Circulation of Respiratory Viruses in the City: Towards an Agent-Based Ecosystem model.

Mathematical models play an important role in management of outbreaks of acute respiratory infections (ARI). While such models are generally used to study the spread of a solitary virus, in reality multiple viruses co-circulate in the population. These viruses have been studied in detail, including the course of infection and immune defense mechanisms. We developed an agent-based model, called ABM-ARI, assimilating heterogeneous data and theoretical knowledge into a biologically motivated system, that allows to reproduce the seasonal patterns of ARI incidence and simulate interventions. ABM-ARI uses city-specific data to create a synthetic population and to construct realistic contact networks in different activity settings. Characteristics of infection, immune protection and non-specific resistance were varied between individuals to account for the population heterogeneity. For the calibration, we minimised the normalised mean absolute error between simulated and observed epidemic curves. ABM-ARI was built based on the quantitative assessment of features of predominant respiratory viruses and epidemiological characteristics of the population. It provides a good fit to the observed epidemic curves for different age groups and viruses. We also simulated one-week school closures when student absences were at or above 10%, 20% or 30% and found that only 10% and 20% thresholds resulted in a reduction of the incidence. ABM-ARI has a great potential in tackling the challenge of emerging infections by simulating and evaluating the effectiveness of various interventions.

Real-space imaging of periodic nanotextures in thin films via phasing of diffraction data.

New properties and exotic quantum phenomena can form due to periodic nanotextures, including Moire patterns, ferroic domains, and topologically protected magnetization and polarization textures. Despite the availability of powerful tools to characterize the atomic crystal structure, the visualization of nanoscale strain-modulated structural motifs remains challenging. Here, we develop nondestructive real-space imaging of periodic lattice distortions in thin epitaxial films and report an emergent periodic nanotexture in a Mott insulator. Specifically, we combine iterative phase retrieval with unsupervised machine learning to invert the diffuse scattering pattern from conventional X-ray reciprocal-space maps into real-space images of crystalline displacements. Our imaging in PbTiO3/SrTiO3 superlattices exhibiting checkerboard strain modulation substantiates published phase-field model calculations. Furthermore, the imaging of biaxially strained Mott insulator Ca2RuO4 reveals a strain-induced nanotexture comprised of nanometer-thin metallic-structure wires separated by nanometer-thin Mott-insulating-structure walls, as confirmed by cryogenic scanning transmission electron microscopy (cryo-STEM). The nanotexture in Ca2RuO4 film is induced by the metal-to-insulator transition and has not been reported in bulk crystals. We expect the phasing of diffuse X-ray scattering from thin crystalline films in combination with cryo-STEM to open a powerful avenue for discovering, visualizing, and quantifying the periodic strain-modulated structures in quantum materials.

Budget impact analysis of a bovine pericardial aortic bioprosthesis versus mechanical aortic valve replacement in adult patients with aortic stenosis in Romania.

AIMS: An analysis of the budget impact of using a bovine pericardial aortic bioprosthesis (BPAB) or a mechanical valve (MV) in aortic stenosis (AS) patients in Romania. MATERIALS AND METHODS: A decision-tree with a partitioned survival model was used to predict the financial outcomes of using either a BPAB (the Carpentier-Edwards Perimount Magna Ease Valve) or MV in aortic valve replacement (AVR) procedure over a 5-year period. The budget impact of various resource consumption including disabling strokes, reoperations, minor thromboembolic events, major bleeding, endocarditis, anticoagulation treatment and monitoring, and echocardiogram assessments were compared for both types of valves. One-way sensitivity analyses (OWSA) were conducted on the input costs and probabilities. RESULTS: The use of BPAB compared to MV approaches budget neutrality due to incremental savings year-on-year. The initial surgical procedure and reoperation costs for BPAB are offset by savings in acenocoumarol use, disabling strokes, major bleeding, minor thromboembolic events, and anticoagulation complications. The cost of the initial procedure per patient is 460 euros higher for a BPAB due to the higher valve acquisition cost, although this is partially offset by a shorter hospital stay. The OWSA shows that the total procedure costs, including the hospital stay, are the primary cost drivers in the model. LIMITATIONS: Results are limited by cost data aggregation in the DRG system, exclusion of costs for consumables and capital equipment use, possible underestimation of outpatient complication costs, age-related variations of event rates, and valve durability. CONCLUSIONS: Adopting BPAB as a treatment option for AS patients in Romania can lead to cost savings and long-term economic benefits. By mitigating procedure costs and increasing anticoagulation treatment costs, BPAB offers a budget-neutral option that can help healthcare providers, policymakers, and patients alike manage the growing burden of AS in Romania.

Right ventricle to pulmonary artery coupling after transcatheter aortic valve implantation-Determinant factors and prognostic impact.

Introduction: Right ventricular (RV) dysfunction and pulmonary hypertension (PH) have been previously associated with unfavorable outcomes in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI), but little is known about the effect of right ventricle (RV) to pulmonary artery (PA) coupling. Our study aimed to evaluate the determinant factors and the prognostic value of RV-PA coupling in patients undergoing TAVI. Methods: One hundred sixty consecutive patients with severe AS were prospectively enrolled, between September 2018 and May 2020. They underwent a comprehensive echocardiogram before and 30 days after TAVI, including speckle tracking echocardiography (STE) for myocardial deformation analysis of the left ventricle (LV), left atrium (LA), and RV function. Complete data on myocardial deformation was available in 132 patients (76.6 ± 7.5 years, 52.5% men) who formed the final study population. The ratio of RV free wall longitudinal strain (RV-FWLS) to PA systolic pressure (PASP) was used as an estimate of RV-PA coupling. Patients were analyzed according to baseline RV-FWLS/PASP cut-off point, determined through time-dependent ROC curve analysis, as follows: normal RV-PA coupling group (RV-FWLS/PASP ≥0.63, n = 65) and impaired RV-PA coupling group (RV-FWLS/PASP < 0.63, n = 67). Results: A significant improvement of RV-PA coupling was observed early after TAVI (0.75 ± 0.3 vs. 0.64 ± 0.3 before TAVI, p < 0.001), mainly due to PASP decrease (p < 0.001). LA global longitudinal strain (LA-GLS) is an independent predictor of RV-PA coupling impairment before and after TAVI (OR = 0.837, p < 0.001, OR = 0.848, p < 0.001, respectively), while RV diameter is an independent predictor of persistent RV-PA coupling impairment after TAVI (OR = 1.174, p = 0.002). Impaired RV-PA coupling was associated with a worse survival rate (66.3% vs. 94.9%, p-value < 0.001) and emerged as an independent predictor of mortality (HR = 5.97, CI = 1.44-24.8, p = 0.014) and of the composite endpoint of death and rehospitalization (HR = 4.14, CI = 1.37-12.5, p = 0.012). Conclusion: Our results confirm that relief of aortic valve obstruction has beneficial effects on the baseline RV-PA coupling, and they occur early after TAVI. Despite significant improvement in LV, LA, and RV function after TAVI, RV-PA coupling remains impaired in some patients, it is mainly related to persistent pulmonary hypertension and is associated with adverse outcomes.

INSULIN AUTOIMMUNE SYNDROME IN A YOUNG CAUCASIAN WOMAN.

A young Caucasian woman presents several episodes of severe fasting hypoglycemia. Fasting lab tests revealed: glycemia 28 mg/dL, insulinemia 143.3 µU/mL, insulin antibodies above 100 U/mL, leading to the diagnosis of insulin autoimmune syndrome. Due to lack of clinical improvement after 2 months, prednisone was started at 0.5 mg/kg/day, and then tapered by 5 mg every 5 days. Three weeks after discontinuing corticotherapy, the patient had no more severe fasting hypoglycemia, but occasionally postprandial mild hypoglycemia. Fasting lab tests showed: glycemia 83 mg/dL, insulinemia 58.6 µU/mL. At 5 hours during oral glucose tolerance test glycemia was 33 mg/dL, insulinemia 152.9 µU/mL.

Flexible Perovskite CsPbBr3 Light Emitting Devices Integrated with GaP Nanowire Arrays in Highly Transparent and Durable Functionalized Silicones.

The architecture of transparent contacts is of utmost importance for creation of efficient flexible light-emitting devices (LEDs) and other deformable electronic devices. We successfully combined the newly synthesized transparent and durable silicone rubbers and the semiconductor materials with original fabrication methods to design LEDs and demonstrate their significant flexibility. We developed electrodes based on a composite GaP nanowire-phenylethyl-functionalized silicone rubber membrane, improved with single-walled carbon nanotube films for a hybrid poly(ethylene oxide)-metal-halide perovskite (CsPbBr3) flexible green LED. The proposed approach provides a novel platform for fabrication of flexible hybrid optoelectronic devices.

Adenine base editing of the DUX4 polyadenylation signal for targeted genetic therapy in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by chromatin relaxation of the D4Z4 repeat resulting in misexpression of the D4Z4-encoded DUX4 gene in skeletal muscle. One of the key genetic requirements for the stable production of full-length DUX4 mRNA in skeletal muscle is a functional polyadenylation signal (ATTAAA) in exon three of DUX4 that is used in somatic cells. Base editors hold great promise to treat DNA lesions underlying genetic diseases through their ability to carry out specific and rapid nucleotide mutagenesis even in postmitotic cells such as skeletal muscle. In this study, we present a simple and straightforward strategy for mutagenesis of the somatic DUX4 polyadenylation signal by adenine base editing in immortalized myoblasts derived from independent FSHD-affected individuals. We show that mutating this critical cis-regulatory element results in downregulation of DUX4 mRNA and its direct transcriptional target genes. Our findings identify the somatic DUX4 polyadenylation signal as a therapeutic target and represent the first step toward clinical application of the CRISPR-Cas9 base editing platform for FSHD gene therapy.

Observation of microsecond luminescence while studying two DNA-stabilized silver nanoclusters emitting in the 800-900 nm range.

We investigated two DNA-stabilized silver nanoclusters (DNA-AgNCs) that show multiple absorption features in the visible region, and emit around 811 nm (DNA811-AgNC) and 841 nm (DNA841-AgNC). Both DNA-AgNCs have large Stokes shifts and can be efficiently excited with red light. A comparison with the commercially available Atto740 yielded fluorescence quantum yields in the same order of magnitude, but a higher photon output above 800 nm since both DNA-AgNCs are more red-shifted. The study of both DNA-AgNCs also revealed previously unobserved photophysical behavior for this class of emitters. The fluorescence quantum yield and decay time of DNA841-AgNC can be increased upon consecutive heating/cooling cycles. DNA811-AgNC has an additional absorption band around 470 nm, which is parallel in orientation to the lowest energy transition at 640 nm. Furthermore, we observed for the first time a DNA-AgNC population (as part of the DNA811-AgNC sample) with green and near-infrared emissive states with nanosecond and microsecond decay times, respectively. A similar dual emissive DNA-AgNC stabilized by a different 10-base DNA strand is also reported in the manuscript. These two examples highlight the need to investigate the presence of red-shifted microsecond emission for this class of emitters.

D-Rhamnan and Pyruvate-Containing Teichuronic Acid from the Cell Wall of Rathayibacter sp. VKM Ac-2759.

Rathayibacter sp. VKM Ac-2759 (family Microbacteriaceae, class Actinobacteria) contains two glycopolymers in the cell wall. The main chain of rhamnan, glycopolymer 1, is built from the repeating tetrasaccharide units carrying terminal arabinofuranose residues at the non-reducing end, →3)-α-[α-D-Araf-(1→2)]-D-Rhap-(1→2)-α-D-Rhap-(1→3)-α-D-Rhap-(1→2)-α-D-Rhap-(1→. Similar to other described Rathayibacter species, rhamnose in the neutral glycopolymer of the VKM Ac-2759 strain is present in the D-configuration. Acetalated with pyruvic acid teichuronic acid, glycopolymer 2, is composed of the repeating tetrasaccharide units, →4)-ß-D-GlcpA-(1→4)-ß-D-Galp-(1→4)-ß-D-Glcp-(1→3)-ß-[4,6-S-Pyr]-D-Manp-(1→. Glycopolymers 1 and 2 were identified in prokaryotic microorganisms for the first time and their structures were established by chemical analysis and NMR spectroscopy. The obtained data can be used in taxonomic research, as well as for elucidating the mechanisms of plant colonization and infection by bacteria of the Rathayibacter genus.

D-rhamnan and teichuronic acid from the cell wall of Rathayibacter caricis VKM Ac-1799T.

The cell wall of Rathayibacter caricis VKM Ac-1799T (family Microbacteriaceae, class Actinobacteria) was found to contain both neutral and acidic glycopolymers. The first one is D-rhamnopyranan with main chain →2)-α-D-Rhap-(1 â†’ 3)-α-D-Rhap-(1→, where a part of 2-substituted residues bears as a side-chain at position 3 α-D-Manp residues or disaccharides α-D-Araf-(1→2)-α-D-Manp-(1 â†’ . The second polymer is a teichuronic acid with a branched repeating units composed of seven monosaccharides →4)-α-[ß-D-Manp-(1 â†’ 3)]-D-Glcp-(1 â†’ 4)-ß-D-GlcpA-(1 â†’ 2)-ß-[4,6Pyr]-D-Manp-(1 â†’ 4)-ß-L-Rhap-(1 â†’ 4)-ß-D-Glcp-(1 â†’ 4)-ß-D-Glcp-(1 â†’ . The structures of the polymers were determined by chemical and NMR spectroscopic methods.

Targeting Oxidative Stress Reduction and Inhibition of HDAC1, MECP2, and NF-kB Pathways in Rats With Experimentally Induced Hyperglycemia by Administration of Thymus marshallianus Willd. Extracts.

The effects of two lyophilized extracts obtained from the aerial parts of Thymus marschallianus Willd. and harvested from wild flora (TMW) and obtained from culture (TMC) were evaluated in Wistar rats with experimentally induced hyperglycemia. The hyperglycemia was induced by streptozotocin (STZ) administration and the obtained results were evaluated in comparison for TMW and TMC. The polyphenolic composition of extracts was evaluated by spectrophotometrical and LC-MS methods. In vitro antioxidant capacity assays (DPPH, FRAP, EPR) were performed in order to preliminary establish the ability of tested samples to protect against free radical induced damage. Afterwards, the effects of these extracts were assessed in vivo on rats with experimental-induced hyperglycemia. Oxidative stress biomarkers (e.g. malondialdehyde-MDA), phosphorylated transcription factor subunit of nuclear kappaB (NF-kB) p65, methyl CpG binding protein (MECP) 2 and histone deacetylase 1 (HDAC1) expressions in hippocampus and frontal lobe were assessed. Open Field Test (OFT) and Elevated Plus Maze (EPM) were conducted on tested animals. Malondialdehyde (MDA) levels and HDAC1and MeCP2 expressions increased significantly in hippocampus (p<0.05) and frontal lobe (p<0.001) of diabetes group compared to the control group in parallel with decreasing of GSH/GSSG ratio. TMW and TMC administration reduced blood glucose levels and diminished lipid peroxidation, HDAC1 expression and enhanced antioxidant capacity in frontal lobe. TMW improved central locomotion of rats, increased phospho-NFkB p65 and diminished MECP2 expressions in hippocampus. Both tested samples exerted a beneficial effect by increasing the antioxidant defense. Our findings indicate that the administration of these extracts might represent a good option in the treatment of diabetes and its complications.

Epidemiology, pathophysiology and contemporary management of cardiogenic shock - a position statement from the Heart Failure Association of the European Society of Cardiology.

Cardiogenic shock (CS) is a complex multifactorial clinical syndrome with extremely high mortality, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large spectrum of CS presentations resulting from the interaction between an acute cardiac insult and a patient's underlying cardiac and overall medical condition. Phenotyping patients with CS may have clinical impact on management because classification would support initiation of appropriate therapies. CS management should consider appropriate organization of the health care services, and therapies must be given to the appropriately selected patients, in a timely manner, whilst avoiding iatrogenic harm. Although several consensus-driven algorithms have been proposed, CS management remains challenging and substantial investments in research and development have not yielded proof of efficacy and safety for most of the therapies tested, and outcome in this condition remains poor. Future studies should consider the identification of the new pathophysiological targets, and high-quality translational research should facilitate incorporation of more targeted interventions in clinical research protocols, aimed to improve individual patient outcomes. Designing outcome clinical trials in CS remains particularly challenging in this critical and very costly scenario in cardiology, but information from these trials is imperiously needed to better inform the guidelines and clinical practice. The goal of this review is to summarize the current knowledge concerning the definition, epidemiology, underlying causes, pathophysiology and management of CS based on important lessons from clinical trials and registries, with a focus on improving in-hospital management.

Unusually large fluorescence quantum yield for a near-infrared emitting DNA-stabilized silver nanocluster.

A near-infrared emitting DNA-stabilized silver nanocluster (DNA-AgNC) with an unusually high fluorescence quantum yield is presented. The steady-state and time-resolved fluorescence properties of the DNA-AgNC were characterized, together with its ability to generate optically activated delayed fluorescence (OADF) and upconversion fluorescence (UCF).

Validation of Appropriate Use Criteria for Coronary Computed Tomographic Angiography for Chest Pain Evaluation in a Tertiary Care Emergency Room.

PURPOSE: Appropriate use criteria (AUC) defines the appropriateness of imaging procedures for specific clinical scenarios to promote evidence-based utilization and improve cost-effective care. The goal of this study was to assess the diagnostic yield and downstream health care resource utilization according to the AUC categorization for coronary computed tomography angiography (CCTA) in emergency department (ED) patients presenting with chest pain. MATERIALS AND METHODS: A total of 789 consecutive patients in the ED with chest pain and no known coronary artery disease (CAD) who underwent CCTA were classified as appropriate, uncertain, or inappropriate use according to the 2010 AUC. We abstracted index and 30-day data from the electronic medical record to determine diagnostic yield (rate of obstructive CAD and revascularization) and health care resource utilization (downstream stress test and 30-d hospital return rate). RESULTS: Rates of appropriate, uncertain, and inappropriate utilization were 48.4%, 48.8%, and 2.8%. Among appropriate, uncertain, and inappropriate classifications, rates of obstructive CAD were 9%, 8%, and 32% (P=0.002); rates of revascularization were 3%, 1%, and 36% (P<0.001); downstream stress test utilization rates were 5% versus 5% versus 14% (P=0.17), and 30-day hospital return rates were 6% versus 6% versus 5% (P>0.99), respectively. CONCLUSIONS: Appropriate and uncertain uses were associated with low diagnostic yield compared with inappropriate use; however, our findings do not demonstrate differences between appropriate use categories with respect to downstream health care resource utilization. Further studies are needed to define the role of AUC for CCTA in the ED setting.

Comprehensive analysis of structural and sequencing data reveals almost unconstrained chain pairing in TCRαß complex.

Antigen recognition by T-cells is guided by the T-cell receptor (TCR) heterodimer formed by α and ß chains. A huge diversity of TCR sequences should be maintained by the immune system in order to be able to mount an effective response towards foreign pathogens, so, due to cooperative binding of α and ß chains to the pathogen, any constraints on chain pairing can have a profound effect on immune repertoire structure, diversity and antigen specificity. By integrating available structural data and paired chain sequencing results we were able to show that there are almost no constraints on pairing in TCRαß complexes, allowing naive T-cell repertoire to reach the highest possible diversity. Additional analysis reveals that the specific choice of contacting amino acids can still have a profound effect on complex conformation. Moreover, antigen-driven selection can distort the uniform landscape of chain pairing, while small, yet significant, differences in the pairing can be attributed to various specialized T-cell subsets such as MAIT and iNKT T-cells, as well as other TCR sets specific to certain antigens.

Validation of the Withdrawal Assessment Tool-1 in Adult Intensive Care Patients.

BACKGROUND: The Withdrawal Assessment Tool-1 (WAT-1) has been validated for assessing iatrogenic withdrawal syndrome in critically ill children receiving mechanical ventilation, but little is known about this syndrome in critically ill adults. OBJECTIVE: To evaluate the validity and reliability of the WAT-1 in critically ill adults. METHODS: A prospective, observational, open-cohort pilot study of critically ill adults receiving mechanical ventilation and regular administration of opioids for at least 72 hours. Patients were assessed for withdrawal twice daily on weekdays and once daily on weekends using the WAT-1 after an opioid weaning episode. The presence of iatrogenic withdrawal syndrome was evaluated once daily using modified Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) criteria. All evaluations were blinded and performed independently. The criterion validity of the WAT-1 and the interrater reliability for WAT-1 and DSM-5 evaluations were determined. RESULTS: During 8 months, 52 adults (median age, 51.5 years) were enrolled. Eight patients (15%) had at least 1 positive assessment during their intensive care unit stay using the DSM-5, compared with 19 patients (37%) using the WAT-1. The overall sensitivity of the WAT-1 was 50%, and its specificity was 65.9%. Agreement between WAT-1 and DSM-5 assessments was poor (κ = 0.102). The interrater reliability for the WAT-1 was 89.1% and for the DSM-5 was 90.1%. CONCLUSION: Despite showing reliability, the WAT-1 is not a valid tool for assessing the presence of iatrogenic withdrawal syndrome in adults.