bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reliability of CD44, CD24, and ALDH1A1 immunohistochemical staining: Pathologist assessment compared to quantitative image analysis
Authors: Yaghjyan Lusine , Heng Yujing J. , Baker Gabrielle M. , Bret-Mounet Vanessa , Murthy Divya , Mahoney Matt B. , Mu Yi , Rosner Bernard , Tamimi Rulla M. 
Published: December 2022

BackgroundThe data on the expression of stem cell markers CD44, CD24, and ALDH1A1 in the breast tissue of cancer-free women is very limited and no previous studies have explored the agreement between pathologist and computational assessments of these markers. We compared the immunohistochemical (IHC) expression assessment for CD44, CD24, and ALDH1A1 by an expert pathologist with the automated image analysis results and assessed the homogeneity of the markers across multiple cores pertaining to each woman.MethodsWe included 81 cancer-free women (399 cores) with biopsy-confirmed benign breast disease in the Nurses’ Health Study (NHS) and NHSII cohorts. IHC was conducted with commercial antibodies [CD44 (Dako, Santa Clara, CA, USA) 1:25 dilution; CD24 (Invitrogen, Waltham, MA, USA) 1:200 dilution and ALDH1A1 (Abcam, Cambridge, United Kingdom) 1:300 dilution]. For each core, the percent positivity was quantified by the pathologist and Definiens Tissue Studio. Correlations between pathologist and computational scores were evaluated with Spearman correlation (for categorical positivity: 0, &gt;0–&lt;1, 1–10, &gt;10–50, and &gt;50%) and sensitivity/specificity (for binary positivity defined with 1 and 10% cut-offs), using the pathologist scores as the gold standard. Expression homogeneity was examined with intra-class correlation (ICC). Analyses were stratified by core [normal terminal duct-lobular units (TDLUs), benign lesions] and tissue type (epithelium, stroma).ResultsSpearman correlation between pathologist and Definiens ranged between 0.40–0.64 for stroma and 0.66–0.68 for epithelium in normal TDLUs cores and between 0.24–0.60 for stroma and 0.61–0.64 for epithelium in benign lesions. For stroma, sensitivity and specificity ranged between 0.92–0.95 and 0.24–0.60, respectively, with 1% cut-off and between 0.43–0.88 and 0.73–0.85, respectively, with 10% cut-off. For epithelium, 10% cut-off resulted in better estimates for both sensitivity and specificity. ICC between the cores was strongest for CD44 for both stroma and epithelium in normal TDLUs cores and benign lesions (range 0.74–0.80). ICC for CD24 and ALDH1A ranged between 0.42–0.63 and 0.44–0.55, respectively.ConclusionOur findings show that computational assessments for CD44, CD24, and ALDH1A1 exhibit variable correlations with manual assessment. These findings support the use of computational platforms for IHC evaluation of stem cell markers in large-scale epidemiologic studies. Pilot studies maybe also needed to determine appropriate cut-offs for defining staining positivity.
Recent changes in the mutational dynamics of the SARS-CoV-2 main protease substantiate the danger of emerging resistance to antiviral drugs
Authors: Parigger Lena , Krassnigg Andreas , Schopper Tobias , Singh Amit , Tappler Katharina , Köchl Katharina , Hetmann Michael , Gruber Karl , Steinkellner Georg , Gruber Christian C. 
Published: December 2022

IntroductionThe current coronavirus pandemic is being combated worldwide by nontherapeutic measures and massive vaccination programs. Nevertheless, therapeutic options such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main-protease (Mpro) inhibitors are essential due to the ongoing evolution toward escape from natural or induced immunity. While antiviral strategies are vulnerable to the effects of viral mutation, the relatively conserved Mpro makes an attractive drug target: Nirmatrelvir, an antiviral targeting its active site, has been authorized for conditional or emergency use in several countries since December 2021, and a number of other inhibitors are under clinical evaluation. We analyzed recent SARS-CoV-2 genomic data, since early detection of potential resistances supports a timely counteraction in drug development and deployment, and discovered accelerated mutational dynamics of Mpro since early December 2021.MethodsWe performed a comparative analysis of 10.5 million SARS-CoV-2 genome sequences available by June 2022 at GISAID to the NCBI reference genome sequence NC_045512.2. Amino-acid exchanges within high-quality regions in 69,878 unique Mpro sequences were identified and time- and in-depth sequence analyses including a structural representation of mutational dynamics were performed using in-house software.ResultsThe analysis showed a significant recent event of mutational dynamics in Mpro. We report a remarkable increase in mutational variability in an eight-residue long consecutive region (R188-G195) near the active site since December 2021.DiscussionThe increased mutational variability in close proximity to an antiviral-drug binding site as described herein may suggest the onset of the development of antiviral resistance. This emerging diversity urgently needs to be further monitored and considered in ongoing drug development and lead optimization.
Audiovisual integration of the dynamic hand-held tool at different stimulus intensities in aging
Authors: Yang Weiping , Yang Xiangfu , Guo Ao , Li Shengnan , Li Zimo , Lin Jinfei , Ren Yanna , Yang Jiajia , Wu Jinglong , Zhang Zhilin 
Published: December 2022

Introduction: In comparison to the audiovisual integration of younger adults, the same process appears more complex and unstable in older adults. Previous research has found that stimulus intensity is one of the most important factors influencing audiovisual integration.Methods: The present study compared differences in audiovisual integration between older and younger adults using dynamic hand-held tool stimuli, such as holding a hammer hitting the floor. Meanwhile, the effects of stimulus intensity on audiovisual integration were compared. The intensity of the visual and auditory stimuli was regulated by modulating the contrast level and sound pressure level.Results: Behavioral results showed that both older and younger adults responded faster and with higher hit rates to audiovisual stimuli than to visual and auditory stimuli. Further results of event-related potentials (ERPs) revealed that during the early stage of 60–100 ms, in the low-intensity condition, audiovisual integration of the anterior brain region was greater in older adults than in younger adults; however, in the high-intensity condition, audiovisual integration of the right hemisphere region was greater in younger adults than in older adults. Moreover, audiovisual integration was greater in the low-intensity condition than in the high-intensity condition in older adults during the 60–100 ms, 120–160 ms, and 220–260 ms periods, showing inverse effectiveness. However, there was no difference in the audiovisual integration of younger adults across different intensity conditions.Discussion: The results suggested that there was an age-related dissociation between high- and low-intensity conditions with audiovisual integration of the dynamic hand-held tool stimulus. Older adults showed greater audiovisual integration in the lower intensity condition, which may be due to the activation of compensatory mechanisms.
Dll1 haploinsufficiency causes brain abnormalities with functional relevance
Authors: Arzate Dulce-María , Valencia Concepción , Dimas Marco-Antonio , Antonio-Cabrera Edwards , Domínguez-Salazar Emilio , Guerrero-Flores Gilda , Gutiérrez-Mariscal Mariana , Covarrubias Luis 
Published: December 2022

IntroductionThe Notch pathway is fundamental for the generation of neurons during development. We previously reported that adult mice heterozygous for the null allele of the gene encoding the Delta-like ligand 1 for Notch (Dll1lacZ) have a reduced neuronal density in the substantia nigra pars compacta. The aim of the present work was to evaluate whether this alteration extends to other brain structures and the behavioral consequences of affected subjects.MethodsBrains of Dll1+/lacZ embryos and mice at different ages were phenotypically compared against their wild type (WT) counterpart. Afterwards, brain histological analyses were performed followed by determinations of neural cell markers in tissue slices. Neurological deficits were diagnosed by applying different behavioral tests to Dll1+/lacZ and WT mice.ResultsBrain weight and size of Dll1+/lacZ mice was significantly decreased compared with WT littermates (i.e., microcephaly), a phenotype detected early after birth. Interestingly, enlarged ventricles (i.e., hydrocephalus) was a common characteristic of brains of Dll1 haploinsufficient mice since early ages. At the cell level, general cell density and number of neurons in several brain regions, including the cortex and hippocampus, of Dll1+/lacZ mice were reduced as compared with those regions of WT mice. Also, fewer neural stem cells were particularly found in the adult dentate gyrus of Dll1+/lacZ mice but not in the subventricular zone. High myelination levels detected at early postnatal ages (P7–P24) were an additional penetrant phenotype in Dll1+/lacZ mice, observation that was consistent with premature oligodendrocyte differentiation. After applying a set of behavioral tests, mild neurological alterations were detected that caused changes in motor behaviors and a deficit in object categorization.DiscussionOur observations suggest that Dll1 haploinsufficiency limits Notch signaling during brain development which, on one hand, leads to reduced brain cell density and causes microcephaly and hydrocephalus phenotypes and, on the other, alters the myelination process after birth. The severity of these defects could reach levels that affect normal brain function. Therefore, Dll1 haploinsufficiency is a risk factor that predisposes the brain to develop abnormalities with functional consequences.
Living on the edge: How to prepare for it?
Authors: Van Puyvelde Martine , Gijbels Daisy , Van Caelenberg Thomas , Smith Nathan , Bessone Loredana , Buckle-Charlesworth Susan , Pattyn Nathalie 
Published: December 2022

IntroductionIsolated, confined, and extreme (ICE) environments such as found at Antarctic, Arctic, and other remote research stations are considered space-analogs to study the long duration isolation aspects of operational space mission conditions.MethodsWe interviewed 24 sojourners that participated in different short/long duration missions in an Antarctic (Concordia, Halley VI, Rothera, Neumayer II) or non-Antarctic (e.g., MDRS, HI-SEAS) station or in polar treks, offering a unique insight based on first-hand information on the nature of demands by ICE-personnel at multiple levels of functioning. We conducted a qualitative thematic analysis to explore how sojourners were trained, prepared, how they experienced the ICE-impact in function of varieties in environment, provided trainings, station-culture, and type of mission.ResultsThe ICE-environment shapes the impact of organizational, interpersonal, and individual working- and living systems, thus influencing the ICE-sojourners' functioning. Moreover, more specific training for operating in these settings would be beneficial. The identified pillars such as sensory deprivation, sleep, fatigue, group dynamics, displacement of negative emotions, gender-issues along with coping strategies such as positivity, salutogenic effects, job dedication and collectivistic thinking confirm previous literature. However, in this work, we applied a systemic perspective, assembling the multiple levels of functioning in ICE-environments.DiscussionA systemic approach could serve as a guide to develop future preparatory ICE-training programs, including all the involved parties of the crew system (e.g., family, on-ground crew) with attention for the impact of organization- and station-related subcultures and the risk of unawareness about the impact of poor sleep, fatigue, and isolation on operational safety that may occur on location.
Dietary inflammatory index, and depression and mortality risk associations in U.S. adults, with a special focus on cancer survivors
Authors: Zhang Yuzheng , Wu Yanhua , Zhang Yangyu , Cao Donghui , He Hua , Cao Xueyuan , Wang Yuehui , Jia Zhifang , Jiang Jing 
Published: December 2022

IntroductionA higher risk for depression and mortality is associated with the inflammatory potential of diet measured through the Dietary Inflammatory Index (DII). The roles of DII in the risk of depression and death in cancer survivors were unclear. We aimed to examine the association between energy-adjusted DII (E-DII) score and risk of depression, and mortality using data from the 2007–2018 National Health and Nutrition Examination Survey (NHANES), with a special focus on cancer survivors.MethodsThe 24-h dietary recall interview was used as a basis to calculate the E-DII score and the Patient Health Questionnaire-9 (PHQ-9) was used to measure the depressive outcomes. Logistic regression analyses were performed to determine the association between quartiles of E-DII score and depression. Cox proportional hazard regression and competing risk analyses were used to estimate the risks of quartiles of E-DII score or depression on mortality.ResultsA total of 27,447 participants were included; including 24,694 subjects without cancer and 2,753 cancer survivors. The E-DII score and depression were not distributed differently between the two groups. However, the E-DII scores were positively associated with within each group’s depression (all P trend &lt; 0.001) and participants with higher E-DII scores had a higher risk of depression (subjects without cancer: ORQ4vsQ1: 2.17, 95% CI: 1.75–2.70; cancer survivors: ORQ4vsQ1: 1.78, 95% CI: 1.09–2.92). The median follow-up time were 87 person-months, a total of 1,701 (4.8%) and 570 (15.2%) all-cause deaths in subjects without cancer and cancer survivors were identified by the end of 2019. The highest E-DII scores quartile was associated with the highest risk of all-cause (HRQ4vsQ1: 1.90, 95% CI: 1.54–2.35) and cardiovascular disease (CVD) cause death (HRQ4vsQ1: 2.50, 95% CI: 1.69–2.3.7) in the subjects without cancer. Moreover, participants with depressive symptoms had higher all-cause mortality (HR: 1.29, 95% CI: 1.04–1.59). No significant correlation was found for E-DII scores or depression with all-cause, cancer-cause or CVD-cause mortality in cancer survivors.ConclusionOur findings demonstrate that E-DII score was positively associated with depression risk. A higher E-DII score or depressive symptom may increase the risks of all-cause and CVD-cause mortality only among general subjects.
Relationship between nutritional status and length of hospital stay among patients with atrial fibrillation – a result of the nutritional status heart study
Authors: Czapla Michał , Uchmanowicz Izabella , Juárez-Vela Raúl , Durante Angela , Kałużna-Oleksy Marta , Łokieć Katarzyna , Baeza-Trinidad Ramón , Smereka Jacek 
Published: December 2022

BackgroundNutritional status is related to the prognosis and length of hospital stay (LOHS) of patients with atrial fibrillation (AF). This study aimed to assess how nutritional status affects LOHS for patients with AF.MethodsWe performed retrospective analysis of the medical records of 1,813 patients admitted urgently with a diagnosis of AF to the Institute of Heart Diseases of the University Clinical Hospital in Wroclaw, Poland.ResultsIn total, 1,813 patients were included in the analysis. The average LOHS in the entire group was 3.53 ± 3.41 days. The mean BMI was 28.7 kg/m2 (SD: 5.02). Patients who were hospitalized longer were statistically more likely to have a Nutritional Risk Score (NRS) ≥3 (p = 0.028). A higher percentage of longer hospitalized patients with LDL levels below 70 mg/dl (p &lt; 0.001) and those with HDL ≥40 mg/dl (p &lt; 0.001) were observed. Study participants with NRS ≥3 were an older group (M = 76.3 years), with longer mean LOHS (M = 4.44 days). The predictors of LOHS in the univariate model were age (OR = 1.04), LDL (OR = 0.99), HDL (OR = 0.98), TC (OR = 0.996), CRP (OR = 1, 02, p &lt; 0.001), lymphocytes (OR = 0.97, p = 0.008) and in the multivariate model were age, LDL (mg/dl), HDL (mg/dl), Na, and K.ConclusionFor nutritional status, factors indicating the risk of prolonged hospitalization in patients with AF are malnutrition, lower serum LDL, HDL, potassium, and sodium levels identified at the time of admission to the cardiology department. Assessment of nutritional status in patients with AF is important both in the context of evaluating obesity and malnutrition status, as both conditions can alter the prognosis of patients. Further studies are needed to determine the exact impact of the above on the risk of prolonged hospitalization.
Development and validation of prognostic nomograms in patients with gallbladder mucinous adenocarcinoma: A population-based study
Authors: Xu Xiaoming , Wang Jingzhi 
Published: December 2022

BackgroundGallbladder mucinous adenocarcinoma (GBMAC) is an uncommon malignant gallbladder tumor. There are few studies on its prognosis, with the majority consisting of small series or individual cases. We sought to develop and validate nomograms for predicting overall survival (OS) and cancer-specific survival (CSS) in GBMAC patients.MethodsThe clinicopathological data of GBMAC patients from 1975 to 2019 was extracted from the Surveillance, Epidemiology, and End Results (SEER) database, and all patients were randomly divided into a training cohort (70%) and a validation cohort (30%). Using multivariate Cox regression analyses based on Akaike information criterion (AIC), prognostic and important variables for GBMAC were determined. On the basis of these factors, nomograms were developed to predict the 1-, 3-, and 5-year OS and CSS rates of patients with GBMAC. Multiple parameters, including the area under the subject operating characteristic curve (AUC), the calibration plots, and the decision curve analysis (DCA), were then used to evaluate the accuracy of nomograms.ResultsFollowing exclusion, a total of 707 GBMAC patients were enrolled, and the training cohort (490, 70%) and validation cohort (217, 30%) were randomly assigned. Grade, surgery, radiation, and SEER stage were predictive factors for patients with GBMAC, as indicated by univariate and multivariate Cox regression analyses based on AIC. We created nomograms for predicting OS and CSS in GBMAC using the four factors. The calibration curves and area under the curves (AUCs) indicated that our nomograms have a moderate degree of predictive accuracy and capability. The results of the DCA revealed that the nomogram has a high predictive value.ConclusionWe established the first nomograms for predicting 1-, 3-, and 5-year OS and CSS in GBMAC patients, thereby contributing to the prognostication of patients and clinical management.
Physiologically based pharmacokinetic modelling and simulation to predict the plasma concentration profile of schaftoside after oral administration of total flavonoids of Desmodium styracifolium
Authors: Li Xue , Chen Chao , Ding Nan , Zhang Tianjiao , Zheng Peiyong , Yang Ming 
Published: December 2022

Introduction: The total flavonoids of Desmodium styracifolium (TFDS) are the flavonoid extracts purified from Desmodii Styracifolii Herba. The capsule of TFDS was approved for the treatment of urolithiasis by NMPA in 2022. Schaftoside is the representative compound of TFDS that possesses antilithic and antioxidant effects. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model of schaftoside to simulate its plasma concentration profile in rat and human after oral administration of the total flavonoids of Desmodium styracifolium.Methods: The physiologically based pharmacokinetic model of schaftoside was firstly developed and verified by the pharmacokinetic data in rats following intravenous injection and oral administration of the total flavonoids of Desmodium styracifolium. Then the PBPK model was extrapolated to human with PK-Sim® software. In order to assess the accuracy of the extrapolation, a preliminary multiple-dose clinical study was performed in four healthy volunteers aged 18–45 years old. The predictive performance of PBPK model was mainly evaluated by visual predictive checks and fold error of Cmax and AUC0-t of schaftoside (the ratio of predicted to observed). Finally, the adult PBPK model was scaled to several subpopulations including elderly and renally impaired patients.Results: Schaftoside underwent poor metabolism in rat and human liver microsomes in vitro, and in vivo it was extensively excreted into urine and bile as an unchanged form. By utilizing literature and experimental data, the PBPK model of schaftoside was well established in rat and human. The predicted plasma concentration profiles of schaftoside were consistent with the corresponding observed data, and the fold error values were within the 2-fold acceptance criterion. No significant pharmacokinetic differences were observed after extrapolation from adult (18–40 years old) to elderly populations (71–80 years) in PK-Sim®. However, the plasma concentration of schaftoside was predicted to be much higher in renally impaired patients. The maximum steady-state plasma concentrations in patients with chronic kidney disease stage 3, 4 and 5 were 3.41, 12.32 and 23.77 times higher, respectively, than those in healthy people.Conclusion: The established PBPK model of schaftoside provided useful insight for dose selection of the total flavonoids of Desmodium styracifolium in different populations. This study provided a feasible way for the assessment of efficacy and safety of herbal medicines.