Prospective validation of the 4C prognostic models for adults hospitalised with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol

Purpose: To prospectively validate two risk scores to predict mortality (4C Mortality) and in-hospital deterioration (4C Deterioration) among adults hospitalised with COVID-19. // Methods: Prospective observational cohort study of adults (age ≥18 years) with confirmed or highly suspected COVID-19 recruited into the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study in 306 hospitals across England, Scotland and Wales. Patients were recruited between 27 August 2020 and 17 February 2021, with at least 4 weeks follow-up before final data extraction. The main outcome measures were discrimination and calibration of models for in-hospital deterioration (defined as any requirement of ventilatory support or critical care, or death) and mortality, incorporating predefined subgroups. // Results: 76 588 participants were included, of whom 27 352 (37.4%) deteriorated and 12 581 (17.4%) died. Both the 4C Mortality (0.78 (0.77 to 0.78)) and 4C Deterioration scores (pooled C-statistic 0.76 (95% CI 0.75 to 0.77)) demonstrated consistent discrimination across all nine National Health Service regions, with similar performance metrics to the original validation cohorts. Calibration remained stable (4C Mortality: pooled slope 1.09, pooled calibration-in-the-large 0.12; 4C Deterioration: 1.00, –0.04), with no need for temporal recalibration during the second UK pandemic wave of hospital admissions. // Conclusion: Both 4C risk stratification models demonstrate consistent performance to predict clinical deterioration and mortality in a large prospective second wave validation cohort of UK patients. Despite recent advances in the treatment and management of adults hospitalised with COVID-19, both scores can continue to inform clinical decision making

Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study

BACKGROUND: Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions. METHODS: We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal-external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London). FINDINGS: 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal-external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [-0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model. INTERPRETATION: The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19. FUNDING: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London

Natural disasters in the history of the eastern Turk empire

This article analyzes the effect of climate extremes on the historical processes that took place (AD 536, 581, 601, 626 and 679) in the Eastern Turk Empire (AD 534–745) in Inner Asia. Climate extremes are sharp, strong and sometimes protracted periods of cooling and drought caused by volcanic eruptions that in this case resulted in a negative effect on the economy of a nomadic society and were often accompanied by famine and illness. In fact, many of these natural catastrophes coincided with the Black Death pandemics among the Eastern Turks and the Chinese living in the north of China. The Turk Empire can be split into several chronological periods during which significant events that led to changes in the course of history of the nomadic state took place: AD 534–545—the rise of the Turk Empire; AD 581–583—the division of the Turk Empire into theWestern and the Eastern Empires; AD 601–603—the rise of Qimin Qaghan; AD 627–630—the Eastern Turks are conquered by China; AD 679–687—the second rise of the Eastern Turk Empire. The research shows that there is clearly-discernable interplay between important historical events and climate extremes in the history of the Turk Empire. This interplay has led us to the conclusion that the climatic factor did have an impact on the historical processes that took place in the eastern part of Inner Asia, especially on the territories with a nomadic economy. © The Author(s) 2019

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Diverging climate trends in Mongolian taiga forests influence growth and regeneration of Larix sibirica

Central and semiarid north-eastern Asia was subject to twentieth century warming far above the global average. Since forests of this region occur at their drought limit, they are particularly vulnerable to climate change. We studied the regional variations of temperature and precipitation trends and their effects on tree growth and forest regeneration in Mongolia. Tree-ring series from more than 2,300 trees of Siberian larch (Larix sibirica) collected in four regions of Mongolia’s forest zone were analyzed and related to available weather data. Climate trends underlie a remarkable regional variation leading to contrasting responses of tree growth in taiga forests even within the same mountain system. Within a distance of a few hundred kilometers (140–490 km), areas with recently reduced growth and regeneration of larch alternated with regions where these parameters remained constant or even increased. Reduced productivity could be correlated with increasing summer temperatures and decreasing precipitation; improved growth conditions were found at increasing precipitation, but constant summer temperatures. An effect of increasing winter temperatures on tree-ring width or forest regeneration was not detectable. Since declines of productivity and regeneration are more widespread in the Mongolian taiga than the opposite trend, a net loss of forests is likely to occur in the future, as strong increases in temperature and regionally differing changes in precipitation are predicted for the twenty-first century

Viral Coinfections in Hospitalized Coronavirus Disease 2019 Patients Recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK Study

Background: We conducted this study to assess the prevalence of viral coinfection in a well characterized cohort of hospitalized coronavirus disease 2019 (COVID-19) patients and to investigate the impact of coinfection on disease severity. Methods: Multiplex real-time polymerase chain reaction testing for endemic respiratory viruses was performed on upper respiratory tract samples from 1002 patients with COVID-19, aged <1 year to 102 years old, recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK study. Comprehensive demographic, clinical, and outcome data were collected prospectively up to 28 days post discharge. Results: A coinfecting virus was detected in 20 (2.0%) participants. Multivariable analysis revealed no significant risk factors for coinfection, although this may be due to rarity of coinfection. Likewise, ordinal logistic regression analysis did not demonstrate a significant association between coinfection and increased disease severity. Conclusions: Viral coinfection was rare among hospitalized COVID-19 patients in the United Kingdom during the first 18 months of the pandemic. With unbiased prospective sampling, we found no evidence of an association between viral coinfection and disease severity. Public health interventions disrupted normal seasonal transmission of respiratory viruses; relaxation of these measures mean it will be important to monitor the prevalence and impact of respiratory viral coinfections going forward

Spatiotemporal Variation in Avian Migration Phenology: Citizen Science Reveals Effects of Climate Change

A growing number of studies have documented shifts in avian migratory phenology in response to climate change, and yet there is a large amount of unexplained variation in the magnitude of those responses across species and geographic regions. We use a database of citizen science bird observations to explore spatiotemporal variation in mean arrival dates across an unprecedented geographic extent for 18 common species in North America over the past decade, relating arrival dates to mean minimum spring temperature. Across all species and geographic locations, species shifted arrival dates 0.8 days earlier for every °C of warming of spring temperature, but it was common for some species in some locations to shift as much as 3–6 days earlier per °C. Species that advanced arrival dates the earliest in response to warming were those that migrate more slowly, short distance migrants, and species with broader climatic niches. These three variables explained 63% of the interspecific variation in phenological response. We also identify a latitudinal gradient in the average strength of phenological response, with species shifting arrival earlier at southern latitudes than northern latitudes for the same degree of warming. This observation is consistent with the idea that species must be more phenologically sensitive in less seasonal environments to maintain the same degree of precision in phenological timing

Determination of the number of wounded nucleons in Pb+Pb collisions at 158 A GeV/c

The charged particle multiplicity distributions measured by two experiments, WA97 and NA57, in Pb+Pb collisions at 158 A GeV/c have been analyzed in the framework of the wounded nucleon model (WNM). We obtain a good description of the data within the centrality range of our samples. This allows us to make use of the measured multiplicities to estimate the number of wounded nucleons of the collision

Implementation of corticosteroids in treatment of COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK: prospective, cohort study

Background: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. Methods: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. Findings: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. Interpretation: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. Funding: UK National Institute for Health Research and UK Medical Research Council

Concerted Regulation of cGMP and cAMP Phosphodiesterases in Early Cardiac Hypertrophy Induced by Angiotensin II

Left ventricular hypertrophy leads to heart failure and represents a high risk leading to premature death. Cyclic nucleotides (cAMP and cGMP) play a major role in heart contractility and cyclic nucleotide phosphodiesterases (PDEs) are involved in different stages of advanced cardiac diseases. We have investigated their contributions in the very initial stages of left ventricular hypertrophy development. Wistar male rats were treated over two weeks by chronic infusion of angiotensin II using osmotic mini-pumps. Left cardiac ventricles were used as total homogenates for analysis. PDE1 to PDE5 specific activities and protein and mRNA expressions were explored