The impact of heat waves and cold spells on mortality rates in the Dutch population.

We conducted the study described in this paper to investigate the impact of ambient temperature on mortality in the Netherlands during 1979-1997, the impact of heat waves and cold spells on mortality in particular, and the possibility of any heat wave- or cold spell-induced forward displacement of mortality. We found a V-like relationship between mortality and temperature, with an optimum temperature value (e.g., average temperature with lowest mortality rate) of 16.5 degrees C for total mortality, cardiovascular mortality, respiratory mortality, and mortality among those [Greater and equal to] 65 year of age. For mortality due to malignant neoplasms and mortality in the youngest age group, the optimum temperatures were 15.5 degrees C and 14.5 degrees C, respectively. For temperatures above the optimum, mortality increased by 0.47, 1.86, 12.82, and 2.72% for malignant neoplasms, cardiovascular disease, respiratory diseases, and total mortality, respectively, for each degree Celsius increase above the optimum in the preceding month. For temperatures below the optimum, mortality increased 0.22, 1.69, 5.15, and 1.37%, respectively, for each degree Celsius decrease below the optimum in the preceding month. Mortality increased significantly during all of the heat waves studied, and the elderly were most effected by extreme heat. The heat waves led to increases in mortality due to all of the selected causes, especially respiratory mortality. Average total excess mortality during the heat waves studied was 12.1%, or 39.8 deaths/day. The average excess mortality during the cold spells was 12.8% or 46.6 deaths/day, which was mostly attributable to the increase in cardiovascular mortality and mortality among the elderly. The results concerning the forward displacement of deaths due to heat waves were not conclusive. We found no cold-induced forward displacement of deaths

THE FRENCH MILITARY’S TRAGIC MISSION TO PROTECT MANKIND: HOW THE GUERRE RÉVOLUTIONNAIRE DOCTRINE FUELLED THE POLITICISATION OF FRENCH OFFICERS IN THE ALGERIAN WAR OF INDEPENDENCE

Democratic governance rests on a precarious relationship between the civilian and military branches of government. This relationship is threatened whenever civil-military relations become polarised. This theme is explored through a case study of the French Army during the Algerian War, in which tensions with the de Gaulle government grew as the Army politicised. This culminated in an attempted coup d’état in 1961 and the rise of the terrorist OAS group. The thesis conducts its analysis through the prism of the guerre révolutionnaire doctrine, which it considers an essential, yet too often overlooked, catalysing factor in the Army’s politicisation

Interventions in childhood epilepsy: pharmacotherapy and ketogenic diet

Epilepsy is the most frequent chronic neurological disorder in children and the majority of children with epilepsy is treated with antiepileptic drugs. Despite the development and availability of more than thirty antiepileptic drugs by now, evidence for their efficacy and tolerability in children with epilepsy is generally limited. However, our studies have shown that the use of newer antiepileptic drugs in the children is still increasing, despite limited evidence and lacking formal registration. More research is therefore needed, but due to logistic, regulatory, legal and ethical issues this remains challenging, as we have experienced ourselves with a randomized controlled trial that had to be stopped prematurely. Changes in the legislation for registration of new antiepileptic drugs for children and international collaborating networks will hopefully lead to more evidence based pharmacotherapy. Furthermore, precision medicine, a personal treatment based on individual characteristics, may become the keystone in the treatment of children with epilepsy. Better insight in the mechanisms of other treatment modalities as cannabidiol, ketogenic diet and neurostimulation, together with advancements in epilepsy surgery, will hopefully lead to broader applicability of all these modalities for children with epilepsy. Introducing ketogenic diet as an all-liquid formulation in an outpatient setting is one of the alternatives we investigated to make ketogenic diet more accessible for some patients/parents. Ketogenic diet can also be considered in children with very rare diseases with comorbid epilepsy, like North See Progressive Myoclonus Epilepsy

A systematic SNP selection approach to identify mechanisms underlying disease aetiology: Linking height to post-menopausal breast and colorectal cancer risk

Data from GWAS suggest that SNPs associated with complex diseases or traits tend to co-segregate in regions of low recombination, harbouring functionally linked gene clusters. This phenomenon allows for selecting a limited number of SNPs from GWAS repositories for large-scale studies investigating shared mechanisms between diseases. For example, we were interested in shared mechanisms between adult-attained height and post-menopausal breast cancer (BC) and colorectal cancer (CRC) risk, because height is a risk factor for these cancers, though likely not a causal factor. Using SNPs from public GWAS repositories at p-values < 1 × 10-5 and a genomic sliding window of 1 mega base pair, we identified SNP clusters including at least one SNP associated with height and one SNP associated with either post-menopausal BC or CRC risk (or both). SNPs were annotated to genes using HapMap and GRAIL and analysed for significantly overrepresented pathways using ConsensuspathDB. Twelve clusters including 56 SNPs annotated to 26 genes were prioritised because these included at least one height- and one BC risk- or CRC risk-associated SNP annotated to the same gene. Annotated genes were involved in Indian hedgehog signalling (p-value = 7.78 × 10-7) and several cancer site-specific pathways. This systematic approach identified a limited number of clustered SNPs, which pinpoint potential shared mechanisms linking together the complex phenotypes height, post-menopausal BC and CRC

Serum albumin and muscle strength: a longitudinal study in older men and women

OBJECTIVES: To examine whether low serum albumin is associated with low muscle strength and future decline in muscle strength in community-dwelling older men and women. DESIGN: Population-based cohort study. SETTING: The Longitudinal Aging Study Amsterdam. PARTICIPANTS: Six hundred seventy-six women and 644 men aged 65 to 88. MEASUREMENTS: Serum albumin was determined at baseline. Muscle strength was assessed using grip strength at baseline, after 3 (n = 1,009), and 6 (n = 741) years. The outcomes were continuous baseline muscle strength, 3- and 6-year change in muscle strength, and a dichotomous indicator for substantial decline (a decrease if ≥1 standard deviations for women = 11 kg, for men = 12 kg) in muscle strength. RESULTS: Mean serum albumin concentration ± standard deviation was 45.0 ± 3.3 g/L for women and 45.2 ± 3.2 g/L for men. At baseline, adjusting for age, lifestyle factors, and chronic conditions, lower serum albumin was cross-sectionally associated with weaker muscle strength (P < .001) in women and men. After 3 years of follow-up, mean decline in muscle strength was -5.6 ± 10.9 kg in women and -9.6 ± 11.9 kg in men. After adjustment for potential confounders, lower serum albumin was associated with muscle strength decline over 3 years (P < .01) in women and men (β = 0.57, standard error (SE) = 0.18; β = 0.37, SE = 0.16, respectively). Lower serum albumin was also associated with substantial decline in muscle strength in women (per unit albumin (g/L) adjusted odds ratio (OR) = 1.14, one-sided 95% confidence limit (CL) = 1.07) and men (per unit albumin (g/L) adjusted OR = 1.14, 95% CL = 1.08). Similar but slightly weaker associations were found between serum albumin and 6-year change in muscle strength (P < .05). CONCLUSION: These results suggest that low serum albumin, even within the normal range, is independently associated with weaker muscle strength and future decline in muscle strength in older women and men. © 2005 by the American Geriatrics Society

Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer

Diversity in colorectal cancer biology is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of metastatic CRC patients. Candidate genes were selected from 389 genes involved in DNA Damage Repair by correlation analyses between gene methylation status and drug response in 32 cell lines. A large series of samples (n=818) from two phase III clinical trials was used to evaluate these candidate genes by correlating methylation status to progression-free survival after treatment with first-line single-agent fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy (Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the discovery (n=185) and initial validation set (n=166), patients with methylated Decoy Receptor 1 (DCR1) did not benefit from CAPIRI over Capecitabine treatment (discovery set: HR=1.2 (95%CI 0.7-1.9, p=0.6), validation set: HR=0.9 (95%CI 0.6-1.4, p=0.5)), whereas patients with unmethylated DCR1 did (discovery set: HR=0.4 (95%CI 0.3-0.6, p=0.00001), validation set: HR=0.5 (95%CI 0.3-0.7, p=0.0008)). These results could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated DCR1 for FOLFIRI over 5FU treatment (methylated DCR1: HR=0.7 (95%CI 0.5-0.9, p=0.01), unmethylated DCR1: HR=0.8 (95%CI 0.6-1.2, p=0.4)). In conclusion, DCR1 promoter hypermethylation status is a potential predictive biomarker for response to treatment with irinotecan, when combined with capecitabine. This finding could not be replicated in an external validation set, in which irinotecan was combined with 5FU. These results underline the challenge and importance of extensive clinical evaluation of candidate biomarkers in multiple trials

Longitudinal associations of former and current alcohol consumption with psychosocial outcomes among colorectal cancer survivors 1–15 years after diagnosis

We aimed to explore positive and negative associations of consuming alcohol with psychosocial outcomes among colorectal cancer (CRC) survivors. We used data of an observational prospective cohort study, consisting of 2625 Dutch CRC survivors enrolled 1-11 years post-diagnosis that were followed-up in 4 yearly surveys. Generalized estimated equation models were used to examine longitudinal associations between alcohol consumption and anxiety, depression, and health-related quality of life (HRQoL), while correcting for sociodemographic, lifestyle and clinical characteristics. Compared to lifetime abstainers, former alcohol consumption was associated with more depressive symptoms, and worse global quality of life and social functioning, while current drinking was associated with less anxiety, depression and better HRQoL. More drinks per week was associated with less nausea/vomiting. Compared to abstainers, moderate (≤7 drinks/week) and heavy alcohol consumption (>7 drinks/week) were associated with less anxiety and depression and better HRQoL, mostly attributable to wine consumption. Whereas current alcohol consumption was longitudinally associated with less anxiety and depression and better HRQoL, former drinking was associated with worse psychosocial outcomes, although based on a small sample size. It is important to consider that besides the potential negative effects of alcohol on patients’ health, alcohol consumption may be positively related with psychosocial outcomes

Levetiracetam Monotherapy in Children with Epilepsy:A Systematic Review

Background Levetiracetam, a second-generation anti-epileptic drug (AED) with a good efficacy and safety profile, is licensed as monotherapy for adults and children older than 16 years with focal seizures with or without secondary generalization. However, it is increasingly being used off-label in younger children. Objectives We critically reviewed the available evidence and discuss the present status of levetiracetam monotherapy in children 0-16 years old. Data Sources We systematically searched the literature using PubMed, Web of Science and Embase up to August 2014 for articles on levetiracetam monotherapy in children. Keywords were levetiracetam, monotherapy and child*. The titles and abstracts of 532 articles were evaluated by AW, of which 480 were excluded. The full texts of the other 52 articles were assessed for relevance. Results We covered one review, one opinion statement and 32 studies in this review, including four randomized controlled trials, ten open-label prospective studies, eight retrospective studies, and ten case reports. The formal evidence for levetiracetam monotherapy in children is minimal: it is potentially efficacious or effective as initial monotherapy in children with benign epilepsy with centrotemporal spikes. In all of the published studies, however, efficacy and tolerability of levetiracetam seemed to be good and comparable to other AEDs. Conclusion The data of 32 studies on levetiracetam monotherapy in children were insufficient to confirm that levetiracetam is effective as initial monotherapy for different types of seizures and/or epilepsy syndromes. There is still an urgent need for well designed trials to justify the widespread use of levetiracetam monotherapy in children of all ages