Pharmacokinetic model-guided enoxaparin dosing in the Neonatal ICU: Retrospective cohort study to plan for prospective feasibility trial.

Traditional milligram per kilogram (mg/kg) dosing of enoxaparin in neonates frequently fails to achieve target anti-Xa levels promptly, necessitating repeated laboratory monitoring and dose adjustments. This study investigated whether a personalized dosing strategy based on predicted individual clearance and volume of distribution could improve outcomes, comparing standard-of-care (SOC) mg/kg dosing to pharmacokinetic (PK) model-informed precision dosing (MIPD). A retrospective analysis was conducted on hospitalized neonates treated with enoxaparin at less than 44 weeks postmenstrual age from 2019 to 2022. Data on demographics, drug dosing, PK model covariates, and clinical outcomes were extracted from electronic health records and analyzed using the Pumas-AI Lyv dosing tool. The primary focus was on comparing the initial SOC dose to the MIPD-recommended dose. The secondary outcome measured was the time required to achieve therapeutic anti-Xa levels. The study included 168 neonates with a median postnatal age of 15 days (range 1-149) and a median dosing weight of 3.1 kg (range: 0.82-5.2). MIPD-recommended initial doses were 20%-60% higher than SOC doses in 32% of the cases and over 60% higher in 11% of cases. Neonates who received SOC doses that were much lower than the MIPD recommendation showed the longest delays in reaching therapeutic anti-Xa levels. The results indicate that PK model-informed of enoxaparin dosing leads to higher initial dosages than SOC in neonates, potentially reducing the time to therapeutic anti-Xa levels. These findings are being utilized to define dosing limits for a prospective trial of MIPD in neonatal intensive care settings.

Outcomes in Children with Provoked Venous Thrombosis and Antiphospholipid Antibodies: Findings from the Kids-DOTT Trial.

Few studies have prospectively evaluated the incidence and outcomes in children with provoked venous thromboembolism (VTE) and transient or persistent antiphospholipid antibodies (aPL). We compared outcomes of patients <21 years old with a first-episode acute provoked VTE and positive aPL at diagnosis enrolled in the Kids-DOTT trial. aPL were tested at enrollment and, when positive, repeated at 6 weeks post-VTE. Subsequent testing was performed at discretion of the treating hematologist. Of 524 patients, 116 (22%) had positive aPL at enrollment. At follow-up, 70 (60%) had transient (n=66) or low titer aPL (n=4), 11 (10%) had persistent aPL meeting criteria for antiphospholipid syndrome (APS), and 35 (30%) had no repeat testing. Patients with APS were older (15.8 vs. 9.9 years, p=.014), and had a statistically significant higher risk of symptomatic recurrent VTE (18% vs. 1%, OR: 12.2 [1.4 - 108], p= .025), and a statistically non-significant but clinically meaningful difference in the risk of anticoagulant-related clinically-relevant bleeding (9% vs. 0%, OR: 20.1 [0.7 - 558], p=0.077) compared to those in the transient or low titer aPL group. In conclusion, aPL are common in young patients with acute provoked VTE and are mostly transitory and clinically insignificant. Patients with APS and provoked VTE appear to have an increased risk of recurrent VTE compared to patients with transitory or low titer aPL. Future collaborative studies should investigate the optimal VTE management of children with provoked VTE who meet criteria for APS.

Synthesis of Poly(L-lactide)-poly(ε-caprolactone)-poly(ethylene glycol) Terpolymer Grafted onto Partially Oxidized Carbon Nanotube Nanocomposites for Drug Delivery.

Nanocomposites prepared with a terpolymer of poly(L-lactide) (PLLA)-poly(ε-caprolactone) (PCL)-poly(ethylene glycol) (PEG) and partially oxidized carbon nanotubes (CNTspo) were synthesized and characterized to evaluate their ability to act as an effective nanocarrier of the anticancer drug methotrexate. The homopolymers of PLLA and PCL were synthesized through ring-opening polymerization (ROP) and characterized through gel permeation chromatography (GPC). The PLLA-PCL-PEG terpolymers were synthesized through a four-step chemical route using oxalyl chloride as a linker agent and analyzed with 1H-NMR, 13C-NMR, and FTIR spectroscopies. Additionally, the nanocomposites were characterized through FTIR, and X-ray photoelectron spectroscopy (XPS), as well as the differential scanning calorimetry (DSC) technique. XPS analysis revealed that PLLA-PCL-PEG terpolymer chains are grafted onto CNTspo. Moreover, evaluations through FTIR and DSC strongly suggest that the PCL-rich domains are preferentially oriented toward CNTspo. The release tests exhibited a "burst effect" profile, which was more evident in the terpolymers than in the nanocomposites. Five models were used to assess methotrexate's in vitro release. For the nanocomposites, the best fit to the experimental data was obtained using the first-order model, whereas the results obtained from the Korsmeyer-Peppas model indicated that Fickian diffusion drives methotrexate's release.

Reliability, usability, and efficiency of video versus print instructions to teach parents a procedural task: A cross-sectional study.

OBJECTIVE: To compare the reliability, usability, and efficiency of video versus print instructions to teach parents a procedural measurement task. We hypothesized that videos would outperform print in all outcomes. STUDY DESIGN: This cross-sectional study included parents/caregivers of children aged 0-18 years with deep vein thrombosis attending the Thrombosis Clinic at The Hospital for Sick Children for post-thrombotic syndrome (PTS) assessment. Participants were randomly assigned to three instruction types: (i) video, which followed the technique used by clinicians; (ii) long pamphlet, which also followed the clinicians' technique; and (iii) short pamphlet, which explained a simplified technique. After measuring their children's arms or legs using the randomly assigned material, participants completed a usability questionnaire. The reliability of the instructions was estimated by comparing parents/caregivers versus clinicians' measurements using the intraclass correlation coefficient (ICC). Reliability, usability, and efficiency (time to task completion) were compared among the three instruction types. RESULTS: In total, 92 participants were randomized to video (n = 31), long pamphlet (n = 31), and short pamphlet (n = 30). While the video had the highest usability, the short pamphlet was the most reliable and efficient. ICCs were .17 (95% confidence interval [CI]: .00-.39) for the video, .53 (95% CI: .30-.72) for the long pamphlet, and .70 (95% CI: .50-.81) for the short pamphlet. CONCLUSION: Although the video had higher usability, the short/simplified print instruction was more reliable and efficient. However, the reliability of the short pamphlet was only moderate/good, suggesting that whenever possible, measurements should still be obtained by trained clinicians.

A Holistic Approach to Producing Anti-Vibrio Metabolites by an Endosymbiotic Dinoflagellate Using Wastewater from Shrimp Rearing.

The aquaculture industry requires green solutions to solve several environmental challenges, including adequate wastewater remediation and natural drug applications to treat bacteria- and virus-related diseases. This study investigated the feasibility of cultivating the dinoflagellate Durusdinium glynnii in aquaculture wastewater from shrimp rearing in a synbiotic system (AWW-SS), with different dilutions of f/2 medium (FM). Interestingly, D. glynnii demonstrated enhanced growth in all AWW-SS treatments compared to the control (FM). The highest growth rates were achieved at AWW-SS:FM dilutions of 75:25 and 50:50. The removal of total nitrogen and total phosphorus reached 50.1 and 71.7%, respectively, of the crude AWW-SS. Biomass extracts of D. glynnii grown with AWW-SS were able to inhibit the growth of the bacteria Vibrio parahaemolyticus (inhibition zone of 10.0 ± 1.7 mm) and V. vulnificus (inhibition zone of 11.7 ± 1.5 mm). The presented results demonstrate that the dinoflagellate D. glynnii is a potential candidate for the development of circularity for sustainable aquaculture production, particularly by producing anti-Vibrio compounds at a near-zero cost.

Lack of correlation between parasite burden and key weight metrics in poultry infected with intestinal ascarids.

Ascaridia galli and Ascaridia dissimilis are the most common and economically impactful nematode parasites of commercial poultry. These infections rarely cause clinical disease, but reduction in feed conversion efficiency is detected. To determine if feed conversion efficiency reductions correlate with any physiological measures independent of clinical disease, we determined if ascarid infections correlate with changes in the weights of the small intestine, liver, or total animal weight (quantitative measures of animal health). No correlation between parasite burden and these metrics were observed, supporting the concept that feed conversion is the only production metric impacted by ascarid infections.

Virtual reality assessment of reaching accuracy in patients with recent cerebellar stroke.

Background: Dysmetria, the inability to accurately estimate distance in motor tasks, is a characteristic clinical feature of cerebellar injury. Even though subjective dysmetria can be quickly detected during the neurological examination with the finger-to-nose test, objective quantification of reaching accuracy for clinical assessment is still lacking. Emerging VR technology allows for the delivery of rich multisensory environmental stimuli with a high degree of control. Furthermore, recent improvements in the hand-tracking feature offer an opportunity to closely examine the speed, accuracy, and consistency of fine hand movements and proprioceptive function. This study aims to investigate the application of virtual reality (VR) with hand tracking in the rapid quantification of reaching accuracy at the bedside for patients with cerebellar stroke (CS). Methods and results: Thirty individuals (10 CS patients and 20 age-matched neurologically healthy controls) performed a simple task that allowed us to measure reaching accuracy using a VR headset (Oculus Quest 2). During this task, the participant was asked to reach for a target placed along a horizontal sixty-degree arc. Once the fingertip passed through the arc, the target immediately extinguished. 50% of the trials displayed a visible, real-time rendering of the hand as the participant reached for the target (visible hand condition), while the remaining 50% only showed the target being extinguished (invisible hand condition). The invisible hand condition isolates proprioception-guided movements by removing the visibility of the participant's hand. Reaching error was calculated as the difference in degrees between the location of the target, and where the fingertip contacted the arc. Both CS patients and age-matched controls displayed higher average reaching error and took longer to perform a reaching motion in the invisible hand condition than in the visible hand condition. Reaching error was higher in CS than in controls in the invisible hand condition but not in the visible hand condition. Average time taken to perform each trial was higher in CS than in controls in the invisible hand conditions but not in the visible hand condition. Conclusions: Reaching accuracy assessed by VR offers a non-invasive and rapid approach to quantifying fine motor functions in clinical settings. Furthermore, this technology enhances our understanding of proprioceptive function in patients with visuomotor disabilities by allowing the isolation of proprioception from vision. Future studies with larger cohorts and longitudinal designs will examine the quantitative changes in reaching accuracy after stroke and explore the long-term benefits of VR in functional recovery.

Variation in induced responses in volatile and non-volatile metabolites among six willow species: Do willow species share responses to herbivory?

Chemical variation is a critical aspect affecting performance among co-occurring plants. High chemical variation in metabolites with direct effects on insect herbivores supports chemical niche partitioning, and it can reduce the number of herbivores shared by co-occurring plant species. In contrast, low intraspecific variation in metabolites with indirect effects, such as induced volatile organic compounds (VOCs), may improve the attraction of specialist predators or parasitoids as they show high specificity to insect herbivores. We explored whether induced chemical variation following herbivory by various insect herbivores differs between VOCs vs. secondary non-volatile metabolites (non-VOCs) and salicinoids with direct effects on herbivores in six closely related willow species. Willow species identity explained most variation in VOCs (18.4%), secondary non-VOCs (41.1%) and salicinoids (60.7%). The variation explained by the independent effect of the herbivore treatment was higher in VOCs (2.8%) compared to secondary non-VOCs (0.5%) and salicinoids (0.5%). At the level of individual VOCs, willow species formed groups, as some responded similarly to the same herbivores. Most non-VOCs and salicinoids were upregulated by sap-suckers compared to other herbivore treatments and control across the willow species. In contrast, induced responses in non-VOCs and salicinoids to other herbivores largely differed between the willows. Our results suggest that induced responses broadly differ between various types of chemical defences, with VOCs and non-VOCs showing different levels of specificity and similarity across plant species. This may further contribute to flexible plant responses to herbivory and affect how closely related plants share or partition their chemical niches.

Genomic Comparative of Pseudomonas aeruginosa Small Colony Variant, Mucoid and Non-mucoid Phenotypes Obtained from a Patient with Cystic Fibrosis During Respiratory Exacerbations.

Pseudomonas aeruginosa, the most prevalent opportunistic pathogen in chronic obstructive pulmonary disease, associated with high morbidity and mortality in patients with cystic fibrosis (CF), is practically impossible to be eradicated from the airways in chronicity. Its extraordinary genomic plasticity is possibly associated with high antimicrobial resistance, virulence factors, and its phenotypic diversity. The occurrence of P. aeruginosa isolates promoting airway infection, showing mucoid, non-mucoid, and small colony variant (SCV) phenotypes, was observed simultaneously, in the present study, in sputum cultures obtained from a male CF young patient with chronic pulmonary infection for over a decade. The isolates belonged to a new ST (2744) were obtained in two moments of exacerbation of the respiratory disease, in which he was hospitalized. Genetic background and phenotypic analysis indicated that the isolates exhibited multi- and pan-antimicrobial resistant profiles, as well as non-susceptible to polymyxin and predominantly hypermutable (HPM) phenotypes. Whole genome sequencing showed variations in genome sizes, coding sequences and their determinants of resistance and virulence. The annotated genomes were compared for antimicrobial resistance, hypermutability, and SCV characteristics. We highlight the lack of reported genetic determinants of SCV emergence and HPM phenotypes, which can be explained in part due to the very short time between collections of isolates. To the best of our knowledge, this is the first report of genome sequencing of P. aeruginosa SCV from a CF patient in Brazil.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

Anticoagulant Medications: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the medications used for anticoagulation for pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE (PEACE). DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Included studies assessed anticoagulation used in pediatric ECMO. DATA EXTRACTION: Two authors reviewed all citations independently, with a third reviewer adjudicating any conflicts. Eighteen references were used for data extraction as well as for creation of recommendations. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-informed recommendations and, when evidence was lacking, expert-based consensus statements, or good practice statements for anticoagulation during pediatric ECMO. A web-based modified Delphi process was used to build consensus via the Research and Development/University of California Appropriateness Method. Consensus was based on a modified Delphi process with agreement defined as greater than 80%. Two recommendations, two consensus statements, and one good practice statement were developed, and, in all, agreement greater than 80% was reached. CONCLUSIONS: There is insufficient evidence to formulate optimal anticoagulation therapy during pediatric ECMO. Additional high-quality research is needed to inform evidence-based practice for anticoagulation during pediatric ECMO.

Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6.

BACKGROUND: The maintenance of skeletal muscle plasticity upon changes in the environment, nutrient supply, and exercise depends on regulatory mechanisms that couple structural and metabolic adaptations. The mechanisms that interconnect both processes at the transcriptional level remain underexplored. Nr2f6, a nuclear receptor, regulates metabolism and cell differentiation in peripheral tissues. However, its role in the skeletal muscle is still elusive. Here, we aimed to investigate the effects of Nr2f6 modulation on muscle biology in vivo and in vitro. METHODS: Global RNA-seq was performed in Nr2f6 knockdown C2C12 myocytes (N = 4-5). Molecular and metabolic assays and proliferation experiments were performed using stable Nr2f6 knockdown and Nr2f6 overexpression C2C12 cell lines (N = 3-6). Nr2f6 content was evaluated in lipid overload models in vitro and in vivo (N = 3-6). In vivo experiments included Nr2f6 overexpression in mouse tibialis anterior muscle, followed by gene array transcriptomics and molecular assays (N = 4), ex vivo contractility experiments (N = 5), and histological analysis (N = 7). The conservation of Nr2f6 depletion effects was confirmed in primary skeletal muscle cells of humans and mice. RESULTS: Nr2f6 knockdown upregulated genes associated with muscle differentiation, metabolism, and contraction, while cell cycle-related genes were downregulated. In human skeletal muscle cells, Nr2f6 knockdown significantly increased the expression of myosin heavy chain genes (two-fold to three-fold) and siRNA-mediated depletion of Nr2f6 increased maximal C2C12 myocyte's lipid oxidative capacity by 75% and protected against lipid-induced cell death. Nr2f6 content decreased by 40% in lipid-overloaded myotubes and by 50% in the skeletal muscle of mice fed a high-fat diet. Nr2f6 overexpression in mice resulted in an atrophic and hypoplastic state, characterized by a significant reduction in muscle mass (15%) and myofibre content (18%), followed by an impairment (50%) in force production. These functional phenotypes were accompanied by the establishment of an inflammation-like molecular signature and a decrease in the expression of genes involved in muscle contractility and oxidative metabolism, which was associated with the repression of the uncoupling protein 3 (20%) and PGC-1α (30%) promoters activity following Nr2f6 overexpression in vitro. Additionally, Nr2f6 regulated core components of the cell division machinery, effectively decoupling muscle cell proliferation from differentiation. CONCLUSIONS: Our findings reveal a novel role for Nr2f6 as a molecular transducer that plays a crucial role in maintaining the balance between skeletal muscle contractile function and oxidative capacity. These results have significant implications for the development of potential therapeutic strategies for metabolic diseases and myopathies.

Color discrimination in fixed saturation level of patients with acute traumatic injury.

Introduction: Traumatic brain injury (TBI) is an important public health concern and that may lead to severe neural sequels, such as color vision deficits. Methods: We evaluated the color vision of 10 TBI patients with normal cognitive function using a color discrimination test in a fixed saturation level. We also analyzed computerized tomography scans to identify the local of the brain damages. Results: Four TBI patients that had lesions in brain areas of the ventral visual streams, five TBI patients had lesions inferred in brain areas of the dorsal visual stream, and one TBI patient had lesion in the occipital area. All the patients had cognitive and color vision screened and they had characterized the chromatic discrimination at high and low saturation. All participants had no significant cognitive impairment in the moment of the color vision test. Additionally, they had perfect performance for discrimination of chromatic stimulus at high saturation and similar to controls (n = 37 age-matched participants). Three of four TBI patients with lesions in the ventral brain and one patient with lesion in the occipital area had impairment of the chromatic discrimination at low saturation. All TBI patients with lesions in the dorsal brain had performance similar or slightly worse than the controls. Conclusion: Chromatic discrimination at low saturation was associated to visual damage in the ventral region of the brain and is a potential tool for functional evaluation of brain damage in TBI patients.

The role of coagulation factors VIII, IX and XI in the prediction and mediation of recurrent thrombotic events in children with non-central venous catheter deep vein thrombosis.

BACKGROUND: The role of elevated coagulation factors VIII (FVIII), FIX, FXI for the prediction of recurrent thrombotic events in children after an index non-central venous catheter (non-CVC) related deep vein thrombosis (DVT) remains unclear. OBJECTIVE: This study investigates the predictive role of FVIII, FIX, and FXI for recurrent thrombosis in children with index non-CVC DVTs, and the mediation effect of FVIII on chronic inflammation and recurrent thrombosis. METHODS: Children aged 0-18 years diagnosed with an index non-CVC related DVT (1993-2020) were included in this single-center retrospective cohort study. Plasma levels of FVIII, FIX, FXI were measured cross-sectionally ≥30 days after the acute DVT. The association between the continuous variables FVIII, FIX, FXI and thrombosis recurrence was investigated using uni- and multivariable logistic regression, adjusting for age, sex, and chronic inflammation. Mediation analysis assessed the role of FVIII as a mediator between chronic inflammation and recurrent thrombosis. Ethics approval was obtained. RESULTS: A total of 139 children with an index non-CVC related DVT were included. Thirty-eight (27 %) had a recurrent thrombosis at a median of 237 days (P25-P75 65-657 days) after the index DVT. In uni- and multivariable-analysis, FVIII, FIX or FXI did not predict thrombosis recurrence; However, chronic inflammation was an independent predictor. There was no evidence that FVIII mediated the effect of chronic inflammation on thrombosis recurrence. CONCLUSION: We found no evidence that elevated FVIII, FIX or FXI predicted thrombosis recurrence, or evidence of a mediating role of FVIII. Underlying chronic inflammation predicted venous recurrent thrombotic events in this cohort.

Altered Fhod3 expression involved in progressive high-frequency hearing loss via dysregulation of actin polymerization stoichiometry in the cuticular plate.

Age-related hearing loss (ARHL) is a common sensory impairment with complex underlying mechanisms. In our previous study, we performed a meta-analysis of genome-wide association studies (GWAS) in mice and identified a novel locus on chromosome 18 associated with ARHL specifically linked to a 32 kHz tone burst stimulus. Consequently, we investigated the role of Formin Homology 2 Domain Containing 3 (Fhod3), a newly discovered candidate gene for ARHL based on the GWAS results. We observed Fhod3 expression in auditory hair cells (HCs) primarily localized at the cuticular plate (CP). To understand the functional implications of Fhod3 in the cochlea, we generated Fhod3 overexpression mice (Pax2-Cre+/-; Fhod3Tg/+) (TG) and HC-specific conditional knockout mice (Atoh1-Cre+/-; Fhod3fl/fl) (KO). Audiological assessments in TG mice demonstrated progressive high-frequency hearing loss, characterized by predominant loss of outer hair cells, and a decreased phalloidin intensities of CP. Ultrastructural analysis revealed loss of the shortest row of stereocilia in the basal turn of the cochlea, and alterations in the cuticular plate surrounding stereocilia rootlets. Importantly, the hearing and HC phenotype in TG mice phenocopied that of the KO mice. These findings suggest that balanced expression of Fhod3 is critical for proper CP and stereocilia structure and function. Further investigation of Fhod3 related hearing impairment mechanisms may lend new insight towards the myriad mechanisms underlying ARHL, which in turn could facilitate the development of therapeutic strategies for ARHL.

Post-COVID-19 condition: systemic inflammation and low functional exercise capacity.

Introduction: Post-COVID-19 condition (PCC) is characterised by a plethora of symptoms, with fatigue appearing as the most frequently reported. The alterations that drive both the persistent and post-acute disease newly acquired symptoms are not yet fully described. Given the lack of robust knowledge regarding the mechanisms of PCC we have examined the impact of inflammation in PCC, by evaluating serum cytokine profile and its potential involvement in inducing the different symptoms reported. Methods: In this cross-sectional study, we recruited 227 participants who were hospitalised with acute COVID-19 in 2020 and came back for a follow-up assessment 6-12 months after hospital discharge. The participants were enrolled in two symptomatic groups: Self-Reported Symptoms group (SR, n = 96), who did not present major organ lesions, yet reported several debilitating symptoms such as fatigue, muscle weakness, and persistent loss of sense of smell and taste; and the Self-Reported Symptoms and decreased Pulmonary Function group (SRPF, n = 54), composed by individuals with the same symptoms described by SR, plus diagnosed pulmonary lesions. A Control group (n = 77), with participants with minor complaints following acute COVID-19, was also included in the study. Serum cytokine levels, symptom questionnaires, physical performance tests and general clinical data were obtained in the follow-up assessment. Results: SRPF presented lower IL-4 concentration compared with Control (q = 0.0018) and with SR (q = 0.030), and lower IFN-α2 serum content compared with Control (q = 0.007). In addition, SRPF presented higher MIP-1ß serum concentration compared with SR (q = 0.029). SR presented lower CCL11 (q = 0.012 and q = 0.001, respectively) and MCP-1 levels (q = 0.052 for both) compared with Control and SRPF. SRPF presented lower G-CSF compared to Control (q = 0.014). Female participants in SR showed lower handgrip strength in relation to SRPF (q = 0.0082). Male participants in SR and SRPF needed more time to complete the timed up-and-go test, as compared with men in the Control group (q = 0.0302 and q = 0.0078, respectively). Our results indicate that different PCC symptom profiles are accompanied by distinct inflammatory markers in the circulation. Of particular concern are the lower muscle function findings, with likely long-lasting consequences for health and quality of life, found for both PCC phenotypes.

Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain.

Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here we introduce a new glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled the rapid derivation of astroglial cells, which account for 25-31% of the cell population within 8-10 weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates pro-inflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling has a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.

Bridge: A New Algorithm for Rooting Orthologous Genes in Large-Scale Evolutionary Analyses.

Orthology information has been used for searching patterns in high-dimensional data, allowing transferring functional information between species. The key concept behind this strategy is that orthologous genes share ancestry to some extent. While reconstructing the history of a single gene is feasible with the existing computational resources, the reconstruction of entire biological systems remains challenging. In this study, we present Bridge, a new algorithm designed to infer the evolutionary root of orthologous genes in large-scale evolutionary analyses. The Bridge algorithm infers the evolutionary root of a given gene based on the distribution of its orthologs in a species tree. The Bridge algorithm is implemented in R and can be used either to assess genetic changes across the evolutionary history of orthologous groups or to infer the onset of specific traits in a biological system.

Polar order, shear banding, and clustering in confined active matter.

We investigate the collective behavior of sterically interacting self-propelled particles confined in a harmonic potential. Our theoretical and numerical study unveils the emergence of distinctive collective polar organizations, revealing how different levels of interparticle torques and noise influence the system. The observed phases include the shear-banded vortex, where the system self organizes in two concentric bands rotating in opposite directions around the potential center; the uniform vortex, where the two bands merge into a close packed configuration rotating uniformly as a quasi-rigid body; and the orbiting polar state, characterized by parallel orientation vectors and the cluster revolving around the potential center, without rotation, as a rigid body. Intriguingly, at lower filling fractions, the vortex and polar phases merge into a single phase where the trapped cluster breaks into smaller polarized clusters, each one orbiting the potential center as a rigid body.

Dabigatran for Treatment and Secondary Prevention of Venous Thromboembolism in Pediatric Congenital Heart Disease.

BACKGROUND: Congenital heart disease (CHD) is common in children and associated with greater risk of thrombotic complications. Management of these complications with standard-of-care treatment is suboptimal for these children. METHODS AND RESULTS: The effectiveness and safety of dabigatran were demonstrated in pivotal pediatric studies for the treatment of acute venous thromboembolism (VTE; NCT01895777) and secondary VTE prevention (NCT02197416). We report safety and efficacy outcomes from subgroup analyses of these studies for children with CHD (diagnosed according to local practice) and those without. In NCT01895777, 17/21 (81.0%) and 16/27 (59.3%) patients with CHD (including cyanotic) treated with dabigatran and standard of care, respectively, met the primary end point (complete thrombus resolution, freedom from recurrent VTE, and freedom from VTE-related death; odds ratio [OR], 0.34 [95% CI, 0.08-1.23]). In patients without CHD, 41.0% (n=64) versus 34.9% (n=22) achieved this end point with the respective treatments (OR, 0.77 [95% CI, 0.42-1.41]). Although numerical differences were observed, no heterogeneity in treatment effect of dabigatran on the composite primary end point was detected in patients with and without CHD (interaction P =0.2674). In NCT02197416, recurrent VTE at 12 months occurred in 0/17 patients with CHD versus 3/194 (1.5%) without. No patient with CHD experienced major or clinically relevant nonmajor bleeding events. CONCLUSIONS: Data on favorable anticoagulant alternatives for the unmet needs of children with CHD are emerging, and our exploratory results suggest that dabigatran could be an appropriate treatment choice, although challenging sample size limitations in pediatric studies require cautious interpretation of findings. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01895777, NCT02197416.