Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study

BACKGROUND: The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population. METHODS: In this prospective longitudinal observational study, we collected data from participants who were self-reporting test results and symptoms in the ZOE COVID app (previously known as the COVID Symptoms Study App). Eligible participants were aged 16-99 years, based in the UK, with a body-mass index between 15 and 55 kg/m2, had received at least two doses of any SARS-CoV-2 vaccine, were symptomatic, and logged a positive symptomatic PCR or lateral flow result for SARS-CoV-2 during the study period. The primary outcome was the likelihood of developing a given symptom (of the 32 monitored in the app) or hospital admission within 7 days before or after the positive test in participants infected during omicron prevalence compared with those infected during delta prevalence. FINDINGS: Between June 1, 2021, and Jan 17, 2022, we identified 63 002 participants who tested positive for SARS-CoV-2 and reported symptoms in the ZOE app. These patients were matched 1:1 for age, sex, and vaccination dose, across two periods (June 1 to Nov 27, 2021, delta prevalent at >70%; n=4990, and Dec 20, 2021, to Jan 17, 2022, omicron prevalent at >70%; n=4990). Loss of smell was less common in participants infected during omicron prevalence than during delta prevalence (16·7% vs 52·7%, odds ratio [OR] 0·17; 95% CI 0·16-0·19, p<0·001). Sore throat was more common during omicron prevalence than during delta prevalence (70·5% vs 60·8%, 1·55; 1·43-1·69, p<0·001). There was a lower rate of hospital admission during omicron prevalence than during delta prevalence (1·9% vs 2·6%, OR 0·75; 95% CI 0·57-0·98, p=0·03). INTERPRETATION: The prevalence of symptoms that characterise an omicron infection differs from those of the delta SARS-CoV-2 variant, apparently with less involvement of the lower respiratory tract and reduced probability of hospital admission. Our data indicate a shorter period of illness and potentially of infectiousness which should impact work-health policies and public health advice. FUNDING: Wellcome Trust, ZOE, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, and Medical Research Council

Broad-Spectrum Antiviral Therapeutics

Currently there are relatively few antiviral therapeutics, and most which do exist are highly pathogen-specific or have other disadvantages. We have developed a new broad-spectrum antiviral approach, dubbed Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer (DRACO) that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad-spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered.National Institute of Allergy and Infectious Diseases (U.S.) (grant AI057159)New England Regional Center of Excellence for Biodefense and Emerging Infectious DiseasesUnited States. Dept. of Defense (Director of Defense Research & Engineering)United States. Defense Threat Reduction AgencyUnited States. Defense Advanced Research Projects Agenc

Different paths to the modern state in Europe: the interaction between domestic political economy and interstate competition

Theoretical work on state formation and capacity has focused mostly on early modern Europe and on the experience of western European states during this period. While a number of European states monopolized domestic tax collection and achieved gains in state capacity during the early modern era, for others revenues stagnated or even declined, and these variations motivated alternative hypotheses for determinants of fiscal and state capacity. In this study we test the basic hypotheses in the existing literature making use of the large date set we have compiled for all of the leading states across the continent. We find strong empirical support for two prevailing threads in the literature, arguing respectively that interstate wars and changes in economic structure towards an urbanized economy had positive fiscal impact. Regarding the main point of contention in the theoretical literature, whether it was representative or authoritarian political regimes that facilitated the gains in fiscal capacity, we do not find conclusive evidence that one performed better than the other. Instead, the empirical evidence we have gathered lends supports to the hypothesis that when under pressure of war, the fiscal performance of representative regimes was better in the more urbanized-commercial economies and the fiscal performance of authoritarian regimes was better in rural-agrarian economie

Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort

Objectives:We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies.Methods: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries.Results: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT(&gt; MIC) (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving beta-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P=0.012]. Additionally, in patients with a SOFA score of &gt;= 9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P=0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P=0.025].Conclusions: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections

Profiles of Volatile Biomarkers Detect Tuberculosis from Skin

Tuberculosis (TB) is an infectious disease that threatens >10 million people annually. Despite advances in TB diagnostics, patients continue to receive an insufficient diagnosis as TB symptoms are not specific. Many existing biodiagnostic tests are slow, have low clinical performance, and can be unsuitable for resource-limited settings. According to the World Health Organization (WHO), a rapid, sputum-free, and cost-effective triage test for real-time detection of TB is urgently needed. This article reports on a new diagnostic pathway enabling a noninvasive, fast, and highly accurate way of detecting TB. The approach relies on TB-specific volatile organic compounds (VOCs) that are detected and quantified from the skin headspace. A specifically designed nanomaterial-based sensors array translates these findings into a point-of-care diagnosis by discriminating between active pulmonary TB patients and controls with sensitivity above 90%. This fulfills the WHO's triage test requirements and poses the potential to become a TB triage test

The seeds of divergence: the economy of French North America, 1688 to 1760

Generally, Canada has been ignored in the literature on the colonial origins of divergence with most of the attention going to the United States. Late nineteenth century estimates of income per capita show that Canada was relatively poorer than the United States and that within Canada, the French and Catholic population of Quebec was considerably poorer. Was this gap long standing? Some evidence has been advanced for earlier periods, but it is quite limited and not well-suited for comparison with other societies. This thesis aims to contribute both to Canadian economic history and to comparative work on inequality across nations during the early modern period. With the use of novel prices and wages from Quebec—which was then the largest settlement in Canada and under French rule—a price index, a series of real wages and a measurement of Gross Domestic Product (GDP) are constructed. They are used to shed light both on the course of economic development until the French were defeated by the British in 1760 and on standards of living in that colony relative to the mother country, France, as well as the American colonies. The work is divided into three components. The first component relates to the construction of a price index. The absence of such an index has been a thorn in the side of Canadian historians as it has limited the ability of historians to obtain real values of wages, output and living standards. This index shows that prices did not follow any trend and remained at a stable level. However, there were episodes of wide swings—mostly due to wars and the monetary experiment of playing card money. The creation of this index lays the foundation of the next component. The second component constructs a standardized real wage series in the form of welfare ratios (a consumption basket divided by nominal wage rate multiplied by length of work year) to compare Canada with France, England and Colonial America. Two measures are derived. The first relies on a “bare bones” definition of consumption with a large share of land-intensive goods. This measure indicates that Canada was poorer than England and Colonial America and not appreciably richer than France. However, this measure overestimates the relative position of Canada to the Old World because of the strong presence of land-intensive goods. A second measure is created using a “respectable” definition of consumption in which the basket includes a larger share of manufactured goods and capital-intensive goods. This second basket better reflects differences in living standards since the abundance of land in Canada (and Colonial America) made it easy to achieve bare subsistence, but the scarcity of capital and skilled labor made the consumption of luxuries and manufactured goods (clothing, lighting, imported goods) highly expensive. With this measure, the advantage of New France over France evaporates and turns slightly negative. In comparison with Britain and Colonial America, the gap widens appreciably. This element is the most important for future research. By showing a reversal because of a shift to a different type of basket, it shows that Old World and New World comparisons are very sensitive to how we measure the cost of living. Furthermore, there are no sustained improvements in living standards over the period regardless of the measure used. Gaps in living standards observed later in the nineteenth century existed as far back as the seventeenth century. In a wider American perspective that includes the Spanish colonies, Canada fares better. The third component computes a new series for Gross Domestic Product (GDP). This is to avoid problems associated with using real wages in the form of welfare ratios which assume a constant labor supply. This assumption is hard to defend in the case of Colonial Canada as there were many signs of increasing industriousness during the eighteenth and nineteenth centuries. The GDP series suggest no long-run trend in living standards (from 1688 to circa 1765). The long peace era of 1713 to 1740 was marked by modest economic growth which offset a steady decline that had started in 1688, but by 1760 (as a result of constant warfare) living standards had sunk below their 1688 levels. These developments are accompanied by observations that suggest that other indicators of living standard declined. The flat-lining of incomes is accompanied by substantial increases in the amount of time worked, rising mortality and rising infant mortality. In addition, comparisons of incomes with the American colonies confirm the results obtained with wages— Canada was considerably poorer. At the end, a long conclusion is provides an exploratory discussion of why Canada would have diverged early on. In structural terms, it is argued that the French colony was plagued by the problem of a small population which prohibited the existence of scale effects. In combination with the fact that it was dispersed throughout the territory, the small population of New France limited the scope for specialization and economies of scale. However, this problem was in part created, and in part aggravated, by institutional factors like seigneurial tenure. The colonial origins of French America’s divergence from the rest of North America are thus partly institutional