APP21 transgenic rats develop age-dependent cognitive impairment and microglia accumulation within white matter tracts.

Background Most of the animal models commonly used for preclinical research into Alzheimer\u27s disease (AD) largely fail to address the pathophysiology, including the impact of known risk factors, of the widely diagnosed sporadic form of the disease. Here, we use a transgenic rat (APP21) that does not develop AD-like pathology spontaneously with age, but does develop pathology following vascular stress. To further the potential of this novel rat model as a much-needed pre-clinical animal model of sporadic AD, we characterize APP21 transgenic rats behaviorally and histologically up to 19 months of age. Methods The open field test was used as a measure of activity; and the Morris water maze was used to assess learning, memory, and strategy shift. Neuronal loss and microglia activation were also assessed throughout the brain. Results APP21 transgenic rats showed deficits in working memory from an early age, yet memory recall performance after 24 and 72 h was equal to that of wildtype rats and did not deteriorate with age. A deficit in strategy shift was observed at 19 months of age in APP21 transgenic rats compared to Fischer wildtype rats. Histologically, APP21 transgenic rats demonstrated accelerated white matter inflammation compared to wildtype rats, but interestingly no differences in neuron loss were observed. Conclusions The combined presence of white matter pathology and executive function deficits mirrored what is often found in patients with mild cognitive impairment or early dementia, and suggests that this rat model will be useful for translationally meaningful studies into the development and prevention of sporadic AD. The presence of widespread white matter inflammation as the only observed pathological correlate for cognitive deficits raises new questions as to the role of neuroinflammation in cognitive decline

Anticipating undiagnosed asthma in symptomatic adults with normal pre- and post-bronchodilator spirometry: a decision tool for bronchial challenge testing

Abstract Background Some patients with asthma demonstrate normal spirometry and remain undiagnosed without further testing. Objective To determine clinical predictors of asthma in symptomatic adults with normal spirometry, and to generate a tool to help clinicians decide who should undergo bronchial challenge testing (BCT). Methods Using random-digit dialling and population-based case-finding, we recruited adults from the community with respiratory symptoms and no previous history of diagnosed lung disease. Participants with normal pre- and post-bronchodilator spirometry subsequently underwent BCT. Asthma was diagnosed in those with symptoms and a methacholine provocative concentration (PC20) of < 8 mg/ml. Sputum and blood eosinophils, and exhaled nitric oxide were measured. Univariate analyses identified potentially predictive variables, which were then used to construct a multivariable logistic regression model to predict asthma. Model sensitivity, specificity, and area under the receiver operating curve (AUC) were calculated. Results Of 132 symptomatic individuals with normal spirometry, 34 (26%) had asthma. Of those ultimately diagnosed with asthma, 33 (97%) answered ‘yes’ to a question asking whether they experienced cough, chest tightness or wheezing provoked by exercise or cold air. Other univariate predictors of asthma included female sex, pre-bronchodilator FEV1 percentage predicted, and percent positive change in FEV1 post bronchodilator. A multivariable model containing these predictive variables yielded an AUC of 0.82 (95% CI: 0.72–0.91), a sensitivity of 82%, and a specificity of 66%. The model was used to construct a nomogram to advise clinicians which patients should be prioritized for BCT. Conclusions Four readily available patient characteristics demonstrated a high sensitivity and AUC for predicting undiagnosed asthma in symptomatic adults with normal pre- and post-bronchodilator spirometry. These characteristics can potentially help clinicians to decide which individuals with normal spirometry should be investigated with bronchial challenge testing. However, further prospective validation of our decision tool is required

Global comparison of readmission rates for patients with heart failure

Background: Heart failure (HF) readmission rates are low in some jurisdictions. However, international comparisons are lacking and could serve as a foundation for identifying regional patient management strategies that could be shared to improve outcomes. Objectives: This study sought to summarize 30-day and 1-year all-cause readmission and mortality rates of hospitalized HF patients across countries and to explore potential differences in rates globally. Methods: We performed a systematic review and meta-analysis using MEDLINE, Embase, and CENTRAL for observational reports on hospitalized adult HF patients at risk for readmission or mortality published between January 2010 and March 2021. We conducted a meta-analysis of proportions using a random-effects model, and sources of heterogeneity were evaluated with meta-regression. Results: In total, 24 papers reporting on 30-day and 23 papers on 1-year readmission were included. Of the 1.5 million individuals at risk, 13.2% (95% CI: 10.5%-16.1%) were readmitted within 30 days and 35.7% (95% CI: 27.1%-44.9%) within 1 year. A total of 33 papers reported on 30-day and 45 papers on 1-year mortality. Of the 1.5 million individuals hospitalized for HF, 7.6% (95% CI: 6.1%-9.3%) died within 30 days and 23.3% (95% CI: 20.8%-25.9%) died within 1 year. Substantial variation in risk across countries was unexplained by countries’ gross domestic product, proportion of gross domestic product spent on health care, and Gini coefficient. Conclusions: Globally, hospitalized HF patients exhibit high rates of readmission and mortality, and the variability in readmission rates was not explained by health care expenditure, risk of mortality, or comorbidities