Long-term health conditions and UK labour market outcomes during the COVID-19 pandemic.

BACKGROUND: Long-term health conditions can affect labour market outcomes. COVID-19 may have increased labour market inequalities, e.g. due to restricted opportunities for clinically vulnerable people. Evaluating COVID-19's impact could help target support. AIM: To quantify the effect of several long-term conditions on UK labour market outcomes during the COVID-19 pandemic and compare them to pre-pandemic outcomes. METHODS: The Understanding Society COVID-19 survey collected responses from around 20,000 UK residents in nine waves from April 2020-September 2021. Participants employed in January/February 2020 with a variety of long-term conditions were matched with people without the condition but with similar baseline characteristics. Models estimated probability of employment, hours worked and earnings. We compared these results with results from a two-year pre-pandemic period. We also modelled probability of furlough and home-working frequency during COVID-19. RESULTS: Most conditions (asthma, arthritis, emotional/nervous/psychiatric problems, vascular/pulmonary/liver conditions, epilepsy) were associated with reduced employment probability and/or hours worked during COVID-19, but not pre-pandemic. Furlough was more likely for people with pulmonary conditions. People with arthritis and cancer were slower to return to in-person working. Few effects were seen for earnings. CONCLUSION: COVID-19 had a disproportionate impact on people with long-term conditions' labour market outcomes.

Allosteric regulation of glycogen breakdown by the second messenger cyclic di-GMP.

Streptomyces are our principal source of antibiotics, which they generate concomitant with a complex developmental transition from vegetative hyphae to spores. c-di-GMP acts as a linchpin in this transition by binding and regulating the key developmental regulators, BldD and WhiG. Here we show that c-di-GMP also binds the glycogen-debranching-enzyme, GlgX, uncovering a direct link between c-di-GMP and glycogen metabolism in bacteria. Further, we show c-di-GMP binding is required for GlgX activity. We describe structures of apo and c-di-GMP-bound GlgX and, strikingly, their comparison shows c-di-GMP induces long-range conformational changes, reorganizing the catalytic pocket to an active state. Glycogen is an important glucose storage compound that enables animals to cope with starvation and stress. Our in vivo studies reveal the important biological role of GlgX in Streptomyces glucose availability control. Overall, we identify a function of c-di-GMP in controlling energy storage metabolism in bacteria, which is widespread in Actinobacteria.

Mental illness and suicide among physicians.

The COVID-19 pandemic has heightened interest in how physician mental health can be protected and optimised, but uncertainty and misinformation remain about some key issues. In this Review, we discuss the current literature, which shows that despite what might be inferred during training, physicians are not immune to mental illness, with between a quarter and a third reporting increased symptoms of mental ill health. Physicians, particularly female physicians, are at an increased risk of suicide. An emerging consensus exists that some aspects of physician training, working conditions, and organisational support are unacceptable. Changes in medical training and health systems, and the additional strain of working through a pandemic, might have amplified these problems. A new evidence-informed framework for how individual and organisational interventions can be used in an integrated manner in medical schools, in health-care settings, and by professional colleagues is proposed. New initiatives are required at each of these levels, with an urgent need for organisational-level interventions, to better protect the mental health and wellbeing of physicians.

Evolution of a σ-(c-di-GMP)-anti-σ switch.

Filamentous actinobacteria of the genus Streptomyces have a complex lifecycle involving the differentiation of reproductive aerial hyphae into spores. We recently showed c-di-GMP controls this transition by arming a unique anti-σ, RsiG, to bind the sporulation-specific σ, WhiG. The Streptomyces venezuelae RsiG-(c-di-GMP)2-WhiG structure revealed that a monomeric RsiG binds c-di-GMP via two E(X)3S(X)2R(X)3Q(X)3D repeat motifs, one on each helix of an antiparallel coiled-coil. Here we show that RsiG homologs are found scattered throughout the Actinobacteria. Strikingly, RsiGs from unicellular bacteria descending from the most basal branch of the Actinobacteria are small proteins containing only one c-di-GMP binding motif, yet still bind their WhiG partners. Our structure of a Rubrobacter radiotolerans (RsiG)2-(c-di-GMP)2-WhiG complex revealed that these single-motif RsiGs are able to form an antiparallel coiled-coil through homodimerization, thereby allowing them to bind c-di-GMP similar to the monomeric twin-motif RsiGs. Further data show that in the unicellular actinobacterium R. radiotolerans, the (RsiG)2-(c-di-GMP)2-WhiG regulatory switch controls type IV pilus expression. Phylogenetic analysis indicates the single-motif RsiGs likely represent the ancestral state and an internal gene-duplication event gave rise to the twin-motif RsiGs inherited elsewhere in the Actinobacteria. Thus, these studies show how the anti-σ RsiG has evolved through an intragenic duplication event from a small protein carrying a single c-di-GMP binding motif, which functions as a homodimer, to a larger protein carrying two c-di-GMP binding motifs, which functions as a monomer. Consistent with this, our structures reveal potential selective advantages of the monomeric twin-motif anti-σ factors.

A case management occupational health model to facilitate earlier return to work of NHS staff with common mental health disorders: a feasibility study.

BACKGROUND: The NHS is the biggest employer in the UK. Depression and anxiety are common reasons for sickness absence among staff. Evidence suggests that an intervention based on a case management model using a biopsychosocial approach could be cost-effective and lead to earlier return to work for staff with common mental health disorders. OBJECTIVE: The objective was to assess the feasibility and acceptability of conducting a trial of the clinical effectiveness and cost-effectiveness of an early occupational health referral and case management intervention to facilitate the return to work of NHS staff on sick leave with any common mental health disorder (e.g. depression or anxiety). DESIGN: A multicentre mixed-methods feasibility study with embedded process evaluation and economic analyses. The study comprised an updated systematic review, survey of care as usual, and development of an intervention in consultation with key stakeholders. Although this was not a randomised controlled trial, the study design comprised two arms where participants received either the intervention or care as usual. PARTICIPANTS: Participants were NHS staff on sick leave for 7 or more consecutive days but less than 90 consecutive days, with a common mental health disorder. INTERVENTION: The intervention involved early referral to occupational health combined with standardised work-focused case management. CONTROL/COMPARATOR: Participants in the control arm received care as usual. PRIMARY OUTCOME: The primary outcome was the feasibility and acceptability of the intervention, study processes (including methods of recruiting participants) and data collection tools to measure return to work, episodes of sickness absence, workability (a worker's functional ability to perform their job), occupational functioning, symptomatology and cost-effectiveness proposed for use in a main trial. RESULTS: Forty articles and two guidelines were included in an updated systematic review. A total of 49 of the 126 (39%) occupational health providers who were approached participated in a national survey of care as usual. Selected multidisciplinary stakeholders contributed to the development of the work-focused case management intervention (including a training workshop). Six NHS trusts (occupational health departments) agreed to take part in the study, although one trust withdrew prior to participant recruitment, citing staff shortages. At mixed intervention sites, participants were sequentially allocated to each arm, where possible. Approximately 1938 (3.9%) NHS staff from the participating sites were on sick leave with a common mental health disorder during the study period. Forty-two sick-listed NHS staff were screened for eligibility on receipt of occupational health management referrals. Twenty-four (57%) participants were consented: 11 (46%) received the case management intervention and 13 (54%) received care as usual. Follow-up data were collected from 11 out of 24 (46%) participants at 3 months and 10 out of 24 (42%) participants at 6 months. The case management intervention and case manager training were found to be acceptable and inexpensive to deliver. Possible contamination issues are likely in a future trial if participants are individually randomised at mixed intervention sites. HARMS: No adverse events were reported. LIMITATIONS: The method of identification and recruitment of eligible sick-listed staff was ineffective in practice because uptake of referral to occupational health was low, but a new targeted method has been devised. CONCLUSION: All study questions were addressed. Difficulties raising organisational awareness of the study coupled with a lack of change in occupational health referral practices by line managers affected the identification and recruitment of participants. Strategies to overcome these barriers in a main trial were identified. The case management intervention was fit for purpose and acceptable to deliver in the NHS. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14621901. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 12. See the NIHR Journals Library website for further project information.

Anxiety and depression are common causes of sickness absence in the NHS. This can harm patient care. Previous research has shown that offering early support to NHS staff on sick leave with a common mental health disorder is important to aid recovery and rehabilitation. However, it is not currently known how best to support staff in returning to work. The purpose of this research was to test the feasibility of a large-scale study to see if specially trained occupational health nurses would be effective in getting NHS staff with these problems back to work quicker. We reviewed the recent scientific literature and did a survey of NHS occupational health departments to find out what was currently offered to such staff. We developed a new work-focused case management intervention and trained six occupational health nurses to deliver it. We recruited 24 NHS staff who were on sick leave with a common mental health disorder (such as depression or anxiety) and allocated 11 to receive the new intervention and the rest to receive usual support. Participants were invited to complete three questionnaires and we collected information from the participating occupational health sites. We also interviewed participants, managers, human resource staff and occupational health nurses to find out what they thought about being involved in the study. We found that the new case management intervention had potential benefits. However, it would not be possible to run a trial to evaluate the intervention until a better way can be found to encourage the early referral of sick staff to occupational health.

c-di-GMP Arms an Anti-σ to Control Progression of Multicellular Differentiation in Streptomyces.

Streptomyces are our primary source of antibiotics, produced concomitantly with the transition from vegetative growth to sporulation in a complex developmental life cycle. We previously showed that the signaling molecule c-di-GMP binds BldD, a master repressor, to control initiation of development. Here we demonstrate that c-di-GMP also intervenes later in development to control differentiation of the reproductive hyphae into spores by arming a novel anti-σ (RsiG) to bind and sequester a sporulation-specific σ factor (σWhiG). We present the structure of the RsiG-(c-di-GMP)2-σWhiG complex, revealing an unusual, partially intercalated c-di-GMP dimer bound at the RsiG-σWhiG interface. RsiG binds c-di-GMP in the absence of σWhiG, employing a novel E(X)3S(X)2R(X)3Q(X)3D motif repeated on each helix of a coiled coil. Further studies demonstrate that c-di-GMP is essential for RsiG to inhibit σWhiG. These findings reveal a newly described control mechanism for σ-anti-σ complex formation and establish c-di-GMP as the central integrator of Streptomyces development.

Structures of MERS1, the 5' processing enzyme of mitochondrial mRNAs in Trypanosoma brucei.

Most mitochondrial mRNAs are transcribed as polycistronic precursors that are cleaved by endonucleases to produce mature mRNA transcripts. However, recent studies have shown that mitochondrial transcripts in the kinetoplastid protozoan, Trypanosoma brucei, are transcribed individually. Also unlike most mitochondrial mRNAs, the 5' end of these transcripts harbor a triphosphate that is hydrolyzed. This modification is carried out by a putative Nudix hydrolase called MERS1. The Nudix motif in MERS1 is degenerate, lacking a conserved glutamic acid, thus it is unclear how it may bind its substrates and whether it contains a Nudix fold. To obtain insight into this unusual hydrolase, we determined structures of apo, GTP-bound and RNA-bound T. brucei MERS1 to 2.30 Å, 2.45 Å, and 2.60 Å, respectively. The MERS1 structure has a unique fold that indeed contains a Nudix motif. The nucleotide bound structures combined with binding studies reveal that MERS1 shows preference for RNA sequences with a central guanine repeat which it binds in a single-stranded conformation. The apo MERS1 structure indicates that a significant portion of its nucleotide binding site folds upon substrate binding. Finally, a potential interaction region for a binding partner, MERS2, that activates MERS1 was identified. The MERS2-like peptide inserts a glutamate near the missing Nudix acidic residue in the RNA binding pocket, suggesting how the enzyme may be activated. Thus, the combined studies reveal insight into the structure and enzyme properties of MERS1 and its substrate-binding activities.

Structures of maintenance of carboxysome distribution Walker-box McdA and McdB adaptor homologs.

Carboxysomes, protein-coated organelles in cyanobacteria, are important in global carbon fixation. However, these organelles are present at low copy in each cell and hence must be segregated to ensure transmission from one generation to the next. Recent studies revealed that a DNA partition-like ParA-ParB system mediates carboxysome maintenance, called McdA-McdB. Here, we describe the first McdA and McdB homolog structures. McdA is similar to partition ParA Walker-box proteins, but lacks the P-loop signature lysine involved in ATP binding. Strikingly, a McdA-ATP structure shows that a lysine distant from the P-loop and conserved in McdA homologs, enables ATP-dependent nucleotide sandwich dimer formation. Similar to partition ParA proteins this ATP-bound form binds nonspecific-DNA. McdB, which we show directly binds McdA, harbors a unique fold and appears to form higher-order oligomers like partition ParB proteins. Thus, our data reveal a new signature motif that enables McdA dimer formation and indicates that, similar to DNA segregation, carboxysome maintenance systems employ Walker-box proteins as DNA-binding motors while McdB proteins form higher order oligomers, which could function as adaptors to link carboxysomes and provide for stable transport by the McdA proteins.

Correction to: Cervical and breast cancer screening uptake among women with serious mental illness: a data linkage study.

Following publication of the original article [1], the authors notified us of an error in the reported percentages in Table 3.

The role of job strain in understanding midlife common mental disorder: a national birth cohort study.

BACKGROUND: Long-standing concerns exist about reverse causation and residual confounding in the prospective association between job strain and risk of future common mental disorders. We aimed to address these concerns through analysis of data collected in the UK National Child Development Study, a large British cohort study. METHODS: Data from the National Child Development Study (n=6870) were analysed by use of multivariate logistic regression to investigate the prospective association between job strain variables at age 45 years and risk of future common mental disorders at age 50 years, controlling for lifetime psychiatric history and a range of other possible confounding variables across the lifecourse. Population attributable fractions were calculated to estimate the public health effect of job strain on midlife mental health. FINDINGS: In the final model, adjusted for all measured confounders, high job demands (odds ratio 1·70, 95% CI 1·25-2·32; p=0·0008), low job control (1·89, 1·29-2·77; p=0·0010), and high job strain (2·22, 1·59-3·09; p<0·0001) remained significant independent predictors of future onset of common mental disorder. If causality is assumed, our findings suggest that 14% of new cases of common mental disorder could have been prevented through elimination of high job strain (population attributable fraction 0·14, 0·06-0·20). INTERPRETATION: High job strain appears to independently affect the risk of future common mental disorders in midlife. These findings suggest that modifiable work-related risk factors might be an important target in efforts to reduce the prevalence of common mental disorders. FUNDING: iCare Foundation and Mental Health Branch, NSW Health.

Depression and anxiety in patients receiving interferon-alpha: The role of illness perceptions.

Development of psychiatric symptoms during interferon-alpha therapy may be influenced by psychological factors. We examined illness perceptions using the Revised Illness Perceptions Questionnaire in 55 patients with chronic hepatitis C virus infection, due to receive interferon-alpha. The Hospital Anxiety and Depression Scale was used to assess the development of symptoms. Negative identity, consequences and emotional representation beliefs were significantly associated with both higher depression and anxiety scores. Negative illness perceptions play a predictive role in the development of interferon-alpha-induced psychiatric symptoms.

A framework to create more mentally healthy workplaces: A viewpoint.

Mental illness is now the leading cause of long-term sickness absence among Australian workers, with significant costs to the individual, their employers and society more broadly. However, to date, there has been little evidence-informed guidance as to what workplaces should be doing to enhance their employees' mental health and wellbeing. In this article, we present a framework outlining the key strategies employers can implement to create more mentally healthy workplaces. The five key strategies outlined are as follows: (1) designing work to minimise harm, (2) building organisational resilience through good management, (3) enhancing personal resilience, (4) promoting early help-seeking and (5) supporting recovery and return to work. A narrative review is utilised to outline the theoretical evidence for this framework and to describe the available research evidence for a number of key example interventions for each of the five strategies. While each workplace needs to develop tailored solutions, the five strategy framework proposed in this review will hopefully provide a simple framework for employers and those advising them to use when judging the adequacy of existing services and considering opportunities for further enhancements.

NIPSA: a new scale for measuring non-illness predictors of sickness absence.

OBJECTIVES: We describe the development and initial validation of a new scale for measuring non-illness factors that are important in predicting occupational outcomes, called the NIPSA (non-illness predictors of sickness absence) scale. METHODS: Forty-two questions were developed which covered a broad range of potential non-illness-related risk factors for sickness absence. 682 participants in the South East London Community Health study answered these questions and a range of questions regarding both short-term and long-term sickness absence. Factor analysis was conducted prior to examining the links between each identified factor and sickness absence outcomes. RESULTS: Exploratory factor analysis using the oblique rotation method suggested the questionnaire should contain 26 questions and extracted four factors with eigenvalues greater than 1: perception of psychosocial work environment (factor 1), perceived vulnerability (factor 2), rest-focused attitude towards recovery (factor 3) and attitudes towards work (factor 4). Three of these factors (factors 1, 2 and 3) showed significant associations with long-term sickness absence measures (p<0.05), meaning a final questionnaire that included 20 questions with three subscales. CONCLUSIONS: The NIPSA is a new tool that will hopefully allow clinicians to quickly assess for the presence of non-illness factors that may be important in predicting occupational outcomes and tailor treatments and interventions to address the barriers identified. To the best of our knowledge, this is the first time that a scale focused on transdiagnostic, non-illness-related predictors of sickness absence has been developed.

Cervical and breast cancer screening uptake among women with serious mental illness: a data linkage study.

BACKGROUND: Breast and cancer screening uptake has been found to be lower among women with serious mental illness (SMI). This study aims to corroborate these findings in the UK and to identify variation in screening uptake by illness/treatment factors, and primary care consultation frequency. METHODS: Linked population-based primary and secondary care data from the London borough of Lambeth (UK) were used to compare breast and cervical screening receipt among linked eligible SMI patients (n = 625 and n = 1393), to those without SMI known only to primary care (n = 106,554 and n = 25,385) using logistic regression models adjusted first for socio-demographic factors and second, additionally for primary care consultation frequency. RESULTS: Eligible SMI patients were less likely to have received breast (adjusted odds ratio (OR) 0.69, 95 % confidence interval (CI), 0.57 - 0.84, p < 0.001) or cervical screening (adjusted OR 0.72, CI: 0.60 - 0.85, p < 0.001). Schizophrenia diagnosis, depot injectable antipsychotic prescription, and illness severity and risk were associated with the lowest odds of uptake of breast (adjusted ORs 0.46 to 0.59, all p < 0.001) and cervical screening (adjusted ORs 0.48 - 0.65, all p < 0.001). Adjustments for consultation frequency further reduced effect sizes for all subgroups of SMI patient, in particular for cervical screening. CONCLUSIONS: Women with SMI are less likely to receive breast and cervical cancer screening than comparable women without SMI. Higher primary care consultation rates among SMI patients is likely a mediating factor between SMI status and uptake, particularly for cervical screening - a service organised in primary care. To tackle health disparities linked to SMI, efforts at increasing screening uptake are key and should be targeted at women with other markers of illness severity or risk, beyond SMI status alone.

Cardiovascular disease treatment among patients with severe mental illness: a data linkage study between primary and secondary care.

BACKGROUND: Suboptimal treatment of cardiovascular diseases (CVD) among patients with severe mental illness (SMI) may contribute to physical health disparities. AIM: To identify SMI characteristics associated with meeting CVD treatment and prevention guidelines. DESIGN AND SETTING: Population-based electronic health record database linkage between primary care and the sole provider of secondary mental health care services in south east London, UK. METHOD: Cardiovascular disease prevalence, risk factor recording, and Quality and Outcomes Framework (QOF) clinical target achievement were compared among 4056 primary care patients with SMI whose records were linked to secondary healthcare records and 270 669 patients without SMI who were not known to secondary care psychiatric services, using multivariate logistic regression modelling. Data available from secondary care records were then used to identify SMI characteristics associated with QOF clinical target achievement. RESULTS: Patients with SMI and with coronary heart disease and heart failure experienced reduced prescribing of beta blockers and angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (ACEI/ARB). A diagnosis of schizophrenia, being identified with any indicator of risk or illness severity, and being prescribed with depot injectable antipsychotic medication was associated with the lowest likelihood of prescribing. CONCLUSION: Linking primary and secondary care data allows the identification of patients with SMI most at risk of undertreatment for physical health problems.

Cohort profile of the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Case Register: current status and recent enhancement of an Electronic Mental Health Record-derived data resource.

PURPOSE: The South London and Maudsley National Health Service (NHS) Foundation Trust Biomedical Research Centre (SLaM BRC) Case Register and its Clinical Record Interactive Search (CRIS) application were developed in 2008, generating a research repository of real-time, anonymised, structured and open-text data derived from the electronic health record system used by SLaM, a large mental healthcare provider in southeast London. In this paper, we update this register's descriptive data, and describe the substantial expansion and extension of the data resource since its original development. PARTICIPANTS: Descriptive data were generated from the SLaM BRC Case Register on 31 December 2014. Currently, there are over 250,000 patient records accessed through CRIS. FINDINGS TO DATE: Since 2008, the most significant developments in the SLaM BRC Case Register have been the introduction of natural language processing to extract structured data from open-text fields, linkages to external sources of data, and the addition of a parallel relational database (Structured Query Language) output. Natural language processing applications to date have brought in new and hitherto inaccessible data on cognitive function, education, social care receipt, smoking, diagnostic statements and pharmacotherapy. In addition, through external data linkages, large volumes of supplementary information have been accessed on mortality, hospital attendances and cancer registrations. FUTURE PLANS: Coupled with robust data security and governance structures, electronic health records provide potentially transformative information on mental disorders and outcomes in routine clinical care. The SLaM BRC Case Register continues to grow as a database, with approximately 20,000 new cases added each year, in addition to extension of follow-up for existing cases. Data linkages and natural language processing present important opportunities to enhance this type of research resource further, achieving both volume and depth of data. However, research projects still need to be carefully tailored, so that they take into account the nature and quality of the source information.