Complex Balance Research Articles

Case Report: A delicate equilibrium of exocrine pancreatic recovery and hepatotoxicity with elexacaftor/tezacaftor/ivacaftor therapy in a pediatric patient with cystic fibrosis

This case report presents a comprehensive evaluation of the complex balance of therapeutic benefits and potential risks associated with the cystic fibrosis transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI) therapy in managing an eight-year-old male with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI). While ETI therapy significantly enhanced exocrine pancreatic function, it led to hepatotoxicity, necessitating therapy discontinuation. Attempts to restart ETI at reduced doses were unsuccessful due to persistent hepatic dysfunction. Reduced ETI dosing frequency, implemented due to hepatic dysfunctions, did not result in substantial therapeutic benefits. Clinical markers showed a resurgence of severe EPI and sustained need for gastrostomy tube feeds, with only modest improvement in hepatic function compared to the period following ETI cessation or during prior use of CFTR modulator therapy with lumacaftor/ivacaftor. This case underscores the importance of personalized therapeutic approaches, biomarker-guided monitoring, and multidisciplinary insights to optimize CF management while also highlighting the ongoing need for research to mitigate hepatotoxicity risks and ensure long-term therapeutic efficacy.

Contrasting behavior of urea in strengthening and weakening confinement effects on polymer collapse.

Biomolecules inhabit a crowded living cell that is packed with high concentrations of cosolutes and macromolecules that result in restricted, confined volumes for biomolecular dynamics. To understand the impact of crowding on the biomolecular structure, the combined effects of the cosolutes (such as urea) and confinement need to be accounted for. This study involves examining these effects on the collapse equilibria of three model 32-mer polymers, which are simplified models of hydrophobic, charge-neutral, and uncharged hydrophilic polymers, using molecular dynamics simulations. The introduction of confinement promotes the collapse of all three polymers. Interestingly, addition of urea weakens the collapse of the confined hydrophobic polymer, leading to non-additive effects, whereas for the hydrophilic polymers, urea enhances the confinement effects by enhancing polymer collapse (or decreasing the polymer unfolding), thereby exhibiting an additive effect. The unfavorable dehydration energy opposes collapse in the confined hydrophobic and charge-neutral polymers under the influence of urea. However, the collapse is driven mainly by the favorable change in polymer-solvent entropy. The confined hydrophilic polymer, which tends to unfold in bulk water, is seen to have reduced unfolding in the presence of urea due to the stabilizing of the collapsed state by urea via cohesive bridging interactions. Therefore, there is a complex balance of competing factors, such as polymer chemistry and polymer-water and polymer-cosolute interactions, beyond volume exclusion effects, which determine the collapse equilibria under confinement. The results have implications to understand the altering of the free energy landscape of proteins in the confined living cell environment.

Molecular Dynamics Simulations Reveal How Competing Protein-Surface Interactions for Glycine, Citrate, and Water Modulate Stability in Antibody Fragment Formulations.

The design of stable formulations remains a major challenge for protein therapeutics, particularly the need to minimize aggregation. Experimental formulation screens are typically based on thermal transition midpoints (Tm), and forced degradation studies at elevated temperatures. Both approaches give limited predictions of long-term storage stability, particularly at low temperatures. Better understanding of the mechanisms of action for formulation of excipients and buffers could lead to improved strategies for formulation design. Here, we identified a complex impact of glycine concentration on the experimentally determined stability of an antibody Fab fragment and then used molecular dynamics simulations to reveal mechanisms that underpin these complex behaviors. Tm values increased monotonically with glycine concentration, but associated ΔSvh measurements revealed more complex changes in the native ensemble dynamics, which reached a maximum at 30 mg/mL. The aggregation kinetics at 65 °C were similar at 0 and 20 mg/mL glycine, but then significantly slower at 50 mg/mL. These complex behaviors indicated changes in the dominant stabilizing mechanisms as the glycine concentration was increased. MD revealed a complex balance of glycine self-interaction, and differentially preferred interactions of glycine with the Fab as it displaced hydration-shell water, and surface-bound water and citrate buffer molecules. As a result, glycine binding to the Fab surface had different effects at different concentrations, and led from preferential interactions at low concentrations to preferential exclusion at higher concentrations. During preferential interaction, glycine displaced water from the Fab hydration shell, and a small number of water and citrate molecules from the Fab surface, which reduced the protein dynamics as measured by root-mean-square fluctuation (RMSF) on the short time scales of MD. By contrast, the native ensemble dynamics increased according to ΔSvh, suggesting increased conformational changes on longer time scales. The aggregation kinetics did not change at low glycine concentrations, and so the opposing dynamics effects either canceled out or were not directly relevant to aggregation. During preferential exclusion at higher glycine concentrations, glycine could only bind to the Fab surface through the displacement of citrate buffer molecules already favorably bound on the Fab surface. Displacement of citrate increased the flexibility (RMSF) of the Fab, as glycine formed fewer bridging hydrogen bonds to the Fab surface. Overall, the slowing of aggregation kinetics coincided with reduced flexibility in the Fab ensemble at the very highest glycine concentrations, as determined by both RMSF and ΔSvh, and occurred at a point where glycine binding displaced neither water nor citrate. These final interactions with the Fab surface were driven by mass action and were the least favorable, leading to a macromolecular crowding effect under the regime of preferential exclusion that stabilized the dynamics of Fab.

Exploring the hemodynamic behavior of residual aneurysms after coiling and clipping: A computational flow dynamic analysis

Background: Residual intracranial aneurysms post-clipping or coiling pose a poorly established risk of rupture. Computational fluid dynamic (CFD) offers insights into hemodynamic changes following such interventions. This study aims to assess hemodynamic parameters in residual aneurysms pre- and post-treatment with surgical clips or coils using CFD. Methods: A retrospective analysis of consecutive patients between January 2015 and January 2024 was conducted. Digital subtraction angiography images were reconstructed using 3D modeling techniques, and hemodynamic parameters were analyzed with ANSYS® software. Results: Six aneurysms were analyzed: Five unruptured and one ruptured. The aneurysms were located at the basilar apex (2), middle cerebral artery bifurcation (2), and origin of the posterior communicating artery (2). Post-treatment, there was a significant reduction in both aneurysm area (median reduction of 33.73%) and volume (median reduction of 25.3%). Five of the six cases demonstrated fewer low wall shear stress (WSS) areas, which could indicate a reduction in regions prone to thrombus formation and diminished risk of rupture. In the unruptured aneurysms, there was a median increase of 137.6% in average WSS. Notably, the only case with increased low WSS area also had the highest increase in average WSS. One basilar artery aneurysm showed increased WSS across all parameters, suggesting a higher rupture risk. Conclusion: The increase in average and high WSS area, along with a decrease in low WSS area, reflects a complex balance between factors of stability and rupture risk. However, a simultaneous increase in all WSS parameters may represent the highest rupture risk due to increased mechanical stress on the aneurysm wall, necessitating closer monitoring.

Bronchoscopic Diagnosis of Severe Respiratory Infections

The diagnosis of severe respiratory infections in intensive care remains an area of uncertainty and involves a complex balancing of risks and benefits. Due to the frequent colonisation of the lower respiratory tract in mechanically ventilated patients, there is an ever-present possibility of microbiological samples being contaminated by bystander organisms. This, coupled with the frequency of alveolar infiltrates arising from sterile insults, risks over-treatment and antimicrobial-associated harm. The use of bronchoscopic sampling to obtain protected lower respiratory samples has long been advocated to overcome this problem. The use of bronchoscopy further enables accurate cytological assessment of the alveolar space and direct inspection of the proximal airways for signs of fungal infection or alternative pathologies. With a growing range of molecular techniques, including those based on nucleic acid amplification and even alveolar visualisation and direct bacterial detection, the potential for bronchoscopy is increasing concomitantly. Despite this, there remain concerns regarding the safety of the technique and its benefits versus less invasive sampling techniques. These discussions are reflected in the lack of consensus among international guidelines on the topic. This review will consider the benefits and challenges of diagnostic bronchoscopy in the context of severe respiratory infection.

Collaborative balance rule learning: Do students’ age, group composition, prior knowledge, and scientific reasoning skills matter?

Research on balance rule learning has focused on studies done in individual settings. This study investigates how students collaboratively learn balance rules and focuses especially on four variables that potentially affect rule development: student age, group composition, prior knowledge, and scientific reasoning skills. Eight-, ten- and twelve-year-old students collaboratively used a designed simulation-based learning environment with an open experimentation space and tasks that required progressively more complex balance rules. Students’ balance rules were tested before and after intervention with the Balance Scale Test and their scientific reasoning skills were tested with items from the Science-P Reasoning Inventory. The results show that the intervention was successful in developing students’ balance rules. Logistic regression show that the students’ previous knowledge was the only variable that affected the likelihood of rule development. Students’ with less complex pre-test rules developed their rules more often than students with more complex pre-test rules when controlling for the other variables. The results go against some previous findings and show that a collaborative setting can lead to balance rule learning with primary school aged students.

Investigating the formation of soot in CH4 pyrolysis reactor: A numerical, experimental, and characterization study

Methane pyrolysis is a promising method for eco-friendly hydrogen production, but soot formation and carbon interaction pose challenges for scaling up. Therefore, understanding the dynamics of soot formation and carbon deposition is crucial. This study delves into the intricacies of soot formation in methane pyrolysis under industrially relevant conditions, namely operations at atmospheric pressure, employing a H2:CH4 ratio of 2 and exploring a range of hot zone temperatures (1473 K, 1573 K, 1673 K, and 1773 K) with a 5 s residence time. Utilizing a detailed gas-phase kinetic model with direct carbon deposition reactions, the research adopts the method of moments coupled with a one-dimensional plug flow reactor model to simulate soot formation. The model is validated by characterizing soot particles that were produced in a pyrolysis reactor by means of transmission electron microscopy, Dynamic light scattering (DLS), and Raman spectroscopy. Results show that lower temperatures lead to nucleation-dominated growth, whereas higher temperatures significantly restrain particle growth due to carbon deposition. DLS data indicate a complex balance between particle growth and deposition processes. These findings provide insights into operational parameters that can enhance reactor performance and sustainability in hydrogen production processes by mitigating soot and carbon deposition.

GRASNet: A novel graph neural network for improving human action recognition and well-being assessment in smart manufacturing

In the manufacturing environment, prioritizing the well-being of workers is both essential and challenging. Recognizing and monitoring workers’ actions in real time is crucial in ensuring safety and health. This study introduces innovative approaches leveraging smart manufacturing technologies and Graph Neural Networks (GNNs) to enhance human action recognition using accessible skeletal data. Traditional Neural Networks encounter limitations in processing readily accessible human-related data, such as image and skeletal data, prompting the development of the Graph Residual Attention SAGE Network (GRASNet). GRASNet exhibits superior capabilities in capturing intricate local connectivity within graph data, ensuring a delicate balance of complexity and efficiency. Furthermore, experimental validations on two manufacturing-related datasets, derived from the NTU RGB + D 120 benchmark dataset, underscore GRASNet’s ability for high-accuracy monitoring of human abnormal behaviors and health issues, positioning it ahead of other existing deep learning models.

The Economic Footprint Of The FIFA World Cup

The FIFA World Cup is a premier global sport, since its inception in 1930, on the 15th of December. The World Cup event has substantial economic implications for its host countries. This study examines the economic footprint of the FIFA World Cup by targeting three key components: immediate benefits, long-term economical impacts, and associated challenges. The research incorporates economic data and impact assessments to offer insights into the complex balance of costs and benefits associated with the FIFA World Cup. Objectives of the Paper: At the outset, this research paper highlights the instant financial gains, such as increased tourism, which boosts local spending in businesses, hotels, and restaurants. The influx of visitors also generates short-term employment possibilities, providing temporary economic boosts. The analysis then turns to the long-term effects, observing that hosting the World Cup can lead to significant infrastructure development, including stadiums and transportation systems, which enhances urban development and quality of life. Additionally, a successful World Cup can improve the host city’s global footprints, possibly attracting future investment and tourism. However, the study also delves into the challenges involved. An overall cost of hosting, including construction, management, and security, can be substantial, sometimes outweighing the immediate benefits. Post-event periods can be complex, with decreased economic activity and maintenance costs for new infrastructure. Case studies of consecutive FIFA world cups including South Africa 2010, Brazil 2014, and Russia 2018 are examined to provide a balanced perspective of the varied experiences of different host nations. In final analysis, while the FIFA World Cup can bring significant economic benefits and long-term development, it also presents considerable financial challenges. The findings underscore the need for careful planning and management to optimize the event’s positive impacts and address possible drawbacks, providing essential lessons for anticipated host cities and nations.1

Assisted Decision Making in the Acute Hospital Setting – Staff Experiences of Working with Older Adults

Abstract Background The Assisted Decision Making (Capacity) Act 2015 was fully implemented in April 2023. This brought changes to how health and social care staff work with patients who may lack decision making capacity for certain decisions. The most significant group impacted by these changes in the acute hospital context is Older People with cognitive impairment. Staff working with these patients have been navigating the complex balance between embracing the guiding principles of the Act, testing the practical requirements of the Act on behalf of patients who require formal decision supports, all in the context of continued demand on unscheduled care. Methods The newly developed role of Principal Social Worker for Assisted Decision Making and Adult Safeguarding has enabled regular access to frontline staff working across 11 hospitals in a large hospital group. Both formal and informal feedback was gathered from a cross section of staff via focussed discussion at local implementation meetings and via individual qualitative interviews with key stakeholders from a broad range of professions. Results Staff were generally very positive about the introduction of the Act and its rights-based approach to providing health and social care. Themes which emerged from the interviews included the need for further education and training, continued forums for case discussion and review, clarity re roles and responsibilities and improved pathways for patients requiring support. Conclusion The enactment of the Assisted Decision-Making Act did not, as many feared, bring the healthcare system to a standstill. However, its impact on resources and time should not be underestimated. Increased investment in staffing, training and supports are needed to ensure continued integration of the Act in the acute hospital setting.

Properties of rhythmogenic currents in spinal Shox2 interneurons across postnatal development.

Locomotor behaviors are performed by organisms throughout life, despite developmental changes in cellular properties, neural connectivity, and biomechanics. The basic rhythmic activity in the central nervous system that underlies locomotion is thought to be generated via a complex balance between network and intrinsic cellular properties. Within mature mammalian spinal locomotor circuitry, we have yet to determine which properties of spinal interneurons (INs) are critical to rhythmogenesis and how they change during development. Here, we combined whole cell patch clamp recordings, immunohistochemistry, and RNAscope targeting lumbar Shox2 INs in mice, which are known to be involved in locomotor rhythm generation. We focused on the properties of putatively rhythmogenic ionic currents and the expression of corresponding ion channels across postnatal time points in mice. We show that subsets of Shox2 INs display voltage-sensitive conductances, in addition to respective ion channels, which may contribute to or shape rhythmic bursting. Persistent inward currents, M-type potassium currents, slow afterhyperpolarization, and T-type calcium currents are enhanced with age. In contrast, the hyperpolarization-activated and A-type potassium currents were either found with low prevalence in subsets of neonatal, juvenile, and adult Shox2 INs or did not developmentally change. We show that Shox2 INs become more electrophysiologically diverse by juvenile and adult ages, when locomotor behavior is weight-bearing. These results suggest a developmental shift in the magnitude of rhythmogenic ionic currents and the expression of corresponding ion channels that may be important for mature, weight-bearing locomotor behavior.

Experiences and Health Outcomes of Emerging Adults with Type 1 Diabetes: A Mixed Methods Study.

Emerging adults with type 1 diabetes are at risk of poorer diabetes-related health outcomes than other age groups. Several factors affecting the health and experiences of the emerging adults are culture and healthcare specific. The aim of this study was to explore the experience of emerging adults living with type 1 diabetes in Lebanon, describe their diabetes self-care and diabetes-related health outcomes (HbA1c and diabetes distress), and identify the predictors of these outcomes. A convergent mixed methods design was used with 90 participants aged 18-29 years. Sociodemographic, clinical data, and measures of diabetes distress, social support, and self-care were collected. Fifteen emerging adults participated in individual semi-structured interviews. Multiple linear regression was used to determine predictors of diabetes outcomes. Thematic analysis was used to analyze qualitative data. Data integration was used to present the mixed methods findings. The study sample had a mean HbA1c of 7.7% (SD = 1.36) and 81.1 % reported moderate to severe diabetes distress levels. The participants had good levels of diabetes self-care and high levels of social support. HbA1c was predicted by insulin treatment type, age at diagnosis, and diabetes self-care; while diabetes distress was predicted by diabetes knowledge, blood glucose monitoring approach, and diabetes self-care. "Living with type 1 diabetes during emerging adulthood: the complex balance of a chemical reaction" was the overarching theme of the qualitative data, with three underlying themes: "Breaking of bonds: changes and taking ownership of their diabetes", "The reactants: factors affecting the diabetes experience", and "Aiming for equilibrium". The integrated mixed methods results revealed one divergence between the qualitative and quantitative findings related to the complexity of the effect of received social support. The suboptimal health of the emerging adults despite good self-care highlights the importance of addressing cultural and healthcare specific factors such as diabetes knowledge and public awareness, social support, and availability of technology to improve diabetes health. Findings of this study can guide future research, practice, and policy development.

Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation

Over the past several decades, a trend toward delayed childbirth has led to increases in parental age at the time of conception. Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. The mechanism(s) linking paternal age with epigenetic changes in sperm remain unknown. The sperm epigenome is shaped in a compartment protected by the blood-testes barrier (BTB) known to deteriorate with age. Permeability of the BTB is regulated by the balance of two mTOR complexes in Sertoli cells where mTOR complex 1 (mTORC1) promotes the opening of the BTB and mTOR complex 2 (mTORC2) promotes its integrity. We hypothesized that this balance is also responsible for age-dependent changes in the sperm epigenome. To test this hypothesis, we analyzed reproductive outcomes, including sperm DNA methylation in transgenic mice with Sertoli cell-specific suppression of mTORC1 (Rptor KO) or mTORC2 (Rictor KO). mTORC2 suppression accelerated aging of the sperm DNA methylome and resulted in a reproductive phenotype concordant with older age, including decreased testes weight and sperm counts, and increased percent of morphologically abnormal spermatozoa and mitochondrial DNA copy number. Suppression of mTORC1 resulted in the shift of DNA methylome in sperm opposite to the shift associated with physiological aging – sperm DNA methylome rejuvenation and mild changes in sperm parameters. These results demonstrate for the first time that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging. Thus, mTOR pathway in Sertoli cells may be used as a novel target of therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers.

Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation.

Over the past several decades, a trend toward delayed childbirth has led to increases in parental age at the time of conception. Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. The mechanism(s) linking paternal age with epigenetic changes in sperm remain unknown. The sperm epigenome is shaped in a compartment protected by the blood-testes barrier (BTB) known to deteriorate with age. Permeability of the BTB is regulated by the balance of two mTOR complexes in Sertoli cells where mTOR complex 1 (mTORC1) promotes the opening of the BTB and mTOR complex 2 (mTORC2) promotes its integrity. We hypothesized that this balance is also responsible for age-dependent changes in the sperm epigenome. To test this hypothesis, we analyzed reproductive outcomes, including sperm DNA methylation in transgenic mice with Sertoli cell-specific suppression of mTORC1 (Rptor KO) or mTORC2 (Rictor KO). mTORC2 suppression accelerated aging of the sperm DNA methylome and resulted in a reproductive phenotype concordant with older age, including decreased testes weight and sperm counts, and increased percent of morphologically abnormal spermatozoa and mitochondrial DNA copy number. Suppression of mTORC1 resulted in the shift of DNA methylome in sperm opposite to the shift associated with physiological aging - sperm DNA methylome rejuvenation and mild changes in sperm parameters. These results demonstrate for the first time that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging. Thus, mTOR pathway in Sertoli cells may be used as a novel target of therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers.

Pathogenicity and Virulence‐Associated Factors of Pseudomonas syringae pv. syringae and [P. amygdali pv. morsprunorum] Strains From New Zealand Sweet Cherry (Prunus avium) Orchards

ABSTRACTPreviously genetically characterised strains of Pseudomonas syringae. pv. syringae (Pss), [P. amygdali pv. morsprunorum] (Pam, syn. P. s. pv. morsprunorum race 1) and Pseudomonas spp. from New Zealand were characterised for their pathogenicity and aggressiveness in plant tissue and associated virulence factors. Lesions on detached, Pss‐inoculated immature fruit increased rapidly in size and, at 10 days post inoculation (dpi), had larger areas under the disease progress curve (AUDPC) than Pam‐inoculated fruit (48.9 and 22.0, respectively). Detached leaves infiltrated with Pss‐developed symptoms within 1 dpi and from 2 dpi for Pam. Necrosis from most Pss strains extended into the leaf veins by 7 dpi, while Pam strains' necrosis was confined to the inoculation site. On detached 1‐year‐old cherry shoots, Pseudomonas spp. strains exhibited the smallest mean lesion size (2.1–2.4 mm), whereas larger mean lesion sizes were observed with Pss strains (5.7–13.7 mm) and Pam strains (3.9–14.0 mm). A functional T3SS was inferred for Pss and Pam strains based on the hypersensitivity reactions observed on tobacco leaves and symptoms elicited on cherry tissue. Syringomycin production was prevalent (88%) among Pss strains. In contrast, only 1.4% of Pam strains produced coronatine. Most Pss strains (97.0%) were able to catalyse ice formation. The coexistence of strains with varying degrees of virulence and non‐pathogenic strains suggests a complex ecological balance, where multiple factors, including genetic variation, virulence traits and environmental conditions, shape the population dynamics and disease outcomes.

Assessment of Respiratory Health Implications of Vaping: A Systematic Review of Toxicity Mechanisms and Adverse Effects of Electronic Nicotine Delivery Systems.

E-cigarettes are thought to aid in tobacco smoking cessation, but there are concerns about their overall effectiveness and safety for the general population, particularly adults. This review aims to investigate the mechanisms of toxicity and adverse effects of e-cigarettes on the respiratory system, comparing these effects with those of conventional smoking. A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were performed on PubMed, Embase, and the Cochrane Library using keywords, controlled vocabulary, and text words, with the following criteria: studies published in English from 2014 to 2024, open access, peer-reviewed, and full-text availability. Study selection, quality assessment, and data extraction were carried out by two independent reviewers. The Cochrane Risk of Bias 2.0 tool was used to evaluate the risk of bias in included randomized controlled trials, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was employed to assess the strength of evidence and determine its generalizability. Electronic nicotine delivery systems (ENDS) have diverse mechanisms of toxicity, including inflammation, hypoxia, cardiovascular stress, and metabolic changes. Reported adverse effects include cough, throat irritation, nausea, and hemodynamic changes. However, ENDS are associated with fewer risks compared to conventional cigarette smoking. ENDS users experience fewer respiratory and cardiovascular issues and have lower levels of biomarkers such as NNAL and CO compared to traditional smokers. Additionally, ENDS are more effective than nicotine replacement therapy (nicotine patches) for smoking cessation, particularly in pregnant women. The side effects of ENDS and nicotine-free vaping are similar to those of conventional smoking in pregnant women, with the exception of a lower birth weight among newborns exposed to ENDS (p < 0.05). ENDS present a complex balance of benefits and risks regarding respiratory health. While there are adverse effects, ENDS are considered less detrimental than conventional smoking and a viable option for smoking cessation. Longitudinal studies are needed to evaluate their safety with long-term use (>16 weeks). Policymakers and health practitioners should use these findings to develop balanced public health policies that weigh the benefits of ENDS against potential health risks, enabling informed decision-making for users.

Molecular fingerprint by omics-based approaches in saliva from patients affected by SARS-CoV-2 infection.

Clinical expression of coronavirus disease 2019 (COVID-19) infectionis widely variable including fatal cases and patients with mild symptoms and a rapid resolution. We studied saliva from 63 hospitalized COVID-19 patients and from 30 healthy controls by integrating large-scale proteomics, peptidomics and targeted metabolomics to assess the biochemical alterations following the infection and to obtain a set of putative biomarkers useful for noninvasive diagnosis. We used an untargeted approach by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomics and peptidomics analysis and targeted LC-multiple reaction monitoring/MS for the analysis of amino acids. The levels of 77 proteins were significantly different in COVID-19 patients. Among these, seven proteins were found only in saliva from patients with COVID-19, four were up-regulated and three were down-regulated at least five-folds in saliva from COVID-19 patients in comparison to controls. The analysis of proteins revealed a complex balance between pro-inflammatory and anti-inflammatory proteins and a reduced amount of several proteins with immune activity that possibly favours the spreading of the virus. Such reduction could be related to the enhanced activity of endopeptidases induced by the infection that in turn caused an altered balance of free peptides. In fact, on a total of 28 peptides, 22 (80%) were differently expressed in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and control subjects. The multivariate analysis of such peptides permits to obtain a diagnostic algorithm that discriminate the two populations with a high diagnostic efficiency. Among amino acids, only threonine resulted significantly different between COVID-19 patients and controls, while alanine levels were significantly different between COVID-19 patients with different severity. In conclusion, the present study defined a set of molecules to be detected with a quick and easy method based on mass spectrometry tandem useful to reveal biochemical alterations involved in the pathogenesis of such a complex disease. Data are available via ProteomeXchange with identifier PXD045612.

The role of coagulopathy and subdural hematoma thickness at admission in predicting the prognoses of patients with severe traumatic brain injury: a multicenter retrospective cohort study from China.

Traumatic brain injury (TBI) is one of the diseases with high disability and mortality worldwide. Recent studies have shown that TBI-related factors may change the complex balance between bleeding and thrombosis, leading to coagulation disorders. The aim of this retrospective study was to investigate the prediction of coagulopathy and subdural hematoma thickness at admission using the Glasgow Outcome Scale (GOS) in patients with severe TBI at 6 months after discharge. In this retrospective cohort study, a total of 1006 patients with severe TBI in large medical centers in three different provinces of China from June 2015 to June 2021 were enrolled after the exclusion criteria, and 800 patients who met the enrollment criteria were included. A receiver operating characteristic (ROC) curve was used to determine the best cut-off values of platelet (PLT), international normalized ratio (INR), activated partial thromboplastin time (APTT), and subdural hematoma (SDH) thickness. The ROC curve, nomogram, calibration curve, and the decision curve were used to evaluate the predictive effect of the coagulopathy and Coagulopathy-SDH(X1) models on the prognoses of patients with severe TBI, and the importance of predictive indicators was ranked by machine learning. Among the patients with severe TBI on admission, 576/800 (72%) had coagulopathy, 494/800 (61%) had SDH thickness ≥14.05mm, and 385/800 (48%) had coagulopathy combined with SDH thickness ≥14.05mm. Multivariate logistic regression analyses showed that age, pupil, brain herniation, WBC, CRP, SDH, coagulopathy, and X1 were independent prognostic factors for GOS after severe TBI. Compared with other single indicators, X1 as a predictor of the prognosis of severe TBI was more accurate. The GOS of patients with coagulopathy and thick SDH (X1, 1 point) at 6 months after discharge was significantly worse than that of patients with coagulopathy and thin SDH (X1, 2 points), patients without coagulopathy and thick SDH (X1, 3 point), and patients without coagulopathy and thin SDH (X1, 4 points). In the training group, the C-index based on the coagulopathy nomogram was 0.900. The C-index of the X1-based nomogram was 0.912. In the validation group, the C-index based on the coagulopathy nomogram was 0.858. The C-index of the X1-based nomogram was 0.877. Decision curve analysis also confirmed that the X1-based model had a higher clinical net benefit of GOS at 6 months after discharge than the coagulopathy-based model in most cases, both in the training and validation groups. In addition, compared with the calibration curve based on the coagulopathy model, the prediction of the X1 model-based calibration curve for the probability of GOS at 6 months after discharge showed better agreement with actual observations. Machine learning compared the importance of each independent influencing factor in the evaluation of GOS prediction after TBI, with results showing that the importance of X1 was better than that of coagulopathy alone. Coagulopathy combined with SDH thickness could be used as a new, accurate, and objective clinical predictor, and X1, based on combining coagulopathy with SDH thickness could be used to improve the accuracy of GOS prediction in patients with TBI, 6 months after discharge.

Online stimulation of the prefrontal cortex during practice increases motor variability and modulates later cognitive transfer: a randomized, double-blinded and sham-controlled tDCS study

The benefits of learning a motor skill extend to improved task-specific cognitive abilities. The mechanistic underpinnings of this motor-cognition relationship potentially rely on overlapping neural resources involved in both processes, an assumption lacking causal evidence. We hypothesize that interfering with prefrontal networks would inhibit concurrent motor skill performance, long-term learning and associated cognitive functions dependent on similar networks (transfer). We conducted a randomised, double-blinded, sham-controlled brain stimulation study using transcranial direct current stimulation (tDCS) in young adults spanning over three weeks to assess the role of the prefrontal regions in learning a complex balance task and long-term cognitive performance. Balance training combined with active tDCS led to higher performance variability in the trained task as compared to the sham group, impacting the process of learning a complex task without affecting the learning rate. Furthermore, active tDCS also positively influenced performance in untrained motor and cognitive tasks. The findings of this study help ascertaining the networks directly involved in learning a complex motor task and its implications on cognitive function. Hence, opening up the possibility of harnessing the observed frontal networks involved in resource mobilization in instances of aging, brain lesion/injury or dysfunction.

Numerical study of the linear and non-linear damping in an acoustically forced cold-flow test rig with coupled cavities

Quantifying the oscillation amplitude of thermoacoustic instabilities remains a critical and challenging issue, as it is a complex balance between driving and damping processes. The New Pressurized Coupled Cavities (NPCCs) setup designed for the study of acoustic damping is analyzed in this work. It is a cold-flow test rig mimicking the geometry of a liquid rocket engine and equipped with an acoustic forcing device. The chamber 1T mode triggers a strong non-linear harmonic response, while the 1T1L and 1T2L exhibit weak non-linearities. Disturbance energy budgets are used in large-eddy simulations to characterize the damping phenomena with the 1T2L and 1T1L forcing. The correct global damping of the system is retrieved, and local damping contributions are extracted. Then, a non-linear term representing the energy transfer to the harmonics is derived from non-linear acoustics theory. Combined with a linear model, this model correctly retrieves the limit-cycle of the 1T mode.