Feasibility of interleukin-6 receptor blockade in cardiac antibody-mediated rejection

BACKGROUND: Antibody-mediated rejection (AMR) remains a significant cause of heart transplant mortality with few effective therapies. METHODS: This study aimed to describe initial experience of using interleukin-6 receptor blockade with tocilizumab in the treatment of acute cardiac AMR at Barnes-Jewish Hospital/Washington University Transplant Center from July 2017 to May 2021 (n = 7). Clinical, echocardiographic, and serum alloantibody data were analyzed before and after treatment. RESULTS: All participants demonstrated marked improvement in functional status. Echocardiographic data following 4-6 mo of tocilizumab revealed significant improvements in biventricular systolic function for all participants. Consistent reductions in donor-specific HLA or angiotensin type I receptor antibodies were not observed, suggesting that tocilizumab may act downstream of antibody production. No patient experienced drug-related complications that necessitated discontinuation of therapy. CONCLUSIONS: These findings provide initial insights into the safety and efficacy of interleukin-6 receptor blockade in the treatment of cardiac AMR and support the design of larger prospective studies

Soil respiration in a northeastern US temperate forest: a 22‐year synthesis

To better understand how forest management, phenology, vegetation type, and actual and simulated climatic change affect seasonal and inter‐annual variations in soil respiration (Rs), we analyzed more than 100,000 individual measurements of soil respiration from 23 studies conducted over 22 years at the Harvard Forest in Petersham, Massachusetts, USA. We also used 24 site‐years of eddy‐covariance measurements from two Harvard Forest sites to examine the relationship between soil and ecosystem respiration (Re). Rs was highly variable at all spatial (respiration collar to forest stand) and temporal (minutes to years) scales of measurement. The response of Rs to experimental manipulations mimicking aspects of global change or aimed at partitioning Rs into component fluxes ranged from −70% to +52%. The response appears to arise from variations in substrate availability induced by changes in the size of soil C pools and of belowground C fluxes or in environmental conditions. In some cases (e.g., logging, warming), the effect of experimental manipulations on Rs was transient, but in other cases the time series were not long enough to rule out long‐term changes in respiration rates. Inter‐annual variations in weather and phenology induced variation among annual Rs estimates of a magnitude similar to that of other drivers of global change (i.e., invasive insects, forest management practices, N deposition). At both eddy‐covariance sites, aboveground respiration dominated Re early in the growing season, whereas belowground respiration dominated later. Unusual aboveground respiration patterns—high apparent rates of respiration during winter and very low rates in mid‐to‐late summer—at the Environmental Measurement Site suggest either bias in Rs and Re estimates caused by differences in the spatial scale of processes influencing fluxes, or that additional research on the hard‐to‐measure fluxes (e.g., wintertime Rs, unaccounted losses of CO2 from eddy covariance sites), daytime and nighttime canopy respiration and its impacts on estimates of Re, and independent measurements of flux partitioning (e.g., aboveground plant respiration, isotopic partitioning) may yield insight into the unusually high and low fluxes. Overall, however, this data‐rich analysis identifies important seasonal and experimental variations in Rs and Re and in the partitioning of Re above‐ vs. belowground

Soil respiration in a northeastern US temperate forest: a 22‐year synthesis

To better understand how forest management, phenology, vegetation type, and actual and simulated climatic change affect seasonal and inter‐annual variations in soil respiration (Rs), we analyzed more than 100,000 individual measurements of soil respiration from 23 studies conducted over 22 years at the Harvard Forest in Petersham, Massachusetts, USA. We also used 24 site‐years of eddy‐covariance measurements from two Harvard Forest sites to examine the relationship between soil and ecosystem respiration (Re). Rs was highly variable at all spatial (respiration collar to forest stand) and temporal (minutes to years) scales of measurement. The response of Rs to experimental manipulations mimicking aspects of global change or aimed at partitioning Rs into component fluxes ranged from −70% to +52%. The response appears to arise from variations in substrate availability induced by changes in the size of soil C pools and of belowground C fluxes or in environmental conditions. In some cases (e.g., logging, warming), the effect of experimental manipulations on Rs was transient, but in other cases the time series were not long enough to rule out long‐term changes in respiration rates. Inter‐annual variations in weather and phenology induced variation among annual Rs estimates of a magnitude similar to that of other drivers of global change (i.e., invasive insects, forest management practices, N deposition). At both eddy‐covariance sites, aboveground respiration dominated Re early in the growing season, whereas belowground respiration dominated later. Unusual aboveground respiration patterns—high apparent rates of respiration during winter and very low rates in mid‐to‐late summer—at the Environmental Measurement Site suggest either bias in Rs and Re estimates caused by differences in the spatial scale of processes influencing fluxes, or that additional research on the hard‐to‐measure fluxes (e.g., wintertime Rs, unaccounted losses of CO2 from eddy covariance sites), daytime and nighttime canopy respiration and its impacts on estimates of Re, and independent measurements of flux partitioning (e.g., aboveground plant respiration, isotopic partitioning) may yield insight into the unusually high and low fluxes. Overall, however, this data‐rich analysis identifies important seasonal and experimental variations in Rs and Re and in the partitioning of Re above‐ vs. belowground

Resolvin D1 prevents injurious neutrophil swarming in transplanted lungs

Neutrophils are the primary cell type involved in lung ischemia-reperfusion injury (IRI), which remains a frequent and morbid complication after organ transplantation. Endogenous lipid mediators that become activated during acute inflammation-resolution have gained increasing recognition for their protective role(s) in promoting the restoration of homeostasis, but their influence on early immune responses following transplantation remains to be uncovered. Resolvin D1,

The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Diseases

This guidance provides a data-supported approach to the diagnostic, therapeutic, and preventive aspects of NAFLD care. A “Guidance” document is different from a “Guideline.” Guidelines are developed by a multidisciplinary panel of experts and rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations, Assessment Development, and Evaluation (GRADE) system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence

Pediatric and adult dilated cardiomyopathy represent distinct pathological entities

Pediatric dilated cardiomyopathy (DCM) is the most common indication for heart transplantation in children. Despite similar genetic etiologies, medications routinely used in adult heart failure patients do not improve outcomes in the pediatric population. The mechanistic basis for these observations is unknown. We hypothesized that pediatric and adult DCM comprise distinct pathological entities, in that children do not undergo adverse remodeling, the target of adult heart failure therapies. To test this hypothesis, we examined LV specimens obtained from pediatric and adult donor controls and DCM patients. Consistent with the established pathophysiology of adult heart failure, adults with DCM displayed marked cardiomyocyte hypertrophy and myocardial fibrosis compared with donor controls. In contrast, pediatric DCM specimens demonstrated minimal cardiomyocyte hypertrophy and myocardial fibrosis compared with both age-matched controls and adults with DCM. Strikingly, RNA sequencing uncovered divergent gene expression profiles in pediatric and adult patients, including enrichment of transcripts associated with adverse remodeling and innate immune activation in adult DCM specimens. Collectively, these findings reveal that pediatric and adult DCM represent distinct pathological entities, provide a mechanistic basis to explain why children fail to respond to adult heart failure therapies, and suggest the need to develop new approaches for pediatric DCM

Evaluating remote sensing of deciduous forest phenology at multiple spatial scales using PhenoCam imagery

Plant phenology regulates ecosystem services at local and global scales and is a sensitive indicator of global change. Estimates of phenophase transition dates, such as the start of spring or end of autumn, can be derived from sensor-based time series data at the near-surface and remote scales, but must be interpreted in terms of biologically relevant events. We use the PhenoCam archive of digital repeat photography to implement a consistent protocol for visual assessment of canopy phenology at 13 temperate deciduous forest sites throughout eastern North America, as well as to perform digital image analysis for time series-based estimates of phenology dates. We then compare these near-surface results to remote sensing metrics of phenology at the landscape scale, derived from the Moderate Resolution Imaging Spectroradiometer (MODIS) and Advanced Very High Resolution Radiometer (AVHRR) sensors. We present a new type of curve fit, using a generalized sigmoid, to estimate phenology dates. We quantify the statistical uncertainty of phenophase transition dates estimated using this method and show that the generalized sigmoid results in less statistical uncertainty than other curve-fitting methods. Additionally, we find that dates derived from analysis of high-frequency PhenoCam imagery have smaller uncertainties than remote sensing metrics of phenology, and that dates derived from the remotely-sensed enhanced vegetation index (EVI) have smaller uncertainty than those derived from the normalized difference vegetation index (NDVI). Near-surface time series estimates for the start of spring are found to closely match visual assessment of leaf out, as well as remote sensing-derived estimates of the start of spring. However late spring and autumn phenology exhibit larger differences between near-surface and remote scales. Differences in late spring phenology between near-surface and remote scales are found to correlate with a landscape metric of deciduous forest cover. These results quantify the effect of landscape heterogeneity when aggregating to the coarser spatial scales of remote sensing, and demonstrate the importance of accurate curve fitting and vegetation index selection when analyzing and interpreting phenology time series.Organismic and Evolutionary Biolog