Miracle-dz/UniFAR-FTUs huggingface dataset:
Respiratory and Cardiovascular Outcomes in Survivors of Extremely Preterm Birth at 19 Years.

Rationale Growth and development during adolescence may modify the respiratory and vascular differences seen among extremely preterm (EP) individuals in childhood and early adolescence. Objective To assess the trajectory of respiratory and cardiovascular outcomes at transition to adulthood in a national longitudinal cohort study of births before 26 weeks of gestation in the UK and Eire. Method 129 EP participants and 65 controls attended for a center-based evaluation at 19 years of age. Standardized measures of spirometry, haemodynamics, functional capacity and markers of inflammation were made in EP subjects with and without neonatal bronchopulmonary dysplasia (BPD) and term born controls, at 19 years of age and compared to previous assessments. Results Compared to controls, the EP group were significantly impaired on all spirometric parameters (Mean FEV1 z score: -1.08 SD (95%CI: -1.40 to -0.77)) and had lower FeNO concentrations (13.9 vs. 24.4 ppb, p<0.001) despite a higher proportion with bronchodilator reversibility (27% vs. 6%). The EP group had significantly impaired exercise capacity. All respiratory parameters were worse following neonatal BPD and respiratory function differences were similar at 11 and 19 years. Augmentation index (AIx) was 6% higher in the EP group and associated with increased total peripheral resistance (difference in means 96.4 (95%CI: 26.6, 166.2) dyne/s/cm-5) and elevation in central but not peripheral blood pressure. Central systolic and diastolic blood pressure increased more quickly over adolescence in the EP group compared to controls. Conclusions Clinicians should address both cardiovascular and respiratory risk in adult survivors of extremely preterm birth.
Opposing effects of HNP1 (α-defensin-1) on plasma cholesterol and atherogenesis

Atherosclerosis, the predominant cause of death in well-resourced countries, may develop in the presence of plasma lipid levels within the normal range. Inflammation may contribute to lesion development in these individuals, but the underlying mechanisms are not well understood. Transgenic mice expressing α-def-1 released from activated neutrophils develop larger lipid and macrophage-rich lesions in the proximal aortae notwithstanding hypocholesterolemia caused by accelerated clearance of α-def-1/low-density lipoprotein (LDL) complexes from the plasma. The phenotype does not develop when the release of α-def-1 is prevented with colchicine. However, ApoE-/- mice crossed with α-def-1 mice or given exogenous α-def-1 develop smaller aortic lesions associated with reduced plasma cholesterol, suggesting a protective effect of accelerated LDL clearance. Experiments were performed to address this seeming paradox and to determine if α-def-1 might provide a means to lower cholesterol and thereby attenuate atherogenesis. We confirmed that exposing ApoE-/- mice to α-def-1 lowers total plasma cholesterol and decreases lesion size. However, lesion size was larger than in mice with total plasma cholesterol lowered to the same extent by inhibiting its adsorption or by ingesting a low-fat diet. Furthermore, α-def-1 levels correlated independently with lesion size in ApoE-/- mice. These studies show that α-def-1 has competing effects on atherogenesis. Although α-def-1 accelerates LDL clearance from plasma, it also stimulates deposition and retention of LDL in the vasculature, which may contribute to development of atherosclerosis in individuals with normal or even low plasma levels of cholesterol. Inhibiting α-def-1 may attenuate the impact of chronic inflammation on atherosclerotic vascular disease.
Detection and genotypes of Toxoplasma gondii DNA in feces of domestic cats in Colombia

The high prevalence of Toxoplasma gondii in the human population in Colombia has been linked to the existence of a high density of urban stray cats, exposing the whole population to a high density of oocysts. The goal of this study was to determine the DNA prevalence of T. gondii by conventional PCR and to phylogenetically analyze ROP18 sequences from positive samples in domestic cat (Felis catus) fecal samples in the city of Armenia, Quindío. Fecal samples from 140 cats were collected from 10 districts around the city. Samples were concentrated using Ritchie’s method and analyzed through optical microscopy. Concentrates were used for DNA extraction followed by nested PCR amplification for T. gondii gene B1. PCR for ROP18 was performed on all B1 positive samples; the ROP18 sequences obtained were related to the Archetype I Brazilian and Chinese strains. No oocysts were detected by optical microscopy; however, 17.8% (25/140) B1 and 24% (6/25) ROP18 PCR-positive samples were detected. Phylogenetic analyses showed that isolates clustered into a single group. We assessed whether associations existed between T. gondii positive fecal samples and survey variables such as cat healthcare and socioeconomic characteristics of owners, but no statistically significant associations were found. The presence of T. gondii in cat feces is an important factor contributing to the high prevalence in the human population of this city.
Bioabsorbable Versus Titanium Screws in Anterior Cruciate Ligament Reconstruction Using Hamstring Autograft: A Prospective, Randomized Controlled Trial With 13-Year Follow-up

Background: Bioabsorbable screws for anterior cruciate ligament reconstruction (ACLR) have been a popular choice, with theoretical advantages in imaging and surgery. Titanium and poly-L-lactic acid with hydroxyapatite (PLLA-HA) screws have been compared, but with less than a decade of follow-up. Purpose/Hypothesis: The purpose was to compare long-term outcomes of hamstring autograft ACLR using either PLLA-HA screws or titanium screws. We hypothesized there would be no difference at 13 years in clinical scores or tunnel widening between PLLA-HA and titanium screw types, along with high-grade resorption and ossification of PLLA-HA screws. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Forty patients undergoing ACLR were randomized to receive either a PLLA-HA screw or a titanium screw for ACL hamstring autograft fixation. Blinded evaluation was performed at 2, 5, and 13 years using the International Knee Documentation Committee score, Lysholm knee score, and KT-1000 arthrometer. Magnetic resonance imaging (MRI) was performed at 2 or 5 years and 13 years to evaluate tunnel volumes, ossification around the screw, graft integration, and cyst formation. Computed tomography (CT) of patients with PLLA-HA was performed at 13 years to evaluate tunnel volumes and intratunnel ossification. Results: No differences were seen in clinical outcomes at 2, 5, or 13 years between the 2 groups. At 13 years, tibial tunnel volumes were smaller for the PLLA-HA group (2.17 cm3) compared with the titanium group (3.33 cm3; P = .004). By 13 years, the PLLA-HA group had complete or nearly complete resorption on MRI or CT scan. Conclusion: Equivalent clinical results were found between PLLA-HA and titanium groups at 2, 5, and 13 years. Although PLLA-HA screws had complete or nearly complete resorption by 13 years, tunnel volumes remained largely unchanged, with minimal ossification.
Seizure First Aid Training For people with Epilepsy (SAFE) frequently attending emergency departments and their significant others: results of a UK multi-centre randomised controlled pilot trial

Objective To determine the feasibility and optimal design of a randomised controlled trial (RCT) of Seizure First Aid Training For Epilepsy (SAFE). Design Pilot RCT with embedded microcosting. Setting Three English hospital emergency departments (EDs). Participants Patients aged ≥16 with established epilepsy reporting ≥2 ED visits in the prior 12 months and their significant others (SOs). Interventions Patients (and their SOs) were randomly allocated (1:1) to SAFE plus treatment-as-usual (TAU) or TAU alone. SAFE is a 4-hour group course. Main outcome measures Two criteria evaluated a definitive RCT’s feasibility: (1) ≥20% of eligible patients needed to be consented into the pilot trial; (2) routine data on use of ED over the 12 months postrandomisation needed securing for ≥75%. Other measures included eligibility, ease of obtaining routine data, availability of self-report ED data and comparability, SAFE’s effect and intervention cost. Results Of ED attendees with a suspected seizure, 424 (10.6%) patients were eligible; 53 (12.5%) patients and 38 SOs consented. Fifty-one patients (and 37 SOs) were randomised. Routine data on ED use at 12 months were secured for 94.1% patients. Self-report ED data were available for 66.7% patients. Patients reported more visits compared with routine data. Most (76.9%) patients randomised to SAFE received it and no related serious adverse events occurred. ED use at 12 months was lower in the SAFE+TAU arm compared with TAU alone, but not significantly (rate ratio=0.62, 95% CI 0.33 to 1.17). A definitive trial would need ~674 patient participants and ~39 recruitment sites. Obtaining routine data was challenging, taking ~8.5 months. Conclusions In satisfying only one predetermined ‘stop/go’ criterion, a definitive RCT is not feasible. The low consent rate in the pilot trial raises concerns about a definitive trial’s finding’s external validity and means it would be expensive to conduct. Research is required into how to optimise recruitment from the target population. Trial registration number ISRCTN13871327
Microstate in resting state: an EEG indicator of tinnitus?

Abstract Background: Tinnitus was a subjective auditory phantom phenomenon which could be highly distressing and had no objective indicators for evaluation. Objectives: The aim of this study was to investigate whether and how did electroencephalography (EEG) microstates of subjective tinnitus patients change in resting state and whether could be an objective indicator for tinnitus. Material and Methods: We enrolled chronic subjective tinnitus patients and matched age and gender with healthy controls. EEG recording, microstate analysis and statistical analysis were performed. Results: We finally had 10 male and 8 female age-matched participants in tinnitus group and healthy control group. Statistical differences were found in the microstate A, C and D durations between the two groups (class A, p = .024; class B, p = .018; class D, p = .029). Microstate durations of class A and D had linear correlation with VAS scores in tinnitus patients (microstate A [R spare = 0.43, p = .003*]; microstate D [R spare = 0.46, p = .002*]). Conclusions: Microstates had changed in chronic tinnitus patients and provided an indicator or perspective to explore the mechanisms of tinnitus. The maintenance of chronic subjective tinnitus may be related to changes in cerebral cortex activity.
Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19

Supplemental Digital Content is available in the text. Rationale: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. Objective: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. Methods and Results: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55–68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57–69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19–0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15–0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12–0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. Conclusions: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.
Endothelial Dysfunction and Inflammation in Ischemic Stroke Pathogenesis.

Stroke is an heterogenous disease andwithin the broad large category of brain ischemia and its subtypesvary dramatically in cause. Endothelium is able to regulate the vascular homeostasis by modulating processes of vascular dilation and constriction by producing and secreting cytokines and chemical mediators and inflammation represent one of the most important factors that contribute to alteration in vessel structure and function by a dysregulation of this fine balance. Endothelial dysfunction represents a basic determinant of the vascular damage which can be identified in all different clinical subtypes of stroke and, recently, it has been recognized as an interesting determinant of cerebrovascular risk. The entire spectrum of inflammatory processes is likely to act in concert and cytokines are important mediators of stroke by inducing immunological/inflammatory reactions, which contribute to brain infarct progression as well as to the disease severity and outcome. Results from recent studies, and ongoing and future researches, will allow to better characterize these complex mechanismsand finally leading to innovative therapeutic strategies that may change significantly the natural history of this severe and disabling disease.
Developments and Applications of Functional Protein Microarrays*

Functional protein microarray is a crucial tool in the study of proteins in native, unbiased, and high-throughput manner. There is a wide variety of applications, including the study of proteome-wide molecular interactions, analysis of post-translational modifications, identification of novel drug targets, and examination of pathogen-host interactions. Functional protein microarray is also useful in profiling antibody specificity, as well as in the discovery of novel biomarkers, especially for autoimmune diseases, infectious diseases, and cancers. Recently, the virion display method has been applied to produce functional GPCR array for various research and pharmaceutical applications. Graphical Abstract Highlights Summarize the development of functional protein microarray. Application of functional proteome microarray in basic research. Application of functional proteome microarray in translational research. Fabrication of functional membrane protein array using virion display method. Protein microarrays are crucial tools in the study of proteins in an unbiased, high-throughput manner, as they allow for characterization of up to thousands of individually purified proteins in parallel. The adaptability of this technology has enabled its use in a wide variety of applications, including the study of proteome-wide molecular interactions, analysis of post-translational modifications, identification of novel drug targets, and examination of pathogen-host interactions. In addition, the technology has also been shown to be useful in profiling antibody specificity, as well as in the discovery of novel biomarkers, especially for autoimmune diseases and cancers. In this review, we will summarize the developments that have been made in protein microarray technology in both in basic and translational research over the past decade. We will also introduce a novel membrane protein array, the GPCR-VirD array, and discuss the future directions of functional protein microarrays.
Museomics identifies genetic erosion in two butterfly species across the 20th century in Finland

Erosion of biodiversity generated by anthropogenic activities has been studied for decades and in many areas at the species level, using taxa monitoring. In contrast, genetic erosion within species has rarely been tracked, and is often studied by inferring past population dynamics from contemporaneous estimators. An alternative to such inferences is the direct examination of past genes, by analysing museum collection specimens. While providing direct access to genetic variation over time, historical DNA is usually not optimally preserved, and it is necessary to apply genotyping methods based on hybridization‐capture to unravel past genetic variation. In this study, we apply such a method (i.e., HyRAD), to large time series of two butterfly species in Finland, and present a new bioinformatic pipeline, namely PopHyRAD, that standardizes and optimizes the analysis of HyRAD data at the within‐species level. In the localities for which the data retrieved have sufficient power to accurately examine genetic dynamics through time, we show that genetic erosion has increased across the last 100 years, as revealed by signatures of allele extinctions and heterozygosity decreases, despite local variations. In one of the two butterflies (Erebia embla), isolation by distance also increased through time, revealing the effect of greater habitat fragmentation over time.
Biophysical mechanisms governing large‐scale brain network dynamics underlying individual‐specific variability of perception

Perception necessitates interaction among neuronal ensembles, the dynamics of which can be conceptualized as the emergent behavior of coupled dynamical systems. Here, we propose a detailed neurobiologically realistic model that captures the neural mechanisms of inter‐individual variability observed in cross‐modal speech perception. From raw EEG signals recorded from human participants when they were presented with speech vocalizations of McGurk‐incongruent and congruent audio–visual (AV) stimuli, we computed the global coherence metric to capture the neural variability of large‐scale networks. We identified that participants' McGurk susceptibility was negatively correlated to their alpha band global coherence. The proposed biophysical model conceptualized the global coherence dynamics emerge from coupling between the interacting neural masses—representing the sensory‐specific auditory/visual areas and modality nonspecific associative/integrative regions. Subsequently, we could predict that an extremely weak direct AV coupling results in a decrease in alpha band global coherence—mimicking the cortical dynamics of participants with higher McGurk susceptibility. Source connectivity analysis also showed decreased connectivity between sensory‐specific regions in participants more susceptible to McGurk effect, thus establishing an empirical validation to the prediction. Overall, our study provides an outline to link variability in structural and functional connectivity metrics to variability of performance that can be useful for several perception and action task paradigms.
High-dimensional mediation analysis in survival models

Mediation analysis with high-dimensional DNA methylation markers is important in identifying epigenetic pathways between environmental exposures and health outcomes. There have been some methodology developments of mediation analysis with high-dimensional mediators. However, high-dimensional mediation analysis methods for time-to-event outcome data are still yet to be developed. To address these challenges, we propose a new high-dimensional mediation analysis procedure for survival models by incorporating sure independent screening and minimax concave penalty techniques for variable selection, with the Sobel and the joint method for significance test of indirect effect. The simulation studies show good performance in identifying correct biomarkers, false discovery rate control, and minimum estimation bias of the proposed procedure. We also apply this approach to study the causal pathway from smoking to overall survival among lung cancer patients potentially mediated by 365,307 DNA methylations in the TCGA lung cancer cohort. Mediation analysis using a Cox proportional hazards model estimates that patients who have serious smoking history increase the risk of lung cancer through methylation markers including cg21926276, cg27042065, and cg26387355 with significant hazard ratios of 1.2497(95%CI: 1.1121, 1.4045), 1.0920(95%CI: 1.0170, 1.1726), and 1.1489(95%CI: 1.0518, 1.2550), respectively. The three methylation sites locate in the three genes which have been showed to be associated with lung cancer event or overall survival. However, the three CpG sites (cg21926276, cg27042065 and cg26387355) have not been reported, which are newly identified as the potential novel epigenetic markers linking smoking and survival of lung cancer patients. Collectively, the proposed high-dimensional mediation analysis procedure has good performance in mediator selection and indirect effect estimation.
Inhibition of TGF-β-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer

Background Immunotherapy with chimeric antigen receptor (CAR)-engineered T-cells is effective in some hematologic tumors. In solid tumors, however, sustained antitumor responses after CAR T-cell therapy remain to be demonstrated both in the pre-clinical and clinical setting. A perceived barrier to the efficacy of CAR T-cell therapy in solid tumors is the hostile tumor microenvironment where immunosuppressive soluble factors like transforming growth factor (TGF)-β are thought to inhibit the cellular immune response. Here, we analyzed whether CAR T-cells specific for the receptor tyrosine kinase-like orphan receptor 1 (ROR1) antigen, that is frequently expressed in triple-negative breast cancer (TNBC), are susceptible to inhibition by TGF-β and evaluated TGF-β-receptor signaling blockade as a way of neutralizing the inhibitory effect of this cytokine. Methods CD8+ and CD4+ ROR1-CAR T-cells were prepared from healthy donors and their antitumor function analyzed using the TNBC cell line MDA-MB-231 in vitro and in a microphysiologic 3D tumor model. Analyses were performed in co-culture assays of ROR1-CAR T-cells and MDA-MB-231 cells with addition of exogenous TGF-β. Results The data show that exposure to TGF-β engages TGF-β-receptor signaling in CD8+ and CD4+ ROR1-CAR T-cells as evidenced by phosphorylation of small mothers against decapentaplegic homolog 2. In the presence of TGF-β, the cytolytic activity, cytokine production and proliferation of ROR1-CAR T-cells in co-culture with MDA-MB-231 TNBC cells were markedly impaired, and the viability of ROR1-CAR T-cells reduced. Blockade of TGF-β-receptor signaling with the specific kinase inhibitor SD-208 was able to protect CD8+ and CD4+ ROR1-CAR T-cells from the inhibitory effect of TGF-β, and sustained their antitumor function in vitro and in the microphysiologic 3D tumor model. Combination treatment with SD-208 also led to increased viability and lower expression of PD-1 on ROR1-CAR T-cells at the end of the antitumor response. Conclusion We demonstrate the TGF-β suppresses the antitumor function of ROR1-CAR T-cells against TNBC in preclinical models. Our study supports the continued preclinical development and the clinical evaluation of combination treatments that shield CAR T-cells from TGF-β, as exemplified by the TGF-β-receptor kinase inhibitor SD-208 in this study.