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

A Unified Approach for the Evaluation of Telehealth Implementations in Australia

This paper was produced as part of a one year study, funded by the University of Melbourne interdisciplinary seed grant. This paper will firstly provide a conceptual framework that incorporates the key dimensions, criteria and measures that need to be considered in the evaluation of telehealth implementations in Australia. Telehealth evaluation can be considered to be the examination of the effectiveness, appropriateness and cost of a telehealth service, by answering four fundamental questions 1) does the intervention work; 2) for whom; 3) at what cost and 4) how does it compare with the alternatives?1 In helping to address these questions for telehealth evaluation in the Australian context, this framework is linked back to a national, validated health performance framework (Australian Institute of Health and Welfare, 2009). The AIHW framework was also used to form a link between the evaluation criteria and measures described in international literature, to health performance indicators. This resulting conceptual framework will be modified and validated with 3 to 5 case studies involving interviews, focus groups with key stakeholders involved in telehealth implementations. This framework will make it more efficient to undertake evaluation of any Australian telehealth implementation, to produce more widely applicable findings, to share these and to improve practice based on the collective results. This paper will be of interest to decision makers, coordinators of telehealth programs or others who are either involved in or concerned about the evaluation of telehealth implementations in Australia. It is a timely and valuable resource, especially in light of the recent recommendations put forth by the Health Innovation and Reform Council, Department of Health, Victoria.2 This paper also provides an evidence base that illustrates the current state of telehealth evaluation on an international scale

Protective porcine influenza virus-specific monoclonal antibodies recognize similar haemagglutinin epitopes as humans.

Pigs are natural hosts for the same subtypes of influenza A viruses as humans and integrally involved in virus evolution with frequent interspecies transmissions in both directions. The emergence of the 2009 pandemic H1N1 virus illustrates the importance of pigs in evolution of zoonotic strains. Here we generated pig influenza-specific monoclonal antibodies (mAbs) from H1N1pdm09 infected pigs. The mAbs recognized the same two major immunodominant haemagglutinin (HA) epitopes targeted by humans, one of which is not recognized by post-infection ferret antisera that are commonly used to monitor virus evolution. Neutralizing activity of the pig mAbs was comparable to that of potent human anti-HA mAbs. Further, prophylactic administration of a selected porcine mAb to pigs abolished lung viral load and greatly reduced lung pathology but did not eliminate nasal shedding of virus after H1N1pdm09 challenge. Hence mAbs from pigs, which target HA can significantly reduce disease severity. These results, together with the comparable sizes of pigs and humans, indicate that the pig is a valuable model for understanding how best to apply mAbs as therapy in humans and for monitoring antigenic drift of influenza viruses in humans, thereby providing information highly relevant to making influenza vaccine recommendations

Aspects of extended impregnation kraft cooking for high-yield pulping of hardwood

The long-term trend regarding wood is an increase in price. Because wood contributes to a large part of production costs, the efficient utilisation of wood is greatly desired to reduce production costs for kraft pulp producers. During the 1990s, the development of improved modified kraft cooking began, which led to higher yields. There was also a trend of terminating kraft cooking at a higher kappa number to maximise the overall yield. For hardwood, the defibration point became a critical setback in allowing this termination at a high kappa number. This thesis discusses how this issue has been tackled in the laboratory by using improved modified kraft cooking combined with extended impregnation to enable a decrease in reject content and shift the defibration point towards a higher kappa number for hardwood. This lab concept is referred to as extended impregnation kraft cooking (EIC), and this thesis reveals that EIC cooking efficiently reduces the reject content for both birch and eucalypt. By using EIC cooking, the defibration point was shifted to a kappa number of ca. 30 from ca. 20 using conventional kraft cooking. This study demonstrates the great potential for achieving a higher overall yield for eucalypt by terminating the EIC cooking at a high kappa number, but with the conditions used in this thesis, no improvement in yield was observed for birch.   An important issue is that the termination of kraft cooking at high kappa number increases the demand for extended oxygen delignification to reach a similar kappa number into bleaching, i.e., due to cost and environmental reasons. Extended oxygen delignification was shown to be possible for both birch and eucalypt EIC pulps (i.e., from kappa number 27 to 10) with an acceptable pulp viscosity number.   The other part of this thesis addresses aspects regarding the limitations in oxygen delignification. It has previously been shown in the literature that a high xylan yield of kraft cooking could negatively affect the efficiency of subsequent oxygen delignification. In this work, the increased xylan content in eucalypt kraft pulp within the range of 8–18% had only a marginally negative impact on the oxygen delignification efficiency after correcting for the HexA contribution to the kappa number. It is also desired to extend the oxygen delignification towards lower kappa number, i.e., below kappa number 10 to decrease the bleaching chemical requirement. In this study, the hypothesis that the reduced efficiency of oxygen delignification at low kappa numbers could partly be due to the formation of oxidisable carbohydrate-related structures (i.e., HexA and/or other non-lignin structures) was also tested. No formation was established. On the other hand, a final oxygen delignification stage in the bleaching could be an attractive alternative for reducing yellowing and enhancing brightness; in fact, this has led to the development of a patent (SE 528066).Ved står för en stor del av produktionskostnaderna vid framställning av sulfatmassa. Då vedpriserna har ökat genom åren är ett effektivt utnyttjande av veden önskvärt för att kunna sänka produktionskostnaderna. Under 1990-talet förbättrades den modifierade sulfatkokningen vilket innebar möjlighet till högre massautbyte. För att maximera massautbytet styrdes kokningsprocessen mot ett högre kappatal. Detta har visat sig vara svårare för lövved än för barrved, eftersom defibrerbarhetspunkten utgör ett kritiskt hinder. I denna avhandling har laborationsstudier utförts där förbättrad modifierad sulfatkokning kombinerats med förlängd impregnering för att kunna sänka spethalten och därmed förskjuta defibrerbarhetspunkten mot ett högre kappatal. Detta koncept kallas för extended impregnation kraft cooking (EIC). EIC-kokning visade sig vara en effektiv metod för att minska spethalten hos björk och eukalyptus. Med EIC-kokning kunde defibrerbarhetspunkten höjas från cirka 20 till cirka 30. I denna avhandling klarläggs att det finns stora möjligheter att öka massautbytet för eukalyptus genom att avsluta sulfatkoket vid ett högre kappatal. För björk kunde ingen ökning av massutbytet uppnås genom ovanstående metod.   Vid ett högre kappatal efter sulfatkoket ställs även krav på förlängd syrgasdelignifiering, för att kunna behålla samma kappatal in till blekeriet. Det visade sig vara fullt möjligt att förlänga syrgasdelignifieringen för de EIC-kokade björk- och eukalyptusmassorna (d.v.s. från kappatal 27 till 10) med accepterad massaviskositet.   Den andra delen av avhandlingen tar upp aspekter på syrgasdelignifieringens begränsningar. Tidigare studier har visat att ett högre utbyte av xylan vid sulfatkokning kan vara negativt för syrgasdelignifieringens effektivitet.  I denna studie har det påvisats att en ökad xylanhalt i intervallet 8–18 procent i eukalyptusmassa endast har en marginell negativ inverkan på syrgasdelignifieringens effektivitet efter att kappatalet korrigerats för HexA. Det är önskvärt att förlänga syrgasdelignifieringen till ett lägre kappatal än 10 för att minska förbrukningen av blekkemikalier. I den här studien prövades hypotesen att syrgasdelignifieringens begränsningar vid låga kappatal, under 10, delvis skulle kunna bero på bildning av oxiderbara kolhydratrelaterade strukturer (d.v.s. HexA och/eller andra okända ”non-lignin”-strukturer). Ingen bildning kunde dock observeras. Däremot indikerades att ett syrgassteg i slutet av bleksekvensen skulle kunna vara ett eftersträvansvärt alternativ för minskad eftergulning och ökad ljushet, vilket ledde till ett patent (SE 528066).QC 2012050