Synthesis, Structures, and Reactivity of Organostannanides and Organogermanides of Copper(I).

Organogermane and organostannane compounds are valuable reagents in cross coupling reactions, and copper(I) germanide and stannanide complexes can provide convenient access to these compounds. This review presents the chemistry of copper(I) germanide and stannanide complexes, with a particular focus on systems at the frontier of organic and inorganic chemistry where structural characterisation of coordination complexes facilitates rationalisation of organic mechanisms. These species show both similarities to, and significant divergences from their lighter silanide congeners. For example, they are all viable sources of the relevant organotetranide anion, but in the cases of both germanium and tin, the tetranides can be accessed via direct deprotonation of the corresponding tetranes, a reaction unknown for silicon. Further divergences between copper(I) germanides and stannanides are highlighted; whilst both can be used in productive organic transformations to access organotetranes, catalytic reactions are only reported for germanium. The rather striking ability of triphenlstannides to acts as sources of the phenyl anion are discussed; the mechanism of this reaction is still subject to discussion, but its absence in the chemistry of germanium and silicon is now well-rationalised. We conclude this review by considering potential research directions in the synthesis and exploitation of copper(I) germanides and stannanides.

Copper(I) Catalysed Diboron(4) Reduction of Nitrous Oxide.

A process for the catalytic reduction of nitrous oxide using NHC-ligated copper(I) tert-butoxide precatalysts and B2pin2 as the reductant is reported. The reaction proceeds under mild conditions via copper(I)-boryl intermediates which react with N2O by facile O-atom insertion into the Cu-B bond and liberate N2. Turnover numbers > 800 can be achieved at 80 °C under 1 bar N2O.

Dial-a-base mechanochemical synthesis of N-heterocyclic carbene copper complexes.

Liquid assisted ball milling of [NHC]HBr (NHC = N-heterocyclic carbene) salts with copper(I) chloride, and a range of alkali metal complexes was shown to efficiently produce (NHC)CuX (NHC = normal or RE-NHC, X = halide, alkoxide, amide, alkyl, aryl; RE-NHC = ring-expanded NHC).

The structures and reactivity of NHC-supported copper(i) triphenylgermyls.

Deprotonation of triphenyl germane with NHC-supported copper alkoxides afforded four novel (NHC)CuGePh3 complexes. Of these, (IPr)CuGePh3 (IPr = :C{N(2,6-iPr2C6H3)CH}2) was selected for further investigation. Analysis by EDA-NOCV indicates it to be a germyl nucleophile and its σ-bond metathesis reaction with a range of p-block halides confirmed it to be a convenient source of [Ph3Ge]-. The Cu-Ge bond of (IPr)CuGePh3 underwent π-bond insertions with tBuNCS, CS2, and PhNCO to furnish a series of germyl substituted carboxylate derivatives, (IPr)CuXC(Y)GePh3 (X = S, NPh; Y = S, NtBu, O), which were structurally characterised. (IPr)CuGePh3 inserted phenyl acetylene, providing both the Markovnikov and anti-Markovnikov products. The (NHC)CuGePh3 compounds were validated as catalytic intermediates; addition of 10 mol% of NHC-copper(i) alkoxide to a mixture of triphenyl germane and a tin(iv) alkoxide resulted in a tin/germanium cross coupling with concomitant formation of alcohol. Moreover, a catalytic hydrogermylation of Michael acceptors was developed with Ph3GeH adding to 7 activated alkenes in good conversions and yields in the presence of 10 mol% of NHC-copper(i) alkoxide. In all cases, this reaction provided the ß-germylated substrate implicating nucleophilicity at germanium.

Anaesthetic efficacy and postinduction hypotension with remimazolam compared with propofol: a multicentre randomised controlled trial.

Remimazolam, a short-acting benzodiazepine, may be used for induction and maintenance of total intravenous anaesthesia, but its role in the management of patients with multiple comorbidities remains unclear. In this phase 3 randomised controlled trial, we compared the anaesthetic efficacy and the incidence of postinduction hypotension during total intravenous anaesthesia with remimazolam vs. propofol. A total of 365 patients (ASA physical status 3 or 4) scheduled for elective surgery were assigned randomly to receive total intravenous anaesthesia with remimazolam (n = 270) or propofol (n = 95). Primary outcome was anaesthetic effect, quantified as the percentage of time with Narcotrend® Index values ≤ 60, during surgery (skin incision to last skin suture), with a non-inferiority margin of -10%. Secondary outcome was the incidence of postinduction hypotensive events. Mean (SD) percentage of time with Narcotrend Index values ≤ 60 during surgery across all patients receiving remimazolam (93% (20.7)) was non-inferior to propofol (99% (4.2)), mean difference (97.5%CI) -6.28% (-8.89-infinite); p = 0.003. Mean (SD) number of postinduction hypotension events was 62 (38.1) and 71 (41.1) for patients allocated to the remimazolam and propofol groups, respectively; p = 0.015. Noradrenaline administration events (requirement for a bolus and/or infusion) were also lower in patients allocated to remimazolam compared with propofol (14 (13.5) vs. 20 (14.6), respectively; p < 0.001). In conclusion, in patients who were ASA physical status 3 or 4, the anaesthetic effect of remimazolam was non-inferior to propofol.

Acyclic Boryl Complexes of Copper(I).

Reaction of (6-Dipp)CuOtBu (6-Dipp=C{NDippCH2 }2 CH2 , Dipp=2,6-iPr2 C6 H3 ) with B2 (OMe)4 provided access to (6-Dipp)CuB(OMe)2 via σ-bond metathesis. (6-Dipp)CuB(OMe)2 was characterised by NMR spectroscopy and X-ray crystallography and shown to be a monomeric acyclic boryl of copper. (6-Dipp)CuB(OMe)2 reacted with ethylene and diphenylacetylene to provide insertion compounds into the Cu-B bond which were characterised by NMR spectroscopy in both cases and X-ray crystallography in the latter. It was also competent in the rapid catalytic deoxygenation of CO2 in the presence of excess B2 (OMe)4 . Alongside π-insertion, (6-Dipp)CuB(OMe)2 reacted with LiNMe2 to provide a salt metathesis reaction at boron, giving (6-Dipp)CuB(OMe)NMe2 , a second monomeric acyclic boryl, which also cuproborated diphenylacetylene. Computational interrogation validated these acyclic boryl species to be electronically similar to (6-Dipp)CuBpin.

The effect of anterior quadratus lumborum block on morphine consumption in minimally invasive colorectal surgery: a multicentre, double-blind, prospective randomised placebo-controlled trial.

We investigated the efficacy and safety of a bilateral anterior quadratus lumborum block in patients undergoing minimally invasive colorectal surgery. This was a two-centre, double-blind, prospective, randomised, placebo-controlled trial including 150 patients undergoing laparoscopic colorectal surgery (left- or right hemicolectomy, sigmoidectomy) who were enrolled in the institutional abdominal enhanced recovery programme. Before induction of anaesthesia, patients received a bilateral anterior quadratus lumborum block in the left and right lateral decubitus position under ultrasound guidance and were allocated randomly to receive 30 ml of ropivacaine 0.375% (n = 75) or placebo (saline 0.9%) (n = 75) bilaterally. Postoperatively, all patients received multimodal intravenous analgesia including paracetamol, ketorolac and patient-controlled analgesia with morphine. The primary outcome was morphine consumption during the first 24 h after tracheal extubation. Secondary outcomes included severity of pain; presence and extent of sensory block; incidence of postoperative nausea and vomiting; and hospital duration of stay. We also investigated the need for, and dose of, rescue analgesia. Safety outcomes included the incidence of adverse events. Mean (SD) 24-hour morphine consumption was no different between patients allocated to ropivacaine and placebo (28.6 (22.3) mg vs. 28.4 (22.5) mg, p = 0.966, respectively). While a sensory block could be detected in significantly more patients allocated to the ropivacaine group, no differences were detected in pain scores or other secondary or safety endpoints. Patient satisfaction scores were high in both groups. In laparoscopic colorectal surgery, adding a bilateral anterior quadratus lumborum block to a standard multimodal analgesia regimen did not reduce opioid consumption or improve pain scores.

High-volume patient-controlled epidural vs. programmed intermittent epidural bolus for labour analgesia: a randomised controlled study.

The aim of neuraxial analgesia is to achieve excellent pain relief with the fewest adverse effects. The most recently introduced technique for epidural analgesia maintenance is the programmed intermittent epidural bolus. In a recent study, we compared this with patient-controlled epidural analgesia without a background infusion and found that a programmed intermittent epidural bolus was associated with less breakthrough pain, lower pain scores, higher local anaesthetic consumption and comparable motor block. However, we had compared 10 ml programmed intermittent epidural boluses with 5 ml patient-controlled epidural analgesia boluses. To overcome this potential limitation, we designed a randomised, multicentre non-inferiority trial using 10 ml boluses in each group. The primary outcome was the incidence of breakthrough pain and total analgesic intake. Secondary outcomes included motor block; pain scores; patient satisfaction; and obstetric and neonatal outcomes. The trial was considered positive if two endpoints were met: non-inferiority of patient-controlled epidural analgesia with respect to breakthrough pain; and superiority of patient-controlled epidural analgesia with respect to local anaesthetic consumption. A total of 360 nulliparous women were allocated randomly to patient-controlled epidural analgesia-only or programmed intermittent epidural bolus groups. The patient-controlled group received 10 ml boluses of ropivacaine 0.12% with sufentanil 0.75 µg.ml-1 ; the programmed intermittent group received 10 ml boluses supplemented by 5 ml patient-controlled boluses. The lockout period was 30 min in each group and the maximum allowed hourly local anaesthetic/opioid consumption was identical between the groups. Breakthrough pain was similar between groups (11.2% patient controlled vs. 10.8% programmed intermittent, p = 0.003 for non-inferiority). Total ropivacaine consumption was lower in the PCEA-group (mean difference 15.3 mg, p < 0.001). Motor block, patient satisfaction scores and maternal and neonatal outcomes were similar across both groups. In conclusion, patient-controlled epidural analgesia is non-inferior to programmed intermittent epidural bolus if equal volumes of patient-controlled epidural analgesia are used to maintain labour analgesia and superior with respect to local anaesthetic consumption.

Neurodevelopmental outcomes after prenatal exposure to anaesthesia for maternal surgery: a propensity-score weighted bidirectional cohort study.

Up to 1% of pregnant women undergo anaesthesia for non-obstetric surgery. This study investigated neurodevelopmental outcomes after prenatal anaesthesia for maternal surgery. A bidirectional cohort study of children born between 2001 and 2018 was performed: neurodevelopmental outcomes of children who had received prenatal anaesthesia for maternal surgery were prospectively compared with unexposed children, with exposure status being assessed retrospectively. Children exposed to anaesthesia for obstetric and fetal surgery were excluded. The primary outcome was the global executive composite of the behaviour rating inventory of executive function score. Our secondary outcomes were: total problems; internalising problems and externalising problems derived from the child behaviour checklist; psychiatric diagnoses; and learning disorders. In 90% of exposed children, there was a single mean (SD) antenatal anaesthesia exposure lasting 91(94) min. There was a broad spectrum of indications, with abdominal surgery being most frequent. Parents of 129 exposed (response rate 68%) and 453 unexposed (response rate 63%) children participated. There were no arguments for non-response bias. After propensity weighting, there were no statistically significant differences in primary outcome, with a weighted mean difference (95%CI) of exposed minus unexposed children of 1.9 (-0.4-4.2), p = 0.10; or any of the secondary outcomes. Sensitivity analyses confirmed the robustness. Exploratory analyses, however, showed significant differences in certain subgroups for the primary outcome, (e.g. for intra-abdominal surgery, exposure duration > 1 h) and some cognitive subdomains (e.g. working memory and attention). This bidirectional cohort study, the largest investigation on the subject to date, has found no evidence in the general population for an association between prenatal exposure to anaesthesia and impaired neurodevelopmental outcomes.

The structures of ring-expanded NHC supported copper(I) triphenylstannyls and their phenyl transfer reactivity towards heterocumulenes.

Three ring-expanded N-heterocyclic carbene-supported copper(I) triphenylstannyls have been synthesised by the reaction of (RE-NHC)CuOtBu with triphenylstannane (RE-NHC = 6-Mes, 6-Dipp, 7-Dipp). The compounds were characterised by NMR spectroscopy and X-ray crystallography. Reaction of (6-Mes)CuSnPh3 with di-p-tolyl carbodiimide, phenyl isocyanate and phenylisothiocyanate gives access to a copper(I) benzamidinate, benzamide and benzothiamide respectively via phenyl transfer from the triphenylstannyl anion with concomitant formation of (Ph2Sn)n. Attempts to exploit this reactivity under a catalytic regime were hindered by rapid copper(I)-catalysed dismutation of Ph3SnH to Ph4Sn, various perphenylated tin oligomers, H2 and a metallic material thought to be Sn(0). Mechanistic insight was provided by reaction monitoring via NMR spectroscopy and mass spectrometry.

A stable ring-expanded NHC-supported copper boryl and its reactivity towards heterocumulenes.

Reaction of bis(pinacolato)diboron with (6-Dipp)CuOtBu generates a ring-expanded N-heterocyclic carbene supported copper(I) boryl, (6-Dipp)CuBpin. This compound showed remarkable stability and was characterised by NMR spectroscopy and X-ray crystallography. (6-Dipp)CuBpin readily dechalcogenated a range of heterocumulenes such as CO2, isocyanates and isothiocyanates to yield (6-Dipp)CuXBpin (X = O, S). In the case of CO2 catalytic reduction to CO is viable in the presence of excess bis(pinacolato)diboron. In contrast, in the case of iso(thio)cyanates, the isocyanide byproduct of dechalcogenation reacted with (6-Dipp)CuBpin to generate a copper(I) borylimidinate, (6-Dipp)CuC(NR)Bpin, which went on to react with heterocumulenes. This off-cycle reactivity gives selective access to a range of novel boron-containing heterocycles bonded to copper, but precludes catalytic reactivity.

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Efficacy of Topical Epinephrine in Tympanoplasty.

OBJECTIVES/HYPOTHESIS: To compare the hemostatic effects of commonly used concentrations of topical epinephrine in tympanoplasty. STUDY DESIGN: Prospective, randomized, controlled clinical trial. METHODS: Patients undergoing tympanoplasty were randomized to receive topical epinephrine at 1:1,000 or 1:10,000. With the investigators blinded, hemostasis was assessed with a modified Boezaart scale. Vasoconstriction was measured by laser Doppler. Blood pressure and pulse were tracked. RESULTS: Thirty patients, 4 to 84 years old, were studied, with 15 patients per group. Boezaart scores dropped a mean of 67% and 62% with 1:1,000 and 1:10,000, respectively (P = .44). Capillary blood flow decreased a mean of 50.4% and 50.9% with 1:1,000 and 1:10,000, respectively (P = .95). The mean change in heart rate and mean arterial pressure after topical epinephrine exposure were -4.9 and -0.73 beats per minute (P = .15), and -0.60 and -0.73 mmHg (P = .96) for 1:1,000 and 1:10,000 respectively. No adverse events occurred in either group. CONCLUSIONS: Topical epinephrine at 1:10,000 has hemostatic efficacy comparable to 1:1,000 in tympanoplasty. Although both concentrations appear safe, use of topical epinephrine 1:10,000 should be considered over 1:1,000 to minimize the potential for adverse events. LEVEL OF EVIDENCE: 2 Laryngoscope, 131:2319-2322, 2021.