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BACKGROUND: Yellow fever virus (YFV) infections are a major global disease concern with high mortality in humans, and as such it is critical to identify clinical correlates of disease severity. While nonstructural protein 1 (NS1) of the related dengue virus is implicated in contributing to vascular leak, little is known about the role of YFV NS1 in severe YF and mechanisms of vascular dysfunction in YFV infections. METHODS: Using serum samples from laboratory-confirmed YF patients with severe (n = 39) or non-severe (n = 18) disease in a well-defined hospital observational cohort in Brazil, plus samples from healthy uninfected controls (n = 11), we investigated factors associated with disease severity and endothelial dysfunction. FINDINGS: We found significantly increased levels of NS1, as well as syndecan-1, a marker of vascular leak, in serum from severe YF as compared to non-severe YF or control groups. We also showed that hyperpermeability of endothelial cell monolayers treated with serum from severe YF patients was significantly higher compared to non-severe YF and control groups, as measured by transendothelial electrical resistance (TEER). Further, we demonstrated that YFV NS1 induces shedding of syndecan-1 from the surface of human endothelial cells. Notably, YFV NS1 serum levels significantly correlated with syndecan-1 serum levels, TEER values, and signs of disease severity. Syndecan-1 levels also significantly correlated with clinical laboratory parameters of disease severity, viral load, hospitalization, and death. INTERPRETATION: This study provides further evidence for endothelial dysfunction as a mechanism of YF pathogenesis in humans and suggests serum quantification of YFV NS1 and syndecan-1 as valuable tools for disease diagnosis and/or prognosis. FUNDING: This work was supported by the US NIH and FAPESP.

Abstract Patient-derived xenografts (PDXs) are tumour fragments engrafted into mice for preclinical studies. PDXs offer clear advantages over simpler in vitro cancer models - such as cancer cell lines (CCLs) and organoids - in terms of structural complexity, heterogeneity, and stromal interactions. Here, we characterise 231 colorectal cancer PDXs at the genomic, transcriptomic, and epigenetic levels, along with their response to cetuximab, an EGFR inhibitor used clinically for metastatic colorectal cancer. After evaluating the PDXs’ quality, stability, and molecular concordance with publicly available patient cohorts, we present results from training, interpreting, and validating the integrative ensemble classifier CeSta. This model takes in input the PDXs’ multi-omic characterisation and predicts their sensitivity to cetuximab treatment, achieving an area under the receiver operating characteristics curve > 0.88. Our study demonstrates that large PDX collections can be leveraged to train accurate, interpretable drug sensitivity models that: (1) better capture patient-derived therapeutic biomarkers compared to models trained on CCL data, (2) can be robustly validated across independent PDX cohorts, and (3) could contribute to the development of future therapeutic biomarkers.

Abstract Background Transpulmonary pressure is the effective pressure across the lung parenchyma and has been proposed as a guide for mechanical ventilation. The pleural pressure is challenging to directly measure in clinical setting and esophageal manometry using esophageal balloon catheters was suggested for estimation. However, the accuracy of using esophageal pressure to estimate pleural pressure is debated due to variability in the mechanical properties of respiratory system, esophagus and esophageal catheter. Furthermore, while a vertical pleural pressure gradient exists across lung regions, esophageal pressure balloon provides a single value, representing, at most, the pressure surrounding the esophagus. Methods In a swine model with a preserved esophagus and a single homogenous, easily measurable intrathoracic pressure, we evaluated esophageal pressure’s agreement with intrathoracic pressure at different positive end-expiratory pressure (PEEP) levels (0, 5, 10, 15 cmH2O). We assessed the improvement of measurement accuracy by correcting absolute esophageal values using a previously described technique, that accounts for the pressure generated by the esophageal wall in response to esophageal balloon inflation. The study involved five swine, wherein two different esophageal catheters were used alongside the four distinct PEEP levels. Swings, uncorrected and corrected absolute esophageal pressures (end-inspiratory, end-expiratory) were compared with their respective intrathoracic pressures. The effect of correction technique was assessed with manual incremental step inflation procedure. Results We found that both catheters significantly overestimated absolute esophageal pressure compared to intrathoracic pressure (5.01 ± 3.32 and 6.06 ± 5.62 cmH2O at end-expiration and end-inspiration, respectively), with error increasing at higher positive end-expiratory pressure levels (end-expiration: 2.36 ± 2.03, 3.77 ± 1.37, 6.24 ± 2.51 and 7.69 ± 4.02 for each PEEP level, P

Abstract Objective Atrial cardiomyopathy is closely associated with atrial fibrillation (AF), and some patients exhibit no dysfunction at rest but demonstrate evident changes in left atrial (LA) function and LA volume during exercise. This study aimed to identify distinguishing signs during exercise stress echocardiography (ESE) among patients in sinus rhythm (SR), with and without history of paroxysmal/persistent AF (PAF). Methods A prospective cohort of 1055 patients in SR was enrolled across 12 centers. The main study cohort was divided into two groups: the modeling group (n = 513) and the verification group (n = 542). All patients underwent ESE, which included B-lines, LA volume index (LAVi), and LA strain of the reservoir phase (LASr). Results Age, resting and stress LAVi and LASr, and B-lines were identified as a combination of detectors for PAF in both groups. In the entire cohort, aside from resting and stress LAVi and LASr, additional parameters differentiating PAF and non-PAF patients were the presence of systemic hypertension, exercise E/e’ > 7, worse right ventricle (RV) contraction during exercise (∆ tricuspid annular plane systolic excursion 4 as the best sensitivity (79%) and specificity (65%). Conclusion ESE can complement rest echocardiography in the identification of previous PAF in patients with SR through the evaluation of LA functional reservoir and volume reserve, LV chronotropic, diastolic, and systolic reserve, and RV contractile reserve. Graphical Abstract A scoring system predicting the probability of PAF. The score was computed using the cutoff values as in the illustration. The score >4 demonstrated a sensitivity of 79% and a specificity of 65% of PAF.

Abstract Amid recent studies that have been exploring the wide impact that COVID-19 containment policies have had across sectors and industries, we investigate how mobility restrictions enacted in French cities during the later stages of the pandemic have affected the usage of smartphones and mobile applications. Leveraging a large-scale dataset of over 14 billion records, we unveil and quantify the substantial incidence of the different measures enforced in urban France to combat the COVID-19 epidemic on mobile service consumption. We present a simple but effective spatial linear model that can relate changes occurring at fine-grained spatial zoning in both global and per-service traffic to a limited set of socioeconomic indicators. Our model unveils some of the mechanisms that drove the significant evolution of mobile data traffic demands during the pandemic. It allows observing how the demand for mobile services has been affected by COVID-19 in very different ways across urban areas characterized by diverse population density, income levels and leisure area presence. It also discloses that usages of individual smartphone applications have been impacted in highly heterogeneous ways by the pandemic, even more so when considering the composite impacts of different transitions between periods characterized by diverse restrictions. Our results can aid governments in understanding how their measures were received across the space and different portions of population, and network operators to comprehend changes in usage due to extraordinary events, which can be used to optimize service provisioning.

Abstract Background In pediatric palliative care, the main caregiver is primarily responsible for managing pharmaceutical therapies. Few data are available regarding the influence of this burden on quality of life in terms of time, concerns as well as a considerable risk of administration errors and adverse effects. This study aims to investigate how caregivers prepared and administrated medication, including errors and associated expectations, to identify improvement interventions. Methods Between October 2022 and March 2023, a descriptive single-center survey study was carried out in the tertiary care pediatric palliative center of the Padova University Hospital. Participants were the caregivers of the patients followed by our center up to 23 years old, receiving at least one drug daily and who cannot self-administer their therapy. The questionnaire consisted of 18 multiple-choice and semi-closed questions, grouped into 4 main topics: therapy preparation, therapy administration, administration errors and therapy assessment. Results A total of 100 caregivers responded to the survey. Mothers represented the main caregiver (91%). The prevalence of polypharmacy was 67% across the patients. 52% of caregivers handled prescriptions at least three times per day and for 32% it took to prepare them more than 5 min each time. Only 59% reported to have been trained for preparing and administrating drugs. 14% reported having made at least a drug administration error due to the tiredness or the complexity of therapeutic regimens in the preceding three months. Nearly one caregiver out of three felt their child was using too many drugs. 73% positively welcomed the possibility of having clinical pharmacist-led counseling. Conclusions Many caregivers of pediatric palliative care patients frequently have trouble planning, preparing and delivering pharmacological therapy to their children. Attempting to simplify medication regimens, choosing formulations that are simpler to administer and measure, investing in improved caregiver training, talking about therapies with carers, and involving clinical pharmacists to clarify their doubts could be all potential strategies to improve this condition and reduce their burden.

Abstract Background Increasing nosocomial infections during the COVID-19 pandemic have been reported. However, data describing peripheral venous catheter associated bloodstream infections (PVC-BSI) are limited. Aims To describe the epidemiology and risk factors for PVC-BSI during the COVID-19 pandemic. Methods We conducted retrospective cohort study of prospectively collected PVC-BSI data in a 2100 bed hospital network in Switzerland. Adult patients with a PVC inserted between January 1, 2020 and December 31, 2021 were included. Risk factors for PVC-BSI were identified through descriptive analysis of patient and catheter characteristics, and univariable marginal Cox models. Results 206,804 PVCs and 37 PVC-BSI were analysed. Most PVC-BSI were attributed to catheters inserted in the Emergency department (76%) or surgical wards (22%). PVC-BSI increased in 2021 compared to 2020 (hazard ratio 2021 vs. 2020 = 2.73; 95% confidence interval 1.19–6.29), with a numerically higher rate of Staphylococcus aureus (1/10, 10%, vs. 5/27, 19%) and polymicrobial infection (0/10, 0% vs. 4/27, 15%). PVC insertions, patient characteristics, and catheter characteristics remained similar across the study period. PVC-BSI risk was associated with admission to the intensive care unit (ICU), and use of wide gauge catheter (