Tunability of DNA Polymerase Stability during Eukaryotic DNA Replication.

Structural and biochemical studies have revealed the basic principles of how the replisome duplicates genomic DNA, but little is known about its dynamics during DNA replication. We reconstitute the 34 proteins needed to form the S. cerevisiae replisome and show how changing local concentrations of the key DNA polymerases tunes the ability of the complex to efficiently recycle these proteins or to dynamically exchange them. Particularly, we demonstrate redundancy of the Pol α-primase DNA polymerase activity in replication and show that Pol α-primase and the lagging-strand Pol δ can be re-used within the replisome to support the synthesis of large numbers of Okazaki fragments. This unexpected malleability of the replisome might allow it to deal with barriers and resource challenges during replication of large genomes.

Informing the management of the post-COVID condition: insights from the Western Australian experience comparing those who tested positive and negative to early COVID-19 strains.

ObjectiveThis study aimed to compare the relative physical recovery and symptoms after SARS-CoV-2 infection between groups confirmed positive or negative to early strains of COVID-19.MethodsA prospective, longitudinal cohort study compared outcomes of metropolitan adults polymerase chain reaction-tested for COVID-19 between March and November 2020 in Western Australia. Control matching was attempted: inpatients (gender, age) and ambulatory clinic (gender, age, asthma, chronic pulmonary disease). One-year follow-up involved three repeated measures: physical function (grip strength and 1-min sit-to-stand) and patient-reported outcomes (Fatigue Severity Scale, modified Medical Research Council dyspnoea scale and Euroqol-5D-5L).ResultsThree hundred and forty-four participants were recruited (154 COVID+, age 54±18years, 75 females [49%]); 190 COVID-, age 52±16years, 67 females [35%]) prior to national vaccination roll-out. No between-group differences in physical function measures were evident at any time point. Fatigue (OR 6.62, 95% CI 2.74-15.97) and dyspnoea (OR 2.21, 95% CI 1.14-4.30) were higher in the COVID+ group at second assessment (T2). On Euroqol-5D-5L, no between-group differences were evident in the physical function domains of self-care, mobility or usual activities at any time point. However, COVID+ participants were less likely to report an absence of anxiety or depression symptoms at T2 (OR 0.41, 95% CI 0.19-0.89).ConclusionsNeither statistical nor clinically meaningful differences in physical function were evident between COVID+ and COVID- participants to 12-months after acute illness. Symptoms of fatigue, dyspnoea, anxiety or depression were more prevalent in the COVID+ group til ~8months after illness with between-group differences no longer evident at 1 year.

Greater In-Hospital Care and Early Rehabilitation Needs in People with COVID-19 Compared with Those without COVID-19.

↔This study aims to compare the characteristics, in-hospital data and rehabilitation needs between those who tested positive versus negative for COVID-19 during hospitalisation with suspected COVID-19. In this cross-sectional study, a convenience sample of adults admitted to Western Australian tertiary hospitals with suspected COVID-19 was recruited. Participants were grouped according to their polymerase chain reaction (PCR) test result into COVID-19 positive (COVID+) and COVID-19 negative (COVID−) groups. Between-group comparisons of characteristics of the participants and hospital admission data were performed. Sixty-five participants were included (38 COVID+ and 27 COVID−; 36 females [55%]). Participants in the COVID+ group had greater acute hospital length of stay (LOS) (median [25−75th percentile] 10 [5−21] vs. 3 [2−5] days; p < 0.05] and only those with COVID+ required mechanical ventilation (8 [21%] participants). Twenty-one percent of the COVID+ participants were discharged to inpatient rehabilitation (7% of the COVID− participants). Of note, pre-existing pulmonary disease was more prevalent in the COVID− group (59% vs. 13%; p < 0.05). Within the COVID+ group, when compared to participants discharged home, those who required inpatient rehabilitation had worse peripheral oxygen saturation (SpO2) on admission (86 ± 5.7% vs. 93 ± 3.8%; p < 0.05) and longer median LOS (30 [23−37] vs. 7 [4−13] days; p < 0.05). Despite having less people with pre-existing pulmonary disease, the COVID+ group required more care and rehabilitation than the COVID− group. In the COVID+ group, SpO2 on hospital presentation was associated with LOS, critical care needs, mechanical ventilation duration and the need for inpatient rehabilitation.

Research lessons during the COVID-19 pandemic: collecting longitudinal physical and mental health outcomes.

BACKGROUND: Participant enrolment, assessment and/or delivery of intervention in many clinical trials during the COVID-19 pandemic were severely impacted by public health measures limiting physical contact. This report describes the lessons learned in completing a repeated measures cohort study involving suspected and confirmed COVID-19 survivors at three sites in Perth, Western Australia. MAIN BODY: An observational analysis of the conduct and data completeness results of the LATER-19 trial. People with COVID19 symptoms who were tested between February and November 2020 were recruited. In both those who tested positive and those who tested negative (control group) for COVID19, data on physical function and mental health were collected at two time points up to eight months after COVID19 testing. Recruitment of the controls was targeted from hospital records for comparison, it was balanced for age and sex and for the non-hospitalised group also comorbidities. A sample of 344 participants was recruited: 155 (45.1%) COVID-19 positive. Taking the research design and environmental adaptations into account, we recorded > 90% participant engagement during the trial. Of the 637 planned assessments, objective measures were completed on 602 (94.5%) occasions; 543 (90.2%) were on-site and 59 (9.8%) were remote. A total of 577 (90.6%) mental health/symptoms surveys, 569 (89.3%) 1-min sit-to-stand tests, and 520 (81.6%) handgrip strength tests were completed. CONCLUSION: The sample size and high completion rate of planned assessments during the LATER-19 trial potentially increases the contextual, groupwise generalisability of the results. The results demonstrate the effectiveness of a simple, rapid, reproducible and adaptable battery of assessments, leveraging telehealth and digital solutions. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registration (ANZCTR): ACTRN12621001067864 .