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Abstract Background Returning to work after long-term sick leave can be challenging, particularly in small- and medium-sized enterprises (SMEs) where support may be limited. Recognizing the responsibilities and challenges of SME employers, a web-based intervention (hereafter the SME tool) has been developed. The SME tool aims to enhance the employer’s intention and ability to support the sick-listed employee. Based on the Self-Determination Theory, it is hypothesized that this intention is enhanced by intervening in the employer’s autonomy, competences, and relatedness targeted at, e.g., communication with sick-listed employee, involvement of other stakeholders, and practical support. This is achieved by means of providing templates, communication videos, and information on legislation. This article describes the design of an effect and process evaluation of the SME tool. Methods A randomized controlled trial (RCT) with a 6-month follow-up will be conducted with a parallel-group design with two arms: an intervention group and a control group. Sick-listed employees (≤ 8 weeks) of SMEs (≤ 250 employees) at risk of long-term sick leave and their employers will be recruited and randomly allocated as a dyad (1:1). Employers randomized to the intervention group receive unlimited access to the SME tool, while those in the control group will receive care as usual. The primary outcome is the satisfaction of the employee with the return to work (RTW) support provided by their employer. Secondary outcomes include social support, work performance, and quality of work life at the employee level and self-efficacy in providing RTW support at the employer level. Outcomes will be assessed using questionnaires at baseline and 1, 3, and 6 months of follow-up. Process evaluation measures include, e.g., recruitment and use of and perceived usefulness of the SME tool. Additionally, semi-structured interviews with employers, employees, and occupational physicians will explore the interpretation of the RCT results and strategies for the national implementation of the SME tool. Discussion The SME tool is hypothesized to be valuable in addition to usual care helping employers to effectively support the RTW of their long-term sick-listed employees, by improving the employers’ intention and ability to support. Trial registration ClinicalTrials.gov, NCT06330415. Registered on February 14, 2024.

Functional analyses are the main method to classify mismatch repair (MMR) gene variants of uncertain significance (VUSs). However, the pathogenicity remains unclear for many variants because of conflicting results between clinical, molecular, and functional data. In this study, we evaluated whether whole exome sequencing (WES) could add another layer of evidence to elucidate the pathogenicity of MMR variants with conflicting interpretations. WES was performed on formalin-fixed paraffin-embedded tumor tissue of eight patients with a constitutional MMR VUS (seven families), including eight colorectal and two endometrial carcinomas and one ovarian carcinoma. Cell-free CIMRA assays were performed to assign Odds of Pathogenicity to these VUSs. In four families, seven tumors showed MMR deficiency-associated mutational signatures, supporting the pathogenicity of the VUS. Moreover, somatic (second) MMR hits identified in the WES data were found to explain MMR staining patterns when the MMR staining was discordant with the reported germline MMR gene variant. In conclusion, WES did not significantly reclassify VUS in these cases but clarified some phenotypic aspects such as age of onset and explanations in case of discordant MMR stainings.

Abstract Background In the last decade, interest in working life expectancy (WLE) and socioeconomic differences in WLE has grown considerably. However, a comprehensive overview of the socioeconomic differences in WLE is lacking. The aim of this review is to systematically map the research literature to improve the insight on differences in WLE and healthy WLE (HWLE) by education, occupational class and income while using different ways of measuring and estimating WLE and to define future research needs. Methods A systematic search was carried out in Web of Science, PubMed and EMBASE and complemented by relevant publications derived through screening of reference lists of the identified publications and expert knowledge. Reports on differences in WLE or HWLE by education, occupational class or income, published until November 2022, were included. Information on socioeconomic differences in WLE and HWLE was synthesized in absolute and relative terms. Results A total of 26 reports from 21 studies on educational and occupational class differences in WLE or HWLE were included. No reports on income differences were found. On average, WLE in persons with low education is 30% (men) and 27% (women) shorter than in those with high education. The corresponding numbers for occupational class difference were 21% (men) and 27% (women). Low-educated persons were expected to lose more working years due to unemployment and disability retirement than high-educated persons. Conclusions The identified socioeconomic inequalities are highly relevant for policy makers and pose serious challenges for equitable pension policies. Many policy interventions aimed at increasing the length of working life follow a one-size-fits-all approach which does not take these inequalities into account. More research is needed on socioeconomic differences in HWLE and potential influences of income on working life duration.

OBJECTIVES: The aim of this study was to evaluate employee return-to-work (RTW) rates and examine predictors of absence duration after COVID-19. RTW rates were referenced against RTW rates after absence due to flu-like symptoms and assessed over the course of the pandemic.METHODS: Routinely collected data from a nationally operating Dutch occupational health service was used. The data were retrieved from employees who reported sick due to COVID-19 (N=30 396) or flu-like symptoms (N=15 862). Data consisted of responses to a triage survey combined with longitudinal register-based information on sickness absence. RTW rates after COVID-19 were evaluated through Kaplan-Meier estimates and compared to RTW rates for flu-like symptoms, and between three periods with different dominant virus variants. Predictors for absence duration were examined through Cox proportional hazards models.RESULTS: RTW after COVID-19 was found to be notably later than after flu-like symptoms (median RTW=10 versus 6 days, respectively). On average, 5.5% of employees who contracted COVID-19 were absent for over 12 weeks. Time-to-RTW shortened as different virus variants became dominant over time. The main predictors contributing to later RTW were older age, female sex, belonging to a risk group, and the symptoms shortness of breath and fatigue.CONCLUSIONS: Estimates of the RTW rate after COVID-19 and identification of predictors may aid healthcare professionals in gaining insight into variations in the disease course and rehabilitation process. The present findings can help employers and policy-makers grasp the impact of COVID-19 on the workplace.

Abstract Background Several occupational health disciplines are involved in return to work guidance, implying that good interdisciplinary collaboration is important. A shared conceptual framework and a common language for the assessment of work capacity and guidance in return to work is expected to be at the benefit of appropriate and sustainable employability of sick employees. The International Classification of Functioning, Disability and Health (ICF) can be considered a shared conceptual framework and is also promising in terms of a common language. The purpose of the current study is to reach multidisciplinary consensus among occupational health professionals on the content of an ICF-based instrument for the assessment of work capacity and guidance in return to work. Methods To obtain multidisciplinary consensus we conducted a modified Delphi study among twelve occupational health experts, including four occupational physicians, four insurance physicians and four labour experts. The study included two e-mail rounds and two virtual meetings. In the consecutive rounds the experts assessed ICF items as well as a list of non-ICF-based work-related environmental factors on their relevance for the assessment of the work capacity and guidance in return to work together with their interpretability. Results The four consecutive Delphi rounds resulted in 20 items that are minimally needed for the assessment of the work capacity and return to work possibilities of employees on sick leave. The final list included six items on personal functioning, seven items on social functioning and seven items on physical functioning. Conclusions This set of items forms the core of an ICF-based instrument, which is expected to facilitate interdisciplinary and intradisciplinary communication because of the use of a shared conceptual framework. As such, it should be of help in the guidance in return to work of employees on sick leave and contribute to appropriate and sustainable employability.

Replication stress, caused by Rev1 deficiency, is associated with mitochondrial dysfunction, and metabolic stress. However, the overall metabolic alterations and possible interventions to rescue the deficits due to Rev1 loss remain unclear. Here, we report that loss of Rev1 leads to intense changes in metabolites and that this can be manipulated by NAD + supplementation. Autophagy decreases in Rev1−/− mouse embryonic fibroblasts (MEFs) and can be restored by supplementing the NAD+ precursor nicotinamide riboside (NR). The abnormal mitochondrial morphology in Rev1−/− MEFs can be partially reversed by NR supplementation, which also protects the mitochondrial cristae from rotenone-induced degeneration. In nematodes rev-1 deficiency causes sensitivity to oxidative stress but this cannot be rescued by NR supplementation. In conclusion, Rev1 deficiency leads to metabolic dysregulation of especially lipid and nucleotide metabolism, impaired autophagy, and mitochondrial anomalies, and all of these phenotypes can be improved by NR replenishment in MEFs.

OBJECTIVES: The aim of this discussion paper is to (i) identify the differentiated roles of health in the work–retirement transition, and, with respect to these, (ii) highlight topics related to conceptual and methodological problems and challenges in research, and (iii) present avenues for future research. METHODS: This discussion paper summarizes an OMEGA-NET working group discussion ongoing from November 2018 to September 2021 with face-to-face and online meetings as well as a written online discourse. RESULTS: ‘Health’ and ‘retirement’ are ambiguous concepts. With respect to both, in retirement research, the choice of concept and indicator influences the findings. In addition, the impact of health on retirement is not necessarily a direct one, but can be influenced by further factors such as the ability, motivation and opportunity to work. The strong overall association of poor health with retiring early (path 1) bears the risk of masking distinct and deviating mechanisms in subgroups. In fact, there is evidence that also good health may lead to early retirement (path 2), while both poor health (path 3) and good health (path 4) may also make people retire later. CONCLUSIONS: An increased awareness of the differentiated roles that health may have in the work–retirement transition as outlined in this discussion paper may support research to address questions relevant for policy and practice and increase the impact of research. Recommendations for occupational health and social research are given.

Aim: To discover what long‐term care (LTC) staff working in self‐managing teams consider necessary to remain sustainably employable. Design: Qualitative study with semi‐structured interviews. Methods: In 2020, semi‐structured interviews were conducted one‐on‐one with 25 LTC workers from a medium‐large Dutch organization providing long‐term care. All interviews were audio‐recorded, anonymously transcribed verbatim and analysed with thematic content analysis in the software program Atlas.ti. Results: LTC workers indicated a need for autonomy. They wanted their control and involvement in decisions to be strengthened. Furthermore, LTC workers indicated a need for relatedness, by experiencing support, a feeling of togetherness and more time to have attention for the residents. Lastly, LTC workers expressed a need for (assistance in) further developing their competence. Conclusion: In order to remain willing and able to work, LTC workers in self‐managing teams want their needs for autonomy, relatedness and competence to be addressed. Working conditions are important to these LTC workers' sustainable employability since they can hinder or promote the satisfaction of their needs. Implications: It is important that management in LTC is aware of the importance of LTC workers' needs for sustainable employability. We recommend that management critically reflect on and invest in addressing these needs by enhancing indicators and limiting inhibitors of the needs. Impact: A robust LTC workforce is necessary to provide care to the aging population. In the context of the increasing implementation of self‐managing teams in LTC organizations, understanding what workers in self‐managing teams need in order to remain sustainably employable is crucial.For sustainable employability (i.e. to remain willing and able to work), interviewees indicated a need for autonomy, relatedness, and competence. Nearly all participants stressed the importance of belonging and feeling connected. Working conditions seemed to relate not only directly to the sustainable employability of LTC staff but also indirectly through their lack of contribution to the satisfaction of workers' psychological needs.The outcomes of this study primarily impact workers and management within LTC organizations with self‐managing teams. They benefit from recognizing the significance of addressing workers' needs to ensure their essential and sustainable employability in the sector. Reporting Method: The Standards for Reporting Qualitative Research and the Consolidated Criteria for Reporting Qualitative (COREQ) research were used. Patient or Public Contribution: Two LTC workers provided advice and feedback regarding the materials and set up of the interviews. These two ambassadors additionally helped in reaching our population, by disseminating information about the study. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Working from home (WfH) is a promising practice that may enable employees to successfully and sustainably combine work and private life. Yet, not every employer facilitates WfH and not every employee has similar needs concerning the practice. The current study aims to examine the association of a WfH mismatch with work–home interference (WHI) and fatigue. METHODS: Data on WfH, WHI, and fatigue of a quasi-representative sample of 2374 Dutch employees in 2012/13 and a follow-up measurement one year later were used. Cross-sectional and longitudinal regression analyses were conducted to investigate the cross-sectional and temporal associations between WfH mismatch on the one hand and (changes in) time-based and strain-based WHI and fatigue on the other hand. RESULTS: In the cross-sectional analyses, WfH mismatch was significantly associated with higher time-based WHI (B=0.13), strain-based WHI (B=0.17) and more fatigue (B=0.32). WfH mismatch was not associated with changes in these outcomes after one year of follow-up. CONCLUSIONS: A tailored WfH organizational policy, in which employees’ need for working from home is taken into account, may be a fruitful approach to utilize WfH as a way for employees to successfully and sustainably combine work and private life to its full potential.

Simple Summary: TIL scoring has been recommended as a biomarker in routine clinical practice in breast cancer patients. Currently, the standard of care for early breast cancer is neoadjuvant treatment. Recent studies have demonstrated the additional predictive value of TIL scoring to the residual cancer burden after neoadjuvant treatment. Although guidelines have been published, the reliability of this biomarker in treated tumor samples has not yet been evaluated. Here, we show that there is good inter-pathologist reproducibility for TIL scoring in patients with clear residual tumor tissue. However, in patients with a (near-)complete response, there is not. This is significant because this demonstrates that it could be a reliable biomarker and help guide adjuvant treatment decisions. Neoadjuvant chemotherapy (NAC) is now the standard of care for patients with locally advanced breast cancer (BC). TIL scoring is prognostic and adds predictive value to the residual cancer burden evaluation after NAC. However, NAC induces changes in the tumor, and the reliability of TIL scoring in post-NAC samples has not yet been studied. H&E- and dual CD3/CD20 chromogenic IHC-stained tissues were scored for stromal and intra-tumoral TIL by two experienced pathologists on pre- and post-treatment BC tissues. Digital TIL scoring was performed using the HALO® image analysis software (version 2.2). In patients with residual disease, we show a good inter-pathologist correlation for stromal TIL on H&E-stained tissues (CCC value 0.73). A good correlation for scoring with both staining methods (CCC 0.81) and the digital TIL scoring (CCC 0.77) was also observed. Overall concordance for TIL scoring in patients with a complete response was however poor. This study reveals there is good reliability for TIL scoring in patients with detectable residual tumors after NAC treatment, which is comparable to the scoring of untreated breast cancer patients. Based on the good consistency observed with digital TIL scoring, the development of a validated algorithm in the future might be advantageous. [ABSTRACT FROM AUTHOR]

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males, 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e., non-monomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ [98%] CD4- [94%] CD5- [97%] CD7+ [97%] CD8+ [90%] CD56+ [86%] CD103+ [80%] cytotoxic marker+ [98%]) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with non-monomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%), JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signaling and encompasses genetic and morphologic variants associated with very high clinical risk.

Abstract Background Immunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT. Methods Data fromr patients undergoing partial hepatectomy for HCC, without preoperative treatment (SURG, n = 32), after preoperative TACE (TACE, n = 16), or preoperative SIRT (n = 12) were analyzed. Clinicopathological factors, tumor-infiltrating lymphocytes (TILs), CD4+ and CD8+ T cells, and granzyme B (GZB) expression in resected HCC, and postoperative overall and progression-free survival were compared between the three groups. Results Clinicopathological and surgical characteristics were similar in the three groups. A significant increase in TILs, CD4+ and CD8+ T cells, and GZB expression was observed in resected HCC in SIRT as compared to TACE and SURG groups. No difference in immune infiltrates was observed between TACE and SURG patients. Within the SIRT group, the dose of irradiation affected the type of immune infiltrate. A significantly higher ratio of CD3+ cells was observed in the peri-tumoral area in patients receiving 100 Gy. Postoperative outcomes were similar in all groups. Irrespective of the preoperative treatment, the type and extent of immune infiltrates did not influence postoperative survival. Conclusions SIRT significantly promotes recruitment/activation of intra-tumor effector-type immune cells compared to TACE or no preoperative treatment. These results suggest that SIRT is a better candidate than TACE to be combined with immunotherapy for treatment of HCC. Evaluation of the optimal doses for SIRT for producing an immunogenic effect and the type of immunotherapy to be used require further evaluation in prospective studies.

Background: FOXP1, a transcriptional regulator of lymphocyte development, is abnormally expressed in some human tumors. This study investigated FOXP1-mediated regulation of tumor infiltrating lymphocytes (TIL) in untreated primary breast cancer (BC). Methods: FOXP1 expression was analyzed in tissues from primary untreated breast tumors, BC cell lines and the METABRIC gene expression BC dataset. Cytokine and chemokine expression and lymphocyte migration in response to primary tumor supernatants (SN) was compared between FOXP1hi and FOXP1lo primary BC. Finding: FOXP1 expression was higher in estrogen receptor positive compared to negative BC. FOXP1hi tumors were significantly associated with lower TIL and fewer tertiary lymphoid structures (TLS) compared to FOXP1lo BC. Silencing FOXP1 in BC cell lines positively impacted cytokine and chemokine expression with the inverse effect associated with overexpression. CXCL9, CXCL10, CXCL11, CXCL13, CX3CL, CCL20, IL2, IL21, GZMB and IFNG expression decreased while IL10 and TGFβ increased in FOXP1hi compared to FOXP1lo primary BC. Lymphocyte migration using primary BC supernatants detected decreased mobility toward FOXP1hi supernatants. FOXP1lo BC expresses higher levels of chemokines driving TIL migration. The METABRIC gene expression dataset analysis show FOXP1 expression is associated with unfavorable BC outcomes. Interpretation: These data identify FOXP1 as an important negative regulator of immune responses in BC via its regulation of cytokine and chemokine expression. Fund: Belgian Fund for Scientific Research (FNRS 3.4513.12F) and Opération Télévie (7.4636.13F and 7.4609.15F), Fonds J.C. Heuson and Fonds Lambeau-Marteaux. Keywords: FOXP1, Breast cancer, Tumor infiltrating lymphocytes, Chemokines, Cytokines