Interconnecting solvent quality, transcription, and chromosome folding in Escherichia coli.

All cells fold their genomes, including bacterial cells, where the chromosome is compacted into a domain-organized meshwork called the nucleoid. How compaction and domain organization arise is not fully understood. Here, we describe a method to estimate the average mesh size of the nucleoid in Escherichia coli. Using nucleoid mesh size and DNA concentration estimates, we find that the cytoplasm behaves as a poor solvent for the chromosome when the cell is considered as a simple semidilute polymer solution. Monte Carlo simulations suggest that a poor solvent leads to chromosome compaction and DNA density heterogeneity (i.e., domain formation) at physiological DNA concentration. Fluorescence microscopy reveals that the heterogeneous DNA density negatively correlates with ribosome density within the nucleoid, consistent with cryoelectron tomography data. Drug experiments, together with past observations, suggest the hypothesis that RNAs contribute to the poor solvent effects, connecting chromosome compaction and domain formation to transcription and intracellular organization.

Nucleoid Size Scaling and Intracellular Organization of Translation across Bacteria.

The scaling of organelles with cell size is thought to be exclusive to eukaryotes. Here, we demonstrate that similar scaling relationships hold for the bacterial nucleoid. Despite the absence of a nuclear membrane, nucleoid size strongly correlates with cell size, independent of changes in DNA amount and across various nutrient conditions. This correlation is observed in diverse bacteria, revealing a near-constant ratio between nucleoid and cell size for a given species. As in eukaryotes, the nucleocytoplasmic ratio in bacteria varies greatly among species. This spectrum of nucleocytoplasmic ratios is independent of genome size, and instead it appears linked to the average population cell size. Bacteria with different nucleocytoplasmic ratios have a cytoplasm with different biophysical properties, impacting ribosome mobility and localization. Together, our findings identify new organizational principles and biophysical features of bacterial cells, implicating the nucleocytoplasmic ratio and cell size as determinants of the intracellular organization of translation.

Mutational robustness and the role of buffer genes in evolvability.

Organisms rely on mutations to fuel adaptive evolution. However, many mutations impose a negative effect on fitness. Cells may have therefore evolved mechanisms that affect the phenotypic effects of mutations, thus conferring mutational robustness. Specifically, so-called buffer genes are hypothesized to interact directly or indirectly with genetic variation and reduce its effect on fitness. Environmental or genetic perturbations can change the interaction between buffer genes and genetic variation, thereby unmasking the genetic variation's phenotypic effects and thus providing a source of variation for natural selection to act on. This review provides an overview of our understanding of mutational robustness and buffer genes, with the chaperone gene HSP90 as a key example. It discusses whether buffer genes merely affect standing variation or also interact with de novo mutations, how mutational robustness could influence evolution, and whether mutational robustness might be an evolved trait or rather a mere side-effect of complex genetic interactions.

Effects of changes in residential fast-food outlet exposure on Body Mass Index change: longitudinal evidence from 92,211 Lifelines participants.

BACKGROUND: Evidence on the association between fast-food outlet exposure and Body Mass Index (BMI) remains inconsistent and is primarily based on cross-sectional studies. We investigated the associations between changes in fast-food outlet exposure and BMI changes, and to what extent these associations are moderated by age and fast-food outlet exposure at baseline. METHODS: We used 4-year longitudinal data of the Lifelines adult cohort (N = 92,211). Participant residential addresses at baseline and follow-up were linked to a register containing fast-food outlet locations using geocoding. Change in fast-food outlet exposure was defined as the number of fast-food outlets within 1 km of the residential address at follow-up minus the number of fast-food outlets within 1 km of the residential address at baseline. BMI was calculated based on objectively measured weight and height. Fixed effects analyses were performed adjusting for changes in covariates and potential confounders. Exposure-moderator interactions were tested and stratified analyses were performed if p < 0.10. RESULTS: Participants who had an increase in the number of fast-food outlets within 1 km had a greater BMI increase (B(95% CI): 0.003 (0.001,0.006)). Decreases in fast-food outlet exposure were not associated with BMI change (B(95% CI): 0.001 (-0.001,0.004)). No clear moderation pattern by age or fast-food outlet exposure at baseline was found. CONCLUSIONS: Increases in residential fast-food outlet exposure are associated with BMI gain, whereas decreases in fast-food outlet exposure are not associated with BMI loss. Effect sizes of increases in fast-food outlet exposure on BMI change were small at individual level. However, a longer follow-up period may have been needed to fully capture the impact of increases in fast-food outlet exposure on BMI change. Furthermore, these effect sizes could still be important at population level considering the rapid rise of fast-food outlets across society. Future studies should investigate the mechanisms and changes in consumer behaviours underlying associations between changes in fast-food outlet exposure and BMI change.

Protein aggregates act as a deterministic disruptor during bacterial cell size homeostasis.

Mechanisms underlying deviant cell size fluctuations among clonal bacterial siblings are generally considered to be cryptic and stochastic in nature. However, by scrutinizing heat-stressed populations of the model bacterium Escherichia coli, we uncovered the existence of a deterministic asymmetry in cell division that is caused by the presence of intracellular protein aggregates (PAs). While these structures typically locate at the cell pole and segregate asymmetrically among daughter cells, we now show that the presence of a polar PA consistently causes a more distal off-center positioning of the FtsZ division septum. The resulting increased length of PA-inheriting siblings persists over multiple generations and could be observed in both E. coli and Bacillus subtilis populations. Closer investigation suggests that a PA can physically perturb the nucleoid structure, which subsequently leads to asymmetric septation.

Vulnerability profiles of workers and the relation with burnout symptoms: results from the Netherlands working conditions survey.

INTRODUCTION: Unfavorable working conditions may place workers in a vulnerable position in the labour market, but studies on the clustering of these factors and their relation to burnout symptoms are lacking. This study aims to identify subgroups of workers in potentially vulnerable positions in the labour market and examine whether burnout symptoms differ across the established subgroups. METHODS: This study utilizes cross-sectional data from 2019 of the Netherlands Working Conditions Survey (n = 55,283). Working conditions included employment contracts, working hours, multiple jobs, tenure, physical strain, autonomy, and workload. Burnout symptoms were measured with five items on a 7-point Likert scale. Latent Class Analysis was used to identify vulnerability subgroups based on working conditions and educational level. Wilcoxon rank-sum tests were used to examine whether burnout symptoms differed between the identified subgroups. RESULTS: Three out of nine subgroups (i.e., classes 4, 6, and 7) presented combinations of multiple unfavourable working conditions. The vulnerability of class 4, characterized by low educational level, physically demanding work, low autonomy, and a high workload, was underscored by a significantly higher burnout symptom score (M = 2.91;SD = 0.97) compared to all other subgroups. Subgroups 3 (M = 2.69;SD = 1.43) and 8 (M = 2.41;SD = 1.41), without striking unfavourable conditions, had the second and third highest scores on burnout symptoms. CONCLUSIONS: Determining vulnerability in the labour market is not straightforward as not all profiles that presented clusters of unfavourable working conditions scored high on burnout symptoms, and vice versa. Future research should investigate whether findings are similar to other mental health outcomes.

Once in NEET, always in NEET? Childhood and adolescent risk factors for different NEET patterns.

BACKGROUND: Young adults in Neither in Employment, Education nor Training (NEET) are at risk of adverse labour market outcomes. Earlier studies often measured NEET status at one time point or compared persistent NEETs with non-NEETs, neglecting other patterns of NEET status. Evidence on early life factors associated with NEET patterns is lacking. This study aims to (i) identify patterns of NEET status over time and (ii) examine whether factors in childhood and adolescence are associated with these patterns. METHODS: Data were used from 1499 participants of the TRacking Adolescents' Individual Lives Survey (TRAILS), a Dutch prospective cohort study with 15-year follow-up. NEET status was assessed at ages 19, 22 and 26. Socioeconomic status of parents (SES), intelligence and negative life events were measured at age 11, educational attainment at age 26 and mental health problems at ages 11, 13.5 and 16. Data were analyzed using multinomial logistic regression analysis. RESULTS: Four NEET patterns were identified: (i) non-NEETs (85.2%), (ii) early NEETs (4.5%), (iii) late NEETs (5.7%) and (iv) persistent NEETs (4.5%). Reporting internalizing problems at age 11 was a risk factor for early and late NEETs [odds ratio (OR) 2.77, 95% confidence interval (CI) 1.16-6.62; OR 5.00, 95% CI 2.22-11.3, respectively]. Low parental SES, lower intelligence scores and negative life events (≥3) were risk factors for persistent NEETs (OR 4.45, 95% CI 2.00-9.91; OR 0.96, 95% CI 0.94-0.98; OR 4.42, 95% CI 1.62-12.08, respectively). CONCLUSIONS: The results highlight the importance of timing and duration of NEET status and emphasize the need for tailored interventions to prevent specific NEET patterns.

Metabolic syndrome and poor self-rated health as risk factors for premature employment exit: a longitudinal study among 55 016 middle-aged and older workers from the Lifelines Cohort Study and Biobank.

BACKGROUND: Poor self-rated health (SRH) is a well-established risk factor for premature employment exit through unemployment, work disability, and early retirement. However, it is unclear whether the premature employment exit risk associated with underlying cardio-metabolic health conditions is fully captured by poor SRH. This study examines the metabolic syndrome (MetS), an early-stage risk factor for cardiovascular disease and type two diabetes mellitus, as a risk factor for premature employment exit while controlling for poor SRH. METHODS: We analyzed data from N = 55 016 Dutch workers (40-64 years) from five waves of the Lifelines Cohort Study and Biobank. MetS components were based on physical measures, blood markers, and medication use. SRH and employment states were self-reported. The associations between MetS, SRH, and premature employment exit types were analyzed using competing risk regression analysis. RESULTS: During 4.3 years of follow-up, MetS remained an independent risk factor for unemployment [adjusted subdistribution hazard ratio (SHR): 1.14, 95% CI: 1.03, 1.25] and work disability (adjusted SHR: 1.33, 95% CI: 1.11, 1.58) when adjusted for poor SRH, common chronic diseases related to labor market participation (i.e., cancer, musculoskeletal-, pulmonary-, and psychiatric diseases), and sociodemographic factors. MetS was not associated with early retirement. CONCLUSIONS: Poor SRH did not fully capture the risk for unemployment and work disability associated with MetS. More awareness about MetS as a 'hidden' cardio-metabolic risk factor for premature employment exit is needed among workers, employers, and occupational health professionals. Regular health check-ups including MetS assessment and MetS prevention might help to prolong healthy working lives.

Inability to Work Fulltime and the Association with Paid Employment One Year After the Work Disability Assessment: A Longitudinal Register-Based Cohort Study.

OBJECTIVES: Disability benefit applicants with residual work capacity are often not able to work fulltime. In Dutch work disability benefit assessments, the inability to work fulltime is an important outcome, indicating the number of hours the applicant can sustain working activities per day. This study aims to gain insight into the association between inability to work fulltime and having paid employment 1 year after the assessment. METHODS: The study is a longitudinal register-based cohort study of work disability applicants who were granted a partial disability benefit (n = 8300). Multivariable logistic regression analyses were conducted to study the association between inability to work fulltime and having paid employment 1 year after the assessment, separately for working and non-working applicants. RESULTS: For disability benefit applicants, whether working (31.9%) or not working (68.1%) at the time of the disability assessment, there was generally no association between inability to work fulltime and having paid employment 1 year later. However, for working applicants diagnosed with a musculoskeletal disease or cancer, inability to work fulltime was positively and negatively associated with having paid employment, respectively. For non-working applicants with a respiratory disease or with multimorbidity, inability to work fulltime was negatively associated with paid employment. CONCLUSIONS: Inability to work fulltime has limited association with paid employment 1 year after the disability benefit assessment, regardless of the working status at the time of assessment. However, within certain disease groups, inability to work fulltime can either increase or decrease the odds of having paid employment after the assessment.

Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study.

BACKGROUND: Patients often report various symptoms after recovery from acute COVID-19. Previous studies on post-COVID-19 condition have not corrected for the prevalence and severity of these common symptoms before COVID-19 and in populations without SARS-CoV-2 infection. We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection. METHODS: This study is based on data collected within Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviours of people living in the north of the Netherlands. All Lifelines participants aged 18 years or older received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 somatic symptoms surrounding COVID-19 diagnoses (due to SARS-CoV-2 alpha [B.1.1.7] variant or previous variants) were assessed using 24 repeated measurements between March 31, 2020, and Aug 2, 2021. Participants with COVID-19 (a positive SARS-CoV-2 test or a physician's diagnosis of COVID-19) were matched by age, sex, and time to COVID-19-negative controls. We recorded symptom severity before and after COVID-19 in participants with COVID-19 and compared that with matched controls. FINDINGS: 76 422 participants (mean age 53·7 years [SD 12·9], 46 329 [60·8%] were female) completed a total of 883 973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90-150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90-150 days after COVID-19 diagnosis or matched timepoint. INTERPRETATION: To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic. Further research that distinguishes potential mechanisms driving post-COVID-19-related symptomatology is required. FUNDING: ZonMw; Dutch Ministry of Health, Welfare, and Sport; Dutch Ministry of Economic Affairs; University Medical Center Groningen, University of Groningen; Provinces of Drenthe, Friesland, and Groningen.

Symptom profiles and their risk factors in patients with post-COVID-19 condition: a Dutch longitudinal cohort study.

BACKGROUND: To improve research and care for patients with post-COVID-19 condition more insight into different subtypes of post-COVID-19 condition and their risk factors is urgently needed. We aimed to identify risk factors of post-COVID-19 condition in general and for specific symptom profiles. METHODS: This study is based on data collected within the Lifelines Coronavirus disease 2019 (COVID-19) cohort (N = 76 503). Mean pre- and post-SARS-CoV-2 infection symptom scores were compared to classify post-COVID-19 condition. Latent Profile Analysis was used to identify symptom profiles. Logistic and multinomial regression analyses were used to examine the association between demographic, lifestyle and health-related risk factors and post-COVID-19 condition, and symptom profiles, respectively. RESULTS: Of the 3465 participants having had COVID-19, 18.5% (n = 642) classified for post-COVID-19 condition. Four symptom profiles were identified: muscle pain, fatigue, cardiorespiratory and ageusia/anosmia. Female sex was a risk factor for the muscle pain and fatigue profiles. Being overweight or obese increased risk for all profiles, except the fatigue profile. Having a chronic disease increased the risk for all profiles except the ageusia/anosmia profile, with the cardiorespiratory profile being only significant in case of multimorbidity. Being unvaccinated increased risk of the ageusia/anosmia profile. CONCLUSIONS: Findings from this study suggest that Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may trigger different pathophysiological mechanisms that may result in different subtypes of post-COVID-19 condition. These subtypes have shared and unique risk factors. Further characterization of symptom profiles and quantification of the individual and societal impact of specific symptom profiles are pressing challenges for future research.

Establishing General Working Population Norms for the Cognitive Symptom Checklist-Work.

PURPOSE: The Cognitive Symptom Checklist-Work (CSC-W) is a self-report measure to assess cognitive symptoms (i.e., memory and executive function) in working adults with cancer. To date, general working population norm data are lacking worldwide. We established CSC-W norm values in the general working population, and assessed associations of CSC-W scores with work and health-related factors. METHODS: This cross-sectional study consisted of 1,000 Dutch working adults, of whom data was collected through an online respondent panel. The sample was stratified for sex and age, and data were weighted. Summary scores of the CSC-W total scale, and memory and executive function symptoms subscales, were determined (e.g., means, percentiles). Z- and T-scores were calculated, and analysis of (co)variance has been applied. RESULTS: Cognitive symptom scores were relatively stable across age groups, but 18-39-year-old respondents reported lower memory and executive function than respondents in other age groups. Symptom scores of memory function (mean 29.1; SD = 16.7) were higher for all age groups and in both sexes compared to executive function (mean 22.1; SD = 16.8). No sex differences in memory and executive function were observed. Higher symptom scores were associated with performing non-manual work only, manual work only, self-reported long-term illness, and higher levels of depressive symptoms and fatigue. CONCLUSION: The CSC-W norms may enhance the interpretation and facilitate the analysis of self-reported cognitive symptoms in patients with cancer at work. Our findings may support health care professionals in identifying working adults with cancer with cognitive symptoms and in developing personalized treatment.

Mediators of the association between educational attainment and type 2 diabetes mellitus: a two-step multivariable Mendelian randomisation study.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus is a major health burden disproportionately affecting those with lower educational attainment (EA). We aimed to obtain causal estimates of the association between EA and type 2 diabetes and to quantify mediating effects of known modifiable risk factors. METHODS: We applied two-step, two-sample multivariable Mendelian randomisation (MR) techniques using SNPs as genetic instruments for exposure and mediators, thereby minimising bias due to confounding and reverse causation. We leveraged summary data on genome-wide association studies for EA, proposed mediators (i.e. BMI, blood pressure, smoking, television watching) and type 2 diabetes. The total effect of EA on type 2 diabetes was decomposed into a direct effect and indirect effects through multiple mediators. Additionally, traditional mediation analysis was performed in a subset of the National Health and Nutrition Examination Survey 2013-2014. RESULTS: EA was inversely associated with type 2 diabetes (OR 0.53 for each 4.2 years of schooling; 95% CI 0.49, 0.56). Individually, the largest contributors were BMI (51.18% mediation; 95% CI 46.39%, 55.98%) and television watching (50.79% mediation; 95% CI 19.42%, 82.15%). Combined, the mediators explained 83.93% (95% CI 70.51%, 96.78%) of the EA-type 2 diabetes association. Traditional analysis yielded smaller effects but showed consistent direction and priority ranking of mediators. CONCLUSIONS/INTERPRETATION: These results support a potentially causal protective effect of EA against type 2 diabetes, with considerable mediation by a number of modifiable risk factors. Interventions on these factors thus have the potential of substantially reducing the burden of type 2 diabetes attributable to low EA.

The association between fast-food outlet proximity and density and Body Mass Index: Findings from 147,027 Lifelines Cohort Study participants.

Unhealthy food environments may contribute to an elevated Body Mass Index (BMI), which is a chronic disease risk factor. We examined the association between residential fast-food outlet exposure, in terms of proximity and density, and BMI in the Dutch adult general population. Additionally, we investigated to what extent this association was modified by urbanisation level. In this cross-sectional study, we linked residential addresses of baseline adult Lifelines Cohort participants (n = 147,027) to fast-food outlet locations using geo-coding. We computed residential fast-food outlet proximity, and density within 500 m, 1, 3, and 5 km. We used stratified (urban versus rural areas) multilevel linear regression models, adjusting for age, sex, partner status, education, employment, neighbourhood deprivation, and address density. The mean BMI of participants was 26.1 (SD 4.3) kg/m2. Participants had a mean (SD) age of 44.9 (13.0), 57.3% was female, and 67.0% lived in a rural area. Having two or more (urban areas) or five or more (rural areas) fast-food outlets within 1 km was associated with a higher BMI (B = 0.32, 95% confidence interval (CI): 0.03, 0.62; B = 0.23, 95% CI: 0.10, 0.36, respectively). Participants in urban and rural areas with a fast-food outlet within <250 m had a higher BMI (B = 0.30, 95% CI: 0.03, 0.57; B = 0.20, 95% CI: 0.09, 0.31, respectively). In rural areas, participants also had a higher BMI when having at least one fast-food outlet within 500 m (B = 0.10, 95% CI: 0.02, 0.18). In conclusion, fast-food outlet exposure within 1 km from the residential address was associated with BMI in urban and rural areas. Also, fast-food outlet exposure within 500 m was associated with BMI in rural areas, but not in urban areas. In the future, natural experiments should investigate changes in the fast-food environment over time.

The association between the presence of fast-food outlets and BMI: the role of neighbourhood socio-economic status, healthy food outlets, and dietary factors.

BACKGROUND: Evidence on the association between the presence of fast-food outlets and Body Mass Index (BMI) is inconsistent. Furthermore, mechanisms underlying the fast-food outlet presence-BMI association are understudied. We investigated the association between the number of fast-food outlets being present and objectively measured BMI. Moreover, we investigated to what extent this association was moderated by neighbourhood socio-economic status (NSES) and healthy food outlets. Additionally, we investigated mediation by frequency of fast-food consumption and amount of fat intake. METHODS: In this cross-sectional study, we used baseline data of adults in Lifelines (N = 149,617). Geo-coded residential addresses were linked to fast-food and healthy food outlet locations. We computed the number of fast-food and healthy food outlets within 1 kilometre (km) of participants' residential addresses (each categorised into null, one, or at least two). Participants underwent objective BMI measurements. We linked data to Statistics Netherlands to compute NSES. Frequency of fast-food consumption and amount of fat intake were measured through questionnaires in Lifelines. Multivariable multilevel linear regression analyses were performed to investigate associations between fast-food outlet presence and BMI, adjusting for individual and environmental potential confounders. When exposure-moderator interactions had p-value < 0.10 or improved model fit (∆AIC ≥ 2), we conducted stratified analyses. We used causal mediation methods to assess mediation. RESULTS: Participants with one fast-food outlet within 1 km had a higher BMI than participants with no fast-food outlet within 1 km (B = 0.11, 95% CI: 0.01, 0.21). Effect sizes for at least two fast-food outlets were larger in low NSES areas (B = 0.29, 95% CI: 0.01, 0.57), and especially in low NSES areas where at least two healthy food outlets within 1 km were available (B = 0.75, 95% CI: 0.19, 1.31). Amount of fat intake, but not frequency of fast-food consumption, explained this association for 3.1%. CONCLUSIONS: Participants living in low SES neighbourhoods with at least two fast-food outlets within 1 km of their residential address had a higher BMI than their peers with no fast-food outlets within 1 km. Among these participants, healthy food outlets did not buffer the potentially unhealthy impact of fast-food outlets. Amount of fat intake partly explained this association. This study highlights neighbourhood socio-economic inequalities regarding fast-food outlets and BMI.

Multimorbidity and exit from paid employment: the effect of specific combinations of chronic health conditions.

BACKGROUND: This study aimed to assess the association between multimorbidity and exit from paid employment, and which combinations of chronic health conditions (CHCs) have the strongest association with exit from paid employment. METHODS: Data from 111 208 workers aged 18-64 years from Lifelines were enriched with monthly employment data from Statistics Netherlands. Exit from paid employment during follow-up was defined as a change from paid employment to unemployment, disability benefits, economic inactivity or early retirement. CHCs included cardiovascular diseases (CVD), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), type 2 diabetes (T2DM) and depression. Cox-proportional hazards models were used to examine the impact of multimorbidity and combinations of CHCs on exit from paid employment. RESULTS: Multimorbidity increased the risk of exiting paid employment compared with workers without CHCs (hazard ratio (HR): 1.52; 95% confidence interval (CI): 1.35-1.71) or one CHC (HR: 1.14; 95% CI: 1.01-1.28). The risk for exit from paid employment increased among workers with COPD if they additionally had CVD (HR: 1.39; 95% CI: 1.03-1.88), depression (HR: 1.46; 95% CI: 1.10-1.93) or RA (HR: 1.44; 95% CI: 1.08-1.91), for workers with T2DM if they additionally had CVD (HR: 1.43; 95% CI: 1.07-1.91) or depression (HR: 2.09; 95% CI: 1.51-2.91) and for workers with depression who also had T2DM (HR: 1.68; 95% CI: 1.21-2.32). CONCLUSION: This study showed that workers with multimorbidity, especially having a combination of COPD and depression or T2DM and depression, have a higher risk for early exit from paid employment and, therefore, may need tailored support at the workplace.

Development and validation of a prediction model for unemployment and work disability among 55 950 Dutch workers.

BACKGROUND: This study developed prediction models for involuntary exit from paid employment through unemployment and disability benefits and examined if predictors and discriminative ability of these models differ between five common chronic diseases. METHODS: Data from workers in the Lifelines Cohort Study (n = 55 950) were enriched with monthly information on employment status from Statistics Netherlands. Potential predictors included sociodemographic factors, chronic diseases, unhealthy behaviours and working conditions. Data were analyzed using cause-specific Cox regression analyses. Models were evaluated with the C-index and the positive and negative predictive values (PPV and NPV, respectively). The developed models were externally validated using data from the Study on Transitions in Employment, Ability and Motivation. RESULTS: Being female, low education, depression, smoking, obesity, low development possibilities and low social support were predictors of unemployment and disability. Low meaning of work and low physical activity increased the risk for unemployment, while all chronic diseases increased the risk of disability benefits. The discriminative ability of the models of the development and validation cohort were low for unemployment (c = 0.62; c = 0.60) and disability benefits (c = 0.68; c = 0.75). After stratification for specific chronic diseases, the discriminative ability of models predicting disability benefits improved for cardiovascular disease (c = 0.81), chronic obstructive pulmonary disease (c = 0.74) and diabetes mellitus type 2 (c = 0.74). The PPV was low while the NPV was high for all models. CONCLUSION: Taking workers' particular disease into account may contribute to an improved prediction of disability benefits, yet risk factors are better examined at the population level rather than at the individual level.

Borrelia burgdorferi peptidoglycan is a persistent antigen in patients with Lyme arthritis.

Lyme disease is a multisystem disorder caused by the spirochete Borrelia burgdorferi A common late-stage complication of this disease is oligoarticular arthritis, often involving the knee. In ∼10% of cases, arthritis persists after appropriate antibiotic treatment, leading to a proliferative synovitis typical of chronic inflammatory arthritides. Here, we provide evidence that peptidoglycan (PG), a major component of the B. burgdorferi cell envelope, may contribute to the development and persistence of Lyme arthritis (LA). We show that B. burgdorferi has a chemically atypical PG (PGBb) that is not recycled during cell-wall turnover. Instead, this pathogen sheds PGBb fragments into its environment during growth. Patients with LA mount a specific immunoglobulin G response against PGBb, which is significantly higher in the synovial fluid than in the serum of the same patient. We also detect PGBb in 94% of synovial fluid samples (32 of 34) from patients with LA, many of whom had undergone oral and intravenous antibiotic treatment. These same synovial fluid samples contain proinflammatory cytokines, similar to those produced by human peripheral blood mononuclear cells stimulated with PGBb In addition, systemic administration of PGBb in BALB/c mice elicits acute arthritis. Altogether, our study identifies PGBb as a likely contributor to inflammatory responses in LA. Persistence of this antigen in the joint may contribute to synovitis after antibiotics eradicate the pathogen. Furthermore, our finding that B. burgdorferi sheds immunogenic PGBb fragments during growth suggests a potential role for PGBb in the immunopathogenesis of other Lyme disease manifestations.

Associations of Genetic Factors, Educational Attainment, and Their Interaction With Kidney Function Outcomes.

Both genetic predisposition and low educational attainment (EA) are associated with higher risk of chronic kidney disease. We examined the interaction of EA and genetic risk in kidney function outcomes. We included 3,597 participants from the Prevention of Renal and Vascular End-Stage Disease Cohort Study, a longitudinal study in a community-based sample from Groningen, the Netherlands (median follow-up, 11 years; 1997-2012). Kidney function was approximated by obtaining estimated glomerular filtration rate (eGFR) from serum creatinine and cystatin C. Individual longitudinal linear eGFR trajectories were derived from linear mixed models. Genotype data on 63 single-nucleotide polymorphisms, with known associations with eGFR, were used to calculate an allele-weighted genetic score (WGS). EA was categorized into high, medium, and low. In ordinary least squares analysis, higher WGS and lower EA showed additive effects on reduced baseline eGFR; the interaction term was nonsignificant. In analysis of eGFR decline, the significant interaction term suggested amplification of genetic risk by low EA. Adjustment for known renal risk factors did not affect our results. This study presents the first evidence of gene-environment interaction between EA and a WGS for eGFR decline and provides population-level insights into the mechanisms underlying socioeconomic disparities in chronic kidney disease.

Protein aggregates encode epigenetic memory of stressful encounters in individual Escherichia coli cells.

Protein misfolding and aggregation are typically perceived as inevitable and detrimental processes tied to a stress- or age-associated decline in cellular proteostasis. A careful reassessment of this paradigm in the E. coli model bacterium revealed that the emergence of intracellular protein aggregates (PAs) was not related to cellular aging but closely linked to sublethal proteotoxic stresses such as exposure to heat, peroxide, and the antibiotic streptomycin. After removal of the proteotoxic stress and resumption of cellular proliferation, the polarly deposited PA was subjected to limited disaggregation and therefore became asymmetrically inherited for a large number of generations. Many generations after the original PA-inducing stress, the cells inheriting this ancestral PA displayed a significantly increased heat resistance compared to their isogenic, PA-free siblings. This PA-mediated inheritance of heat resistance could be reproduced with a conditionally expressed, intracellular PA consisting of an inert, aggregation-prone mutant protein, validating the role of PAs in increasing resistance and indicating that the resistance-conferring mechanism does not depend on the origin of the PA. Moreover, PAs were found to confer robustness to other proteotoxic stresses, as imposed by reactive oxygen species or streptomycin exposure, suggesting a broad protective effect. Our findings therefore reveal the potential of intracellular PAs to serve as long-term epigenetically inheritable and functional memory elements, physically referring to a previous cellular insult that occurred many generations ago and meanwhile improving robustness to a subsequent proteotoxic stress. The latter is presumably accomplished through the PA-mediated asymmetric inheritance of protein quality control components leading to their specific enrichment in PA-bearing cells.