Association of Lithium in Drinking Water With the Incidence of Dementia.

Importance: Results from animal and human studies suggest that lithium in therapeutic doses may improve learning and memory and modify the risk of developing dementia. Additional preliminary studies suggest that subtherapeutic levels, including microlevels of lithium, may influence human cognition. Objective: To investigate whether the incidence of dementia in the general population covaries with long-term exposure to microlevels of lithium in drinking water. Design, Setting, and Participants: This Danish nationwide, population-based, nested case-control study examined longitudinal, individual geographic data on municipality of residence and data from drinking water measurements combined with time-specific data from all patients aged 50 to 90 years with a hospital contact with a diagnosis of dementia from January 1, 1970, through December 31, 2013, and 10 age- and sex-matched control individuals from the Danish population. The mean lithium exposure in drinking water since 1986 was estimated for all study individuals. Data analysis was performed from January 1, 1995, through December 31, 2013. Main Outcomes and Measures: A diagnosis of dementia in a hospital inpatient or outpatient contact. Diagnoses of Alzheimer disease and vascular dementia were secondary outcome measures. In primary analyses, distribution of lithium exposure was compared between patients with dementia and controls. Results: A total of 73 731 patients with dementia and 733 653 controls (median age, 80.3 years; interquartile range, 74.9-84.6 years; 44 760 female [60.7%] and 28 971 male [39.3%]) were included in the study. Lithium exposure was statistically significantly different between patients with a diagnosis of dementia (median, 11.5 µg/L; interquartile range, 6.5-14.9 µg/L) and controls (median, 12.2 µg/L; interquartile range, 7.3-16.0 µg/L; P < .001). A nonlinear association was observed. Compared with individuals exposed to 2.0 to 5.0 µg/L, the incidence rate ratio (IRR) of dementia was decreased in those exposed to more than 15.0 µg/L (IRR, 0.83; 95% CI, 0.81-0.85; P < .001) and 10.1 to 15.0 µg/L (IRR, 0.98; 95% CI, 0.96-1.01; P = .17) and increased with 5.1 to 10.0 µg/L (IRR, 1.22; 95% CI, 1.19-1.25; P < .001). Similar patterns were found with Alzheimer disease and vascular dementia as outcomes. Conclusions and Relevance: Long-term increased lithium exposure in drinking water may be associated with a lower incidence of dementia in a nonlinear way; however, confounding from other factors associated with municipality of residence cannot be excluded.

Lithium in drinking water and the incidence of bipolar disorder: A nation-wide population-based study.

OBJECTIVE: Animal data suggest that subtherapeutic doses, including micro doses, of lithium may influence mood, and lithium levels in drinking water have been found to correlate with the rate of suicide. It has never been investigated whether consumption of lithium may prevent the development of bipolar disorder (primary prophylaxis). In a nation-wide population-based study, we investigated whether long-term exposure to micro levels of lithium in drinking water correlates with the incidence of bipolar disorder in the general population, hypothesizing an inverse association in which higher long-term lithium exposure is associated with lower incidences of bipolar disorder. METHODS: We included longitudinal individual geographical data on municipality of residence, data from drinking water lithium measurements and time-specific data from all cases with a hospital contact with a diagnosis of mania/bipolar disorder from 1995 to 2013 (N=14 820) and 10 age- and gender-matched controls from the Danish population (N= 140 311). Average drinking water lithium exposure was estimated for all study individuals. RESULTS: The median of the average lithium exposure did not differ between cases with a diagnosis of mania/bipolar disorder (12.7 µg/L; interquartile range [IQR]: 7.9-15.5 µg/L) and controls (12.5 µg/L; IQR: 7.6-15.7 µg/L; P=.2). Further, the incidence rate ratio of mania/bipolar disorder did not decrease with higher long-term lithium exposure, overall, or within age categories (0-40, 41-60 and 61-100 years of age). CONCLUSION: Higher long-term lithium exposure from drinking water was not associated with a lower incidence of bipolar disorder. The association should be investigated in areas with higher lithium levels than in Denmark.

Lithium in Drinking Water and Incidence of Suicide: A Nationwide Individual-Level Cohort Study with 22 Years of Follow-Up.

Suicide is a major public health concern. High-dose lithium is used to stabilize mood and prevent suicide in patients with affective disorders. Lithium occurs naturally in drinking water worldwide in much lower doses, but with large geographical variation. Several studies conducted at an aggregate level have suggested an association between lithium in drinking water and a reduced risk of suicide; however, a causal relation is uncertain. Individual-level register-based data on the entire Danish adult population (3.7 million individuals) from 1991 to 2012 were linked with a moving five-year time-weighted average (TWA) lithium exposure level from drinking water hypothesizing an inverse relationship. The mean lithium level was 11.6 µg/L ranging from 0.6 to 30.7 µg/L. The suicide rate decreased from 29.7 per 100,000 person-years at risk in 1991 to 18.4 per 100,000 person-years in 2012. We found no significant indication of an association between increasing five-year TWA lithium exposure level and decreasing suicide rate. The comprehensiveness of using individual-level data and spatial analyses with 22 years of follow-up makes a pronounced contribution to previous findings. Our findings demonstrate that there does not seem to be a protective effect of exposure to lithium on the incidence of suicide with levels below 31 µg/L in drinking water.

The dose-response relationship between the amount of straw provided on the floor and gastric ulceration of pars oesophagea in growing pigs.

The aim of the present study was (1) to determine the dose-response relationship between the amount of straw provided on the floor and oesophageal ulceration in pigs kept under typical Danish production conditions (18 pigs/pen, 0.7m2/pig, partly slatted floor, ad libitum access to feed), (2) to reveal whether straw ingestion explains the effect of straw provision on the stomach health and (3) to elucidate the effect of straw ingestion on the stomach conditions. Data were collected at slaughter (approximately 100kg body weight) on pigs provided with straw amounts in the range 10g to 500g wheat straw/pig/day from 30kg body weight and fed a wheat-based pelleted feed added 15% non-heated and non-pelleted rolled barley. Aims (1) and (2) included 712 pigs kept in 42 pens, whereas (3) was studied on a subset of 37 pigs with either none or obvious amounts of straw in the stomach. The amount of straw provided affected stomach health in a curvilinear manner. Provision of up to approximately 300gstraw/pig/day progressively decreased the risk of oesophageal ulceration and scarring. At larger amounts of straw the ulceroprotective effect of straw was reduced which requires further investigation. Straw ingestion appeared to be an essential intermediary factor for the improvement of stomach health. The number of pigs without straw in the stomach decreased linearly with the logarithm of the amount of straw provided, which explained the effect of straw provision on stomach health. The structure of the stomach contents increased as revealed by the increased weight and dry matter content and decreased sedimentation of the digesta. Provision of approximately 300gstraw/pig/day on the floor may be a potential strategy to reduce, but not inevitably eliminate, oesophageal ulceration in pigs in commercial pig production.

[Median arcuate ligament syndrome]. / Truncus coeliacus-kompressionssyndrom.

The median arcuate ligament syndrome is a rare entity and poorly described in Danish literature. The syndrome is a diagnosis of exclusion and is characterized by chronic abdominal pain, postprandial pain and weight loss. It is believed that the median arcuate ligament, being a fibrous structure of diaphragm, compresses the coeliac trunk thus causing stenosis and malperfusion of the gastrointestinal organs. Until recently, there has been some reluctance to consider intervention with revascularization or ligament release. Within the latest decade minimally invasive techniques, including laparoscopic release of the median arcuate ligament, have shown promising results.

Nitrate reduction in geologically heterogeneous catchments--a framework for assessing the scale of predictive capability of hydrological models.

In order to fulfil the requirements of the EU Water Framework Directive nitrate load from agricultural areas to surface water in Denmark needs to be reduced by about 40%. The regulations imposed until now have been uniform, i.e. the same restrictions for all areas independent of the subsurface conditions. Studies have shown that on a national basis about 2/3 of the nitrate leaching from the root zone is reduced naturally, through denitrification, in the subsurface before reaching the streams. Therefore, it is more cost-effective to identify robust areas, where nitrate leaching through the root zone is reduced in the saturated zone before reaching the streams, and vulnerable areas, where no subsurface reduction takes place, and then only impose regulations/restrictions on the vulnerable areas. Distributed hydrological models can make predictions at grid scale, i.e. at much smaller scale than the entire catchment. However, as distributed models often do not include local scale hydrogeological heterogeneities, they are typically not able to make accurate predictions at scales smaller than they are calibrated. We present a framework for assessing nitrate reduction in the subsurface and for assessing at which spatial scales modelling tools have predictive capabilities. A new instrument has been developed for airborne geophysical measurements, Mini-SkyTEM, dedicated to identifying geological structures and heterogeneities with horizontal and lateral resolutions of 30-50 m and 2m, respectively, in the upper 30 m. The geological heterogeneity and uncertainty are further analysed by use of the geostatistical software TProGS by generating stochastic geological realisations that are soft conditioned against the geophysical data. Finally, the flow paths within the catchment are simulated by use of the MIKE SHE hydrological modelling system for each of the geological models generated by TProGS and the prediction uncertainty is characterised by the variance between the predictions of the different models.

Leaching of azoxystrobin and its degradation product R234886 from Danish agricultural field sites.

The objective was to estimate leaching of the fungicide azoxystrobin (methyl (αE)-2-[[6-(2-cyanophenoxy)-4-pyrimidinyl]oxy]-α-(methoxymethylene)benzene-acetate) and one of its primary degradation products R234886 ([(E)-2-(2-[6-cyanophenoxy)-pyrimidin-4-yloxyl]-phenyl-3-methoxyacrylic acid], major fraction) at four agricultural research fields (one sandy and three loamy) in Denmark. Water was sampled from tile drains, suction cups and groundwater wells for a minimum period of two years after application of azoxystrobin. Neither azoxystrobin nor R234886 were detected at the sandy site, but did leach through loamy soils. While azoxystrobin was generally only detected during the first couple of months following application, R234886 leached for a longer period of time and at higher concentrations (up to 2.1µgL(-1)). Azoxystrobin is classified as very toxic to aquatic organisms and R234886 as very harmful. Our study shows that azoxystrobin and R234886 can leach through loamy soils for a long period of time following application of the pesticide and thereby pose a potential threat to vulnerable aquatic environments and drinking water resources. We thus recommend the inclusion of azoxystrobin and R234886 in pesticide monitoring programmes and further investigation of their long-term ecotoxicological effects.

Glycaemic control in diabetic patients during hospital admission is not optimal.

INTRODUCTION: The aim of this pilot study was to evaluate glycaemic control in diabetic patients admitted to hospital. MATERIAL AND METHODS: Patients were prospectively identified at 11 consecutive Wednesdays in one medical and one surgery department and information from the previous three days of admission was collected, including: bedside p-glucose readings, scheduled and supplemental insulin treatment. RESULTS: In total, 111 observation days were included from 37 diabetic patients (27 medical and ten surgical). P-glucose was measured on average four and 2.5 times daily at the medical and the surgery department, respectively. The median p-glucose level was 8.6 mmol/l (range 4.0-22), with no obvious difference between the two departments and no trend towards improvement observed. Approximately one third of the patients had median p-glucose values > 10 mmol/l. 7% of the patients at the medical and none at the surgery department had a p-glucose < 3 mmol/l. Supplemental insulin was prescribed to the majority of patients at the medical department and to 30% at the surgery department with a median p-glucose threshold of 12 and 14 mmol/l at the two departments, respectively. Supplemental insulin was not given despite being indicated in 37% of the elevated glucose episodes. Increments in scheduled insulin dose were rarely observed despite being indicated. CONCLUSION: Despite acceptable median p-glucose levels, hyperglycaemia was frequent. The number of glucose readings was low and clinical inertia was observed, both with regard to intensification the scheduled insulin and with regard to administration of supplemental insulin. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

History of suicide attempts among patients with depression in the GENDEP project.

BACKGROUND: It has been proposed that a history of suicide attempts could be a correlate of severe depressive disorder and that suicide attempters (SA) could represent a particular subtype of subjects suffering from major depressive disorder. We investigated clinical and demographic characteristics associated with SA and tested the hypothesis that a history of suicide attempts predicts poor response to antidepressants. METHODS: One-hundred-and-forty-one SA and 670 non-SA subjects with major depressive disorder (MDD) were treated for twelve weeks with escitalopram or nortriptyline in GENDEP, a part-randomized multi-center clinical and pharmacogenetic study. Baseline characteristics were compared using linear and logistic regression. Linear mixed models were used to analyse continuous outcomes during the twelve weeks of follow-up. RESULTS: At baseline, SA subjects suffered from more severe depression (mean Montgomery-Asberg Depression Rating Scale: 30.29 (7.61) vs 28.43 (6.54), p=0.0002), reported higher level of suicidal ideation (1.21 (0.82) vs 0.73 (0.48), p<0.0001), had a younger age of onset and experienced more depressive episodes, had higher harm avoidance scores and poorer socio-demographic environment than non-SA individuals. However, during the twelve weeks of treatment and after adjustment for baseline severity of depression there was no difference in treatment response between SA and non-SA. LIMITATIONS: Due to its retrospective design, it is possible that more severely depressed subjects might report more suicide attempts than less depressed individuals. CONCLUSIONS: While SA differed from non-SA in several clinical and demographic characteristics, the antidepressants were similarly effective in SA as in comparably severely depressed subjects without a history of suicide attempts.

Suicidal ideation during treatment of depression with escitalopram and nortriptyline in genome-based therapeutic drugs for depression (GENDEP): a clinical trial.

BACKGROUND: Suicidal thoughts and behaviours during antidepressant treatment, especially during the first weeks of treatment, have prompted warnings by regulatory bodies. The aim of the present study is to investigate the course and predictors of emergence and worsening of suicidal ideation during tricyclic antidepressant and serotonin reuptake inhibitor treatment. METHODS: In a multicentre part-randomised open-label study, 811 adult patients with moderate to severe unipolar depression were allocated to flexible dosage of escitalopram or nortriptyline for 12 weeks. The suicidality items of three standard measures were integrated in a suicidal ideation score. Increases in this score were classified as treatment emergent suicidal ideation (TESI) or treatment worsening suicidal ideation (TWOSI) according to the absence or presence of suicidal ideation at baseline. RESULTS: Suicidal ideation decreased during antidepressant treatment. Rates of TESI and TWOSI peaked in the fifth week. Severity of depression predicted TESI and TWOSI. In men, nortriptyline was associated with a 9.8-fold and 2.4-fold increase in TESI and TWOSI compared to escitalopram, respectively. Retirement and history of suicide attempts predicted TWOSI. CONCLUSION: Increases in suicidal ideation were associated with depression severity and decreased during antidepressant treatment. In men, treatment with escitalopram is associated with lower risk of suicidal ideation compared to nortriptyline. Clinicians should remain alert to suicidal ideation beyond the initial weeks of antidepressant treatment. TRIAL REGISTRATION: EudraCT (No.2004-001723-38) and ISRCTN (No. 03693000).

Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project.

The aim of this study was to investigate genetic predictors of an increase in suicidal ideation during treatment with a selective serotonin reuptake inhibitor or a tricyclic antidepressant. A total of 796 adult patients with major depressive disorder who were treated with a flexible dosage of escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP) were included in the sample and provided data on suicidal ideation. Nine candidate genes involved in neurotrophic, serotonergic, and noradrenergic pathways were selected based on previous association studies with suicidal ideation or behavior. Using a logistic regression model, 123 polymorphisms in these genes were compared between subjects with an increase in suicidal ideation and those without any increase in suicidal ideation. Polymorphisms in BDNF, the gene encoding the brain-derived neurotrophic factor, were significantly associated with an increase in suicidal ideation. The strongest association was observed for rs962369 in BDNF (p=0.0015). Moreover, a significant interaction was found between variants in BDNF and NTRK2, the gene encoding the BNDF receptor (p=0.0003). Among men taking nortriptyline, suicidality was also associated with rs11195419 SNP in the alpha(2A)-adrenergic receptor gene (ADRA2A) (p=0.007). The associations observed with polymorphisms in BDNF suggest the involvement of the neurotrophic system in vulnerability to suicidality. Epistasis between BDNF and NTRK2 suggests that genetic variations in the two genes are involved in the same causal mechanisms leading to suicidality during antidepressant treatment. Among men, genetic variation in noradrenergic signaling may interact with norepinephrine reuptake-inhibiting antidepressants, thereby contributing to suicidality.

Differential efficacy of escitalopram and nortriptyline on dimensional measures of depression.

BACKGROUND: Tricyclic antidepressants and serotonin reuptake inhibitors are considered to be equally effective, but differences may have been obscured by internally inconsistent measurement scales and inefficient statistical analyses. AIMS: To test the hypothesis that escitalopram and nortriptyline differ in their effects on observed mood, cognitive and neurovegetative symptoms of depression. METHOD: In a multicentre part-randomised open-label design (the Genome Based Therapeutic Drugs for Depression (GENDEP) study) 811 adults with moderate to severe unipolar depression were allocated to flexible dosage escitalopram or nortriptyline for 12 weeks. The weekly Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression, and Beck Depression Inventory were scored both conventionally and in a more novel way according to dimensions of observed mood, cognitive symptoms and neurovegetative symptoms. RESULTS: Mixed-effect linear regression showed no difference between escitalopram and nortriptyline on the three original scales, but symptom dimensions revealed drug-specific advantages. Observed mood and cognitive symptoms improved more with escitalopram than with nortriptyline. Neurovegetative symptoms improved more with nortriptyline than with escitalopram. CONCLUSIONS: The three symptom dimensions provided sensitive descriptors of differential antidepressant response and enabled identification of drug-specific effects.

The inadequacy of monitoring without modelling support.

There is much to gain in joining monitoring and modelling efforts, especially in the present process of implementing the European Water Framework Directive and in the coming implementation of the Groundwater Directive. Nevertheless, present practises in the water management world suggest that most often models are not considered an option when monitoring obligations in the WFD are solved. The present paper analyses the constraints, such as perceived insufficiency of data for modelling, lack of explicit requirement for modelling in the WFD and its associated technical guidance documents, lack of awareness about what models can do and lack of confidence in models by water managers and policy makers. The findings have mainly emerged from a series of Harmoni-CA workshops aiming at bringing the monitoring and modelling communities together for a discussion of benefits and constraints in the joint use of monitoring and modelling. The workshops were attended by scientists, water managers, policy makers, stakeholders and consultants. The overall conclusion is that modelling can significantly improve the benefits of monitoring data; by quality assurance of data, interpolation and extrapolation in space and time, development of process understanding (conceptual models), and the assessment of impacts of pressures and effects of programmes of measures.

Proactive administration of platelets and plasma for patients with a ruptured abdominal aortic aneurysm: evaluating a change in transfusion practice.

BACKGROUND: Continued hemorrhage remains a major contributor of mortality in massively transfused patients and those who survive have a higher platelet (PLT) count and a shorter prothrombin time and activated partial thromboplastin time (APTT) than nonsurvivors. It was considered that early substitution with PLTs and fresh-frozen plasma (FFP) would prevent development of coagulopathy and thus improve survival. STUDY DESIGN AND METHODS: Survival of patients undergoing surgery for a ruptured abdominal aortic aneurysm (rAAA) was compared after implementing a proactive transfusion therapy encompassing two pooled buffy-coat PLT concentrates (PBPCs) immediately when a rupture of the aorta was suspected and again 30 minutes before aortic unclamping together with FFP administered in a 1:1 ratio to the amount of red blood cells (RBCs) with that of a control group receiving transfusion therapy according to existing recommendations. RESULTS: The intervention group (n = 50) had a higher PLT count at arrival at the intensive care unit compared to the control group (n = 82; 155 x 10(9)/L vs. 69 x 10(9)/L; p < 0.0001), shorter APTT (39 sec vs. 44 sec; p < 0.001), fewer postoperative transfusions (RBCs, 2 vs. 6; FFP, 2 vs. 4; and PBPCs, 0 vs. 1; p < 0.01), and a higher 30-day survival rate (66% vs. 44%; p = 0.02). CONCLUSION: This study suggests that proactive administration of PLTs and FFP improves coagulation competence, reduces postoperative hemorrhage, and increases survival in massively bleeding rAAA patients.

Early investigation and treatment of obstructive sleep apnoea after acute stroke.

Obstructive sleep apnoea (OSA) is an independent risk factor for hypertension, which is a major cause of stroke. The prevalence and associations of OSA in a cohort of stroke patients were studied. The safety and tolerability of early treatment with nasal continuous airways pressure (nCPAP) was also assessed. Consecutive subjects admitted with acute stroke were assessed clinically, radiologically and with scales assessing prior OSA risk, dysphagia and disability. Sleep studies were performed within the first few days of admission using a portable diagnostic system. Twenty-nine of 55 (53%) subjects had evidence of OSA, using an apnoea-hypopnoea index (AHI) of 10 or greater. The AHI was significantly associated with an index of prior OSA symptoms, but not with history of hypertension, degree of dysphagia, or type and severity of stroke. Use of a portable diagnostic system for detecting OSA in the acute stroke setting was well tolerated. OSA is common after acute stroke and exceeds rates seen in control populations of similar age (53% vs. 11%). Early treatment with nCPAP was effective and well tolerated.

Quality assurance and certification of health IT-systems communicating data in primary and secondary health sector.

Each year more than 70% (25 mill) of all electronic health documents between secondary and primary health sector in Denmark are exchanged electronically using European EDI standards. Despite this widely use there have been several problems in showing the transferred data in correct and full context. These problems are solved in the 3 years MedCom certification and consolidation project. The project financed by Ministry of Health, Danish County Association and others through MedCom, involved all relevant health professional groups, organisations, all SW suppliers and all local governments. A new detailed and exact documentation with recommendations and obligatory needs published in "The Good EDI letters" was made, followed by training courses for programmers, test and certification of IT systems by MedCom and finally implementation of certified systems by all users in the country. The certification and implementation process are followed on www.medcom.dk The results are now a high quality of information and the state of art: One and only way of exchanging documents which are accepted by health professionals and implemented by all SW companies at all users. To day only MedCom certified IT systems are used[2] and the certification is a must for SW companies to be in the market.