Characterising the role of small airways in severe asthma using low frequency forced oscillations: A combined computational and clinical approach

Background: Within asthma, the small airways (≤ 2mm in diameter) play an important role in pathophysiology. Using a combined clinical-computational approach, we sought to more precisely evaluate the contribution of the small airways to deep-breath induced airway dilation (in the absence of bronchial challenge), which may be impaired in severe asthma.Methods: A patient-based computational model of the FOT was used to examine the sensitivity and specificity of FOT signals to small airways constriction at frequencies of 2 & 8 Hz. A clinical study of moderate to severe asthmatics (n=24), and healthy volunteers (n=10) was performed to evaluate correlations between baseline and post deep inspiration (following bronchodilator withhold and in the absence of prior bronchial challenge) forced oscillation technique (FOT) responses (at 2Hz and 8Hz) and asthma treatment intensity, spirometry, airway hyper-responsiveness and airway inflammation.Results: Computational modelling demonstrated that baseline resistance measures at 2Hz are both sensitive and specific to anatomical narrowing in the small airways. Furthermore, small airways resistance was significantly increased in asthmatics compared to health. Despite these differences, there were no noticeable differences between asthmatics and healthy volunteers in resistive measures following deep inspiration (DI) and DI responses of small airways were amplified in the presence of spirometry defined airflow limitation.Conclusions: These results suggest that the small airways demonstrate increased resistance in moderate-to-severe asthma but dilate normally in response to deep inspirations in the absence of bronchial challenge. This suggests that effective targeting of the small airways is required to achieve functional improvements in moderate-severe asthmatic patients

Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2−/− mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36−/− and Mertk−/− mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

A meshfree radial basis function method for simulation of multi-dimensional conservation problems

Many computational fluid dynamics problems utilize finite volume frameworks for simulation, due to the simplifications provided by conservative formulation of the driving partial differential equations (PDEs). However, fluid dynamics applications can often involve temporal shifts in the domain structure—such as moving boundaries, or pore structure changes—requiring mesh adaptation throughout computation. These mesh adaptations often render classical numerical methods such as the finite volume method infeasible, due to their reliance on a well-defined static mesh structure. This limitation has led to the development of a wide variety of meshless methods—techniques that can simulate PDEs without requiring a rigid connective structure between nodes. However, most meshless methods are typically based on finite element or finite difference formulations, and the limited number of meshless finite volume methods (MFVMs) either introduce a weak background mesh, or use weak-form approximations that do not take full advantage of the strong conservative form of the driving equations. Addressing this gap within this study we outline a meshfree numerical scheme for simulation of partial different equations, based on strong-form finite volume style formulations. Building upon the previously developed MFVM, this technique uses radial basis functions to interpolate the problem domain, and approximate fluxes in a disjoint finite volume scheme, removing reliance on a mesh structure. We present method derivation, including promising new techniques for enforcing boundary conditions in a meshless environment. Following this we discuss method accuracy and computational performance across a variety of problems in two and three dimensions. We then illustrate how this method may prove beneficial for applications in porous media modeling, and computational fluid dynamics. For completeness, we provide a sensitivity analysis of the method hyper-parameters and investigate the conservative properties of the method. We also illustrate similarities of this approach to the widely used meshless point collocation methods. We close with a discussion of the strengths, limitations, and broader applicability of the technique.</p

A meshfree radial basis function method for simulation of multi-dimensional conservation problems

Many computational fluid dynamics problems utilize finite volume frameworks for simulation, due to the simplifications provided by conservative formulation of the driving partial differential equations (PDEs). However, fluid dynamics applications can often involve temporal shifts in the domain structure—such as moving boundaries, or pore structure changes—requiring mesh adaptation throughout computation. These mesh adaptations often render classical numerical methods such as the finite volume method infeasible, due to their reliance on a well-defined static mesh structure. This limitation has led to the development of a wide variety of meshless methods—techniques that can simulate PDEs without requiring a rigid connective structure between nodes. However, most meshless methods are typically based on finite element or finite difference formulations, and the limited number of meshless finite volume methods (MFVMs) either introduce a weak background mesh, or use weak-form approximations that do not take full advantage of the strong conservative form of the driving equations. Addressing this gap within this study we outline a meshfree numerical scheme for simulation of partial different equations, based on strong-form finite volume style formulations. Building upon the previously developed MFVM, this technique uses radial basis functions to interpolate the problem domain, and approximate fluxes in a disjoint finite volume scheme, removing reliance on a mesh structure. We present method derivation, including promising new techniques for enforcing boundary conditions in a meshless environment. Following this we discuss method accuracy and computational performance across a variety of problems in two and three dimensions. We then illustrate how this method may prove beneficial for applications in porous media modeling, and computational fluid dynamics. For completeness, we provide a sensitivity analysis of the method hyper-parameters and investigate the conservative properties of the method. We also illustrate similarities of this approach to the widely used meshless point collocation methods. We close with a discussion of the strengths, limitations, and broader applicability of the technique.</p

A meshfree radial basis function method for simulation of multi-dimensional conservation problems

Many computational fluid dynamics problems utilize finite volume frameworks for simulation, due to the simplifications provided by conservative formulation of the driving partial differential equations (PDEs). However, fluid dynamics applications can often involve temporal shifts in the domain structure—such as moving boundaries, or pore structure changes—requiring mesh adaptation throughout computation. These mesh adaptations often render classical numerical methods such as the finite volume method infeasible, due to their reliance on a well-defined static mesh structure. This limitation has led to the development of a wide variety of meshless methods—techniques that can simulate PDEs without requiring a rigid connective structure between nodes. However, most meshless methods are typically based on finite element or finite difference formulations, and the limited number of meshless finite volume methods (MFVMs) either introduce a weak background mesh, or use weak-form approximations that do not take full advantage of the strong conservative form of the driving equations. Addressing this gap within this study we outline a meshfree numerical scheme for simulation of partial different equations, based on strong-form finite volume style formulations. Building upon the previously developed MFVM, this technique uses radial basis functions to interpolate the problem domain, and approximate fluxes in a disjoint finite volume scheme, removing reliance on a mesh structure. We present method derivation, including promising new techniques for enforcing boundary conditions in a meshless environment. Following this we discuss method accuracy and computational performance across a variety of problems in two and three dimensions. We then illustrate how this method may prove beneficial for applications in porous media modeling, and computational fluid dynamics. For completeness, we provide a sensitivity analysis of the method hyper-parameters and investigate the conservative properties of the method. We also illustrate similarities of this approach to the widely used meshless point collocation methods. We close with a discussion of the strengths, limitations, and broader applicability of the technique.</p

Analysing the predictive capacity and dose-response of wellness in load monitoring

This study aimed to identify the predictive capacity of wellness questionnaires on measures of training load using machine learning methods. The distributions of, and dose–response between, wellness and other load measures were also examined, offering insights into response patterns. Data (n= 14,109) were collated from an athlete management systems platform (Catapult Sports, Melbourne, Australia) and were split across three sports (cricket, rugby league and football) with data analysis conducted in R (Version 3.4.3). Wellness (sleep quality, readiness to train, general muscular soreness, fatigue, stress, mood, recovery rating and motivation) as the dependent variable, and sRPE, sRPE-TL and markers of external load (total distance and m.min−1) as independent variables were included for analysis. Classification and regression tree models showed high cross-validated error rates across all sports (i.e., > 0.89) and low model accuracy (i.e., < 5% of variance explained by each model) with similar results demonstrated using random forest models. These results suggest wellness items have limited predictive capacity in relation to internal and external load measures. This result was consistent despite varying statistical approaches (regression, classification and random forest models) and transformation of wellness scores. These findings indicate practitioners should exercise caution when interpreting and applying wellness responses.</p

Comparing COVID-19 vaccine allocation strategies in India: A mathematical modelling study

BACKGROUND: The development and widespread use of an effective SARS-CoV-2 vaccine could prevent substantial morbidity and mortality associated with COVID-19 and mitigate the secondary effects associated with non-pharmaceutical interventions. METHODS: We used an age-structured, expanded SEIR model with social contact matrices to assess age-specific vaccine allocation strategies in India. We used state-specific age structures and disease transmission coefficients estimated from confirmed incident cases of COVID-19 between 1 July and 31 August 2020. Simulations were used to investigate the relative reduction in mortality and morbidity of vaccine allocation strategies based on prioritizing different age groups, and the interactions of these strategies with concurrent non-pharmaceutical interventions. Given the uncertainty associated with COVID-19 vaccine development, we varied vaccine characteristics in the modelling simulations. RESULTS: Prioritizing COVID-19 vaccine allocation for older populations (i.e., &gt;60 years) led to the greatest relative reduction in deaths, regardless of vaccine efficacy, control measures, rollout speed, or immunity dynamics. Preferential vaccination of this group often produced relatively higher total symptomatic infections and more pronounced estimates of peak incidence than other assessed strategies. Vaccine efficacy, immunity type, target coverage, and rollout speed significantly influenced overall strategy effectiveness, with the time taken to reach target coverage significantly affecting the relative mortality benefit comparative to no vaccination. CONCLUSIONS: Our findings support global recommendations to prioritize COVID-19 vaccine allocation for older age groups. Relative differences between allocation strategies were reduced as the speed of vaccine rollout was increased. Optimal vaccine allocation strategies will depend on vaccine characteristics, strength of concurrent non-pharmaceutical interventions, and region-specific goals

Modelling the effect of gravity on inert-gas washout outputs

Multiple-breath washout (MBW) is a pulmonary function test (PFT) that is used to infer lung function through measurement of ventilation heterogeneity (VH). However, the body position that a test is taken in may also influence VH, due to the "Slinky" effect of gravity on the lungs. In healthy subjects this has minimal effect, but in unhealthy groups, PFT outputs have been seen to change drastically with body position. In this study, we used a combined computational and clinical approach to better understand the response of outputs from the MBW to body position. A patient-specific model of the MBW was developed, then validated against clinically measured washout data, as well as broader results in the literature. This model was then used to compare changes in MBW outputs with respect to body position, showing that output changes sensitively predict regional airway size differences between lobes. We then highlight cases in which body position effects may bias MBW outputs, leading to elevated or masked responses to bronchoconstriction. We close by placing this result in context with broader clinical practice, and showing how it can help improve interpretation of test outputs