Studies on the infection of honey bee larvae with Ascosphaera apis

The fungus Ascosphaera apis causes the disease chalk brood in larvae of the honey bee, Apis mellifera. Ascospores were recognised as the agents of disease, but the site of their germination to initiate infection had not been established. In this study larval surface cuticle was initially investigated as a possible site, but spores did not even activate here. Therefore, potential inhibitors of spore germination were studied, including water and chloroform washings of larval cuticle; 4 larval food constituents - pollen, honey, brood food, royal jelly; and a variety of medium-chain fatty acids a t concentrations of 1, 0.1 and 0. 01%. Royal jelly exhibited a severe inhibitory effect on all germination stages. Larvae were successfully infected by feeding them food Containing A. apis spores, both in vitro and in vivo. A histological study of infected larvae demonstrated germination of spores in the mid-gut lumen, followed by penetration of the peritrophic membrane and gut epithelium by developing hyphae; and subsequent invasion of larval tissues by mycelia. Various aspects of spore physiology were investigated. Spore activation and enlargement were shown to be independent of temperature within the ranges of 10 to 40°C and 25 to 40°C respectively, while germ-tube production was closely temperature related, only occurring between 25 and 37°C - with an optimum between 31 and 35°C . However, all 3 germination stages were found to be independent of environmental pH within the range of pH 5 to 7.8. Studies on the nutritional requirements for germination revealed the need for exogenous supplies of both a carbon and nitrogen source to support germ-tube production. The ‘spore-ball phenomenon’ was investigated and a supplementary amino acid source was identified . The etiology of chalk brood is discussed in the light of these findings

Only Connect? : Aspects of Intertextuality in Zadie Smith's On Beauty

Tutkielma käsittelee intertekstuaalisuuden eri muotoja Zadie Smithin romaanissa On Beauty (suom. Kauneudesta). Tutkimuksen tarkoitus on osoittaa kuinka oleellisesti intertekstuaalisuuden teoria on vaikuttanut kirjallisuustieteen metodeihin ja postmoderniin kirjallisuuskäsitykseen, sekä käsitellä sen soveltuvuutta nykykirjallisuuden tutkimiseen analysoimalla teorian sisäistä monimuotoisuutta ja ristiriitoja. Tutkimusmateriaalina käytetään Smithin romaanin lisäksi E. M. Forsterin romaania Howards End (suom. Talo jalavan varjossa), johon On Beauty tietoisesti viittaa. Teoreettisena viitekehyksenä tutkielmassa toimii Gérard Genetten teoksessa Palimpsests sekä Roland Barthesin esseessä Tekijän kuolema esille tuodut kirjallisuusteoreettiset käsitykset. Valittu metodologia antaa mahdollisuuden hahmottaa intertekstuaalisuus kahdella eri tavalla: Genetten strukturalistinen lähestymistapa soveltuu teosten välisten viittaussuhteiden tutkimiseen, kun taas Barthesin jälkistrukturalistinen diskurssi auttaa ymmärtämään tekstienvälisyyden osana merkityksen jatkuvaa epävakautta. Tutkielman ensimmäinen osio keskittyy analysoimaan lähiluvun keinoin romaanien On Beauty ja Howards End välistä strukturalistista suhdetta vertailemalla teosten eroja ja yhtäläisyyksiä Genetten intertekstuaalisuusteorian valossa. Vertailussa kiinnetetään erityisesti huomiota teosten juoneen, rakenteeseen, aikaan ja paikkaan, sekä uudelleenkirjoitusten yleiseen tendenssiin päivittää alkuperäistä tarinaa kohdeyleisölle paremmin sopivaksi. Toisessa osiossa tutkimusta esille nousee jälkistrukturalistinen näkemys intertekstuaalisuudesta osana lukijan tuottaman merkityksen tulkinnanvaraisuutta. Osiossa käsitellään Rembrandtin taideteosten roolia Smithin romaanissa ja analysoidaan hahmojen tulkintoja sekä suhtautumista Rembrandtin tuotantoon Barthesin teoreettisten käsitteiden kautta. Keskeiseksi analyysin kohteeksi nousee lukija sekä lukijan tuottamat tulkinnat ja niiden merkitys Smithin romaanin tematiikassa. Tutkielmassa osoitetaan kuinka intertekstuaalisuus ei ole niin yksinkertainen termi kuin sen laaja käyttö niin kirjallisuustieteessä kuin mediassakin antaa ymmärtää, sekä selvitetään intertekstuaalisuuden teorian kehitystä 60-luvulta nykypäivään. Vaikka strukturalistisessa muodossa käsite soveltuu etenkin kahden toisiinsa kytkeytyneen teoksen tutkimiseen, vertaileva analyysi kuitenkin osoittaa, että On Beauty ei ole pelkkä uudelleenkirjoitus, vaan romaanin tulkintaan tarvitaan myös jälkistrukturalistisen dekonstruktion käsitteitä, jotta laajemmat tekstuaalisuuden verkostot aukeavat lukijalle. Romaanissa esiintyvä taitelijakuva myös osoittaa, että Smith itse on hyvin tietoinen kirjallisuusteoreettisesta keskustelusta

Improving the diagnosis and management of Lewy body dementia: the DIAMOND-Lewy research programme including pilot cluster RCT

Background: Lewy body dementia, comprising both dementia with Lewy bodies and Parkinson’s disease dementia, is the second commonest cause of neurodegenerative dementia. Existing evidence suggests that it is underdiagnosed and without a consistent approach to management. Objectives: To improve the diagnosis and management of Lewy body dementia by (1) understanding current diagnostic practice for dementia with Lewy bodies and Parkinson’s disease dementia; (2) identifying barriers to and facilitators of diagnosis and management; (3) developing evidence-based assessment toolkits to improve diagnosis of dementia with Lewy bodies and Parkinson’s disease dementia; (4) producing a management toolkit to facilitate management; and (5) undertaking a pilot cluster randomised clinical trial. Design: Work package 1 assessed clinical diagnostic rates from case notes for dementia with Lewy bodies and Parkinson’s disease dementia before and after (work package 1 repeated) introduction of an assessment toolkit. In work package 2, we developed a management toolkit for Lewy body dementia. In work package 3, we developed assessment toolkits for dementia with Lewy bodies and Parkinson’s disease dementia and piloted these and the management toolkit in a clinical service. In work package 4, we undertook a pilot study of 23 services in nine NHS trusts that were cluster randomised to receiving and using the management toolkit or standard care. Work package 5 comprised a series of qualitative studies, examining barriers to and facilitators of diagnosis and management. Setting: Secondary care memory assessment and movement disorder services in England. Interventions: Assessment toolkits for Lewy body dementia consisted of questions for diagnostic symptoms, and management toolkits comprised 161 guidance statements grouped under five symptom domains. Review methods: The systematic reviews of pharmacological and non-pharmacological management were based on published literature, with meta-analysis when possible, following a search of several electronic databases and the grey literature using terms related to Lewy body dementia, without restriction on time or language. Participants: Participants aged ≥ 50 years diagnosed with dementia with Lewy bodies or Parkinson’s disease dementia and, for work package 1 and work package 1 repeated, non-dementia with Lewy bodies and non-Parkinson’s disease dementia controls. The qualitative studies included people with Lewy body dementia, carers and professionals. Main outcome measures: For work packages 1 and 1 repeated, diagnostic rates for dementia with Lewy bodies and Parkinson’s disease dementia as a proportion of all dementia or Parkinson’s disease. For work packages 2 and 3, the production of diagnostic and management toolkits. For work package 4, feasibility of undertaking a cluster randomised trial of the toolkits, measured by number of participants recruited and use of the toolkits, assessed qualitatively. Results: Work package 1 – 4.6% of dementia cases in secondary care received a dementia with Lewy bodies diagnosis (with significant differences in diagnostic rates between services) and 9.7% of those with Parkinson’s disease had a diagnosis of Parkinson’s disease dementia. There was evidence of delays in diagnosis for both dementia with Lewy bodies and Parkinson’s disease dementia compared with control patients, and the costs of dementia with Lewy bodies and Parkinson’s disease dementia were also greater than those for matched controls (p < 0.01 for both). Work package 2 – we produced 252 statements regarding Lewy body dementia management and, following a Delphi process, 161 statements were included in a management toolkit. Work package 3 – piloting indicated that separate assessment toolkits for use in memory clinic and movement disorder services were preferred, but a single toolkit for Lewy body dementia management was suitable. Work package 4 – we were able to recruit Lewy body dementia patients to target and recruited 131 patients within 6 months (target n = 120), of whom > 80% were retained in the study at 6 months. Work package 5 – barriers to diagnosis and management of Lewy body dementia were complex. Managing Lewy body dementia often requires input from a range of specialties and, therefore, care pathways may be fragmented. Positive attitudes to diagnosing Lewy body dementia, working with a team with expertise in Lewy body dementia and opportunities for cross-specialty discussion of patients with complex needs facilitated diagnosis and management. The toolkits were generally well received, particularly the management toolkit. Implementation, however, varied, reflecting differences in attitudes, skills, time and local leadership. Work package 1 repeated – following introduction of the assessment toolkit, we found that 9.7% of dementia cases had dementia with Lewy bodies (a significant increase from baseline; p = 0.0019), but Parkinson’s disease dementia rates were similar (8.2%) to baseline. Limitations: We included only two geographical regions and evidence informing the management toolkit was limited. Work package 4 was a pilot study and, therefore, we did not set out to assess the extent to which use of the management toolkit altered outcomes at the individual patient level. We noted implementation of the toolkits was variable. The increase in diagnostic rates in dementia with Lewy bodies following introduction of the assessment toolkits cannot be necessarily causally attributed to them. Conclusions: Dementia with Lewy bodies and Parkinson’s disease dementia were diagnosed in secondary care NHS services, with a lower frequency (around half) than that expected from known prevalence rates. The introduction of assessment toolkits for dementia with Lewy bodies and Parkinson’s disease dementia was associated with increased diagnostic rates of dementia with Lewy bodies, but not Parkinson’s disease dementia. Qualitative studies indicated inherent complexities of the disease itself, with treatment requiring input from different specialties and the potential for fragmented services, a workforce with variable training and confidence in Lewy body dementia, and negative attitudes towards diagnosis. The cluster randomised pilot trial demonstrated that patients could be successfully recruited, and provided preliminary evidence that the toolkits could be implemented in clinical services. Future work: The evidence base informing the management of Lewy body dementia is limited, especially for non-pharmacological interventions. More well-designed randomised controlled trials for both cognitive and non-cognitive symptoms are needed. Trial registration: Current Controlled Trials ISRCTN11083027. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 7. See the NIHR Journals Library website for further project information

Improving the diagnosis and management of Lewy body dementia: the DIAMOND-Lewy research programme including pilot cluster RCT

Background Lewy body dementia, comprising both dementia with Lewy bodies and Parkinson’s disease dementia, is the second commonest cause of neurodegenerative dementia. Existing evidence suggests that it is underdiagnosed and without a consistent approach to management. Objectives To improve the diagnosis and management of Lewy body dementia by (1) understanding current diagnostic practice for dementia with Lewy bodies and Parkinson’s disease dementia; (2) identifying barriers to and facilitators of diagnosis and management; (3) developing evidence-based assessment toolkits to improve diagnosis of dementia with Lewy bodies and Parkinson’s disease dementia; (4) producing a management toolkit to facilitate management; and (5) undertaking a pilot cluster randomised clinical trial. Design Work package 1 assessed clinical diagnostic rates from case notes for dementia with Lewy bodies and Parkinson’s disease dementia before and after (work package 1 repeated) introduction of an assessment toolkit. In work package 2, we developed a management toolkit for Lewy body dementia. In work package 3, we developed assessment toolkits for dementia with Lewy bodies and Parkinson’s disease dementia and piloted these and the management toolkit in a clinical service. In work package 4, we undertook a pilot study of 23 services in nine NHS trusts that were cluster randomised to receiving and using the management toolkit or standard care. Work package 5 comprised a series of qualitative studies, examining barriers to and facilitators of diagnosis and management. Setting Secondary care memory assessment and movement disorder services in England. Interventions Assessment toolkits for Lewy body dementia consisted of questions for diagnostic symptoms, and management toolkits comprised 161 guidance statements grouped under five symptom domains. Review methods The systematic reviews of pharmacological and non-pharmacological management were based on published literature, with meta-analysis when possible, following a search of several electronic databases and the grey literature using terms related to Lewy body dementia, without restriction on time or language. Participants Participants aged ≥ 50 years diagnosed with dementia with Lewy bodies or Parkinson’s disease dementia and, for work package 1 and work package 1 repeated, non-dementia with Lewy bodies and non-Parkinson’s disease dementia controls. The qualitative studies included people with Lewy body dementia, carers and professionals. Main outcome measures For work packages 1 and 1 repeated, diagnostic rates for dementia with Lewy bodies and Parkinson’s disease dementia as a proportion of all dementia or Parkinson’s disease. For work packages 2 and 3, the production of diagnostic and management toolkits. For work package 4, feasibility of undertaking a cluster randomised trial of the toolkits, measured by number of participants recruited and use of the toolkits, assessed qualitatively. Results Work package 1 – 4.6% of dementia cases in secondary care received a dementia with Lewy bodies diagnosis (with significant differences in diagnostic rates between services) and 9.7% of those with Parkinson’s disease had a diagnosis of Parkinson’s disease dementia. There was evidence of delays in diagnosis for both dementia with Lewy bodies and Parkinson’s disease dementia compared with control patients, and the costs of dementia with Lewy bodies and Parkinson’s disease dementia were also greater than those for matched controls (p  80% were retained in the study at 6 months. Work package 5 – barriers to diagnosis and management of Lewy body dementia were complex. Managing Lewy body dementia often requires input from a range of specialties and, therefore, care pathways may be fragmented. Positive attitudes to diagnosing Lewy body dementia, working with a team with expertise in Lewy body dementia and opportunities for cross-specialty discussion of patients with complex needs facilitated diagnosis and management. The toolkits were generally well received, particularly the management toolkit. Implementation, however, varied, reflecting differences in attitudes, skills, time and local leadership. Work package 1 repeated – following introduction of the assessment toolkit, we found that 9.7% of dementia cases had dementia with Lewy bodies (a significant increase from baseline; p = 0.0019), but Parkinson’s disease dementia rates were similar (8.2%) to baseline. Limitations We included only two geographical regions and evidence informing the management toolkit was limited. Work package 4 was a pilot study and, therefore, we did not set out to assess the extent to which use of the management toolkit altered outcomes at the individual patient level. We noted implementation of the toolkits was variable. The increase in diagnostic rates in dementia with Lewy bodies following introduction of the assessment toolkits cannot be necessarily causally attributed to them. Conclusions Dementia with Lewy bodies and Parkinson’s disease dementia were diagnosed in secondary care NHS services, with a lower frequency (around half) than that expected from known prevalence rates. The introduction of assessment toolkits for dementia with Lewy bodies and Parkinson’s disease dementia was associated with increased diagnostic rates of dementia with Lewy bodies, but not Parkinson’s disease dementia. Qualitative studies indicated inherent complexities of the disease itself, with treatment requiring input from different specialties and the potential for fragmented services, a workforce with variable training and confidence in Lewy body dementia, and negative attitudes towards diagnosis. The cluster randomised pilot trial demonstrated that patients could be successfully recruited, and provided preliminary evidence that the toolkits could be implemented in clinical services. Future work The evidence base informing the management of Lewy body dementia is limited, especially for non-pharmacological interventions. More well-designed randomised controlled trials for both cognitive and non-cognitive symptoms are needed

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

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