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Schizophrenia (SCZ) is a chronic, severe, and complex psychiatric disorder that affects all aspects of personal functioning. While SCZ has a very strong biological component, there are still no objective diagnostic tests. Lately, special attention has been given to epigenetic biomarkers in SCZ. In this study, we introduce a three-step, automated machine learning (AutoML)-based, data-driven, biomarker discovery pipeline approach, using genome-wide DNA methylation datasets and laboratory validation, to deliver a highly performing, blood-based epigenetic biosignature of diagnostic clinical value in SCZ. Publicly available blood methylomes from SCZ patients and healthy individuals were analyzed via AutoML, to identify SCZ-specific biomarkers. The methylation of the identified genes was then analyzed by targeted qMSP assays in blood gDNA of 30 first-episode drug-naïve SCZ patients and 30 healthy controls (CTRL). Finally, AutoML was used to produce an optimized disease-specific biosignature based on patient methylation data combined with demographics. AutoML identified a SCZ-specific set of novel gene methylation biomarkers including IGF2BP1, CENPI, and PSME4. Functional analysis investigated correlations with SCZ pathology. Methylation levels of IGF2BP1 and PSME4, but not CENPI were found to differ, IGF2BP1 being higher and PSME4 lower in the SCZ group as compared to the CTRL group. Additional AutoML classification analysis of our experimental patient data led to a five-feature biosignature including all three genes, as well as age and sex, that discriminated SCZ patients from healthy individuals [AUC 0.755 (0.636, 0.862) and average precision 0.758 (0.690, 0.825)]. In conclusion, this three-step pipeline enabled the discovery of three novel genes and an epigenetic biosignature bearing potential value as promising SCZ blood-based diagnostics., (© 2024. The Author(s).)

Data comparing surgical systemic-to-pulmonary artery shunt and patent ductus arteriosus (PDA) stent as the initial palliation procedure for patients with pulmonary atresia with intact ventricular septum (PA-IVS) are limited. We sought to compare characteristics and outcomes in a multicenter cohort of patients with PA-IVS undergoing surgical shunts versus PDA stents. We retrospectively reviewed neonates with PA-IVS from 2009 to 2019 in 19 United States centers. Bivariate comparisons and multivariable logistic regression analysis were performed to determine the relationship between initial palliation strategy and outcomes including major adverse cardiovascular events (MACE): stroke, mechanical circulatory support, cardiac arrest, or death. 187 patients were included: 38 PDA stents and 149 surgical shunts. Baseline characteristics did not differ statistically between groups. Post-procedural MACE occurred in 4 patients (11%) with PDA stents versus 38 (26%) with surgical shunts, p = 0.079. Overall, the initial palliation strategy was not significantly associated with MACE (aOR:0.37; 95% CI,0.13-1.02). In patients with moderate-to-severe right ventricle hypoplasia, PDA stents were significantly associated with decreased odds of MACE (aOR:0.36; 95% CI,0.13-0.99). PDA stents were associated with lower vasoactive inotrope scores (median 0 versus 5, p < 0.001), greater likelihood to be extubated at the end of their procedure (37% versus 4%, p < 0.001), and shorter duration of mechanical ventilation (median 24 versus 96 h, p < 0.001). PDA stents were associated with significantly more unplanned reinterventions for hypoxemia compared to surgical shunts (42% vs. 20%, p = 0.009). In this multicenter study, neonates with PA-IVS who underwent PDA stenting received less vasoactive and ventilatory support postoperatively compared to those who had surgical shunts. Furthermore, patients with the most severe morphology had decreased odds of MACE., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The fields of Metagenomics and Metatranscriptomics involve the examination of complete nucleotide sequences, gene identification, and analysis of potential biological functions within diverse organisms or environmental samples. Despite the vast opportunities for discovery in metagenomics, the sheer volume and complexity of sequence data often present challenges in processing analysis and visualization. This article highlights the critical role of advanced visualization tools in enabling effective exploration, querying, and analysis of these complex datasets. Emphasizing the importance of accessibility, the article categorizes various visualizers based on their intended applications and highlights their utility in empowering bioinformaticians and non-bioinformaticians to interpret and derive insights from meta-omics data effectively., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Contemporary multicenter data regarding midterm outcomes for neonates with pulmonary atresia with intact ventricular septum are lacking. We sought to describe outcomes in a contemporary multicenter cohort, determine factors associated with end-states, and evaluate the effect of right ventricular coronary dependency and coronary atresia on transplant-free survival. Neonates treated during 2009-2019 in 19 United States centers were reviewed. Competing risks analysis was performed to determine cumulative risk of each end-state, and multivariable regression analyses were performed to identify factors associated with each end-state and transplant-free survival. We reviewed 295 patients. Median tricuspid valve Z-score was - 3.06 (25%, 75%: - 4.00, - 1.52). Final end-state was biventricular repair for 45 patients (15.2%), one-and-a half ventricle for 16 (5.4%), Fontan for 75 (25.4%), cardiac transplantation for 29 (9.8%), and death for 54 (18.3%). Seventy-six patients (25.7%) remained in mixed circulation. Cumulative risk estimate of death was 10.9%, 16.1%, 16.9%, and 18.8% at 1, 6 months, 1 year, and 5 years, respectively. Tricuspid valve Z-score was inversely, and coronary atresia positively associated with death or transplantation [odds ratio (OR) = 0.46, (95% confidence interval (CI) = 0.29-0.75, p < 0.001) and OR = 3.75 (95% CI 1.46-9.61, p = 0.011), respectively]. Right ventricular coronary dependency and left coronary atresia had a significant effect on transplant-free survival (log-rank p < 0.001). In a contemporary multicenter cohort of patients with PAIVS, consisting predominantly of patients with moderate-to-severe right ventricular hypoplasia, we observed favorable survival outcomes. Right ventricular coronary dependency and left, but not right, coronary atresia significantly worsens transplant-free survival., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: To evaluate the alterations of the retinal microvasculature and foveal avascular zone in patients with Parkinson's disease (PD) using optical coherence tomography angiography (OCT-A)., Methods: A retrospective study of PD patients examined in the Ophthalmology Department of the General Hospital of Athens, "Georgios Gennimatas" from March 2021 to March 2022 was conducted. Totally 44 patients with PD were included and 18 healthy controls were examined, hence a total of 124 eyes were enrolled in the study. The foveal and parafoveal superficial and deep capillary plexus vascular density (fSCP-VD, fDCP-VD, pSCP-VD, pDCP-CD) and foveal avascular zone (FAZ) were quantified with OCTA. Optical coherence tomography (OCT) was used to measure macular thickness. Our statistical analysis was conducted by using a mixed effect linear regression model., Results: After adjustment for age and gender, the mean parafoveal superficial capillary plexus vascular density (pSCP-VD) and mean parafoveal deep capillary plexus vascular density (pDCP-VD) were significantly decreased in individuals with PD ( P <0.001 in both) by -2.35 (95%CI -3.3, -1.45) and -7.5 (95%CI -10.4, -4.6) respectively. fSCP-VD and fDCP-VD didn't approach statistical significance. The FAZ area and perimeter were significantly decreased ( P <0.001 in both) by -0.1 mm 2 (95%CI -0.13, -0.07) and -0.49 mm 2 (95%CI -0.66, -0.32) respectively. Circularity didn't approach statistical significance. Central retinal thickness (CRT) was significantly decreased in individuals with PD ( P <0.001) by -23.1 µm (95%CI -30.2, -16) and temporal retinal thickness (TRT) was decreased ( P =0.025) by -11 µm (95%CI -22, -1.5) while nasal retinal thickness (NRT) only approached statistical significance ( P =0.066)., Conclusion: The mean pSCP-VD, pDCP-VD, CRT and TRT are significantly decreased and FAZ is altered in individuals with PD. These findings can be potentially used as biomarkers for the diagnosis and evaluation of early PD., (International Journal of Ophthalmology Press.)

Introduction: Even though shoulder dislocation is thought to be the most common dislocation treated in the Emergency Department, inferior ones, known as Luxatio Erecta, comprise only 0.5% of them. Taking into consideration the rareness of unilateral Luxatio Erecta, bilateral cases should be even fewer. The purpose of this paper is to identify the reported number of cases of Traumatic Bilateral Luxatio Erecta in the literature over the last 100 years and to summarize the mechanism of injury, the initial management, and the complications of these patients., Materials and Methods: We performed a systematic review of the literature regarding Traumatic Bilateral Luxatio Erecta. All articles published until 31st of December 2022 in PubMed and Google Scholar databases were searched using the terms "luxatio erecta", 'inferior dislocation", and "bilateral"., Results: Eighty-two articles were retrieved from PubMed and Google Scholar search. Forty-four of them were initially included in our review. Six additional articles meeting the inclusion criteria were found from cross-references., Conclusion: The presence of this injury is extremely rare with only 51 cases in the literature. The incidence of concomitant injuries and complications seems to be extremely high and neurological deficits were detected on 42.8% of patients with Bilateral Luxatio Erecta. To our knowledge, this is the first systematic review of the literature regarding Traumatic Bilateral Luxatio Erecta that includes articles not only in English, a fact that provides more reliability on the estimation of the real number of cases of this rare injury compared to any other review on this subject to date., (© 2023. The Author(s).)

Several selective macroautophagy receptor and adaptor proteins bind members of the Atg8 (autophagy related 8) family using short linear motifs (SLiMs), most often referred to as Atg8-family interacting motifs (AIMs) or LC3-interacting regions (LIRs). AIM/LIR motifs have been extensively studied during the last fifteen years, since they can uncover the underlying biological mechanisms and possible substrates for this key catabolic process of eukaryotic cells. Prompted by the fact that experimental information regarding LIR motifs can be found scattered across heterogeneous literature resources, we have developed LIRcentral (https://lircentral.eu), a freely available online repository for user-friendly access to comprehensive, high-quality information regarding LIR motifs from manually curated publications. Herein, we describe the development of LIRcentral and showcase currently available data and features, along with our plans for the expansion of this resource. Information incorporated in LIRcentral is useful for accomplishing a variety of research tasks, including: (i) guiding wet biology researchers for the characterization of novel instances of LIR motifs, (ii) giving bioinformaticians/computational biologists access to high-quality LIR motifs for building novel prediction methods for LIR motifs and LIR containing proteins (LIRCPs) and (iii) performing analyses to better understand the biological importance/features of functional LIR motifs. We welcome feedback on the LIRcentral content and functionality by all interested researchers and anticipate this work to spearhead a community effort for sustaining this resource which will further promote progress in studying LIR motifs/LIRCPs. Abbreviations : AIM, Atg8-family interacting motif; Atg8, autophagy related 8; GABARAP, GABA type A receptor-associated protein; LIR, LC3-interacting region; LIRCP, LIR-containing protein; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; PMID, PubMed identifier; PPI, protein-protein interaction; SLiM, short linear motif.

Public-domain availability for bioinformatics software resources is a key requirement that ensures long-term permanence and methodological reproducibility for research and development across the life sciences. These issues are particularly critical for widely used, efficient, and well-proven methods, especially those developed in research settings that often face funding discontinuities. We re-launch a range of established software components for computational genomics, as legacy version 1.0.1, suitable for sequence matching, masking, searching, clustering and visualization for protein family discovery, annotation and functional characterization on a genome scale. These applications are made available online as open source and include MagicMatch, GeneCAST, support scripts for CoGenT-like sequence collections, GeneRAGE and DifFuse, supported by centrally administered bioinformatics infrastructure funding. The toolkit may also be conceived as a flexible genome comparison software pipeline that supports research in this domain. We illustrate basic use by examples and pictorial representations of the registered tools, which are further described with appropriate documentation files in the corresponding GitHub release., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Vasileiou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study aimed to investigate the association between objective baropodometric and radiological measurements and patient self-reported functional outcomes, assessed through the Knee Injury and Osteoarthritis Outcome Score (KOOS). Additionally, it sought to evaluate the effectiveness of static baropodometry in predicting short-term KOOS results following unilateral total knee arthroplasty (TKA). We conducted a prospective single-center study involving 32 patients who underwent unilateral TKA for knee osteoarthritis (KOA). Patients were evaluated both preoperatively and six months postoperatively, utilizing objective measurements derived from static baropodometric analysis in a normal, relaxed, bipedal standing position using a multi-platform Plantar Pressure Analysis System (PPAS) and radiographic measurements of the femorotibial angle (FTA) and subjective assessments through the national validated version of the KOOS. The study found an insignificant average correction of -0.69° ± 4.12° in the preoperative FTA at the sixth month after TKA. Moreover, there were no significant differences in the KOOS based on different types of knee alignment (KA) both pre- and postoperatively ( p > 0.05). No significant correlations were observed between the KOOS, and total average affected and unaffected plantar pressures (TAAPP and TAUPP) pre- and postoperatively, as well as KA pre- and postoperatively. However, significant changes were observed in TAAPP and TAUPP measurements after unilateral TKA. TAAPP demonstrated a significant increase postoperatively (mean change (SD) = 18.60 (47.71); p = 0.035). In conclusion, this study found no significant correlation between KA, static baropodometric measurements, including pre- and postoperative differences, and KOOS outcomes. Therefore, static plantar pressure measurements alone might not serve as a reliable predictor of short-term clinical outcomes after unilateral TKA, as reported by patients.

Metagenomes encode an enormous diversity of proteins, reflecting a multiplicity of functions and activities 1,2 . Exploration of this vast sequence space has been limited to a comparative analysis against reference microbial genomes and protein families derived from those genomes. Here, to examine the scale of yet untapped functional diversity beyond what is currently possible through the lens of reference genomes, we develop a computational approach to generate reference-free protein families from the sequence space in metagenomes. We analyse 26,931 metagenomes and identify 1.17 billion protein sequences longer than 35 amino acids with no similarity to any sequences from 102,491 reference genomes or the Pfam database 3 . Using massively parallel graph-based clustering, we group these proteins into 106,198 novel sequence clusters with more than 100 members, doubling the number of protein families obtained from the reference genomes clustered using the same approach. We annotate these families on the basis of their taxonomic, habitat, geographical and gene neighbourhood distributions and, where sufficient sequence diversity is available, predict protein three-dimensional models, revealing novel structures. Overall, our results uncover an enormously diverse functional space, highlighting the importance of further exploring the microbial functional dark matter., (© 2023. The Author(s).)

Background: This study aimed to investigate the molecular profiles of 237 stage III CRC patients from the international IDEA study. It also sought to correlate these profiles with Toll-like and vitamin D receptor polymorphisms, clinicopathological and epidemiological characteristics, and patient outcomes., Methods: Whole Exome Sequencing and PCR-RFLP on surgical specimens and blood samples, respectively, were performed to identify molecular profiling and the presence of Toll-like and vitamin D polymorphisms. Bioinformatic analysis revealed mutational status., Results: Among the enrolled patients, 63.7% were male, 66.7% had left-sided tumors, and 55.7% received CAPOX as adjuvant chemotherapy. Whole exome sequencing identified 59 mutated genes in 11 different signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) CRC panel. On average, patients had 8 mutated genes (range, 2-21 genes). Mutations in ARAF and MAPK10 emerged as independent prognostic factors for reduced DFS ( p = 0.027 and p < 0.001, respectively), while RAC3 and RHOA genes emerged as independent prognostic factors for reduced OS ( p = 0.029 and p = 0.006, respectively). Right-sided tumors were also identified as independent prognostic factors for reduced DFS ( p = 0.019) and OS ( p = 0.043). Additionally, patients with tumors in the transverse colon had mutations in genes related to apoptosis, PIK3 - Akt , Wnt , and MAPK signaling pathways., Conclusions: Molecular characterization of tumor cells can enhance our understanding of the disease course. Mutations may serve as promising prognostic biomarkers, offering improved treatment options. Confirming these findings will require larger patient cohorts and international collaborations to establish correlations between molecular profiling, clinicopathological and epidemiological characteristics and clinical outcomes.

As a result of social progress and improved living conditions, which have contributed to a prolonged life expectancy, the prevalence of strokes has increased and has become a significant phenomenon. Despite the available stroke treatment options, patients frequently suffer from significant disability after a stroke. Initial stroke severity is a significant predictor of functional dependence and mortality following an acute stroke. The current study aims to collect and analyze data from the hyperacute and acute phases of stroke, as well as from the medical history of the patients, in order to develop an explainable machine learning model for predicting stroke-related neurological deficits at discharge, as measured by the National Institutes of Health Stroke Scale (NIHSS). More specifically, we approached the data as a binary task problem: improvement of NIHSS progression vs. worsening of NIHSS progression at discharge, using baseline data within the first 72 h. For feature selection, a genetic algorithm was applied. Using various classifiers, we found that the best scores were achieved from the Random Forest (RF) classifier at the 15 most informative biomarkers and parameters for the binary task of the prediction of NIHSS score progression. RF achieved 91.13% accuracy, 91.13% recall, 90.89% precision, 91.00% f1-score, 8.87% FN rate and 4.59% FP rate . Those biomarkers are: age, gender, NIHSS upon admission, intubation, history of hypertension and smoking, the initial diagnosis of hypertension, diabetes, dyslipidemia and atrial fibrillation, high-density lipoprotein (HDL) levels, stroke localization, systolic blood pressure levels, as well as erythrocyte sedimentation rate (ESR) levels upon admission and the onset of respiratory infection. The SHapley Additive exPlanations (SHAP) model interpreted the impact of the selected features on the model output. Our findings suggest that the aforementioned variables may play a significant role in determining stroke patients' NIHSS progression from the time of admission until their discharge.

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS), characterized by the diffuse grey and white matter damage. Cognitive impairment (CI) is a frequent clinical feature in patients with MS (PwMS) that can be prevalent even in early disease stages, affecting the physical activity and active social participation of PwMS. Limited information is available regarding the influence of MS in social cognition (SC), which may occur independently from the overall neurocognitive dysfunction. In addition, the available information regarding the factors that influence SC in PwMS is limited, e.g., factors such as a patient's physical disability, different cognitive phenotypes, mood status, fatigue. Considering that SC is an important domain of CI in MS and may contribute to subjects' social participation and quality of life, we herein conceptualize and present the methodological design of a cross-sectional study in 100 PwMS of different disease subtypes. The study aims (a) to characterize SC impairment in PwMS in the Greek population and (b) to unveil the relationship between clinical symptoms, phenotypes of CI, mood status and fatigue in PwMS and the potential underlying impairment on tasks of SC.

Objectives: To reduce unnecessary antibiotic exposure in a pediatric cardiac intensive care unit (CICU)., Design: Single-center, quality improvement initiative. Monthly antibiotic utilization rates were compared between 12-month baseline and 18-month intervention periods., Setting: A 25-bed pediatric CICU., Patients: Clinically stable patients undergoing infection diagnosis were included. Patients with immunodeficiency, mechanical circulatory support, open sternum, and recent culture-positive infection were excluded., Interventions: The key drivers for improvement were standardizing the infection diagnosis process, order-set creation, limitation of initial antibiotic prescription to 24 hours, discouraging indiscriminate vancomycin use, and improving bedside communication and situational awareness regarding the infection diagnosis protocol., Results: In total, 109 patients received the protocol; antibiotics were discontinued in 24 hours in 72 cases (66%). The most common reasons for continuing antibiotics beyond 24 hours were positive culture (n = 13) and provider preference (n = 13). A statistical process control analysis showed only a trend in monthly mean antibiotic utilization rate in the intervention period compared to the baseline period: 32.6% (SD, 6.1%) antibiotic utilization rate during the intervention period versus 36.6% (SD, 5.4%) during the baseline period (mean difference, 4%; 95% CI, -0.5% to -8.5%; P = .07). However, a special-cause variation represented a 26% reduction in mean monthly vancomycin use during the intervention period. In the patients who had antibiotics discontinued at 24 hours, delayed culture positivity was rare., Conclusions: Implementation of a protocol limiting empiric antibiotic courses to 24 hours in clinically stable, standard-risk, pediatric CICU patients with negative cultures is feasible. This practice appears safe and may reduce harm by decreasing unnecessary antibiotic exposure.

Background: Outcomes after lung transplant (LTx) in children have slowly improved. Although atrial arrhythmia (AA) is a common and adverse complication following LTx among adults, there is limited data on pediatric recipients. We detail our pediatric single-center experience while providing further insights on occurrence and management of AA following LTx., Methods: A retrospective analysis of LTx recipients at a pediatric LTx program from 2014 to 2022 was performed. We investigated timing of occurrence and management of AA following LTx, and its effect on post-LTx outcome., Results: Three out of nineteen (15%) pediatric LTx recipients developed AA. The timing of occurrence was 9-10 days following LTx. Those patients in the older age group (age >12 years old) were the only ones who developed AA. Developing AA did not have a negative effect on hospital stay duration or short-term mortality. All LTx recipients with AA were discharged home on therapy that was discontinued at 6 months for those who was on mono-therapy without recurrence of AA., Conclusions: AA is an early post-operative complication in older children and younger adults undergoing LTx at a pediatric center. Early recognition and aggressive management can mitigate any morbidity or mortality. Future investigations should explore factors that place this population at risk for AA in order to prevent this complication post-operatively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Sill, Baskar, Zang, Spar, Iliopoulos, Morales, Hayes Jr and Koh.)

Background: Multicenter contemporary data describing short-term outcomes after initial interventions of neonates with pulmonary atresia with intact ventricular septum (PA-IVS) are limited. This multicenter study describes characteristics and outcomes of PA-IVS neonates after their initial catheter or surgical intervention and identifies factors associated with major adverse cardiac events (MACE)., Methods: Neonates with PA-IVS who underwent surgical or catheter intervention between 2009 and 2019 in 19 centers were reviewed. Risk factors for MACE, defined as cardiopulmonary resuscitation, mechanical circulatory support, stroke, or in-hospital mortality, were analyzed using multivariable logistic regression models., Results: We reviewed 279 neonates: 79 (28%) underwent right ventricular decompression, 151 (54%) underwent systemic-to-pulmonary shunt or ductal stent placement only, 36 (13%) underwent right ventricular decompression with shunt or ductal stent placement, and 11 (4%) underwent transplantation. MACE occurred in 57 patients (20%): 26 (9%) received mechanical circulatory support, 37 (13%) received cardiopulmonary resuscitation, stroke occurred in 16 (6%), and 23 (8%) died. The presence of 2 major coronary artery stenoses (adjusted odds ratio, 4.99; 95% CI, 1.16-21.39) and lower weight at first intervention (adjusted odds ratio, 1.52; 95% CI, 1.01-2.27) were significantly associated with MACE. Coronary ischemia was the most frequent presumed mechanism of death (n = 10)., Conclusions: In a multicenter cohort, 1 in 5 neonates with PA-IVS experienced MACE after their initial intervention. Patients with 2 major coronary artery stenoses or lower weight at the time of the initial procedure were most likely to experience MACE and warrant vigilance during preintervention planning and postintervention management., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Fingolimod is the first approved oral therapy for relapsing-remitting multiple sclerosis (RRMS). The present study aimed to further characterize fingolimod's safety profile, and to assess the patient-reported treatment satisfaction and impact of fingolimod on the quality of life (QoL) of patients with multiple sclerosis (MS) treated in routine care in Greece., Methods: This was a multicenter, prospective, observational, 24-month study conducted in Greece by hospital-based and private practice neurologists who specialize in MS. Eligible patients had initiated fingolimod within 15 days in accordance with the locally approved label. Safety outcomes included any adverse event (AE) observed during the study period and efficacy outcomes included both objective (disability progression and 2-year annualized relapse rate) and patient-reported assessments (Treatment Satisfaction Questionnaire for Medication (TSQM) v1.4 and the EuroQol (EQ)-5-dimension (5D) 3-level instruments)., Results: A total of 489 eligible patients (age 41.2 ± 9.8 years; 63.7% female; 4.2% treatment-naive) were exposed to fingolimod for a median of 23.7 months. During the observation period, 20.5% of the participants experienced 233 AEs. Lymphopenia (8.8%), leukopenia (4.2%), hepatic enzyme increased (3.4%), and infections (3.0%) were the most common. Most patients (89.3%) did not experience disability progression; the 2-year annualized relapse rate decreased by 94.7% compared to baseline. The median EQ-visual analogue scale (VAS) was 74.5 at month 24 vs. 65.0 at enrollment (p < 0.001) and the EQ-5D index score was 0.80 vs. 0.78, respectively. Significant improvements were noted in the TSQM global satisfaction and effectiveness domain scores between 6 and 24 months post enrollment (median scores at month 24, 71.4 and 66.7, respectively) (p < 0.001). Significant increases from enrollment to the 24th month were also noted in the patients' global satisfaction and effectiveness domain scores [mean change of 7.4 ± 17.7 (p = 0.005) and mean increase of 5.4 ± 16.2) (p = 0.043), respectively]., Conclusion: In the real-world setting of Greece, fingolimod demonstrates a clinical benefit and a predictable and manageable safety profile, which contribute towards high patient-reported treatment satisfaction and improvements in the QoL of patients with MS., (© 2023. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Objectives: Near-infrared spectroscopy (NIRS) has been increasingly accepted as a noninvasive marker of regional tissue oxygenation despite concerns of imprecision and wide limits of agreement (LOA) with invasive oximetry. New generation absolute monitors may have improved accuracy compared with trend monitors. We sought to compare the concordance with invasive venous oximetry of a new generation absolute NIRS-oximeter (FORESIGHT ELITE; CASMED, Branford, CT) with a modern widely used trend monitor (INVOS 5100C; Medtronic, Minneapolis, MN)., Design: Prospective single-center study., Setting: Tertiary pediatric heart center., Patients: Children undergoing elective cardiac catheterization under general anesthesia. Time-paired venous oximetry samples (jugular and renal) were compared with NIRS-derived oximetry by two monitors using regression and Bland-Altman analysis., Interventions: None., Measurements and Main Results: We enrolled 36 children (19 female, 10 cyanotic) with median age 4.1 years (25-75%, 2.5-7.8 yr) and weight 16.7 kg (12.3-29.1 kg). The absolute difference between NIRS-derived and invasive jugular oximetry was less than 10% in 67% of occasions for both monitors. Correlation was fair (Spearman rs = 0.40; p = 0.001) for the FORESIGHT ELITE and poor ( rs = 0.06; p = 0.71) for the INVOS 5100C. Bias and LOA were +6.7% (+22%, -9%) versus +1.3% (LOA = +24%, -21%), respectively. The absolute difference between NIRS-derived and invasive renal oximetry was less than 10% in 80% of occasions with moderate correlation ( rs = 0.57; p < 0.001) for the FORESIGHT ELITE and in 61% of occasions with moderate correlation ( rs = 0.58; p < 0.001) for the INVOS 5100C; bias and LOA were +3.6% (+19%, -12%) and -1.4 % (+27%, -30%), respectively. NIRS correlation with renal venous oximetry was worse for cyanotic versus noncyanotic patients ( p = 0.02)., Conclusions: Concordance and LOA of NIRS-derived oximetry with invasive venous oximetry in the cerebral and renal vascular beds was suboptimal for clinical decision-making. Cyanosis adversely affected NIRS performance in the renal site., Competing Interests: Dr. Iliopoulos disclosed that the FORESIGHT ELITE Monitor and sensors were provided by CAS Medical Systems, Branford, Connecticut, free of charge for the duration of the study. Drs. Cooper and Goldstein received funding from Medtronic. Dr. Goldstein reports consulting relationships with Medtronic, W. L. Gore & Associates, Mezzion Pharma and PECA Labs. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Research on tumor-associated neutrophils (TAN) currently surges because of the well-documented strong clinical relevance of tumor-infiltrating neutrophils. This relevance is illustrated by strong correlations between high frequencies of intratumoral neutrophils and poor outcome in the majority of human cancers. Recent high-dimensional analysis of murine neutrophils provides evidence for unexpected plasticity of neutrophils in murine models of cancer and other inflammatory non-malignant diseases. New analysis tools enable deeper insight into the process of neutrophil differentiation and maturation. These technological and scientific developments led to the description of an ever-increasing number of distinct transcriptional states and associated phenotypes in murine models of disease and more recently also in humans. At present, functional validation of these different transcriptional states and potential phenotypes in cancer is lacking. Current functional concepts on neutrophils in cancer rely mainly on the myeloid-derived suppressor cell (MDSC) concept and the dichotomous and simple N1-N2 paradigm. In this manuscript, we review the historic development of those concepts, critically evaluate these concepts against the background of our own work and provide suggestions for a refinement of current concepts in order to facilitate the transition of TAN research from experimental insight to clinical translation., (© 2022 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.)

Pancreatic ductal adenocarcinoma (PDAC), the second most prevalent gastrointestinal malignancy and the most common type of pancreatic cancer is linked with poor prognosis and, eventually, with high mortality rates. Early detection is seldom, while tumor heterogeneity and microarchitectural alterations benefit PDAC resistance to conventional therapeutics. Although emerging evidence suggest the core role of cancer stem cells (CSCs) in PDAC aggressiveness, unique stem signatures are poorly available, thus limiting the efforts of anti-CSC-targeted therapy. Herein, we report the findings of the first genome-wide analyses of mRNA/lncRNA transcriptome profiling and co-expression networks in PDAC cell line-derived CD133+/CD44+ cells, which were shown to bear a CSC-like phenotype in vitro and in vivo. Compared to CD133-/CD44- cells, the CD133+/CD44+ population demonstrated significant expression differences in both transcript pools. Using emerging bioinformatic tools, we performed lncRNA target coding gene prediction analysis, which revealed significant Gene Ontology (GO), pathway, and network enrichments in many dyregulated lncRNA nearby ( cis or trans ) mRNAs, with reported involvement in the regulation of CSC phenotype and functions. In this context, the construction of lncRNA/mRNA networks by ingenuity platforms identified the lncRNAs ATF2, CHEK1, DCAF8, and PAX8 to interact with "hub" SC-associated mRNAs. In addition, the expressions of the above lncRNAs retrieved by TCGA-normalized RNAseq gene expression data of PAAD were significantly correlated with clinicopathological features of PDAC, including tumor grade and stage, nodal metastasis, and overall survival. Overall, our findings shed light on the identification of CSC-specific lncRNA signatures with potential prognostic and therapeutic significance in PDAC.

Background: Truncus arteriosus with interrupted aortic arch (TA-IAA) is a rare congenital heart defect with historically poor outcomes. Contemporary multicenter data are limited., Methods: A retrospective cohort study of children who underwent repair of TA-IAA between 2009 and 2016 at 12 tertiary care referral centers within the United States was performed. Major adverse cardiac events (MACE) were defined as postoperative extracorporeal membrane oxygenation, cardiopulmonary resuscitation, or operative mortality. TA-IAA patients were compared with TA patients who underwent repair during the study period from the same institutions., Results: We reviewed 35 patients with TA-IAA. MACE occurred in 12 patients (34%). Improvement over time was observed during the study period with 11 events (92%) occurring in the first half of the study period (P = .03). Factors associated with MACE included moderate or severe truncal valve insufficiency (P < .01), concomitant truncal valve repair (P = .04), and longer cardiopulmonary bypass duration (P = .02). In comparison with 216 patients who underwent TA repair, patients with TA-IAA had a higher rate of MACE, but this finding was not statistically significant (34% vs 20%, respectively; P = .07). Additionally no differences between TA-IAA and TA groups were observed for unplanned reoperations (14% vs 22%, respectively; P = .3), hospital length of stay (24 vs 23 days, P = .65), or late deaths (7% vs 7%, P = 1.00)., Conclusions: In this contemporary, multicenter cohort the rate of MACE after repair of TA-IAA was high but improved during the study period. Early childhood outcomes of patients with TA-IAA were similar to those with TA., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose/aim of the Study: The impairment of neurocognitive functions occurs in all subtypes of multiple sclerosis, even from the earliest stages of the disease. Commonly reported manifestations of cognitive impairment include deficits in attention, conceptual reasoning, processing efficiency, information processing speed, memory (episodic and working), verbal fluency (language), and executive functions. Multiple sclerosis patients also suffer from social cognition impairment, which affects their social functioning. The objective of the current paper is to assess the effect of neurocognitive impairment and its potential correlation with social cognition performance and impairment in multiple sclerosis patients., Materials and Methods: An overview of the available-to-date literature on neurocognitive impairment and social cognition performance in multiple sclerosis patients by disease subtype was performed., Results: It is not clear if social cognition impairment occurs independently or secondarily to neurocognitive impairment. There are associations of variable strengths between neurocognitive and social cognition deficits and their neural basis is increasingly investigated., Conclusions: The prompt detection of neurocognitive predictors of social cognition impairment that may be applicable to all multiple sclerosis subtypes and intervention are crucial to prevent further neural and social cognition decline in multiple sclerosis patients.

Rheumatoid arthritis (RA) is characterized by autoimmune joint destruction with debilitating consequences. Despite treatment advancements with biologic therapies, a significant proportion of RA patients show an inadequate clinical response, and restoration of immune self-tolerance represents an unmet therapeutic need. We have previously described a tolerogenic phenotype of plasmacytoid dendritic cells (pDCs) in RA patients responding to anti-TNF-α agents. However, the molecular mechanisms involved in tolerogenic reprogramming of pDCs in RA remain elusive. In this study, guided by transcriptomic analysis of CD303+CD123+ pDCs from RA patients in remission, we revealed enhanced expression of IL-6R and its downstream signaling compared with healthy pDCs. Functional assessment demonstrated that IL-6R engagement resulted in marked reduction of TNF-α secretion by pDCs whereas intracellular TNF-α was significantly increased. Accordingly, pharmacologic inhibition of IL-6R signaling restored TNF-α secretion levels by pDCs. Mechanistic analysis demonstrated impaired activity and decreased lysosomal degradation of ADAM17 (a disintegrin and metalloproteinase 17) sheddase in pDCs, which is essential for TNF-α cleavage. Importantly, reduction of TNF-α secretion by IL-6-treated pDCs attenuated the inflammatory potential of RA patient-derived synovial fibroblasts. Collectively, these findings position pDCs as an important source of TNF-α in RA pathogenesis and unravel an anti-inflammatory mechanism of IL-6 by limiting the pDC-derived TNF-α secretion., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Nearly one third of Saccharomyces cerevisiae protein coding sequences correspond to duplicate genes, equally split between small-scale duplicates (SSD) and whole-genome duplicates (WGD). While duplicate genes have distinct properties compared to singletons, to date, there has been no systematic analysis of their positional preferences. In this work, we show that SSD and WGD genes are organized in distinct gene clusters that occupy different genomic regions, with SSD being more peripheral and WGD more centrally positioned close to centromeric chromatin. Duplicate gene clusters differ from the rest of the genome in terms of gene size and spacing, gene expression variability and regulatory complexity, properties that are also shared by singleton genes residing within them. Singletons within duplicate gene clusters have longer promoters, more complex structure and a higher number of protein-protein interactions. Particular chromatin architectures appear to be important for gene evolution, as we find SSD gene-pair co-expression to be strongly associated with the similarity of nucleosome positioning patterns. We propose that specific regions of the yeast genome provide a favourable environment for the generation and maintenance of small-scale gene duplicates, segregating them from WGD-enriched genomic domains. Our findings provide a valuable framework linking genomic innovation with positional genomic preferences., (© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Protein-protein interactions (PPIs) are of key importance for understanding how cells and organisms function. Thus, in recent decades, many approaches have been developed for the identification and discovery of such interactions. These approaches addressed the problem of PPI identification either by an experimental point of view or by a computational one. Here, we present an updated version of UniReD, a computational prediction tool which takes advantage of biomedical literature aiming to extract documented, already published protein associations and predict undocumented ones. The usefulness of this computational tool has been previously evaluated by experimentally validating predicted interactions and by benchmarking it against public databases of experimentally validated PPIs. In its updated form, UniReD allows the user to provide a list of proteins of known implication in, e.g., a particular disease, as well as another list of proteins that are potentially associated with the proteins of the first list. UniReD then automatically analyzes both lists and ranks the proteins of the second list by their association with the proteins of the first list, thus serving as a potential biomarker discovery/validation tool.

By integrating phylogenomic and comparative analyses of 1104 high-quality genome sequences, we identify the core proteins and the lineage-specific fingerprint proteins of the various evolutionary clusters (clades/groups/species) of the Bacillus genus. As fingerprints, we denote those core proteins of a certain lineage that are present only in that particular lineage and absent in any other Bacillus lineage. Thus, these lineage-specific fingerprints are expected to be involved in particular adaptations of that lineage. Intriguingly, with a few notable exceptions, the majority of the Bacillus species demonstrate a rather low number of species-specific fingerprints, with the majority of them being of unknown function. Therefore, species-specific adaptations are mostly attributed to highly unstable (in evolutionary terms) accessory proteomes and possibly to changes at the gene regulation level. A series of comparative analyses consistently demonstrated that the progenitor of the Cereus Clade underwent an extensive genomic expansion of chromosomal protein-coding genes. In addition, the majority (76-82%) of the B. subtilis proteins that are essential or play a significant role in sporulation have close homologs in most species of both the Subtilis and the Cereus Clades. Finally, the identification of lineage-specific fingerprints by this study may allow for the future development of highly specific vaccines, therapeutic molecules, or rapid and low-cost molecular tests for species identification.

Hypothesis: Interpenetrating networks consisting of a polymer network with dynamic cross-links and a supramolecular network allow obtaining hydrogels with significantly enhanced mechanical properties., Experiments: Binary hydrogels composed of a dynamically cross-linked poly(vinyl alcohol) (PVA) network and a transient network of entangled highly charged mixed wormlike micelles (WLMs) of surfactants (potassium oleate and n-octyltrimethylammonium bromide) were prepared and studied by rheometry, SANS, USANS, cryo-TEM, and NMR spectroscopy., Findings: Binary hydrogels show significantly enhanced rheological properties (a 3400-fold higher viscosity and 27-fold higher plateau modulus) as compared to their components taken separately. This is due to the microphase separation leading to local concentrating of PVA and WLMs providing larger number of polymer-polymer contacts for cross-linking and longer WLMs with more entanglements. Such materials are very promising for the application in many areas, ranging from enhanced oil recovery to biomedical uses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Finding, exploring and filtering frequent sentence-based associations between a disease and a biomedical entity, co-mentioned in disease-related PubMed literature, is a challenge, as the volume of publications increases. Darling is a web application, which utilizes Name Entity Recognition to identify human-related biomedical terms in PubMed articles, mentioned in OMIM, DisGeNET and Human Phenotype Ontology (HPO) disease records, and generates an interactive biomedical entity association network. Nodes in this network represent genes, proteins, chemicals, functions, tissues, diseases, environments and phenotypes. Users can search by identifiers, terms/entities or free text and explore the relevant abstracts in an annotated format.

Tissue-specific gene methylation events are key to the pathogenesis of several diseases and can be utilized for diagnosis and monitoring. Here, we established an in silico pipeline to analyze high-throughput methylome datasets to identify specific methylation fingerprints in three pathological entities of major burden, i.e., breast cancer (BrCa), osteoarthritis (OA) and diabetes mellitus (DM). Differential methylation analysis was conducted to compare tissues/cells related to the pathology and different types of healthy tissues, revealing Differentially Methylated Genes (DMGs). Highly performing and low feature number biosignatures were built with automated machine learning, including: (1) a five-gene biosignature discriminating BrCa tissue from healthy tissues (AUC 0.987 and precision 0.987), (2) three equivalent OA cartilage-specific biosignatures containing four genes each (AUC 0.978 and precision 0.986) and (3) a four-gene pancreatic β-cell-specific biosignature (AUC 0.984 and precision 0.995). Next, the BrCa biosignature was validated using an independent ccfDNA dataset showing an AUC and precision of 1.000, verifying the biosignature's applicability in liquid biopsy. Functional and protein interaction prediction analysis revealed that most DMGs identified are involved in pathways known to be related to the studied diseases or pointed to new ones. Overall, our data-driven approach contributes to the maximum exploitation of high-throughput methylome readings, helping to establish specific disease profiles to be applied in clinical practice and to understand human pathology.

Dual transient networks were prepared by mixing highly charged long wormlike micelles of surfactants with polysaccharide chains of hydroxypropyl guar above the entanglement concentration for each of the components. The wormlike micelles were composed of two oppositely charged surfactants potassium oleate and n-octyltrimethylammonium bromide with a large excess of anionic surfactant. The system is macroscopically homogeneous over a wide range of polymer and surfactant concentrations, which is attributed to a stabilizing effect of surfactants counterions that try to occupy as much volume as possible in order to gain in translational entropy. At the same time, by small-angle neutron scattering (SANS) combined with ultrasmall-angle neutron scattering (USANS), a microphase separation with the formation of polymer-rich and surfactant-rich domains was detected. Rheological studies in the linear viscoelastic regime revealed a synergistic 180-fold enhancement of viscosity and 65-fold increase of the longest relaxation time in comparison with the individual components. This effect was attributed to the local increase in concentration of both components trying to avoid contact with each other, which makes the micelles longer and increases the number of intermicellar and interpolymer entanglements. The enhanced rheological properties of this novel system based on industrially important polymer hold great potential for applications in personal care products, oil recovery and many other fields.

Objectives: We aimed to describe characteristics and operative outcomes from a multicenter cohort of infants who underwent repair of anomalous left coronary artery from the pulmonary artery. We also aimed to identify factors associated with major adverse cardiovascular events following anomalous left coronary artery from the pulmonary artery repair., Design: Retrospective chart review., Setting: Twenty-one tertiary-care referral centers., Patients: Infants less than 365 days old who underwent anomalous left coronary artery from the pulmonary artery repair., Interventions: None., Measurements and Main Results: Major adverse cardiovascular events were defined as the occurrence of postoperative extracorporeal membrane oxygenation, cardiopulmonary resuscitation, left ventricular assist device, heart transplantation, or operative mortality. Factors independently associated with major adverse cardiovascular events were identified using multivariable logistic regression analysis. We reviewed 177 infants (< 365 d old) who underwent anomalous left coronary artery from the pulmonary artery repair between January 2009 and March 2018. Major adverse cardiovascular events occurred in 36 patients (20%). Twenty-nine patients (16%) received extracorporeal membrane oxygenation, 14 (8%) received cardiopulmonary resuscitation, four (2%) underwent left ventricular assist device placement, two (1%) underwent heart transplantation, and six (3.4%) suffered operative mortality. In multivariable analysis, preoperative inotropic support (odds ratio, 3.5; 95% CI, 1.4-8.5), cardiopulmonary bypass duration greater than 150 minutes (odds ratio, 6.9 min; 95% CI, 2.9-16.7 min), and preoperative creatinine greater than 0.3 mg/dL (odds ratio, 2.4 mg/dL; 95% CI, 1.1-5.6 mg/dL) were independently associated with major adverse cardiovascular events. In patients with preoperative left ventricular end-diastolic diameter measurements available (n = 116), left ventricular end-diastolic diameter z score greater than 6 was also independently associated with major adverse cardiovascular events (odds ratio, 7.6; 95% CI, 2.0-28.6)., Conclusions: In this contemporary multicenter analysis, one in five children who underwent surgical repair of anomalous left coronary artery from the pulmonary artery experienced major adverse cardiovascular events. Preoperative characteristics such as inotropic support, creatinine, and left ventricular end-diastolic diameter z score should be considered when planning for potential postoperative complications., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Extracting and processing information from documents is of great importance as lots of experimental results and findings are stored in local files. Therefore, extracting and analyzing biomedical terms from such files in an automated way is absolutely necessary. In this article, we present OnTheFly 2.0 , a web application for extracting biomedical entities from individual files such as plain texts, office documents, PDF files or images. OnTheFly 2.0 can generate informative summaries in popup windows containing knowledge related to the identified terms along with links to various databases. It uses the EXTRACT tagging service to perform named entity recognition (NER) for genes/proteins, chemical compounds, organisms, tissues, environments, diseases, phenotypes and gene ontology terms. Multiple files can be analyzed, whereas identified terms such as proteins or genes can be explored through functional enrichment analysis or be associated with diseases and PubMed entries. Finally, protein-protein and protein-chemical networks can be generated with the use of STRING and STITCH services. To demonstrate its capacity for knowledge discovery, we interrogated published meta-analyses of clinical biomarkers of severe COVID-19 and uncovered inflammatory and senescence pathways that impact disease pathogenesis. OnTheFly 2.0 currently supports 197 species and is available at http://bib.fleming.gr:3838/OnTheFly/ and http://onthefly.pavlopouloslab.info., (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

ETS2 repressor factor (ERF) haploinsufficiency causes late-onset craniosynostosis (CRS) (OMIM entry 600775; CRS4) in humans, while in mice Erf insufficiency also leads to a similar multisuture synostosis phenotype preceded by mildly reduced calvarium ossification. However, neither the cell types affected nor the effects per se have been identified so far. Here, we establish an ex vivo system for the expansion of suture-derived mesenchymal stem and progenitor cells (sdMSCs) and analyze the role of Erf levels in their differentiation. Cellular data suggest that Erf insufficiency specifically decreases osteogenic differentiation of sdMSCs, resulting in the initially delayed mineralization of the calvarium. Transcriptome analysis indicates that Erf is required for efficient osteogenic lineage commitment of sdMSCs. Elevated retinoic acid catabolism due to increased levels of the cytochrome P450 superfamily member Cyp26b1 as a result of decreased Erf levels appears to be the underlying mechanism leading to defective differentiation. Exogenous addition of retinoic acid can rescue the osteogenic differentiation defect, suggesting that Erf affects cranial bone mineralization during skull development through retinoic acid gradient regulation.

Bottom-up proteomics analyses have been proved over the last years to be a powerful tool in the characterization of the proteome and are crucial for understanding cellular and organism behaviour. Through differential proteomic analysis researchers can shed light on groups of proteins or individual proteins that play key roles in certain, normal or pathological conditions. However, several tools for the analysis of such complex datasets are powerful, but hard-to-use with steep learning curves. In addition, some other tools are easy to use, but are weak in terms of analytical power. Previously, we have introduced ProteoSign, a powerful, yet user-friendly open-source online platform for protein differential expression/abundance analysis designed with the end-proteomics user in mind. Part of Proteosign's power stems from the utilization of the well-established Linear Models For Microarray Data (LIMMA) methodology. Here, we present a substantial upgrade of this computational resource, called ProteoSign v2, where we introduce major improvements, also based on user feedback. The new version offers more plot options, supports additional experimental designs, analyzes updated input datasets and performs a gene enrichment analysis of the differentially expressed proteins. We also introduce the deployment of the Docker technology and significantly increase the speed of a full analysis. ProteoSign v2 is available at http://bioinformatics.med.uoc.gr/ProteoSign., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

We describe the successful treatment of a 10-month-old female with respiratory distress secondary to Coronavirus disease 2019 (COVID-19) with the nebulized investigational drug, DAS181. Therapy was well tolerated, and the patient had minimal side effects. The patient's respiratory distress and positive viral polymerase chain reaction rapidly resolved after initiation of therapy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Pine honey is a unique type of honeydew honey produced exclusively in Eastern Mediterranean countries like Greece and Turkey. Although the antioxidant and anti-inflammatory properties of pine honey are well documented, few studies have investigated so far its antibacterial activity. This study investigates the antibacterial effects of pine honey against P . aeruginosa PA14 at the molecular level using a global transcriptome approach via RNA-sequencing. Pine honey treatment was applied at sub-inhibitory concentration and short exposure time (0.5× of minimum inhibitory concentration -MIC- for 45 min). Pine honey induced the differential expression (>two-fold change and p ≤ 0.05) of 463 genes, with 274 of them being down-regulated and 189 being up-regulated. Gene ontology (GO) analysis revealed that pine honey affected a wide range of biological processes (BP). The most affected down-regulated BP GO terms were oxidation-reduction process, transmembrane transport, proteolysis, signal transduction, biosynthetic process, phenazine biosynthetic process, bacterial chemotaxis, and antibiotic biosynthetic process. The up-regulated BP terms, affected by pine honey treatment, were those related to the regulation of DNA-templated transcription, siderophore transport, and phosphorylation. Pathway analysis revealed that pine honey treatment significantly affected two-component regulatory systems, ABC transporter systems, quorum sensing, bacterial chemotaxis, biofilm formation and SOS response. These data collectively indicate that multiple mechanisms of action are implicated in antibacterial activity exerted by pine honey against P . aeruginosa .

DNA methylation plays an important role in breast cancer (BrCa) pathogenesis and could contribute to driving its personalized management. We performed a complete bioinformatic analysis in BrCa whole methylome datasets, analyzed using the Illumina methylation 450 bead-chip array. Differential methylation analysis vs. clinical end-points resulted in 11,176 to 27,786 differentially methylated genes (DMGs). Innovative automated machine learning (AutoML) was employed to construct signatures with translational value. Three highly performing and low-feature-number signatures were built: (1) A 5-gene signature discriminating BrCa patients from healthy individuals (area under the curve (AUC): 0.994 (0.982-1.000)). (2) A 3-gene signature identifying BrCa metastatic disease (AUC: 0.986 (0.921-1.000)). (3) Six equivalent 5-gene signatures diagnosing early disease (AUC: 0.973 (0.920-1.000)). Validation in independent patient groups verified performance. Bioinformatic tools for functional analysis and protein interaction prediction were also employed. All protein encoding features included in the signatures were associated with BrCa-related pathways. Functional analysis of DMGs highlighted the regulation of transcription as the main biological process, the nucleus as the main cellular component and transcription factor activity and sequence-specific DNA binding as the main molecular functions. Overall, three high-performance diagnostic/prognostic signatures were built and are readily available for improving BrCa precision management upon prospective clinical validation. Revisiting archived methylomes through novel bioinformatic approaches revealed significant clarifying knowledge for the contribution of gene methylation events in breast carcinogenesis.

The directed self-assembly (DSA) of block copolymers (BCPs) is a powerful method for the manufacture of high-resolution features. Critical issues remain to be addressed for successful implementation of DSA, such as dewetting and controlled orientation of BCP domains through physicochemical manipulations at the BCP interfaces, and the spatial positioning and registration of the BCP features. Here, we introduce novel top-coat (TC) materials designed to undergo cross-linking reactions triggered by thermal or photoactivation processes. The cross-linked TC layer with adjusted composition induces a mechanical confinement of the BCP layer, suppressing its dewetting while promoting perpendicular orientation of BCP domains. The selection of areas of interest with perpendicular features is performed directly on the patternable TC layer via a lithography step and leverages attractive integration pathways for the generation of locally controlled BCP patterns and nanostructured BCP multilayers.

We sought to describe the clinical course and outcomes of patients who are diagnosed with anomalous left coronary artery from the pulmonary artery (ALCAPA) after infancy. We conducted a retrospective evaluation of patients who underwent ALCAPA surgery between January 2009 to March 2018 at 21 US centers. Clinical presentation, inpatient management, and postoperative outcomes of patients repaired ≥1 year of age were described. To characterize this cohort, we compared these data to patients repaired before 1 year of age. Of 248 ALCAPA patients, 71 (29%) underwent repair ≥1 year of age. Among this subset, the median age at diagnosis was 8.3 years. Chronic arrhythmia occurred in 7%. Patients had good postoperative recovery of left ventricle (LV) dysfunction (90%) and LV dilation (75%), although a low incidence of recovery of mitral regurgitation (40%). Compared to infants, older patients were more likely to present with cardiac arrest (11% vs 1%) and less likely to have moderate or worse LV dysfunction or mitral regurgitation. Older patients had significantly less postoperative extracorporeal membrane oxygenation use, and shorter ICU and hospital stay. In the older cohort, operative mortality occurred in only 1 patient and no patient died after discharge (median follow-up 2.7 years). Survival of patients who presented with ALCAPA beyond infancy was excellent, although chronic mitral regurgitation and chronic arrhythmia were not uncommon. Patients who underwent ALCAPA repair ≥1 year of age were less likely to present with LV dysfunction but more likely to present with cardiac arrest than younger patients., (Published by Elsevier Inc.)

Objective: The potentialities of improving the penetration of millimeter waves for breast cancer imaging are here explored., Methods: A field focusing technique based on a convex optimization method is proposed, capable of increasing the field level inside a breast-emulating stratification., Results: The theoretical results are numerically validated via the design and simulation of two circularly polarized antennas. The experimental validation of the designed antennas, using tissue-mimicking phantoms, is provided, being in good agreement with the theoretical predictions., Conclusion: The possibility of focusing, within a lossy medium, the electromagnetic power at millimeter-wave frequencies is demonstrated., Significance: Field focusing can be a key for using millimeter waves for breast cancer detection.

We conducted a candidate gene association study to test the hypothesis that different gene polymorphisms will be associated with corticosteroid responsiveness and study outcomes among children undergoing congenital heart surgery. This is a prospective observational cohort study at a large, tertiary pediatric cardiac center on children undergoing corrective or palliative congenital heart surgery. A total of 83 children were enrolled. DNA was isolated for three polymorphisms of interest namely N363 (rs56149945) and 9β (rs6198) associated with increased sensitivity to corticosteroids and Bcl I (rs41423247) associated with decreased sensitivity to corticosteroids. Duration of inotropic use, low cardiac output scores (LCOS), and vasoactive inotrope scores were examined in relation to these three polymorphisms. Using Kaplan-Meier analysis, heterozygous individuals showed longer transcriptional intermediary factor (TIF) compared with wild type for N363 polymorphism ( p  = 0.05). In multivariable Cox regression, heterozygous alleles for 9β polymorphism showed significantly shorter TIF compared with wild type (hazard ratio = 2.04 [1.08-3.87], p  = 0.03). The relationship between lower LCOS scores and alleles groups was significant for 9β heterozygous polymorphism only (1.5 [1-2.2], p  = 0.01) in comparison to wild type and homozygous. The presence of heterozygote alleles for the increased corticosteroid sensitivity is associated with longer TIF compared with wild type. Conversely, the presence of heterozygous alleles for the decreased sensitivity to corticosteroids is associated with shorter TIF compared with wild type., Competing Interests: Conflicts of Interest None declared., (Thieme. All rights reserved.)

Truncal valve management in patients with truncus arteriosus is a clinical challenge, and indications for truncal valve intervention have not been defined. We sought to evaluate truncal valve dysfunction and primary valve intervention in patients with truncus arteriosus and determine risk factors for later truncal valve intervention. We conducted a retrospective cohort study of children who underwent truncus arteriosus repair at 15 centers between 2009 and 2016. Multivariable competing risk analysis was performed to determine risk factors for later truncal valve intervention. We reviewed 252 patients. Forty-two patients (17%) underwent truncal valve intervention during their initial surgery. Postoperative extracorporeal support, CPR, and operative mortality for patients who underwent truncal valve interventions were statistically similar to the rest of the cohort. Truncal valve interventions were performed in 5 of 64 patients with mild insufficiency; 5 of 16 patients with mild-to-moderate insufficiency; 17 of 35 patients with moderate insufficiency; 5 of 9 patients with moderate-to-severe insufficiency; and all 10 patients with severe insufficiency. Twenty patients (8%) underwent later truncal valve intervention, five of whom had no truncal valve intervention during initial surgical repair. Multivariable analysis revealed truncal valve intervention during initial repair (HR 11.5; 95% CI 2.5, 53.2) and moderate or greater truncal insufficiency prior to initial repair (HR 4.0; 95% CI 1.1, 14.5) to be independently associated with later truncal valve intervention. In conclusion, in a multicenter cohort of children with truncus arteriosus, 17% had truncal valve intervention during initial surgical repair. For patients in whom variable truncal valve insufficiency is present and primary intervention was not performed, late interventions were uncommon. Conservative surgical approach to truncal valve management may be justifiable.

Neutrophil-lymphocyte ratio has been associated with clinical outcomes in several groups of cardiac patients, including patients with coronary artery disease, cardiac failure, and cardiac transplant recipients. We hypothesised that pre- and/or post-operative haematological cell counts are associated with clinical outcomes in children undergoing cardiac surgery for CHD. We performed a post hoc analysis of data collected as part of a prospective observational cohort study (n = 83, data available n = 47) of children evaluated for glucocorticoid receptor levels after cardiac surgery (July 2015-January 2016). The association of neutrophil-lymphocyte ratio with low cardiac output syndrome, time to inotrope free, and vasoactive-inotropic score was examined using proportional odds analysis, cox regression, and linear regression models, respectively. A majority (80%) of patients were infants (median/interquartile range 4.1/0.2-7.6 months) with conotruncal (36%) and left-sided obstructed lesions (28%). Two patients required mechanical circulatory support and three died. Higher pre-operative neutrophil-lymphocyte ratio was associated with higher cumulative odds of severe/moderate versus mild low cardiac output on post-operative day 1 (odds ratio 2.86; 95% confidence interval 1.18-6.93; p = 0.02). Pre-operative neutrophil-lymphocyte ratio was not significantly associated with time to inotrope free or vasoactive-inotrope score. Post-operative neutrophil-lymphocyte ratio was also not associated with outcomes. In children after congenital heart surgery, higher pre-operative neutrophil-lymphocyte ratio was associated with a higher chance of low cardiac output in the early post-operative period. Pre-operative neutrophil-lymphocyte ratio maybe a useful prognostic marker in children undergoing congenital heart surgery.

The in-depth study of protein-protein interactions (PPIs) is of key importance for understanding how cells operate. Therefore, in the past few years, many experimental as well as computational approaches have been developed for the identification and discovery of such interactions. Here, we present UniReD, a user-friendly, computational prediction tool which analyses biomedical literature in order to extract known protein associations and suggest undocumented ones. As a proof of concept, we demonstrate its usefulness by experimentally validating six predicted interactions and by benchmarking it against public databases of experimentally validated PPIs succeeding a high coverage. We believe that UniReD can become an important and intuitive resource for experimental biologists in their quest for finding novel associations within a protein network and a useful tool to complement experimental approaches (e.g. mass spectrometry) by producing sorted lists of candidate proteins for further experimental validation. UniReD is available at http://bioinformatics.med.uoc.gr/unired/., (© The Author(s) 2019. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)