A Guided Workbook Intervention (WorkPlan) to Support Work-Related Goals Among Cancer Survivors: Protocol of a Feasibility Randomized Controlled Trial

Background: Returning to and staying at work following illness is associated with better physical and psychological functioning. Not working has been shown to be associated with reduced self-esteem, lowered self-efficacy, and decreased belief in one's ability to return to the workplace. Although there is a growing body of research looking at what predicts return to work following cancer treatment, there are fewer studies examining interventions targeting return to work. Objective: The primary objective is to assess the feasibility and acceptability of a theoretically led workbook intervention designed to support cancer patients in returning to work to inform a fully powered randomized controlled trial (RCT). Methods: This is a multicenter feasibility RCT where the main analysis uses a qualitative approach. Sixty participants (aged 18-65 years) who have received a diagnosis of cancer and who intend to return to work will be randomized to either the WorkPlan intervention group or a usual care group (ratio 1:1). Participants in the intervention group will receive a guided workbook intervention (which contains activities aimed at eliciting thoughts and beliefs, identifying targets and actions, and concrete steps to achieve goals) and will receive telephone support over a 4-week period. The primary outcome measure is time taken to return to work (in days), and secondary outcome measures include mood, quality of life, illness perceptions, and job satisfaction. Data will be collected through postal questionnaires administered immediately postintervention and at 6- and 12-month follow-ups. In addition, interviews will be undertaken immediately postintervention (to explore acceptability of the intervention and materials) and at 12-month follow-up (to explore perceptions of participation in the trial and experiences of returning to work). Results: Enrollment for the study will be completed in May 2016. Data analysis will commence in April 2017, and the first results are expected to be submitted for publication in late 2017. Conclusions: Currently no standardized return-to-work intervention based on targeting cancer patient beliefs is in existence. If the intervention is shown to be feasible and acceptable, the results of this study will inform a future full RCT with the potential to provide a valuable and cost-efficient tool in supporting cancer survivors in the return-to-work process

A participatory physical and psychosocial intervention for balancing the demands and resources among industrial workers (PIPPI): study protocol of a cluster-randomized controlled trial

Background: Need for recovery and work ability are strongly associated with high employee turnover, well-being and sickness absence. However, scientific knowledge on effective interventions to improve work ability and decrease need for recovery is scarce. Thus, the present study aims to describe the background, design and protocol of a cluster randomized controlled trial evaluating the effectiveness of an intervention to reduce need for recovery and improve work ability among industrial workers. Methods/Design: A two-year cluster randomized controlled design will be utilized, in which controls will also receive the intervention in year two. More than 400 workers from three companies in Denmark will be aimed to be cluster randomized into intervention and control groups with at least 200 workers (at least 9 work teams) in each group. An organizational resources audit and subsequent action planning workshop will be carried out to map the existing resources and act upon initiatives not functioning as intended. Workshops will be conducted to train leaders and health and safety representatives in supporting and facilitating the intervention activities. Group and individual level participatory visual mapping sessions will be carried out allowing team members to discuss current physical and psychosocial work demands and resources, and develop action plans to minimize strain and if possible, optimize the resources. At all levels, the intervention will be integrated into the existing organization of work schedules. An extensive process and effect evaluation on need for recovery and work ability will be carried out via questionnaires, observations, interviews and organizational data assessed at several time points throughout the intervention period. Discussion: This study primarily aims to develop, implement and evaluate an intervention based on the abovementioned features which may improve the work environment, available resources and health of industrial workers, and hence their need for recovery and work ability

Working with pain : sustainable work participation of workers with chronic nonspecific musculoskeletal pain

Dit proefschrift is een van de eerste studies specifiek gericht op mensen die blijven werken met chronische pijn aan het bewegingsapparaat. Unieke kennis over duurzame arbeidsparticipatie van werknemers met chronische pijn werd vergaard. Doel van dit promotieonderzoek was meer inzicht te krijgen in de groep mensen die werkt met pijn en te achterhalen hoe zij in staat zijn ondanks hun klachten te blijven werken. In het proefschrift staan kenmerken en determinanten beschreven van werknemers die doorwerken met chronische pijn, waardoor een completer beeld is ontstaan van arbeidsparticipatie bij mensen met chronische pijn aan het bewegingsapparaat. Uit de vergelijking van mensen die doorwerken ondanks chronische pijn en mensen met arbeidsverzuim die in revalidatiebehandeling komen met chronische pijn blijkt dat deze groepen op diverse factoren significant verschillen. In het onderzoek werd onder andere aangetoond dat de motivatie voor werk, zelfmanagementvaardigheden en het belang dat wordt toegekend aan pijn, belangrijke factoren zijn die werken met chronische pijn faciliteren. Chronische pijn op zichzelf is vaak niet de reden voor arbeidsverzuim, maar meestal spelen persoonlijke- en omgevingsfactoren daarin een beslissende rol. Deze factoren kunnen dienen als aangrijpingspunt voor het verhogen van duurzame inzetbaarheid en preventie van arbeidsverzuim van mensen met chronische pijn aan het bewegingsapparaat. De effectieve manier waarop deelnemende werknemers in het onderzoek met hun pijn omgingen en productief bleven, kan anderen inspireren aan het werk te blijven. Daarnaast biedt het onderzoek een nieuw referentiekader voor de bedrijfs-, verzekerings-, en revalidatiegeneeskunde. This thesis was one of the first studies that focused specifically on people who continued work with chronic nonspecific musculoskeletal pain (CMP), and collected (identified) unique data concerning sustainable work participation of workers with CMP. It provides a large range of characteristics of workers with CMP who continued work despite pain, which has added to our understanding of sustainable work participation in people suffering from CMP. Comparison of workers who continued work with CMP with sick listed workers with CMP admitted for rehabilitation revealed that these groups differ significantly on several factors. In this thesis, evidence was found that the workers’ motivation to work, self-management skills, and the attributed importance of pain on their (working) lives are important factors to manage staying at work with CMP. It is recommended to be aware of the fact that CMP standing on itself is often not the reason for sick leave and disability, but regularly personal and environmental factors play an additional decisive role. Because these factors can be influenced, they offer opportunity to promote staying at work. In the process of guiding workers back to work, the results of the project ‘Working with pain’ may be used. The findings of this thesis potentially contribute to promotion of sustained work participation and prevention of sick-leave in workers with CMP. The effective way workers in this project coped with CMP and remained productive, may inspire others in their efforts to stay work. Finally, this thesis offers a new reference for rehabilitation-, occupational-,and insurance medicine.

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease

Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

This is the final version. Available on open access from the Public Library of Science via the DOI in this recordData Availability: This is a meta-analysis that was conducted on summary level results. Individual level data was not shared amongst the authors of the manuscript, and the corresponding authors are not in a position to make the individual level data available. For most of the samples included, individual level data deposition is precluded by existing consents, and other issues related to individual privacy. Summary level data from the meta-analysis are available from the DIAGRAM (http://www.diagram-consortium.org/Mahajan_2014_ExomeChip/) and LocusZoom (http://csg.sph.umich.edu/locuszoom/) website.Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights

A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in fasting plasma insulin (FI) levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-hour insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio=1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.Academy of Finland (129293, 128315, 129330, 131593, 139635, 139635, 121584, 126925, 124282, 129378, 258753); Action on Hearing Loss (G51); Ahokas Foundation; American Diabetes Association (#7-12-MN-02); Atlantic Canada Opportunities Agency; Augustinus foundation; Becket foundation; Benzon Foundation; Biomedical Research Council; British Heart Foundation (SP/04/002); Canada Foundation for Innovation; Commission of the European Communities, Directorate C-Public Health (2004310); Copenhagen County; Danish Centre for Evaluation and Health Technology Assessment; Danish Council for Independent Research; Danish Heart Foundation (07-10-R61-A1754-B838-22392F); Danish Medical Research Council; Danish Pharmaceutical Association; Emil Aaltonen Foundation; European Research Council Advanced Research Grant; European Union FP7 (EpiMigrant, 279143; FP7/2007-2013; 259749); Finland's Slottery Machine Association; Finnish Cultural Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Foundation of Cardiovascular Research; Finnish Medical Society; Finnish National Public Health Institute; Finska Läkaresällskapet; Folkhälsan Research Foundation; Foundation for Life and Health in Finland; German Center for Diabetes Research (DZD) ; German Federal Ministry of Education and Research; Health Care Centers in Vasa, Närpes and Korsholm; Health Insurance Foundation (2012B233) ; Helsinki University Central Hospital Research Foundation; Hospital districts of Pirkanmaa, Southern Ostrobothnia, North Ostrobothnia, Central Finland, and Northern Savo; Ib Henriksen foundation; Juho Vainio Foundation; Korea Centers for Disease Control and Prevention (4845–301); Korea National Institute of Health (2012-N73002-00); Li Ka Shing Foundation; Liv och Hälsa; Lundbeck Foundation; Marie-Curie Fellowship (PIEF-GA-2012-329156); Medical Research Council (G0601261, G0900747-91070, G0601966, G0700931); Ministry of Education in Finland; Ministry of Social Affairs and Health in Finland; MRC-PHE Centre for Environment and Health;Municipal Heath Care Center and Hospital in Jakobstad; Närpes Health Care Foundation; National Institute for Health Research (RP-PG-0407-10371); National Institutes of Health (U01 DK085526, U01 DK085501, U01 DK085524, U01 DK085545, U01 DK085584, U01 DK088389, RC2-DK088389, DK085545, DK098032, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN, R01MH107666 and K12CA139160268201300050C, U01 DK062370, R01 DK066358, U01DK085501, R01HL102830, R01DK073541, PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R01 MH101820, R01MH090937, P30DK020595, R01 DK078616, NIDDK K24 DK080140, 1RC2DK088389, T32GM007753); National Medical Research Council; National Research Foundation of Korea (NRF-2012R1A2A1A03006155); Nordic Center of Excellence in Disease Genetics; Novo Nordisk; Ollqvist Foundation; OrionFarmos Research Foundation; Paavo Nurmi Foundation; Perklén Foundation; Samfundet Folkhälsan; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; South East Norway Health Authority (2011060); Swedish Cultural Foundation in Finland; Swedish Heart-Lung Foundation; Swedish Research Council; Swedish Research Council (Linné and Strategic Research Grant); The American Federation for Aging Research; The Einstein Glenn Center; The European Commission (HEALTH-F4-2007-201413); The Finnish Diabetes Association; The Folkhälsan Research Foundation; The Påhlssons Foundation; The provinces of Newfoundland and Labrador, Nova Scotia, and New Brunswick; The Sigrid Juselius Foundation; The Skåne Regional Health Authority; The Swedish Heart-Lung Foundation; Timber Merchant Vilhelm Bang’s Foundation; Turku University Foundation; Uppsala University; Wellcome Trust (064890, 083948, 085475, 086596, 090367, 090532, 092447, 095101/Z/10/Z, 200837/Z/16/Z, 095552, 098017, 098381, 098051, 084723, 072960/2/ 03/2, 086113/Z/08/Z, WT098017, WT064890, WT090532, WT098017, 098051, WT086596/Z/08/A and 086596/Z/08/Z). Detailed acknowledgment of funding sources is provided in the Additional Acknowledgements section of the Supplementary Materials

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes(1). Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel(2)) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries

Improving Work Ability and Return to Work among Women on Long-term Sick Leave

The overall aim of this thesis was to gain new knowledge of factors and interventions that improve work ability and return to work (RTW) among women on long-term sick leave from human service organizations (HSOs). The specific aims of the studies were: to evaluate the associations between the self-rated Work Ability Index (WAI) and Work Ability Score (WAS), and the relationship with prospective sick leave, symptoms, and health (Paper I); to investigate whether intervention with myofeedback training or intensive muscular strength training could decrease pain and increase work ability among women with neck pain (Paper II); to examine the associations between workplace rehabilitation and the combination of supportive conditions at work with work ability and RTW over time (Paper III); and to explore experiences, views, and strategies in the rehabilitation process for RTW (Paper IV). This thesis is based on a prospective cohort study (n=324) and a randomized controlled study (RCT) (n=60, participants with neck pain). Both quantitative and qualitative methods were used. The data collection consisted of questionnaires, laboratory-observed data, register-based data, and interviews. The results showed a very strong association between WAI and WAS, and results predicted future sick leave degree, health-related quality of life, vitality, neck pain, self-rated general health, self-rated mental health, behavioral stress, and current stress (Paper I). In the RCT (Paper II), individuals in the myofeedback intervention group increased their vitality and work ability over time and individuals in the intensive musculoskeletal strength training group increased their WAI, WAS, and mental health over time. WAI, WAS, and RTW increased over time among individuals provided with workplace rehabilitation and supportive conditions at work (Paper III) such as a sense of feeling welcome back at work, influence at work, possibilities for development, degree of freedom at work, meaning of work, quality of leadership, social support, sense of community, and work satisfaction. Women described (Paper IV) how they were striving to work and how they had different views, strategies, and approaches in the rehabilitation process for RTW. They expressed a desire to work, their goals for work, and their wishes for work. In the rehabilitation process for RTW they described their interaction with stakeholders as either controlling the interaction or struggling in the interaction. They described strategies to cope with RTW in terms of yo-yo (fluctuating) working: yo-yo working as a strategy or yo-yo working as a consequence. This thesis identifies factors of importance in improving work ability and RTW among women on long-term sick leave from HSOs. For women with neck pain, the intervention study showed feasibility of the intervention and demonstrated improved work ability and decreased pain (Paper II). The intensive muscular strength training program, which is easy for the individual to learn and perform at home, was associated with increased work ability. The results regarding rehabilitation highlight the importance of integrating workplace rehabilitation with supportive conditions at work to increase work ability and improve RTW (Paper III). Women expressed that they were striving to work and that they wanted to work (Paper IV). These women were “going in and out” of work participation (yo-yo working) as a way to handle the rehabilitation process. For assessing the status and progress of work ability among women on long-term sick leave, the single-question WAS may be used as a compliment to the full WAI as a simple indicator (Paper I)