Population Ecology and Genetics of the Marsh Fritillary Butterfly Euphydryas aurinia

The past two decades have witnessed an unprecedented decline in Lepidopteran species, with more than a third of the UK’s butterflies now either considered threatened, or already lost from the country. The vulnerable marsh fritillary, Euphydryas aurinia, after a long term loss in the UK of 73% in abundance, has become an almost iconic species as the target of many well-funded conservation projects across the UK. Despite extensive ecological studies, populations of E. aurinia are shown in Chapter 2 to still be declining in south-west UK even after recommended management strategies have been implemented. This necessitates the need for prompt research beyond that of management requirements and butterfly habitat preferences. In Chapter 3, microsatellite markers (EST-SSRs) were developed for E. aurinia and using these markers in Chapter 4, it is shown that E. aurinia populations in southern UK and Catalonia, Spain, are severely genetically differentiated at all geographical scales, and genetically depauperate, causing huge concerns for the conservation of this enigmatic and ecologically important species. Dispersal is fundamental to metapopulation existence and survival. Phosphoglucose isomerase (PGI – an enzyme in the glycolysis pathway) is a well-endorsed candidate gene for dispersal, extensively studied in the Glanville fritillary (Melitaea cinxia) and Orange Sulphur (Colias eurytheme). In Chapter 5, an analysis across 27 sites in the UK discovered six non-synonymous SNPs (single nucleotide polymorphisms) within PGI. A single charge-changing SNP of interest showed no evidence of balancing selection, contrary to findings in M. cinxia, instead appearing to be neutral when analysed alongside microsatellite markers developed in Chapter 3. No link was found between genotype and flight, morphology or population trend. These findings challenge the emerging perspective that PGI could be used as an adaptive molecular marker for arthropods. Wolbachia are endosymbiotic bacteria capable of dramatically altering the reproductive system of their host. In Chapter 6, a PCR-based diagnostic in conjunction with MLST (multi-locus sequence typing) identified 100% prevalence of a single strain of Wolbachia across all sampled E. aurinia populations in the UK. Total prevalence suggests that Wolbachia probably has little phenotypic impact on its host, but the potential impacts of this endosymbiont on uninfected populations should be considered during any management plans for the conservation of E. aurinia. Current management plans will need to incorporate all areas of research, from basic ecological requirements to molecular adaptation and unseen manipulators of host biology, to be able to fully and effectively conserve declining fragmented species.Biotechnology and Biological Sciences Research Council (BBSRC) with CASE partner Butterfly Conservation (BC

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

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Population ecology and genetics of the marsh fritillary butterfly Euphydryas aurinia

The past two decades have witnessed an unprecedented decline in Lepidopteran species, with more than a third of the UK’s butterflies now either considered threatened, or already lost from the country. The vulnerable marsh fritillary, Euphydryas aurinia, after a long term loss in the UK of 73% in abundance, has become an almost iconic species as the target of many well-funded conservation projects across the UK. Despite extensive ecological studies, populations of E. aurinia are shown in Chapter 2 to still be declining in south-west UK even after recommended management strategies have been implemented. This necessitates the need for prompt research beyond that of management requirements and butterfly habitat preferences. In Chapter 3, microsatellite markers (EST-SSRs) were developed for E. aurinia and using these markers in Chapter 4, it is shown that E. aurinia populations in southern UK and Catalonia, Spain, are severely genetically differentiated at all geographical scales, and genetically depauperate, causing huge concerns for the conservation of this enigmatic and ecologically important species. Dispersal is fundamental to metapopulation existence and survival. Phosphoglucose isomerase (PGI – an enzyme in the glycolysis pathway) is a well-endorsed candidate gene for dispersal, extensively studied in the Glanville fritillary (Melitaea cinxia) and Orange Sulphur (Colias eurytheme). In Chapter 5, an analysis across 27 sites in the UK discovered six non-synonymous SNPs (single nucleotide polymorphisms) within PGI. A single charge-changing SNP of interest showed no evidence of balancing selection, contrary to findings in M. cinxia, instead appearing to be neutral when analysed alongside microsatellite markers developed in Chapter 3. No link was found between genotype and flight, morphology or population trend. These findings challenge the emerging perspective that PGI could be used as an adaptive molecular marker for arthropods. Wolbachia are endosymbiotic bacteria capable of dramatically altering the reproductive system of their host. In Chapter 6, a PCR-based diagnostic in conjunction with MLST (multi-locus sequence typing) identified 100% prevalence of a single strain of Wolbachia across all sampled E. aurinia populations in the UK. Total prevalence suggests that Wolbachia probably has little phenotypic impact on its host, but the potential impacts of this endosymbiont on uninfected populations should be considered during any management plans for the conservation of E. aurinia. Current management plans will need to incorporate all areas of research, from basic ecological requirements to molecular adaptation and unseen manipulators of host biology, to be able to fully and effectively conserve declining fragmented species.EThOS - Electronic Theses Online ServiceBiotechnology and Biological Sciences Research Council (BBSRC) : Butterfly Conservation (BC)GBUnited Kingdo

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

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