 training:test cohort ratio, training cohort AUC difference = −0.035 (p &lt; 0.0001), and test cohort AUC difference = 0.001 (p=0.965)].ConclusionBlood test biomarkers currently do not have sufficient predictive power to predict irAE development in atezolizumab-treated advanced NSCLC patients. Nevertheless, biomarkers related to adaptive immunity and liver or thyroid dysfunction warrant further investigation.
Cellular and Humoral Immune Response to a Third Dose of BNT162b2 COVID-19 Vaccine – A Prospective Observational Study
Authors: Herzberg Jonas , Fischer Bastian , Becher Heiko , Becker Ann-Kristin , Honarpisheh Human , Guraya Salman Yousuf , Strate Tim , Knabbe Cornelius 
Published: July 2022

BackgroundSince the introduction of various vaccines against SARS-CoV-2 at the end of 2020, infection rates have continued to climb worldwide. This led to the establishment of a third dose vaccination in several countries, known as a booster. To date, there has been little real-world data about the immunological effect of this strategy.MethodsWe compared the humoral- and cellular immune response before and after the third dose of BioNTech/Pfizer vaccine BNT162b2, following different prime-boost regimen in a prospective observational study. Humoral immunity was assessed by determining anti-SARS-CoV-2 binding antibodies using a standardized quantitative assay. In addition, neutralizing antibodies were measured using a commercial surrogate ELISA-assay. Interferon-gamma release was measured after stimulating blood-cells with SARS-CoV-2 specific peptides using a commercial assay to evaluate the cellular immune response.ResultsWe included 243 health-care workers who provided blood samples and questionnaires pre- and post- third vaccination. The median antibody level increased significantly after the third vaccination dose to 2663.1 BAU/ml vs. 101.4 BAU/ml (p &lt; 0.001) before administration of the booster dose. This was also detected for neutralizing antibodies with a binding inhibition of 99.68% ± 0.36% vs. 69.06% ± 19.88% after the second dose (p &lt; 0.001). 96.3% of the participants showed a detectable T-cell-response after the booster dose with a mean interferon-gamma level of 2207.07 mIU/ml ± 1905 mIU/ml.ConclusionThis study detected a BMI-dependent antibody increase after the third dose of BNT162b2 following different vaccination protocols. All participants showed a significant increase in their immune response. This, in combination with the low rate of post-vaccination-symptoms underlines the potential beneficial effect of a BNT162b2-booster dose.
Healthcare Workers From Diverse Ethnicities and Their Perceptions of Risk and Experiences of Risk Management During the COVID-19 Pandemic: Qualitative Insights From the United Kingdom-REACH Study
Authors: Qureshi Irtiza , Gogoi Mayuri , Wobi Fatimah , Chaloner Jonathan , Al-Oraibi Amani , Hassan Osama , Pan Daniel , Nellums Laura B. , Pareek Manish 
Published: July 2022

IntroductionHealthcare workers (HCWs) are at higher risk of being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Previous studies have examined factors relating to infection amongst HCWs, including those from ethnic minority groups, but there is limited data regarding the lived experiences of HCWs in relation to self-protection and how they deal with SARS-CoV-2 infection prevention. In this study, we presented data from an ethnically diverse sample of HCWs in the United Kingdom (UK) to understand their perceptions of risks and experiences with risk management whilst working throughout the COVID-19 pandemic.MethodsWe undertook a qualitative study as part of the United Kingdom Research study into Ethnicity and COVID-19 outcomes among Healthcare workers (United Kingdom-REACH) conducting semi-structured interviews and focus groups which were recorded with participants’ permission. Recordings were transcribed and thematically analyzed.FindingsA total of 84 participants were included in the analysis. Five broad themes emerged. First, ethnic minority HCWs spoke about specific risks and vulnerabilities they faced in relation to their ethnicity. Second, participants’ experience of risk assessments at work varied; some expressed satisfaction while many critiqued it as a “tick-box” exercise. Third, most participants shared about risks related to shortages, ambiguity in guidance, and inequitable distribution of Personal Protective Equipment (PPE), particularly during the start of the pandemic. Fourth, participants reported risks resulting from understaffing and inappropriate redeployment. Finally, HCWs shared the risk mitigation strategies which they had personally employed to protect themselves, their families, and the public.ConclusionHealthcare workers identified several areas where they felt at risk and/or had negative experiences of risk management during the pandemic. Our findings indicate that organizational shortcomings may have exposed some HCWs to greater risks of infection compared with others, thereby increasing their emotional and mental burden. Ethnic minority HCWs in particular experienced risks stemming from what they perceived to be institutional and structural racism, thus leading to a loss of trust in employers. These findings have significance in understanding staff safety, wellbeing, and workforce retention in multiethnic staff groups and also highlight the need for more robust, inclusive, and equitable approaches to protect HCWs going forward.
A Prospective Study Evaluating Cumulative Incidence and a Specific Prediction Rule in Pulmonary Embolism in COVID-19
Authors: Suarez Castillejo Carla , Toledo-Pons Nuria , Calvo Néstor , Ramon-Clar Luisa , Martínez Joaquín , Hermoso de Mendoza Sara , Morell-García Daniel , Bauça Josep Miquel , Berga Francisco , Núñez Belén , Preda Luminita , Sauleda Jaume , Argente Castillo Paula , Ballesteros Antonieta , Martín Luisa , Sala-Llinas Ernest , Alonso-Fernández Alberto 
Published: July 2022

RationaleAbnormal values of hypercoagulability biomarkers, such as D-dimer, have been described in Coronavirus Disease 2019 (COVID-19), which has also been associated with disease severity and in-hospital mortality. COVID-19 patients with pneumonia are at greater risk of pulmonary embolism (PE). However, the real incidence of PE is not yet clear, since studies have been limited in size, mostly retrospective, and PE diagnostic procedures were only performed when PE was clinically suspected.Objectives(1) To determine the incidence, clinical, radiological, and biological characteristics, and clinical outcomes of PE among patients hospitalized for COVID-19 pneumonia with D-dimer &gt; 1,000 ng/mL. (2) To develop a prognostic model to predict PE in these patients.MethodsSingle-center prospective cohort study. Consecutive confirmed cases of COVID-19 pneumonia with D-dimer &gt; 1,000 ng/mL underwent computed tomography pulmonary angiography (CTPA). Demographic and laboratory data, comorbidities, CTPA scores, treatments administered, and clinical outcomes were analyzed and compared between patients with and without PE. A risk score was constructed from all these variables.ResultsBetween 6 April 2020 and 2 February 2021, 179 consecutive patients were included. The overall incidence of PE was 39.7% (71 patients) (CI 95%, 32–47%). In patients with PE, emboli were located mainly in segmental/subsegmental arteries (67%). Patients with PE did not differ from the non-PE group in sex, age, or risk factors for thromboembolic disease. Higher urea, D-Dimer, D-dimer-to-ferritin and D-dimer-to-lactate dehydrogenase (LDH) ratios, platelet distribution width (PDW), and neutrophil-to-lymphocyte ratio (NLR) values were found in patients with PE when compared to patients with non-PE. Besides, lymphocyte counts turned out to be lower in patients with PE. A score for PE prediction was constructed with excellent overall performance [area under the ROC curve-receiver operating characteristic (AUC-ROC) 0.81 (95% CI: 0.73–0.89)]. The PATCOM score stands for Pulmonary Artery Thrombosis in COVID-19 Mallorca and includes platelet count, PDW, urea concentration, and D-dimer-to-ferritin ratio.ConclusionCOVID-19 patients with pneumonia and D-dimer values &gt; 1,000 ng/mL were presented with a very high incidence of PE, regardless of clinical suspicion. Significant differences in urea, D-dimer, PDW, NLR, and lymphocyte count were found between patients with PE and non-PE. The PATCOM score is presented in this study as a promising PE prediction rule, although validation in further studies is required.