Deposition of Inhaled Levofloxacin in Cystic Fibrosis Lungs Assessed by Functional Respiratory Imaging

Pulmonary infections caused by Pseudomonas aeruginosa (PA) represent the leading cause of pulmonary morbidity in adults with cystic fibrosis (CF). In addition to tobramycin, colistin, and aztreonam, levofloxacin has been approved in Europe to treat PA infections. Nevertheless, no lung deposition data on inhaled levofloxacin are yet available. We conducted a Functional Respiratory Imaging (FRI) study to predict the lung deposition of levofloxacin in the lungs of patients with CF. Three-dimensional airway models were digitally reconstructed from twenty high-resolution computed tomography scans obtained from historical patients’ records. Levofloxacin aerosols generated with the corresponding approved nebuliser were characterised according to pharmacopeia. The obtained data were used to inform a computational fluid dynamics simulation of levofloxacin lung deposition using breathing patterns averaged from actual CF patients’ spirometry data. Levofloxacin deposition in the lung periphery was significantly reduced by breathing patterns with low inspiratory times and high inspiratory flow rates. The intrathoracic levofloxacin deposition percentages for moderate and mild CF lungs were, respectively, 37.0% ± 13.6 and 39.5% ± 12.9 of the nominal dose. A significant albeit modest correlation was found between the central-to-peripheral deposition (C/P) ratio of levofloxacin and FEV1. FRI analysis also detected structural differences between mild and moderate CF airways. FRI revealed a significant intrathoracic deposition of levofloxacin aerosols, which distributed preferentially to the lower lung lobes, with an influence of the deterioration of FEV1 on the C/P ratio. The three-dimensional rendering of CF airways also detected structural differences between the airways of patients with mild and moderate CF.

Intra-Tumoral Pharmacokinetics of Pazopanib in Combination with Radiotherapy in Patients with Non-Metastatic Soft-Tissue Sarcoma

There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149–200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib (ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells (p > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.

Variations in Salivary Stress Biomarkers and Their Relationship with Anxiety, Self-Efficacy and Sleeping Quality in Emergency Health Care Professionals

Hospital healthcare workers of emergency departments (EDs) face a variety of occupational stressors on a daily basis. We have recently published that emergency professionals display increased salivary levels of α-amylase and dehydroepiandrosterone during the working day. The pattern of these markers may suggest a counteracting mechanism of dehydroepiandrosterone against the stress reflected by amylase increases. In order to verify this hypothesis, we have analysed different psychological aspects in the same group of healthcare professionals through different tests related to behaviours resulting from stress. These include the state-trait anxiety inventory, the self-efficacy test and the sleeping quality questionnaire. The tests were provided at the beginning of the working day and collected at the end. STAI scores (trait and state) were indicative of no anxiety. Self-efficacy scores were considered optimal, as well as those from the sleeping quality questionnaire. This is supported by the modest correlation between STAI scores and salivary levels of α-amylase and dehydroepiandrosterone. In conclusion, the emergency professionals of the studied hospitals seem to have adequate work management. Altogether it means that the stress generated during work performance is controlled, allowing a correct adaptation to the demanding situations undergone in emergency departments.

THE ROLE OF MEDHYA RASAYANA IN THE MANAGEMENT OF MENTAL DISORDER

WHO has proposed that mental health is - ' A state of well-being in which the individual realizes his or her abili- ties can cope with the normal stresses of life, can work productively and fruitfully and can make a contribution to his or her community.’ Mental disability has become one of the most dreadful conditions across the world. It is prevalent in almost every society and creates an enormous social and economic burden. Mental illness is charac- terized by disturbance in person, emotion, thoughts, or behaviour. The term mental illness (Mental behaviour) includes a wide variety of disorders, ranging from mild distress to severe impairment of social and occupational functioning. In 2017, 197.3 million people had mental disorders in India, including 45.7 million with depressive disorder and 44.9 million with anxiety disorder. A significant, but modest, correlation between the prevalence of depressive disorder and the suicide death rate at the state level for females and males. Medhya Rasayana affects the human psyche and mainly work at the level of neurotransmitters. Daily use of Medhya Rasayana is not only good for memory but also promotion of mental health. So, these media rasayan (Yashtimadhu, Guduchi, Shankhpushpi, Mandukaparni) drugs are effective in the treatment of mental disorders. Keywords: Medhya, Rasayan, Anxiety, Neurotransmitters.

Evaluation of the Apnea-Hypopnea Index Determined by Adaptive Servo-Ventilation Devices in Patients With Heart Failure and Sleep-Disordered Breathing

Introduction: Adaptive servo-ventilation (ASV) devices are designed to suppress central respiratory events, and therefore effective for sleep-disordered breathing (SDB) in patients with heart failure (HF) and provide information about their residual respiratory events. However, whether the apnea-hypopnea index (AHI), determined by the ASV device AutoSet CS (ASC), correlates with the AHI calculated by polysomnography (PSG) in patients with HF and SDB remains to be evaluated.Methods: Consecutive patients with SDB titrated on ASC were included in the study. We assessed the correlation between AHI determined by manual scoring during PSG (AHI-PSG) and that determined by the ASC device (AHI-ASC) during an overnight session.Results: Thirty patients with HF and SDB (age, 68.8 ± 15.4 years; two women; left ventricular ejection fraction, 53.8 ± 17.9%) were included. The median AHI in the diagnostic study was 28.4 events/h, including both obstructive and central respiratory events. During the titration, ASC markedly suppressed the respiratory events (AHI-PSG, 3.3 events/h), while the median AHI-ASC was 12.8 events/h. We identified a modest correlation between AHI-PSG and AHI-ASC (r = 0.36, p = 0.048). The Brand-Altman plot indicated that the ASC device overestimated the AHI, and a moderate agreement was observed with PSG.Conclusions: There was only a modest correlation between AHI-PSG and AHI-ASC. The discrepancy may be explained by either the central respiratory events that occur during wakefulness or the other differences between PSG and ASC in the detected respiratory events. Therefore, clinicians should consider this divergence when assessing residual respiratory events using ASC.

Is biventricular vascular coupling a better indicator of ventriculo-ventricular interaction in congenital heart disease?

Background: Ventriculo-ventricular interactions are known to exist, though not well quantified. We hypothesised that the ventricular–vascular coupling ratio assessed by cardiovascular MRI would provide insight into this relationship. We also sought to compare MRI-derived ventricular–vascular coupling ratio to echocardiography and patient outcomes. Methods: Children with cardiac disease and biventricular physiology were included. Sanz’s and Bullet methods were used to calculate ventricular–vascular coupling ratio by MRI and echocardiography, respectively. Subgroup analysis was performed for right and left heart diseases. Univariate and multivariate regressions were performed to determine associations with outcomes. Results: A total of 55 patients (age 14.3 ± 2.5 years) were included. Biventricular ventricular–vascular coupling ratio by MRI correlated with each other (r = 0.41; p = 0.003), with respect to ventricle’s ejection fraction (r = −0.76 to −0.88; p < 0.001) and other ventricle’s ejection fraction (r = −0.42 to −0.47; p < 0.01). However, biventricular ejection fraction had only weak correlation with each other (r = 0.31; p = 0.02). Echo underestimated ventricular–vascular coupling ratio for the left ventricle (p < 0.001) with modest correlation to MRI-derived ventricular–vascular coupling ratio (r = 0.43; p = 0.002). There seems to be a weak correlation between uncoupled right ventricular–vascular coupling ratio with the need for intervention and performance on exercise testing (r = 0.33; p = 0.02). Conclusion: MRI-derived biventricular ventricular–vascular coupling ratio provides a better estimate of ventriculo-ventricular interaction in children and adolescents with CHD. These associations are stronger than traditional parameters and applicable to right and left heart conditions.

SARS-CoV-2 RNA load in the lower respiratory tract, viral RNAemia and N-antigenemia in critically ill adult COVID-19 patients: relationship with biomarkers of disease severity

Background: Little is known about the comparative kinetics of SARS-CoV-RNA load in the lower respiratory tract and in blood compartment in patients admitted to the intensive care unit, and how these relate to biomarkers of COVID-19 severity. Methods: Seventy-three consecutive critically ill COVID-19 patients (median age, 65 years) were recruited. Serial lower respiratory tract (n=165) and plasma (n=340) specimens were collected. RT-PCR and lateral flow immunochromatography assay were used for SARS-CoV-2 RNA quantitation and N protein detection in plasma, respectively. Serum levels of inflammatory and tissue-damage biomarkers in paired specimens were analyzed. Results: SARS-CoV-RNA was detected in the lower respiratory tract of most patients (92%). Viral RNAemia and N-antigenemia were documented in 35.6% and 40.1% of patients, respectively. Viral RNAemia and N-antigenemia cleared at a faster rate than SARS-CoV-2 RNA in tracheal aspirates (TA). SARS-CoV-2 RNA load was higher (P<0.001) in TA than in plasma, and correlated significantly (Rho, 0.41; P<0.001). A modest correlation was found between SARS-CoV-2 RNA load in TA and plasma and levels of ferritin and lactose dehydrogenase (Rho≤0.3; P≤0.008) in paired serum specimens. Neither the dynamics of SARS-CoV-2 RNA load in TA and plasma, nor N-antigenemia detection rate differed between surviving and deceased patients. Yet, a trend towards a higher mortality was seen in patients with viral RNAemia (OR; 2.82; 95% CI, 0.94-8.47; P=0.06).

Identification of Potential Human Protein Targets for Soybean Isoflavones

Soy isoflavones have been reported as endocrine disruptors due to their ability to modulate the activity of estrogen receptors (ERs) in mammals; however, its ability to modulate other metabolic pathways is not entirely clear, which makes it necessary to identify new pharmacological targets that interact with these compounds present in soybean. In this work, a virtual screening was executed to identify potential targets of nine soy isoflavones, employing human proteins target from PharmMapper. The best 25 fit scores were selected and prepared for AutoDock Vina docking protocols. The results suggest that equol, daidzein and biochanin A, have the potential to interact with targets such as phenylethanolamine N-methyltransferase, sex hormone-binding globulin and vitamin D3 receptor, respectively. The validations of docking protocols showed good pose reproducibility (root-mean-square deviation (RMSD) ranged 0.001-3.854 Å) and a modest correlation between binding affinities and agonist concentration, AC50 (correlation coefficient (R) = 0.643, p < 0.001). Protein interaction network revealed that predicted targets for soy isoflavones are involved in different pathways, including neurotransmission, metabolism, and cancer remarking the need of a better understanding of the effects of these compounds on human health.

Patterns and persistence of SARS-CoV-2 IgG antibodies in a US metropolitan site

BackgroundEstimates of seroprevalence to SARS-CoV-2 vary widely. We ascertained IgG levels across a single US metropolitan site, Chicago, over the 2020 summer, a period when restrictions on activities had been lifted.MethodsWe utilized a self-sampled dried blood spot assay to quantitatively monitor antibodies to the receptor binding domain (RBD) of the spike glycoprotein of SARS-CoV-2 in 1545 participants, with return of blood spot cards either by mail or in-person drop-off.ResultsSeroprevalence was 19.8%, with no significant difference between method of contact, or between essential and non-essential workers. Only a small number (1.2%) of participants reported having had a diagnosis of COVID-19 based on virus detection, consistent with a 16-fold greater exposure to SARS-CoV-2 measured by serology than detected by viral testing. Only a modest correlation was observed between having antibodies to SARS-CoV-2 nucleocapsid compared to RBD, with many only having detectable anti-RBD antibodies. From a subset of those who participated in repeat testing, three-quarters of seropositive individuals retained detectable antibodies for at least 120 days. One seropositive individual experienced a strong boost in IgG levels following a symptomatic illness, suggestive of potential re-exposure.ConclusionsThese data underscore the importance of a self-collected, quantitative assay with adequate sensitivity to detect antibodies at the lower levels among non-hospitalized persons with community-acquired exposure to COVID-19.

Abstract 13198: Immunohematologic Failure Identifies Fibrotic Phenotype in Heart Failure With Preserved Ejection Fraction

Background: We have shown that immunohematologic failure (IHF: lymphopenia (absolute lymphocyte count (ALC)<1.5 x10 3 /μL) and anisocytosis (red cell distribution width, RDW > 14.5%)) is associated with risk of heart failure. Lymphopenic patients have elevated numbers of regulatory T cells with profibrotic phenotype. Hypothesis: We hypothesized that IHF is associated with fibrosis in HFpEF. Methods: We investigated the association between ALC, RDW, and IHF with markers of fibrosis (galectin-3 and Corboxy-Terminal Telopeptide of Collagen Type I [CITP]) in patients enrolled in RELAX trial of HFpEF (Clinicaltrials.gov NCT00763867) using linear regression, and adjusting for age, sex, race, eGFR, BMI and diabetes status. Results: A total of 122 patients with both ALC and RDW were included. There was a modest correlation between ALC and RDW (Spearman’s rho=-0.22, P=0.017). Both ALC and RDW were significantly associated with galectin 3 and CITP (figure). A total of 33 (27%) patients had IHF. Patients with IHF had lower GFR (62±25 vs 53 ± 21 ml/min/1.73 m 2 , P<0.001), lower peak VO2 (12.5±2.8 vs 11.0 ± 3.0 ml/kg/min, P=0.007), lower exercise capacity (78 ± 26 vs 64 ± 35 watts, P=0.018), higher NT-proBNP (900±1152 vs 1615 ± 1247 pg/mL, P=0.004), galectin-3 (13.3 ± 4.1 vs 17.7 ± 5.8, P<0.001 ng/mL) and CITP (6.1 ± 3.5 vs 11.0 ± 5.7 μg/L, P<0.001) but no difference in age, sex, race, CRP or diabetes status. After multiple adjustments, IHF was associated with higher galectin-3 levels (P=0.01) and CITP (P<0.001). Conclusions: Immunohematologic failure is common in HFpEF and is associated with fibrotic phenotype. The mechanisms linking IHF and fibrosis need to be elucidated in future studies.