Miracle-dz/UniFAR-FTUs huggingface dataset:
Executive functions and psychosocial impairment in children following arterial ischemic stroke

ABSTRACT This study examined the executive function (EF) of children with a history of arterial ischemic stroke (AIS) and preserved intellectual abilities, with reference to age at stroke onset, lesion characteristics, language, and motor functioning. In addition, the associations between EF and emotional and behavioral functioning were investigated. A battery of standardized neuropsychological tests was administered to children with previous AIS aged 7–12 in order to assess EF, including inhibition, working memory, cognitive flexibility, and attention. Parents rated questionnaires regarding real-life emotional and behavioral functioning. Finally, clinical and neuroradiological data were also gathered. Thirty patients were enrolled. Eight children fall in the lower end of the normative range or below in more than half of the EF measures, with working memory, inhibition and cognitive flexibility equally impaired, and attention relatively better preserved. Larger lesion size and language deficits were significantly associated with higher EF impairment. Emotional and behavioral functioning was lower in children with weaker EF. Children with a history of AIS, even those with preserved intellectual functioning, have a high risk of showing poor EF, mostly regardless of clinical features or functional impairment. EF difficulties are in turn associated with emotional and behavioral problems. Therefore, a standardized evaluation of EF in this population is mandatory as part of the follow-up, in order to ensure an early intervention and prevent related difficulties.
Intramyocardial Adiposity After Myocardial Infarction: New Implications of a Substrate for Ventricular Tachycardia

Background— Collagen has been attributed as the principal structural substrate of ventricular tachycardia (VT) after myocardial infarction (MI), even though adiposity of myocardium after MI is well recognized histologically. We investigated the effects of intramyocardial adiposity compared with collagen on electrophysiological properties, connexin43 expression, and VT induction after MI. Methods and Results— Simultaneous left ventricular plunge-needle, noncontact mapping was performed in sheep without MI (MI−; n=5), with MI and inducible VT (MI+VT+; n=7), and with MI and no inducible VT (MI+VT−; n=8). Histological intramyocardial quantity of adipose and collagen and degree of discontinuity were coregistered with electrophysiological parameters (MI+; 290 specimens). Additional assessment of connexin43 expression was performed. Left ventricular scar contained a body mass–independent abundance of adipocytes (adipose:collagen=0.8). Increased adipose density and discontinuity contributed to a greater inverse correlation (r) with conduction velocity (r for adipose=0.39, r for discontinuity=0.45, r for collagen=0.26) and electrogram amplitude (r for adipose=0.73, r for contiguity=0.77, r for collagen=0.68) compared with collagen. Collagen density was similar between the MI+ groups (P>0.29). However, the MI+VT+ group demonstrated a significant (all P⩽0.01) increase in adipose (8%) and discontinuity (qualitative) and decrease in conduction velocity (13%) and electrogram amplitude (21%) at MI borders compared with the MI+VT− group. In scar, myocytes adjacent to fibrofatty interfaces demonstrated increased connexin43 lateralization. A gradient increase in adipose was observed at sites that supported preferential presystolic VT activation and exhibited attenuation of excitation wavelength (P<0.001). Conclusions— Intramyocardial adiposity, in association with myocardial discontinuity within left ventricular scar borders, is a significant factor associated with altered electrophysiological properties, aberrant connexin43 expression, and increased propensity for VT after MI.
Predicting which genes will respond to transcription factor perturbations

Abstract The ability to predict which genes will respond to the perturbation of a transcription factor serves as a benchmark for our systems-level understanding of transcriptional regulatory networks. In previous work, machine learning models have been trained to predict static gene expression levels in a biological sample by using data from the same or similar samples, including data on their transcription factor binding locations, histone marks, or DNA sequence. We report on a different challenge—training machine learning models to predict which genes will respond to the perturbation of a transcription factor without using any data from the perturbed cells. We find that existing transcription factor location data (ChIP-seq) from human cells have very little detectable utility for predicting which genes will respond to perturbation of a transcription factor. Features of genes, including their preperturbation expression level and expression variation, are very useful for predicting responses to perturbation of any transcription factor. This shows that some genes are poised to respond to transcription factor perturbations and others are resistant, shedding light on why it has been so difficult to predict responses from binding locations. Certain histone marks, including H3K4me1 and H3K4me3, have some predictive power when located downstream of the transcription start site. However, the predictive power of histone marks is much less than that of gene expression level and expression variation. Sequence-based or epigenetic properties of genes strongly influence their tendency to respond to direct transcription factor perturbations, partially explaining the oft-noted difficulty of predicting responsiveness from transcription factor binding location data. These molecular features are largely reflected in and summarized by the gene’s expression level and expression variation. Code is available at https://github.com/BrentLab/TFPertRespExplainer.
Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis

Objective To evaluate the dose-response relationship of 10, 20, and 40 mg ponesimod and long-term efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and Extension studies in patients with relapsing-remitting multiple sclerosis (RRMS). Methods In the Core study, 464 patients were randomized (1:1:1:1): placebo (n = 121), 10 mg (n = 108), 20 mg (n = 116), or 40 mg ponesimod (n = 119) once daily for 24 weeks. Patients who completed the Core study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks) and TP2 and TP3 (up to 432 weeks). The 40 mg dose was discontinued due to low tolerability at the end of TP1, and the 10 mg dose was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated. Results A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg = 139, 20 mg = 145, and 40 mg = 151) at any time during the Core and/or the Extension study. As of March 31, 2019, 214 patients were still on ponesimod treatment. The median (range) of ponesimod exposure was 7.95 (0–9.36) years. Ponesimod 20 mg, from Core up to the end of TP3, was associated with sustained low clinical activity (ARR for confirmed relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9%, and 6-month CDA was 20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common adverse events were nasopharyngitis (30%), headache (24%), and upper respiratory tract infection (21%). Conclusion The effects on multiple sclerosis disease control were maintained with ponesimod 20 mg for approximately 8 years with no new safety concerns identified. Classification of Evidence This study provides Class IV evidence that in individuals with RRMS, long-term treatment with ponesimod 20 mg was associated with a sustained low annualized confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free. Trial Registration Information EudraCT Number 2008-006786-92 (Core study) and EudraCT Number 2009-011470-15 (Extension study).
Adverse perinatal outcomes associated with timing of initiation of antiretroviral therapy: Systematic review and meta‐analysis

The World Health Organization (WHO) recommends immediate initiation of lifelong antiretroviral therapy (ART) for all people living with HIV, including pregnant women. As a result, an increasing number of women living with HIV conceive while taking ART, the vast majority of whom reside in low‐ and middle‐income countries (LMICs). We aimed to assess the association between timing of ART initiation and perinatal outcomes.
The space-time profiles of sleep spindles and their coordination with slow oscillations on the electrode manifold

Abstract Sleep spindles are important for sleep quality and cognitive functions, with their coordination with slow oscillations (SOs) potentially organizing cross-region reactivation of memory traces. Here, we describe the organization of spindles on the electrode manifold and their relation to SOs. We analyzed the sleep night EEG of 34 subjects and detected spindles and SOs separately at each electrode. We compared spindle properties (frequency, duration, and amplitude) in slow wave sleep (SWS) and Stage 2 sleep (S2); and in spindles that coordinate with SOs or are uncoupled. We identified different topographical spindle types using clustering analysis that grouped together spindles co-detected across electrodes within a short delay (±300 ms). We then analyzed the properties of spindles of each type, and coordination to SOs. We found that SWS spindles are shorter than S2 spindles, and spindles at frontal electrodes have higher frequencies in S2 compared to SWS. Furthermore, S2 spindles closely following an SO (about 10% of all spindles) show faster frequency, shorter duration, and larger amplitude than uncoupled ones. Clustering identified Global, Local, Posterior, Frontal-Right and Left spindle types. At centro-parietal locations, Posterior spindles show faster frequencies compared to other types. Furthermore, the infrequent SO-spindle complexes are preferentially recruiting Global SO waves coupled with fast Posterior spindles. Our results suggest a non-uniform participation of spindles to complexes, especially evident in S2. This suggests the possibility that different mechanisms could initiate an SO-spindle complex compared to SOs and spindles separately. This has implications for understanding the role of SOs-spindle complexes in memory reactivation.
Recurrent ancient geomagnetic field anomalies shed light on future evolution of the South Atlantic Anomaly

Significance Earth’s magnetic field, which is generated through convection in the liquid iron–rich outer core, acts as a shield against harmful particle radiation. During the past two centuries, the field strength has decreased rapidly as an area of weak field has expanded over the South Atlantic Ocean. The decreased shielding effect of the magnetic field in this area has important implications for low Earth-orbiting satellites and space travel. Using archeological and geological records, we have reconstructed the variations of Earth’s magnetic field over the past 9,000 y. We find evidence for recurrent magnetic field anomalies, similar to the present-day South Atlantic Anomaly, which provides insights into underlying geodynamo processes that may help predict the future development of Earth’s magnetic field.
MutL binds to 3′ resected DNA ends and blocks DNA polymerase access

Abstract DNA mismatch repair removes mis-incorporated bases after DNA replication and reduces the error rate a 100–1000-fold. After recognition of a mismatch, a large section of up to a thousand nucleotides is removed from the daughter strand followed by re-synthesis. How these opposite activities are coordinated is poorly understood. Here we show that the Escherichia coli MutL protein binds to the 3′ end of the resected strand and blocks access of Pol I and Pol III. The cryo-EM structure of an 85-kDa MutL-DNA complex, determined to 3.7 Å resolution, reveals a unique DNA binding mode that positions MutL at the 3′ end of a primer-template, but not at a 5′ resected DNA end or a blunt DNA end. Hence, our work reveals a novel role for MutL in the final stages of mismatch repair by preventing premature DNA synthesis during removal of the mismatched strand.
Sex moderates the effects of total sleep deprivation and sleep restriction on risk preference

Abstract Sleep loss has been shown to alter risk preference during decision-making. However, research in this area has largely focussed on the effects of total sleep deprivation (TSD), while evidence on the effects of sleep restriction (SR) or the potentially moderating role of sex on risk preference remains scarce and unclear. The present study investigated risky decision-making in 47 healthy young adults who were assigned to either of two counterbalanced protocols: well-rested (WR) and TSD, or WR and SR. Participants were assessed on the Lottery Choice Task (LCT), which requires a series of choices between two risky gambles with varying risk levels. Analyses on the pooled dataset indicated across all sleep conditions, participants were generally more risk-seeking when trying to minimise financial loss (LOSSES) than while trying to maximise financial gain (GAINS). On GAINS trials, female participants were more risk-averse during TSD and SR, whereas male participants remained unchanged. On LOSSES trials, female participants remained unchanged during TSD and SR, whereas male participants became more risk-seeking during TSD. Our findings suggest the relationship between sleep loss and risk preference is moderated by sex, whereby changes in risk preference after TSD or SR differ in men and women depending on whether the decision is framed in terms of gains or losses.
Destination unknown: Parents and healthcare professionals' perspectives on transition from paediatric to adult care in Down syndrome

Abstract Background Transitioning from paediatric medical care to adult care is a challenging process for children, parents and healthcare professionals. The aim of this study was to explore the experiences, concerns and needs of parents of children with Down syndrome and of professionals regarding this transition. Method A qualitative study was performed using semi‐structured interviews with 20 parents of children with Down syndrome and six healthcare professionals. Results We showed that parents and professionals have concerns during each of the three distinct phases of transition (preparation, transfer and integration). Data disclose specific concerns regarding communication, continuity of care and rebuilding trust. We propose a framework for the transition to adult care. Conclusions The transition in medical care for children with Down syndrome should be flexible, patient‐centred and coordinated together with patients and parents. Only in ensuring continuity of care will individuals with Down syndrome not get lost in transition.
Biomarkers for Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced/Metastatic Breast Cancer: Translation to Clinical Practice

PURPOSE Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as effective treatments for patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced/metastatic breast cancer (mBC). Dedicated research efforts have been undertaken to find predictive biomarkers of response or resistance to these therapies although no molecular biomarkers for mBC have reached the clinic so far. This review aims to summarize and evaluate the performance of biomarkers in predicting progression-free survival in phase II and III clinical trials of CDK4/6 inhibitors in HR+/HER2– mBC. METHODS For this narrative review, a structured literature search of PubMed, Embase, and the Cochrane library (CENTRAL) was performed. Phase II or III clinical trials of a CDK4/6 inhibitor in patients with HR+/HER2– mBC reporting on at least one molecular biomarker analysis of progression-free survival were included. Publications and selected conference abstracts were included up until November 2021. RESULTS Twenty-two articles reporting biomarker results of 12 clinical trials were included. Retinoblastoma protein status and cyclin E1 mRNA expression were promising baseline biomarkers, whereas PIK3CA circulating tumor DNA ratio on treatment relative to baseline, change in plasma thymidine kinase activity, and circulating tumor cell count were potential dynamic biomarkers of response. A number of biomarkers were unsuccessful, despite a strong mechanistic rationale, and others are still being explored. CONCLUSION Our review of clinical trials showed that there are a number of promising biomarkers at baseline and several dynamic biomarkers that might predict response to CDK4/6 inhibitors. Validation of these findings and assessment of clinical utility are crucial to make the final translation to clinical practice. Better understanding of disease heterogeneity and further elucidation of resistance mechanisms could inform future studies of rationally selected biomarkers.
Global longitudinal strain and outcome after endoscopic mitral valve repair

Identification of heart failure (HF) patients with secondary mitral regurgitation (SMR) that benefit from mitral valve (MV) repair remains challenging. We have focused on the role of left ventricular global longitudinal strain (LV‐GLS) and reservoir left atrial longitudinal strain (LASr) for the prediction of long‐term survival and reverse remodelling in patients with SMR undergoing endoscopic MV repair.
The intracellular pathogen Francisella tularensis escapes from adaptive immunity by metabolic adaptation

This study shows that metabolic adaptation allows the intracellular bacterial pathogen Francisella tularensis to escape recognition by the host adaptive immunity. Intracellular pathogens lose many metabolic genes during their evolution from free-living bacteria, but the pathogenic consequences of their altered metabolic programs on host immunity are poorly understood. Here, we show that a pathogenic strain of Francisella tularensis subsp. tularensis (FT) has five amino acid substitutions in RibD, a converting enzyme of the riboflavin synthetic pathway responsible for generating metabolites recognized by mucosal-associated invariant T (MAIT) cells. Metabolites from a free-living strain, F. tularensis subsp. novicida (FN), activated MAIT cells in a T-cell receptor (TCR)–dependent manner, whereas introduction of FT-type ribD to the free-living strain was sufficient to attenuate this activation in both human and mouse MAIT cells. Intranasal infection in mice showed that the ribDFT-expressing FN strain induced impaired Th1-type MAIT cell expansion and resulted in reduced bacterial clearance and worsened survival compared with the wild-type free-living strain FN. These results demonstrate that F. tularensis can acquire immune evasion capacity by alteration of metabolic programs during evolution. Graphical Abstract
Online Unsupervised Domain Adaptation via Reducing Inter- and Intra-Domain Discrepancies

Unsupervised domain adaptation (UDA) transfers knowledge from a labeled source domain to an unlabeled target domain on cross-domain object recognition by reducing a distribution discrepancy between the source and target domains (interdomain discrepancy). Prevailing methods on UDA were presented based on the premise that target data are collected in advance. However, in online scenarios, the target data often arrive in a streamed manner, such as visual image recognition in daily monitoring, which means that there is a distribution discrepancy between incoming target data and collected target data (intradomain discrepancy). Consequently, most existing methods need to re-adapt the incoming data and retrain a new model on online data. This paradigm is difficult to meet the real-time requirements of online tasks. In this study, we propose an online UDA framework via jointly reducing interdomain and intradomain discrepancies on cross-domain object recognition where target data arrive in a streamed manner. Specifically, the proposed framework comprises two phases: classifier training and online recognition phases. In the former, we propose training a classifier on a shared subspace where there is a lower interdomain discrepancy between the two domains. In the latter, a low-rank subspace alignment method is introduced to adapt incoming data to the shared subspace by reducing the intradomain discrepancy. Finally, online recognition results can be obtained by the trained classifier. Extensive experiments on DA benchmarks and real-world datasets are employed to evaluate the performance of the proposed framework in online scenarios. The experimental results show the superiority of the proposed framework in online recognition tasks.
Predictors of Substance Use Disorder Treatment Initiation and Engagement among Adolescents Enrolled in Medicaid

Background: Adolescents with substance use disorders (SUD) should receive timely access to treatment to improve lifelong outcomes. The Healthcare Effectiveness Data and Information Set (HEDIS) initiation and engagement in treatment (IET) performance measure was intended to promote quality improvement for patients with SUD. Yet, few studies have assessed predictors of measure performance among adolescents or other engagement in mental health services, which is critical to understanding disparities in treatment quality or opportunities for targeted improvement strategies. The present study reports the rates and predictors of IET among adolescents with SUD, as well as receipt of any mental health services. Methods: The sample included adolescents enrolled in Medicaid in 14 states who had a qualifying diagnosis for SUD (2009–2013) and met HEDIS IET performance measure eligibility criteria. Three outcomes were assessed, including initiation of SUD treatment within 14 days of qualifying diagnosis, engagement in SUD treatment (2 or more encounters) within 30 days of initiation, and receipt of any mental health services (1 or more encounters) within 30 days of initiation. Logistic regression was used to identify demographic and clinical characteristics associated with outcomes. Results: Among 20,602 adolescents who met eligibility criteria, 49.5% initiated SUD treatment, 48.5% engaged in SUD treatment, and 70% received any mental health service. Adolescents with higher levels of clinical need (e.g., medical complexity, mental health comorbidity, and multiple SUD diagnoses) had significantly higher odds of initiating, but lower odds of engaging in treatment or receiving any mental health service. Conclusions: To increase the delivery of SUD treatment, efforts should target adolescents with co-occurring mental health needs, many of whom are receiving mental health services after SUD diagnosis. Integrating addiction and mental health services could address these missed opportunities.