Circadian Clock and Hypoxia.

The timing of life on Earth is remarkable: between individuals of the same species, a highly similar temporal pattern is observed, with shared periods of activity and inactivity each day. At the individual level, this means that over the course of a single day, a person alternates between two states. They are either upright, active, and communicative or they lie down in a state of (un)consciousness called sleep where even the characteristic of neuronal signals in the brain shows distinctive properties. The circadian clock governs both of these time stamps-activity and (apparent) inactivity-making them come and go consistently at the same approximate time each day. This behavior thus represents the meeting of two pervasive systems: the circadian clock and metabolism. In this article, we will describe what is known about how the circadian clock anticipates daily changes in oxygen usage, how circadian clock regulation may relate to normal physiology, and to hypoxia and ischemia that can result from pathologies such as myocardial infarction and stroke.

Climate change impact and adaptation assessment for road drainage systems.

Climate change exhibits a clear trend of escalating frequency and intensity of extreme weather events, posing heightened risks to drainage systems along the existing road networks. However, very few studies to date have investigated the consequences of projected future changes in rainfall on main road drainage and the resulting risk of road flooding. The work presented in this paper builds on the limited research by introducing a probabilistic model for assessing the impact of climate change on road drainage systems, incorporating climate uncertainty and drainage system variation. The probabilistic scenario-based model and associated framework offer a practical and innovative method for estimating the impact of short-duration storms under future climates for 2071-2100, in the absence of fine-resolution spatio-temporal data. The model also facilitates the assessment of the effectiveness of a climate adaptation strategy. An illustrative case-study of a road drainage system located in the south of Ireland is presented. It was found that the probability of road flooding during intense rainfall is projected to surpass the current acceptable limits set by Irish standards. Assessment of a proactive climate adaptation strategy implemented in 2015 indicated it may need to be adjusted to further reduce climate change impacts and optimise adaptation costs.

Advances in microfluidic in vitro systems for neurological disease modeling.

Neurological disorders are the leading cause of disability and the second largest cause of death worldwide. Despite significant research efforts, neurology remains one of the most failure-prone areas of drug development. The complexity of the human brain, boundaries to examining the brain directly in vivo, and the significant evolutionary gap between animal models and humans, all serve to hamper translational success. Recent advances in microfluidic in vitro models have provided new opportunities to study human cells with enhanced physiological relevance. The ability to precisely micro-engineer cell-scale architecture, tailoring form and function, has allowed for detailed dissection of cell biology using microphysiological systems (MPS) of varying complexities from single cell systems to "Organ-on-chip" models. Simplified neuronal networks have allowed for unique insights into neuronal transport and neurogenesis, while more complex 3D heterotypic cellular models such as neurovascular unit mimetics and "Organ-on-chip" systems have enabled new understanding of metabolic coupling and blood-brain barrier transport. These systems are now being developed beyond MPS toward disease specific micro-pathophysiological systems, moving from "Organ-on-chip" to "Disease-on-chip." This review gives an outline of current state of the art in microfluidic technologies for neurological disease research, discussing the challenges and limitations while highlighting the benefits and potential of integrating technologies. We provide examples of where such toolsets have enabled novel insights and how these technologies may empower future investigation into neurological diseases.

Methodological challenges in European ethics approvals for a genetic epidemiology study in critically ill patients: the GenOSept experience.

BACKGROUND: During the set-up phase of an international study of genetic influences on outcomes from sepsis, we aimed to characterise potential differences in ethics approval processes and outcomes in participating European countries. METHODS: Between 2005 and 2007 of the FP6-funded international Genetics Of Sepsis and Septic Shock (GenOSept) project, we asked national coordinators to complete a structured survey of research ethic committee (REC) approval structures and processes in their countries, and linked these data to outcomes. Survey findings were reconfirmed or modified in 2017. RESULTS: Eighteen countries participated in the study, recruiting 2257 patients from 160 ICUs. National practices differed widely in terms of composition of RECs, procedures and duration of the ethics approval process. Eight (44.4%) countries used a single centralised process for approval, seven (38.9%) required approval by an ethics committee in each participating hospital, and three (16.7%) required both. Outcomes of the application process differed widely between countries because of differences in national legislation, and differed within countries because of interpretation of the ethics of conducting research in patients lacking capacity. The RECs in four countries had no lay representation. The median time from submission to final decision was 1.5 (interquartile range 1-7) months; in nine (50%) approval was received within 1 month; six took over 6 months, and in one 24 months; had all countries been able to match the most efficient approvals processes, an additional 74 months of country or institution-level recruitment would have been available. In three countries, rejection of the application by some local RECs resulted in loss of centres; and one country rejected the application outright. CONCLUSIONS: The potential benefits of the single application portal offered by the European Clinical Trials Regulation will not be realised without harmonisation of research ethics committee practices as well as national legislation.

Formyl-Peptide Receptor 2/3/Lipoxin A4 Receptor Regulates Neutrophil-Platelet Aggregation and Attenuates Cerebral Inflammation: Impact for Therapy in Cardiovascular Disease.

BACKGROUND: Platelet activation at sites of vascular injury is essential for hemostasis, but it is also a major pathomechanism underlying ischemic injury. Because anti-inflammatory therapies limit thrombosis and antithrombotic therapies reduce vascular inflammation, we tested the therapeutic potential of 2 proresolving endogenous mediators, annexin A1 N-terminal derived peptide (AnxA1Ac2-26) and aspirin-triggered lipoxin A4 (15-epi-lipoxin A4), on the cerebral microcirculation after ischemia/reperfusion injury. Furthermore, we tested whether the lipoxin A4 receptor formyl-peptide receptor 2/3 (Fpr2/3; ortholog to human FPR2/lipoxin A4 receptor) evoked neuroprotective functions after cerebral ischemia/reperfusion injury. METHODS AND RESULTS: Using intravital microscopy, we found that cerebral ischemia/reperfusion injury was accompanied by neutrophil and platelet activation and neutrophil-platelet aggregate formation within cerebral microvessels. Moreover, aspirin-triggered lipoxin A4 activation of neutrophil Fpr2/3 regulated neutrophil-platelet aggregate formation in the brain and inhibited the reactivity of the cerebral microvasculature. The same results were obtained with AnxA1Ac2-26 administration. Blocking Fpr2/lipoxin A4 receptor with the antagonist Boc2 reversed this effect, and treatments were ineffective in Fpr2/3 knockout mice, which displayed an exacerbated disease severity, evidenced by increased infarct area, blood-brain barrier dysfunction, increased neurological score, and elevated levels of cytokines. Furthermore, aspirin treatment significantly reduced cerebral leukocyte recruitment and increased endogenous levels of aspirin-triggered lipoxin A4, effects again mediated by Fpr2/3. CONCLUSION: Fpr2/lipoxin A4 receptor is a therapeutic target for initiating endogenous proresolving, anti-inflammatory pathways after cerebral ischemia/reperfusion injury.

Both MC1 and MC3 Receptors Provide Protection From Cerebral Ischemia-Reperfusion-Induced Neutrophil Recruitment.

OBJECTIVE: Neutrophil recruitment is a key process in the pathogenesis of stroke, and may provide a valuable therapeutic target. Targeting the melanocortin (MC) receptors has previously shown to inhibit leukocyte recruitment in peripheral inflammation, however, it is not known whether treatments are effective in the unique cerebral microvascular environment. Here, we provide novel research highlighting the effects of the MC peptides on cerebral neutrophil recruitment, demonstrating important yet discrete roles for both MC1 and MC3. APPROACH AND RESULTS: Using intravital microscopy, in 2 distinct murine models of cerebral ischemia-reperfusion (I/R) injury, we have investigated MC control for neutrophil recruitment. After global I/R, pharmacological treatments suppressed pathological neutrophil recruitment. MC1 selective treatment rapidly inhibited neutrophil recruitment while a nonselective MC agonist provided protection even when coadministered with an MC3/4 antagonist, suggesting the importance of early MC1 signaling. However, by 2-hour reperfusion, MC1-mediated effects were reduced, and MC3 anti-inflammatory circuits predominated. Mice bearing a nonfunctional MC1 displayed a transient exacerbation of neutrophil recruitment after global I/R, which diminished by 2 hours. However importantly, enhanced inflammatory responses in both MC1 mutant and MC3 (-/-) mice resulted in increased infarct size and poor functional outcome after focal I/R. Furthermore, we used an in vitro model of leukocyte recruitment to demonstrate these anti-inflammatory actions are also effective in human cells. CONCLUSIONS: These studies reveal for the first time MC control for neutrophil recruitment in the unique pathophysiological context of cerebral I/R, while also demonstrating the potential therapeutic value of targeting multiple MCs in developing effective therapeutics.

Admission Plasma Troponin I Is Associated With Mortality in Pediatric Intensive Care.

OBJECTIVES: Assessment of whether admission plasma troponin I level is associated with mortality or requirement for vasoactive drugs in pediatric intensive care. DESIGN: Retrospective cohort study. SETTING: Single centre, tertiary referral general PICU, without a cardiac surgical program. PATIENTS: Three hundred and nineteen patients 0-18 years old in two cohorts. Cohort 1 was admitted between January 2009 and September 2012 and the cohort 2 between April 2014 and April 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma troponin I was measured in patients in cohort 1 only if the attending physician ordered the test due to clinical concern regarding myocardial injury. The second cohort had plasma troponin I routinely measured at admission. The primary outcome was death during PICU admission, and the secondary outcome was maximum inotrope requirement during PICU stay, measured by Vasoactive Inotrope Score. Plasma troponin I was a discriminator for mortality in both cohorts (area under the receiver-operating characteristic curve of 0.73 and 0.86 in cohorts 1 and 2, respectively). In an adjusted analysis using Cox regression, accounting for Pediatric Index of Mortality 2 risk of mortality and age, elevated plasma troponin I was significantly associated with death in both cohorts (hazard ratio, 4.99; p = 0.033; hazard ratio, 10.5; p = 0.026 in cohorts 1 and 2, respectively). Elevated plasma troponin I was only associated with increased Vasoactive Inotrope Score following multivariate analysis in the cohort 2. CONCLUSIONS: Detectable plasma troponin I at admission to PICU is independently associated with death. The utility of troponin I as a stratification biomarker requires further evaluation.

Variants in the Mannose-binding Lectin Gene MBL2 do not Associate With Sepsis Susceptibility or Survival in a Large European Cohort.

BACKGROUND: Sepsis is an increasingly common condition, which continues to be associated with unacceptably high mortality. A large number of association studies have investigated susceptibility to, or mortality from, sepsis for variants in the functionally important immune-related gene MBL2. These studies have largely been underpowered and contradictory. METHODS: We genotyped and analyzed 4 important MBL2 single nucleotide polymorphisms (SNPs; rs5030737, rs1800450, rs1800451, and rs7096206) in 1839 European community-acquired pneumonia (CAP) and peritonitis sepsis cases, and 477 controls from the United Kingdom. We analyzed the following predefined subgroups and outcomes: 28-day and 6 month mortality from sepsis due to CAP or peritonitis combined, 28-day mortality from CAP sepsis, peritonitis sepsis, pneumococcal sepsis or sepsis in younger patients, and susceptibility to CAP sepsis or pneumococcal sepsis in the United Kingdom. RESULTS: There were no significant associations (all P-values were greater than .05 after correction for multiple testing) between MBL2 genotypes and any of our predefined analyses. CONCLUSIONS: In this large, well-defined cohort of immune competent adult patients, no associations between MBL2 genotype and sepsis susceptibility or outcome were identified.

Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort.

INTRODUCTION: Patients admitted to intensive care following surgery for faecal peritonitis present particular challenges in terms of clinical management and risk assessment. Collaborating surgical and intensive care teams need shared perspectives on prognosis. We aimed to determine the relationship between dynamic assessment of trends in selected variables and outcomes. METHODS: We analysed trends in physiological and laboratory variables during the first week of intensive care unit (ICU) stay in 977 patients at 102 centres across 16 European countries. The primary outcome was 6-month mortality. Secondary endpoints were ICU, hospital and 28-day mortality. For each trend, Cox proportional hazards (PH) regression analyses, adjusted for age and sex, were performed for each endpoint. RESULTS: Trends over the first 7 days of the ICU stay independently associated with 6-month mortality were worsening thrombocytopaenia (mortality: hazard ratio (HR) = 1.02; 95% confidence interval (CI), 1.01 to 1.03; P < 0.001) and renal function (total daily urine output: HR =1.02; 95% CI, 1.01 to 1.03; P < 0.001; Sequential Organ Failure Assessment (SOFA) renal subscore: HR = 0.87; 95% CI, 0.75 to 0.99; P = 0.047), maximum bilirubin level (HR = 0.99; 95% CI, 0.99 to 0.99; P = 0.02) and Glasgow Coma Scale (GCS) SOFA subscore (HR = 0.81; 95% CI, 0.68 to 0.98; P = 0.028). Changes in renal function (total daily urine output and renal component of the SOFA score), GCS component of the SOFA score, total SOFA score and worsening thrombocytopaenia were also independently associated with secondary outcomes (ICU, hospital and 28-day mortality). We detected the same pattern when we analysed trends on days 2, 3 and 5. Dynamic trends in all other measured laboratory and physiological variables, and in radiological findings, changes in respiratory support, renal replacement therapy and inotrope and/or vasopressor requirements failed to be retained as independently associated with outcome in multivariate analysis. CONCLUSIONS: Only deterioration in renal function, thrombocytopaenia and SOFA score over the first 2, 3, 5 and 7 days of the ICU stay were consistently associated with mortality at all endpoints. These findings may help to inform clinical decision making in patients with this common cause of critical illness.

Global high-resolution growth projections dataset for rooftop area consistent with the shared socioeconomic pathways, 2020-2050.

Assessment of current and future growth in the global rooftop area is important for understanding and planning for a robust and sustainable decentralised energy system. These estimates are also important for urban planning studies and designing sustainable cities thereby forwarding the ethos of the Sustainable Development Goals 7 (clean energy), 11 (sustainable cities), 13 (climate action) and 15 (life on land). Here, we develop a machine learning framework that trains on big data containing ~700 million open-source building footprints, global land cover, road, and population datasets to generate globally harmonised estimates of growth in rooftop area for five different future growth narratives covered by Shared Socioeconomic Pathways. The dataset provides estimates for ~3.5 million fishnet tiles of 1/8 degree spatial resolution with data on gross rooftop area for five growth narratives covering years 2020-2050 in decadal time steps. This single harmonised global dataset can be used for climate change, energy transition, biodiversity, urban planning, and disaster risk management studies covering continental to conurbation geospatial levels.

Leukocyte recruitment in the brain in sepsis: involvement of the annexin 1-FPR2/ALX anti-inflammatory system.

Unregulated inflammation underlies many diseases, including sepsis. Much interest lies in targeting anti-inflammatory mechanisms to develop new treatments. One such target is the anti-inflammatory protein annexin A1 (AnxA1) and its receptor, FPR2/ALX. Using intravital videomicroscopy, we investigated the role of AnxA1 and FPR2/ALX in a murine model of endotoxin-induced cerebral inflammation [intraperitoneal injection of lipopolysaccharide (LPS)]. An inflammatory response was confirmed by elevations in proinflammatory serum cytokines, increased cerebrovascular permeability, elevation in brain myeloperoxidase, and increased leukocyte rolling and adhesion in cerebral venules of wild-type (WT) mice, which were further exacerbated in AnxA1-null mice. mRNA expression of TLR2, TLR4, MyD-88, and Ly96 was also assessed. The AnxA1-mimetic peptide, AnxA1(Ac2-26) (100 µg/mouse, ∼33 µmol) mitigated LPS-induced leukocyte adhesion in WT and AnxA1-null animals without affecting leukocyte rolling, in comparison to saline control. AnxA1(Ac2-26) effects were attenuated by Boc2 (pan-FPR antagonist, 10 µg/mouse, ∼12 nmol), and by minocycline (2.25 mg/mouse, ∼6.3 nmol). The nonselective Fpr agonists, fMLP (6 µg/mouse, ∼17 nmol) and AnxA1(Ac2-26), and the Fpr2-selective agonist ATLa (5 µg/mouse, ∼11 nmol) were without effect in Fpr2/3(-/-) mice. In summary, our novel results demonstrate that the AnxA1/FPR2 system has an important role in effecting the resolution of cerebral inflammation in sepsis and may, therefore, provide a novel therapeutic target.

Reinventing the Penumbra - the Emerging Clockwork of a Multi-modal Mechanistic Paradigm.

The concept of the ischemic penumbra was originally defined as the area around a necrotic stroke core and seen as the tissue at imminent risk of further damage. Today, the penumbra is generally considered as time-sensitive hypoperfused brain tissue with decreased oxygen and glucose availability, salvageable tissue as treated by intervention, and the potential target for neuroprotection in focal stroke. The original concept entailed electrical failure and potassium release but one short of neuronal cell death and was based on experimental stroke models, later confirmed in clinical imaging studies. However, even though the basic mechanisms have translated well, conferring brain protection, and improving neurological outcome after stroke based on the pathophysiological mechanisms in the penumbra has yet to be achieved. ï»¿Recent findings shape the modern understanding of the penumbra revealing a plethora of molecular and cellular pathophysiological mechanisms. We now propose a new model of the penumbra, one which we hope will lay the foundation for future translational success. We focus on the availability of glucose, the brain's central source of energy, and bioenergetic failure as core pathophysiological concepts. We discuss the relation of mitochondrial function in different cell types to bioenergetics and apoptotic cell death mechanisms, autophagy, and neuroinflammation, to glucose metabolism in what is a dynamic ischemic penumbra.

Novel, Emerging Chip Models of the Blood-Brain Barrier and Future Directions.

The use of microfluidic chips is now allowing for more advanced modelling of the blood-brain barrier (BBB) in vitro, recapitulating heterotypic interactions, 3D architecture, and physiological flow. This chapter will give an introduction to these new technologies and how they are being applied to model the BBB and neurovascular unit (NVU). A foundational understanding of the fluid dynamics germane to the effective use of these chips will be set and an overview of how physical phenomena at the microscale can be exploited to enable new possibilities to control the cell culture environment. The four main approaches to construct microfluidic blood vessel mimetics will be discussed with examples of how these techniques are being applied to model the BBB and more recently to study specific neurovascular disease processes. Finally, practical guidance will be given for researchers wishing to adopt these new techniques along with a summary of the challenges, limitations faced, and new opportunities opened up by these advanced cell culture systems.

Applications of Uncrewed Aerial Vehicles (UAV) Technology to Support Integrated Coastal Zone Management and the UN Sustainable Development Goals at the Coast.

Data and information obtained from low-cost uncrewed aerial vehicles (UAVs), commonly referred to as 'drones', can be used to support integrated coastal zone management (ICZM) and sustainable development at the coast. Several recent studies in various disciplines, including ecology, engineering, and several branches of physical and human geography, describe the applications of UAV technology with practical coastal management potential, yet the extent to which such data can contribute to these activities remains underexplored. The main objective of this paper is to collate this knowledge to highlight the areas in which UAV technology can contribute to ICZM and can influence the achievement of the UN Sustainable Development Goals (SDGs) at the coast. We focus on applications with practical potential for coastal management activities and assess their accessibility in terms of cost, ease of use, and maturity. We identified ten (out of the 17) SDGs to which UAVs can contribute data and information. Examples of applications include surveillance of illegal fishing and aquaculture activities, seaweed resource assessments, cost-estimation of post-storm damages, and documentation of natural and cultural heritage sites under threat from, for example, erosion and sea-level rise. An awareness of how UAVs can contribute to ICZM, as well as the limitations of the technology, can help coastal practitioners to evaluate their options for future management activities. Supplementary Information: The online version contains supplementary material available at 10.1007/s12237-021-01001-5.

Keeping an eye on circadian time in clinical research and medicine.

BACKGROUND: Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms. CONTENT: The goal of this manuscript is to provide guidance on best practices in measuring metrics of endogenous circadian rhythms in humans and promote the inclusion of circadian rhythms assessments in studies of health and disease. Circadian rhythms affect all aspects of physiology. By specifying minimal experimental conditions for studies, we aim to improve the quality, reliability and interpretability of research into circadian and daily (i.e., time-of-day) rhythms and facilitate the interpretation of clinical and translational findings within the context of human circadian rhythms. We describe protocols, variables and analyses commonly used for studying human daily rhythms, including how to assess the relative contributions of the endogenous circadian system and other daily patterns in behaviours or the environment. We conclude with recommendations for protocols, variables, analyses, definitions and examples of circadian terminology. CONCLUSION: Although circadian rhythms and daily effects on health outcomes can be challenging to distinguish in practice, this distinction may be important in many clinical settings. Identifying and targeting the appropriate underlying (patho)physiology is a medical goal. This review provides methods for identifying circadian effects to aid in the interpretation of published work and the inclusion of circadian factors in clinical research and practice.

High resolution global spatiotemporal assessment of rooftop solar photovoltaics potential for renewable electricity generation.

Rooftop solar photovoltaics currently account for 40% of the global solar photovoltaics installed capacity and one-fourth of the total renewable capacity additions in 2018. Yet, only limited information is available on its global potential and associated costs at a high spatiotemporal resolution. Here, we present a high-resolution global assessment of rooftop solar photovoltaics potential using big data, machine learning and geospatial analysis. We analyse 130 million km2 of global land surface area to demarcate 0.2 million km2 of rooftop area, which together represent 27 PWh yr-1 of electricity generation potential for costs between 40-280 $ MWh-1. Out of this, 10 PWh yr-1 can be realised below 100 $ MWh-1. The global potential is predominantly spread between Asia (47%), North America (20%) and Europe (13%). The cost of attaining the potential is lowest in India (66 $ MWh-1) and China (68 $ MWh-1), with USA (238 $ MWh-1) and UK (251 $ MWh-1) representing some of the costliest countries.

Droplet Microfluidics with Reagent Micromixing for Investigating Intrinsic Platelet Functionality.

INTRODUCTION: Precision mapping of the functional structure of platelet populations holds great promise for the identification of hyper-reactive subtypes that are likely to be disease drivers, having value in prognostics and as therapeutic targets. However, the ability to measure the intrinsic functional capacity of individual platelets is confounded by potent paracrine cross-talk, resulting in phenotypic remodeling of the entire platelet population, and in doing so obscuring the identity of hyper-reactive platelets. METHODS: To address this we have developed a droplet microfluidics strategy for single platelet confinement to exclude paracrine signaling. Consideration of the Poisson distribution was used for high throughput single platelet encapsulation and the preparation of minimal platelet collectives serving as digital models for understanding the role of hyper-reactive platelets coordinating system-level behavior by paracrine signaling. Platelets are retrieved from the droplets for phenotyping using standard flow cytometry. In addition, we have incorporated a staggered herringbone micromixing element for accurate agonist and antibody dispensing in droplets. RESULTS: The methodology was used for characterizing sensitivity distributions from healthy blood donors in response to convulxin (agonist of the GPVI receptor, the major platelet receptor for collagen). P-selectin exposure and α IIb ß 3 integrin activation were used as analytical end-points to demonstrate the existence of hyper-reactive platelets that direct 20-fold gains in system level sensitivity. CONCLUSIONS: The analytical workflow represents an enabling tool for the accurate classification of platelet subtypes and description of their underlying biology. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s12195-020-00665-6) contains supplementary material, which is available to authorized users.

Vitamin D insufficiency in COVID-19 and influenza A, and critical illness survivors: a cross-sectional study.

OBJECTIVES: The steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Plasma was obtained from 295 hospitalised people with COVID-19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009-2010 H1N1 pandemic) and 139 survivors of non-selected critical illness (prior to the COVID-19 pandemic). Total 25(OH)D was measured by liquid chromatography-tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-19 samples. OUTCOME MEASURES: Receipt of invasive mechanical ventilation (IMV) and in-hospital mortality. RESULTS: Vitamin D insufficiency (total 25(OH)D 25-50 nmol/L) and deficiency (<25 nmol/L) were prevalent in COVID-19 (29.3% and 44.4%, respectively), influenza A (47.3% and 37.6%) and critical illness survivors (30.2% and 56.8%). In COVID-19 and influenza A, total 25(OH)D measured early in illness was lower in patients who received IMV (19.6 vs 31.9 nmol/L (p<0.0001) and 22.9 vs 31.1 nmol/L (p=0.0009), respectively). In COVID-19, biologically active free 25(OH)D correlated with total 25(OH)D and was lower in patients who received IMV, but was not associated with selected circulating inflammatory mediators. CONCLUSIONS: Vitamin D deficiency/insufficiency was present in majority of hospitalised patients with COVID-19 or influenza A and correlated with severity and persisted in critical illness survivors at concentrations expected to disrupt bone metabolism. These findings support early supplementation trials to determine if insufficiency is causal in progression to severe disease, and investigation of longer-term bone health outcomes.

Full color-tunable vertically stacked quantum dot light emitting diodes for next-generation displays and lighting.

We report solution-processed color tunable vertically stacked electroluminescent red, green, and blue quantum dot light emitting diodes (QLEDs). These QLEDs can be independently driven to produce all primary, secondary, and white lights. We have fabricated the device by chemical and electrical isolation of each QLED with transparent polymers and by the use of transparent electrodes. These stacked QLEDs can be used for next-generation display and lighting applications that need high pixel density along with quantum dots' intrinsic benefits such as low turn-on voltage, color purity, and solution processability.