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Comprehensive psychiatry ; 2022.
Article in English | EuropePMC | ID: covidwho-1837229


Background Australia experienced significant COVID-19 lockdown restrictions throughout 2020 that had an impact on mental health and disrupted health-promoting lifestyle behaviours. Lockdowns may have exacerbated existing mental health concerns among tertiary students, who experience higher levels of mental health concerns compared to the wider community. This study aimed to investigate the association between modifiable lifestyle factors and wellbeing of students at a Melbourne-based tertiary education institution during COVID-19 lockdown. Methods This quantitative, cross-sectional study was conducted across campuses in Melbourne and Sydney. Data was collected via online questionnaire during the 7th week of a second-wave lockdown. Descriptive statistics were calculated for demographic variables (n = 239). Linear regression models were estimated to determine multivariate associations between lifestyle variables and psychological distress. Results Participants were on average 30.98 years old (SD = 9.78), predominantly female, domestic students, undergraduate, not the first member of their family to attend university and living out of family home. Mindfulness, diet quality, sleep quality and moderate-vigorous physical activity (MVPA) were all inversely correlated with psychological distress. Unadjusted and adjusted models show that mindfulness, sleep quality, and MVPA were all independently inversely related to psychological distress. Greater mindfulness, sleep quality and engagement in MVPA were associated with lower psychological distress during COVID-19 lockdowns. Limitations As this study is cross-sectional and we cannot rule out reverse causality. Conclusion This study highlights the potential for lifestyle focused mental-health promotion delivered through tertiary education institutions to support students in times of crisis as well as more generally.

medrxiv; 2022.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2022.02.10.22270799


Introduction Viral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings. Methods We conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data-collection period, followed by intervention periods comprising 8 weeks of 'rapid' (<48h) and 4 weeks of 'longer-turnaround' (5-10 day) sequencing using a sequence reporting tool (SRT). Data were collected on all hospital onset COVID-19 infections (HOCIs; detected [≥]48h from admission). The impact of the sequencing intervention on IPC knowledge and actions, and on incidence of probable/definite hospital-acquired infections (HAIs) was evaluated. Results A total of 2170 HOCI cases were recorded from October 2020-April 2021, with sequence reports returned for 650/1320 (49.2%) during intervention phases. We did not detect a statistically significant change in weekly incidence of HAIs in longer-turnaround (IRR 1.60, 95%CI 0.85-3.01; P=0.14) or rapid (0.85, 0.48-1.50; P=0.54) intervention phases compared to baseline phase. However, IPC practice was changed in 7.8% and 7.4% of all HOCI cases in rapid and longer-turnaround phases, respectively, and 17.2% and 11.6% of cases where the report was returned. In a per-protocol sensitivity analysis there was an impact on IPC actions in 20.7% of HOCI cases when the SRT report was returned within 5 days. Conclusion While we did not demonstrate a direct impact of sequencing on the incidence of nosocomial transmission, our results suggest that sequencing can inform IPC response to HOCIs, particularly when returned within 5 days.

medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.06.24.21259107


Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.1.7 has been associated with an increased rate of transmission and disease severity among subjects testing positive in the community. Its impact on hospitalised patients is less well documented. Methods We collected viral sequences and clinical data of patients admitted with SARS-CoV-2 and hospital-onset COVID-19 infections (HOCIs), sampled 16/11/2020 - 10/01/2021, from eight hospitals participating in the COG-UK-HOCI study. Associations between the variant and the outcomes of all-cause mortality and intensive therapy unit (ITU) admission were evaluated using mixed effects Cox models adjusted by age, sex, comorbidities, care home residence, pregnancy and ethnicity. Results Sequences were obtained from 2341 inpatients (HOCI cases = 786) and analysis of clinical outcomes was carried out in 2147 inpatients with all data available. The hazard ratio (HR) for mortality of B.1.1.7 compared to other lineages was 1.01 (95% CI 0.79-1.28, P=0.94) and for ITU admission was 1.01 (95% CI 0.75-1.37, P=0.96). Analysis of sex-specific effects of B.1.1.7 identified increased risk of mortality (HR 1.30, 95% CI 0.95-1.78) and ITU admission (HR 1.82, 95% CI 1.15-2.90) in females infected with the variant but not males (mortality HR 0.82, 95% CI 0.61-1.10; ITU HR 0.74, 95% CI 0.52-1.04). Conclusions In common with smaller studies of patients hospitalised with SARS-CoV-2 we did not find an overall increase in mortality or ITU admission associated with B.1.1.7 compared to other lineages. However, women with B.1.1.7 may be at an increased risk of admission to intensive care and at modestly increased risk of mortality.

biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.12.15.412809


In this study, we developed ACE2-specific, peptide-derived 68Ga-labeled radiotracers, based on the hypotheses that (1) ACE2 is an important determinant of SARS-CoV-2 susceptibility, and (2) that modulation of ACE2 in COVID-19 drives severe organ injury. Methods: A series of NOTA-conjugated peptides derived from the known ACE2 inhibitor DX600 were synthesized, with variable linker identity. Since DX600 bears two cystine residues, both linear and cyclic peptides were studied. A commercially available ACE2 inhibition assay was used to identify lead compounds, which were used to synthesize 68Ga-chelated peptide radiotracers ([68Ga]-NOTA-ACE2pep). The aminocaproate-derived radiotracer [68Ga]-NOTA-ACE2pep4 was subsequently studied in a humanized ACE2 (hACE2) transgenic model, with in vivo results correlated with ACE2 activity. Results: Cyclic DX-600 derived peptides had markedly lower IC50s than their linear counterparts, a result confirmed by TCEP reduction of disulfide bridges. The three cyclic peptides derived from triglycine, aminocaproate, and polyethylene glycol linkers had calculated IC50s similar to, or lower than the parent DX600 molecule. Peptides were readily labeled with 68Ga, and the normal biodistribution of [68Ga]-NOTA-ACE2pep4 was determined in a hACE2 transgenic murine cohort. Pharmacologic concentrations of co-administered NOTA-ACE2pep (blocking) showed significant reduction of [68Ga]-NOTA-ACE2pep4 signals in the in the heart, liver, lungs, and small intestine. Ex vivo hACE2 activity in these organs was confirmed as a correlate to in vivo results. Conclusions: NOTA-conjugated, cyclic peptides derived from the known ACE2 inhibitor DX600 retain their activity when N-conjugated for 68Ga chelation. In vivo studies in a transgenic hACE2 murine model using the lead tracer [68Ga]-NOTA-ACE2pep4 showed specific binding in the heart, liver, lungs and intestine- organs known to be affected in SARS-CoV-2 infection. These results suggest that [68Ga]-NOTA-ACE2pep4 may detect organ-specific suppression of ACE2 in SARS-CoV-2 infected murine models and COVID-19 patients.

medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.11.18.20230599


While changes in SARS-CoV-2 viral load over time have been documented, detailed information on the impact of remdesivir and how it might alter intra-host viral evolution is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 recovered from the upper respiratory tract of hospitalised children revealed that remdesivir treatment suppressed viral RNA levels in one patient but not in a second infected with an identical strain. Evidence of drug resistance to explain this difference was not found. Reduced levels of subgenomic (sg) RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication that is independent of viral RNA levels. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. We conclude that these are likely to have arisen from within-host evolution, and not co-transmission, although superinfection cannot be excluded in one case. Sample-to-sample heterogeneity in the abundances of variant genotypes is best explained by the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalisation is well described in serious lung infections caused by influenza and Mycobacterium tuberculosis and has been associated with poor drug penetration, suboptimal treatment and drug resistance. Our data provide evidence that remdesivir is able to suppress SARS-CoV-2 replication in vivo but that its efficacy may be compromised by factors reducing penetration into the lung. Based on data from influenza and Mycobacterium tuberculosis lung infections we conclude that early use of remdesivir combined with other agents should now be evaluated. Summary SentenceDeep sequencing of longitudinal samples from SARS-CoV-2 infected paediatric patients identifies evidence of remdesivir-associated inhibition of viral replication in vivo and uncovers evidence of within host evolution of distinct viral genotypes.

medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.11.12.20230326


Background: Rapid identification and investigation of healthcare-associated infections (HCAIs) is important for suppression of SARS-CoV-2, but the infection source for hospital onset COVID-19 infections (HOCIs) cannot always be readily identified based only on epidemiological data. Viral sequencing data provides additional information regarding potential transmission clusters, but the low mutation rate of SARS-CoV-2 can make interpretation using standard phylogenetic methods difficult. Methods: We developed a novel statistical method and sequence reporting tool (SRT) that combines epidemiological and sequence data in order to provide a rapid assessment of the probability of HCAI among HOCI cases (defined as first positive test >48 hours following admission) and to identify infections that could plausibly constitute outbreak events. The method is designed for prospective use, but was validated using retrospective datasets from hospitals in Glasgow and Sheffield collected February-May 2020. Results: We analysed data from 326 HOCIs. Among HOCIs with time-from-admission [≥]8 days the SRT algorithm identified close sequence matches from the same ward for 160/244 (65.6%) and in the remainder 68/84 (81.0%) had at least one similar sequence elsewhere in the hospital, resulting in high estimated probabilities of within-ward and within-hospital transmission. For HOCIs with time-from-admission 3-7 days, the SRT probability of healthcare acquisition was >0.5 in 33/82 (40.2%). Conclusions: The methodology developed can provide rapid feedback on HOCIs that could be useful for infection prevention and control teams, and warrants further prospective evaluation. The integration of epidemiological and sequence data is important given the low mutation rate of SARS-CoV-2 and its variable incubation period.