A novel counterbalanced implementation study design : methodological description and application to implementation research

Background: Implementation research is increasingly being recognised for optimising the outcomes of clinical practice. Frequently, the benefits of new evidence are not implemented due to the difficulties applying traditional research methodologies to implementation settings. Randomised controlled trials are not always practical for the implementation phase of knowledge transfer, as differences between individual and organisational readiness for change combined with small sample sizes can lead to imbalances in factors that impede or facilitate change between intervention and control groups. Within-cluster repeated measure designs could control for variance between intervention and control groups by allowing the same clusters to receive a sequence of conditions. Although in implementation settings, they can contaminate the intervention and control groups after the initial exposure to interventions. We propose the novel application of counterbalanced design to implementation research where repeated measures are employed through crossover, but contamination is averted by counterbalancing different health contexts in which to test the implementation strategy. Methods: In a counterbalanced implementation study, the implementation strategy (independent variable) has two or more levels evaluated across an equivalent number of health contexts (e.g. community-acquired pneumonia and nutrition for critically ill patients) using the same outcome (dependent variable). This design limits each cluster to one distinct strategy related to one specific context, and therefore does not overburden any cluster to more than one focussed implementation strategy for a particular outcome, and provides a ready-made control comparison, holding fixed. The different levels of the independent variable can be delivered concurrently because each level uses a different health context within each cluster to avoid the effect of treatment contamination from exposure to the intervention or control condition. Results: An example application of the counterbalanced implementation design is presented in a hypothetical study to demonstrate the comparison of 'video-based' and 'written-based' evidence summary research implementation strategies for changing clinical practice in community-acquired pneumonia and nutrition in critically ill patient health contexts. Conclusion: A counterbalanced implementation study design provides a promising model for concurrently investigating the success of research implementation strategies across multiple health context areas such as community-acquired pneumonia and nutrition for critically ill patients. © 2019 The Author(s). **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Jennifer Martin" is provided in this record*

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

New N- and O-donor ligand environments in organoscandium chemistry

The synthesis and characterisation of three new classes of organoscandium compound with non-cyclopentadienyl, mono- or di-anionic supporting ligands possessing N4-, N3O- or N2O2-donor atom sets are described. © 2002 Elsevier Science B.V. All rights reserved

New group 4 organometallic and imido compounds of diamide-diamine and related dianionic O2N2-donor ligands

New group 4 compounds supported by the tetradentate diamide-diamine ligand N2NN′ are reported (N2NN′ = (2-C 5H4N)CH2N(CH2CH 2NSiMe3)2) along with some comparative studies with the new bis(alkoxide)-diamine ligand O2NN′ (O 2NN′ = (2-C5H4N)CH2N(CH 2-CMe2O)2). Reaction of the previously described ZrCl2(N2NN′) (1) with 2 equiv of MeLi or PhCH2MgCl gave ZrR2(N2NN′) (R = Me (2) or CH2Ph (3)). Reaction of 1 with 1 equiv of RCH2MgCl gave the monoalkyl analogues ZrCl(R)(N2NN′) (R = CH2Ph (6) or CH2SiMe3 (7)). Reaction of Zr(CH2R) 4 (R = SiMe3 or CMe3) with H2N 2NN′ in C6D6 gave the corresponding Zr(CH2R)2(N2NN′), but these decomposed over several hours. Reaction of 1 with allylmagnesium chloride gave ZrCl{(2-NC5(6-C3H5)H4)CH 2N(CH2CH2NSiMe3)2}, in which the pyridyl group has undergone nucleophilic attack. Reaction of 2 with BArF3 (ArF = C6F5) in benzene led to the cyclometalated cation [Zr{(2-NC5H 4)CH2N(CH2CH2NSiMe 3)(CH2CH2NSiMe2CH 2-)}]+ via SiMe3 group C-H activation, but in the presence of THF the methyl cation [ZrMe-(THF)(N2NN′)] + was formed. Reaction of 6 with BAr3F gave the chloride cation [ZrCl(N2-NN′)]+. Reaction of Li2N2NN′ with Ti(NR)Cl2(py)3 gave the five-coordinate imides Ti(NR)(N2NN′) (R = tBu or Ar (15), Ar = 2,6-C6H3iPr2). Zirconium imides Zr(NAr)(N2NN′) and Zr(NtBu)-(py)(N2NN′) (18) were prepared by sequential reaction of 1 with LiCH2SiMe3 (2 equiv) and the appropriate amine and pyridine for the latter. Reaction of 1 with LiNH tBu (2 equiv) gave Zr(NHtBu)2(N 2NN′). Reaction of 18 with piperidine gave Zr(NH tBu)(NC5H10)(N2NN′) (19) via N-H bond activation. For comparative purposes the group 5 imides M(N tBu)Cl(N2NN′) (M = Nb (20) or Ta (21)) were prepared from Li2N2NN′ and the corresponding M(N t-Bu)Cl3(py)2. Reaction of 2- aminomethylpyridine with an excess of isobutylene oxide afforded H 2O2NN′ (22). Reaction of H2O 2NN′ (1 or 2 equiv) with Ti(NMe2)4 gave Ti(O2NN′)2, which reacted with TiCl 4(THF)2 to form TiCl2(O2NN′). Reaction of H2O2NN′ with Zr(CH2SiMe 3)2-Cl2(Et2O)2, Zr(NMe2)4, or Zr(CH2SiMe3) 4 gave ZrX2(O2NN′) (X = Cl, NMe 2, or CH2SiMe3 (27)). Reaction of 27 with BAr3F in the presence of THF formed [Zr(CH 2SiMe3)(THF)(O2NN′)]+, but in the absence of a Lewis base the μ-alkoxide-bridged dimer [Zr 2(CH2SiMe3)2(O2NN′) 2]2+ was formed. The compounds 3, 6, 15, 19, 21, 22, and 27 were crystallographically characterized. © 2005 American Chemical Society