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Functional decline following hospitalization remains an important problem in health care, especially for frail older adults. Modifiable factors related to reduction in harms of hospitalization are not well described. One particularly pervasive factor is emergency department (ED) boarding time; time waiting from decision to admit, until transfer to an in-patient medical unit. We sought to investigate how the functional status of frail older adults correlated with the length of time spent boarded in the ED. We found that patients who waited for 24 hours or more exhibited functional decline in both the Barthel Index and Hierarchical Assessment of Balance and Mobility and an increase in the Clinical Frailty Scale from discharge to 6 months post discharge. In conclusion, there is a need for additional investigation into ED focused interventions to reduce ED boarding time for this population or to improve access to specialized geriatric services within the ED.
OBJECTIVES/GOALS: Re-administration of inhaled gene therapies has the potential to overcome low correction efficiencies and limiting immune responses observed in previous trials of gene therapy for Cystic Fibrosis. We therefore tested the hypothesis that pre-treatment with a B-cell depleting α ± CD20 antibody would permit vector re-administration. METHODS/STUDY POPULATION: We first selected Adenoviral (Ad) vectors to study initially due to their well-known ability to elicit potent immune responses. Mice were dosed with a depleting α ± CD20 antibody or isotype control 2 days prior to delivery of Ad-Luc. 4 weeks later, mice were euthanized to assess the development of anti-vector immune responses. Flow cytometry and single-cell RNA sequencing were used to evaluate the development of lung-resident memory cells. Serum and airway antibody responses were assessed by ELISA. After 4 weeks, mice were dosed with Ad-LacZ and euthanized 3 days later to assess efficiency of second-round gene transfer by β-galactosidase activity assay. Similar methods were used in a pilot experiment with Adeno-associated virus vector (AAV), but with euthanasia 3 weeks after secondary gene transfer. RESULTS/ANTICIPATED RESULTS: Delivery of Ad vectors leads to the development of lung-resident memory B and T-cells. The depletion of B-cells prior to first-round vector delivery attenuated airway T-cell infiltration and serum IgG production, abrogated mucosal IgG and IgA production, and completely rescued secondary gene transfer. Genetically modified mouse models suggest secreted antibodies are critical in prevention of vector redosing. AAV vectors were found to be less immunogenic than Ad vectors, with only partial reduction of second-round gene transfer. However, anti-CD20 provided no benefit for AAV redelivery. DISCUSSION/SIGNIFICANCE: Mucosal humoral immunity is critical in preventing re-administration of Adenoviral vectors. Impairment of B-cell responses by α ± CD20 treatment prior to vector delivery allows re-administration and may help overcome low efficiencies of CF gene therapy. AAV vectors may be less susceptible to neutralization by pre-existing immunity.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
Aims
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
Method
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
Results
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Conclusions
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Optical tracking systems typically trade off between astrometric precision and field of view. In this work, we showcase a networked approach to optical tracking using very wide field-of-view imagers that have relatively low astrometric precision on the scheduled OSIRIS-REx slingshot manoeuvre around Earth on 22 Sep 2017. As part of a trajectory designed to get OSIRIS-REx to NEO 101955 Bennu, this flyby event was viewed from 13 remote sensors spread across Australia and New Zealand to promote triangulatable observations. Each observatory in this portable network was constructed to be as lightweight and portable as possible, with hardware based off the successful design of the Desert Fireball Network. Over a 4-h collection window, we gathered 15 439 images of the night sky in the predicted direction of the OSIRIS-REx spacecraft. Using a specially developed streak detection and orbit determination data pipeline, we detected 2 090 line-of-sight observations. Our fitted orbit was determined to be within about 10 km of orbital telemetry along the observed 109 262 km length of OSIRIS-REx trajectory, and thus demonstrating the impressive capability of a networked approach to Space Surveillance and Tracking.
Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.
We propose the nasal administration of calcium-enriched physiological salts as a new hygienic intervention with possible therapeutic application as a response to the rapid and tenacious spread of COVID-19. We test the effectiveness of these salts against viral and bacterial pathogens in animals and humans. We find that aerosol administration of these salts to the airways diminishes the exhalation of the small particles that face masks fail to filter and, in the case of an influenza swine model, completely block airborne transmission of disease. In a study of 10 human volunteers (5 less than 65 years and 5 older than 65 years), we show that delivery of a nasal saline comprising calcium and sodium salts quickly (within 15 min) and durably (up to at least 6 h) diminishes exhaled particles from the human airways. Being predominantly smaller than 1 μm, these particles are below the size effectively filtered by conventional masks. The suppression of exhaled droplets by the nasal delivery of calcium-rich saline with aerosol droplet size of around 10 μm suggests the upper airways as a primary source of bioaerosol generation. The suppression effect is especially pronounced (99%) among those who exhale large numbers of particles. In our study, we found this high-particle exhalation group to correlate with advanced age. We argue for a new hygienic practice of nasal cleansing by a calcium-rich saline aerosol, to complement the washing of hands with ordinary soap, use of a face mask, and social distancing.
Each year our Clinical and Translational Science Award pilot projects program awards approximately $500,000 in translational pilot funding to advance health in South Texas. We identified needs to improve the timeliness, transparency, and efficiency of the review process by surveying applicants. Lean six sigma methodologies, following a “Define, Measure, Analyze, Improve, Control” approach, were used to streamline the pilot project application and review by identifying and removing bottlenecks from process flows. We evaluated the impact of our reorganized review process by surveying applicants and reviewers. Process mapping identified pilot project review as the main source of delay, leading to the implementation of a study section-style review mechanism. After one cycle, 90.3% of pilot applicants and 100% of reviewers were highly satisfied with the new processes and time to award notice was reduced by 2 months. All reviewers familiar with both review processes preferred the study section. We demonstrated how lean six sigma, a methodology not commonly applied in research administration, can be used to evaluate processes in translational science in academic health centers. Through our efforts, we were able to improve timeliness, transparency, and efficiency of the review process.
Spectral ellipsometry in the range 240 nm to 540 nm has been used to investigate the influence of surface damage induced by mechanical polishing and surface films of CuO on the optical properties of pure synthetic cuprite. Comparison is made between bulk CuO and thin film CuO produced by low-temperature oxidation of cuprite. The effects of strain and disorder are discussed in relation to the suppression of excitonic transitions. Recently developed techniques have been used to simplify the analysis and take full advantage of the spectral data.
The persistence of alachlor [2-chloro-2′,6′-diethyl-N-(methoxymethyl) acetanilide], metolachlor [2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetamide], and propachlor (2-chloro-N-isopropylacetanilide) in soil was examined under laboratory and field conditions using sorghum (Sorghum vulgare Pers. ‘NB280S′) or annual ryegrass (Lolium multiflorum Lam.) as bioassay species. In laboratory studies, degradation rate of alachlor and propachlor was greater at 50 and 80% than at 20% field capacity at 20 C. Degradation of metolachlor was greater at 80 than at 20% field capacity. Degradation rate of alachlor and metolachlor at 50% field capacity was greater at higher temperatures. Propachlor degradation rate varied with temperature. Under irrigated, cropped field conditions, the order of persistence was metolachlor > alachlor > > propachlor.
As part of a program to study surge-type glaciers, a radar-depth survey, using a frequency of 620 MHz, has been made of Trapridge Glacier, Yukon Territory. Soundings were taken at 26 locations on the glacier surface and a maximum ice thickness of 143 m was measured. A rapid change in surface slope in the lower ablation region marks the boundary between active and stagnant ice and is suggestive of an “ice dam” or the water “collection zone” postulated by Robin and Weertman for surging glaciers.
Response tests are widely used in ground-water studies to assess the hydraulic properties of sub-surface water-flow systems. The simplicity of such tests also makes them attractive for investigation of subglacial hydraulic conditions. This paper describes a systematic, quantitative approach to the analysis of borehole-response test data. The approach uses the theoretical model of Stone and Clarke (1993), which describes water motion in a coupled borehole—subglacial flow system; this framework provides the basis for an inversion scheme that is focused on quantifying physical properties of the basal-flow system, as it is characterized in the theoretical model. The inversion procedure was applied to response-test data from Trapridge Glacier, Yukon Territory, Canada. Results of the inversions suggest that the subglacial drainage network can be described as a confined layer comprising coarse-sand-to fine-gravel-sized sediments, having a thickness of 0.1 – 0.3 m, and a hydraulic conductivity of about 5 × 10−4ms−1. Based on the water-drainage rates from boreholes, as they connect with the subglacial water-flow system, specific storage of the sediment layer was estimated to be approximately 1 × 10−4m−1. Further consideration of subglacial water-flow conditions suggests that connection drainage test results may tend to underestimate specific storage of the overall glacier substrate.
Intestinal health is important for maximising the health, welfare, and performance of poultry. In addition, intestinal health issues in poultry can have devastating financial impacts for producers, and food safety concerns for consumers. Until recently, intestinal health issues were seen as a handful of known infectious agents leading to a set of severe and identifiable named diseases. There is however an emerging area which depicts intestinal health as a more complex and multifaceted system than previously known. Recent progress in technology suitable for microbial community analysis has evolved our understanding of the chicken intestinal microbiome. It is now understood that shifts in the composition of microbial communities can occur. These shifts can result in a series of implications, including: disease, welfare, environmental, and food safety concerns. Minor shifts in intestinal microbial balance can result in a wide continuum of disease presentations ranging from severe to mild clinical, subclinical or asymptotic. Differential diagnosis of poultry intestinal health issues may be challenging and is important for applying appropriate treatment options. This review discusses new and emerging topics in broiler chicken intestinal health, with a focus on microbial composition, newly discovered microbial shifts in classical poultry diseases, range in severity of enteric diseases, newly identified organisms in normal intestinal flora, implications of shifts in intestinal microbial communities and diagnosis of emerging intestinal health issues in poultry.