Peptide secondary structure mimetics: The alpha-helix and beta-turn

This thesis describes research undertaken in peptidomimetic chemistry, concerned with stabilisation of peptide secondary structure. The first section describes the successful synthesis of two triazepinediones for potential application as cis prolyl mimetics and/or β-turn mimetics. The first triazepinedione 64, carrying an N-phenyl substituent, was subjected to reductive conditions in an unsuccessful attempt to generate a cis prolyl peptide. The second triazepinedione 72 was designed as a Gly-cw Pro-Phe peptidomimetic. Its synthesis proceeded in 8 steps, via a chiral a-hydrazino acid. Triazepinedione 72 was extended from both the N and C termini, demonstrating that it could be incorporated into a peptide. The second section describes the design and attempted synthesis of an N-terminal template for stabilisation of a-helical structure in an attached peptide. Preliminary efforts to produce a Pro-Pro-Ala macrocycle 91 and a Pro-Pro-Pro ether macrocycle 98 were unsuccessful. Attempts to synthesise a Pro-Pro-Pro thioether macrocycle 112 resulted in formation of a cyclic dimer 122. The formation of this dimer was proposed to be due to excessive steric hindrance in the transition state to cyclisation. Attempts to stabilise the desired folded transition state by α-methylation of proline residues or hydrogen bonding did not allow synthesis of any of the desired monomeric cyclic material. A monomeric cyclic compound was finally obtained by increasing the flexibility of the linear precursor, affording a Pro-(2R)-Ala-Pro thioether macrocycle 151. X-Ray crystallography and 2D NMR studies established that this macrocycle lacked the required arrangement of carbonyl groups conducive to initiation of an α-helix. Further NMR studies of macrocycle-peptide conjugates suggested that the macrocycle exerted a conformational influence only over the first residue of the attached peptide. The carbonyl groups of the macrocycle were found to adopt a significant degree of α-helical geometry upon attachment of a C-terminal cationic trialkylammonium group

Accurate Redeterminations of 1,1'-Dibenzoylferrocene and (4-Nitrophenyl)ferrocene

In the solid state, molecules of 1,1'-dibenzoylferrocene, [Fe(C₁₂H₉O)₂], (I), are linked to form infinite chains in the [100] direction via (cyclopentadienyl)C-H...O hydrogen bonds [C...O 3.354 (4) Å]. In the structure of (4-nitrophenyl)ferrocene, [Fe(C₅H₅)(C₁₁H₈NO₂)], (II), there are no C-H...O hydrogen bonds and molecules are separated by normal van der Waals distances. For earlier determinations see Struchkov [Dokl. Akad. Nauk SSSR (1956), 110, 67-70] for (I) and Roberts et al. [J. Chem. Soc. Dalton Trans. (1988), pp. 1549-1556] for (II)

Four consecutive yearly point-prevalence studies in Wales indicate lack of improvement in sepsis care on the wards

The ‘Sepsis Six’ bundle was promoted as a deliverable tool outside of the critical care settings, but there is very little data available on the progress and change of sepsis care outside the critical care environment in the UK. Our aim was to compare the yearly prevalence, outcome and the Sepsis Six bundle compliance in patients at risk of mortality from sepsis in non-intensive care environments. Patients with a National Early Warning Score (NEWS) of 3 or above and suspected or proven infection were enrolled into four yearly 24-h point prevalence studies, carried out in fourteen hospitals across Wales from 2016 to 2019. We followed up patients to 30 days between 2016–2019 and to 90 days between 2017 and 2019. Out of the 26,947 patients screened 1651 fulfilled inclusion criteria and were recruited. The full ‘Sepsis Six’ care bundle was completed on 223 (14.0%) occasions, with no significant difference between the years. On 190 (11.5%) occasions none of the bundle elements were completed. There was no significant correlation between bundle element compliance, NEWS or year of study. One hundred and seventy (10.7%) patients were seen by critical care outreach; the ‘Sepsis Six’ bundle was completed significantly more often in this group (54/170, 32.0%) than for patients who were not reviewed by critical care outreach (168/1385, 11.6%; p < 0.0001). Overall survival to 30 days was 81.7% (1349/1651), with a mean survival time of 26.5 days (95% CI 26.1–26.9) with no difference between each year of study. 90-day survival for years 2017–2019 was 74.7% (949/1271), with no difference between the years. In multivariate regression we identified older age, heart failure, recent chemotherapy, higher frailty score and do not attempt cardiopulmonary resuscitation orders as significantly associated with increased 30-day mortality. Our data suggests that despite efforts to increase sepsis awareness within the NHS, there is poor compliance with the sepsis care bundles and no change in the high mortality over the study period. Further research is needed to determine which time-sensitive ward-based interventions can reduce mortality in patients with sepsis and how can these results be embedded to routine clinical practice

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 ≥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 5·0 months (IQR 4·2–6·3) 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&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; 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 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) 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

Accurate Redeterminations of 1,1\u27-Dibenzoylferrocene and (4-Nitrophenyl)ferrocene

In the solid state, molecules of 1,1\u27-dibenzoylferrocene, [Fe(C₁₂H₉O)₂], (I), are linked to form infinite chains in the [100] direction via (cyclopentadienyl)C-H...O hydrogen bonds [C...O 3.354 (4) Å]. In the structure of (4-nitrophenyl)ferrocene, [Fe(C₅H₅)(C₁₁H₈NO₂)], (II), there are no C-H...O hydrogen bonds and molecules are separated by normal van der Waals distances. For earlier determinations see Struchkov [Dokl. Akad. Nauk SSSR (1956), 110, 67-70] for (I) and Roberts et al. [J. Chem. Soc. Dalton Trans. (1988), pp. 1549-1556] for (II)

Impaired Blood Neutrophil Function in the Frequent Exacerbator of Chronic Obstructive Pulmonary Disease: A Proof-of-Concept Study

Purpose The underlying biological mechanisms of the frequent exacerbator phenotype of COPD remain unclear. We compared systemic neutrophil function in COPD patients with or without frequent exacerbations. Methods Whole blood from COPD frequent exacerbators (defined as ?2 moderate–severe exacerbations in the previous 2 years) and non-exacerbators (no exacerbations in the preceding 2 years) was assayed for neutrophil function. Neutrophil function in healthy ex-smoking volunteers was also measured as a control (reference) group. Results A total of 52 subjects were included in this study: 26 frequent exacerbators, 18 non-exacerbators and 8 healthy controls. COPD frequent exacerbators had blunted blood neutrophil fMLP-stimulated oxidative burst compared to both non-exacerbators (p < 0.01) and healthy controls (p < 0.001). There were no differences between COPD frequent exacerbators and non-exacerbators in blood neutrophil PMA-stimulated oxidative burst, but both COPD groups had reduced responses compared to healthy controls (p < 0.001). Bacterial-stimulated neutrophil degranulation was greater in frequent exacerbators than non-exacerbators (p < 0.05). Conclusion This study is the first to report aberrant receptor-mediated blood neutrophil function in the frequent exacerbator of COPD

Cognitive and psychiatric symptom trajectories 2–3 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 ≥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 2–3 years, and whether symptoms at 2–3 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 2–3 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 [40·2%] females and 284 [59·8%] males; mean age 58·26 [SD 11·13] years) who were discharged from one of 83 hospitals provided data at the 2–3-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 0·71 SD below the mean [IQR 0·16–1·04]; p<0·0001). Most participants reported at least mild depression (263 [74·5%] of 353), anxiety (189 [53·5%] of 353), fatigue (220 [62·3%] of 353), or subjective cognitive decline (184 [52·1%] of 353), and more than a fifth reported severe depression (79 [22·4%] of 353), fatigue (87 [24·6%] of 353), or subjective cognitive decline (88 [24·9%] of 353). Depression, anxiety, and fatigue were worse at 2–3 years than at 6 months or 12 months, with evidence of both worsening of existing symptoms and emergence of new symptoms. Symptoms at 2–3 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 35·0–48·8% 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 7·0–17·2% 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 2–3 years were not predicted by any of the factors tested, except for cognitive deficits at 6 months, explaining 10·6% of their variance. 95 of 353 participants (26·9% [95% CI 22·6–31·8]) 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] 1·51 [95% CI 1·04–2·22] for every SD decrease in overall cognitive score) and subjective cognitive decline (OR 1·54 [1·21–1·98] for every point increase in CCI-20). Interpretation: Psychiatric and cognitive symptoms appear to increase over the first 2–3 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