Longitudinal lung function assessment of patients hospitalised with COVID-19 using 1H and 129Xe lung MRI

BACKGROUND: Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear. RESEARCH QUESTION: Do patients hospitalised due to COVID-19 without evidence of architectural distortion on structural imaging show longitudinal improvements in lung function measured using 1H and 129Xe magnetic resonance imaging between 6-52 weeks after hospitalisation? STUDY DESIGN AND METHODS: Patients who were hospitalised due to COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25 and 51 weeks after hospital admission in a prospective cohort study between 11/2020 and 02/2022. Imaging protocol: 1H ultra-short echo time, contrast enhanced lung perfusion, 129Xe ventilation, 129Xe diffusion weighted and 129Xe spectroscopic imaging of gas exchange. RESULTS: 9 patients were recruited (57±14 [median±interquartile range] years, 6/9 male). Patients underwent MRI at 6 (N=9), 12 (N=9), 25 (N=6) and 51 (N=8) weeks after hospital admission. Patients with signs of interstitial lung damage were excluded. At 6 weeks, patients demonstrated impaired 129Xe gas transfer (red blood cell to membrane fraction) but lung microstructure was not increased (apparent diffusion coefficient and mean acinar airway dimensions). Minor ventilation abnormalities present in four patients were largely resolved in the 6-25 week period. At 12 weeks, all patients with lung perfusion data (N=6) showed an increase in both pulmonary blood volume and flow when compared to 6 weeks, though this was not statistically significant. At 12 weeks, significant improvements in 129Xe gas transfer were observed compared to 6-week examinations, however 129Xe gas transfer remained abnormally low at weeks 12, 25 and 51. INTERPRETATION: 129Xe gas transfer was impaired up to one year after hospitalisation in patients who were hospitalised due to COVID-19 pneumonia, without evidence of architectural distortion on structural imaging, whereas lung ventilation wa normal at 52 weeks

Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories—DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis—with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy. Profiling multi-platform genomics of 110 cancer patients with an exceptional therapeutic response, Wheeler et al. identify putative molecular mechanisms explaining this survival phenotype in ∼23% of cases. Therapeutic success is related to rare molecular features of responding tumors, exploiting synthetic lethality and oncogene addiction

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Re-Shaping Hysteresis: Seismic Semi-Active Control Experiments for a 1/5th Scale Structure

Semi-active resetable devices can improve seismic response. Novel 2-4 devices independently control each device chamber to customise structural hysteresis loops to reduce both displacement and base shear demands. Here, 2-4 devices are experimentally validated on a one-fifth scale test structure weighing 35kN with a natural period of 0.6 seconds. Four seismic inputs over a wide range of intensity levels are use in 27 tests. Results for resetable semi-active devices that modify hysteretic behaviour using different control laws are compared to spectral response analyses that predict ~30-50% peak displacement reductions. Fully uncontrolled tests were also done for lower intensity ground motions, along with fail-safe valves-open tests. Results show 25-50% peak displacement reductions compared to the valves open case, depending on the semi-active control law used and matching spectral analysis results. Additionally, a semi-active control law designed to simultaneously reduce base shear reduces it 10-20%. In contrast, 10-20% increases are seen for other approaches, as predicted. Overall, these are the first large-scale tests of this type of novel resetable devices. The results validate prior simulation and spectral analyses, and clearly show the potential. Finally, semi-active methods that re-shape hysteresis to control response and simultaneously limit base shear demand, are experimentally demonstrated for the first time

Evaluation of Acute Supplementation With the Ketone Ester (R)-3-Hydroxybutyl-(R)-3-Hydroxybutyrate (deltaG) in Healthy Volunteers by Cardiac and Skeletal Muscle P-31 Magnetic Resonance Spectroscopy

In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal muscle PCr recovery using phosphorus magnetic resonance spectroscopy (P-31-MRS) before and after ingestion of a ketone ester drink. We recruited 28 healthy individuals: 12 aged 23-70 years for cardiac P-31-MRS, and 16 aged 60-75 years for skeletal muscle P-31-MRS. Baseline and post-intervention resting cardiac and dynamic skeletal muscle P-31-MRS scans were performed in one visit, where 25 g of the ketone monoester, deltaG(R), was administered after the baseline scan. Administration was timed so that post-intervention P-31-MRS would take place 30 min after deltaG(R) ingestion. The deltaG(R) ketone drink was well-tolerated by all participants. In participants who provided blood samples, post-intervention blood glucose, lactate and non-esterified fatty acid concentrations decreased significantly (-28.8%, p MUCH LESS-THAN 0.001; -28.2%, p = 0.02; and -49.1%, p MUCH LESS-THAN 0.001, respectively), while levels of the ketone body D-beta-hydroxybutyrate significantly increased from mean (standard deviation) 0.7 (0.3) to 4.0 (1.1) mmol/L after 30 min (p MUCH LESS-THAN 0.001). There were no significant changes in cardiac PCr/ATP or skeletal muscle metabolic parameters between baseline and post-intervention. Acute ketone supplementation caused mild ketosis in blood, with drops in glucose, lactate, and free fatty acids; however, such changes were not associated with changes in P-31-MRS measures in the heart or in skeletal muscle. Future work may focus on the effect of longer-term ketone supplementation on tissue energetics in groups with compromised mitochondrial function

Evaluation of Acute Supplementation With the Ketone Ester (R)-3-Hydroxybutyl-(R)-3-Hydroxybutyrate (deltaG) in Healthy Volunteers by Cardiac and Skeletal Muscle P-31 Magnetic Resonance Spectroscopy

In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal muscle PCr recovery using phosphorus magnetic resonance spectroscopy (P-31-MRS) before and after ingestion of a ketone ester drink. We recruited 28 healthy individuals: 12 aged 23-70 years for cardiac P-31-MRS, and 16 aged 60-75 years for skeletal muscle P-31-MRS. Baseline and post-intervention resting cardiac and dynamic skeletal muscle P-31-MRS scans were performed in one visit, where 25 g of the ketone monoester, deltaG(R), was administered after the baseline scan. Administration was timed so that post-intervention P-31-MRS would take place 30 min after deltaG(R) ingestion. The deltaG(R) ketone drink was well-tolerated by all participants. In participants who provided blood samples, post-intervention blood glucose, lactate and non-esterified fatty acid concentrations decreased significantly (-28.8%, p MUCH LESS-THAN 0.001; -28.2%, p = 0.02; and -49.1%, p MUCH LESS-THAN 0.001, respectively), while levels of the ketone body D-beta-hydroxybutyrate significantly increased from mean (standard deviation) 0.7 (0.3) to 4.0 (1.1) mmol/L after 30 min (p MUCH LESS-THAN 0.001). There were no significant changes in cardiac PCr/ATP or skeletal muscle metabolic parameters between baseline and post-intervention. Acute ketone supplementation caused mild ketosis in blood, with drops in glucose, lactate, and free fatty acids; however, such changes were not associated with changes in P-31-MRS measures in the heart or in skeletal muscle. Future work may focus on the effect of longer-term ketone supplementation on tissue energetics in groups with compromised mitochondrial function.Radiolog