Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation ...study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait.
The 2014–2016 Northeast Pacific marine heatwave (MHW) induced the warmest 3‐year period on record in the California Current Ecosystem. We tested whether larval fish assemblage structure, phenology, ...and diversity dynamics were comparable to past warming events from 1951 to 2013. First, we hypothesized, based on past observations of biological effect of warming, that mesopelagic species with southern distributions relative to southern California and Pacific sardine Sardinops sagax (a coastal pelagic species) would increase during the MHW while northern mesopelagics and northern anchovy Engraulis mordax (coastal pelagic) abundances would decline. Similar to past warming, southern mesopelagics increased and northern mesopelagics decreased. Unexpectedly, however, a common southern mesopelagic, Mexican lampfish Triphoturus mexicanus, was approximately three times more abundant than the previous annual high. Furthermore, whereas sardine abundance did not increase, larval anchovy abundance rose to near‐record highs in summer 2016. Second, we hypothesized that fishes would spawn earlier during the MHW. Fishes did not spawn in an earlier season within a year, but five of six southern mesopelagic taxa spawned earlier than typical within winter and spring. Third, we predicted that species richness would increase moderately due to an influx of southern and exodus of northern species. Richness, however, was very high in all seasons and the highest ever during the summer as multiple species with primarily southern distributions were recorded spawning for the first time in southern California. The richness of northern species was also unexpectedly high during the MHW. Northern species likely persisted in the study area because in addition to the warm water, pockets of cold water were consistently present. If, as predicted, conditions similar to the MHW become more common as oceans warm, this unique and largely unexpected combination of fishes may reflect future biological conditions.
The warmest 3‐year period on record occurred in the California Current Ecosystem from 2014 to 2016. The 2014–2016 larval fish assemblage differed from all past sampled years (1951–2013), as there were extremely high abundances of both northern anchovy (Engraulis mordax) and mesopelagic fishes. The response of fishes to this large marine heatwave was largely unexpected based on past warming events and suggests that fish assemblage dynamics may be nuanced as oceans warm.
The Deep Propagating Gravity Wave Experiment (DEEPWAVE) was designed to quantify gravity wave (GW) dynamics and effects from orographic and other sources to regions of dissipation at high altitudes. ...The core DEEPWAVE field phase took place from May through July 2014 using a comprehensive suite of airborne and ground-based instruments providing measurements from Earth’s surface to ∼100 km. Austral winter was chosen to observe deep GW propagation to high altitudes. DEEPWAVE was based on South Island, New Zealand, to provide access to the New Zealand and Tasmanian “hotspots” of GW activity and additional GW sources over the Southern Ocean and Tasman Sea. To observe GWs up to ∼100 km, DEEPWAVE utilized three new instruments built specifically for the National Science Foundation (NSF)/National Center for Atmospheric Research (NCAR) Gulfstream V (GV): a Rayleigh lidar, a sodium resonance lidar, and an advanced mesosphere temperature mapper. These measurements were supplemented by in situ probes, dropsondes, and a microwave temperature profiler on the GV and by in situ probes and a Doppler lidar aboard the German DLR Falcon. Extensive ground-based instrumentation and radiosondes were deployed on South Island, Tasmania, and Southern Ocean islands. Deep orographic GWs were a primary target but multiple f lights also observed deep GWs arising from deep convection, jet streams, and frontal systems. Highlights include the following: 1) strong orographic GW forcing accompanying strong cross-mountain flows, 2) strong high-altitude responses even when orographic forcing was weak, 3) large-scale GWs at high altitudes arising from jet stream sources, and 4) significant flight-level energy fluxes and often very large momentum fluxes at high altitudes.
Abstract
Background
Institutional practices regarding care for septic arthritis (SA) patients varies. To streamline the care of SA patients we established a clinical pathway with two care delivery ...expectations: % of patients on appropriate antibiotics and % of patients with time to diagnostic joint fluid aspiration < 24 hours after admission.
Key driver diagram
Lyme and non-Lyme bacterial arthritis patients since 2020
Methods
Quality improvement initiative aimed to streamline the care and key drivers were established (Figure 1). Interventions included development management algorithm, consensus building among infectious diseases physicians. The pre-study baseline period was January 1, 2020 to May 31, 2021, and the study period was from June 1, 2021, to March 1, 2023. Control charts were used to assess the interventions.
Results
Of the 97 patients admitted during the baseline and study period 42 patients were diagnosed with non-Lyme associated SA, 39 had Lyme arthritis, 16 had reactive arthritis. Significant increase in Lyme arthritis patients were observed since 2021 (Figure2) coinciding with reported geographic expansion of ticks in Ohio attributed to climate change. Length of hospitalization for Lyme arthritis (median: 2.35 days, IQR 1.29) was shorter than non-Lyme associated SA (median: 3 days, IQ 1.48). 18 (42.9%) of non-Lyme SA patients and 10 (25.6%) of Lyme arthritis patients underwent surgical washouts. 27 (69 %) of Lyme arthritis patients were initially treated with anti-staphylococcal antimicrobial agents. Lyme serologies took 1-3 days to result causing delays in diagnosis and management. 7 (18%) of patients were discharged home on no antibiotics or with antibiotics not appropriate for Lyme arthritis.
Conclusion
Our streamlined approach led to timely and appropriate diagnostic and therapeutic approach in non-Lyme associated SA patients. Rapidly evolving Lyme epidemiology in central Ohio created challenges in prompt diagnosis and management of Lyme arthritis patients.
Disclosures
All Authors: No reported disclosures
Experiments were conducted to quantify the temperature and pressure effects on the solubility of titanium in coesite. Powdered amorphous silica, titania (anatase), zirconia, and water were added to ...silver capsules and run in the coesite stability field (at 32, 35, and 40 kbar) from 700 to 1050 °C using a piston–cylinder apparatus. Crystallization of coesite, rutile, and zircon from silica-, titania-, and zircon-saturated aqueous fluids was confirmed by Raman spectroscopy. Cathodoluminescence images and electron microprobe measurements showed that coesite crystals are relatively homogenous. The Ti concentrations of coesite crystals are significantly higher than concentrations predicted using the Ti-in-quartz calibration (Wark and Watson in Contrib Mineral Petrol 152:743–754,
2006
.
https://doi.org/10.1007/s00410-006-0132-1
; Thomas et al. in Contrib Mineral Petrol 160:743–759,
2010
.
https://doi.org/10.1007/s00410-010-0505-3
). Titanium K-edge X-ray absorption near edge structure (XANES) measurements demonstrate that Ti
4+
substitutes for Si
4+
on fourfold tetrahedral sites in coesite at all conditions studied. A model was calibrated to describe the effects of pressure and temperature on the solubility of titanium in coesite by using a least-squares method to fit Ti concentrations in coesite to the simple expression:
R
T
ln
X
TiO
2
coesite
=
-
55.068
+
0.00195
×
T
(
K
)
-
1.234
×
P
(
kbar
)
+
R
T
ln
a
TiO
2
rutile
,
where
R
is the gas constant 8.3145 × 10
−3
kJ/K,
P
is pressure in kbar,
T
is temperature in kelvin,
X
TiO
2
coesite
is the mole fraction of TiO
2
in coesite, and
a
TiO
2
rutile
is the activity of TiO
2
in the system referenced to rutile. Ti-in-coesite solubility can be used as a thermobarometer for natural samples when used in combination with another indicator of temperature or pressure, such as another thermobarometer in a cogenetic mineral (e.g. rutile) or other phase equilibria (e.g. graphite = diamond). Applications of the Ti-in-coesite thermobarometer to samples from the western Alps and Papua New Guinea are presented.
IntroductionAntimicrobial resistance undermines our ability to treat bacterial infections, leading to longer hospital stays, increased morbidity and mortality, and a mounting burden to the healthcare ...system. Antimicrobial stewardship is increasingly important to safeguard the efficacy of existing drugs, as few new drugs are in the developmental pipeline. While significant progress has been made with respect to stewardship in hospitals, relatively little progress has been made in the primary care setting, where the majority of antimicrobials are prescribed. OPEN Stewardship is an international collaboration to develop an automated feedback platform to improve responsible antimicrobial prescribing among primary care physicians and capable of being deployed across heterogeneous healthcare settings. We describe the protocol for an evaluation of this automated feedback intervention with two main objectives: assessing changes in antimicrobial prescribing among participating physicians and determining the usability and usefulness of the reports.Methods and analysisA non-randomised evaluation of the automated feedback intervention (OPEN Stewardship) will be conducted among approximately 150 primary care physicians recruited from Ontario, Canada and Southern Israel, based on a series of targeted stewardship messages sent using the platform. Using a controlled interrupted time-series analysis and multilevel negative binomial modelling, we will compare the antimicrobial prescribing rates of participants before and after the intervention, and also to the prescribing rates of non-participants (from the same healthcare network) during the same period. We will examine outcomes targeted by the stewardship messages, including prescribing for antimicrobials with duration longer than 7 days and prescribing for indications where antimicrobials are typically unnecessary. Participants will also complete a series of surveys to determine the usability and usefulness of the stewardship reports.Ethics and disseminationAll sites have obtained ethics committee approval to recruit providers and access anonymised prescribing data. Dissemination will occur through open-access publication, stakeholder networks and national/international meetings.
Malaria is a devastating disease that causes significant morbidity worldwide. The development of new antimalarial chemotypes is urgently needed because of the emergence of resistance to frontline ...therapies. Independent phenotypic screening campaigns against the Plasmodium asexual parasite, including our own, identified the aryl amino acetamide hit scaffold. In a prior study, we identified the STAR-related lipid transfer protein (PfSTART1) as the molecular target of this antimalarial chemotype. In this study, we combined structural elements from the different aryl acetamide hit subtypes and explored the structure-activity relationship. It was shown that the inclusion of an endocyclic nitrogen, to generate the tool compound WJM-715, improved aqueous solubility and modestly improved metabolic stability in rat hepatocytes. Metabolic stability in human liver microsomes remains a challenge for future development of the aryl acetamide class, which was underscored by modest systemic exposure and a short half-life in mice. The optimized aryl acetamide analogs were cross resistant to parasites with mutations in PfSTART1, but not to other drug-resistant mutations, and showed potent binding to recombinant PfSTART1 by biophysical analysis, further supporting PfSTART1 as the likely molecular target. The optimized aryl acetamide analogue, WJM-715 will be a useful tool for further investigating the druggability of PfSTART1 across the lifecycle of the malaria parasite.
Display omitted
•A screen against P. falciparum identified the aryl amino acetamide hit chemotype.•Optimization led to WJM-715 with potent asexual and sexual parasite activity.•Resistance and biophysical studies confirmed PfSTART1 as the target of WJM-715.•WJM-715 will be useful for investigating the role of PfSTART1 in P. falciparum.
To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of ...neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.
Spectrum of care: more than treatment options Brown, Carolyn R; Garrett, Laura D; Gilles, William K ...
Journal of the American Veterinary Medical Association,
10/2021, Letnik:
259, Številka:
7
Journal Article
For many avian species, spatial migration patterns remain largely undescribed, especially across hemispheric extents. Recent advancements in tracking technologies and high‐resolution species ...distribution models (i.e., eBird Status and Trends products) provide new insights into migratory bird movements and offer a promising opportunity for integrating independent data sources to describe avian migration. Here, we present a three‐stage modeling framework for estimating spatial patterns of avian migration. First, we integrate tracking and band re‐encounter data to quantify migratory connectivity, defined as the relative proportions of individuals migrating between breeding and nonbreeding regions. Next, we use estimated connectivity proportions along with eBird occurrence probabilities to produce probabilistic least‐cost path (LCP) indices. In a final step, we use generalized additive mixed models (GAMMs) both to evaluate the ability of LCP indices to accurately predict (i.e., as a covariate) observed locations derived from tracking and band re‐encounter data sets versus pseudo‐absence locations during migratory periods and to create a fully integrated (i.e., eBird occurrence, LCP, and tracking/band re‐encounter data) spatial prediction index for mapping species‐specific seasonal migrations. To illustrate this approach, we apply this framework to describe seasonal migrations of 12 bird species across the Western Hemisphere during pre‐ and postbreeding migratory periods (i.e., spring and fall, respectively). We found that including LCP indices with eBird occurrence in GAMMs generally improved the ability to accurately predict observed migratory locations compared to models with eBird occurrence alone. Using three performance metrics, the eBird + LCP model demonstrated equivalent or superior fit relative to the eBird‐only model for 22 of 24 species–season GAMMs. In particular, the integrated index filled in spatial gaps for species with over‐water movements and those that migrated over land where there were few eBird sightings and, thus, low predictive ability of eBird occurrence probabilities (e.g., Amazonian rainforest in South America). This methodology of combining individual‐based seasonal movement data with temporally dynamic species distribution models provides a comprehensive approach to integrating multiple data types to describe broad‐scale spatial patterns of animal movement. Further development and customization of this approach will continue to advance knowledge about the full annual cycle and conservation of migratory birds.
PDF
