Catalytically Relevant Organocopper(III) Complexes Formed through Aryl-Radical-Enabled Oxidative Addition.

Stepwise oxidative addition of copper(I) complexes to form copper(III) species via single electron transfer (SET) events has been widely proposed in copper catalysis. However, direct observation and detailed investigation of these fundamental steps remain elusive owing largely to the typically slow oxidative addition rate of copper(I) complexes and the instability of the copper(III) species. We report herein a novel aryl-radical-enabled stepwise oxidative addition pathway that allows for the formation of well-defined alkyl-CuIII species from CuI complexes. The process is enabled by the SET from a CuI species to an aryl diazonium salt to form a CuII species and an aryl radical. Subsequent iodine abstraction from an alkyl iodide by the aryl radical affords an alkyl radical, which then reacts with the CuII species to form the alkyl-CuIII complex. The structure of resultant [(bpy)CuIII(CF3)2(alkyl)] complexes has been characterized by NMR spectroscopy and X-ray crystallography. Competition experiments have revealed that the rate at which different alkyl iodides undergo oxidative addition is consistent with the rate of iodine abstraction by carbon-centered radicals. The CuII intermediate formed during the SET process has been identified as a four-coordinate complex, [CuII(CH3CN)2(CF3)2], through electronic paramagnetic resonance (EPR) studies. The catalytic relevance of the high-valent organo-CuIII has been demonstrated by the C-C bond-forming reductive elimination reactivity. Finally, localized orbital bonding analysis of these formal CuIII complexes indicates inverted ligand fields in σ(Cu-CH2) bonds. These results demonstrate the stepwise oxidative addition in copper catalysis and provide a general strategy to investigate the elusive formal CuIII complexes.

Copper-Carbon Homolysis Competes with Reductive Elimination in Well-Defined Copper(III) Complexes.

Despite the recent advancements of Cu catalysis for the cross-coupling of alkyl electrophiles and the frequently proposed involvement of alkyl-Cu(III) complexes in such reactions, little is known about the reactivity of these high-valent complexes. Specifically, although the reversible interconversion between an alkyl-CuIII complex and an alkyl radical/CuII pair has been frequently proposed in Cu catalysis, direct observation of such steps in well-defined CuIII complexes remains elusive. In this study, we report the synthesis and investigation of alkyl-CuIII complexes, which exclusively undergo a Cu-C homolysis pathway to generate alkyl radicals and CuII species. Kinetic studies suggest a bond dissociation energy of 28.6 kcal/mol for the CuIII-C bonds. Moreover, these four-coordinate complexes could be converted to a solvated alkyl-CuIII-(CF3)2, which undergoes highly efficient C-CF3 bond-forming reductive elimination even at low temperatures (-4 °C). These results provide strong support for the reversible recombination of alkyl radicals with CuII to form alkyl-CuIII species, an elusive step that has been proposed in Cu-catalyzed mechanisms. Furthermore, our work has demonstrated that the reactivity of CuIII complexes could be significantly influenced by subtle changes in the coordination environment. Lastly, the observation of the highly reactive neutral alkyl-CuIII-(CF3)2 species (or with weakly bound solvent molecules) suggests they might be the true intermediates in many Cu-catalyzed trifluoromethylation reactions.

Nitrite Formation at a Diiron Dinitrosyl Complex.

Pathogenic bacteria employ iron-containing enzymes to detoxify nitric oxide (NO•) produced by mammals as part of their immune response. Two classes of diiron proteins, flavodiiron nitric oxide reductases (FNORs) and the hemerythrin-like proteins from mycobacteria (HLPs), are upregulated in bacteria in response to an increased local NO• concentration. While FNORs reduce NO• to nitrous oxide (N2O), the HLPs have been found to either reduce nitrite to NO• (YtfE), or oxidize NO• to nitrite (Mka-HLP). Various structural and functional models of the diiron site in FNORs have been developed over the years. However, the NO• oxidation reactivity of Mka-HLP has yet to be replicated with a synthetic complex. Compared to the FNORs, the coordination environment of the diiron site in Mka-HLP contains one less carboxylate ligand and, therefore, is expected to be more electron-poor. Herein, we synthesized a new diiron complex that models the electron-poor coordination environment of the Mka-HLP diiron site. The diferrous precursor FeIIFeII reacts with NO• to form a diiron dinitrosyl species ({FeNO}72), which is in equilibrium with a mononitrosyl diiron species (FeII{FeNO}7) in solution. Both complexes can be isolated and fully characterized. However, only oxidation of {FeNO}72 produced nitrite in high yield (71%). Our study provides the first model that reproduces the NO• oxidase reactivity of Mka-HLP and suggests intermediacy of an {FeNO}6/{FeNO}7 species.

Two-State Hydrogen Atom Transfer Reactivity of Unsymmetric [Cu2(O)(NO)]2+ Complexes.

We report the temperature-dependent spin switching of dicopper oxo nitrosyl [Cu2(O)(NO)]2+ complexes and their influence on hydrogen atom transfer (HAT) reactivity. Electron paramagnetic resonance (EPR) and Evans method analysis suggest that [Cu2(O)(NO)]2+ complexes transition from the S = 1/2 to the S = 3/2 state around ca. 202 K. At low temperatures (198 K) where S = 3/2 dominates, a strong correlation between the rate of HAT (kHAT) and the population of the S = 1/2 state was identified (R2 = 0.988), suggesting that the HAT by [Cu2(O)(NO)]2+ complexes proceeds by the S = 1/2 isomer. Installation of functional groups that introduce an unsymmetric secondary coordination environment accelerates the HAT rates through perturbation of the spin equilibria. Given the often unsymmetric coordination sphere of bimetallic active sites in natural proteins, we anticipate that similar strategies could be employed by metalloenzymes to control HAT reactions.

Associations of Multimorbidity With Stroke Severity, Subtype, Premorbid Disability, and Early Mortality: Oxford Vascular Study.

BACKGROUND AND OBJECTIVES: Patients with multimorbidity are underrepresented in clinical trials. Inclusion in stroke trials is often limited by exclusion based on premorbid disability, concerns about worse poststroke outcomes in acute treatment trials, and a possibly increased proportion of hemorrhagic vs ischemic stroke in prevention trials. Multimorbidity is associated with an increased mortality after stroke, but it is unclear whether this is driven by an increased stroke severity or is confounded by particular stroke subtypes or premorbid disability. We aimed to determine the independent association of multimorbidity with stroke severity taking account of these main potential confounders. METHODS: In a population-based incidence study (Oxford Vascular Study; 2002-2017), prestroke multimorbidity (Charlson Comorbidity Index [CCI]; unweighted/weighted) in all first-in-study strokes was related to postacute severity (≈24 hours; NIH Stroke Scale [NIHSS]), stroke subtype (hemorrhagic vs ischemic; Trial of Org 10172 in Acute Stroke Treatment [TOAST]), and premorbid disability (modified Rankin scale [mRS] score ≥2) using age-adjusted/sex-adjusted logistic and linear regression models and to 90-day mortality using Cox proportional hazard models. RESULTS: Among 2,492 patients (mean/SD age = 74.5/13.9 years; 1,216/48.8% male; 2,160/86.7% ischemic strokes; mean/SD NIHSS = 5.7/7.1), 1,402 (56.2%) had at least 1 CCI comorbidity, and 700 (28.1%) had multimorbidity. Although multimorbidity was strongly related to premorbid mRS ≥2 (adjusted odds ratio [aOR] per CCI comorbidity 1.42, 1.31-1.54, p < 0.001), and comorbidity burden was crudely associated with an increased severity of ischemic stroke (OR per comorbidity 1.12, 1.01-1.23 for NIHSS 5-9, p = 0.027; 1.15, 1.06-1.26 for NIHSS ≥10; p = 0.001), no association with severity remained after stratification by TOAST subtype (aOR 1.02, 0.90-1.14, p = 0.78 for NIHSS 5-9 vs 0-4; 0.99, 0.91-1.07, p = 0.75 for NIHSS ≥10 vs 0-4), or within any individual subtype. The proportion of intracerebral hemorrhage vs ischemic stroke was lower in patients with multimorbidity (aOR per comorbidity 0.80, 0.70-0.92, p < 0.001), and multimorbidity was only weakly associated with 90-day mortality after adjustment for age, sex, severity, and premorbid disability (adjusted hazard ratio per comorbidity 1.09, 1.04-1.14, p < 0.001). Results were unchanged using the weighted CCI. DISCUSSION: Multimorbidity is common in patients with stroke and is strongly related to premorbid disability but is not independently associated with an increased ischemic stroke severity. Greater inclusion of patients with multimorbidity is unlikely therefore to undermine the effectiveness of interventions in clinical trials but would increase external validity.

Reductive NO Coupling at Dicopper Center via a [Cu2(NO)2]2+ Diamond-Core Intermediate.

Treatment of a dicopper(I,I) complex with excess amounts of NO leads to the formation of a dicopper dinitrosyl [Cu2(NO)2]2+ complex capable of (i) releasing two equivalents of NO reversibly in 90% yield and (ii) reacting with another equivalent of NO to afford N2O and dicopper nitrosyl oxo species [Cu2(NO)(O)]2+. Resonance Raman characterization of the [Cu2(NO)2]2+ complex shows a 15N-sensitive N═O stretch at 1527.6 cm-1 and two Cu-N stretches at 390.6 and 414.1 cm-1, supporting a symmetric diamond-core structure with bis-µ-NO ligands. The conversion of [Cu2(NO)2]2+ to [Cu2(NO)O]2+ occurs via a rate-limiting reaction with NO and bypasses the dicopper oxo intermediate, a mechanism distinct from that of diFe-mediated NO reduction to N2O.

Federal and state cooperation necessary but not sufficient for effective regional mental health systems: insights from systems modelling and simulation.

For more than a decade, suicide rates in Australia have shown no improvement despite significant investment in reforms to support regionally driven initiatives. Further recommended reforms by the Productivity Commission call for Federal and State and Territory Government funding for mental health to be pooled and new Regional Commissioning Authorities established to take responsibility for efficient and effective allocation of 'taxpayer money.' This study explores the sufficiency of this recommendation in preventing ongoing policy resistance. A system dynamics model of pathways between psychological distress, the mental health care system, suicidal behaviour and their drivers was developed, tested, and validated for a large, geographically diverse region of New South Wales; the Hunter New England and Central Coast Primary Health Network (PHN). Multi-objective optimisation was used to explore potential discordance in the best-performing programs and initiatives (simulated from 2021 to 2031) across mental health outcomes between the two state-governed Local Health Districts (LHDs) and the federally governed PHN. Impacts on suicide deaths, mental health-related emergency department presentations, and service disengagement were explored. A combination of family psychoeducation, post-attempt aftercare, and safety planning, and social connectedness programs minimises the number of suicides across the PHN and in the Hunter New England LHD (13.5% reduction; 95% interval, 12.3-14.9%), and performs well in the Central Coast LHD (14.8% reduction, 13.5-16.3%), suggesting that aligned strategic decision making between the PHN and LHDs would deliver substantial impacts on suicide. Results also highlighted a marked trade-off between minimising suicide deaths versus minimising service disengagement. This is explained in part by the additional demand placed on services of intensive suicide prevention programs leading to increases in service disengagement as wait times for specialist community based mental health services and dissatisfaction with quality of care increases. Competing priorities between the PHN and LHDs (each seeking to optimise the different outcomes they are responsible for) can undermine the optimal impact of investments for suicide prevention. Systems modelling provides essential regional decision analysis infrastructure to facilitate coordinated federal and state investments for optimal impacts.

Reversible PCET and Ambient Catalytic Oxidative Alcohol Dehydrogenation by {V=O} Perfluoropinacolate Complexes.

A new air-stable catalyst for the oxidative dehydrogenation of benzylic alcohols under ambient conditions has been developed. The synthesis and characterization of this compound and the related monomeric and dimeric V(IV)- and V(V)-pinF (pinF = perfluoropinacolate) complexes are reported herein. Monomeric V(IV) complex (Me4N)2[V(O)(pinF)2] (1) and dimeric (µ-O)2-bridged V(V) complex (Me4N)2[V2(O)2(µ-O)2(pinF)2] (3a) are prepared in water under ambient conditions. Monomeric V(V) complex (Me4N)[V(O)(pinF)2] (2) may be generated via chemical oxidation of 1 under an inert atmosphere, but dimerizes to 3a upon exposure to air. Complexes 1 and 2 display a perfectly reversible VIV/V couple at 20 mV (vs Ag/AgNO3), whereas a quasi-reversible VIV/V couple at -865 mV is found for 3a. Stoichiometric reactions of 3a with both fluorenol and TEMPOH result in the formation of (Me4N)2[V2(O)2(µ-OH)2(pinF)2] (4a), which contains two V(IV) centers that display antiferromagnetic coupling. In order to structurally characterize the dinuclear anion of 4a, {K(18C6)}+ countercations were employed, which formed stabilizing K···O interactions between the counterion and each terminal oxo moiety and H-bonding between the oxygen atoms of the crown ether and µ-OH bridges of the dimer, resulting in {K(18C6)}2[V2(O)2(µ-OH)2(pinF)2] (4b). The formal storage of H2 in 4a is reversible and proton-coupled electron transfer (PCET) from crystals of 4a regenerates 3a upon exposure to air over the course of several days. Furthermore, the reaction of 3a (2%) under ambient conditions with excess fluorenol, cinnamyl alcohol, or benzyl alcohol resulted in the selective formation of fluorenone (82% conversion), cinnamaldehyde (40%), or benzaldehyde (7%), respectively, reproducing oxidative alcohol dehydrogenation (OAD) chemistry known for VOx surfaces and demonstrating, in air, the thermodynamically challenging selective oxidation of alcohols to aldehydes/ketones.

Sensitivity of Administrative Coding in Identifying Inpatient Acute Strokes Complicating Procedures or Other Diseases in UK Hospitals.

Background Administrative hospital diagnostic coding data are increasingly used in "big data" research and to assess complication rates after surgery or acute medical conditions. Acute stroke is a common complication of several procedures/conditions, such as carotid interventions, but data are lacking on the sensitivity of administrative coding in identifying acute stroke during inpatient stay. Methods and Results Using all acute strokes ascertained in a population-based cohort (2002-2017) as the reference, we determined the sensitivity of hospital administrative diagnostic codes ( International Classification of Diseases, Tenth Revision; ICD-10) for identifying acute strokes that occurred during hospital admission for other reasons, stratified by coding strategies, study periods, and stroke severity (National Institutes of Health Stroke Score

Persistent behavioral and neurochemical sensitization to an acute injection of methamphetamine following unpredictable stress.

Prior research in humans and animals suggest that exposure to chronic stress alters the response to drugs of abuse, increasing vulnerability to drug addiction. Chronic unpredictable stress (CUS) has been shown to augment the increase of dopamine in the striatum when challenged with high doses of methamphetamine immediately following stress exposure, however it is not known whether this neurochemical stress-sensitization continues after the cessation of the stressors or if behavioral sensitization is also present. Therefore, the current study examined the immediate and delayed effects of CUS on methamphetamine-induced behaviors and striatal dopamine levels. Male rats were exposed to 10 days of CUS and then tested in either an open field box to assess locomotion or underwent in vivo microdialysis to measure striatal dopamine levels immediately following CUS or after a 1-2 week delay. All rats exposed to CUS showed a potentiated locomotor response immediately following an acute injection of 7.5mg/kg methamphetamine compared to non-stressed control rats. Both groups of CUS rats also showed augmented dopamine release and rectal temperatures following methamphetamine with prolonged increases in the CUS rats tested after a delay. These results suggest that CUS increases the sensitivity of a rat to a single injection of methamphetamine and that the increased sensitivity persists for up to 2 weeks following the last stressor.

Systematic review and stratified meta-analysis of the efficacy of RhoA and Rho kinase inhibitors in animal models of ischaemic stroke.

BACKGROUND: There is currently only one clinically approved drug, tissue plasminogen activator (tPA), for the treatment of acute ischaemic stroke. The RhoA pathway, including RhoA and its downstream effector Rho kinase (ROCK), has been identified as a possible therapeutic target. Our aim was to assess the impact of study design characteristics and study quality on reported measures of efficacy and to assess for the presence and impact of publication bias. METHODS: We conducted a systematic review and meta-analysis on publications describing the efficacy of RhoA and ROCK inhibitors in animal models of focal cerebral ischaemia where outcome was assessed as a change in lesion size or neurobehavioural score, or both. RESULTS: We identified 25 published papers which met our inclusion criteria. RhoA and ROCK inhibitors reduced lesion size by 37.3% in models of focal cerebral ischaemia (95% CI, 28.6% to 46.0%, 41 comparisons), and reduced neurobehavioural data by 40.5% (33.4% to 47.7%, 30 comparisons). Overall study quality was low (median=4, interquartile range 3-5) and measures to reduce bias were seldom reported. Publication bias was prevalent and associated with a substantial overstatement of efficacy for lesion size. CONCLUSIONS: RhoA and ROCK inhibitors appear to be effective in animal models of stroke. However the low quality score, publication bias and limited number of studies are areas which need attention prior to conducting clinical trials.

Juvenile exposure to methamphetamine attenuates behavioral and neurochemical responses to methamphetamine in adult rats.

Previous research has shown that children living in clandestine methamphetamine (MA) labs are passively exposed to the drug [1]. The long-term effects of this early exposure on the dopaminergic systems are unknown, but may be important for adult behaviors mediated by dopamine, such as drug addiction. The current study sought to determine if juvenile exposure to low doses of MA would lead to altered responsiveness to the stimulant in adulthood. Young male and female rats (PD20-34) were injected daily with 0 or 2 mg/kg MA or left undisturbed and then tested at PD90. In the open field, adult rats exposed to MA during preadolescence had reduced locomotor activity compared to control non-exposed rats following an acute injection of MA (2 mg/kg). Likewise, methamphetamine-induced dopamine increases in the dorsal striatum were attenuated in male and female rats that had been exposed to MA as juveniles, although there were no changes in basal in vivo or ex vivo dopamine levels. These findings suggest that exposure of juveniles to MA leads to persistent changes in the behavioral and neurochemical responses to stimulants in adulthood.

Is there information contained within the sentence-writing component of the mini mental state examination? A retrospective study of community dwelling older people.

OBJECTIVE: To investigate the relationship between features of the MMSE written sentence and cognitive function, depression and disability. METHODS: MMSE sentences from 191 community dwelling individuals without dementia from the Lothian Birth Cohort 1921 (LBC1921) study were: (a) photocopied and (b) typed as written. Sentences were rated for objective criteria: word number and frequency, first person usage, time orientation, and letter case. Twenty healthy raters (50% male, age 20-26 years), blind to all other data, rated each handwritten and typed sentence for subjective criteria: legibility, 'emotional' tone (positive to negative), estimated age, health, and intelligence. As part of the LBC1921 volunteers had results available for cognitive ability tests (from which we extracted a general cognitive ability factor, g), Hospital Anxiety and Depression Score (HADS), and Townsend disability scores. RESULTS: 43.5% of subjects were male, mean age 78.6, SD 0.43 years. There was no significant association between the objective sentence criteria, legibility or tone and measured cognitive ability or physical disability. However, estimates of intelligence from the MMSE written sentence correlated significantly with current cognitive ability (r = 0.29, p < 0.001). There was a trend towards sentences with a negative tone being associated with a higher HADS-depression score (rho = -0.12, p = 0.09). CONCLUSION: In community dwelling people aged around 80 years, despite no association between objectively rated features of the MMSE sentence and intelligence or disability, raters were able to make better-than-chance estimates of subjects' intelligence test scores.

Adult Henoch-schönlein purpura in a patient with myelodysplastic syndrome and a history of follicular lymphoma.

GOAL: To understand Henoch-Schönlein purpura (HSP) to better manage patients with the condition. OBJECTIVES: Upon completion of this activity, dermatologists and general practitioners should be able to: 1. Describe the criteria for diagnosing HSP. 2. Explain the association of malignancy and HSP. 3. Discuss the prevalence of HSP in adults. Henoch-Schönlein purpura (HSP) is a systemic leukocytoclastic vasculitis involving arterioles and venules most commonly in the skin, glomeruli, and gastrointestinal tract. In skin, it is associated with IgA deposition around dermal blood vessels. While an exact cause of HSP has not been elucidated, several processes have been implicated in its development, including infections; drugs; and allergic, rheumatologic, and neoplastic diseases. We present a 57-year-old woman with a history of follicular lymphoma who developed HSP likely associated with myelodysplastic syndrome. This case is clinically significant because the patient was thought to be in remission of her hematologic disease until her skin findings prompted further evaluation. Her diagnosis of HSP was based on clinical presentation with palpable purpura and abdominal pain, and was confirmed with biopsy and immunohistochemical analyses of purpuric papules demonstrating leukocytoclastic vasculitis and strong anti-IgA labeling in the dermal endothelial cells consistent with immunocomplex deposition. The occurrence of vasculitis and malignant disease in the same patient often is difficult to interpret, as some patients may exhibit both diseases independently and by chance, while others may have vasculitis as a paraneoplastic syndrome. We review cases of adult HSP associated with malignancy in the literature.

The delayed effects of chronic unpredictable stress on anxiety measures.

Previous research has found that exposure to unpredictable stress can augment anxiety in humans and animals. The appearance of anxiety symptoms in humans frequently develop after stress exposure has terminated, but few rodent studies have systematically examined the delayed anxiogenic effects of unpredictable stress. Therefore, the current study investigated whether anxiety-like behaviors in rats would increase at several time intervals following exposure to chronic unpredictable stress (CUS). Unconditioned and conditioned response tasks were used to assess anxiety in male rats 1, 7 or 14 days following exposure to 10 days of a variety of stressors. Rats exposed to CUS showed increased burying behaviors and immobility during the defensive burying test, a conditioned anxiety test. The effects on burying behavior were apparent 7 and 14 days after the termination of the unpredictable stress procedure, but not when tested 1 day after CUS. Total time immobile in the defensive burying test also increased 14 days after termination of the last stressor. In contrast, there were no significant effects of CUS on behavioral measures in the unconditioned response tasks, the elevated plus-maze or light-dark box, at any time point following exposure to CUS. The current findings suggest that CUS may be a useful model of human conditioned anxiety that develops subsequent to chronic stress exposure.