Elucidation of 1H NMR Paramagnetic Features of Heterotrimetallic Lanthanide(III)/Manganese(III) 12-MC-4 Complexes

The paramagnetic one-dimensional 1H NMR spectra of twelve LnIIINaI(OAc)4[12-MCMnIII(N)shi-4] complexes, where LnIII is PrIII-YbIII (except PmIII) and YIII, are reported. Their solid-state isostructural nature is confirmed in methanol-d4 solution, as a similar pattern in the 1H NMR spectra is observed along the series. Notably, a relatively well-resolved spectrum is reported for the GdIII complex. The chemical shift data are analyzed using the "all lanthanides" method, and the Fermi contact and pseudo-contact contributions are calculated for the lanthanide-induced shift (LIS). For the TbIII-YbIII complexes, the pseudo-contact contributions are typically 1 order of magnitude higher than the Fermi contact contributions; however, for the GdIII complex, the Fermi contact is the main contribution to the paramagnetic chemical shift. For the methyl protons of the axial acetate (-OAc) ligands, the LIS is opposite in sign, with respect to that of the aromatic salicylhydroximate (shi3-) protons, because of structural rearrangements that occur upon dissociation of the NaI cation in solution. The calculated crystal field parameters (BLn) for the TbIII (360 cm-1), DyIII (250 cm-1), HoIII (380 cm-1), ErIII (410 cm-1), TmIII (620 cm-1), and YbIII (380 cm-1) complexes are not constant, likely as a consequence of the inaccuracy of the Bleaney's constants and, to a smaller extent, the small structural changes that occur in solution. Overall, the metallacrown scaffold retains structural integrity and similarity in solution for the entire series; however, small structural features, which do not affect the overall similarity, do likely occur

Three-Dimensional Porous Architectures Based on Mn II/III Three-Blade Paddle Wheel Metallacryptates

hree metallacryptate supramolecular assemblies have been obtained using salicylhydroxamic acid derivatives. The periphery of the ligands has been designed to obtain interactions between the metallacryptate units. By the use of ligands which bear amino (NH2) or 4-pyridyl groups the units assemble into parallel chains and into a MOF-like structure, respectively. In both solids, a honeycomb porous structure is obtained

Unique Dimerization Topology and Countercation Binding Modes in 12-Metallacrown-4 Compounds

Seven dimeric metallacrowns (MC) based on Ln[12-MCM(III)N(shi)-4], where LnIII=Dy, Ho, Yb, or Y, MIII=Mn or Ga, and shi3− is salicylhydroximate, have been synthesized and characterized by single-crystal X-ray diffraction, and for the dysprosium-manganese dimers, the magnetic properties have been measured. In each dimer two Ln[12-MCM(III)N(shi)-4] units are linked by four bridging dicarboxylate anions (isophthalate, trimesate, dinicotinate, or 2,2′-dithiodibenzoate). Three different countercations (sodium, gallium(III), or pyridinium) were used to maintain charge balance of the dimer. While pyridinium does not bind to the dimer, the choice of the dicarboxylate dictates where the countercations Na+ or GaIII bind. With isophthalate and trimesate, the sodium ion binds to the central MC cavity opposite of the LnIII, and with dinicotinate the sodium or gallium(III) ions bind to the pyridyl nitrogen of the dinicotinate. All three Dy2Mn8 dimers exhibit an out-of-phase magnetic susceptibility signal consistent with a shallow barrier to magnetization relaxation.The structures of seven dimeric heterometallic metallacrowns are described. Each dimer consists of two 12-metallacrown-4 units (ring metals Mn3+ or Ga3+) linked together by dicarboxylate anions (isophthalate, trimesate, dinicotinate, or 2,2′-dithiodibenzoate). Each metallacrown unit also contains one lanthanide ion bound to the central cavity. Lastly, the magnetism of the dysprosium-manganese dimers is examined, and each display slow magnetic relaxation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175227/1/ejic202200439_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175227/2/ejic202200439.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175227/3/ejic202200439-sup-0001-misc_information.pd

Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis: The MERCY Randomized Clinical Trial

Importance: Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes. Objective: To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis. Design, setting, and participants: A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022. Interventions: Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304). Main outcomes and measures: The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events. Results: All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients). Conclusions and relevance: In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. Trial registration: ClinicalTrials.gov Identifier: NCT03452839

Continuous infusion versus intermittent administration of meropenem in critically ill patients (MERCY): A multicenter randomized double-blind trial. Rationale and design

Meropenem is a β-lactam, carbapenem antibacterial agent with antimicrobial activity against gram-negative, gram-positive and anaerobic micro-organisms and is important in the empirical treatment of serious infections in Intensive Care Unit (ICU) patients. Multi-drug resistant gram-negative organisms, coupled with scarcity of new antibiotic classes, forced healthcare community to optimize the therapeutic potential of available antibiotics. Our aim is to investigate the effect of continuous infusion of meropenem against bolus administration, as indicated by a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens in a population of ICU patients

High dose esomeprazole as an anti-inflammatory agent in sepsis: Protocol for a randomized controlled trial

Background: Sepsis is caused by dysregulated immune responses due to infection and still presents high mortality rate and limited efficacious therapies, apart from antibiotics. Recent evidence suggests that very high dose proton pump inhibitors might regulate major sepsis mediators' secretion by monocytes, which might attenuate excessive host reactions and improve clinical outcomes. This effect is obtained with doses which are approximately 50 times higher than prophylactic esomeprazole single daily administration and 17 times higher than the cumulative dose of a three day prophylaxis. We aim to perform a randomized trial to investigate if high dose esomeprazole reduces organ dysfunction in patients with sepsis or septic shock. Methods: This study, called PPI-SEPSIS, is a multicenter, randomized, double blind, placebo-controlled clinical trial on critically ill septic patients admitted to the emergency department or intensive care unit. A total of 300 patients will be randomized to receive high dose esomeprazole (80 mg bolus followed by 12 mg/h for 72 h and a second 80 mg bolus 12 h after the first one) or equivolume placebo (sodium chloride 0.9%), with 1:1 allocation. The primary endpoint of the study will be mean daily Sequential Organ Failure Assessment (SOFA) score over 10 days. Secondary outcomes will include antibiotic-free days, single organ failure severity, intensive care unit-free days at day 28, and mortality. Discussion: This trial aims to test the efficacy of high dose esomeprazole to reduce acute organ dysfunction in patients with septic shock. Trial registration: This trial was registered on ClinicalTrials.gov with the trial identification NCT03452865 in March 2018

A Bayesian reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial

Background Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%], − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation

Regional Practice Variation and Outcomes in the Standard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) Trial: A Post Hoc Secondary Analysis.

ObjectivesAmong patients with severe acute kidney injury (AKI) admitted to the ICU in high-income countries, regional practice variations for fluid balance (FB) management, timing, and choice of renal replacement therapy (RRT) modality may be significant.DesignSecondary post hoc analysis of the STandard vs. Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial (ClinicalTrials.gov number NCT02568722).SettingOne hundred-fifty-three ICUs in 13 countries.PatientsAltogether 2693 critically ill patients with AKI, of whom 994 were North American, 1143 European, and 556 from Australia and New Zealand (ANZ).InterventionsNone.Measurements and main resultsTotal mean FB to a maximum of 14 days was +7199 mL in North America, +5641 mL in Europe, and +2211 mL in ANZ (p p p p p p p p = 0.007).ConclusionsAmong STARRT-AKI trial centers, significant regional practice variation exists regarding FB, timing of initiation of RRT, and initial use of continuous RRT. After adjustment, such practice variation was associated with lower ICU and hospital stay and 90-day mortality among ANZ patients compared with other regions