Best Care at Lower Cost: The Path to Continuously Learning Health Care in America

http://www.iom.edu/Reports/2012/Best-Care-at-Lower-Cost-The-Path-to-Continuously-Learning-Health-Care-in-America.asp

Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model.

BACKGROUND: Cancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and with regard to the underlying mechanisms. RESULTS: Combined treatment with precision RT and checkpoint inhibitor IT achieved control of tumor growth. However, BALB/c mice receiving combined treatment demonstrated changes in measures of anxiety levels, regardless of tumor status. C57BL/6J mice with tumors demonstrated increased anxiety, except following combined treatment. Object recognition memory was impaired in C57BL/6J mice without tumors following combined treatment. All mice with tumors showed impaired object recognition, except those treated with RT alone. Mice with tumors demonstrated impaired amygdala-dependent cued fear memory, while maintaining hippocampus-dependent context fear memory. These behavioral alterations and cognitive impairments were accompanied by increased microglial activation in mice receiving immunotherapy alone or combined with RT. Finally, based on tumor status, there were significant changes in proinflammatory cytokines (IFN-γ, IL-6, IL-5, IL-2, IL-10) and a growth factor (FGF-basic). MATERIALS AND METHODS: Here we test the hypothesis that IT combined with peripheral RT have detrimental behavioral and cognitive effects as a result of an enhanced proinflammatory environment in the brain. BALB/c mice with or without injected hind flank CT26 colorectal carcinoma or C57BL/6J mice with or without Lewis Lung carcinoma were used for all experiments. Checkpoint inhibitor IT, using an anti-CTLA-4 antibody, and precision CT-guided peripheral RT alone and combined were used to closely model clinical treatment. We assessed behavioral and cognitive performance and investigated the immune environment using immunohistochemistry and multiplex assays to analyze proinflammatory mediators. CONCLUSIONS: Although combined treatment achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation

Nondestructive Evaluation of Standing Trees With a Stress Wave Method

The primary objective of this study was to investigate the usefulness of a stress wave technique for evaluating wood strength and stiffness of young-growth western hemlock and Sitka spruce in standing trees. A secondary objective was to determine if the effects of silvicultural practices on wood quality can be identified using this technique. Stress wave measurements were conducted on 168 young-growth western hemlock and Sitka spruce trees. After in situ measurements, a 0.61-m-long bole section in the test span was taken from 56 felled trees to obtain small, clear wood specimens. Stress wave and static bending tests were then performed on these specimens to determine strength and stiffness. Results of this study indicate that in situ stress wave measurements could provide relatively accurate and reliable information that would enable nondestructive evaluation of wood properties in standing trees. The mean values of stress wave speed and dynamic modulus of elasticity for trees agreed with those determined from small, clear wood specimens. Statistical regression analyses revealed good correlations between stress wave properties of trees and static bending properties of small, clear wood specimens obtained from the trees. Regression models showed statistical significance at the 0.01 confidence level. Results of this study also demonstrate that the effect of silvicultural practices on wood properties can be identified with the stress wave properties of trees. This indicates that this nondestructive stress wave technique can be used to track property changes in trees and help determine how forests could be managed to meet desired wood and fiber qualities

Lead exposure of mainland Australia\u27s top avian predator

Lead (Pb) toxicity, through ingestion of lead ammunition in carcasses, is a threat to scavenging birds worldwide, but has received little attention in Australia. We analyzed lead exposure in the wedge-tailed eagle (Aquila audax), the largest raptor species found in mainland Australia and a facultative scavenger. Eagle carcasses were collected opportunistically throughout south-eastern mainland Australia between 1996 and 2022. Lead concentrations were measured in bone samples from 62 animals via portable X-ray fluorescence (XRF). Lead was detected (concentration \u3e 1 ppm) in 84% (n = 52) of the bone samples. The mean lead concentration of birds in which lead was detected was 9.10 ppm (±SE 1.66). Bone lead concentrations were elevated (10–20 ppm) in 12.9% of samples, and severe ( \u3e 20 ppm) in 4.8% of samples. These proportions are moderately higher than equivalent data for the same species from the island of Tasmania, and are comparable to data from threatened eagle species from other continents. Lead exposure at these levels is likely to have negative impacts on wedge-tailed eagles at the level of the individual and perhaps at a population level. Our results suggest that studies of lead exposure in other Australian avian scavenger species are warranted

Norspermidine is not a self-produced trigger for biofilm disassembly

SummaryFormation of Bacillus subtilis biofilms, consisting of cells encapsulated within an extracellular matrix of exopolysaccharide and protein, requires the polyamine spermidine. A recent study reported that (1) related polyamine norspermidine is synthesized by B. subtilis using the equivalent of the Vibrio cholerae biosynthetic pathway, (2) exogenous norspermidine at 25 μM prevents B. subtilis biofilm formation, (3) endogenous norspermidine is present in biofilms at 50–80 μM, and (4) norspermidine prevents biofilm formation by condensing biofilm exopolysaccharide. In contrast, we find that, at concentrations up to 200 μM, exogenous norspermidine promotes biofilm formation. We find that norspermidine is absent in wild-type B. subtilis biofilms at all stages, and higher concentrations of exogenous norspermidine eventually inhibit planktonic growth and biofilm formation in an exopolysaccharide-independent manner. Moreover, orthologs of the V. cholerae norspermidine biosynthetic pathway are absent from B. subtilis, confirming that norspermidine is not physiologically relevant to biofilm function in this species

AMULET: a novel read count-based method for effective multiplet detection from single nucleus ATAC-seq data.

Detecting multiplets in single nucleus (sn)ATAC-seq data is challenging due to data sparsity and limited dynamic range. AMULET (ATAC-seq MULtiplet Estimation Tool) enumerates regions with greater than two uniquely aligned reads across the genome to effectively detect multiplets. We evaluate the method by generating snATAC-seq data in the human blood and pancreatic islet samples. AMULET has high precision, estimated via donor-based multiplexing, and high recall, estimated via simulated multiplets, compared to alternatives and identifies multiplets most effectively when a certain read depth of 25K median valid reads per nucleus is achieved