10 research outputs found
Pd-Catalyzed Cascade Reactions of Aziridines: One-step Access to Complex Tetracyclic Amines
The combination of palladium catalysis and thermal cycloaddition is shown to transform tricyclic aziridines into complex, stereodefined tetracyclic products in a single step. This highly unusual cascade process involves a diverted TsujiāTrost sequence leading to a surprisingly facile intramolecular DielsāAlder reaction. The starting materials are accessible on multigram scales from the photochemical rearrangement of simple pyrroles. The tetracyclic amine products can be further elaborated through routine transformations, highlighting their potential as scaffolds for medicinal chemistry
Rapid Access to Azabicyclo[3.3.1]nonanes by a Tandem Diverted TsujiāTrost Process
A three-step synthesis of the 2-azabicyclo[3.3.1]nonane ring system from simple pyrroles, employing a combined photochemical/palladium-catalyzed approach is reported. Substrate scope is broad, allowing the incorporation of a wide range of functionality relevant to medicinal chemistry. Mechanistic studies demonstrate that the process occurs via acid-assisted C-N bond Ć-hydride elimination to form a reactive diene, demonstrating that efficient control of what might be considered off-cycle reactions can result in productive tandem catalytic processes. This represents a short and versatile route to the biologically important morphan scaffold
Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study
Introduction:
The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures.
Methods:
In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ā„18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025.
Findings:
Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5Ā·0 months (IQR 4Ā·2ā6Ā·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0Ā·0001) and independently associated with COVID-19 status (odds ratio [OR] 2Ā·9 [95% CI 1Ā·5ā5Ā·8]; padjusted=0Ā·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0Ā·0001; parenchymal abnormalities), brain abnormalities (p<0Ā·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0Ā·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4ā10]; mean age of 59Ā·8 years [SD 11Ā·7] with multiorgan abnormalities vs mean age of 52Ā·8 years [11Ā·9] without multiorgan abnormalities; p<0Ā·0001), more likely to have three or more comorbidities (OR 2Ā·47 [1Ā·32ā4Ā·82]; padjusted=0Ā·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3Ā·55 [1Ā·23ā11Ā·88]; padjusted=0Ā·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation.
Interpretation:
After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification
Fast Ring-Opening of an Intermediary Ī±-Stannyl-Ī²-Cyclopropylvinyl Radical Does Not Support Formation of an Ī±-Stannylvinyl Cation in the O-Directed Free Radical Hydrostannation of Dialkyl Acetylenes
O-Directed free radical hydrostannation of a Ī²-cyclopropyl propargylic
alcohol probe with stannanes and cat. Et3B in THF/H2O, or
PhMe/MeOH, failed to deliver any detectable products of Ī±-stannylvinyl cation capture.
Instead only Ī±-stannyl-Ī²-cyclopropylvinyl radical
intermediates could be detected, which underwent fast H-atom abstraction and/or cyclopropane
ring-opening as a result of fast eliminative Ī²-scission. These outcomes strongly rule against the claimed intermediacy of Ī±-stannylvinyl cations in the O-directed free radical hydrostannation of disubstituted acetylenes, and provide further good supporting evidence for such reactions proceeding by an exclusively free radical O-coordinatively-controlled mechanism
Cognitive and psychiatric symptom trajectories 2ā3 years after hospital admission for COVID-19: a longitudinal, prospective cohort study in the UK
Background: COVID-19 is known to be associated with increased risks of cognitive and psychiatric outcomes after the acute phase of disease. We aimed to assess whether these symptoms can emerge or persist more than 1 year after hospitalisation for COVID-19, to identify which early aspects of COVID-19 illness predict longer-term symptoms, and to establish how these symptoms relate to occupational functioning. Methods: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study of adults (aged ā„18 years) who were hospitalised with a clinical diagnosis of COVID-19 at participating National Health Service hospitals across the UK. In the C-Fog study, a subset of PHOSP-COVID participants who consented to be recontacted for other research were invited to complete a computerised cognitive assessment and clinical scales between 2 years and 3 years after hospital admission. Participants completed eight cognitive tasks, covering eight cognitive domains, from the Cognitron battery, in addition to the 9-item Patient Health Questionnaire for depression, the Generalised Anxiety Disorder 7-item scale, the Functional Assessment of Chronic Illness Therapy Fatigue Scale, and the 20-item Cognitive Change Index (CCI-20) questionnaire to assess subjective cognitive decline. We evaluated how the absolute risks of symptoms evolved between follow-ups at 6 months, 12 months, and 2ā3 years, and whether symptoms at 2ā3 years were predicted by earlier aspects of COVID-19 illness. Participants completed an occupation change questionnaire to establish whether their occupation or working status had changed and, if so, why. We assessed which symptoms at 2ā3 years were associated with occupation change. People with lived experience were involved in the study. Findings: 2469 PHOSP-COVID participants were invited to participate in the C-Fog study, and 475 participants (191 [40Ā·2%] females and 284 [59Ā·8%] males; mean age 58Ā·26 [SD 11Ā·13] years) who were discharged from one of 83 hospitals provided data at the 2ā3-year follow-up. Participants had worse cognitive scores than would be expected on the basis of their sociodemographic characteristics across all cognitive domains tested (average score 0Ā·71 SD below the mean [IQR 0Ā·16ā1Ā·04]; p<0Ā·0001). Most participants reported at least mild depression (263 [74Ā·5%] of 353), anxiety (189 [53Ā·5%] of 353), fatigue (220 [62Ā·3%] of 353), or subjective cognitive decline (184 [52Ā·1%] of 353), and more than a fifth reported severe depression (79 [22Ā·4%] of 353), fatigue (87 [24Ā·6%] of 353), or subjective cognitive decline (88 [24Ā·9%] of 353). Depression, anxiety, and fatigue were worse at 2ā3 years than at 6 months or 12 months, with evidence of both worsening of existing symptoms and emergence of new symptoms. Symptoms at 2ā3 years were not predicted by the severity of acute COVID-19 illness, but were strongly predicted by the degree of recovery at 6 months (explaining 35Ā·0ā48Ā·8% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); by a biocognitive profile linking acutely raised D-dimer relative to C-reactive protein with subjective cognitive deficits at 6 months (explaining 7Ā·0ā17Ā·2% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); and by anxiety, depression, fatigue, and subjective cognitive deficit at 6 months. Objective cognitive deficits at 2ā3 years were not predicted by any of the factors tested, except for cognitive deficits at 6 months, explaining 10Ā·6% of their variance. 95 of 353 participants (26Ā·9% [95% CI 22Ā·6ā31Ā·8]) reported occupational change, with poor health being the most common reason for this change. Occupation change was strongly and specifically associated with objective cognitive deficits (odds ratio [OR] 1Ā·51 [95% CI 1Ā·04ā2Ā·22] for every SD decrease in overall cognitive score) and subjective cognitive decline (OR 1Ā·54 [1Ā·21ā1Ā·98] for every point increase in CCI-20). Interpretation: Psychiatric and cognitive symptoms appear to increase over the first 2ā3 years post-hospitalisation due to both worsening of symptoms already present at 6 months and emergence of new symptoms. New symptoms occur mostly in people with other symptoms already present at 6 months. Early identification and management of symptoms might therefore be an effective strategy to prevent later onset of a complex syndrome. Occupation change is common and associated mainly with objective and subjective cognitive deficits. Interventions to promote cognitive recovery or to prevent cognitive decline are therefore needed to limit the functional and economic impacts of COVID-19. Funding: National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Wolfson Foundation, MQ Mental Health Research, MRC-UK Research and Innovation, and National Institute for Health and Care Research.</p