Obstetric and long-term kidney outcomes in renal transplant recipients: a 40 year single-centre study

Female renal transplant recipients of childbearing age may ask what the outcomes are for pregnancy and whether pregnancy will affect graft function. We analyzed obstetric and transplant outcomes among renal transplant recipients in our center who have been pregnant between 1973 and 2013. A case−cohort study was performed identifying 83 pairs of pregnant and non-pregnant controls matched for sex, age, transplant vintage, and creatinine. There were 138 pregnancies reported from 89 renal transplant recipients. There were live births in 74% of pregnancies with high prevalence of prematurity (61%), low birth weight (52%), and pre-eclampsia (14%). Lower eGFR (OR 0.98; p = 0.05) and higher uPCR (OR 1.86; p = 0.02) at conception were independent predictors for poor composite obstetric outcome. Lower eGFR (OR 0.98; p = 0.04), higher uPCR (OR 1.50; p = 0.04), and live organ donation (OR 0.35; p = 0.02) were predictors of ≥20% loss of eGFR between immediately pre-pregnancy and one yr after delivery. There was no difference in eGFR at one, five, and 10 yr in pregnant women compared with non-pregnant controls and a pregnancy was not associated with poorer 10-yr transplant or 20-yr patient survival. Despite high rates of obstetric complications, most women had successful pregnancies with good long-term transplant function

'Nordic' Hamstrings Exercise - Engagement Characteristics and Training Responses

The present study examined the neuromuscular activation characteristics of the hamstrings during the 'Nordic' hamstrings exercise (NHE) and changes in the eccentric strength of the knee flexors with NHE training. Initially, the normalised root mean square electromyographic (EMG) activity of the hamstrings of both limbs during various phases (90-61 degrees, 60-31 degrees and 30-0 degrees of knee extension) of the NHE were determined in 18 soccer players. Subsequently participants were randomly allocated to either a training (n = 10) or control group. The isokinetic eccentric peak torques of the dominant and non-dominant limbs were recorded at 60, 120 and 240 degrees/s pre- and post-training. The EMG values of both limbs were comparable (P = 0.184) and greater EMG activity was recorded at more extended knee positions of the NHE (P = 0.001). 4 weeks of NHE training significantly improved peak torque by up to 21% in all assessment conditions. Data indicate the hamstrings of both limbs are engaged identically during the NHE and training results in gains in the eccentric peak torque of the hamstrings of both limbs; these gains may augment the force that the hamstrings can withstand when forcefully stretched, attenuating injury risk

Proton Aurora on Mars: A Dayside Phenomenon Pervasive in Southern Summer

We present observations of proton aurora at Mars made using the Imaging UltraViolet Spectrograph (IUVS) onboard the Mars Atmosphere and Volatile EvolutioN (MAVEN) spacecraft. Martian proton aurora display a prominent intensity enhancement in the hydrogen Lyman‐alpha (121.6 nm) emission between ~110 and 150 km altitude. Using altitude‐intensity profiles from periapsis limb scan data spanning nearly two Martian years, we create a comprehensive database of proton aurora and characterize their phenomenology. Due to Mars\u27 lack of a global dipole magnetic field, Martian proton aurora are expected to form on the dayside via electron stripping and charge exchange between solar wind protons and the neutral corona. We observe proton aurora in ~14% of dayside periapsis profiles (with notable seasonal variability), making proton aurora the most commonly observed type of aurora at Mars. We determine that the primary factors influencing proton aurora occurrence rates are solar zenith angle and season. The highest proton aurora occurrence rates are at low solar zenith angles on the Mars dayside, consistent with known formation processes. Proton aurora have highest emission enhancements, peak intensities, peak altitudes, and occurrence rates (nearing 100%) around southern summer solstice. This time period corresponds with the seasonal inflation of the neutral lower atmosphere, the onset of Martian dust storm season, seasonally increased coronal hydrogen column densities, and higher atmospheric temperature and solar wind flux following perihelion. The results of our study provide a new understanding of the primary factors influencing proton aurora, and the long‐term variability of these phenomena as observed over multiple Mars years

Genome-wide transcript and protein analysis highlights the role of protein homeostasis in the aging mouse heart.

Investigation of the molecular mechanisms of aging in the human heart is challenging because of confounding factors, such as diet and medications, as well as limited access to tissues from healthy aging individuals. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyze transcriptome and proteome data from 185 genetically diverse male and female mice at ages 6, 12, and 18 mo to characterize molecular changes that occur in the aging heart. Transcripts and proteins reveal activation of pathways related to exocytosis and cellular transport with age, whereas processes involved in protein folding decrease with age. Additional changes are apparent only in the protein data including reduced fatty acid oxidation and increased autophagy. For proteins that form complexes, we see a decline in correlation between their component subunits with age, suggesting age-related loss of stoichiometry. The most affected complexes are themselves involved in protein homeostasis, which potentially contributes to a cycle of progressive breakdown in protein quality control with age. Our findings highlight the important role of post-transcriptional regulation in aging. In addition, we identify genetic loci that modulate age-related changes in protein homeostasis, suggesting that genetic variation can alter the molecular aging process

Advancing Our Understanding of Martian Proton Aurora through a Coordinated Multi-Model Comparison Campaign

Proton aurora are the most commonly observed yet least studied type of aurora at Mars. In order to better understand the physics and driving processes of Martian proton aurora, we undertake a multi-model comparison campaign. We compare results from four different proton/hydrogen precipitation models with unique abilities to represent Martian proton aurora: Jolitz model (3-D Monte Carlo), Kallio model (3-D Monte Carlo), Bisikalo/Shematovich et al. model (1-D kinetic Monte Carlo), and Gronoff et al. model (1-D kinetic). This campaign is divided into two steps: an inter-model comparison and a data-model comparison. The inter-model comparison entails modeling five different representative cases using similar constraints in order to better understand the capabilities and limitations of each of the models. Through this step we find that the two primary variables affecting proton aurora are the incident solar wind particle flux and velocity. In the data-model comparison, we assess the robustness of each model based on its ability to reproduce a MAVEN/IUVS proton aurora observation. All models are able to effectively simulate the data. Variations in modeled intensity and peak altitude can be attributed to differences in model capabilities/solving techniques and input assumptions (e.g., cross sections, 3-D versus 1-D solvers, and implementation of the relevant physics and processes). The good match between the observations and multiple models gives a measure of confidence that the appropriate physical processes and their associated parameters have been correctly identified and provides insight into the key physics that should be incorporated in future models

Healthcare systems data in the context of clinical trials - A comparison of cardiovascular data from a clinical trial dataset with routinely collected data

BACKGROUND: Routinely-collected healthcare systems data (HSD) are proposed to improve the efficiency of clinical trials. A comparison was undertaken between cardiovascular (CVS) data from a clinical trial database with two HSD resources. METHODS: Protocol-defined and clinically reviewed CVS events (heart failure (HF), acute coronary syndrome (ACS), thromboembolic stroke, venous and arterial thromboembolism) were identified within the trial data. Data (using pre-specified codes) was obtained from NHS Hospital Episode Statistics (HES) and National Institute for Cardiovascular Outcomes Research (NICOR) HF and myocardial ischaemia audits for trial participants recruited in England between 2010 and 2018 who had provided consent. The primary comparison was trial data versus HES inpatient (APC) main diagnosis (Box-1). Correlations are presented with descriptive statistics and Venn diagrams. Reasons for non-correlation were explored. RESULTS: From 1200 eligible participants, 71 protocol-defined clinically reviewed CVS events were recorded in the trial database. 45 resulted in a hospital admission and therefore could have been recorded by either HES APC/ NICOR. Of these, 27/45 (60%) were recorded by HES inpatient (Box-1) with an additional 30 potential events also identified. HF and ACS were potentially recorded in all 3 datasets; trial data recorded 18, HES APC 29 and NICOR 24 events respectively. 12/18 (67%) of the HF/ACS events in the trial dataset were recorded by NICOR. CONCLUSION: Concordance between datasets was lower than anticipated and the HSD used could not straightforwardly replace current trial practices, nor directly identify protocol-defined CVS events. Further work is required to improve the quality of HSD and consider event definitions when designing clinical trials incorporating HSD

Development of novel methods for non-canonical myeloma protein analysis with an innovative adaptation of immunofixation electrophoresis, native top-down mass spectrometry, and middle-down de novo sequencing

OBJECTIVES: Multiple myeloma (MM) is a malignant plasma cell neoplasm, requiring the integration of clinical examination, laboratory and radiological investigations for diagnosis. Detection and isotypic identification of the monoclonal protein(s) and measurement of other relevant biomarkers in serum and urine are pivotal analyses. However, occasionally this approach fails to characterize complex protein signatures. Here we describe the development and application of next generation mass spectrometry (MS) techniques, and a novel adaptation of immunofixation, to interrogate non-canonical monoclonal immunoproteins. METHODS: Immunoprecipitation immunofixation (IP-IFE) was performed on a Sebia Hydrasys Scan2. Middle-down de novo sequencing and native MS were performed with multiple instruments (21T FT-ICR, Q Exactive HF, Orbitrap Fusion Lumos, and Orbitrap Eclipse). Post-acquisition data analysis was performed using Xcalibur Qual Browser, ProSight Lite, and TDValidator. RESULTS: We adapted a novel variation of immunofixation electrophoresis (IFE) with an antibody-specific immunosubtraction step, providing insight into the clonal signature of gamma-zone monoclonal immunoglobulin (M-protein) species. We developed and applied advanced mass spectrometric techniques such as middle-down de novo sequencing to attain in-depth characterization of the primary sequence of an M-protein. Quaternary structures of M-proteins were elucidated by native MS, revealing a previously unprecedented non-covalently associated hetero-tetrameric immunoglobulin. CONCLUSIONS: Next generation proteomic solutions offer great potential for characterizing complex protein structures and may eventually replace current electrophoretic approaches for the identification and quantification of M-proteins. They can also contribute to greater understanding of MM pathogenesis, enabling classification of patients into new subtypes, improved risk stratification and the potential to inform decisions on future personalized treatment modalities

The cost effectiveness of REACH-HF and home-based cardiac rehabilitation compared with the usual medical care for heart failure with reduced ejection fraction:a decision model-based analysis

This is the final version. Available from Sage Publications via the DOI in this record.Background The REACH-HF (Rehabilitation EnAblement in CHronic Heart Failure) trial found that the REACH-HF home-based cardiac rehabilitation intervention resulted in a clinically meaningful improvement in disease-specific health-related quality of life in patients with reduced ejection fraction heart failure (HFrEF). The aims of this study were to assess the long-term cost-effectiveness of the addition of REACH-HF intervention or home-based cardiac rehabilitation to usual care compared with usual care alone in patients with HFrEF. Design and methods A Markov model was developed using a patient lifetime horizon and integrating evidence from the REACH-HF trial, a systematic review/meta-analysis of randomised trials, estimates of mortality and hospital admission and UK costs at 2015/2016 prices. Taking a UK National Health and Personal Social Services perspective we report the incremental cost per quality-adjusted life-year (QALY) gained, assessing uncertainty using probabilistic and deterministic sensitivity analyses. Results In base case analysis, the REACH-HF intervention was associated with per patient mean QALY gain of 0.23 and an increased mean cost of £400 compared with usual care, resulting in a cost per QALY gained of £1720. Probabilistic sensitivity analysis indicated a 78% probability that REACH-HF is cost effective versus usual care at a threshold of £20,000 per QALY gained. Results were similar for home-based cardiac rehabilitation versus usual care. Sensitivity analyses indicate the findings to be robust to changes in model assumptions and parameters. Conclusions Our cost-utility analyses indicate that the addition of the REACH-HF intervention and home-based cardiac rehabilitation programmes are likely to be cost-effective treatment options versus usual care alone in patients with HFrEF.National Institute for Health Research (NIHR