Global-scale regionalization of hydrologic model parameters

Current state-of-the-art models typically applied at continental to global scales (hereafter called macroscale) tend to use a priori parameters, resulting in suboptimal streamflow (Q) simulation. For the first time, a scheme for regionalization of model parameters at the global scale was developed. We used data from a diverse set of 1787 small-to-medium sized catchments ( 10-10,000 km(2)) and the simple conceptual HBV model to set up and test the scheme. Each catchment was calibrated against observed daily Q, after which 674 catchments with high calibration and validation scores, and thus presumably good-quality observed Q and forcing data, were selected to serve as donor catchments. The calibrated parameter sets for the donors were subsequently transferred to 0.5 degrees grid cells with similar climatic and physiographic characteristics, resulting in parameter maps for HBV with global coverage. For each grid cell, we used the 10 most similar donor catchments, rather than the single most similar donor, and averaged the resulting simulated Q, which enhanced model performance. The 1113 catchments not used as donors were used to independently evaluate the scheme. The regionalized parameters outperformed spatially uniform (i.e., averaged calibrated) parameters for 79% of the evaluation catchments. Substantial improvements were evident for all major Koppen-Geiger climate types and even for evaluation catchments>5000 km distant from the donors. The median improvement was about half of the performance increase achieved through calibration. HBV with regionalized parameters outperformed nine state-of-the-art macroscale models, suggesting these might also benefit from the new regionalization scheme. The produced HBV parameter maps including ancillary data are available via

Improving preclinical to clinical translation in Alzheimer\u27s disease research.

Introduction: Preclinical testing in animal models is a critical component of the drug discovery and development process. While hundreds of interventions have demonstrated preclinical efficacy for ameliorating cognitive impairments in animal models, none have confirmed efficacy in Alzheimer\u27s disease (AD) clinical trials. Critically this lack of translation to the clinic points in part to issues with the animal models, the preclinical assays used, and lack of scientific rigor and reproducibility during execution. In an effort to improve this translation, the Preclinical Testing Core (PTC) of the Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) consortium has established a rigorous screening strategy with go/no-go decision points that permits unbiased assessments of therapeutic agents. Methods: An initial screen evaluates drug stability, formulation, and pharmacokinetics (PK) to confirm appreciable brain exposure in the disease model at the pathologically relevant ages, followed by pharmacodynamics (PD) and predictive PK/PD modeling to inform the dose regimen for long-term studies. The secondary screen evaluates target engagement and disease modifying activity using non-invasive positron emission tomography/magnetic resonance imaging (PET/MRI). Provided the compound meets its go criteria for these endpoints, evaluation for efficacy on behavioral endpoints are conducted. Results: Validation of this pipeline using tool compounds revealed the importance of critical quality control (QC) steps that researchers need to be aware of when executing preclinical studies. These include confirmation of the active pharmaceutical ingredient and at the precise concentration expected; and an experimental design that is well powered and in line with the Animal Research Reporting of In vivo Experiments (ARRIVE) guidelines. Discussion: Taken together our experience executing a rigorous screening strategy with QC checkpoints provides insight to the challenges of conducting translational studies in animal models. The PTC pipeline is a National Institute on Aging (NIA)-supported resource accessible to the research community for investigators to nominate compounds for testing (https://stopadportal.synapse.org/), and these resources will ultimately enable better translational studies to be conducted

The cigarette box as an advertising vehicle in the UK : a case for plain packaging

This research aimed to study tobacco advertising between 1950-2003 and to evaluate the role of the cigarette box in advertising. Tobacco company advertisements (n = 204) were coded for content and meanings used to promote their product. There was a significant shift from cigarettes being displayed to the cigarette box only. Changes in advertising and the meanings evoked were unrelated to changes in smoking behaviour. It is argued that the cigarette box has absorbed the meanings associated with smoking and has become an effective vehicle for advertising. It is also argued that this can only be minimised with plain packaging

Regional spread of an atypical ESBL-producing Escherichia coli ST131H89 clone among different human and environmental reservoirs in Western Switzerland

We describe the inter-regional spread of a novel ESBL-producing Escherichia coli subclone (ST131H89) in long-term care facility residents, general population, and environmental water sources in Western Switzerland between 2017 and 2020. The study highlights the importance of molecular surveillance for tracking emerging antibiotic-resistant pathogens in healthcare and community settings

A novel systems biology approach to evaluate mouse models of late-onset Alzheimer\u27s disease.

BACKGROUND: Late-onset Alzheimer\u27s disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimer\u27s have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes. RESULTS: This resource enables precise gene-based alignment between new animal models and human molecular signatures of disease. Here, we describe a new resource to efficiently screen mouse models for LOAD relevance. A new NanoString nCounter® Mouse AD panel was designed to correlate key human disease processes and pathways with mRNA from mouse brains. Analysis of the 5xFAD mouse, a widely used amyloid pathology model, and three mouse models based on LOAD genetics carrying APOE4 and TREM2*R47H alleles demonstrated overlaps with distinct human AD modules that, in turn, were functionally enriched in key disease-associated pathways. Comprehensive comparison with full transcriptome data from same-sample RNA-Seq showed strong correlation between gene expression changes independent of experimental platform. CONCLUSIONS: Taken together, we show that the nCounter Mouse AD panel offers a rapid, cost-effective and highly reproducible approach to assess disease relevance of potential LOAD mouse models

Amplification of asynchronous inhibition-mediated synchronization by feedback in recurrent networks

Synchronization of 30-80 Hz oscillatory activity of the principle neurons in the olfactory bulb (mitral cells) is believed to be important for odor discrimination. Previous theoretical studies of these fast rhythms in other brain areas have proposed that principle neuron synchrony can be mediated by short-latency, rapidly decaying inhibition. This phasic inhibition provides a narrow time window for the principle neurons to fire, thus promoting synchrony. However, in the olfactory bulb, the inhibitory granule cells produce long lasting, small amplitude, asynchronous and aperiodic inhibitory input and thus the narrow time window that is required to synchronize spiking does not exist. Instead, it has been suggested that correlated output of the granule cells could serve to synchronize uncoupled mitral cells through a mechanism called "stochastic synchronization", wherein the synchronization arises through correlation of inputs to two neural oscillators. Almost all work on synchrony due to correlations presumes that the correlation is imposed and fixed. Building on theory and experiments that we and others have developed, we show that increased synchrony in the mitral cells could produce an increase in granule cell activity for those granule cells that share a synchronous group of mitral cells. Common granule cell input increases the input correlation to the mitral cells and hence their synchrony by providing a positive feedback loop in correlation. Thus we demonstrate the emergence and temporal evolution of input correlation in recurrent networks with feedback. We explore several theoretical models of this idea, ranging from spiking models to an analytically tractable model. © 2010 Marella, Ermentrout

Absolute risk representation in cardiovascular disease prevention: comprehension and preferences of health care consumers and general practitioners involved in a focus group study

Background Communicating risk is part of primary prevention of coronary heart disease and stroke, collectively referred to as cardiovascular disease (CVD). In Australia, health organisations have promoted an absolute risk approach, thereby raising the question of suitable standardised formats for risk communication. Methods Sixteen formats of risk representation were prepared including statements, icons, graphical formats, alone or in combination, and with variable use of colours. All presented the same risk, i.e., the absolute risk for a 55 year old woman, 16% risk of CVD in five years. Preferences for a five or ten-year timeframe were explored. Australian GPs and consumers were recruited for participation in focus groups, with the data analysed thematically and preferred formats tallied. Results Three focus groups with health consumers and three with GPs were held, involving 19 consumers and 18 GPs. Consumers and GPs had similar views on which formats were more easily comprehended and which conveyed 16% risk as a high risk. A simple summation of preferences resulted in three graphical formats (thermometers, vertical bar chart) and one statement format as the top choices. The use of colour to distinguish risk (red, yellow, green) and comparative information (age, sex, smoking status) were important ingredients. Consumers found formats which combined information helpful, such as colour, effect of changing behaviour on risk, or comparison with a healthy older person. GPs preferred formats that helped them relate the information about risk of CVD to their patients, and could be used to motivate patients to change behaviour. Several formats were reported as confusing, such as a percentage risk with no contextual information, line graphs, and icons, particularly those with larger numbers. Whilst consumers and GPs shared preferences, the use of one format for all situations was not recommended. Overall, people across groups felt that risk expressed over five years was preferable to a ten-year risk, the latter being too remote. Conclusions Consumers and GPs shared preferences for risk representation formats. Both groups liked the option to combine formats and tailor the risk information to reflect a specific individual's risk, to maximise understanding and provide a good basis for discussion

A Bayesian adaptive design for biomarker trials with linked treatments.

BACKGROUND: Response to treatments is highly heterogeneous in cancer. Increased availability of biomarkers and targeted treatments has led to the need for trial designs that efficiently test new treatments in biomarker-stratified patient subgroups. METHODS: We propose a novel Bayesian adaptive randomisation (BAR) design for use in multi-arm phase II trials where biomarkers exist that are potentially predictive of a linked treatment's effect. The design is motivated in part by two phase II trials that are currently in development. The design starts by randomising patients to the control treatment or to experimental treatments that the biomarker profile suggests should be active. At interim analyses, data from treated patients are used to update the allocation probabilities. If the linked treatments are effective, the allocation remains high; if ineffective, the allocation changes over the course of the trial to unlinked treatments that are more effective. RESULTS: Our proposed design has high power to detect treatment effects if the pairings of treatment with biomarker are correct, but also performs well when alternative pairings are true. The design is consistently more powerful than parallel-groups stratified trials. CONCLUSIONS: This BAR design is a powerful approach to use when there are pairings of biomarkers with treatments available for testing simultaneously.This work was supported by the Medical Research Council (grant number G0800860) and the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/bjc.2015.27

SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings from the COV-AD Study

BACKGROUND: Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood. OBJECTIVES: COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination. METHODS: Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs. RESULTS: A total of 5.6% (n = 320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n = 168) compared with 100% of healthy controls (n = 205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p = 0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p = 0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine. CONCLUSION: SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection