In 2012, NASA's Curiosity rover landed on Mars to assess its potential as a habitat for past life and investigate the paleoclimate record preserved by sedimentary rocks inside the ...~150-kilometer-diameter Gale impact crater. Geological reconstructions from Curiosity rover data have revealed an ancient, habitable lake environment fed by rivers draining into the crater. We synthesize geochemical and mineralogical data from lake-bed mudstones collected during the first 1300 martian solar days of rover operations in Gale. We present evidence for lake redox stratification, established by depth-dependent variations in atmospheric oxidant and dissolved-solute concentrations. Paleoclimate proxy data indicate that a transition from colder to warmer climate conditions is preserved in the stratigraphy. Finally, a late phase of geochemical modification by saline fluids is recognized.
Clinical prediction models are often not evaluated properly in specific settings or updated, for instance, with information from new markers. These key steps are needed such that models are fit for ...purpose and remain relevant in the long-term. We aimed to present an overview of methodological guidance for the evaluation (i.e., validation and impact assessment) and updating of clinical prediction models.
We systematically searched nine databases from January 2000 to January 2022 for articles in English with methodological recommendations for the post-derivation stages of interest. Qualitative analysis was used to summarize the 70 selected guidance papers.
Key aspects for validation are the assessment of statistical performance using measures for discrimination (e.g., C-statistic) and calibration (e.g., calibration-in-the-large and calibration slope). For assessing impact or usefulness in clinical decision-making, recent papers advise using decision-analytic measures (e.g., the Net Benefit) over simplistic classification measures that ignore clinical consequences (e.g., accuracy, overall Net Reclassification Index). Commonly recommended methods for model updating are recalibration (i.e., adjustment of intercept or baseline hazard and/or slope), revision (i.e., re-estimation of individual predictor effects), and extension (i.e., addition of new markers). Additional methodological guidance is needed for newer types of updating (e.g., meta-model and dynamic updating) and machine learning-based models.
Substantial guidance was found for model evaluation and more conventional updating of regression-based models. An important development in model evaluation is the introduction of a decision-analytic framework for assessing clinical usefulness. Consensus is emerging on methods for model updating.
Background
Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between ...patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers.
Method
The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG‐subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE‐FAB and IgE‐BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?).
Results
All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed.
Conclusions
It is recommended to explore the use of allergen‐specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE‐FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.
Key points
We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, ...modestly improves glucose tolerance and slows fat mass gain.
In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice.
Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high‐fat, high‐sugar diet.
A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure.
We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets.
Obesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched‐chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin‐resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet‐induced obese mice with pre‐existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet‐induced obesity and improves glucoregulatory control in diet‐induced obese mice. Most dramatically, mice eating an otherwise unhealthy high‐calorie, high‐sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance.
Key points
We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain.
In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice.
Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high‐fat, high‐sugar diet.
A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure.
We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets.
The impact of COVID-19 on social life has been drastic and global. However, the different numbers of cases and different actions in different countries have been leading to various interesting yet ...unexplored effects on human behavior. In the present study, we compare the physical activity and recreational screen time of a representative sample of 1711 4- to 17-year-olds before and during the strictest time of the first COVID-19 lockdown in Germany. We found that sports activity declined whereas recreational screen time increased. However, a substantial increase in habitual physical activities leads to an overall increase in physical activity among children and adolescents in Germany. The effects differ in size but not in their direction between age groups and are stable for boys and girls. We conclude from this natural experiment that physical activity among children and adolescents is highly context-driven and mutual and does not act as a functional opposite to recreational screen time.
There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in CSF are being used in clinical practice. One of ...the most critical factors in CSF biomarker research is the inadequate powering of studies because of the lack of sufficient samples that can be obtained in single-center studies. Therefore, collaboration between investigators is needed to establish large biobanks of well-defined samples. Standardized protocols for biobanking are a prerequisite to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by preanalytical factors. Here, a consensus report on recommendations for CSF collection and biobanking is presented, formed by the BioMS-eu network for CSF biomarker research in multiple sclerosis. We focus on CSF collection procedures, preanalytical factors, and high-quality clinical and paraclinical information. The biobanking protocols are applicable for CSF biobanks for research targeting any neurologic disease.
Key observational indicators of climate change in the Arctic, most spanning a 47 year period (1971-2017) demonstrate fundamental changes among nine key elements of the Arctic system. We find that, ...coherent with increasing air temperature, there is an intensification of the hydrological cycle, evident from increases in humidity, precipitation, river discharge, glacier equilibrium line altitude and land ice wastage. Downward trends continue in sea ice thickness (and extent) and spring snow cover extent and duration, while near-surface permafrost continues to warm. Several of the climate indicators exhibit a significant statistical correlation with air temperature or precipitation, reinforcing the notion that increasing air temperatures and precipitation are drivers of major changes in various components of the Arctic system. To progress beyond a presentation of the Arctic physical climate changes, we find a correspondence between air temperature and biophysical indicators such as tundra biomass and identify numerous biophysical disruptions with cascading effects throughout the trophic levels. These include: increased delivery of organic matter and nutrients to Arctic near-coastal zones; condensed flowering and pollination plant species periods; timing mismatch between plant flowering and pollinators; increased plant vulnerability to insect disturbance; increased shrub biomass; increased ignition of wildfires; increased growing season CO2 uptake, with counterbalancing increases in shoulder season and winter CO2 emissions; increased carbon cycling, regulated by local hydrology and permafrost thaw; conversion between terrestrial and aquatic ecosystems; and shifting animal distribution and demographics. The Arctic biophysical system is now clearly trending away from its 20th Century state and into an unprecedented state, with implications not only within but beyond the Arctic. The indicator time series of this study are freely downloadable at AMAP.no.
Arthropod predators and parasitoids provide valuable ecosystem services in agricultural crops by suppressing populations of insect herbivores. Many natural enemies are influenced by non-crop habitat ...surrounding agricultural fields, and understanding if, and at what scales, land use patterns influence natural enemies is essential to predicting how landscape alters biological control services. Here we focus on biological control of soybean aphid, Aphis glycines Matumura, a specialist crop pest recently introduced to the north-central United States. We measured the amount of biological control service supplied to soybean in 26 replicate fields across Michigan, Wisconsin, Iowa, and Minnesota across two years (2005—2006). We measured the impact of natural enemies by experimentally excluding or allowing access to soybean aphid infested plants and comparing aphid population growth over 14 days. We also monitored aphid and natural enemy populations at large in each field. Predators, principally coccinellid beetles, dominated the natural enemy community of soybean in both years. In the absence of aphid predators, A. glycines increased significantly, with 5.3-fold higher aphid populations on plants in exclusion cages vs. the open field after 14 days. We calculated a biological control services index (BSI) based on relative suppression of aphid populations and related it to landscape diversity and composition at multiple spatial scales surrounding each site. We found that BSI values increased with landscape diversity, measured as Simpson's D. Landscapes dominated by corn and soybean fields provided less biocontrol service to soybean compared with landscapes with an abundance of crop and non-crop habitats. The abundance of Coccinellidae was related to landscape composition, with beetles being more abundant in landscapes with an abundance of forest and grassland compared with landscapes dominated by agricultural crops. Landscape diversity and composition at a scale of 1.5 km surrounding the focal field explained the greatest proportion of the variation in BSI and Coccinellidae abundance. This study indicates that natural enemies provide a regionally important ecosystem service by suppressing a key soybean pest, reducing the need for insecticide applications. Furthermore, it suggests that management to maintain or enhance landscape diversity has the potential to stabilize or increase biocontrol services.
To determine the association between daily levels of registered nurse (RN) and nursing assistant staffing and hospital mortality.
This is a retrospective longitudinal observational study using ...routinely collected data. We used multilevel/hierarchical mixed-effects regression models to explore the association between patient outcomes and daily variation in RN and nursing assistant staffing, measured as hours per patient per day relative to ward mean. Analyses were controlled for ward and patient risk.
138 133 adult patients spending >1 days on general wards between 1 April 2012 and 31 March 2015.
In-hospital deaths.
Hospital mortality was 4.1%. The hazard of death was increased by 3% for every day a patient experienced RN staffing below ward mean (adjusted HR (aHR) 1.03, 95% CI 1.01 to 1.05). Relative to ward mean, each additional hour of RN care available over the first 5 days of a patient's stay was associated with 3% reduction in the hazard of death (aHR 0.97, 95% CI 0.94 to 1.0). Days where admissions per RN exceeded 125% of the ward mean were associated with an increased hazard of death (aHR 1.05, 95% CI 1.01 1.09). Although low nursing assistant staffing was associated with increases in mortality, high nursing assistant staffing was also associated with increased mortality.
Lower RN staffing and higher levels of admissions per RN are associated with increased risk of death during an admission to hospital. These findings highlight the possible consequences of reduced nurse staffing and do not give support to policies that encourage the use of nursing assistants to compensate for shortages of RNs.
Galactic cosmic rays consist of protons, electrons and ions, most of which are believed to be accelerated to relativistic speeds in supernova remnants. All components of the cosmic rays show an ...intensity that decreases as a power law with increasing energy (for example as E-2.7). Electrons in particular lose energy rapidly through synchrotron and inverse Compton processes, resulting in a relatively short lifetime (about 105 years) and a rapidly falling intensity, which raises the possibility of seeing the contribution from individual nearby sources (less than one kiloparsec away). Here we report an excess of galactic cosmic-ray electrons at energies of ∼300-800 GeV, which indicates a nearby source of energetic electrons. Such a source could be an unseen astrophysical object (such as a pulsar or micro-quasar) that accelerates electrons to those energies, or the electrons could arise from the annihilation of dark matter particles (such as a Kaluza-Klein particle with a mass of about 620 GeV).
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