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Systematic review of the effect of the psychosocial working environment on cognition and dementia
  1. Francisca S Then1,2,
  2. Tobias Luck1,3,
  3. Melanie Luppa1,
  4. Marleen Thinschmidt4,
  5. Stefanie Deckert4,
  6. Karen Nieuwenhuijsen5,
  7. Andreas Seidler4,
  8. Steffi G Riedel-Heller1
  1. 1Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany
  2. 2LIFE—Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
  3. 3Douglas Mental Health University Institute, McGill University, Montreal, Canada
  4. 4Institute and Policlinic for Occupational and Social Medicine, Medical Faculty of TU Dresden, Dresden, Germany
  5. 5Coronel Institute of Occupational Health, Academic Medical Center, Amsterdam, The Netherlands
  1. Correspondence to Francisca S Then, Institute of Social Medicine, Occupational Health and Public Health (ISAP), Medical Faculty, University of Leipzig, Philipp-Rosenthal-Str 55, Leipzig 04103, Germany; Francisca.Then{at}medizin.uni-leipzig.de

Abstract

The high incidence of cognitive impairment in the ageing population, together with the challenges it imposes to health systems, raises the question of what affect working life has on cognitive abilities. The study, therefore, reviews recent work on the longitudinal impact of psychosocial work conditions on cognitive functioning and on dementia. Relevant articles were identified by a systematic literature search in PubMed and PsycINFO using a standardised search string and specific inclusion and exclusion criteria. We included articles reporting longitudinal effects that were investigated in cohort studies, case–control studies or randomised controlled trials in the working population. Two independent reviewers evaluated the studies in three subsequent phases: (i) title–abstract screening, (ii) full-text screening and (iii) checklist-based quality assessment.Methodical evaluation of the identified articles resulted in 17 studies of adequate quality. We found evidence for a protective effect of high job control and high work complexity with people and data on the risk of cognitive decline and dementia. Moreover, cognitively demanding work conditions seem to be associated with a decreased risk of cognitive deterioration in old age.Psychosocial work conditions can have an impact on cognitive functioning and even on the risk of dementia. As the world of work is undergoing fundamental changes, such as accelerated technological advances and an ageing working population, optimising work conditions is essential in order to promote and maintain cognitive abilities into old age.

https://doi.org/10.1136/oemed-2013-101760

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    Introduction

    Dementia affects more than six million people in Europe and, owing to demographic changes, its prevalence is expected to rise dramatically.1 The economic burden of dementia in the EU was estimated to be €189 billion in 2007.2 Moreover, the projections do not include individuals with mild cognitive impairment, which would put an additional burden on the health systems.3

    Over recent years important advances in our understanding of the pathology of dementia have been made. Major risk factors for dementia include non-modifiable factors (eg, E4 allele of an apolipoprotein genotype) and also modifiable factors such as tobacco use, diabetes, lack of physical and cognitive activities (review by Plassman et al4). With cognitive activities as an important risk factor, it can be assumed that cognitive activities at work, one aspect of psychosocial work conditions, might influence the pathogenic process that is causing dementia. Psychosocial work conditions include demand characteristics of work tasks, impediments to task fulfilment, social conditions and the organisational setting.5 Particularly stressful psychosocial work conditions have been linked to cardiovascular diseases, mental diseases and recently also, to cognitive deficits.6–8

    Two models explain how psychosocial work conditions might affect cognitive functioning: the malleable attentional resources theory9 and the cognitive-energetical control mechanism model.10 The malleable attentional resources theory suggests that tasks with low demands initiate processes that result in a lack of appropriate attentional control and, thus, worse performance, as experimental findings have shown.9 In the long run, low work demands have been shown to lead to cognitive decline.11 Seen from that perspective, the level of work demands will directly affect the level of cognitive abilities. The cognitive-energetical control mechanism model10 focuses specifically on the balance between demand and capacities. An imbalance, either through a decrease of internal capacities (eg, sleep deprivation) or an increase of an external variable (eg, noise), impairs cognitive abilities. Accordingly, any psychosocial work condition that shifts the balance between internal abilities and external task demands—whether it is long working hours or a high work load—will affect cognitive abilities. Empirically it has been shown that work conditions, such as high job stress, are associated with cognitive failures at work12 and cognitive deficits.13 Importantly, both models imply that psychosocial work conditions might enhance or impair cognitive abilities in the long term. Since most of the population spends a great part of their life at the workplace and work conditions determine daily the quantity and quality of cognitive demands, it is reasonable to assume that these conditions affect cognitive abilities and might even influence the risk of developing dementia. However, to the best of our knowledge, no systematic review summarising research evidence on the effects of psychosocial work conditions on cognition and dementia has been published.

    We therefore sought to provide such a systematic review. In order to provide information on long-term effects of psychosocial work conditions on cognition, the review focused on longitudinal studies that were conducted in the working population and that investigated effects on (i) clinical dementia, (ii) global cognitive functioning and (iii) performance in specific cognitive abilities. With the goal in mind to create a work environment that promotes cognitive abilities, the review deals with work-related risk factors, and focuses also on work-related protective factors potentially enhancing cognition.

    Material and methods

    Search strategy

    We carried out a systematic literature search in the databases Medline via the PubMed interface and PsycINFO via the EBSCO host interface for articles published up to 31 March 2011. Specific inclusion and exclusion criteria are shown in table 1. Only scientific journal articles in German and English reporting longitudinal cohort studies, case–control studies or randomised controlled trials were included. We did not include intervention studies since they usually describe short-term effects only. A specific search string for studies on psychosocial work conditions and their impact on dementia, global cognitive functioning and performance in specific cognitive abilities was developed based on search terms describing Population-Exposure-Outcome and Study Design criteria.14 The search string was adapted to the interfaces of each database (see online supplementary appendix 1a and 1b). For further applicable studies, we also conducted an interview with an expert (KN), screened the reference lists of already identified articles and ran an updated search on 13 September 2013.

    View this table:
    Table 1

    Inclusion and exclusion criteria

    Study evaluation

    We evaluated the search results in three subsequent phases. In the first phase, we screened titles and abstracts of all identified studies. In the second phase, the full texts of the potentially eligible studies were evaluated and in the final third phase, the quality of the studies was assessed. Each phase was documented in a review protocol.

    Title–abstract screening

    Title–abstract screening was carried out by two researchers (FST, MT). Based on the criteria for inclusion and exclusion (table 1), the two reviewers independently rated each study with either ‘yes’ (fulfilling the inclusion and exclusion criteria) or ‘no’ (not fulfilling the criteria). All studies with at least one ‘yes’ rating were included in the next phase. The evaluation of the two independent reviewers reached a consensus of 97.4% (Cohen's κ=0.49).

    Full-text screening

    The full-text screening of all articles, which were classified as potentially eligible in the title–abstract screening, was carried out by the same two independent reviewers (FST, MT). The study design, population source, number of subjects, follow-up period, exposure assessment, outcome measurement, adjustment for confounding variables, statistical methods and potential biases of all studies were evaluated. Studies that strictly adhered to the inclusion and exclusion criteria (table 1) received a ‘yes’ rating and were eligible for inclusion in the study. Studies that were rated differently by the two independent reviewers (FST, MT) were discussed at a consensus meeting (AS, FST, MT, SD, SGR-H, TL) until a consensus decision on eligibility/non-eligibility was reached.

    Quality assessment

    All articles that were classified as eligible in the full-text screening, either through a ‘yes’ rating of both reviewers (FST, MT) or through the decision of the consensus meeting (AS, FST, MT, SD, SGR-H, TL), underwent a quality assessment according to the criteria described by SIGN (Scottish Intercollegiate Guidelines Network15) and CASP (Critical Appraisal Skills Programme16) checklists. Depending on the study design of the articles, the reviewers (FST, MT) independently completed checklists either for cohort studies, for case–control studies or for controlled trials. Quality criteria of each checklist included an adequate study design to answer the research question, an unbiased recruitment procedure, the validity of the exposure and outcome measurements, the adjustment for important confounders, a sufficient length of the follow-up period, a low loss to follow-up, the appropriateness of the statistical method and others (see SIGN15 and CASP1,6 for more information). To be considered of adequate quality, a study had to fulfil the criteria for internal validity and the criteria showing that a potential bias was believed unlikely to alter the inference on the causal relationship between exposure and effect. Hence, studies with insufficient internal validity and/or a substantial risk of bias, which might have led to incorrect conclusions about the effect, were excluded. The two independent reviewers (FST, MT) documented details on whether or not the articles fulfilled each of the quality criteria on the checklists and rated the quality. Experienced third reviewers (AS, SGR-H) compared the ratings of the two independent reviewers (FST, MT) and—when ratings diverged—made a final decision. Only studies of adequate quality were included in the review. Studies that were excluded owing to poor quality are listed in the online supplementary appendix 2.18–25

    Results

    Figure 1 shows a flowchart of the systematic literature search and review process. We identified 17 articles of adequate quality (table 2). The exposure factors investigated in the identified studies varied widely, ranging from mental work demands to work time arrangements. Nine studies examined the impact of psychosocial work conditions on clinical dementia, five studies reported on global cognitive functioning and three studies focused on performance in specific cognitive abilities. Owing to the observed heterogeneity of the identified studies for exposure, outcome and statistical approach, a meta-analysis could not be conducted (ie, criteria for meta-analytical summarising of existing literature26 were not fulfilled).

    View this table:
    Table 2

    Studies on the impact of psychosocial work conditions on dementia, global cognitive functioning and specific cognitive abilities

    Figure 1
    Figure 1

    Flowchart of the systematic literature search and review process.

    Clinical dementia

    As shown in table 2, all of the nine identified studies that analysed the impact of psychosocial work conditions on clinical dementia focused on incident dementia cases at an age of ≥65 years.

    Four of the nine studies—two population-based cohort studies27 ,28 and two case–control studies29 ,30—investigated the effect of complexity of work tasks on the incidence of dementia. Complexity of work tasks covers three dimensions: (i) complexity with data (eg, performing arithmetic operations), (ii) complexity with people (eg, instructing, teaching or training others) and (iii) complexity with things (eg, using body members, tools or special devices to work).31 Three studies reported a significant association between higher work complexity with people27 ,28 ,30 and higher complexity with data27 ,29 ,30 and a reduced dementia risk. The strongest effects were found in twin pair analysis with regard to Alzheimer's disease.30 Only one study showed a protective effect of higher complexity with things on dementia risk.28 In the following paragraphs, each of the four studies is explained in detail.

    The study of Karp et al27 used a population-based sample of the Kungsholmen Project. The authors found significant protective associations between high work task complexity with data and people and a lower dementia risk in a Cox proportional hazards model adjusted for age and gender as well as in an education-subgroup analysis.27 Importantly, the study sample was characterised by a very high response rate of 94%.27

    The Canadian Study of Health and Aging (CSHA), a population-based study consisting of a slightly younger sample (median age=73) and adjusting for numerous lifestyle factors, including cardiovascular diseases, also detected a beneficial relationship between high complexity with people and a reduced dementia risk.28 Moreover, in the subanalysis of individuals who kept their job for longer than 23 years, all complexities (people, things and data) were identified as significant protectors.28

    The study by Andel et al30 examined participants in the Swedish twin registry and showed that complexity with people significantly protected dementia in the case–control and twin pair analysis. Furthermore, the twin pair analysis for Alzheimer's disease—analysing only pairs discordant for complexity—showed a strong impact of complexity with data and people in reducing dementia risk.30

    The last of the four studies on complexity of work tasks included participants of the Duke Twins Study of Memory in Aging.29 A case–control analysis showed an increased dementia risk for low complexity with data, particularly for twin pairs who were discordant for dementia.29 In this study, cases were on average 10 years younger than in the other studies on complexity. The impact on dementia of work complexity with people, however, might be more pronounced in advanced age.

    Five of the nine studies on dementia investigated the effect of demands in the workplace on dementia. The first study examined mental and social demands in a selected population.32 The findings of a confounder-adjusted analysis of variance pairwise comparison showed significant impacts of mental demands in preventing Alzheimer's disease.32 Importantly, the exposure variables in this study were weighted for the time worked in each occupation, which might be a strong indicator of the actual exposure intensity.

    The second study was a case–control study based on the Swedish twin registry.33 The authors investigated the effect of self-reported, work-related stress on clinical dementia 40 years later.33 Fully adjusted logistic regression by twin pair did not show any significant impact of work-related stress on the incidence of dementia; only ‘reactivity to stress’ significantly affected dementia risk.33

    The third study on the impact of work demands on dementia recruited cases from general practices and controls from a random sample of local residents in Germany and included a broader scope of workplace factors (challenge at work, social climate, control, work load, risk of errors, social demands, supervisor support, work time arrangements).34 In a well-adjusted logistic regression model, higher challenge at work, more control at work and high social demands were significantly associated with a smaller risk of dementia.34 High perceived risk for error, however, significantly increased the likelihood of dementia.34

    The fourth study on work demands and dementia was also a case–control study (Swedish twin registry).35 The authors particularly examined the effects of job demands, job control, job strain and social support on future dementia using generalised estimating equation models. They found significant associations between low job control and low social support and higher risk of dementia.35

    The fifth and last study, based on a cohort of the Swedish Kungsholmen project, also showed a significant association between low job control and a higher dementia risk, but no significant effects of low job demands on dementia.36 In this study, however, high job strain also significantly increased the risk of developing dementia.36

    Global cognitive functioning

    Five studies examined the impact of psychosocial work conditions on global cognitive functioning (see table 2). Three of the five studies—two cohort studies8 ,37 and one case–control study38—particularly examined long-term effects on global cognitive functioning. The two cohort studies showed a significant impact of high job control as well as high complexity of data on better global cognitive functioning.8 ,37 For the case–control study,38 high intellectual demands of the job were associated with preserved cognitive functioning, and long visual attention with decreased global cognitive functioning.38 These studies are explained in detail in the following paragraphs.

    Andel et al8 analysed data of the population-based SWEOLD study (Swedish Panel Study of Living Conditions of the Oldest Old). Global cognitive functioning was measured using the Mini-Mental State Examination (MMSE). In confounder-adjusted logistic regression models, job control was highly significant when measured subjectively or objectively, implying a positive association between high job control and better MMSE scores.8

    Andel et al37 carried out another study on global cognitive functioning of participants of the SWEOLD cohort. The researchers analysed the effect of work task complexity on global cognitive functioning. The study weighted complexity scores for the time spent in each occupation. The data showed significant associations between higher complexity of data and people and better MMSE scores.37 However, complexity of people lost significance when adjusted for occupational status.37 For both studies of the SWEOLD sample, it is unclear whether subject attrition of about 35% might have affected the results, especially since potentially demented individuals might have moved into nursing homes and dropped out of the study as non-responders.

    The only case–control study on cognitive functioning was carried out by Potter et al.38 The study included participants of the World War II veteran registry and examined the impact of intellectual demands, human interaction/communication and visual attention on cognitive functioning.38 Cognitive functioning was measured by the telephone version of the MMSE. Well-adjusted twin pair analysis identified intellectual demands and visual attention as significant protectors against cognitive decline.38 The effects were higher for dizygotic twins, but non-significant for monozygotic twins: an indication of the role of genes in the interplay between work complexity and cognitive decline.38 However, the study was based on a sample of World War II veterans and generalisation of the results requires caution.

    Two further cohort studies examined the effects of mental demands in the workplace on global cognitive functioning in younger individuals,39 ,40 and results indicated a significant association between higher demands and better global cognitive functioning.

    The first study, the VISAT cohort study (French study on Aging, Health and Work: Vieillissement, Santé, Travail), focused particularly on the impact of cognitive stimulation at work on cognitive functioning (an index of several cognitive tests).39 Within three measurement points every 5 years, middle-aged participants of the working population underwent cognitive testing and completed a questionnaire on ‘cognitive stimulation’.39 Analysis via well-adjusted, linear mixed-models showed a significant association between higher cognitive stimulation and a better cognitive performance at follow-up.39

    The second study was a population-based cohort study analysing the effect of mental workload on global cognitive functioning in a 3-year follow-up.40 Cognitive impairment was defined as the poorest 10th centile in a set of cognitive tests. A small but significant effect was found for the composite mental workload in a fully adjusted model.40 A more detailed analysis showed that strong concentration, great precision and time pressure, but not mental demands or task complexity, were significantly associated with a decreased risk of cognitive impairment.40 However, it is possible that the recruitment procedure via general practitioners and the low initial response rate might have biased the results.

    Specific cognitive abilities

    The systematic literature search disclosed three population-based cohort studies41–43 that longitudinally explored the effect of psychosocial work conditions on specific cognitive abilities in elderly workers (see table 2).

    The first two studies are based on data from the Whitehall II study, which examined London civil servants at intervals of 2–3 years for a period of 20 years.41 ,42 In the first study, self-reported working hours were analysed for their impact on cognitive abilities. At follow-up, perceptual reasoning and vocabulary were significantly decreased in individuals working more than 55 h a week.41 For perceptual reasoning, working more than 55 h a week was highly significant in each model and adjustment for a large number of confounders did not change the effect.41 Scores on the verbal tests and memory scores remained non-significant.41 The strong effect of working hours on perceptual reasoning provides an example of how a psychosocial work condition affects only one specific cognitive domain while leaving other cognitive abilities unaffected.

    The second analysis of the Whitehall II data focused on the effect of organisational justice on cognitive abilities.42 At follow-up, all cognitive abilities (memory, reasoning, vocabulary, verbal fluency) were significantly decreased in individuals who reported low levels of organisational justice.42

    The last study was a cohort study by Finkel et al43 that examined work task complexity. Individuals of the Swedish Adoption/Twin Study of Aging underwent cognitive testing every 3 years for a period of almost 20 years. The researchers analysed the data using a two-slope latent growth curve model that was centred on retirement age. Results showed that work complexity with data and things was non-significant for each cognitive ability.43 High complexity with people was significantly associated with better perceptual reasoning.43 Memory and verbal performance were not significantly associated with any type of complexity.43 However, even though growth curve models can handle missing data quite efficiently, we cannot be certain about the high proportion of cognitively impaired individuals who dropped out of the study and whether this might have affected the results.

    Discussion

    This systematic review aimed at providing information on the longitudinal impact of psychosocial work conditions on cognitive functioning and dementia. The review indicates that a great variety of psychosocial work conditions are associated with cognitive functioning and dementia risk. As hypothesised, certain psychosocial work conditions enhance cognitive abilities whereas other conditions are associated with a higher risk of cognitive decline in the long term.

    A substantial number of studies investigated the effect of work complexity on cognitive functioning and dementia. The majority of studies that examined work complexity with things, however, showed no significant impact on cognitive functioning or the incidence of dementia. Higher work complexity with data was significantly associated with a lower incidence of dementia, especially in twin studies on Alzheimer's disease. The results support the assumption that cognitive activities at work protect against cognitive decline. Higher work complexity with people was also found to be associated with significantly reduced dementia risk and better cognitive performance. Theories on possible underlying mechanisms hypothesise that high social interaction (a) enhances prefrontal cortical synaptic plasticity44 and/or (b) activates the brain reward system, which then upregulates learning-relevant neurotransmitters.45 Such underlying mechanisms need to be investigated in more detail.

    Protective effects of cognitive activities at work on the risk of cognitive impairment and dementia, similar to those of high work complexity, were found for high challenge at work, high intellectual demands, high cognitive stimulation and high mental workload. Eventually, in the case of low demands at work, certain cortical areas in the brain might switch off owing to the activation of automation processes, as proposed by the malleable attentional resources theory.9 Seen from that perspective, higher work demands are necessary to ameliorate and maintain higher cortical functions, which then again preserve cognitive abilities up to old age. However, ‘job demands’ were not always statistically significant. The findings may lead to the assumption that the effect of demanding work conditions on the risk of cognitive deterioration in old age might indeed depend on internal capacities, as proposed by the cognitive-energetical control mechanism model.10 Since these studies did not assess these aspects—such as stress coping mechanisms or cognitive abilities at baseline—there is no evidence for that. Furthermore, individuals cannot randomly be allocated to their job and individual predispositions (ie, cognitive ability level, personality) might have influenced the type of occupation and, hence, the observed effects (reverse causality). For example, people with higher cognitive abilities are likely to be selected for jobs that require higher cognitive demands.

    The psychosocial work condition ‘job control’ was examined in four studies. In all studies, high job control was significantly associated with a better cognitive status. A possible explanation for such an association is that a high level of job control enhances the active use of executive cognitive functions. The level of executive functioning has shown to be related to dementia risk.46 Another possible explanation is that a high level of job control allows the individual to plan work tasks independently, which naturally prevents work overload and stress. When the individual can plan his/her work tasks independently, he or she can create an optimal balance between external job demands and internal abilities, which would then reduce the risk of cognitive decline—according to the cognitive-energetical control mechanism model.10

    Only two of the identified studies on the impact of psychosocial work conditions on cognitive functions dealt with organisational aspects of work. One study investigated the effect of long working hours on performance in specific cognitive abilities and the other study investigated the effect of low levels of organisational justice. Both studies observed a significant decline in cognitive performance. It is likely that long working hours as well as low organisational justice cause chronic stress which then impairs different aspects of cognitive processing.47 Chronic stress generates an imbalance—according to the cognitive-energetical control mechanism model10—which negatively affects cognitive functioning.

    Several other psychosocial work conditions were also found to be significant protective factors (cognitive stimulation, great challenge at work, high work load, strong concentration, great precision, great time pressure) or risk factors (long visual attention, high risk of errors) for cognitive performance and/or dementia. These findings, however, were based on results from single studies and need to be validated in further studies.

    In general, interpretation of the review findings should be made with caution, as we cannot exclude the possibilities of a publication bias or selective reporting within the identified studies. Besides, we included only observational studies from two databases. Moreover, even though we aimed at including a broad range of psychosocial work conditions, we cannot be sure that there might not be others which we did not consider. Nonetheless, the results showed that the identified studies are heterogeneous with respect to exposure, outcome and study design, which prevented us from combining the results in a meta-analysis. In order to test the consistency of the results, a meta-analysis should be conducted as soon as enough evidence has been produced. On the other hand, however, it is unclear at present whether individual predispositions (eg, level of cognitive functioning) or symptoms of preclinical dementia might influence the type of job held. Such a potential influence might affect the observed associations (reverse causation).

    Even so, the available evidence suggests that there may be an association between psychosocial workplace factors (eg, high job control, high work complexity with people and data, intellectually demanding work) and better cognitive functioning as well as a reduced dementia risk. These protective effects tend to be more pronounced in Alzheimer's disease than in other types of dementia.28 ,30 ,34 The findings are in concordance with scientific theories, which suggest that intellectually demanding conditions may continuously train cognitive abilities,48 and, thus, delay the onset of clinical manifestation by building up a cognitive reserve. A cognitive reserve is the ability to compensate for brain damage, which then leads to a delayed expression of clinical dementia symptoms.49 The hypothesised processes emphasise a direct relationship between psychosocial work conditions and a reduced dementia risk. At present, there is no evidence for an indirect effect—for example, via cardiovascular diseases. Adjusting for cardiovascular problems did not affect the association for cognitive impairment8 ,40 or incidence of dementia28; neither did adjusting for socioeconomic indicators.37 ,40 ,41 Clearly, there is a great need for further studies in order to establish firm causal directions of the effects of work conditions on cognition.

    Essentially, the impact of psychosocial work factors on cognitive abilities is of interest for national health and economic efficiency. Health systems aspire to preserve the cognitive functioning of individuals as long as possible, as a high incidence of dementia, and consequent care-giving expenses, place a high financial burden on society. This is particularly relevant, since the population is ageing and the number of patients with dementia is increasing rapidly. The economic interest lies in providing a work environment that enhances cognitive performance for maximising employee productivity. In order to create a work environment that promotes and maintains cognitive functioning, future research should (a) replicate and validate findings, (b) test the validity of psychosocial stress models on cognitive functions and (c) conduct high-quality intervention studies strengthening demanding work conditions and job control.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • AS and SGR-H shared last authorship

    • Contributors Conception and design of the work and supervision of the study: AS and SGR-H. Acquisition of data (carrying out the literature search): FST and MT. Analysis and interpretation of data: FST, TL, ML, MT, KN and SD. Writing the first draft: FST. Commenting and revising the manuscript: AS, KN, ML, MT, SD, SGR-H and TL. Final approval of the version to be published: AS, FST, KN, ML, MT, SD, SGR-H and TL.

    • Funding The project was funded by the German Federal Institute for Occupational Safety and Health (Bundesanstalt für Arbeitsschutz und Arbeitsmedizin). FST is supported by LIFE—Leipzig Research Center for Civilisation Diseases, Universität Leipzig, by means of the European Social Fund and the Free State of Saxony (LIFE-102P7). TL was supported by a research fellowship of the German Research Foundation (grant: Lu 1730/1-1).

    • Competing interests None.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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