Safety and Glycemic Outcomes During the MiniMedTM Advanced Hybrid Closed-Loop System Pivotal Trial in Children and Adolescents with Type 1 Diabetes.

Background: During MiniMed™ advanced hybrid closed-loop (AHCL) use by adolescents and adults in the pivotal trial, glycated hemoglobin (A1C) was significantly reduced, time spent in range (TIR) was significantly increased, and there were no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). The present study investigated the same primary safety and effectiveness endpoints during AHCL use by a younger cohort with type 1 diabetes (T1D). Methods: An intention-to-treat population (N = 160, aged 7-17 years) with T1D was enrolled in a single-arm study at 13 investigational centers. There was a run-in period (∼25 days) using HCL or sensor-augmented pump with/without predictive low-glucose management, followed by a 3-month study period with AHCL activated at two glucose targets (GTs; 100 and 120 mg/dL) for ∼45 days each. The mean ± standard deviation values of A1C, TIR, mean sensor glucose (SG), coefficient of variation (CV) of SG, time at SG ranges, and insulin delivered between run-in and study were analyzed (Wilcoxon signed-rank test or t-test). Results: Compared with baseline, AHCL use was associated with reduced A1C from 7.9 ± 0.9% (N = 160) to 7.4 ± 0.7% (N = 136) (P < 0.001) and overall TIR increased from the run-in 59.4 ± 11.8% to 70.3 ± 6.5% by end of study (P < 0.001), without change in CV, time spent below range (TBR) <70 mg/dL, or TBR <54 mg/dL. Relative to longer active insulin time (AIT) settings (N = 52), an AIT of 2 h (N = 19) with the 100 mg/dL GT increased mean TIR to 73.4%, reduced TBR <70 mg/dL from 3.5% to 2.2%, and reduced time spent above range (TAR) >180 mg/dL from 28.7% to 24.4%. During AHCL use, there was no severe hypoglycemia or DKA. Conclusions: In children and adolescents with T1D, MiniMed AHCL system use was safe, A1C was lower, and TIR was increased. The lowest GT and shortest AIT were associated with the highest TIR and lowest TBR and TAR, all of which met consensus-recommended glycemic targets. ClinicalTrials.gov ID: NCT03959423.

BioXmark® liquid fiducials to enable radiotherapy tumor boosting in rectal cancer, a feasibility trial.

Background and purpose: Dose-escalation in rectal cancer (RCa) may result in an increased complete response rate and thereby enable omission of surgery and organ preservation. In order to implement dose-escalation, it is crucial to develop a technique that allows for accurate image-guided radiotherapy. The aim of the current study was to determine the performance of a novel liquid fiducial marker (BioXmark®) in RCa patients during the radiotherapy course by assessing its positional stability on daily cone-beam CT (CBCT), technical feasibility, visibility on different imaging modalities and safety. Materials and methods: Prospective, non-randomized, single-arm feasibility trial with inclusion of twenty patients referred for neoadjuvant chemoradiotherapy for locally advanced RCa. Primary study endpoint was positional stability on CBCT. Furthermore, technical aspects, safety and clinical performance of the marker, such as visibility on different imaging modalities, were evaluated. Results: Seventy-four markers from twenty patients were available for analysis. The marker was stable in 96% of the cases. One marker showed clinically relevant migration, one marker was lost before start of treatment and one marker was lost during treatment. Marker visibility was good on computed tomography (CT) and CBCT, and moderate on electronic portal imaging (EPI). Marker visibility on magnetic resonance imaging (MRI) was poor during response evaluation. Conclusion: The novel liquid fiducial marker demonstrated positional stability. We provide evidence of the feasibility of the novel fiducial marker for image-guided radiotherapy on daily cone beam CT for RCa patients.

Safety and Glycemic Outcomes During the MiniMed™ Advanced Hybrid Closed-Loop System Pivotal Trial in Adolescents and Adults with Type 1 Diabetes.

Introduction: This trial assessed safety and effectiveness of an advanced hybrid closed-loop (AHCL) system with automated basal (Auto Basal) and automated bolus correction (Auto Correction) in adolescents and adults with type 1 diabetes (T1D). Materials and Methods: This multicenter single-arm study involved an intent-to-treat population of 157 individuals (39 adolescents aged 14-21 years and 118 adults aged ≥22-75 years) with T1D. Study participants used the MiniMed™ AHCL system during a baseline run-in period in which sensor-augmented pump +/- predictive low glucose management or Auto Basal was enabled for ∼14 days. Thereafter, Auto Basal and Auto Correction were enabled for a study phase (∼90 days), with glucose target set to 100 or 120 mg/dL for ∼45 days, followed by the other target for ∼45 days. Study endpoints included safety events and change in mean A1C, time in range (TIR, 70-180 mg/dL) and time below range (TBR, <70 mg/dL). Run-in and study phase values were compared using Wilcoxon signed-rank test or paired t-test. Results: Overall group time spent in closed loop averaged 94.9% ± 5.4% and involved only 1.2 ± 0.8 exits per week. Compared with run-in, AHCL reduced A1C from 7.5% ± 0.8% to 7.0% ± 0.5% (<0.001, Wilcoxon signed-rank test, n = 155), TIR increased from 68.8% ± 10.5% to 74.5% ± 6.9% (<0.001, Wilcoxon signed-rank test), and TBR reduced from 3.3% ± 2.9% to 2.3% ± 1.7% (<0.001, Wilcoxon signed-rank test). Similar benefits to glycemia were observed for each age group and were more pronounced for the nighttime (12 AM-6 AM). The 100 mg/dL target increased TIR to 75.4% (n = 155), which was further optimized at a lower active insulin time (AIT) setting (i.e., 2 h), without increasing TBR. There were no severe hypoglycemic or diabetic ketoacidosis events during the study phase. Conclusions: These findings show that the MiniMed AHCL system is safe and allows for achievement of recommended glycemic targets in adolescents and adults with T1D. Adjustments in target and AIT settings may further optimize glycemia and improve user experience. Clinical Trial Registration number: NCT03959423.

COSMOS next generation - A public knowledge base leveraging chemical and biological data to support the regulatory assessment of chemicals.

The COSMOS Database (DB) was originally established to provide reliable data for cosmetics-related chemicals within the COSMOS Project funded as part of the SEURAT-1 Research Initiative. The database has subsequently been maintained and developed further into COSMOS Next Generation (NG), a combination of database and in silico tools, essential components of a knowledge base. COSMOS DB provided a cosmetics inventory as well as other regulatory inventories, accompanied by assessment results and in vitro and in vivo toxicity data. In addition to data content curation, much effort was dedicated to data governance - data authorisation, characterisation of quality, documentation of meta information, and control of data use. Through this effort, COSMOS DB was able to merge and fuse data of various types from different sources. Building on the previous effort, the COSMOS Minimum Inclusion (MINIS) criteria for a toxicity database were further expanded to quantify the reliability of studies. COSMOS NG features multiple fingerprints for analysing structure similarity, and new tools to calculate molecular properties and screen chemicals with endpoint-related public profilers, such as DNA and protein binders, liver alerts and genotoxic alerts. The publicly available COSMOS NG enables users to compile information and execute analyses such as category formation and read-across. This paper provides a step-by-step guided workflow for a simple read-across case, starting from a target structure and culminating in an estimation of a NOAEL confidence interval. Given its strong technical foundation, inclusion of quality-reviewed data, and provision of tools designed to facilitate communication between users, COSMOS NG is a first step towards building a toxicological knowledge hub leveraging many public data systems for chemical safety evaluation. We continue to monitor the feedback from the user community at support@mn-am.com.

Screening and characterization of a diverse panel of metagenomic imine reductases for biocatalytic reductive amination.

Finding faster and simpler ways to screen protein sequence space to enable the identification of new biocatalysts for asymmetric synthesis remains both a challenge and a rate-limiting step in enzyme discovery. Biocatalytic strategies for the synthesis of chiral amines are increasingly attractive and include enzymatic asymmetric reductive amination, which offers an efficient route to many of these high-value compounds. Here we report the discovery of over 300 new imine reductases and the production of a large (384 enzymes) and sequence-diverse panel of imine reductases available for screening. We also report the development of a facile high-throughput screen to interrogate their activity. Through this approach we identified imine reductase biocatalysts capable of accepting structurally demanding ketones and amines, which include the preparative synthesis of N-substituted ß-amino ester derivatives via a dynamic kinetic resolution process, with excellent yields and stereochemical purities.

Identification of treatment error types for lung cancer patients using convolutional neural networks and EPID dosimetry.

BACKGROUND/PURPOSE: Electronic portal imaging device (EPID) dosimetry aims to detect treatment errors, potentially leading to treatment adaptation. Clinically used threshold classification methods for detecting errors lead to loss of information (from multi-dimensional EPID data to a few numbers) and cannot be used for identifying causes of errors. Advanced classification methods, such as deep learning, can use all available information. In this study, convolutional neural networks (CNNs) were trained to detect and identify error type and magnitude of simulated treatment errors in lung cancer patients. The purpose of this simulation study is to provide a proof-of-concept of CNNs for error identification using EPID dosimetry in an in vivo scenario. MATERIALS AND METHODS: Clinically realistic ranges of anatomical changes, positioning errors and mechanical errors were simulated for lung cancer patients. Predicted portal dose images (PDIs) containing errors were compared to error-free PDIs using the widely used gamma analysis. CNNs were trained to classify errors using 2D gamma maps. Three classification levels were assessed: Level 1 (main error type, e.g., anatomical change), Level 2 (error subtype, e.g., tumor regression) and Level 3 (error magnitude, e.g., >50% tumor regression). RESULTS: CNNs showed good performance for all classification levels (training/test accuracy 99.5%/96.1%, 92.5%/86.8%, 82.0%/72.9%). For Level 3, overfitting became more apparent. CONCLUSION: This simulation study indicates that deep learning is a promising powerful tool for identifying types and magnitude of treatment errors with EPID dosimetry, providing additional information not currently available from EPID dosimetry. This is a first step towards rapid, automated models for identification of treatment errors using EPID dosimetry.

External validation of a hidden Markov model for gamma-based classification of anatomical changes in lung cancer patients using EPID dosimetry.

PURPOSE: To externally validate a hidden Markov model (HMM) for classifying gamma analysis results of in vivo electronic portal imaging device (EPID) measurements into different categories of anatomical change for lung cancer patients. Additionally, the relationship between HMM classification and deviations in dose-volume histogram (DVH) metrics was evaluated. METHODS: The HMM was developed at CHU de Québec (CHUQ), and trained on features extracted from gamma analysis maps of in vivo EPID measurements from 483 fractions (24 patients, treated with three-dimensional 3D-CRT or intensity modulated radiotherapy), using the EPID measurement of the first treatment fraction as reference. The model inputs were the average gamma value, standard deviation, and average value of the highest 1% of gamma values, all averaged over all beams in a fraction. The HMM classified each fraction into one of three categories: no anatomical change (Category 1), some anatomical change (no clinical action needed, Category 2) and severe anatomical change (clinical action needed, Category 3). The external validation dataset consisted of EPID measurements from 263 fractions of 30 patients treated at Maastro with volumetric modulated arc therapy (VMAT) or hybrid plans (containing both static beams and VMAT arcs). Gamma analysis features were extracted in the same way as in the CHUQ dataset, by using the EPID measurement of the first fraction as reference (γQ), and additionally by using an EPID dose prediction as reference (γM). For Maastro patients, cone beam computed tomography (CBCT) scans and image-guided radiotherapy (IGRT) classification of these images were available for each fraction. Contours were propagated from the planning CT to the CBCTs, and the dose was recalculated using a Monte Carlo dose engine. Dose-volume histogram metrics for targets and organs-at-risk (OARs: lungs, heart, mediastinum, spinal cord, brachial plexus) were extracted for each fraction, and compared to the planned dose. HMM classification of the external validation set was compared to threshold classification based on the average gamma value alone (a surrogate for clinical classification at CHUQ), IGRT classification as performed at Maastro, and differences in DVH metrics extracted from 3D dose recalculations on the CBCTs. RESULTS: The HMM achieved 65.4%/65.0% accuracy for γQ and γM, respectively, compared to average gamma threshold classification. When comparing HMM classification with IGRT classification, the overall accuracy was 29.7% for γQ and 23.2% for γM. Hence, HMM classification and IGRT classification of anatomical changes did not correspond. However, there is a trend towards higher deviations in DVH metrics with classification into higher categories by the HMM for large OARs (lungs, heart, mediastinum), but not for the targets and small OARs (spinal cord, brachial plexus). CONCLUSION: The external validation shows that transferring the HMM for anatomical change classification to a different center is challenging, but can still be valuable. The HMM trained at CHUQ cannot be used directly to classify anatomical changes in the Maastro data. However, it may be possible to use the model in a different capacity, as an indicator for changes in the 3D dose based on two-dimensional EPID measurements.

Tall fescue as an alternative to timothy fed with or without alfalfa to dairy cows.

Tall fescue might be an alternative to timothy in northeastern North America because of its tolerance of recurring drought periods and its good summer regrowth, but is not always considered as an option in dairy rations because of its possible lack of palatability. The objective of this study was to evaluate the effects on the performance of lactating dairy cows of (1) replacing timothy silage by tall fescue silage, offered as sole forage in the diet or in combination with alfalfa silage, and (2) feeding tall fescue as silage (35% dry matter, DM) or haylage (55% DM). Experimental diets with a forage-to-concentrate ratio of 70:30 were (1) 100% timothy silage (TS); (2) 100% tall fescue silage (TFS); (3) 55:45 timothy:alfalfa silages (TS + AS); (4) 55:45 tall fescue:alfalfa silages (TFS + AS); and (5) 100% tall fescue haylage (TFH). Fifteen Holstein cows in mid-lactation (5 fitted with a rumen fistula) were randomly assigned to treatments in a triple 5 × 5 Latin square design with treatment periods of 21 d. Preplanned contrasts were timothy versus tall fescue silages, sole grass species versus grass-alfalfa, interaction between sole grass species and grass-alfalfa, and TFS versus TFH. Grass species did not affect dry matter intake (DMI) or milk yield and fat concentration. Milk protein concentration was not affected by grass species when offered in combination with alfalfa, but it was higher with the TS diet than the TFS diet when offered as sole forages. Adding alfalfa to either tall fescue or timothy silage resulted in greater DMI and milk yield, but lower milk fat concentration, than when the grass silages were the sole forage in the diet. The molar proportion of propionate in the rumen was greater when cows were fed diets with tall fescue silage compared with timothy silage, which resulted in a lower acetate-to-propionate ratio. Milk fat concentrations of fatty acids from microbial origin, namely branched-chain fatty acids, were greater when grass silage, and especially timothy silage, were fed as sole forages rather than with alfalfa silage. Feeding TFH rather than TFS caused a decrease in DMI and tended to lower milk protein concentration, but did not affect milk yield. A more fibrolytic fermentation profile was observed in rumen of cows fed TFH compared with TFS, as indicated by the increase in the molar proportion of acetate and the higher acetate-to-propionate ratio in rumen fluid, and a concomitant increase in branched-chain fatty acid concentration in milk fat. Tall fescue as silage or haylage is a valuable alternative to timothy silage for lactating dairy cows.

Radiotherapy quality assurance for mesorectum treatment planning within the multi-center phase II STAR-TReC trial: Dutch results.

BACKGROUND: The STAR-TReC trial is an international multi-center, randomized, phase II study assessing the feasibility of short-course radiotherapy or long-course chemoradiotherapy as an alternative to total mesorectal excision surgery. A new target volume is used for both (chemo)radiotherapy arms which includes only the mesorectum. The treatment planning QA revealed substantial variation in dose to organs at risk (OAR) between centers. Therefore, the aim of this study was to determine the treatment plan variability in terms of dose to OAR and assess the effect of a national study group meeting on the quality and variability of treatment plans for mesorectum-only planning for rectal cancer. METHODS: Eight centers produced 25 × 2 Gy treatment plans for five cases. The OAR were the bowel cavity, bladder and femoral heads. A study group meeting for the participating centers was organized to discuss the planning results. At the meeting, the values of the treatment plan DVH parameters were distributed among centers so that results could be compared. Subsequently, the centers were invited to perform replanning if they considered this to be necessary. RESULTS: All treatment plans, both initial planning and replanning, fulfilled the target constraints. Dose to OAR varied considerably for the initial planning, especially for dose levels below 20 Gy, indicating that there was room for trade-offs between the defined OAR. Five centers performed replanning for all cases. One center did not perform replanning at all and two centers performed replanning on two and three cases, respectively. On average, replanning reduced the bowel cavity V20Gy by 12.6%, bowel cavity V10Gy by 22.0%, bladder V35Gy by 14.7% and bladder V10Gy by 10.8%. In 26/30 replanned cases the V10Gy of both the bowel cavity and bladder was lower, indicating an overall lower dose to these OAR instead of a different trade-off. In addition, the bowel cavity V10Gy and V20Gy showed more similarity between centers. CONCLUSIONS: Dose to OAR varied considerably between centers, especially for dose levels below 20 Gy. The study group meeting and the distribution of the initial planning results among centers resulted in lower dose to the defined OAR and reduced variability between centers after replanning. TRIAL REGISTRATION: The STAR-TReC trial, ClinicalTrials.gov Identifier: NCT02945566. Registered 26 October 2016, https://clinicaltrials.gov/ct2/show/NCT02945566).

In vivo dosimetry in gynecological applications-A feasibility study.

PURPOSE: To investigate the feasibility of in vivo dosimetry using microMOSFET dosimeters in patients treated with brachytherapy using two types of gynecological applicators. METHODS AND MATERIALS: In this study, a microMOSFET was placed in an empty needle of an Utrecht Interstitial Fletcher applicator or MUPIT (Martinez Universal Perineal Interstitial Template) applicator for independent verification of treatment delivery. Measurements were performed in 10 patients, with one to three microMOSFETs per applicator and repeated for one to four fractions, resulting in 50 in vivo measurements. Phantom measurements were used to determine characteristics of the microMOSFETs. RESULTS: Phantom measurements showed a linear relationship between dose and microMOSFET threshold voltage, and a calibration coefficient (mV/cGy) was determined. Reproducibility of repeated 50 cGy irradiations was 2% (1 standard deviation). Distance and angle dependencies were measured and correction factors were determined. Subsequently, three microMOSFETs were placed in a phantom to measure a validation plan. The difference between predicted and measured dose was less than the measurement uncertainty (±9%, 2 standard deviations). In vivo measurements were corrected for distance and angle dependencies. Differences between predicted and measured dose in the patients were smaller than the measurement uncertainty for the majority of the measurements. CONCLUSIONS: In vivo dosimetry using microMOSFETs in MUPIT and Utrecht Interstitial Fletcher applicators has proved to be feasible. Reimaging should be performed after detection of differences larger than 10% between predicted and measured dose to verify the applicator configuration. Movement of the applicator relative to the target or organs at risk is undetectable with this method.

An automated curation procedure for addressing chemical errors and inconsistencies in public datasets used in QSAR modelling.

The increasing availability of large collections of chemical structures and associated experimental data provides an opportunity to build robust QSAR models for applications in different fields. One common concern is the quality of both the chemical structure information and associated experimental data. Here we describe the development of an automated KNIME workflow to curate and correct errors in the structure and identity of chemicals using the publicly available PHYSPROP physicochemical properties and environmental fate datasets. The workflow first assembles structure-identity pairs using up to four provided chemical identifiers, including chemical name, CASRNs, SMILES, and MolBlock. Problems detected included errors and mismatches in chemical structure formats, identifiers and various structure validation issues, including hypervalency and stereochemistry descriptions. Subsequently, a machine learning procedure was applied to evaluate the impact of this curation process. The performance of QSAR models built on only the highest-quality subset of the original dataset was compared with the larger curated and corrected dataset. The latter showed statistically improved predictive performance. The final workflow was used to curate the full list of PHYSPROP datasets, and is being made publicly available for further usage and integration by the scientific community.

Effects of acute exercise on lipid content and dietary lipid uptake in liver and skeletal muscle of lean and diabetic rats.

Insulin resistance is associated with ectopic lipid accumulation. Physical activity improves insulin sensitivity, but the impact of exercise on lipid handling in insulin-resistant tissues remains to be elucidated. The present study characterizes the effects of acute exercise on lipid content and dietary lipid partitioning in liver and skeletal muscle of lean and diabetic rats by use of magnetic resonance spectroscopy (MRS). After baseline measurements, rats were randomized to exercise or no-exercise groups. A subset of animals was subjected to MRS directly after 1 h of treadmill running for measurement of total intrahepatocellular lipid (IHCL) and intramyocellular lipid (IMCL) content (n=7 lean and diabetic rats). The other animals were administered 13C-labeled lipids orally after treadmill visit (with or without exercise) followed by MRS measurements after 4 and 24 h to determine the 13C enrichment of IHCL and IMCL (n=8 per group). Total IHCL and IMCL content were fivefold higher in diabetic vs. lean rats (P<0.001). Exercise did not significantly affect IHCL content but reduced IMCL by 25±7 and 33±4% in lean and diabetic rats (P<0.05), respectively. Uptake of dietary lipids in liver and muscle was 2.3-fold greater in diabetic vs. lean rats (P<0.05). Prior exercise did not significantly modulate dietary lipid uptake into muscle, but in liver of both lean and diabetic rats, lipid uptake was 44% reduced after acute exercise (P<0.05). In conclusion, IMCL but not IHCL represents a viable substrate source during exercise in both lean and diabetic rats, and exercise differentially affects dietary lipid uptake in muscle and liver.

Simulation techniques in hyperthermia treatment planning.

Abstract Clinical trials have shown that hyperthermia (HT), i.e. an increase of tissue temperature to 39-44 °C, significantly enhance radiotherapy and chemotherapy effectiveness [1]. Driven by the developments in computational techniques and computing power, personalised hyperthermia treatment planning (HTP) has matured and has become a powerful tool for optimising treatment quality. Electromagnetic, ultrasound, and thermal simulations using realistic clinical set-ups are now being performed to achieve patient-specific treatment optimisation. In addition, extensive studies aimed to properly implement novel HT tools and techniques, and to assess the quality of HT, are becoming more common. In this paper, we review the simulation tools and techniques developed for clinical hyperthermia, and evaluate their current status on the path from 'model' to 'clinic'. In addition, we illustrate the major techniques employed for validation and optimisation. HTP has become an essential tool for improvement, control, and assessment of HT treatment quality. As such, it plays a pivotal role in the quest to establish HT as an efficacious addition to multi-modality treatment of cancer.

Clinical integration of software tool VEDO for adaptive and quantitative application of phased array hyperthermia in the head and neck.

BACKGROUND AND PURPOSE: In Rotterdam, patient-specific hyperthermia (HT) treatment planning (HTP) is applied for all deep head and neck (H&N) HT treatments. In this paper we introduce VEDO (the Visualisation Tool for Electromagnetic Dosimetry and Optimisation), the software tool required, and demonstrate its value for HTP-guided online complaint-adaptive (CA) steering based on specific absorption rate (SAR) optimisation during a H&N HT treatment. MATERIALS AND METHODS: VEDO integrates CA steering, visualisation of the SAR patterns and mean tumour SAR (SAR(target)) optimisation in a single screen. The pre-calculated electromagnetic fields are loaded into VEDO. During treatment, VEDO shows the SAR pattern, overlaid on the patients' CT-scan, corresponding to the actually applied power settings and it can (re-)optimise the SAR pattern to minimise SAR at regions where the patient senses discomfort while maintaining a high SAR(target). RESULTS: The potential of the quantitative SAR steering approach using VEDO is demonstrated by analysis of the first treatment in which VEDO was used for two patients using the HYPERcollar. These cases show that VEDO allows response to power-related complaints of the patient and to quantify the change in absolute SAR: increasing either SAR(target) from 96 to 178 W/kg (case 1); or show that the first SAR distribution was already optimum (case 2). CONCLUSION: This analysis shows that VEDO facilitates a quantitative treatment strategy allowing standardised application of HT by technicians of different HT centres, which will potentially lead to improved treatment quality and the possibility of tracking the effectiveness of different treatment strategies.

Changing climate and overgrazing are decimating Mongolian steppes.

Satellite observations identify the Mongolian steppes as a hotspot of global biomass reduction, the extent of which is comparable with tropical rainforest deforestation. To conserve or restore these grasslands, the relative contributions of climate and human activities to degradation need to be understood. Here we use a recently developed 21-year (1988-2008) record of satellite based vegetation optical depth (VOD, a proxy for vegetation water content and aboveground biomass), to show that nearly all steppe grasslands in Mongolia experienced significant decreases in VOD. Approximately 60% of the VOD declines can be directly explained by variations in rainfall and surface temperature. After removing these climate induced influences, a significant decreasing trend still persists in the VOD residuals across regions of Mongolia. Correlations in spatial patterns and temporal trends suggest that a marked increase in goat density with associated grazing pressures and wild fires are the most likely non-climatic factors behind grassland degradation.

Afternoon rain more likely over drier soils.

Land surface properties, such as vegetation cover and soil moisture, influence the partitioning of radiative energy between latent and sensible heat fluxes in daytime hours. During dry periods, soil-water deficit can limit evapotranspiration, leading to warmer and drier conditions in the lower atmosphere. Soil moisture can influence the development of convective storms through such modifications of low-level atmospheric temperature and humidity, which in turn feeds back on soil moisture. Yet there is considerable uncertainty in how soil moisture affects convective storms across the world, owing to a lack of observational evidence and uncertainty in large-scale models. Here we present a global-scale observational analysis of the coupling between soil moisture and precipitation. We show that across all six continents studied, afternoon rain falls preferentially over soils that are relatively dry compared to the surrounding area. The signal emerges most clearly in the observations over semi-arid regions, where surface fluxes are sensitive to soil moisture, and convective events are frequent. Mechanistically, our results are consistent with enhanced afternoon moist convection driven by increased sensible heat flux over drier soils, and/or mesoscale variability in soil moisture. We find no evidence in our analysis of a positive feedback--that is, a preference for rain over wetter soils-at the spatial scale (50-100 kilometres) studied. In contrast, we find that a positive feedback of soil moisture on simulated precipitation does dominate in six state-of-the-art global weather and climate models--a difference that may contribute to excessive simulated droughts in large-scale models.

Reduced satellite cell numbers with spinal cord injury and aging in humans.

INTRODUCTION: Both sarcopenia and spinal cord injury (SCI) are characterized by the loss of skeletal muscle mass and function. Despite obvious similarities in atrophy between both models, differences in muscle fiber size and satellite cell content may exist on a muscle fiber type-specific level. METHODS: In the present study, we compared skeletal muscle fiber characteristics between wheelchair-dependent young males with SCI (n = 8, 32 ± 4 yr), healthy elderly males (n = 8, 75 ± 2 yr), and young controls (n = 8, 31 ± 3 yr). Muscle biopsies were collected to determine skeletal muscle fiber type composition, fiber size, and satellite cell content. RESULTS: Severe atrophy and a shift toward approximately 90% Type II muscle fibers were observed in muscle obtained from males with SCI. Muscle fiber size was substantially smaller in both the SCI (Types I and II fibers) and elderly subjects (Type II fibers) when compared with the controls. Satellite cell content was substantially lower in the wheelchair-dependent SCI subjects in both the Types I and II muscle fibers (0.049 ± 0.019 and 0.050 ± 0.005 satellite cells per fiber, respectively) when compared with the young controls (0.104 ± 0.011 and 0.117 ± 0.009 satellite cells per fiber, respectively). In the elderly, the number of satellite cells was lower in the Type II muscle fibers only (0.042 ± 0.005 vs 0.117 ± 0.009 satellite cells per fiber in the elderly vs young controls, respectively). CONCLUSION: This is the first study to show that muscle fiber atrophy as observed with SCI (Types I and II fibers) and aging (Type II fibers) is accompanied by a muscle fiber type-specific reduction in satellite cell content in humans.

Implementation of treatment planning in the routine clinical procedure of regional hyperthermia treatment of cervical cancer: an overview and the Rotterdam experience.

PURPOSE: This manuscript provides an overview in the field of hyperthermia treatment planning (HTP) in cervical cancer. Treatment planning techniques: The workflow of an HTP assisted treatment generally consists of patient imaging, tissue segmentation, model generation, electromagnetic (EM) and thermal calculations, optimisation, and clinical implementation. A main role in HTP is played by numerical simulations, for which currently a number of software packages are available in hyperthermia. To implement these simulations, accurate applicator models and accurate knowledge of dielectric and thermal parameters is mandatory. Model validation is necessary to check if this is implemented well. In the translation from HTP models to the clinic, the main aspect is accurate representation of the actual treatment situation in the HTP models. Accurate patient positioning and organ-specific segmentation can be helpful in minimising the differences between model and clinic. STEERING STRATEGIES: In the clinic, different approaches are possible: simple, i.e. target centre point (TCP) steering, often called 'target steering', or only pretreatment planning versus advanced, i.e. active HTP guided steering or image guided hyperthermia by non-invasive thermometry (NIT). The Rotterdam experience: To illustrate the implementation of HTP guided steering, the Rotterdam approach of complaint adaptive steering is elaborated, in which optimisation is adapted with increased constraints on tissues with heat-induced discomfort. CONCLUSIONS: Many publications on HTP show that HTP can be considered a feasible method to optimise and control a hyperthermia treatment, with the objective to enhance treatment quality and documentation. Ultimately, after overcoming the various uncertainties, this may lead to dose prescription.

Effective US health system websites: establishing benchmarks and standards for effective consumer engagement.

Hospitals and health systems are playing increasingly important roles as care coordination hubs and consumer information sources. In particular, the accountable care organization (ACO) and medical home models promoted in the Affordable Care Act place hospitals at the center of many activities related to health information exchange. Therefore, it is important for these organizations to have effective websites, and the need for a social media presence to connect with consumers is growing quickly. The purpose of this study is to assess the websites of hospitals and health systems on four dimensions: accessibility, content, marketing, and technology. In addition, an overall score is calculated to identify the top 25 hospital and health system websites. Specific website elements that healthcare managers can inspect visually are described for each dimension in the discussion section. Generally, hospital and health system websites can be more effective from an end user's perspective. In particular, hospitals and health systems lagged on the accessibility scale that measures the education level required to understand the language used on a site. The scale also assesses the extent to which web pages are designed for ease of movement from page to page using embedded links. Given that healthcare consumers come from every demographic and stratum of society, it is important that user-friendliness be optimized for a broadly defined audience. Hospital and health system websites can also be improved on the technology scale, as many sites do not return clear descriptions of links to search engines such as Google and Bing that use webcrawlers to collect information.

Multitissue assessment of in vivo postprandial intracellular lipid partitioning in rats using localized 1H-[13C] magnetic resonance spectroscopy.

Excess accumulation of lipids in nonadipose tissues such as skeletal muscle and liver has been implicated in the development of obesity-related disorders, but the cause of this ectopic lipid overload remains unknown. The aim of this study was to determine in vivo postprandial lipid partitioning in rat skeletal muscle and liver, using localized 1H-[13C] magnetic resonance spectroscopy in combination with the oral administration of 13C-labeled lipids. Six rats were measured at baseline and 5 and 24 h after administration of 400 mg [U-13C]-labeled algal lipids. Five hours after administration, fractional 13C enrichments of the lipid pools in muscle and liver were increased 3.9-fold and 4.6-fold (P<0.05), respectively, indicating that part of the ingested lipids had been taken up by muscle and liver tissue. At 24 h, fractional 13C enrichments of muscle and liver lipids were decreased 1.6-fold and 2.2-fold (P<0.05), respectively, compared with the 5 h values. This can be interpreted as a depletion of 13C-labeled lipids from the intracellular lipid pools as a consequence of lipid turnover. In conclusion, the novel application of 1H-[13C] magnetic resonance spectroscopy in combination with the oral administration of 13C-labeled lipids is applicable for the longitudinal assessment of in vivo lipid partitioning between multiple tissues.