Search

Background: Hyponatremia is a common condition with unspecific symptoms and a complicated etiology. The impact of outdoor temperature on hyponatremia is not well-studied and varies depending on the climate and location. This study aimed to investigate the association between outdoor temperature and the prevalence of severe hyponatremia., Methods: This retrospective register-based cohort study based on the Stockholm Sodium Cohort investigated the association between ambient temperatures and severe hyponatremia (<125 mmol/L) in adults. Prevalence rates of severe hyponatremia were calculated as the number of days of severe hyponatremia divided by person-days at risk for the same temperature, using mean daily temperatures at the area of residence of each study participant to calculate exposure time. A prediction model incorporating changes in demographics and climate was used to estimate the burden of severe hyponatremia in Stockholm by 2050., Results: We identified 51,143 episodes of severe hyponatremia in 21,924 adults. A near linear modest increase in prevalence with rising temperatures was observed up to 20°C, followed by rapidly increasing rates at higher temperatures. The prevalence was higher with older age, reaching >100 days of hyponatremia per million person-days among +80-years-olds at temperatures over 22°C. Women experienced twice the rate observed in men. Temperature rises of 1°C or 2°C by the year 2050 are expected to be associated with higher prevalence rates by 66% and 73%, respectively., Conclusions: There was a strong association between high temperatures and severe hyponatremia. The higher prevalence of severe hyponatremia was most pronounced among elderly., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Objective: Hyponatremia is associated with considerable morbidity and mortality, but causal links have been difficult to establish. Here, we describe the establishment and representativeness of the Stockholm Sodium Cohort (SSC), designed to study etiologies and outcomes of hyponatremia., Study Design and Setting: All residents of Stockholm County undertaking at least one serum sodium test between 2005-2018 were included in the SSC. Individual-level test results from over 100 laboratory parameters relevant to hyponatremia were collected and linked to data on demographics, socioeconomic status, healthcare contacts, diagnoses and dispensed prescription medications using national registers., Results: A total of 1,632,249 individuals, corresponding to 64% of the population of Stockholm County, were included in the SSC. Coverage increased with advancing age, ranging from 32% in children and adolescents (≤18 years) to 97% among the oldest (≥80 years). The coverage of SSC included the vast majority of patients in Stockholm County diagnosed with diabetes mellitus (93%), myocardial infarction (98%), ischemic stroke (97%), cancer (85%), pneumonias requiring inpatient care (95%) and deaths (88%)., Conclusion: SSC is the first cohort specifically designed to investigate sodium levels in a large, population-based setting. It includes a wide range of administrative health data and laboratory analyses. The coverage is high, particularly among elderly and individuals with comorbidities. Consequently, the cohort has a large potential for exploration of various aspects of hyponatremia., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Rodents may serve as reservoirs of zoonotic species of Cryptosporidium ; however, data from molecular surveys in support of this hypothesis are still scarce. In this study, we screened faeces and rectal content from murid and cricetid rodents ( N  = 58) caught around three farms in Zealand, Denmark, for Cryptosporidium spp. by amplicon-based next-generation sequencing (NGS) of ribosomal genes. Selected samples were further examined using nested conventional PCR targeting SSU rRNA, gp60, and actin genes. Cryptosporidium- specific DNA was identified in 40/58 (69%) samples, and in 12 (30%) of the 40 positive animals, mixed cryptosporidial infections were observed. Cryptosporidium ditrichi was the species most commonly identified, found in 28 (48%) of the animals. Cryptosporidium parvum was identified in 4 (7%) of the animals, all of which were co-infected with C. ditrichi . The present study is the first to utilize NGS-based screening for Cryptosporidium species in wild rodents. Moreover, it is the first study to provide molecular data on Cryptosporidium in rodents sampled in Denmark and to detect DNA of C. ditrichi in Mus musculus, Myodes glareolus, and Microtus agrestis. The NGS approach was successfully applied to yield new knowledge, and the results showed that zoonotic species of Cryptosporidium are common in murid and cricetid rodents in Zealand, Denmark., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christen Rune Stensvold reports financial support was provided by Statens Serum Institut, Department of Bacteria, Parasites and Fungi, Infectious Disease Preparedness, Laboratory of Parasitology. Pikka Jokelainen and Christen Rune Stensvold were supported by funding for projects TOXOSOURCES, PARADISE and OH-HARMONY-CAP from the 10.13039/501100000780European Union's Horizon 2020 Research and Innovation programme under grant agreement No 773830: One Health European Joint Programme. The funding sources had no involvement in the study design, writing of the report or submission of the paper., (© 2023 The Authors.)

Objective: Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood., Design: Cross-sectional study., Methods: We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH., Results: Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = -0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (-0.15 normalized protein expression [NPX], P = .0001, and -0.25 NPX, P = .0003, respectively)., Conclusions: We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

The Gram-negative bacterium A. salmonicida is the causal agent of furunculosis and used to be one of the most loss-causing bacterial infections in the salmonid aquaculture industry with a mortality rate of about 90% until the 1990s, when an inactivated vaccine with mineral oil as adjuvant was successfully implemented to control the disease. However, the use of this vaccine is associated with inflammatory side effects in the peritoneal cavity as well as autoimmune reactions in Atlantic salmon, and incomplete protection has been reported in rainbow trout. We here aimed at developing and testing a recombinant alternative vaccine based on virus-like particles (VLPs) decorated with VapA, the key structural surface protein in the outer A-layer of A. salmonicida . The VLP carrier was based on either the capsid protein of a fish nodavirus, namely red grouper nervous necrotic virus (RGNNV) or the capsid protein of Acinetobacter phage AP205. The VapA and capsid proteins were expressed individually in E. coli and VapA was fused to auto-assembled VLPs using the SpyTag/SpyCatcher technology. Rainbow trout were vaccinated/immunized with the VapA-VLP vaccines by intraperitoneal injection and were challenged with A. salmonicida 7 weeks later. The VLP vaccines provided protection comparable to that of a bacterin-based vaccine and antibody response analysis demonstrated that vaccinated fish mounted a strong VapA-specific antibody response. To our knowledge, this is the first demonstration of the potential use of antigen-decorated VLPs for vaccination against a bacterial disease in salmonids., Competing Interests: Employees of AdaptVac LG and AFS, a company working with virus-like particle display technology and vaccine development, including several patents. AFS is listed as co-inventor on a patent application covering the AP205 VLP vaccine platform technology WO2016112921 A1 licensed to AdaptVac. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Sepúlveda, Vardia, Skov, Goksøyr, Sander and Lorenzen.)

Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison's disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin., Methods: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS)., Results: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min ( p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points ( p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges., Conclusion: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD.

Purpose: The aim of this study was to explore the time-course of hospitalization due to hyponatremia associated with omeprazole and esomeprazole., Methods: In this register-based case-control study, we compared patients hospitalized with a main diagnosis of hyponatremia (n = 11,213) to matched controls (n = 44,801). We used multiple regression to investigate time-related associations between omeprazole and esomeprazole and hospitalization because of hyponatremia., Results: The overall adjusted OR (aOR) between proton pump inhibitor (PPI) exposure, regardless of treatment duration and hospitalization with a main diagnosis of hyponatremia, was 1.23 (95% confidence interval CI 1.15-1.32). Exposure to PPIs was associated with a prompt increase in risk of hospitalization for hyponatremia from the first week (aOR 6.87; 95% CI 4.83-9.86). The risk then gradually declined, reaching an aOR of 1.64 (0.96-2.75) the fifth week. The aOR of ongoing PPI treatment was 1.10 (1.03-1.18)., Conclusion: The present study shows a marked association between omeprazole and esomeprazole and hyponatremia related to recently initiated treatment. Consequently, newly initiated PPIs should be considered a potential culprit in any patient suffering from hyponatremia. However, if the patient has had this treatment for a longer time, the PPI should be considered a less likely cause., (© 2022. The Author(s).)

Despite vaccination, outbreaks of vibriosis still occur in sea-reared rainbow trout in Denmark. Vibriosis outbreaks are caused mainly by V. anguillarum serotypes O1 and O2a, and bacterins of both serotypes are included in the commonly used vaccine against this disease in Danish aquaculture. However, while the strains belonging to serotype O1 are genetically similar, the strains belonging to serotype O2a are highly diverse. This work aimed first at examining how the antibody response and protection induced by bacterin-based vaccines were affected by the antigenic variability within V. anguillarum serotype O2a strains. Following vaccination of rainbow trout with either a commercial or an experimental vaccine, specific antibody reactivity in serum from vaccinated fish was examined by ELISA against 23 strains of V. anguillarum serotype O2a (VaO2a). The strains were divided into 4 distinct subgroups according to the observed detection pattern. Seven strains were strongly recognized only by sera from fish vaccinated with the experimental vaccine (EV-I antisera), while 13 other strains were primarily recognized by sera from fish vaccinated with the commercial vaccine (CV antisera). Two strains were recognized by both EV-I and CV antisera, but with intermediate reactivity, while one strain was not recognized at all. A partly similar recognition pattern was observed when purified lipopolysaccharide (LPS) was used as antigen in the examination of antibody reactivity in Western blotting. The level of protection was highly dependent on both the vaccine and the strain used for challenge and showed no consistent correlation with antibody reactivity. Secondly, we attempted to use a bacterin vaccine based on one of the V. anguillarum O2a strains intermediately recognized by both EV-I and CV antisera to investigate whether that could potentially provide protection across strain variability. The immunized fish did mount a cross-reactive antibody response, but protection still varied depending on the strain used for challenge. Interestingly, the grouping of strains according to antibody reactivity correlated not only with genotyping based on single nucleotides polymorphisms analysis (SNP) but also with variability in the accessory genome, indicating that presence or absence of protein antigens or proteins associated with the biosynthesis of antigenic epitopes may explain the observed distinct serological subgrouping within VaO2a strains by trout immune sera. In terms of vaccination against VaO2a, our results demonstrate that it is important to take (local) antigen variations into account when using bacterin-based vaccines but also that alternatives to traditional bacterin-based vaccines might be needed to induce protection against the highly virulent Vibrio anguillarum serotype O2a strains., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Prebiotics are known to have a positive impact on fish health and growth rate, and β-glucans are among the most used prebiotics on the market. In this study, rainbow trout (Oncorhynchus mykiss) were treated with a β-1,3;1,6-glucan dietary supplement (at a dose of 0 g, 1 g, 10 g, and 50 g β-glucan per kg of feed). After 6 weeks, the effect of the β-glucan was evaluated by determining the changes in the microbiota and the blood serum metabolites in the fish. The impact of β-glucan on the immune system was evaluated through a challenge experiment with the bacterial fish pathogen Yersinia ruckeri., Results: The microbiota showed a significant change in terms of composition following β-glucan treatment, notably an increase in the relative abundance of members of the genus Aurantimicrobium, associated with a decreased abundance of the genera Carnobacterium and Deefgea. Furthermore, analysis of more than 200 metabolites revealed that the relative levels of 53 metabolites, in particular compounds related to phosphatidylcholines, were up- or downregulated in response to the dietary supplementation, this included the amino acid alanine that was significantly upregulated in the fish that had received the highest dose of β-glucan. Meanwhile, no strong effect could be detected on the resistance of the fish to the bacterial infection., Conclusions: The present study illustrates the ability of β-glucans to modify the gut microbiota of fish, resulting in alteration of the metabolome and affecting fish health through the lipidome of rainbow trout., (© 2022. The Author(s).)

Objective: Depression is common in individuals with endocrine-metabolic disorders and vice versa, and a better understanding of the underlying factors contributing to the comorbidity of these disorders is needed. This study investigated the familial coaggregation of depression and endocrine-metabolic disorders and estimated the contribution of genetic and environmental factors to their co-occurrence., Methods: This population-based cohort study included 2.2 million individuals born in Sweden between 1973 and 1996, with follow-up through 2013. Participants were linked to their biological parents, allowing identification of full siblings, maternal half siblings, and paternal half siblings. Diagnoses of depression and endocrine-metabolic conditions were investigated, with the latter grouped into autoimmune disorders (autoimmune hypothyroidism, Graves' disease, and type 1 diabetes) and non-autoimmune disorders (type 2 diabetes, obesity, and polycystic ovary syndrome). Logistic regression and Cox regression were used to estimate the associations between endocrine-metabolic disorders and depression within the same individual and across siblings. Quantitative genetic modeling was performed to investigate the relative contribution of genetic and environmental influences., Results: Individuals with endocrine-metabolic disorders had a significantly higher risk of depression, with odds ratios ranging from 1.43 (95% CI=1.30, 1.57) for Graves' disease to 3.48 (95% CI=3.25, 3.72) for type 2 diabetes. Increased risks extended to full and half siblings. These correlations were mainly explained by shared genetic influences for non-autoimmune conditions, and by nonshared environmental factors for autoimmune disorders, especially for type 1 diabetes., Conclusions: These findings provide phenotypic and etiological insights into the co-occurrence of depression and various endocrine-metabolic conditions, which could guide future research aiming at identifying pathophysiological mechanisms and intervention targets.

Context: A seasonal variation in hyponatremia, with higher incidence rates during hot summer days, has been demonstrated. Whether this applies to cool temperate regions is currently unknown., Objective: The aim of this study was to investigate the influence of ambient temperature on hyponatremia in the Swedish population under current and future climate scenarios., Methods: This nationwide cohort study identified all patients hospitalized with a first-ever principal diagnosis of hyponatremia between October 2005 and December 2014. Incidence rates for hyponatremia were calculated as number of hospitalizations divided by person-days at risk in the adult Swedish population at a given temperature, in increments of 1 °C., Results: The incidence of hyponatremia was stable at 0.3 per million person-days from -10 to 10 °C, but increased rapidly at 24-hour mean temperatures above 15 °C, with 2.26 hospitalizations per million days at the highest recorded temperature of 25 °C. Women and elderly carried the greatest risk, with an incidence of 35 hospitalizations per million days in individuals ≥ 80 years of age on the hottest days, corresponding to a 15-fold increase in incidence compared with cool days. A future 1 or 2 °C increase in mean temperature is expected to increase the incidence of hyponatremia by 6.3% and 13.9%, respectively., Conclusion: The risk of hospitalization due to hyponatremia increases rapidly at temperatures above 15 °C, indicating a threshold effect. Over the next decades, rising global temperatures are expected to increase the inpatient burden of hyponatremia by approximately 10%. Strategies for protecting vulnerable groups are necessary to reduce this risk., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Type 1 diabetes and Hashimoto's thyroiditis frequently cluster in individuals and in families, indicating shared origins. The objective of this study was to investigate familial co-aggregation of these diseases and to quantify shared genetic and environmental factors., Design: This study is a twin cohort study., Methods: National health registers were used to identify cases among 110 814 Swedish twins. Co-aggregation was calculated as risk ratios for type 1 diabetes among co-twins of individuals with Hashimoto's thyroiditis, and vice-versa. Variance explained by genetics (i.e. heritability), and the proportions thereof shared between the diseases, was estimated by contrasting associations in monozygotic and dizygotic twins using structural equation models., Results: Individuals with one disease were at a high risk for the other disease (adjusted risk ratio: 11.4 (95% CI: 8.5-15.3)). Co-aggregation was more common in monozygotic than in dizygotic pairs, with adjusted risk ratios of 7.0 (95% CI: 3.2-15.1) and 1.7 (95% CI: 0.7-4.1), respectively. Genetic effects shared across diseases accounted for 11% of the variance for type 1 diabetes and 9% of the variance for Hashimoto's thyroiditis, while environmental factors unique to individual twins, but shared across diseases, accounted for 10% of the variance for type 1 diabetes and 18% of the variance for Hashimoto's thyroiditis., Conclusions: Both genes and environment unique to individual twins contribute to considerable etiologic overlap between type 1 diabetes and Hashimoto's thyroiditis. These findings add to the current knowledge on the mechanisms behind autoimmune disease clustering and could guide future research aimed at identifying pathophysiological mechanisms and intervention targets., (The authors 2022.)

Purpose: Thiazide diuretics are the most common origin of drug-induced hyponatremia. However, population-based studies on clinical outcomes are lacking. We therefore explored the time course and absolute risk of thiazide-associated hospitalization due to hyponatremia in Sweden., Methods: Population-based case-control study including patients hospitalized with a principal diagnosis of hyponatremia (n = 11,213) compared with controls (n = 44,801). Linkage of registers was used to acquire data. Multivariable regression was applied to explore time-dependent associations between thiazide diuretics and hospitalization due to hyponatremia. Attributable risks were calculated assessing the disease burden attributable to thiazides., Results: Individuals initiating thiazide treatment were exposed to an immediate increase in risk for hospitalization with adjusted odds ratio (aOR) (95% CI) of 48 (28-89). The associations gradually declined reaching an aOR of 2.9 (2.7-3.1) for individuals treated for longer than 13 weeks. The attributable risk of hyponatremia-associated hospitalization due to thiazides of any treatment length was 27% (3095/11,213). Among 806 patients initiating treatment < 90 days before hospitalization, hyponatremia could be attributed to thiazides in 754. Based on nationwide data, 616,678 individuals were initiated on thiazides during the 8-year study period suggesting an absolute risk of 0.12% (754/661,678) for subsequent hospitalization with a main diagnosis of hyponatremia., Conclusions: Thiazide diuretics attributed to more than one in four individuals hospitalized due to hyponatremia. The risk increase was very pronounced during the first month of treatment and then gradually declined, without returning to normal. However, the absolute risk for the development of hyponatremia demanding hospitalization may for most individuals be modest.

Purpose: Drug-induced hyponatremia is common, with medications from many drug-classes implicated. Lipid-lowering agents are among the most prescribed drugs. Limited evidence suggests an inverse association between statins and hyponatremia, while data on other lipid-lowering agents is absent. The objective of this investigation was to study the association between lipid-lowering drugs and hospitalization due to hyponatremia., Methods: This was a register-based case-control study of the general Swedish population. Those hospitalized with a main diagnosis of hyponatremia (n = 11,213) were compared with matched controls (n = 44,801). Multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations, and socioeconomic factors was used to explore the association between severe hyponatremia and the use of lipid-lowering drugs., Results: Unadjusted ORs (95% CI) for hospitalization due to hyponatremia were 1.28 (1.22-1.35) for statins, 1.09 (0.79-1.47) for ezetimibe, 1.38 (0.88-2.12) for fibrates, and 2.12 (1.31-3.35) for resins. After adjustment for confounding factors the adjusted odds ratios (95% CI) compared with controls were 0.69 (0.64-0.74) for statins, 0.60 (0.41-0.86) for ezetimibe, 0.87 (0.51-1.42) for fibrates, and 1.21 (0.69-2.06) for resins., Conclusions: Use of statins and ezetimibe was inversely correlated with severe hyponatremia. Consequently, these drugs are unlikely culprits in patients with hyponatremia, and they appear safe to initiate in hyponatremic patients. A potential protective effect warrants further studies on how statins and other lipid-lowering drugs are linked to dysnatremias.

Context: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are known to coaggregate in families, but the magnitude and nature of a shared etiology is unknown., Objectives: To estimate the shared genetic influence on overt HT and GD and to examine if the heritability differs between men and women., Design, Setting, and Patients: We used national health registries to identify cases of HT and GD in a cohort of 110 814 Swedish twins. By comparing intra-class and cross-twin cross-trait correlations in dizygotic and monozygotic twins, we calculated heritability and the proportions thereof shared between the diseases. Univariate estimates of heritability were calculated by sex., Results: The heritability for HT and GD was 65% (95% CI, 61-70) and 63% (95% CI, 55-72), respectively. The genetic correlation was 0.35 (95% CI, 0.20-0.50) and shared genetic effects accounted for 8% of the variance for both HT and GD. Univariate heritability was significantly higher in men than in women for HT (90% vs 60%, P < 0.001) but not for GD (79% vs 63%, P = 0.085)., Conclusions: From a genetic perspective, HT and GD appear to be only modestly related diseases. Hence, the term "autoimmune thyroid disease," used to cluster these disorders, may have limited validity in a genetic context. Moreover, the mechanisms contributing to HT are partly different for the sexes, with genetic components more important in men., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Glucose-lowering medications have occasionally been reported to cause hyponatremia, but the evidence is scarce., Objectives: To explore the association between glucose-lowering medications and severe hyponatremia., Design, Setting, and Participants: Subjects hospitalized with a principal diagnosis of hyponatremia (n = 14,359) were compared with matched controls (n = 57,383). Data were derived by linkage of national population-based registers. Multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations, and socioeconomic factors was used to explore the association between hospitalization for hyponatremia and the use of different glucose-lowering medications. Furthermore, newly initiated (≤90 days) and ongoing use was investigated separately., Main Outcome Measures: Hospitalization due to hyponatremia., Results: The unadjusted ORs (95% CI) for hospitalization due to hyponatremia were 1.41 (1.29-1.54) for insulins, 1.38 (1.27-1.50) for metformin, and 1.22 (1.07-1.38) for sulfonylureas. However, after adjustment for confounding factors the association was consistently reversed. Thus, for any glucose-lowering medication the adjusted OR was 0.63 (0.58-0.68). For insulins, metformin and sulfonylureas, adjusted ORs (95% CI) were 0.58 (0.52-0.65), 0.81 (0.72-0.90) and 0.81 (0.69-0.94), respectively. Odds ratios for newly initated medications were overall higher while those for ongoing treatment were further decreased. Thus, adjusted ORs (95% CI) for ongoing treatment with insulins, metformin, and sulfonylureas were 0.54 (0.48-0.61), 0.82 (0.73-0.91) and 0.78 (0.66-0.92)., Conclusions: Glucose-lowering medications did not increase the risk for hospitalization due to severe hyponatremia. In fact, the association was inverse across all investigated drugs. The association may be mediated by pharmacologic mechanisms, but the uniform effects across drug-classes suggest properties of the diabetic disease are of importance.

Purpose: In a patient with clinically significant hyponatremia without other clear causes, thiazide treatment should be replaced with another drug. Data describing to which extent this is being done are scarce. The aim of this study was to investigate sociodemographic and socioeconomic factors that may be of importance for the withdrawal of thiazide diuretics in patients hospitalized due to hyponatremia., Methods: The study population was sampled from a case-control study investigating individuals hospitalized with a main diagnosis of hyponatremia. For every case, four matched controls were included. In the present study, cases (n = 5204) and controls (n = 7425) that had been dispensed a thiazide diuretic prior to index date were identified and followed onward regarding further dispensations. To investigate the influence of socioeconomic and sociodemographic factors, multiple logistic regression was used., Results: The crude prevalence of thiazide withdrawal for cases and controls was 71.9% and 10.8%, respectively. Thiazide diuretics were more often withdrawn in medium-sized towns (adjusted OR, 1.52; 95% CI, 1.21-1.90) and rural areas (aOR, 1.81; 95% CI, 1.40-2.34) compared with metropolitan areas and less so among divorced (aOR, 0.72; 95% CI, 0.53-0.97). However, education, employment status, income, age, country of birth, and gender did not influence withdrawal of thiazides among patients with hyponatremia., Conclusions: Thiazide diuretics were discontinued in almost three out of four patients hospitalized due to hyponatremia. Educational, income, gender, and most other sociodemographic and socioeconomic factors were not associated with withdrawal of thiazides., (© 2019 John Wiley & Sons, Ltd.)

Purpose: Several studies have reported an association between hyponatremia and lethality. However, it remains elusive whether hyponatremia independently contributes to lethality. The aim of the study was to investigate associations between hyponatremia and lethality and differences in lethality between men and women hospitalized due to hyponatremia., Methods: Four registries were utilized in this population-based retrospective study: The National Patient Registry, the Cause of Death Register, the Swedish Prescribed Drug Register and the Total Population Register (NPR) from which the controls were sampled. All hospitalized patients with a first-ever principal ICD10 diagnosis of hyponatremia or syndrome of inappropriate ADH secretion in the NPR between 1 October 2005 and 31 December 2014 were defined as cases. Cox regression with adjustment for potential confounders was used., Results: 14,359 individuals with a principal diagnosis of hyponatremia, and 57,382 matched controls were identified. Median age was 76 years and the majority were women (72%). Median age for women and men was 79 and 68 years, respectively. Adjusted hazard ratios (and 95% CI) for lethality in those with hyponatremia compared with controls were for the entire population 5.5 (4.4-7.0) and in the subgroup free from previously known underlying disease 6.7 (3.3-13.3). Lethality in women with hyponatremia was lower compared with men: HR: 0.56 (0.49-0.64). In the healthier group the lethality remained lower for women: HR: 0.49 (0.34-0.71)., Conclusions: Patients hospitalized due to hyponatremia faced an increased subsequent lethality that was independent of concomitant disease. This increase was nearly twice as large among men compared with women.

Background: Although tramadol and codeine occasionally have been reported to cause hyponatremia the evidence is scarce. The objective of this investigation was to study the association between weak opioids (tramadol and codeine) and hospitalization due to hyponatremia., Methods: This was a register-based case-control study of the general Swedish population. Those hospitalized with a principal diagnosis of hyponatremia (n = 14,359) were compared with matched controls (n = 57,383). Multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations and socioeconomic factors was used to explore the association between severe hyponatremia and the use of tramadol or codeine. Furthermore, newly initiated (≤90 days) and ongoing use was investigated separately., Results: Compared to controls, the unadjusted OR (95%CI) for hospitalization due to hyponatremia was 2.45 (2.26-2.66) for tramadol and 3.19 (2.92-3.47) for codeine. However, after adjustment for confounding factors the risk decreased (adjusted OR: 1.17 [1.08-1.26] and 1.14 [1.03-1.26], respectively). Newly initiated treatment with tramadol or codeine showed a significant association (adjusted OR 2.34 [95%CI 2.01-2.72] and 2.20 [95%CI 1.87-2.60], respectively). In contrast, for ongoing therapy the corresponding adjusted ORs were not elevated (adjusted OR: 0.70 [95%CI 0.61-0.80] and 1.14 [95%CI 0.99-1.30, respectively)., Conclusions: Associations were found between tramadol or codeine usage and hospitalization due to hyponatremia which were markedly increased in those newly initiated. The risk associated with long-term use was not increased. The association may be causally related to the drugs, although an effect due to pain, nausea or the underlying disease cannot be excluded., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Antipsychotics have been claimed to cause hyponatremia. The risk associated with individual antipsychotics, or groups (first-generation [FGAs] or second-generation [SGAs] antipsychotics), is not well-documented. The objective of this study was to investigate the association between antipsychotics and hospitalization due to hyponatremia., Methods: The general Swedish population was the base of this register-based case-control study. Comparisons were made between patients hospitalized with a principal diagnosis of hyponatremia (n = 14,359) and matched controls (n = 57,383). Multivariable logistic regression adjusting for concomitant drugs, medical conditions, previous hospitalizations and socioeconomic factors was performed to investigate the association between hyponatremia and antipsychotic use. In addition newly initiated (≤90 days) or ongoing use was analysed separately., Results: Compared to controls, the adjusted OR (95%CI) for hospitalization due to hyponatremia was for any antipsychotic 1.67(1.5-1.86). Individuals on FGA were more likely to experience severe hyponatremia (2.12[1.83-2.46]) than those on any SGA (1.32[1.15-1.51]). No increased risks, neither as newly initiated nor ongoing therapy, were found for risperidone (0.86[0.56-1.31] and 0.83[0.67-1.02]) and aripiprazole (1.16[0.30-4.46] and 0.62[0.27-1.34]), respectively., Conclusions: There was an association between antipsychotic therapy and hospitalization due to hyponatremia. The association was stronger for FGAs than SGAs. Risperidone was not associated with an increased risk., (Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Small observational studies and case reports have indicated that proton pump inhibitors (PPIs) may cause hyponatremia. Whether there is a difference between the individual PPIs is yet unknown. Since PPIs are one of the most commonly prescribed groups of drugs, even a rare adverse reaction may have large implications. The objective was to study the association between PPIs and hospitalization due to hyponatremia., Methods: This register-based case-control study was based on the general Swedish population. Patients hospitalized with a principal diagnosis of hyponatremia (n = 14,359) were compared to matched controls (n = 57,383). The association between newly initiated (≤90 days) and ongoing PPI use was explored using multivariable logistic regression adjusting for concomitant drugs, medical conditions, previous hospitalizations and socioeconomic factors., Results: Adjusted ORs (95%CI) for hospitalization due to hyponatremia, compared to controls, were for newly initiated: omeprazole 2.67 (2.37-3.01); pantoprazole 2.06 (1.32-3.19); lansoprazole 1.19 (0.72-1.94); esomeprazole 2.89 (2.21-3.79) and any PPI 2.78 (2.48-3.11). Only one individual had been newly initiated on rabeprazole and had been hospitalized due to hyponatremia. Adjusted ORs (95%CI) for individuals with ongoing treatment were for: omeprazole 1.04 (0.97-1.11); pantoprazole 0.81 (0.62-1.05); lansoprazole 0.90 (0.70-1.15); rabeprazole 3.34 (0.84-11.43); esomeprazole 1.12 (0.94-1.33) and any PPI 1.04 (0.98-1.11)., Conclusions: With the exception of lansoprazole, this study suggests an association between any newly initiated PPI-treatment and hospitalization due to hyponatremia. Ongoing PPI use was not associated with an increased risk., (Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Purpose: Hyponatremia induced by antiepileptic drugs is common, but detailed evidence is lacking. This can be problematic for the treating neurologist confronted with a patient with severe hyponatremia in need of an alternative drug. The objective of this study was to examine the association between individual antiepileptic drugs and hospitalization due to hyponatremia., Methods: This was a register-based case-control study of patients in the general Swedish population. We included 14,359 individuals with a principal diagnosis of hyponatremia and 57,383 matched controls. The association between newly initiated (≤90 days) and ongoing antiepileptic treatment was investigated using multivariable logistic regression adjusting for concomitant drugs, medical conditions, previous hospitalizations and sociaoeconomic factors., Results: For newly initiated antiepileptic drugs, adjusted ORs (95% CI) for hospitalization due to hyponatremia, compared to controls, were: carbamazepine 9.63 (6.18-15.33); phenytoin 4.83 (1.14-25.76); valproate 4.96 (2.44-10.66); lamotrigine 1.67 (0.70-4.08); levetiracetam 9.76 (4.02-27.59) and gabapentin 1.61 (1.08-2.38). Newly initiated oxcarbazepine treatment was only found in the hyponatremia group and not in controls. Adjusted ORs (CI) for individuals with ongoing treatment ranged from 7.97 (3.70-18.50) for oxcarbazepine to 0.83 (0.64-1.06) for gabapentin., Conclusion: There was a strong association between newly initiated treatment with carbamazepine, oxcarbazepine and levetiracetam, and hospitalization due to hyponatremia. The corresponding association for phenytoin and valproate was moderate. The risk for hyponatremia was lower during ongoing treatment. Lamotrigine and gabapentin had the lowest risk both during initiation and ongoing treatment and may be advantageous in patients at risk of developing hyponatremia., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

Purpose: The pathophysiology behind autoimmune Addison's disease (AAD) is poorly understood, and the relative influence of genetic and environmental factors remains unclear. In this study, we examined the heritability of AAD and explored disease-associated autoimmune comorbidity among Swedish twins., Methods: A population-based longitudinal cohort of 112,100 Swedish twins was used to calculate the heritability of AAD, and to explore co-occurrence of 10 organ-specific autoimmune disorders in twin pairs with AAD. Diagnoses were collected 1964-2012 through linkage to the Swedish National Patient Register. The Swedish Prescribed Drug Register was used for additional diagnostic precision. When available, biobank serum samples were used to ascertain the AAD diagnosis through identification of 21-hydroxylase autoantibodies., Results: We identified 29 twins with AAD. Five out of nine (5/9) monozygotic pairs and zero out of fifteen (0/15) dizygotic pairs were concordant for AAD. The probandwise concordance for monozygotic twins was 0.71 (95% CI 0.40-0.90) and the heritability 0.97 (95% CI 0.88-99). Autoimmune disease patterns of monozygotic twin pairs affected by AAD displayed a higher degree of similarity than those of dizygotic twins, with an incidence rate ratio of 15 (95% CI 1.8-116) on the number of shared autoimmune diagnoses within pairs., Conclusions: The heritability of AAD appears to be very high, emphasizing the need for further research on the genetic etiology of the disease. Monozygotic twin concordance for multiple autoimmune manifestations suggests strong genetic influence on disease specificity in organ-specific autoimmunity.

Eye flukes of the genus Diplostomum were recorded with a prevalence of 7.4% and a mean intensity of 11.9 (range 1-75) parasites per fish in eye lenses of a total of 188 Atlantic cod, Gadus morhua, sampled in the Southeastern Baltic Sea from March 2013 to February 2014. A slight decrease of infection level, among the fish with body length ranging from 30 to 89.5 cm, was found when data were compared to a corresponding survey in the 1980s. Due to imprecise species identification of eye flukes based on morphometric analyses we present, as a baseline for further studies, rDNA sequences from a subsample of 19 eye flukes based on sequencing of a part of 18S, ITS-1, 5.8S, ITS-2 and part of 28S. We discuss the use of eye fluke recordings in Baltic cod as an environmental indicator due to the dependence of the parasite's life cycle on biotic (occurrence of snail and bird hosts) and abiotic (temperature and salinity) parameters.

Baltic cod Gadus morhua (a total of total 224 specimens) captured east of the island of Bornholm in the southern Baltic Sea were subjected to a parasitological investigation between March 2013 and April 2014. Full artificial digestion of fillets from 188 cod and additional investigation of livers from 36 cod were performed. Cod or seal worm Pseudoterranova decipiens was recorded in musculature (prevalences up to 55% and intensities up to 56 worms per fish) associated with a negative correlation between worm intensity and condition factor. Liver worm Contracaecum osculatum (100% prevalence with intensities up to 320 worms per fish) in liver tissue were recorded but only a slight negative correlation between intensity and condition factor was noted. Seals act as final host for both worm species and the increased occurrence during recent years is associated with the increasing grey seal population in the area. Infection with Anisakis simplex (the herring or whale worm) in Baltic cod was found at a low level corresponding to previous studies., (Copyright © 2014 Elsevier B.V. All rights reserved.)