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Background: The COVID-19 pandemic has had enormous implications for the world of work. However, there has been relatively little focus on the employment and workforce challenges of the virus in relation to workforce health, beyond the immediate management of the spread of the disease. There is an important gap in understanding the ongoing workforce issues created by the significant incidence of Long COVID in the population., Aim: This paper examines the effects of Long COVID on employment and workers' mental health to contribute to understanding of work-limiting health conditions and to offer policy implications for COVID-19 and similar health conditions on employment and the workforce., Methods: A large national panel study for the UK is used to estimate the likelihood of exiting employment as well as on changes in working hours and general mental health and happiness of those who remain in work. The sample includes individuals 16 years and older who were in employment in January/February 2020 and followed during the pandemic 2020-2021. Long COVID is self-reported in the data. Informed by conceptual consideration of employment protection in the UK, two groups of individuals with Long COVID are defined based on the duration of symptoms. Group 1 has Long COVID 5-28 weeks after an infection with COVID-19, which is up to the maximum length of Statutory Sick Pay in the UK. Group 2 has symptoms for 29+ weeks, which is beyond the statutory entitlement to sickness pay. Panel regression models are fitted both with fixed-effects and random-effects. Individual and job characteristics are used as controls Those with no COVID-19 symptoms are the reference group., Results: In between-person comparison, Group 2 is at higher risk of exiting employment compared to those with no COVID-19 symptoms. Between-person estimates of mental health and well-being show negative effects of Long COVID for both groups but these are greatest in Group 2. Within-person estimates suggest that factors associated with earnings mediate the negative Long COVID effects on mental health in Group 1 and that Group 2 adapts to working with Long COVID. Group 1 is at risk of working zero hours (i.e. being on sick leave) but neither Group 1 nor Group 2 have a higher probability of working fewer hours compared to those with no COVID-19 symptoms. The negative impact of Long COVID on working hours stems primarily from working zero hours (sickness leave) rather than working fewer hours, suggesting a lack of accommodation by employers of Long COVID at work., Policy Implications: The extension of Statutory Sickness Pay and greater flexibility to manage partial (returns to) work would help preserve employment and mental health. Those with Long COVID for 12 months are likely to meet the definition of disability and so have a right to receive reasonable workplace adjustments., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Reuschke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Human cytomegalovirus (HCMV) persists as a subclinical, lifelong infection in the normal human host, maintained at least in part by its carriage in the absence of detectable infectious virus--the hallmark of latent infection. Reactivation from latency in immunocompromised individuals, in contrast, often results in serious disease. Latency and reactivation are defining characteristics of the herpesviruses and key to understanding their biology. However, the precise cellular sites in which HCMV is carried and the mechanisms regulating its latency and reactivation during natural infection remain poorly understood. This review will detail our current knowledge of where HCMV is carried in healthy individuals, which viral genes are expressed upon carriage of the virus and what effect this has on cellular gene expression. It will also address the accumulating evidence suggesting that reactivation of HCMV from latency appears to be linked intrinsically to the differentiation status of the myeloid cell, and how the cellular mechanisms that normally control host gene expression play a critical role in the differential regulation of viral gene expression during latency and reactivation.

Extract: Human cytomegalovirus (HCMV) is a member of the Herpesvirus family of viruses and is a ubiquitous human pathogen. Primary infection of immunocompetent individuals is rarely problematic, but congenital or neonatal infection, or infection in immunosuppressed individuals, can cause severe disease. An important biological characteristic of HCMV, with obvious clinical importance, is the ability of the virus to establish lifelong persistence in the host following the initial, normally asymptomatic, infection. A key strategy used by all herpesviruses to persist in the infected individual is the establishment of cellular sites of viral latency. Viral latency is operationally defined as the persistence of the viral genome in absence of the production of infectious virions, but with the ability of the viral genome to reactivate under certain conditions. HCMV can remain latent in peripheral blood cells throughout the host's lifetime and sporadic reactivation events are generally well controlled by cell-mediated immunosurveillance, particularly virus-specific CD4+ and CD8+ T lymphocytes. However, in immunocompromised AIDS patients or immunosuppressed transplant patients, HCMV replication becomes uncontrolled and can cause serious morbidity and mortality, due to disease in the eye (retinitis), lung, nervous system and other organs. Analyses of virus strains during HCMV infection of organ transplant patients have shown that infection is predominantly due to reactivation of the transplant recipient's own HCMV, although it can also result from virus transferred from the donor. Consequently, an understanding of the cellular sites of latency and reactivation, and the mechanisms that control latency in these cells, are of major importance for further understanding of HCMV pathogenesis, as it follows reactivation.

Objective: To determine whether the Alexander Technique, alongside normal treatment, is of benefit to people disabled by idiopathic Parkinson's disease., Design: A randomized controlled trial with three groups, one receiving lessons in the Alexander Technique, another receiving massage and one with no additional intervention. Measures were taken pre- and post-intervention, and at follow-up, six months later., Setting: The Polyclinic at the University of Westminster, Central London., Subjects: Ninety-three people with clinically confirmed idiopathic Parkinson's disease., Interventions: The Alexander Technique group received 24 lessons in the Alexander Technique and the massage group received 24 sessions of massage., Main Outcome Measures: The main outcome measures were the Self-assessment Parkinson's Disease Disability Scale (SPDDS) at best and at worst times of day. Secondary measures included the Beck Depression Inventory and an Attitudes to Self Scale., Results: The Alexander Technique group improved compared with the no additional intervention group, pre-intervention to post-intervention, both on the SPDDS at best, p = 0.04 (confidence interval (CI) -6.4 to 0.0) and on the SPDDS at worst, p = 0.01 (CI -11.5 to -1.8). The comparative improvement was maintained at six-month follow-up: on the SPDDS at best, p = 0.04 (CI -7.7 to 0.0) and on the SPDDS at worst, p = 0.01 (CI -11.8 to -0.9). The Alexander Technique group was comparatively less depressed post-intervention, p = 0.03 (CI -3.8 to 0.0) on the Beck Depression Inventory, and at six-month follow-up had improved on the Attitudes to Self Scale, p = 0.04 (CI -13.9 to 0.0)., Conclusions: There is evidence that lessons in the Alexander Technique are likely to lead to sustained benefit for people with Parkinson's disease.

Human cytomegalovirus (HCMV) infection is largely asymptomatic in the immunocompetent host, but remains a major cause of morbidity in immunosuppressed individuals. Using the recently described technique of staining antigen-specific CD8(+) T cells with peptide-HLA tetrameric complexes, we have demonstrated high levels of antigen-specific cells specific for HCMV peptides and show that this may exceed 4% of CD8(+) T cells in immunocompetent donors. Moreover, by staining with tetramers in combination with antibodies to cell surface markers and intracellular cytokines, we demonstrate functional heterogeneity of HCMV-specific populations. A substantial proportion of these are effector cytotoxic T lymphocytes, as demonstrated by their ability to lyse peptide-pulsed targets in "fresh" killing assays. These data suggest that the immune response to HCMV is periodically boosted by a low level of HCMV replication and that sustained immunological surveillance contributes to the maintenance of host-pathogen homeostasis. These observations should improve our understanding of the immunobiology of persistent viral infection.

Major histocompatibility complex-restricted cytotoxic T lymphocytes (CTL) are part of the cellular immune response to persistent virus infections. Candidate vaccines against human immunodeficiency virus type 1 (HIV-1) should elicit broad cross-reactive immunity to confer protection against different strains of HIV-1. As it is likely that candidate vaccines will include the envelope gene product Env, we determined the proportion of CTL clones which recognized variable and conserved determinants in three env variants during natural infection. Limiting dilution analysis was used to characterize numerous short-term CTL clones derived from peripheral blood of HIV-1-infected subjects, using split-well analysis to assay cytotoxicity against target cells expressing gp160env of HIV-1 strains IIIB, MN, and RF. In 9 of 12 HIV-1-infected subjects, at the clonal level most env-specific CTL recognized determinant(s) within one env variant but not in the other variants. In some subjects, CTL recognized multiple nonconserved determinants in different variants. The pattern of recognition of different env variants was relatively stable over time. In most of the patients studied, the proportion of CTL which showed cross-recognition of conserved determinants shared among the three strains was low. Two novel CTL epitopes within gp41 were identified by using 15-mer peptides of the HIV-SF2 sequence. When specific peptide was used to stimulate CTL precursors in vitro, the frequency of peptide-specific CTL precursors was very high, but the CTL elicited by this stimulation were highly strain specific. We conclude that the use of a single HIV env variant to detect CTL activity can underestimate the magnitude and complexity of the env-specific CTL response. The low prevalence of CTL clones which show cross-recognition of conserved determinants may have implications for immunization strategies based solely on env; to elicit broadly cross-reactive CTL other, more conserved viral antigens are likely to be needed in addition to env. Because of its capacity to distinguish CTL responses against different virus strains, limiting dilution analysis is particularly appropriate to quantitate the immune responses generated by candidate env-based vaccines.

The cellular sites and mechanisms of human cytomegalovirus (HCMV) latency are still poorly defined. Although evidence suggests that peripheral blood monocytes are one site of latency in the healthy carrier, it is unlikely that monocytes represent a site of primary HCMV infection. Consequently, we have analysed CD34+ bone marrow progenitors, precursors of monocytes, to determine whether they are a site of HCMV carriage in normal virus carriers. For the first time, we demonstrate the presence of endogenous HCMV within bone marrow progenitors in the absence of HCMV lytic gene expression. These findings are consistent with previous evidence showing that the permissiveness of myeloid cells for HCMV is critically dependent on the differentiation state of the cell.

Human cytomegalovirus (HCMV), like all herpesviruses, persists in the host after primary infection, with reactivation often occurring as a result of immunosuppression. The lack of a model system has made analysis of HCMV latency and reactivation difficult. However, the ability to analyse which specific cell types in vivo carry the virus and the relative levels of permissiveness of these cell types for viral gene expression and productive infection is beginning to help us understand these complex molecular events.

Monocytes are one site of carriage of the human cytomegalovirus (HCMV) genome in healthy human carriers. However, as there are conflicting data detailing the level of HCMV gene expression during persistence in these cells, we have analyzed monocytes for evidence of viral immediate-early, early, and late transcription by using reverse transcription followed by PCR. We were unable to find evidence of HCMV lytic gene transcription in freshly isolated peripheral blood monocytes from HCMV-seropositive subjects. However, as differentiation of monocytes to monocyte-derived macrophages results in increased permissiveness to infection with HCMV in vitro, we examined whether such differentiation could result in reactivation of endogenous viral gene expression. Here we show that in vitro differentiation of monocytes does result in expression of endogenous HCMV immediate-early genes. Although this differentiation led to reactivation of endogenous viral immediate-early expression, we were unable to detect any early or late viral transcription. Cocultivation experiments correlated with this level of gene induction, as no productive infection was detected. These data strongly suggest a mechanism of persistence of HCMV in the peripheral blood that is independent of HCMV lytic gene expression and that initial phases of lytic gene expression in monocytes can be induced by differentiation of these cells to monocyte-derived macrophages.

Major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) are part of the cellular immune response to human persistent virus infections. Measurements of the frequency and specificity of human immunodeficiency virus type 1 (HIV-1)-specific CTL and their variation with time may indicate their relative importance in modulating the progression of HIV-1 infection. We have used limiting dilution analysis (LDA) to derive quantitative estimates of the frequency of HIV-1-specific CTL precursors in a cross-sectional study of 23 patients at different clinical stages of HIV-1 infection and to compare these with the frequency of CTL precursors specific for another persistent virus (Epstein-Barr virus [EBV]) in the same patients. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with autologous HIV-1-infected lymphoblasts and assayed for cytotoxicity in 51Cr release assays against autologous and MHC-mismatched lymphoblastoid B cells infected with recombinant vaccinia viruses expressing the three HIV-1 structural gene products. The frequency of MHC-restricted precursors was high in asymptomatic HIV-1-infected patients (env-specific CTL precursors up to 73/10(6) PBMC; gag-specific CTL precursors up to 488/10(6) PBMC), although the relative frequency against the different structural gene products varied from patient to patient. The HIV-1-specific CTL precursor frequency was reduced in patients who had more severe (< 400/microliters) CD4+ lymphocyte depletion, while in the majority of such patients the frequency of CTL precursors against EBV was maintained at levels observed in healthy controls. Direct CTL activity in unstimulated PBMC was observed in three of nine patients but no correlation was found between the presence of an activated CTL response and the magnitude of the CTL response detected after stimulation in LDA. Thus, CTL precursors were detected against all three HIV-1 structural gene products in patients with CD4+ lymphocyte counts > 400/microliters, at frequencies that are high compared with those reported for other persistent viruses. A CTL response directed against multiple protein antigens of HIV-1 may protect the patient against epitope variation. The fact that the EBV-specific CTL precursor frequencies were maintained in advanced HIV-1 infection suggests that there may be selective impairment of the HIV-1-specific CTL response associated with disease progression.

Growth-regulating cellular genes or genes encoding proteins involved in cell cycle control are likely to be major targets of viral gene products in the establishment of a cellular state favourable for a permissive infection. We have examined whether infection of permissive fibroblasts with human cytomegalovirus (HCMV) results in trans-regulation of such cellular genes. Here we have shown that the proto-oncogenes c-fos and c-myc are specifically induced during immediate early (IE) and early times of HCMV infection, as has recently been shown for the heat shock protein 70 gene (hsp70). Deletion analyses and transfection assays of all three promoters showed that previously defined control sequences upstream of the constitutive promoters and downstream of the mRNA cap site are not required for this up-regulation by HCMV, such that the minimal inducible promoters of c-fos, c-myc and the hsp70 gene contained only 50 to 60 bp upstream of the transcription start site. Cotransfection assays with vectors expressing HCMV major IE cDNAs showed that the 72K IE1 and 80K IE2 proteins are involved in the up-regulation of these promoters. IE1 and IE2 products independently were able to up-regulate the minimal constitutive promoters of the constructs tested here, but trans-activation by IE1 and IE2 together was synergistic. In the case of the hsp70 promoter, promoter constructs containing a variety of different TATA elements could be activated by the 72K IE1 and 80K IE2 proteins.

We studied the effects of adding cytomegalovirus (CMV) in vitro to normal human bone marrow mononuclear cells (BM-MNCs), committed myeloid progenitor cells, primitive myeloid blast-colony forming cells, and pre-formed marrow stromal cell monolayers in order to shed light on the mechanism by which hemopoiesis is suppressed in patients who acquire systemic CMV infection after allogeneic bone marrow transplantation. Incubation of BM-MNCs or committed progenitor cells with laboratory strain AD169 or wild strain CMV had no significant effect on total colony numbers or the morphology of component cells. CMV mRNA was not identified by in situ hybridization. In contrast, incubating marrow stromal monolayers with CMV produced specific cytopathic effects in fibroblasts and adipocytes and reduced the capacity of the stromal layers to support the proliferation of primitive myeloid progenitor cells. We conclude that CMV infection may impair hemopoiesis in vivo by a direct effect on the cellular components of the marrow stroma.

Four consecutive patients with relapsing peritonitis due to coagulase-negative staphylococci have been successfully treated by the addition of urokinase to their treatment regime, having failed to respond to appropriate antibiotic therapy alone. The organisms isolated from each episode of peritonitis in an individual patient were shown to be identical by antibiotic sensitivity, phage typing, slime production and immunoblot analysis. The action of urokinase is unknown but it may act by fibrinolysis, allowing antibiotics access to a source of infection previously protected by fibrin. The technique described is a simple, safe and effective treatment of relapsing peritonitis due to coagulase-negative staphylococci, and its use can markedly reduce the morbidity associated with this infection.