Variola minor, a true type of smallpox with special reference to a recent outbreak

For the past few years considerable attention has been directed towards the outbreaks of smallpox in various parts of England and Wales. These have caused groat expense and inconvenience to the communities concerned, The type of disease has been mild, differing in some points from the classical type, and giving rise to a groat, deal of discussion as to whether we are not encountering a different disease.Although in vaccination we have a prophylactic remedy capable of stamping out smallpox, the laxity with which our present vaccination laws are framed has caused largo numbers of our population to be unprotected, forming an apparently inexhaustible reservoir which affords material for epidemics to recur. These epidemics if left alone increase rapidly, may become seasonal, and may even, in some cases, take on an endemic character.As an Assistant Medical Officer of Health for Derby, I have been in touch with one of these outbreaks of smallpox, one which has now lasted some four years and which has every appearance of continuingIn this thesis I propose to describe my experi_ ences / 2. experiences in connection with the outbreak, my observations being based on nearly two thousand cases of the disease. It shall be my endeavour to prove the important fact that we are dealing with true smallpox. Further, as vaccination and smallpox are so closely connected, I also propose to discuss some of the problems arising with regard to the former.1. A recent outbreak in Derby, of Smallpox (variola minor) is described.2. The cases have been shown to be predominantly mild, but there has been a small number of severe cases of the classical type.3. The epidemiological features of the outbreak are described,4. Clinical cases are given illustrating the out_ break. These show that the likeness to the major disease is very marked.5. The differences between "alastrim" `and variola have been discussed. It has been shown that many were non-existant in the outbreak.6. Finally, "alastrim" and variola are one disease. They differ only in severity

Towards the 3D Web with Open Simulator

Continuing advances and reduced costs in computational power, graphics processors and network bandwidth have led to 3D immersive multi-user virtual worlds becoming increasingly accessible while offering an improved and engaging Quality of Experience. At the same time the functionality of the World Wide Web continues to expand alongside the computing infrastructure it runs on and pages can now routinely accommodate many forms of interactive multimedia components as standard features - streaming video for example. Inevitably there is an emerging expectation that the Web will expand further to incorporate immersive 3D environments. This is exciting because humans are well adapted to operating in 3D environments and it is challenging because existing software and skill sets are focused around competencies in 2D Web applications. Open Simulator (OpenSim) is a freely available open source tool-kit that empowers users to create and deploy their own 3D environments in the same way that anyone can create and deploy a Web site. Its characteristics can be seen as a set of references as to how the 3D Web could be instantiated. This paper describes experiments carried out with OpenSim to better understand network and system issues, and presents experience in using OpenSim to develop and deliver applications for education and cultural heritage. Evaluation is based upon observations of these applications in use and measurements of systems both in the lab and in the wild

Growing the use of Virtual Worlds in education : an OpenSim perspective

The growth in the range of disciplines that Virtual Worlds support for educational purposes is evidenced by recent applications in the fields of cultural heritage, humanitarian aid, space exploration, virtual laboratories in the physical sciences, archaeology, computer science and coastal geography. This growth is due in part to the flexibility of OpenSim, the open source virtual world platform which by adopting Second Life protocols and norms has created a de facto standard for open virtual worlds that is supported by a growing number of third party open source viewers. Yet while this diversity of use-cases is impressive and Virtual Worlds for open learning are highly popular with lecturers and learners alike immersive education remains an essentially niche activity. This paper identifies functional challenges in terms of Management, Network Infrastructure, the Immersive 3D Web and Programmability that must be addressed to enable the wider adoption of Open Virtual Worlds as a routine learning technology platform. We refer to specific use-cases based on OpenSim and abstract generic requirements which should be met to enable the growth in use of Open Virtual Worlds as a mainstream educational facility. A case study of a deployment to support a formal education curriculum and associated informal learning is used to illustrate key points.Postprin

Has the gender gap in voter turnout really disappeared?

According to conventional wisdom, the traditional gender gap in voting has disappeared or even reversed in most established democracies. Drawing on the existing literature on sex differences in political engagement and on pioneering voter turnout theories, this article questions the conventional assumption and hypothesises that women still participate at lower rates in less important elections. It systematically tests this hypothesis by exploring the impact of sex on voter turnout in different electoral arenas. The empirical analyses of two cross-national datasets (Making Electoral Democracy Work and the European Election Study) demonstrate that although there is generally no gender gap in first-order elections, women tend to vote less than men in second-order contests. This reflects women’s weaker interest in politics and their lower levels of knowledge about politics in second-order electoral arenas

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection