| 11. |
- Alexanderson, K., et al.
(författare)
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Diagnosis-specific sick leave as a long-term predictor of disability pension : a 13-year follow-up of the GAZEL cohort study
- 2012
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Ingår i: Journal of Epidemiology and Community Health. - : BMJ. - 0143-005X .- 1470-2738. ; 66:2, s. 155-159
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Tidskriftsartikel (refereegranskat)abstract
- Background Factors that increase the risk of labour market exclusion are poorly understood. In this study, we examined the extent to which all-cause and diagnosis-specific sick leave predict subsequent disability pension (DP).Methods Prospective cohort study of 20 434 persons employed by the French national gas and electric company (the GAZEL study). New sick-leave spells >7 days in 1990–1992 were obtained from company records. Follow-up for DP was from 1994 to 2007.Results The HR, adjusted for age and occupational position, for DP was 3.5 (95% CI 2.7 to 4.5) in men and 2.6 (95% CI 1.9 to 3.5) in women with one or more sick-leave spells >7 days compared with those with no sick leave. The strongest predictor of DP was sick leave with a psychiatric diagnosis, HR 7.6 (95% CI 5.2 to 10.9) for men and 4.1 (95% CI 2.9 to 5.9) for women. Corresponding HRs for sick leave due to circulatory diagnoses in men and women were 5.6 (95% CI 3.7 to 8.6) and 3.1 (95% CI 1.8 to 5.3), for respiratory diagnoses 3.9 (95% CI 2.6 to 5.8) and 2.6 (95% CI 1.7 to 4.0), and musculoskeletal diagnoses 4.6 (95% CI 3.4 to 6.4) and 3.3 (95% CI 2.2 to 4.8), respectively.Conclusions Sick leave with a psychiatric diagnosis is a major risk factor for subsequent DP, especially among men. Sick leave due to musculoskeletal or circulatory disorders was also a strong predictor of DP. Diagnosis-specific sick leave should be recognised as an early risk marker for future exclusion from the labour market.
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| 12. |
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| 14. |
- Ferrie, J E, et al.
(författare)
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Diagnosis-specific sickness absence and all-cause mortality in the GAZEL study.
- 2009
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Ingår i: Journal of epidemiology and community health. - : BMJ. - 1470-2738 .- 0143-005X. ; 63:1, s. 50-5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This study aims to examine diagnosis-specific sickness absence as a risk marker for all-cause mortality. METHODS: Prospective occupational cohort (the GAZEL study). Medically certified sickness absence spells >7 days for 15 diagnostic categories, 1990-1992, were examined in relation to all-cause mortality, January 1993-February 2007. The reference group for each diagnostic category was participants with no spell >7 days for that diagnosis. The participants were French public utility workers (5271 women and 13 964 men) aged 37-51 years in 1990, forming the GAZEL study. Over the follow-up period, there were 144 deaths in women and 758 in men. RESULTS: 7875 employees (41.0%) had at least one spell of sickness absence >7 days over the 3-year period. The commonest diagnoses were mental disorders, musculoskeletal diseases, respiratory diseases and external causes in both sexes; genitourinary diseases in women, and digestive and circulatory diseases in men. Of these common diagnoses, mental disorders in women, hazard ratio (95% confidence intervals) 1.24 (1.1 to 1.4), and mental disorders 1.35 (1.3 to 1.5), digestive diseases 1.29 (1.1 to 1.6) and circulatory diseases 1.35 (1.2 to 1.6) in men were associated with mortality after adjustment for age, employment grade and sickness absence in all other diagnostic categories. CONCLUSIONS: Employees with medically certified absence spells of 1 week or more over a 3-year period had a 60% excess risk of early death. In women and men this excess risk was associated with some of the commonest diagnoses of sickness absence, in particular mental disorders. Sickness absence for mental disorders may be a useful early indicator of groups at increased risk of fatal disease.
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| 15. |
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| 16. |
- Kivimäki, M, et al.
(författare)
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Sickness absence as a prognostic marker for common chronic conditions : analysis of mortality in the GAZEL study.
- 2008
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Ingår i: Occup Environ Med. - : BMJ. - 1470-7926 .- 1351-0711. ; 65:12, s. 820-6
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Tidskriftsartikel (refereegranskat)abstract
- Sickness absence as a prognostic marker for common chronic conditions: analysis of mortality in the GAZEL study.Kivimäki M, Head J, Ferrie JE, Singh-Manoux A, Westerlund H, Vahtera J, Leclerc A, Melchior M, Chevalier A, Alexanderson K, Zins M, Goldberg M.Department of Epidemiology and Public Health, University College London, London, UK. m.kivimaki@ucl.ac.ukOBJECTIVES: To determine whether sickness absence is a prognostic marker in terms of mortality among people with common chronic conditions. METHODS: Prospective occupational cohort study of 13,077 men and 4871 women aged 37-51 from the National Gas and Electricity Company, France. Records of physician-certified sickness absences over a 3-year period were obtained from employers' registers. Chronic conditions were assessed in annual surveys over the same period. The main outcome measure was all-cause mortality (803 deaths, mean follow-up after assessment of sickness absence: 13.9 years). RESULTS: In Cox proportional hazard models adjusted for age, sex, socioeconomic position and co-morbidity, >28 annual sickness-absence days versus no absence days was associated with an excess mortality risk among those with cancer (hazard ratio 5.4, 95% CI 2.2 to 13.1), depression (1.7, 1.1 to 2.8), chronic bronchitis or asthma (2.7, 1.6 to 4.6) and hypertension (1.6, 1.0 to 2.6). The corresponding hazard ratios for more than five long (>14 days) sickness-absence episodes per 10 person-years versus no such episodes were 5.4 (2.2 to 13.1), 1.8 (1.3 to 2.7), 2.0 (1.3 to 3.2) and 1.8 (1.2 to 2.7), respectively. Areas under receiver operating characteristics curves for these absence measures varied between 0.56 and 0.73, indicating the potential of these measures to distinguish groups at high risk of mortality. The findings were consistent across sex, age and socioeconomic groups and in those with and without co-morbid conditions. CONCLUSION: Data on sickness absence may provide useful prognostic information for common chronic conditions at the population level.
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| 17. |
- Pantazis, A., et al.
(författare)
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Tracking the motion of the KV1.2 voltage sensor reveals the molecular perturbations caused by a de novo mutation in a case of epilepsy
- 2020
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Ingår i: Journal of Physiology. - : Blackwell Publishing Ltd. - 0022-3751 .- 1469-7793.
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Tidskriftsartikel (refereegranskat)abstract
- Key points: KV1.2 channels, encoded by the KCNA2 gene, regulate neuronal excitability by conducting K+ upon depolarization. A new KCNA2 missense variant was discovered in a patient with epilepsy, causing amino acid substitution F302L at helix S4, in the KV1.2 voltage-sensing domain. Immunocytochemistry and flow cytometry showed that F302L does not impair KCNA2 subunit surface trafficking. Molecular dynamics simulations indicated that F302L alters the exposure of S4 residues to membrane lipids. Voltage clamp fluorometry revealed that the voltage-sensing domain of KV1.2-F302L channels is more sensitive to depolarization. Accordingly, KV1.2-F302L channels opened faster and at more negative potentials; however, they also exhibited enhanced inactivation: that is, F302L causes both gain- and loss-of-function effects. Coexpression of KCNA2-WT and -F302L did not fully rescue these effects. The proband's symptoms are more characteristic of patients with loss of KCNA2 function. Enhanced KV1.2 inactivation could lead to increased synaptic release in excitatory neurons, steering neuronal circuits towards epilepsy. Abstract: An exome-based diagnostic panel in an infant with epilepsy revealed a previously unreported de novo missense variant in KCNA2, which encodes voltage-gated K+ channel KV1.2. This variant causes substitution F302L, in helix S4 of the KV1.2 voltage-sensing domain (VSD). F302L does not affect KCNA2 subunit membrane trafficking. However, it does alter channel functional properties, accelerating channel opening at more hyperpolarized membrane potentials, indicating gain of function. F302L also caused loss of KV1.2 function via accelerated inactivation onset, decelerated recovery and shifted inactivation voltage dependence to more negative potentials. These effects, which are not fully rescued by coexpression of wild-type and mutant KCNA2 subunits, probably result from the enhancement of VSD function, as demonstrated by optically tracking VSD depolarization-evoked conformational rearrangements. In turn, molecular dynamics simulations suggest altered VSD exposure to membrane lipids. Compared to other encephalopathy patients with KCNA2 mutations, the proband exhibits mild neurological impairment, more characteristic of patients with KCNA2 loss of function. Based on this information, we propose a mechanism of epileptogenesis based on enhanced KV1.2 inactivation leading to increased synaptic release preferentially in excitatory neurons, and hence the perturbation of the excitatory/inhibitory balance of neuronal circuits.
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| 19. |
- Bahira, M., et al.
(författare)
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A ruthenium dimer complex with a flexible linker slowly threads between DNA bases in two distinct steps
- 2015
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 43:18, s. 8856-8867
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Tidskriftsartikel (refereegranskat)abstract
- Several multi-component DNA intercalating small molecules have been designed around ruthenium-based intercalating monomers to optimize DNA binding properties for therapeutic use. Here we probe the DNA binding ligand [mu-C-4(cpdppz)(2)(phen)(4)Ru-2](4+), which consists of two Ru(phen)(2)dppz(2+) moieties joined by a flexible linker. To quantify ligand binding, double-stranded DNA is stretched with optical tweezers and exposed to ligand under constant applied force. In contrast to other bis-intercalators, we find that ligand association is described by a two-step process, which consists of fast bimolecular intercalation of the first dppz moiety followed by similar to 10-fold slower intercalation of the second dppz moiety. The second step is rate-limited by the requirement for a DNA-ligand conformational change that allows the flexible linker to pass through the DNA duplex. Based on our measured force-dependent binding rates and ligand-induced DNA elongation measurements, we are able to map out the energy landscape and structural dynamics for both ligand binding steps. In addition, we find that at zero force the overall binding process involves fast association (similar to 10 s), slow dissociation (similar to 300 s), and very high affinity (K-d similar to 10 nM). The methodology developed in this work will be useful for studying the mechanism of DNA binding by other multi-step intercalating ligands and proteins.
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| 20. |
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