Dementia in Scottish military veterans: early evidence from a retrospective cohort study.

BACKGROUND: Few studies have examined whether UK military veterans are at an increased risk of dementia. We explored the risk of dementia in Scottish military veterans aged up to 73 years in comparison with people who have never served. METHODS: Retrospective cohort study of 78 000 veterans and 253 000 people with no record of service, matched for age, sex and area of residence, with up to 37 years follow-up, using Cox proportional hazard analysis to compare risk of dementia in veterans and non-veterans, overall and by subgroup. RESULTS: Dementia was recorded in 0.2% of both veterans and non-veterans overall, Cox proportional hazard ratio 0.98, 95% confidence interval (CI) 0.82-1.19, p = 0.879 (landmark age: 50 years), with no difference for men but increased risk in veteran women and Early Service Leavers. Post-traumatic stress disorder (PTSD) was associated with a higher risk of dementia in both veterans and non-veterans, although possibly to a lesser degree in veterans. A history of mood disorder was strongly associated with developing dementia, greater in veterans than in non-veterans, odds ratio 1.54, 95% CI 1.01-2.35, p = 0.045. CONCLUSIONS: There was no evidence to suggest that military service increased the risk of dementia, although this may change as the cohort ages. The well-documented association with PTSD shows no evidence of being stronger in veterans; by contrast, the association of mood disorder with dementia is much stronger in veterans. Healthcare providers should carefully assess the cognitive status of older veterans presenting with depressive illness in order to identify early dementia and ensure optimum management.

Do Junior Entrants to the UK Armed Forces have worse outcomes than Standard Entrants?

INTRODUCTION: The UK is the only permanent member of the UN Security Council that has a policy of recruiting 16 and 17 year old individuals into its regular Armed Forces. Little is known about the consequences of enlisting as a Junior Entrant (JE), although concerns have been expressed. We compare the mental health, deployment history, and pre-enlistment and post-enlistment experiences of personnel who had enlisted as JEs with personnel who joined as Standard Entrants (SEs). METHOD: Participants from a large UK military cohort study completed a self-report questionnaire between 2014 and 2016 that included symptoms of probable post-traumatic stress disorder (PTSD), common mental disorders, alcohol consumption, physical symptoms and lifetime self-harm. Data from regular non-officer participants (n=4447) from all service branches were used in the analysis. JEs were defined as having enlisted before the age of 17.5 years. A subgroup analysis of participants who had joined or commenced adult service after April 2003 was carried out. RESULTS: JEs were not more likely to deploy to Iraq or Afghanistan but were more likely to hold a combat role when they did (OR 1.25, 95% CI 1.00 to 1.56). There was no evidence of an increase in symptoms of common mental disorders, PTSD, multiple somatic symptoms (MSS), alcohol misuse or self-harm in JEs in the full sample, but there was an increase in alcohol misuse (OR 1.84, 95% CI 1.18 to 2.87), MSS (OR 1.51, 95% CI 1.04 to 2.20) and self-harm (OR 2.13, 95% CI 1.15 to 3.95) in JEs who had commenced adult service after April 2003. JEs remain in adult service for longer and do not have more difficulties when they leave service. CONCLUSIONS: JEs do not have worse mental health than SEs, but there is uncertainty in relation to alcohol misuse, MSS and self-harm in more recent joiners. Monitoring these concerns is advisable.

Novel human-derived EML4-ALK fusion cell lines identify ribonucleotide reductase RRM2 as a target of activated ALK in NSCLC.

INTRODUCTION: Echinoderm microtubule-associated protein-like 4 (EML4)-Anaplastic Lymphoma Kinase (ALK) rearrangements occur in 3% to 7% of lung adenocarcinomas and are targets for treatment with tyrosine kinase inhibitors (TKIs). Here we have developed three novel EML4-ALK-positive patient-derived Non-Small-Cell-Lung-Cancer (NSCLC) cancer cell lines, CUTO8 (variant 1), CUTO9 (variant 1) and CUTO29 (variant 3) and included a fourth ALK-positive cell line YU1077 (variant 3) to study ALK-positive signaling and responses. Variants 1 and 3 are the most common EML4-ALK variants expressed in ALK-positive NSCLC, and currently cell lines representing these EML4-ALK variants are limited. MATERIALS AND METHODS: Resazurin assay was performed to evaluate cell viability. Protein levels were determined using western blotting. RNA sequencing was performed in all four cell lines to identify differentially expressed genes. Whole-genome sequencing was performed to determine the presence of EML4-ALK fusion and ALK tyrosine kinase inhibitor resistance mutations. RESULTS: In this study, we have confirmed expression of the corresponding ALK fusion protein and assessed their sensitivity to a range of ALK tyrosine kinase inhibitors. These patient derived cell lines exhibit differential sensitivity to lorlatinib, brigatinib and alectinib, with EML4-ALK variant 3 containing cell lines exhibiting increased sensitivity to lorlatinib and brigatinib as compared to alectinib. These cell lines were further characterized by whole genome sequencing and RNA-seq analysis that identified the ribonucleotide reductase regulatory subunit 2 (RRM2) as a downstream and potential therapeutic target in ALK-positive NSCLC. CONCLUSION: We provide a characterization of four novel EML4-ALK-positive NSCLC cell lines, highlighting genomic heterogeneity and differential responses to ALK TKI treatment. The RNA-Seq characterization of ALK-positive NSCLC CUTO8, CUTO9, CUTO29 and YU1077 cell lines reported here, has been compiled in an interactive ShinyApp resource for public data exploration (https://ccgg.ugent.be/shiny/nsclc_rrm2_2022/).

Risk factors for mental ill health in UK Army personnel: an overview.

Women in the UK military are more commonly diagnosed with a mental health disorder than men, but the reasons for this difference are not fully understood. This literature review identifies the risk factors for mental ill health in military personnel before serving, during service and as a veteran. The interaction of risk factors is complex and, in some cases, may be synergistic, such as experiencing adverse events in childhood and exposure to combat. Identification of risk factors allows further research to better understand differences between men and women, and the impact of these risk factors on army personnel. In turn this will inform better preventive strategies, which could be targeted at the primary, secondary or tertiary levels.

Altered plasma serine and 1-deoxydihydroceramide profiles are associated with diabetic neuropathy in type 2 diabetes and obesity.

Recent studies suggest that the accumulation of atypical, 1-deoxysphingolipids that lack the C1 hydroxyl group may be associated with diabetic neuropathy (DN). We hypothesized that specific plasma 1-deoxysphingolipids associate with DN severity, and that alterations in plasma serine and alanine associate with 1-deoxysphingolipid elevation in patients with type 2 diabetes (T2D). We examined individual 1-deoxysphingolipid species using LC/MS/MS in plasma samples from 75 individuals including lean controls (LC, n = 19), those with obesity (n = 19), obesity with T2D without DN (ob/T2D, n = 18), and obesity with T2D with DN (Ob/T2D/DN, n = 19). We observed a step wise increase in 1-deoxydihydroceramides across these four groups (spearman correlation coefficient r = 0.41, p = 0.0002). Mean total concentrations of 1-deoxydihydroceramides, and most individual 1-deoxydihydroceramide species, were higher in ob/T2D/DN versus LC group (8.939 vs. 5.195 pmol/100 µL for total 1-deoxydihydroceramides p = 0.005). No significant differences in 1-deoxydihydroceramides were observed between the ob/T2D and ob/T2D/DN groups. l-alanine was higher and l-serine lower in ob/T2D/DN versus LC groups (326.2 vs. 248.0 µM, p = 0.0086 and 70.2 vs. 89.8 µM, p = 0.0110), consistent with a potential contribution of these changes to the observed 1-deoxysphingolipids profiles. 1-deoxydihydroceramides correlated inversely with leg intraepidermal nerve fiber density (CC -0.40, p = 0.003). These findings indicate that 1-deoxydihydroceramides may be important biomarkers and/or mediators of DN.

Low-molecular-weight heparin adherence and effects on survival within a randomised phase III lung cancer trial (RASTEN).

BACKGROUND: Coagulation activation is a hallmark of cancer, and anticoagulants have shown tumour-inhibiting properties. However, recent trials have failed to demonstrate improved survival with low-molecular-weight heparin (LMWH) in cancer populations. This has raised the question of suboptimal adherence as a possible explanation for the lack of benefit. Still, there is no standardised method to directly monitor LMWH in patient plasma. Here, we directly determine LMWH levels in patients using the Heparin Red assay to objectively assess adherence and how this associates with the patient outcome in the RASTEN trial. METHODS: RASTEN is a multicentre, randomised phase III trial investigating if the addition of LMWH to standard therapy can improve survival in small-cell lung cancer. LMWH was measured in plasma (N = 258) by the Heparin Red assay and compared with the anti-factor Xa (anti-FXa) activity assay. RESULTS: Both methods could differentiate patients in the LMWH arm from the control arm and patients receiving therapeutic LMWH owing to thrombosis. Receiver Operating Characteristic (ROC) analysis yielded adherence rates of 85% for anti-FXa and 68% for Heparin Red. No survival benefits were found in the adherent subgroup compared with the control arm (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 0.95-1.67; P = 0.105 and HR: 1.19; 95% CI: 0.89-1.60; P = 0.248 for anti-FXa and Heparin Red, respectively). Heparin Red could define patients with high probability of adherence to LMWH treatment, which warrants prospective studies for further validation. Our finding that the LMWH-adherent subpopulation did not show improved survival excludes that the negative outcome of RASTEN was due to poor adherence.

Healthy workers or less healthy leavers? Mortality in military veterans.

BACKGROUND: The 'healthy worker effect' predicts that longer employment is positively associated with reduced mortality, but few studies have examined mortality in military veterans irrespective of exposure to conflict. AIMS: To examine mortality in a large national cohort of Scottish veterans by length of service. METHODS: Retrospective cohort study comparing survival in up to 30-year follow-up among 57 000 veterans and 173 000 people with no record of service, matched for age, sex and area of residence, who were born between 1945 and 1985. We compared antecedent diagnoses in the two groups to provide information on probable risk factors. RESULTS: By the end of follow-up, 3520 (6%) veterans had died, compared with 10 947 (6%) non-veterans. Cox proportional hazard analysis confirmed no significant difference overall unadjusted or after adjusting for deprivation. On subgroup analysis, those who left prematurely (early service leavers) were at significantly increased risk of death (hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.09-1.24, P < 0.001), although the increase became non-significant after adjusting for socioeconomic status (HR 1.05, 95% CI 0.99-1.12). Longer-serving veterans were at significantly lower risk of death than non-veterans; the risk decreased both with length of service and in more recent birth cohorts. Smoking-related disease was the greatest contributor to increased mortality in early leavers. CONCLUSIONS: Among longer-serving veterans, there was evidence of a HWE partly attributable to selective attrition of early service leavers, but birth cohort analysis suggests improvements over time which may also reflect a causal effect of improved in-service health promotion.

Peripheral arterial disease in Scottish military veterans: a retrospective cohort study of 57 000 veterans and 173 000 matched non-veterans.

BACKGROUND: While traumatic limb loss in military personnel is widely known, the threat posed by peripheral arterial disease (PAD) in those who have served is less well recognized. The aim of our study was to examine the risk of PAD in a Scotland-wide cohort of veterans who served between 1960 and 2012. METHODS: Retrospective 30-year cohort study of 56 205 veterans born 1945-85, and 172 741 non-veterans, matched for age, sex and area of residence, using Cox proportional hazard models to examine the association between veteran status, birth cohort, length of service and risk of PAD leading to hospitalization or death. RESULTS: Overall, veterans were at increased risk of PAD compared with non-veterans, unadjusted hazard ratio (HR) = 1.46, 95% confidence intervals (CI): 1.33-1.60, P < 0.001. The highest risk was in veterans born between 1950 and 1954, HR = 1.76, 95% CI: 1.50-2.07, P < 0.001, and in those with the shortest service (early service leavers), HR = 1.84, 95% CI: 1.49-2.27, P < 0.001. CONCLUSIONS: The findings provide evidence for a hidden burden of life- and limb-threatening PAD in older veterans and are consistent with the higher rates of military smoking which have been reported previously. The study emphasizes the need for vascular preventive measures in this group.

Coagulation biomarkers and prediction of venous thromboembolism and survival in small cell lung cancer: A sub-study of RASTEN - A randomized trial with low molecular weight heparin.

Coagulation activation and venous thromboembolism (VTE) are hallmarks of cancer; however, there is an unmet need of improved biomarkers for individualized anticoagulant treatment. The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE risk and outcome in a homogenous cancer patient population. RASTEN is a multicenter, randomized phase-3 trial investigating the survival effect of low molecular weight heparin enoxaparin when added to standard treatment in newly diagnosed small cell lung cancer (SCLC) patients. Plasma collected at baseline, during treatment, and at follow-up was used in this ad hoc sub-study (N = 242). Systemic coagulation was assessed using four assays reflecting various facets of the coagulation system: Total tissue factor (TF); extracellular vesicle associated TF (EV-TF); procoagulant phospholipids (PPL); and thrombin generation (TG). We found small variations of biomarker levels between baseline, during treatment and at follow-up, and appeared independent on low molecular weight heparin treatment. Overall, none of the measured biomarkers at any time-point did significantly associate with VTE incidence, although increased total TF at baseline showed significant association in control patients not receiving low molecular weight heparin (P = 0.03). Increased TG-Peak was significantly associated with decreased overall survival (OS; P = 0.03), especially in patients with extensive disease. Low baseline EV-TF predicted a worse survival in the low molecular weight heparin as compared with the control group (HR 1.42; 95% CI 1.04-1.95; P = 0.03; P for interaction = 0.12). We conclude that the value of the analyzed coagulation biomarkers for the prediction of VTE risk was very limited in SCLC patients. The associations between TG-Peak and EV-TF with patient survival and response to low molecular weight heparin therapy, respectively, warrant further studies on the role of coagulation activation in SCLC aggressiveness.

Witnessing history: a personal view of half a century in public health.

Former Chief Medical Officer Sir Kenneth Calman recently celebrated 50 years in medicine. It was a period which saw the evolution of the public health agenda from communicable diseases to diseases of lifestyle, the change from a hospital-orientated health service to one dominated by community-based services, and the increasing recognition of inequalities as a major determinant of health. This paper documents selected highlights from his career including the Aberdeen typhoid outbreak, AIDS, bovine spongiform encephalopathy, foot and mouth disease, radioactive fallout, the invention of computerised tomography and magnetic resonance imaging, and draws parallels between the development of the modern understanding of public health and the theoretical background to the science 100 years earlier.

Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial.

Background: Coagulation activation and venous thromboembolism (VTE) are hallmarks of malignant disease and represent a major cause of morbidity and mortality in cancer. Coagulation inhibition with low-molecular-weight heparin (LMWH) may improve survival specifically in small-cell lung cancer (SCLC) patients by preventing VTE and tumor progression; however, randomized trials with well-defined patient populations are needed to obtain conclusive data. The aim of RASTEN was to investigate the survival effect of LMWH enoxaparin in a homogenous population of SCLC patients. Patients and methods: We carried out a randomized, multicenter, open-label trial to investigate the addition of enoxaparin at a supraprophylactic dose (1 mg/kg) to standard treatment in patients with newly diagnosed SCLC. The primary outcome was overall survival (OS), and secondary outcomes were progression-free survival (PFS), incidence of VTE and hemorrhagic events. Results: In RASTEN, 390 patients were randomized over an 8-year period (2008-2016), of whom 186 and 191 were included in the final analysis in the LMWH and control arm, respectively. We found no evidence of a difference in OS or PFS by the addition of enoxaparin [hazard ratio (HR), 1.11; 95% confidence interval (CI) 0.89-1.38; P = 0.36 and HR, 1.18; 95% CI 0.95-1.46; P = 0.14, respectively]. Subgroup analysis of patients with limited and extensive disease did not show reduced mortality by enoxaparin. The incidence of VTE was significantly reduced in the LMWH arm (HR, 0.31; 95% CI 0.11-0.84; P = 0.02). Hemorrhagic events were more frequent in the LMWH-treated group but fatal bleedings occurred in both arms. Conclusion: LMWH enoxaparin in addition to standard therapy did not improve OS in SCLC patients despite being administered at a supraprophylactic dose and despite resulting in a significant reduction in VTE incidence. Addition of LMWH cannot be generally recommended in the management of SCLC patients, and predictive biomarkers of VTE and LMWH-associated bleeding in cancer patients are warranted.

Suicide in Scottish military veterans: a 30-year retrospective cohort study.

BACKGROUND: Although reassuring data on suicide risk in UK veterans of the 1982 Falklands conflict and 1991 Gulf conflict have been published, there have been few studies on long-term overall suicide risk in UK veterans. AIMS: To examine the risk of suicide in a broad population-based cohort of veterans in Scotland, irrespect ive of length of service or exposure to conflict, in comparison with people having no record of military service. METHODS: A retrospective 30-year cohort study of 56205 veterans born 1945-85 and 172741 matched non-veterans, using Cox proportional hazard models to compare the risk of suicide and fatal self-harm overall, by sex, birth cohort, length of service and year of recruitment. RESULTS: There were 267 (0.48%) suicides in the veterans compared with 918 (0.53%) in non-veterans. The difference was not statistically significant overall [adjusted hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.86-1.13]. The incidence was lower in younger veterans and higher in veterans aged over 40. Early service leavers were at non-significantly increased risk (adjusted HR 1.13; 95% CI 0.91-1.40) but only in the older age groups. Women veterans had a significantly higher risk of suicide than non-veteran women (adjusted HR 2.44; 95% CI 1.32-4.51, P < 0.01) and comparable risk to veteran men. Methods of suicide did not differ significantly between veterans and non-veterans, for either sex. CONCLUSIONS: The Scottish Veterans Health Study adds to the emerging body of evidence that there is no overall difference in long-term risk of suicide between veterans and non-veterans in the UK. However, female veterans merit further study.

Detection of BMAA in the human central nervous system.

Amyotrophic lateral sclerosis (ALS) is an extremely devastating neurodegenerative disease with an obscure etiology. The amino acid ß-N-methylamino-l-alanine (BMAA) produced by globally widespread phytoplankton has been implicated in the etiology of human motor neuron diseases [corrected]. BMAA was recently proven to be present in Baltic Sea food webs, ranging from plankton to larger Baltic Sea organisms, some serving as important food items (fish) for humans. To test whether exposure to BMAA in a Baltic Sea setting is reflected in humans, blood and cerebrospinal fluid (CSF) from individuals suffering from ALS were analyzed, together with sex- and age-matched individuals not inflicted with ALS. Ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and multiple reaction monitoring (MRM), in conjunction with diagnostic transitions revealed BMAA in three (12%) of the totally 25 Swedish individuals tested, with no preference for those suffering from ALS. The three BMAA-positive samples were all retrieved from the CSF, while BMAA was not detected in the blood. The data show that BMAA, potentially originating from Baltic Sea phytoplankton, may reach the human central nervous system, but does not lend support to the notion that BMAA is resident specifically in ALS-patients. However, while dietary exposure to BMAA may be intermittent and, if so, difficult to detect, our data provide the first demonstration of BMAA in the central nervous system of human individuals ante mortem quantified with UHPLC-MS/MS, and therefore calls for extended research efforts.

Chain of care in chest pain--differences between three hospitals in an urban area.

AIM: To describe differences in treatment and delay times in acute chest pain at the three hospitals in Göteborg, Sweden. METHODS: All patients admitted to the three hospitals within Sahlgrenska University (SU) (Sahlgrenska: SU/S, Östra: SU/Ö and Mölndal: SU/M) with acute chest pain during 3 months in 2008 were evaluated for diagnosis, early treatment and outcome. RESULTS: In all, 2588 visits by 2393 patients were included (visits n=1253 SU/S; n=853 SU/Ö; n=482 SU/M) of which 50%, 63% and 51% were hospitalised (p<0.0001). Among hospitalised patients, a diagnosis of ACS was reported in 26%, 9% and 22% respectively (p<0.0001). Among ACS patients, 83%, 66% and 57% respectively underwent coronary angiography (p=0.004). The median delay to coronary angiography in ST-elevation myocardial infarction (STEMI) was 42 min at SU/S, 3h 47 min at SU/Ö and 2h 34 min at SU/M (p=0.008). The corresponding values for coronary angiography in unstable coronary artery disease were 42h 7min, 48h 35 min and 123h 42 min (p=0.007). Overall mortality at 30 days was 3.6%, 3.2% and 1.5% (NS) and, at 1 year, it was 9.9%, 9.6% and 7.3% respectively (NS). CONCLUSION: In acute chest pain in the Municipality of Göteborg, there was a marked difference between hospitals in: 1) the percentage of hospitalised patients, 2) the percentage of ACS among hospitalised patients and 3) the delay to and rate of coronary angiography. The clinical consequences of these deviations remain to be proven.

Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans.

AIMS/HYPOTHESIS: We sought to evaluate if the cellular localisation and molecular species of diacylglycerol (DAG) were related to insulin sensitivity in human skeletal muscle. METHODS: Healthy sedentary obese controls (Ob; n = 6; mean±SEM age 39.5 ± 2.3 years; mean ± SEM BMI 33.3 ± 1.4 kg/m(2)), individuals with type 2 diabetes (T2D; n = 6; age 44 ± 1.8 years; BMI 30.1 ± 2.3 kg/m(2)), and lean endurance-trained athletes (Ath; n = 10; age 35.4 ± 3.1 years; BMI 23.3 ± 0.8 kg/m(2)) were studied. Insulin sensitivity was determined using an IVGTT. Muscle biopsy specimens were taken after an overnight fast, fractionated using ultracentrifugation, and DAG species measured using liquid chromatography/MS/MS. RESULTS: Total muscle DAG concentration was higher in the Ob (mean ± SEM 13.3 ± 1.0 pmol/µg protein) and T2D (15.2 ± 1.0 pmol/µg protein) groups than the Ath group (10.0 ± 0.78 pmol/µg protein, p = 0.002). The majority (76-86%) DAG was localised in the membrane fraction for all groups, but was lowest in the Ath group (Ob, 86.2 ± 0.98%; T2D, 84.2 ± 1.2%; Ath, 75.9 ± 2.7%; p = 0.008). There were no differences in cytoplasmic DAG species (p > 0.12). Membrane DAG species C18:0/C20:4, Di-C16:0 and Di-C18:0 were significantly more abundant in the T2D group. Cytosolic DAG species were negatively related to activation of protein kinase C (PKC)ε but not PKCθ, whereas membrane DAG species were positively related to activation of PKCε, but not PKCθ. Only total membrane DAG (r = -0.624, p = 0.003) and Di-C18:0 (r = -0.595, p = 0.004) correlated with insulin sensitivity. Disaturated DAG species were significantly lower in the Ath group (p = 0.001), and significantly related to insulin sensitivity (r = -0.642, p = 0.002). CONCLUSIONS/INTERPRETATION: These data indicate that both cellular localisation and composition of DAG influence the relationship to insulin sensitivity. Our results suggest that only saturated DAG in skeletal muscle membranes are related to insulin resistance in humans.

Association of insulin sensitivity to lipids across the lifespan in people with Type 1 diabetes.

AIMS: Insulin resistance and dyslipidaemia both increase cardiovascular risk in Type 1 diabetes. However, little data exist on the associations of insulin resistance to lipids in Type 1 diabetes. Our objective was to explore the associations between insulin resistance (assessed by glucose infusion rate) and lipids in people with Type 1 diabetes and determine whether adiposity and/or average glycaemia influence these associations. METHODS: Hyperinsulinaemic-euglycaemic clamp studies were performed in 60 subjects with Type 1 diabetes aged 12-19 years (age 15±2 years, 57% female, duration of diabetes 6.3±3.8 years, HbA(1c) 8.6±1.5%, IFCC=70 mmol/mol) and 40 subjects with Type 1 diabetes aged 27-61 years (age 45±9 years, 53% female, duration of diabetes 23±8 years, HbA(1c) 7.5±0.9%, IFCC=58 mmol/mol). Multiple linear regression models were fit to examine the association between glucose infusion rate and fasting lipid levels with adjustment for possible confounders. RESULTS: Lower glucose infusion rate was significantly associated with lower levels of HDL cholesterol in youths with Type 1 diabetes and with higher levels of triglycerides and higher triglyceride/HDL ratio in both youths and adults. The magnitude of the associations between glucose infusion rate and lipid levels translate into interquartile differences of 0.098 mmol/l for HDL cholesterol, 0.17 mmol/l for triglycerides and 1.06 for triglycerides/HDL in the adolescents and 0.20 mmol/l for triglycerides and 1.01 for triglycerides/HDL in the adults. The associations were attenuated and no longer statistically significant by adjustment for adiposity among adults, while adjustment for HbA(1c) had a small effect in youths and adults. CONCLUSIONS: Lower insulin sensitivity is associated with a more atherogenic lipid profile in both youths and adults with Type 1 diabetes.

Glycaemic variability is associated with coronary artery calcium in men with Type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes study.

AIMS: We investigated coronary artery calcium in association with glucose levels and variability measured using continuous glucose monitoring in adults with Type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes study. METHODS: Coronary artery calcium was measured by electron beam tomography. The presence of any coronary artery calcium was analysed with respect to glucose levels [mean(T) (mean glucose), % of values < 3.9 mmol/l, > 10 mmol/l and either < 3.9 or > 10 mmol/l] and glycaemic variability [sd(T) (sd of all glucose values); sd(dm) (sd of the daily mean glucose levels) and sd(hh:mm) (glucose sd for a specified time of day, over all days)] using 3-5 days of continuous glucose monitoring from 75 subjects (45 women, 30 men), age 42 ± 9 years (mean ± sd) and diabetes duration of 29 ± 8 years using logistic regression. RESULTS: We observed significant associations between coronary artery calcium and mean(T) (OR = 4.4, 95% CI 1.1-18.6), % of values > 10 mmol/l (OR = 5.5, 95% CI 1.3-22.6), % of measures < 3.9 or > 10 mmol/l (OR = 5.7, 95% CI 1.3-24.9), sd(T) (OR = 4.7, 95% CI 1.1-19.7), sd(dm) (OR = 6.0, 95% CI 1.2-30.4) and sd(hh:mm) (OR = 4.0, 95% CI 1.1-15.4), among men, but none of these variables were associated with the presence of coronary artery calcium in women. CONCLUSIONS: We report the novel finding that subclinical atherosclerosis is associated with glucose levels and variability in men with Type 1 diabetes. The relationship of coronary artery calcium and glucose variability in Type 1 diabetes, and potential gender differences in this association, deserve further study.

Work family balance, stress, and salivary cortisol in men and women academic physicians.

BACKGROUND: The stress of medical practice has been recurrently studied, but work- and family-related determinants of health by gender remain under researched. PURPOSE: To test the hypothesis that cortisol excretion would be affected by the perceived severity of total workload imbalance. METHOD: By hierarchical regression analysis, the associations between work-family balance and diurnal salivary cortisol levels by sex in academic physicians (n = 40) were investigated. RESULTS: Men physicians reported more paid work hours per week than women physicians and women more time in childcare, but their total working hours were similar. Controlling for sex and age, the mean of the diurnal cortisol release was associated with a combined effect of sex and responsibility at home. When morning cortisol, sex, and children at home were held constant, cortisol levels in the evening were associated with responsibility at home without significant gender interaction. CONCLUSION: With increasing responsibility at home, women and men reacted differently with regard to cortisol responses over the day. However, in the evening, controlling for the morning cortisol, these gender differences were not as obvious. These findings highlight traditional gender patterns among both women and men physicians in the challenge of finding a balance between work and family.

Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.

This randomised multicentre trial was conducted to establish the optimal duration of palliative chemotherapy in advanced non-small-cell lung cancer (NSCLC). We compared a policy of three vs six courses of new-generation platinum-based combination chemotherapy with regard to effects on quality of life (QoL) and survival. Patients with stage IIIB or IV NSCLC and WHO performance status (PS) 0-2 were randomised to receive three (C3) or six (C6) courses of carboplatin (area under the curve (AUC) 4, Chatelut's formula, equivalent to Calvert's AUC 5) on day 1 and vinorelbine 25 mg m(-2) on days 1 and 8 of a 3-week cycle. Key end points were QoL at 18 weeks, measured with EORTC Quality of Life Questionnaire (QLQ)-C30 and QLQ-LC13, and overall survival. Secondary end points were progression-free survival and need of palliative radiotherapy. Two hundred and ninety-seven patients were randomised (C3 150, C6 147). Their median age was 65 years, 30% had PS 2 and 76% stage IV disease. Seventy-eight and 54% of C3 and C6 patients, respectively, completed all scheduled chemotherapy courses. Compliance with QoL questionnaires was 88%. There were no significant group differences in global QoL, pain or fatigue up to 26 weeks. The dyspnoea palliation rate was lower in the C3 arm at 18 and 26 weeks (P<0.05), but this finding was inconsistent across different methods of analysis. Median survival in the C3 group was 28 vs 32 weeks in the C6 group (P=0.75, HR 1.04, 95% CI 0.82-1.31). One- and 2-year survival rates were 25 and 9% vs 25 and 5% in the C3 and C6 arm, respectively. Median progression-free survival was 16 and 21 weeks in the C3 and C6 groups, respectively (P=0.21, HR 0.86, 95% CI 0.68-1.08). In conclusion, palliative chemotherapy with carboplatin and vinorelbine beyond three courses conveys no survival or consistent QoL benefits in advanced NSCLC.