Tobacco smoking is associated with combined pulmonary fibrosis and emphysema and worse outcomes in interstitial lung disease.

Tobacco smoking is an established cause of pulmonary disease whose contribution to interstitial lung disease (ILD) is incompletely characterized. We hypothesized that compared with nonsmokers, subjects who smoked tobacco would differ in their clinical phenotype and have greater mortality. We performed a retrospective cohort study of tobacco smoking in ILD. We evaluated demographic and clinical characteristics, time to clinically meaningful lung function decline (LFD), and mortality in patients stratified by tobacco smoking status (ever vs. never) within a tertiary center ILD registry (2006-2021) and replicated mortality outcomes across four nontertiary medical centers. Data were analyzed by two-sided t tests, Poisson generalized linear models, and Cox proportional hazard models adjusted for age, sex, forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), ILD subtype, antifibrotic therapy, and hospital center. Of 1,163 study participants, 651 were tobacco smokers. Smokers were more likely to be older, male, have idiopathic pulmonary fibrosis (IPF), coronary artery disease, CT honeycombing and emphysema, higher FVC, and lower DLCO than nonsmokers (P < 0.01). Time to LFD in smokers was shorter (19.7 ± 20 mo vs. 24.8 ± 29 mo; P = 0.038) and survival time was decreased [10.75 (10.08-11.50) yr vs. 20 (18.67-21.25) yr; adjusted mortality HR = 1.50, 95%CI 1.17-1.92; P < 0.0001] compared with nonsmokers. Smokers had 12% greater odds of death for every additional 10 pack yr of smoking (P < 0.0001). Mortality outcomes remained consistent in the nontertiary cohort (HR = 1.51, 95%CI = 1.03-2.23; P = 0.036). Tobacco smokers with ILD have a distinct clinical phenotype strongly associated with the syndrome of combined PF and emphysema, shorter time to LFD, and decreased survival. Smoking prevention may improve ILD outcomes.NEW & NOTEWORTHY Smoking in ILD is associated with combined pulmonary fibrosis and emphysema and worse clinical outcomes.

The effect of donor alcohol abuse on outcomes following heart transplantation.

BACKGROUND: Current guidelines recommend against the use of hearts from donors that abuse alcohol. We explored the effect of donor alcohol abuse (AA) on cardiac allograft function and outcomes in heart transplant (HTx) recipients. METHODS: Overall, 370 HTx recipients were divided into two groups: (a) the alcoholic donor group (AD, n = 58) and (b) the non-alcoholic donor group (NAD, n = 312). RESULTS: Recipients in the AD group had a slower heart rate (86 ± 13 vs 93 ± 13, P = 0.004) and an increased incidence of early atrial fibrillation (AF) (30% vs 11%, P = 0.003). Echocardiographic left ventricular mass was higher among alcoholic donors (171.7 ± 66.7 vs 151.6 ± 54.7, P = 0.02). This difference remained present 1 year following HTx (185 ± 43 vs 166 ± 42, P = 0.007). E/E' was higher in the AD group (9.5 ± 3.9 vs 8.4 ± 2.9, P = 0.04) and a larger number of AD recipients had a ventilatory equivalent for VCO2  > 34 (50% vs 31%, P = 0.04) on cardiopulmonary exercise test. There was no significant difference in rejection, cardiac allograft vasculopathy (CAV), or survival between the groups. CONCLUSIONS: Our data suggest that donor AA does not impact rejection, CAV, or intermediate-term survival, but may cause increased incidence of post-HTx AF and impaired cardiac allograft diastolic function.

A semi-automated finite difference mesh creation method for use with immersed boundary software IB2d and IBAMR.

Numerous fluid-structure interaction problems in biology have been investigated using the immersed boundary method. The advantage of this method is that complex geometries, e.g., internal or external morphology, can easily be handled without the need to generate matching grids for both the fluid and the structure. Consequently, the difficulty of modeling the structure lies often in discretizing the boundary of the complex geometry (morphology). Both commercial and open source mesh generators for finite element methods have long been established; however, the traditional immersed boundary method is based on a finite difference discretization of the structure. Here we present a software library for obtaining finite difference discretizations of boundaries for direct use in the 2D immersed boundary method. This library provides tools for extracting such boundaries as discrete mesh points from digital images. We give several examples of how the method can be applied that include passing flow through the veins of insect wings, within lymphatic capillaries, and around starfish using open-source immersed boundary software.

Sleep and diurnal rest-activity rhythm disturbances in a mouse model of Alzheimer's disease.

STUDY OBJECTIVES: Accumulating evidence suggests a strong association between sleep, amyloid-beta (Aß) deposition, and Alzheimer's disease (AD). We sought to determine if (1) deficits in rest-activity rhythms and sleep are significant phenotypes in J20 AD mice, (2) metabotropic glutamate receptor 5 inhibitors (mGluR5) could rescue deficits in rest-activity rhythms and sleep, and (3) Aß levels are responsive to treatment with mGluR5 inhibitors. METHODS: Diurnal rest-activity levels were measured by actigraphy and sleep-wake patterns by electroencephalography, while animals were chronically treated with mGluR5 inhibitors. Behavioral tests were performed, and Aß levels measured in brain lysates. RESULTS: J20 mice exhibited a 4.5-h delay in the acrophase of activity levels compared to wild-type littermates and spent less time in rapid eye movement (REM) sleep during the second half of the light period. J20 mice also exhibited decreased non-rapid eye movement (NREM) delta power but increased NREM sigma power. The mGluR5 inhibitor CTEP rescued the REM sleep deficit and improved NREM delta and sigma power but did not correct rest-activity rhythms. No statistically significant differences were observed in Aß levels, rotarod performance, or the passive avoidance task following chronic mGluR5 inhibitor treatment. CONCLUSIONS: J20 mice have disruptions in rest-activity rhythms and reduced homeostatic sleep pressure (reduced NREM delta power). NREM delta power was increased following treatment with a mGluR5 inhibitor. Drug bioavailability was poor. Further work is necessary to determine if mGluR5 is a viable target for treating sleep phenotypes in AD.

Vortex Dynamics in Trabeculated Embryonic Ventricles.

Proper heart morphogenesis requires a delicate balance between hemodynamic forces, myocardial activity, morphogen gradients, and epigenetic signaling, all of which are coupled with genetic regulatory networks. Recently both in vivo and in silico studies have tried to better understand hemodynamics at varying stages of veretebrate cardiogenesis. In particular, the intracardial hemodynamics during the onset of trabeculation is notably complex-the inertial and viscous fluid forces are approximately equal at this stage and small perturbations in morphology, scale, and steadiness of the flow can lead to significant changes in bulk flow structures, shear stress distributions, and chemical morphogen gradients. The immersed boundary method was used to numerically simulate fluid flow through simplified two-dimensional and stationary trabeculated ventricles of 72, 80, and 120 h post fertilization wild type zebrafish embryos and ErbB2-inhibited embryos at seven days post fertilization. A 2D idealized trabeculated ventricular model was also used to map the bifurcations in flow structure that occur as a result of the unsteadiness of flow, trabeculae height, and fluid scale ( R e ). Vortex formation occurred in intertrabecular regions for biologically relevant parameter spaces, wherein flow velocities increased. This indicates that trabecular morphology may alter intracardial flow patterns and hence ventricular shear stresses and morphogen gradients. A potential implication of this work is that the onset of vortical (disturbed) flows can upregulate Notch1 expression in endothelial cells in vivo and hence impacts chamber morphogenesis, valvulogenesis, and the formation of the trabeculae themselves. Our results also highlight the sensitivity of cardiac flow patterns to changes in morphology and blood rheology, motivating efforts to obtain spatially and temporally resolved chamber geometries and kinematics as well as the careful measurement of the embryonic blood rheology. The results also suggest that there may be significant changes in shear signalling due to morphological and mechanical variation across individuals and species.