Diene incorporation by a dehydratase domain variant in modular polyketide synthases.

Modular polyketide synthases (PKSs) are biosynthetic assembly lines that construct structurally diverse natural products with wide-ranging applications in medicine and agriculture. Various mechanisms contribute to structural diversification during PKS-mediated chain assembly, including dehydratase (DH) domain-mediated elimination of water from R and S-configured 3-hydroxy-thioesters to introduce E- and Z-configured carbon-carbon double bonds, respectively. Here we report the discovery of a DH domain variant that catalyzes the sequential elimination of two molecules of water from a (3R, 5S)-3,5-dihydroxy thioester during polyketide chain assembly, introducing a conjugated E,Z-diene into various modular PKS products. We show that the reaction proceeds via a (2E, 5S)-2-enoyl-5-hydroxy-thioester intermediate and involves an additional universally conserved histidine residue that is absent from the active site of most conventional DH domains. These findings expand the diverse range of chemistries mediated by DH-like domains in modular PKSs, highlighting the catalytic versatility of the double hotdog fold.

Mental health self-care during the COVID-19 pandemic: a prospective cohort study in Australia.

INTRODUCTION: Pandemic public health measures have affected mental health for many people. We sought to determine how people were managing their mental health concerns during the pandemic, and to identify worker characteristics where actions were more common. METHODS: A prospective cohort of 1646 Australians, who were in paid employment prior to the pandemic, completed a survey during 27 April- 26 July 2020 on changes in work, health, and actions taken to manage their mental health concerns. Descriptive statistics were calculated to determine actions taken to manage mental health concerns during the prior month, such as lifestyle changes, exercise, use of online resources, and talking to others. Regression models identify worker characteristics where actions were more common. RESULTS: Lifestyle changes were the most frequently reported action to manage mental health concerns (78%), and were more common for women (OR = 2.33, 95%CI=[1.82, 3.03]), and people experiencing recent work loss (OR = 1.54, 95%CI=[1.04, 2.28]). Overall, mental health self-care was more common for people experiencing psychological distress, or with pre-existing mental conditions. Talking to friends about mental health, and making changes to diet and exercise, was more common for women and those aged 18-24 years. Psychological distress was a significant indicator for consulting with health professionals. CONCLUSION: Actions to manage mental health concerns during the pandemic were common, as were conversations with friends or family members. During economic crises, support and services should focus on reducing barriers to formal mental health care, particularly for people who less commonly seek help, and those experiencing moderate to high levels of psychological distress.

Use of General Practitioner Services Among Workers with Work-Related Low Back Pain: A Systematic Review.

PURPOSE: Work-related low back pain (WRLBP) is a highly prevalent health problem worldwide leading to work disability and increased healthcare utilisation. General practitioners (GPs) play an important role in the management of WRLBP. Despite this, understanding of GP service use for WRLBP is limited. This systematic review aimed to determine the prevalence, patterns and determinants of GP service use for WRLBP. METHODS: MEDLINE, Embase via Ovid, Scopus and Web of Science were searched for relevant peer-reviewed articles published in English without any restriction on time of publications. Low back pain (LBP) was considered work-related if the study included workers' compensation claim data analysis, participants with accepted workers' compensation claims or reported a connection with work and LBP. The eligibility criteria for GP service use are met if there is any reported consultation with family practitioner, medical doctor or General Practitioner. Two reviewers screened articles and extracted data independently. Narrative synthesis was conducted. RESULTS: Seven eligible studies reported prevalence of GP service use among workers with WRLBP ranging from 11% to 99.3%. Only studies from Australia, Canada and the United States met the eligibility criteria. The prevalence of GP service use was higher in Australia (70%) and Canada (99.3%) compared to the United States (25.3% to 39%). The mean (standard deviation) number of GP visits ranged from 2.6 (1.6) to 9.6 (12.4) over a two-year time interval post-WRLBP onset. Determinants of higher GP service use included prior history of low back pain, more severe injury, prior GP visits and younger age. CONCLUSION: Only seven studies met the eligibility indicating a relative lack of evidence, despite the acknowledged important role that GPs play in the care of workers with low back pain. More research is needed to understand the prevalence, patterns and determinants to support effective service delivery and policy development.

Nanoliposomes Reduce Stroke Injury Following Middle Cerebral Artery Occlusion in Mice.

BACKGROUND AND PURPOSE: Neuroprotective strategies for stroke remain inadequate. Nanoliposomes comprised of phosphatidylcholine, cholesterol, and monosialogangliosides (nanoliposomes) induced an antioxidant protective response in endothelial cells exposed to amyloid insults. We tested the hypotheses that nanoliposomes will preserve human neuroblastoma (SH-SY5Y) and human brain microvascular endothelial cells viability following oxygen-glucose deprivation (OGD)-reoxygenation and will reduce injury in mice following middle cerebral artery occlusion. METHODS: SH-SY5Y and human brain microvascular endothelial cells were exposed to oxygen-glucose deprivation-reoxygenation (3 hours 0.5%-1% oxygen and glucose-free media followed by 20-hour ambient air/regular media) without or with nanoliposomes (300 µg/mL). Viability was measured (calcein-acetoxymethyl fluorescence) and protein expression of antioxidant proteins HO-1 (heme oxygenase-1), NQO1 (NAD[P]H quinone dehydrogenase 1), and SOD1 (superoxide dismutase 1) were measured by Western blot. C57BL/6J mice were treated with saline (n=8) or nanoliposomes (10 mg/mL lipid, 200 µL, n=7) while undergoing 60-minute middle cerebral artery occlusion followed by reperfusion. Day 2 postinjury neurological impairment score and infarction size were compared. RESULTS: SH-SY5Y and human brain microvascular endothelial cells showed reduced viability post-oxygen-glucose deprivation-reoxygenation that was reversed by nanoliposomes. Nanoliposomes increased protein expressions of HO-1, NQO1 in both cell types and SOD1 in human brain microvascular endothelial cells. Nanoliposomes-treated mice showed reduced neurological impairment and brain infarct size (18.8±2% versus 27.3±2.3%, P=0.017) versus controls. CONCLUSIONS: Nanoliposomes reduced stroke injury in mice subjected to middle cerebral artery occlusion likely through induction of an antioxidant protective response. Nanoliposome is a candidate novel agent for stroke.

ELEVATE - evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial.

BACKGROUND: For patients with oesophagogastric adenocarcinoma, surgery is the only curative option and despite the use of multimodality therapy, which combines it with chemotherapy and/or radiotherapy, more than 50% of patients will relapse and die. Many UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab, a checkpoint blockade inhibitor, has been found to work in some advanced cancers. It is proposed, for those where immunotherapy hasn't worked, that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act. METHODS: ELEVATE is a single arm phase II trial testing the overall response to nivolumab following temozolomide treatment in patients with advanced unresectable previously treated adenocarcinoma which is O6-methylguanine-DNA-methyltransferase (MGMT) methylated. 18 patients are being recruited from UK secondary care sites. To be eligible, participants must have been treated with at least 3 months of platinum and fluoropyrimidine chemotherapy. Participants will receive 50 mg/m2 temozolomide continuously for 3 months. If their disease progresses during the 3 months, they will stop temozolomide and start nivolumab at a dose of 240mg every 2 weeks. If there is no progression after 3 months the participant will continue taking temozolomide in combination with nivolumab. All treatment will stop once the participant progresses on nivolumab. The primary endpoint is the best overall response to nivolumab, using both Response Evaluation Criteria in Solid Tumours version 1.1 and immunotherapy modified Response Evaluation Criteria in Solid Tumours. Secondary endpoints include progression-free survival, overall survival, and quality of life. DISCUSSION: ELEVATE will provide evidence for whether giving nivolumab after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma is safe and biologically effective prior to future randomised trials. TRIAL REGISTRATIONS: EudraCT Number: 2020-004771-41 (issued 01 October 2020); ISCRTN11398887 (registered 14 July 2021).

Changes in work and health of Australians during the COVID-19 pandemic: a longitudinal cohort study.

BACKGROUND: Engagement in work is an important determinant of health. In response to the COVID-19 pandemic, public health measures imposed to reduce viral transmission resulted in large-scale loss of work during the early stages of the pandemic, contributing to declined mental and physical health. As the pandemic unfolded, the Australian economy began to recover and some people could return to work, whilst localised lockdowns resulted in further loss of work for others. The long-term health effects of work loss remain unexplored within the COVID-19 pandemic context, in addition to whether any health effects are persistent upon returning to work. METHODS: A prospective longitudinal cohort study of 2603 participants across Australia monitored changes in health and work between March and December 2020, with participants completing surveys at baseline and 1, 3 and 6 months later. Outcomes described psychological distress, and mental and physical health. Linear mixed regression models examined associations between changes in health and experiences of work loss, and return to work, over time. RESULTS: Losing work during the early stages of the pandemic was associated with long-term poorer mental health, which began to recover over time as some returned to work. Physical health deteriorated over time, greater for people not working at baseline. Being out of work was associated with poorer mental health, but better physical health. These effects were larger for people that had recently lost work than for people with sustained work loss, and retaining employment played a protective role. Generally, returning to work resulted in poorer physical health and improvements in mental health, although this depended on the broader context of changes in work. CONCLUSIONS: Work cessation during the pandemic led to poor health outcomes and had long-lasting effects. Returning to work benefits mental health but may reduce physical activity in the short-term. We encourage the provision of accessible mental health supports and services immediately following loss of work, and for people with prolonged forms of work loss. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12620000857909 .

Returning to the Workplace During the COVID-19 Pandemic: The Concerns of Australian Workers.

Purpose To determine the nature and prevalence of workers' concerns regarding workplaces reopening during the pandemic. To identify characteristics of workers and industries where particular concerns are more common. Method Prospective cohort study of 1063 employed Australian adults, enrolled at the start of the pandemic. Data on attitudes to workplaces reopening were collected 1 July-30 September 2020. The frequency of concerns describes infection risk and changes to work and impact on home life. Regression models examined associations between demographic and industry factors with reopening concerns. Results More than four in five (82.4%) of workers reported concerns about workplace infection risk. Just over half (53.4%) reported concerns about impacts to work and home life. Concerns were more prevalent for workers reporting psychological distress, financial stress, and among those exclusively working from home. Concerns regarding infection risk were common for workers in health care (IRR 1.16, 95% CI [1.01, 1.33]), retail (IRR 1.31, 95% CI [1.06, 1.61]), and accommodation/food service industries (IRR 1.25, 95% CI [1.01, 1.55]). Concerns regarding changes to work and home life were more common for female workers (IRR 1.24, 95% CI [1.07, 1.43]), and partners/spouses with dependent children (IRR 1.44, 95% CI [1.16, 1.79]). Conclusion Concerns of COVID-19 infection in the workplace are common. Many workers are also concerned about changes to their work and home life. The prevalence of concerns is related to the nature of work and responsibilities at home. Actions that reduce risk of workplace transmission, coupled with effective communication of infection controls, may alleviate worker concerns whilst recognising workers' family and social circumstances.

The Impact of Work Loss on Mental and Physical Health During the COVID-19 Pandemic: Baseline Findings from a Prospective Cohort Study.

Purpose To determine if losing work during the COVID-19 pandemic is associated with mental and physical health status. To determine if social interactions and financial resources moderate the relationship between work loss and health. Methods Participants were Australians aged 18 + years that were employed in paid work prior to the COVID-19 pandemic who responded to an online or telephone survey from 27th March to 12th June 2020 as part of a prospective longitudinal cohort study. Outcome measures include Kessler-6 score > 18 indicating high psychological distress, and Short Form 12 (SF-12) mental health or physical health component score < = 45 indicating poor mental or physical health. Results The cohort consisted of 2,603 respondents, including groups who had lost their job (N = 541), were not working but remained employed (N = 613), were working less (N = 660), and whose work was unaffected (N = 789). Three groups experiencing work loss had greater odds of high psychological distress (AOR = 2.22-3.66), poor mental (AOR = 1.78-2.27) and physical health (AOR = 2.10-2.12) than the unaffected work group. Poor mental health was more common than poor physical health. The odds of high psychological distress (AOR = 5.43-8.36), poor mental (AOR = 1.92-4.53) and physical health (AOR = 1.93-3.90) were increased in those reporting fewer social interactions or less financial resources. Conclusion Losing work during the COVID-19 pandemic is associated with mental and physical health problems, and this relationship is moderated by social interactions and financial resources. Responses that increase financial security and enhance social connections may alleviate the health impacts of work loss. Registration Australian New Zealand Clinical Trials Registry: ACTRN12620000857909.

Mechanism of intersubunit ketosynthase-dehydratase interaction in polyketide synthases.

Modular polyketide synthases (PKSs) produce numerous structurally complex natural products that have diverse applications in medicine and agriculture. PKSs typically consist of several multienzyme subunits that utilize structurally defined docking domains (DDs) at their N and C termini to ensure correct assembly into functional multiprotein complexes. Here we report a fundamentally different mechanism for subunit assembly in trans-acyltransferase (trans-AT) modular PKSs at the junction between ketosynthase (KS) and dehydratase (DH) domains. This mechanism involves direct interaction of a largely unstructured docking domain (DD) at the C terminus of the KS with the surface of the downstream DH. Acyl transfer assays and mechanism-based crosslinking established that the DD is required for the KS to communicate with the acyl carrier protein appended to the DH. Two distinct regions for binding of the DD to the DH were identified using NMR spectroscopy, carbene footprinting, and mutagenesis, providing a foundation for future elucidation of the molecular basis for interaction specificity.

Binding of Distinct Substrate Conformations Enables Hydroxylation of Remote Sites in Thaxtomin D by Cytochrome P450 TxtC.

Cytochromes P450 (CYPs) catalyze various oxidative transformations in drug metabolism, xenobiotic degradation, and natural product biosynthesis. Here we report biochemical, structural, and theoretical studies of TxtC, an unusual bifunctional CYP involved in the biosynthesis of the EPA-approved herbicide thaxtomin A. TxtC was shown to hydroxylate two remote sites within the Phe residue of its diketopiperazine substrate thaxtomin D. The reactions follow a preferred order, with hydroxylation of the α-carbon preceding functionalization of the phenyl group. To illuminate the molecular basis for remote site functionalization, X-ray crystal structures of TxtC in complex with the substrate and monohydroxylated intermediate were determined. Electron density corresponding to a diatomic molecule (probably dioxygen) was sandwiched between the heme iron atom and Thr237 in the TxtC-intermediate structure, providing insight into the mechanism for conversion of the ferrous-dioxygen complex into the reactive ferryl intermediate. The substrate and monohydroxylated intermediate adopted similar conformations in the active site, with the π-face of the phenyl group positioned over the heme iron atom. Docking simulations reproduced this observation and identified a second, energetically similar but conformationally distinct binding mode in which the α-hydrogen of the Phe residue is positioned over the heme prosthetic group. Molecular dynamics simulations confirmed that the α-hydrogen is sufficiently close to the ferryl oxygen atom to be extracted by it and indicated that the two substrate conformations cannot readily interconvert in the active site. These results indicate that TxtC is able to hydroxylate two spatially remote sites by binding distinct conformations of the substrate and monohydroxylated intermediate.

Mutualistic interaction between dichloromethane- and chloromethane-degrading bacteria in an anaerobic mixed culture.

The microbial mixed culture RM grows with dichloromethane (DCM) as the sole energy source generating acetate, methane, chloride and biomass as products. Chloromethane (CM) was not an intermediate during DCM utilization consistent with the observation that CM could not replace DCM as a growth substrate. Interestingly, cultures that received DCM and CM together degraded both compounds concomitantly. Transient hydrogen (H2 ) formation reaching a maximum concentration of 205 ± 13 ppmv was observed in cultures growing with DCM, and the addition of exogenous H2 at concentrations exceeding 3000 ppmv impeded DCM degradation. In contrast, CM degradation in culture RM had a strict requirement for H2 . Following five consecutive transfers on CM and H2 , Acetobacterium 16S rRNA gene sequences dominated the culture and the DCM-degrader Candidatus Dichloromethanomonas elyunquensis was eliminated, consistent with the observation that the culture lost the ability to degrade DCM. These findings demonstrate that culture RM harbours different populations responsible for anaerobic DCM and CM metabolism, and further imply that the DCM and CM degradation pathways are mechanistically distinct. H2 generated during DCM degradation is consumed by the hydrogenotrophic CM degrader, or may fuel other hydrogenotrophic processes, including organohalide respiration, methanogenesis and H2 /CO2 reductive acetogenesis.

Clinical relevance of midline fluid percussion brain injury: Acute deficits, chronic morbidities and the utility of biomarkers.

BACKGROUND: After 30 years of characterisation and implementation, fluid percussion injury (FPI) is firmly recognised as one of the best-characterised reproducible and clinically relevant models of TBI, encompassing concussion through diffuse axonal injury (DAI). Depending on the specific injury parameters (e.g. injury site, mechanical force), FPI can model diffuse TBI with or without a focal component and may be designated as mild-to-severe according to the chosen mechanical forces and resulting acute neurological responses. Among FPI models, midline FPI may best represent clinical diffuse TBI, because of the acute behavioural deficits, the transition to late-onset behavioural morbidities and the absence of gross histopathology. REVIEW: The goal here was to review acute and chronic physiological and behavioural deficits and morbidities associated with diffuse TBI induced by midline FPI. In the absence of neurodegenerative sequelae associated with focal injury, there is a need for biomarkers in the diagnostic, prognostic, predictive and therapeutic approaches to evaluate outcomes from TBI. CONCLUSIONS: The current literature suggests that midline FPI offers a clinically-relevant, validated model of diffuse TBI to investigators wishing to evaluate novel therapeutic strategies in the treatment of TBI and the utility of biomarkers in the delivery of healthcare to patients with brain injury.

Bioaugmentation with distinct Dehalobacter strains achieves chloroform detoxification in microcosms.

Chloroform (CF) is a widespread groundwater contaminant not susceptible to aerobic degradation. Under anoxic conditions, CF can undergo abiotic and cometabolic transformation but detoxification is generally not achieved. The recent discovery of distinct Dehalobacter strains that respire CF to dichloromethane (DCM) and ferment DCM to nonchlorinated products promises that bioremediation of CF plumes is feasible. To track both strains, 16S rRNA gene-based qPCR assays specific for either Dehalobacter strain were designed and validated. A laboratory treatability study explored the value of bioaugmentation and biostimulation to achieve CF detoxification using anoxic microcosms established with aquifer material from a CF-contaminated site. Microcosms that received 6% (v/v) of the CF-to-DCM-dechlorinating culture Dhb-CF to achieve an initial Dehalobacter cell titer of 1.6 ± 0.9 × 10(4) mL(-1) dechlorinated CF to stoichiometric amounts of DCM. Subsequent augmentation with 3% (v/v) of the DCM-degrading consortium RM to an initial Dehalobacter cell abundance of 1.2 ± 0.2 × 10(2) mL(-1) achieved complete DCM degradation in microcosms amended with 10 mM bicarbonate. Growth of the CF-respiring and the DCM-degrading Dehalobacter populations and detoxification were also observed in microcosms that received both inocula simultaneously. These findings suggest that anaerobic bioremediation (e.g., bioaugmentation) is a possible remedy at CF- and DCM-contaminated sites without CT, which strongly inhibited CF organohalide respiration and DCM organohalide fermentation.

"They Were Talking to an Idea They Had About Me": A Qualitative Analysis of Transgender Individuals' Experiences Using Dating Apps.

Dating app use is common and has become particularly relevant for transgender and non-binary people seeking platonic, romantic, and sexual connections with others. In this qualitative study, 15 transgender and non-binary individuals (M = 22.67 years, SD = 3.09 years) were interviewed to explore their experiences using dating apps. Thematic analysis was used to generate themes and subthemes. Six themes were identified: 1) connection to queer community; 2) expression of gender identity on dating apps; 3) fetishization on dating apps; 4) impacts of dating apps on sexual experiences; 5) safety on dating apps; and 6) recommendations for dating app developers. Results show that dating apps are an important tool used by trans/non-binary individuals to connect with others in the queer community and find platonic, romantic, and sexual partners. However, there are concerns about their use such as fears for safety and experiences of fetishization. More research, education, and implementations of app development, including the involvement of trans and non-binary people, are needed to address these concerns.

IL-21 conditions antigen-presenting human γδ T-cells to promote IL-10 expression in naïve and memory CD4+ T-cells.

Direct interaction between T-cells exerts a major influence on tissue immunity and inflammation across multiple body sites including the human gut, which is highly enriched in 'unconventional' lymphocytes such as γδ T-cells. We previously reported that microbial activation of human Vγ9/Vδ2+ γδ T-cells in the presence of the mucosal damage-associated cytokine IL-15 confers the ability to promote epithelial barrier defence, specifically via induction of IL-22 expression in conventional CD4+ T-cells. In the current report, we assessed whether other cytokines enriched in the gut milieu also functionally influence microbe-responsive Vγ9/Vδ2 T-cells. When cultured in the presence of IL-21, Vγ9/Vδ2 T-cells acquired the ability to induce expression of the immunoregulatory cytokine IL-10 in both naïve and memory CD4+ T-cells, at levels surpassing those induced by monocytes or monocyte-derived DCs. These findings identify an unexpected influence of IL-21 on Vγ9/Vδ2 T-cell modulation of CD4+ T-cell responses. Further analyses suggested a possible role for CD30L and/or CD40L reverse signalling in mediating IL-10 induction by IL-21 conditioned Vγ9/Vδ2 T-cells. Our findings indicate that the local microenvironment exerts a profound influence on Vγ9/Vδ2 T-cell responses to microbial challenge, leading to induction of distinct functional profiles among CD4+ T-cells that may influence inflammatory events at mucosal surfaces. Targeting these novel pathways may offer therapeutic benefit in disorders such as inflammatory bowel disease.

Peg Forest Rehabilitation - A novel spatial navigation based cognitive rehabilitation paradigm for experimental neurotrauma.

Traumatic brain injury (TBI) results from mechanical forces applied to the head. Ensuing cascades of complex pathophysiology transition the injury event into a disease process. The enduring constellation of emotional, somatic, and cognitive impairments degrade quality of life for the millions of TBI survivors suffering from long-term neurological symptoms. Rehabilitation strategies have reported mixed results, as most have not focused on specific symptomatology or explored cellular processes. The current experiments evaluated a novel cognitive rehabilitation paradigm for brain-injured and uninjured rats. The arena is a plastic floor with a cartesian grid of holes for plastic dowels to create new environments with the rearrangement of threaded pegs. Rats received either two weeks of Peg Forest rehabilitation (PFR) or open field exposure starting at 7 days post-injury; or one week starting at either day 7 or 14 post-injury; or served as caged controls. Cognitive performance was assessed on a battery of novel object tasks at 28 days post-injury. The results revealed that two weeks of PFR was required to prevent the onset of cognitive impairments, while one week of PFR was insufficient regardless of when rehabilitation was initiated after injury. Further assessment of the task showed that novel daily arrangements of the environment were required to impart the cognitive performance benefits, as exposure to a static arrangement of pegs for PFR each day did not improve cognitive performance. The results indicate that PFR prevents the onset of cognitive disorders following acquired a mild to moderate brain injury, and potentially other neurological conditions.

Transition between social protection systems for workers with long term health problems: A controlled retrospective cohort study.

Many nations have established workers' compensation systems as a feature of their social protection system. These systems typically provide time-limited entitlements such as wage replacement benefits and funding for medical treatment. Entitlements may end for workers with long-term health conditions before they have returned to employment. We sought to determine the prevalence of transitions to alternative forms of social protection, specifically social security benefits, among injured workers with long-term disability, when workers' compensation benefits end. We linked Australian workers' compensation and social security data to examine receipt of social security payments one year before and after workers' compensation benefit cessation. Study groups included (1) injured workers whose workers' compensation benefits ceased due to reaching a 260-week limit introduced by legislative reform (N = 2761), (2) a control group of injured workers with at least 104 weeks workers compensation income support (N = 3890), and (3) a matched community control group (N = 10,114). Adjusted binary logistic regression examined the odds of transitions to social security in the injured worker groups relative to the community control group. Within 12 months of workers' compensation benefit cessation, 60% (N = 1669) of the exposed group received social security payments, of which 41% (N = 1120) received the unemployment allowance and 19% (N = 516) the disability pension. Among the work injured control group, 42% (N = 1676) received social security payments after workers compensation benefits ceased. Transitions to social security payments were significantly more common than community levels for both exposed (OR 25.0, 95%CI = 20.7, 30.1) and work injured control groups (OR 4.7, 95%CI = 4.2, 5.3). Many injured workers with long-term health problems transition to social security when their workers' compensation benefits cease. Transitions were more common among workers whose claims ended due to legislative reform which time-limited benefits. Design and implementation of system level policy reform should consider the social and economic impacts of transitions between separate social protection systems.

Evaluating niraparib versus active symptom control in patients with previously treated mesothelioma (NERO): a study protocol for a multicentre, randomised, two-arm, open-label phase II trial in UK secondary care centres.

BACKGROUND: Malignant mesothelioma is a rapidly lethal cancer that has been increasing at an epidemic rate over the last three decades. Targeted therapies for mesothelioma have been lacking. A previous study called MiST1 (NCT03654833), evaluated the efficacy of Poly (ADP-ribose) polymerase (PARP) inhibition in mesothelioma. This study met its primary endpoint with 15% of patients having durable responses exceeding 1 year. Therefore, there is a need to evaluate PARP inhibitors in relapsed mesothelioma patients, where options are limited. Niraparib is the PARP inhibitor used in NERO. METHODS: NERO is a multicentre, two-arm, open-label UK randomised phase II trial designed to evaluate the efficacy of PARP inhibition in relapsed mesothelioma. 84 patients are being recruited. NERO is not restricted by line of therapy; however, eligible participants must have been treated with an approved platinum based systemic therapy. Participants will be randomised 2:1, stratified according to histology and response to prior platinum-based chemotherapy, to receive either active symptom control (ASC) and niraparib or ASC alone, for up to 24 weeks. Participants will be treated until disease progression, withdrawal, death or development of significant treatment limiting toxicity. Participants randomised to niraparib will receive 200 or 300 mg daily in a 3-weekly cycle. The primary endpoint is progression-free survival, where progression is determined by modified Response Evaluation Criteria in Solid Tumors (mRECIST) or RECIST 1.1; investigator reported progression; or death from any cause, whichever comes first. Secondary endpoints include overall survival, best overall response, 12-week and 24 week disease control, duration of response, treatment compliance and safety/tolerability. If NERO shows niraparib to be safe and biologically effective, it may lead to future late phase randomised controlled trials in relapsed mesothelioma. ETHICS AND DISSEMINATION: The study received ethical approval from London-Hampstead Research Ethics Committee on 06-May-2022 (22/LO/0281). Data from all centres will be analysed together and published as soon as possible. TRIAL REGISTRATION NUMBER: ISCRTN16171129; NCT05455424.

The health impacts of a 4-month long community-wide COVID-19 lockdown: Findings from a prospective longitudinal study in the state of Victoria, Australia.

OBJECTIVES: To determine health impacts during, and following, an extended community lockdown and COVID-19 outbreak in the Australian state of Victoria, compared with the rest of Australia. METHODS: A national cohort of 898 working-age Australians enrolled in a longitudinal cohort study, completing surveys before, during, and after a 112-day community lockdown in Victoria (8 July- 27 October 2020). Outcomes included psychological distress, mental and physical health, work, social interactions and finances. Regression models examined health changes during and following lockdown. RESULTS: The Victorian lockdown led to increased psychological distress. Health impacts coincided with greater social isolation and work loss. Following the extended lockdown, mental health, work and social interactions recovered to an extent whereby no significant long-lasting effects were identified in Victoria compared to the rest of Australia. CONCLUSION: The Victorian community lockdown had adverse health consequences, which reversed upon release from lockdown. Governments should weigh all potential health impacts of lockdown. Services and programs to reduce the negative impacts of lockdown may include increases in mental health care, encouraging safe social interactions and supports to maintain employment relationships.