Miracle-dz/UniFAR-FTUs huggingface dataset:
Thrombosis is associated with worse survival in children with acute lymphoblastic leukemia: A report from CYP‐C

There are conflicting data about whether the development of cancer‐associated thrombo‐embolism (TE) negatively impacts survival in children. The objective was to determine whether TE during treatment was associated with overall survival (OS) and event‐free survival (EFS) in children with acute lymphoblastic leukemia (ALL). We performed a population‐based retrospective cohort study using the Cancer in Young People‐Canada registry. Children <15 years of age were diagnosed with de novo ALL (2000–2016). The primary exposure variable was radiologically‐confirmed thrombo‐embolism requiring medical intervention. Multivariable Cox regression models were used to determine the impact of thrombo‐embolism on survival, where TE was time‐dependent. We included 2006 children (median age: 4 years, 88.5% precursor B‐cell ALL). Thrombo‐embolism occurred in 113 patients (5.6%), at a median time of 107 days (interquartile range: 35–184 days) after ALL diagnosis. Among standard/low‐risk patients, 41/1165 (3.5%) developed TE while among high/very high‐risk patients, 72/841 (8.6%) developed TE. Patients with TE had a significantly worse OS (adjusted HR [aHR] of death: 2.61, 95% CI: 1.62–4.22, p < 0.001) and EFS (aHR of an event [death, relapse, second malignancy]: 2.03, 95% CI: 1.35–3.05, p = 0.001), compared with patients without TE. No statistically significant difference was seen in standard/low risk ALL for OS and EFS, but TE was associated with a significantly lower OS and EFS in children with high/very high‐risk ALL (aHR of death: 2.90, 95% CI: 1.79–4.72, p < 0.001; aHR of an event: 2.02, 95% CI: 1.30–3.12, p = 0.002). Thus, TE led to a statistically significant reduction in OS and EFS in children with high risk/very high‐risk leukemia.
The impact of COVID‐19 on body‐dissatisfied female university students

Abstract Objective This study investigated the impact of COVID‐19 on young women's disordered eating and their responses to online interventions to reduce disordered eating. Method University students at risk of developing an eating disorder (N = 100) were randomly assigned to either receiving an online intervention to reduce disordered eating or not. Forty‐one participants entered the study from September 2019 to March 2020 (pre‐COVID) and 59 after physical distancing was introduced due to COVID pandemic (during COVID). Online assessments were conducted at baseline and 1‐week follow up. Results There was a significant increase in weight concerns, disordered eating, and negative affect among participants entering the trial during COVID compared to pre‐COVID. The increases in the first two variables remained when adjusting for baseline negative affect. No significant interactions between time, condition and COVID status were observed. Discussion Young women experienced increased levels of disordered eating after the onset of COVID. While no interactions with COVID were detected, changes to within‐group effect sizes for disordered eating more than doubled for both online interventions and assessment from pre‐COVID to during COVID, suggesting any attention to issues related to disordered eating in the context of reduced social contact may be beneficial.
Colloid Formation and Sorption of Radionuclides in Natural Systems

Natural systems comprising sediments and groundwaters of low and of high salinity are investigated with respect to the formation and the influence of coarsely dispersed particles and finely dispersed particles (colloids). Equations are derived for the sorption equilibria in such systems and it is shown that the efficiencies of mutual separation of coarsely dispersed particles, finely dispersed particles and sediments (efficiencies of filtering) strongly influence the sorption ratios that are observed. In groundwater without sediments the formation of colloids of radioactive Ce is demonstrated, whereas Cs and Sr ì + do not form colloids under these conditions, as expected. The amounts of elements and of colloids given off by the sediments into the groundwaters are measured for the samples of low and of high salinity and the influence of agitation is shown. Sorption ratios of radioactive Cs, Sr î + , and Ce are investigated as function of the ratio of the groundwater volume to the mass of the sediment without filtration, after filtration through 0.45 Mm filters and after ultrafiltration. The results are discussed on the basis of the equations derived. It is shown that Cs ions are sorbed mainly on the clay particles and that the larger amount of these clay particles has grain sizes greater than 0.45 Mm under the experimental conditions of smooth shaking. Sr + ions are mainly sorbed on the sediments with a relatively low sorption ratio. Ce + ions form colloids ("Eigenkolloide") that are retained by ultrafiltration.
Reply to: “Gaps, Controversies, and Proposed Roadmap for Research in Normal Pressure Hydrocephalus”

I congratulate Fasano et al for their excellent systematic approach in dealing with a variety of diagnostic and treatment issues related to normal pressure hydrocephalus (NPH) and proposing a roadmap for future research. In my, and others’, clinical experience, several other considerations are also important that were not fully addressed in this article and could merit further discussion. First, the utility of a levodopa trial, as part of a standardized protocol, to unmask levodopa-responsive parkinsonism as a contributing factor to gait impairment, could have been discussed further in this review. Not only atypical parkinsonism, similar to progressive supranuclear palsy, but also Parkinson’s disease (and of course Lewy body dementia) can be present in patients with cerebral ventriculomegaly. Moreover, the role of spine imaging to exclude myelopathy seems in my opinion to be also clinically relevant, and in my practice, I tend to image both the cervical and lumbar spine. In addition, this article did not fully address other radiographic parameters as possible diagnostic tools and predictors of shunt responsiveness, such as aqueductal cerebrospinal fluid stroke volume and flow. Whether the neuroimaging composite scores such as the NPH Radscale mentioned in the article by Fasano et al can also serve as predictors of shunt responsiveness is worth further exploration in future studies. A discussion about differences, if any, in the clinical manifestation of late-onset aqueductal stenosis and the role of endoscopic third ventriculostomy could have been worthwhile as well. Finally, it could be worth emphasizing the importance of a multidisciplinary approach to the diagnosis and treatment of NPH, including an experienced geriatric neurologist, neurosurgeon, neuropsychologist, and physical therapist.
Right ventricular outflow tract stenting in symptomatic infants without the use of a long delivery sheath

Right ventricular outflow tract (RVOT) stenting improves systemic oxygenation and facilitates pulmonary arterial growth in symptomatic infants prior to repair of tetralogy of Fallot. The aim of this study was to evaluate the safety and efficacy of RVOT stenting without the use of a long delivery sheath.
Effectiveness of Chinese herbal medicine combined with Western medicine on deferring dialysis initiation for nondialysis chronic kidney disease stage 5 patients: a multicenter prospective nonrandomized controlled study

Background In clinical practice, Chinese herbal medicine (CHM) purportedly has beneficial therapeutic effects for chronic kidney disease (CKD), which include delaying disease progression and dialysis initiation. However, there is a lack of high-quality evidence-based results to support this. Therefore, this study aimed to evaluate the efficacy of CHM combined with Western medicine in the treatment of stage 5 CKD. Methods This was a prospective nonrandomized controlled study. Stage 5 CKD (nondialysis) patients were recruited form 29 AAA class hospitals across China from July 2014 to April 2019. According to doctors’ advice and the patients’ wishes, patients were assigned to the CHM group (Western medicine + CHM) and the non-CHM group (Western medicine). Patient demographic data, primary disease, blood pressure, Chinese and Western medical drugs, clinical test results, and time of dialysis initiation were collected during follow-up. Results A total of 908 patients were recruited in this study, and 814 patients were finally included for further analysis, including 747 patients in the CHM group and 67 patients in the non-CHM group. 482 patients in the CHM group and 52 patients in the non-CHM group initiated dialysis. The median time of initiating dialysis was 9 (7.90, 10.10) and 3 (0.98,5.02) months in the CHM group and non-CHM group, respectively. The multivariate Cox regression analysis showed that patients in the CHM group had a significantly lower risk of dialysis [adjusted hazard ratio (aHR): 0.38; 95% confidence interval (CI): 0.28, 0.53] compared to those in the non-CHM group. After 1:2 matching, the outcomes of 160 patients were analyzed. The multivariate Cox regression analysis showed that patients in the CHM group had a significantly lower risk of dialysis (aHR: 0.32; 95% CI: 0.21, 0.48) compared to patients in the non-CHM group. Also, the Kaplan-Meier analysis demonstrated that the cumulative incidence of dialysis in the CHM group was significantly lower than that in the non-CHM group (log-rank test, P<0.001) before and after matching. Conclusions This study suggest that the combination of CHM and Western medicine could effectively reduce the incidence of dialysis and delay the time of dialysis initiation in stage 5 CKD patients.
Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein

Many viruses adapt rapidly to novel selection pressures, such as antiviral drugs. Understanding how pathogens evolve under drug selection is critical for the success of antiviral therapy against human pathogens. ABSTRACT RNA viruses, such as hepatitis C virus (HCV), influenza virus, and SARS-CoV-2, are notorious for their ability to evolve rapidly under selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation. However, less attention has been paid to the underlying fitness landscape that represents the selection forces on viral genomes, especially under different selection conditions. Here, we systematically quantified the distribution of fitness effects of about 1,600 single amino acid substitutions in the drug-targeted region of NS5A protein of HCV. We found that the majority of nonsynonymous substitutions incur large fitness costs, suggesting that NS5A protein is highly optimized. The replication fitness of viruses is correlated with the pattern of sequence conservation in nature, and viral evolution is constrained by the need to maintain protein stability. We characterized the adaptive potential of HCV by subjecting the mutant viruses to selection by the antiviral drug daclatasvir at multiple concentrations. Both the relative fitness values and the number of beneficial mutations were found to increase with the increasing concentrations of daclatasvir. The changes in the spectrum of beneficial mutations in NS5A protein can be explained by a pharmacodynamics model describing viral fitness as a function of drug concentration. Overall, our results show that the distribution of fitness effects of mutations is modulated by both the constraints on the biophysical properties of proteins (i.e., selection pressure for protein stability) and the level of environmental stress (i.e., selection pressure for drug resistance). IMPORTANCE Many viruses adapt rapidly to novel selection pressures, such as antiviral drugs. Understanding how pathogens evolve under drug selection is critical for the success of antiviral therapy against human pathogens. By combining deep sequencing with selection experiments in cell culture, we have quantified the distribution of fitness effects of mutations in hepatitis C virus (HCV) NS5A protein. Our results indicate that the majority of single amino acid substitutions in NS5A protein incur large fitness costs. Simulation of protein stability suggests viral evolution is constrained by the need to maintain protein stability. By subjecting the mutant viruses to selection under an antiviral drug, we find that the adaptive potential of viral proteins in a novel environment is modulated by the level of environmental stress, which can be explained by a pharmacodynamics model. Our comprehensive characterization of the fitness landscapes of NS5A can potentially guide the design of effective strategies to limit viral evolution.
Nox3-Derived Superoxide in Cochleae Induces Sensorineural Hearing Loss

Reactive oxygen species (ROS) produced by NADPH oxidases (Nox) contribute to the development of different types of sensorineural hearing loss (SNHL), a common impairment in humans with no established treatment. Although the essential role of Nox3 in otoconia biosynthesis and its possible involvement in hearing have been reported in rodents, immunohistological methods targeted at detecting Nox3 expression in inner ear cells reveal ambiguous results. Therefore, the mechanism underlying Nox3-dependent SNHL remains unclear and warrants further investigation. We generated Nox3-Cre knock-in mice, in which Nox3 was replaced with Cre recombinase (Cre). Using Nox3-Cre;tdTomato mice of either sex, in which tdTomato is expressed under the control of the Nox3 promoter, we determined Nox3-expressing regions and cell types in the inner ear. Nox3-expressing cells in the cochlea included various types of supporting cells, outer hair cells, inner hair cells, and spiral ganglion neurons. Nox3 expression increased with cisplatin, age, and noise insults. Moreover, increased Nox3 expression in supporting cells and outer hair cells, especially at the basal turn of the cochlea, played essential roles in ROS-related SNHL. The extent of Nox3 involvement in SNHL follows the following order: cisplatin-induced hearing loss > age-related hearing loss > noise-induced hearing loss. Here, on the basis of Nox3-Cre;tdTomato, which can be used as a reporter system (Nox3-Cre+/−;tdTomato+/+ and Nox3-Cre+/+;tdTomato+/+), and Nox3-KO (Nox3-Cre+/+;tdTomato+/+) mice, we demonstrate that Nox3 inhibition in the cochlea is a promising strategy for ROS-related SNHL, such as cisplatin-induced HL, age-related HL, and noise-induced HL. SIGNIFICANCE STATEMENT We found Nox3-expressing regions and cell types in the inner ear, especially in the cochlea, using Nox3-Cre;tdTomato mice, a reporter system generated in this study. Nox3 expression increased with cisplatin, age, and noise insults in specific cell types in the cochlea and resulted in the loss (apoptosis) of outer hair cells. Thus, Nox3 might serve as a molecular target for the development of therapeutics for sensorineural hearing loss, particularly cisplatin-induced, age-related, and noise-induced hearing loss.
Sera neutralizing activities against SARS-CoV-2 and multiple variants six month after hospitalization for COVID-19

Abstract Background Humoral response to SARS-CoV-2 occurs within the first weeks after COVID-19. Those antibodies exert a neutralizing activity against SARS-CoV-2, whose evolution overtime after COVID-19 as well as efficiency against novel variants are however poorly characterized. Methods In this prospective study, sera of 107 patients hospitalized with COVID-19 were collected at 3- and 6-months post-infection. We performed quantitative neutralization experiments on top of high-throughput serological assays evaluating anti-Spike (S) and anti-Nucleocapsid (NP) IgG. Findings Levels of sero-neutralization and IgG rates against the ancestral strain decreased significantly over time. After 6 months, 2.8% of the patients had a negative serological status for both anti-S and anti-NP IgG. However, all sera had a persistent and effective neutralizing effect against SARS-CoV-2. IgG levels correlated with sero-neutralization and this correlation was stronger for anti-S than for anti-NP antibodies. The level of sero-neutralization quantified at 6 months correlated with markers of initial severity, notably admission in intensive care units and the need for mechanical invasive ventilation. In addition, sera collected at 6 months were tested against multiple SARS-CoV-2 variants and showed efficient neutralizing effects against D614G, B.1. 1.7 and P.1 variants but a significantly weaker activity against B.1. 351 variant. Interpretation Decrease of IgG rates and serological assays becoming negative did not imply loss of neutralizing capacity. Our results indicate a sustained humoral response against the ancestral strain and the D614G, B.1. 1.7 and P.1 variants for at least 6 months in patients previously hospitalized for COVID-19. A weaker protection was however observed for the B.1. 351 variant.
Structure–property relationships in twist-bend nematogens: the influence of terminal groups

ABSTRACT The synthesis and characterisation of a range of non-symmetric liquid crystal dimers designed to exhibit the twist-bend nematic phase is reported. Beginning with 1-(4-cyanobiphenyl-4′-yloxy)-6-(4-cyanobiphenyl-4′-yl) hexane, each nitrile group is exchanged systematically for a methoxy group. The behaviour of these dimers is interpreted in terms of their bent shape being the predominant driving force for the formation of the twist-bend nematic phase, and the small differences between the twist-bend nematic–nematic transition temperatures are attributed to the differences between the interaction strength parameters of the mesogenic units. The 4-alkyloxyphenyl 4-[6-(4′-cyanobiphenyl-4-yl)hexyloxy]benzoates with ethyl, butyl, hexyl and octyl chains show the twist-bend nematic phase, whereas the corresponding 4-alkyloxyphenyl 4-[5-(4′-cyanobiphenyl-4-yloxy)pentyloxy]benzoates do not. This difference in behaviour is attributed to the more bent structure of the former. Increasing the terminal chain length initially decreases the twist-bend nematic–nematic transition temperature and this suggests that the chain disrupts the interactions between the mesogenic units. Subsequent increases in chain length have a smaller effect suggesting that the chain can be accommodated within an intercalated arrangement. The transitional behaviour of 1-(4-cyanobiphenyl-4′-yloxy)-6-(4-butyloxybiphenyl-4′-yl) hexane is compared to that of 1-(4-cyanobiphenyl-4′-yloxy)-6-(4-((S)-2-methyl)butyloxybiphenyl-4′-yl) hexane, and it is shown that chain branching strongly destabilises the twist-bend nematic phase. This is attributed to difficulties associated with packing the dimers. Graphical Abstract
The application of precision dosing in the use of sertraline throughout pregnancy for poor and ultrarapid metabolizer CYP 2C19 subjects: A virtual clinical trial pharmacokinetics study

Sertraline is known to undergo changes in pharmacokinetics during pregnancy. CYP 2C19 has been implicated in the interindividual variation in clinical effect associated with sertraline activity. However, knowledge of suitable dose titrations during pregnancy and within CYP 2C19 phenotypes is lacking. A pharmacokinetic modeling virtual clinical trials approach was implemented to: (i) assess gestational changes in sertraline trough plasma concentrations for CYP 2C19 phenotypes, and (ii) identify appropriate dose titration strategies to stabilize sertraline levels within a defined therapeutic range throughout gestation. Sertraline trough plasma concentrations decreased throughout gestation, with maternal volume expansion and reduction in plasma albumin being identified as possible causative reasons. All CYP 2C19 phenotypes required a dose increase throughout gestation. For extensive metabolizer (EM) and ultrarapid metabolizer (UM) phenotypes, doses of 100–150 mg daily are required throughout gestation. For poor metabolizers (PM), 50 mg daily during trimester 1 followed by a dose of 100 mg daily in trimesters 2 and 3 are required.
Feasibility of deep learning‐based fully automated classification of microsatellite instability in tissue slides of colorectal cancer

High levels of microsatellite instability (MSI‐H) occurs in about 15% of sporadic colorectal cancer (CRC) and is an important predictive marker for response to immune checkpoint inhibitors. To test the feasibility of a deep learning (DL)‐based classifier as a screening tool for MSI status, we built a fully automated DL‐based MSI classifier using pathology whole‐slide images (WSIs) of CRCs. On small image patches of The Cancer Genome Atlas (TCGA) CRC WSI dataset, tissue/non‐tissue, normal/tumor and MSS/MSI‐H classifiers were applied sequentially for the fully automated prediction of the MSI status. The classifiers were also tested on an independent cohort. Furthermore, to test how the expansion of the training data affects the performance of the DL‐based classifier, additional classifier trained on both TCGA and external datasets was tested. The areas under the receiver operating characteristic curves were 0.892 and 0.972 for the TCGA and external datasets, respectively, by a classifier trained on both datasets. The performance of the DL‐based classifier was much better than that of previously reported histomorphology‐based methods. We speculated that about 40% of CRC slides could be screened for MSI status without molecular testing by the DL‐based classifier. These results demonstrated that the DL‐based method has potential as a screening tool to discriminate molecular alteration in tissue slides.
Different roles of subcortical inputs in V1 responses to luminance and contrast

Cells in the primary visual cortex (V1) generally respond weakly to large uniform luminance stimuli. Only a subset of V1 cells is thought to encode uniform luminance information. In natural scenes, local luminance is an important feature for defining an object that varies and coexists with local spatial contrast. However, the strategies used by V1 cells to encode local mean luminance for spatial contrast stimuli remain largely unclear. Here, using extracellular recordings in anesthetized cats, we investigated the responses of V1 cells by comparing with those of retinal ganglion (RG) cells and lateral geniculate nucleus (LGN) cells to simultaneous and rapid changes in luminance and spatial contrast. Almost all V1 cells exhibited a strong monotonic increasing luminance tuning when they were exposed to high spatial contrast. Thus, V1 cells encode the luminance carried by spatial contrast stimuli with the monotonically increasing response function. Moreover, high contrast decreased luminance tuning of OFF cells but increased that of in ON cells in RG and LGN. The luminance and contrast tunings of LGN ON cells were highly separable as V1 cells, whereas those of LGN OFF cells were lowly separable. These asymmetrical effects of spatial contrast on ON/OFF channels might underlie the robust ability of V1 cells to perform luminance tuning when exposed to spatial contrast stimuli.