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IntroductionChronic low-grade inflammation might contribute to hyperandrogenemia and metabolic complications in polycystic ovary syndrome (PCOS). The proinflammatory cytokine interleukin (IL)-1 stimulates androgen production from ovarian cells, whereas blockade of the IL-1 pathway improves cardiometabolic health. We aimed to investigate whether blocking the IL-1 pathway ameliorates hyperandrogenemia in patients with PCOS.MethodsThis is a prospective, interventional, single-arm, proof-of-concept trial performed at a tertiary hospital in Switzerland (August 2018 to July 2020) in 18 premenopausal women with a diagnosis of PCOS according to the Rotterdam criteria, total testosterone levels ≥ 1.7 nmol/L, and C-reactive protein (CRP) ≥ 1.0 mg/L. Patients received 100 mg/day of the IL-1-receptor antagonist anakinra for 28 days and underwent weekly blood sampling until 1 week after the end of treatment. The primary endpoint was the change in serum androstenedione levels on day 7 of treatment, assessed with liquid chromatography–tandem mass spectrometry. Seven of these women participated in a subsequent observational sub-study (May 2021 to December 2021).ResultsMedian [interquartile range (IQR)] androstenedione increased by 0.5 [−0.1, 1.6] nmol/L (p = 0.048) with anakinra and by 1.3 [0.08, 2.4] nmol/L [p = 0.38] without anakinra between baseline and day 7. Anakinra reduced CRP levels on days 7, 21, and 28 (p < 0.001) but did not lead to an absolute reduction in androgens. However, four of six patients (67%) had smaller areas under the curves for androstenedione and/or testosterone during the 28-day intervention with anakinra as compared to 28 days without treatment.DiscussionOur findings suggest that anakinra suppresses IL-1-mediated chronic low-grade inflammation in PCOS and might attenuate biochemical hyperandrogenemia.

Abstract Background Several trials and meta-analyses found a benefit of adjunct corticosteroids for community-acquired pneumonia with respect to short-term outcome, but there is uncertainty about longer-term health effects. Herein, we evaluated clinical outcomes at long term in patients participating in the STEP trial (Corticosteroid Treatment for Community-Acquired Pneumonia). Methods This predefined secondary analysis investigated 180-day outcomes in 785 adult patients hospitalized with community-acquired pneumonia included in STEP, a randomised, placebo-controlled, double-blind trial. The primary endpoint was time to death from any cause at 180 days verified by telephone interview. Additional secondary endpoints included pneumonia-related death, readmission, recurrent pneumonia, secondary infections, new hypertension, and new insulin dependence. Results From the originally included 785 patients, 727 were available for intention-to-treat analysis at day 180. There was no difference between groups with respect to time to death from any cause (HR for corticosteroid use 1.15, 95% CI 0.68 to 1.95, p = 0.601). Compared to placebo, corticosteroid-treated patients had significantly higher risks for recurrent pneumonia (OR 2.57, 95% CI 1.29 to 5.12, p = 0.007), secondary infections (OR 1.94, 95% CI 1.25 to 3.03, p = 0.003) and new insulin dependence (OR 8.73, 95% CI 1.10 to 69.62, p = 0.041). There was no difference regarding pneumonia-related death, readmission and new hypertension. Conclusions In patients with community-acquired pneumonia, corticosteroid use was associated with an increased risk for recurrent pneumonia, secondary infections and new insulin dependence at 180 days. Currently, it is uncertain whether these long-term adverse effects outweigh the short-term effects of corticosteroids in moderate CAP. Trial registration This trial was registered with ClinicalTrials. gov, number NCT00973154 before the recruitment of the first patient. First posted: September 9, 2009. Last update posted: April 21, 2015.

BACKGROUND: Lipoprotein (a) [Lp(a)] serum levels are highly genetically determined and promote atherogenesis. High Lp(a) levels are associated with increased cardiovascular morbidity. Serum Lp(a) levels have recently been associated with large artery atherosclerosis (LAA) stroke. We aimed to externally validate this association in an independent cohort. METHODS: This study stems from the prospective multicentre CoRisk study (CoPeptin for Risk Stratification in Acute Stroke patients [NCT00878813]), conducted at the University Hospital Bern, Switzerland, between 2009 and 2011, in which Lp(a) plasma levels were measured within the first 24 hours after stroke onset. We assessed the association of Lp(a) with LAA stroke using multivariable logistic regression and performed interaction analyses to identify potential effect modifiers. RESULTS: Of 743 patients with ischaemic stroke, 105 (14%) had LAA stroke aetiology. Lp(a) levels were higher for LAA stroke than non-LAA stroke patients (23.0 nmol/l vs 16.3 nmol/l, p = 0.01). Multivariable regression revealed an independent association of log10 Lp(a) with LAA stroke aetiology (aOR 1.47 [95% CI 1.03–2.09], p = 0.03). The interaction analyses showed that Lp(a) was not associated with LAA stroke aetiology among patients with diabetes. CONCLUSIONS: In a well-characterised cohort of patients with ischaemic stroke, we validated the association of higher Lp(a) levels with LAA stroke aetiology, independent of traditional cardiovascular risk factors. These findings may inform randomised clinical trials investigating the effect of Lp(a) lowering agents on cardiovascular outcomes. The CoRisk (CoPeptin for Risk Stratification in Acute Patients) study is registered on ClinicalTrials.gov. Registration number: NCT00878813.

Summary: Background: Smoking cessation is challenging, despite making use of established smoking cessation therapies. Preclinical studies and one clinical pilot study suggest the antidiabetic drug glucagon-like peptide-1 (GLP-1) analogue to modulate addictive behaviours and nicotine craving. Previously, we reported the short-term results of a randomised, double-blind, placebo-controlled trial. Herein we report long-term abstinence rates and weight developments after 24 and 52 weeks. Methods: This single-centre, randomised, double-blind, placebo-controlled, parallel group trial was done at the University Hospital Basel in Switzerland. We randomly assigned (1:1) individuals with at least a moderate nicotine dependence willing to quit smoking to either a 12-week treatment with dulaglutide 1.5 mg or placebo subcutaneously once weekly in addition to standard of care smoking cessation therapy (varenicline 2 mg/day and behavioural counselling). After 12 weeks, dulaglutide or placebo injections were discontinued and the participants were followed up at week 24 and 52. The primary outcome of self-reported and biochemically confirmed point prevalence abstinence rate, and secondary outcome of secondary outcome of weight change were assessed at weeks 24 and 52. All participants who received one dose of the study drug were included in the intention to treat set and participants who received at least 10/12 doses of the study drug formed the per protocol set. The trial was registered at ClinicalTrials.gov, NCT03204396. Findings: Of the 255 participants who were randomly assigned between June 22, 2017 and December 3, 2020, 63% (80/127) (dulaglutide group) and 65% (83/128) (placebo group) were abstinent after 12 weeks. These abstinence rates declined to 43% (54/127) and 41% (52/128), respectively, after 24 weeks and to 32% (41/127) and 32% (41/128), respectively, after 52 weeks. Post-cessation weight gain was prevented in the dulaglutide group (−1.0 kg, standard deviation [SD] 2.7) as opposed to the placebo group (+1.9 kg, SD 2.4) after 12 weeks. However, at week 24, increases in weight from baseline were observed in both groups (median, interquartile range [IQR]: dulaglutide: +1.5 kg, [−0.4, 4.1], placebo: +3.0 kg, [0.6, 4.6], baseline-adjusted difference in weight change −1.0 kg (97.5% CI [−2.16, 0.16])), and at week 52 the groups showed similar weight gain (median, IQR: dulaglutide: +2.8 kg [−0.4, 4.7], placebo: +3.1 kg [−0.4, 6.0], baseline-adjusted difference in weight change: −0.35 kg (95% CI [−1.72, 1.01])). In the follow-up period (week 12 to week 52) 51 (51%) and 48 (48%) treatment-unrelated adverse events were recorded in the dulaglutide and the placebo group, respectively. No treatment-related serious adverse events or deaths occurred. Interpretation: Dulaglutide does not improve long-term smoking abstinence, but has potential to counteract weight gain after quitting. However, 3 months of treatment did not have a sustained beneficial effect on weight at 1 year. As post-cessation weight gain is highest in the first year after quitting smoking, future studies should consider a longer treatment duration with a GLP-1 analogue in abstinent individuals. Funding: Swiss National Science Foundation, the Gottfried and Julia Bangerter-Rhyner Foundation, the Goldschmidt-Jacobson Foundation, the Hemmi-Foundation, the University of Basel, the Swiss Academy of Medical Sciences.

Abstract Objective This study evaluates the predictive value of copeptin for syndrome of inappropriate antidiuresis (SIAD) postpituitary transsphenoidal surgery (TSS). Design Data from 133 consecutive patients undergoing TSS (November 2017–October 2022) at Oxford University Hospitals NHS trust are presented in this retrospective study. Methods Logistic regression (LR) and receiver operating characteristic (ROC) curves were performed to evaluate the diagnostic utility of copeptin. The Mann–Whitney U test was used to compare copeptin levels between the SIAD and no SIAD groups. Results Fourteen patients (10.8%) developed SIAD. Copeptin was available in 121, 53 and 87 patients for Days 1, 241 and 8 post‐TSS, respectively. LR for Day 1 copeptin to predict SIAD gave an odds ratio (OR) of 1.0 (95%CI 42 0.84–1.20, p = .99), area under‐ROC curve (AUC) was 0.49; Day 2 copeptin OR was 0.65 (95%CI 0.39–1.19, 43 p = .77), AUC was 0.57 LR for Day 1 sodium to predict SIAD gave an odds ratio (OR) of 1.0 (95%CI 0.85–1.21, p = .99), AUC was 0.50. Conclusions In conclusion, our data provide no evidence for copeptin as a predictive marker for post‐TSS SIAD.

Background Women seem to have more difficulty quitting smoking than men. This is particularly concerning as smoking puts women at a higher risk of developing smoking-associated diseases. Greater concerns about postcessation weight gain in women have been postulated as a possible explanation.Methods Predefined secondary analysis of a placebo-controlled, double-blind, parallel-group, superiority randomised trial including 255 adults who smoke daily (155 women, 100 men). Participants received weekly dulaglutide (1.5 mg) or placebo (0.9% sodium chloride) in addition to standardised smoking cessation care (varenicline 2 mg/day plus behavioural counselling) over 12 weeks. We aimed to investigate gender differences in weight change after dulaglutide-assisted smoking cessation. Weight change between baseline and week 12 was analysed as absolute and revative weight change and as substantial weight gain (defined as >6% increase).Results No gender differences were observed in absolute or relative weight change neither on dulaglutide nor placebo treatment. However, substantial weight gain (defined as >6% increase) in the placebo group was almost five times more frequent in females than males (24% vs 5%). Female patients were less likely to have substantial weight gain on dulaglutide compared with placebo (1% (n=1/83) vs 24% (n=17/72); p

Abstract Background Cigarette smoking is the leading preventable cause of premature death. Despite dedicated programmes, quit rates remain low due to barriers such as nicotine withdrawal syndrome or post-cessation weight gain. Glucagon-like peptide-1 (GLP-1) analogues reduce energy intake and body weight and seem to modulate addictive behaviour. These GLP-1 properties are of major interest in the context of smoking cessation. The aim of this study is to evaluate the GLP-1 analogue dulaglutide as a new therapy for smoking cessation. Methods This is a placebo-controlled, double-blind, parallel group, superiority, single-centre randomized study including 255 patients. The intervention consists of a 12-week dulaglutide treatment phase with 1.5 mg once weekly or placebo subcutaneously, in addition to standard of care (behavioural counselling and pharmacotherapy with varenicline). A 40-week non-treatment phase follows. The primary outcome is the point prevalence abstinence rate at week 12. Smoking status is self-reported and biochemically confirmed by end-expiratory exhaled carbon monoxide measurement. Further endpoints include post-cessational weight gain, nicotine craving analysis, glucose homeostasis and long-term nicotine abstinence. Two separate substudies assess behavioural, functional and structural changes by functional magnetic resonance imaging and measures of energy metabolism (i.e. resting energy expenditure, body composition). Discussion Combining behavioural counselling and medical therapy, e.g. with varenicline, improves abstinence rates and is considered the standard of care. We expect a further increase in quit rates by adding a second component of medical therapy and assume a dual effect of dulaglutide treatment (blunting nicotine withdrawal symptoms and reducing post-cessational weight gain). This project is of high relevance as it explores novel treatment options aimed at preventing the disastrous consequences of nicotine consumption and obesity. Trial registration ClinicalTrials.gov NCT03204396 . Registered on June 26, 2017.

BACKGROUND Alcohol use disorder has a detrimental impact on global health and new treatment targets are needed. Preclinical studies show attenuating effects of glucagon-like peptide-1 (GLP-1) agonists on addiction-related behaviors in rodents and nonhuman primates. Some trials have shown an effect of GLP-1 agonism on reward processes in humans; however, results from clinical studies remain inconclusive.METHODS This is a predefined secondary analysis of a double-blind, randomized, placebo-controlled trial evaluating the GLP-1 agonist dulaglutide as a therapy for smoking cessation. The main objective was to assess differences in alcohol consumption after 12 weeks of treatment with dulaglutide compared to placebo. The effect of dulaglutide on alcohol consumption was analyzed using a multivariable generalized linear model.RESULTS In the primary analysis, participants out of the cohort (n = 255) who reported drinking alcohol at baseline and who completed 12 weeks of treatment (n = 151; placebo n = 75, dulaglutide n = 76) were included. The median age was 42 (IQR 33–53) with 61% (n = 92) females. At week 12, participants receiving dulaglutide drank 29% less (relative effect = 0.71, 95% CI 0.52–0.97, P = 0.04) than participants receiving placebo. Changes in alcohol consumption were not correlated with smoking status at week 12.CONCLUSION These results provide evidence that dulaglutide reduces alcohol intake in humans and contribute to the growing body of literature promoting the use of GLP-1 agonists in treatment of substance use disorders.TRIAL REGISTRATION ClinicalTrials.gov NCT03204396.FUNDING Swiss National Foundation, Gottfried Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Hemmi Foundation, University of Basel, University Hospital Basel, Swiss Academy of Medical Science.

Background and Aims: The clinical, prognostic, and therapeutic impact of adrenal insufficiency in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) remains controversial and exact diagnostic criteria are lacking. We sought to determine the diagnostic and therapeutic value of cortisol measurement and glucocorticoid (GC) treatment in ALF and ACLF. Methods: 28-day transplant-free survival (TFS) was studied in relation to absolute cortisol concentrations and to GC treatment in ALF (n = 30) and ACLF (n = 34) patients. Cortisol concentrations and short synacthen test were assessed by chemiluminescence immunoassay and liquid chromatography-mass spectrometry. Clinicians decided independently on GC treatment. In relation, phenotypic and functional characteristics of circulating monocytes were assessed. Results: In ALF, baseline cortisol concentrations

Abstract In a murine model of acute ischemic stroke, SIRT6 knockdown resulted in larger cerebral infarct size, worse neurological outcome, and higher mortality, indicating a possible neuro-protective role of SIRT6. In this study, we aimed at evaluating the prognostic value of serum SIRT6 levels in patients with acute ischemic stroke (AIS). Serum levels of SIRT6, collected within 72 h from symptom-onset, were measured in 317 consecutively enrolled AIS patients from the COSMOS cohort. The primary endpoint of this analysis was 90-day mortality. The independent prognostic value of SIRT6 was assessed with multivariate logistic and Cox proportional regression models. 35 patients (11%) deceased within 90-day follow-up. After adjustment for established risk factors (age, NIHSS, heart failure, atrial fibrillation, and C reactive protein), SIRT6 levels were negatively associated with mortality. The optimal cut-off for survival was 634 pg/mL. Patients with SIRT6 levels below this threshold had a higher risk of death in multivariable Cox regression. In this pilot study, SIRT6 levels were significantly associated with 90-day mortality after AIS; these results build on previous molecular and causal observations made in animal models. Should this association be confirmed, SIRT6 could be a potential prognostic predictor and therapeutic target in AIS.

‘What’s in a name? That which we call a rose/By any other name would smell as sweet’ (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare’s implication is that a name is nothing but a word, and it therefore represents a convention with no intrinsic meaning. While this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rationale for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology, and pediatric endocrine societies now proposes changing the name of ‘diabetes insipidus’ to ‘arginine vasopressin deficiency (AVP-D)’ for central etiologies, and ‘arginine vasopr essin resistance (AVP-R)’ for nephrogenic etiologies. This article provides both the historical context and the rationale for this proposed name change.

Objective: Hyponatremia in COVID-19 is often due to the syndrome of inadequate antidiuresis (SIAD), possibly mediated by interleukin-6 (IL-6)-induced non-osmotic arginine vasopressin (AVP) secretion. We hypothesized an inverse association between IL-6 and plasma sodium concentration, stronger in COVID-19 compared to other respiratory infections. Design: Secondary analysis of a prospective cohort study including patients with COVID- 19 suspicion admitted to the Emergency Department, University Hospital of Basel, Switzerland, between March and July 2020. Methods: We included patients with PCR-confirmed COVID-19 and patients w ith similar symptoms, further subclassified into bacterial and other viral r espiratory infections. The primary objective was to investigate the association between plasma sodium and IL-6 levels. Results: A total of 500 patients were included, 184 (37%) with COVID-19, 92 (18%) with bacterial respiratory infections, and 224 (45%) with other viral respiratory infections. In all groups, median (IQR) IL-6 levels were significantly higher i n hyponatremic compared to normonatremic patients (COVID-19: 43.4 (28.4, 59.8) vs 9.2 (2.8, 32.7) pg/mL, P < 0.001; bacterial: 122.1 (63.0, 282.0) vs 67.1 (24.9, 252.0) pg/mL, P < 0.05; viral: 14.1 (6.9, 84.7) vs 4.3 (2.1, 14.4) pg/mL, P < 0.05). IL-6 levels were negatively correlated with plasma so dium levels in COVID-19, whereas the correlation in bacterial and other viral infections was weaker (COVID-19: R = −0.48, P < 0.001; bacterial: R = −0.25, P = 0.05, viral: R = −0.27, P < 0.001).

Summary: Background: Quitting smoking is difficult due to barriers such as craving for cigarettes and post-cessation weight gain. Recent experimental data suggest a role of glucagon-like peptide-1 (GLP-1) in the pathophysiology of addiction in addition to appetite regulation and weight control. We hypothesized that a pharmacological intervention with the GLP-1 analogue dulaglutide during smoking cessation may improve abstinence rates and reduce post-cessation weight gain. Methods: This is a single-centre, randomized, double-blind, placebo-controlled, parallel group, superiority study conducted in the University Hospital Basel in Switzerland. We included adult smokers with at least moderate cigarette dependence who wanted to quit. Participants were randomly assigned to a 12-week treatment with dulaglutide 1.5 mg once weekly or placebo subcutaneously in addition to standard of care including behavioural counselling and oral varenicline pharmacotherapy of 2 mg/day. The primary outcome was self-reported and biochemically confirmed point prevalence abstinence rate at week 12. Secondary outcomes included post-cessation weight, glucose metabolism, and craving for smoking. All participants who received one dose of study drug were included in the primary and safety analyses. The trial was registered on ClinicalTrials.gov (NCT03204396). Findings: Between June 22, 2017, and December 3, 2020, 255 participants were enrolled and randomly assigned to each group (127 in the dulaglutide group and 128 in the placebo group). After 12 weeks, 63% (80/127) participants on dulaglutide and 65% (83/128) on placebo treatment were abstinent (difference in proportions −1.9% [95% Confidence interval (CI) −10.7, 14.4], p-value (p) = 0.859). Dulaglutide decreased post-cessation weight (−1 kg [standard deviation (SD) 2.7]), while weight increased on placebo (+1.9 kg [SD 2.4]). The baseline-adjusted difference in weight change between groups was −2.9 kg (95% CI −3.59, −2.3, p

“What's in a name? That which we call a rose / By any other name would smell as sweet” (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rational for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology and endocrine pediatric societies now proposes changing the name of “diabetes insipidus” to “Arginine Vasopressin Deficiency (AVP-D)” for central etiologies, and “Arginine Vasopressin Resistance (AVP-R)” for nephrogenic etiologies This editorial provides both the historical context and the rational for this proposed name change.

Abstract Background Obesity is associated with an increased risk for several chronic conditions and mortality. However, there are data in support of beneficial outcome in acute medical conditions such as community-acquired pneumonia (CAP), termed “obesity paradox”. The aim of this study was to test the association of BMI with clinical outcomes in a large randomized clinical trial of patients hospitalized with CAP. Design and Methods In total, 773 patients hospitalized with CAP were included in this study. Patients were stratified into four groups according to their baseline BMI (underweight 30 kg/m2). The primary endpoint was time to clinical stability (TTCS). Secondary endpoints included 30-day mortality, ICU admission rate, CAP complications, and duration of antibiotic treatment. Results BMI and TTCS had a U-shaped association with shortest TTCS among patients at an overweight BMI of 28 kg/m2. In patients with obesity, there was a trend towards reduced hazards to reach clinical stability when compared to patients with normal weight (HR 0.82; 95%CI, 0.67–1.02; p = 0.07). In underweight BMI group TTCS was prolonged by 1 day (HR 0.63; 95%CI, 0.45–0.89; p = 0.008). There was no difference in mortality or ICU admission rates between BMI groups (p > 0.05). While in the underweight BMI group the total duration of antibiotic treatment was prolonged by 2.5 days (95%CI, 0.88–4.20, p = 0.003), there was no difference in patients with obesity. Conclusions The overweight BMI group had shortest time to clinical stability. While underweight patients face adverse clinical outcomes, there is neither beneficial, nor adverse outcome in patients with obesity hospitalized for CAP. ClinicalTrials.gov (registration no. NCT00973154).

Abstract The aim of this study was to correlate three commercially available copeptin assays and their diagnostic accuracy in the differential diagnosis of the polyuria-polydipsia syndrome. Analyzed data include repeated copeptin measures of 8 healthy volunteers and 40 patients with polyuria-polydipsia syndrome undergoing osmotic stimulation and of 40 patients hospitalized with pneumonia. Copeptin was measured using the automated Brahms KRYPTOR, the manual Brahms LIA and the manual Cloud Clone ELISA assay. Primary outcome was the interrater correlation coefficient (ICC) and diagnostic accuracy in the polyuria-polydipsia syndrome of the three assays. In healthy volunteers, there was a moderate correlation for the KRYPTOR and LIA (ICC 0.74; 95% CI 0.07 to 0.91), and a poor correlation for the KRYPTOR and ELISA (ICC 0.07; 95% CI − 0.06 to 0.29), as for the LIA and ELISA (ICC 0.04; 95% CI − 0.04 to 0.17). The KRYPTOR had the highest diagnostic accuracy (98% (95% CI 83 to100)), comparable to the LIA (88% (95% CI 74 to 100)), while the ELISA had a poor diagnostic accuracy (55% (95% CI 34 to 68)) in the differential diagnosis of the polyuria-polydipsia syndrome. The KRYPTOR and LIA yield comparable copeptin concentrations and high diagnostic accuracy, while the ELISA correlates poorly with the other two assays and shows a poor diagnostic accuracy for polyuria-polydipsia patients. The current copeptin cut-off is valid for the KRYPTOR and LIA assay. Our results indicate that interpretation with other assays should be performed with caution and separate validation studies are required before their use in differentiating patients with polyuria-polydipsia syndrome. Trial registration: NCT02647736 January 6, 2016/NCT01940614 September 12, 2013/NCT00973154 September 9, 2009.

Objective: Hyperkalemia has been reported upon different hypertonic saline infusion protocols. Since hypertonic saline test has recently been valid ated for the differential diagnosis of diabetes insipidus (DI), we aimed to investigate the course of plasma potassium during the test. Design: We analyzed data of 90 healthy volunteers and 141 patients with polyuria– polydipsia syndrome (PPS) from two prospective studies evaluating the hypertonic saline test. Our primary outcome was the incidence rate of hypertonic saline-induced hyperkalemia > 5 mmol/L. Methods: Participants received a 250 mL bolus of 3% NaCl solution, followed by 0.15 mL/min/kg body weight continuously infused targeting a plasma sodium level of 150 mmol/L. Blood samples and clinical data were collected every 30 min. Results: Of the 231 participants, 16% (n = 37/231) developed hyperkalemia. The incidence of hyperkalemia was higher in healthy volunteers and in patients with primary polydipsia (25.6% (n = 23/90) and 9.9% (n = 14/141), respectively), and only occurred in 3.4% (n = 2/59) of patients with diabetes insipidus. Hyperkalemia developed mostly at or after 90-min test duration (81.1%, n = 30/37). Predictors of hyperkalemia (OR (95% CI)) were male sex (2.9 (1.2–7.4), P = 0.02), a plasma potassium at baseline > 3.9 mmol/L (5.2 (1.8–17.3), P = 0.004), normonatremia at 30-min test duration (3.2 (1.2–9.5), P = 0.03), and an increase in potassium levels already at 30-min test duration as compared to baseline (4.5 (1.7–12.3), P = 0.003). Hyperkalemia was transient and resolved spontaneously in all cases. Conclusion: The hypertonic saline test can lead to hyperkalemia, especially in patients with primary polydipsia who experience a longer test duration. Monitoring potassium levels in these patients is recommended.

Abstract Fibroblast growth factor-21 (FGF21) is elevated in patients with the metabolic syndrome. Although the exact underlying mechanisms remain ill-defined, chronic low-grade inflammation with increased Interleukin-(IL)-1β expression may be responsible. The aim of this study was to investigate effects of two different anti-inflammatory treatments (IL-1 antagonism or high-dose corticosteroids) on FGF21 in patients with the metabolic syndrome. This is a secondary analysis of two interventional studies in patients with obesity and features of the metabolic syndrome. Trial A was an interventional trial (n = 73) investigating short-term effects of the IL-1 antagonist anakinra and of dexamethasone. Trial B was a randomized, placebo-controlled, double-blinded trial (n = 67) investigating longer-term effects of IL-1 antagonism. In total, 140 patients were included in both trials. Median age was 55 years (IQR 44–66), 26% were female and median BMI was 37 kg/m2 (IQR 34–39). Almost half of the patients were diabetic (45%) and had increased c-reactive protein levels of 3.4 mg/L. FGF21 levels correlated with fasting glucose levels, HOMA-index, C-peptide levels, HbA1c and BMI. Short-term treatment with anakinra led to a reduction of FGF21 levels by − 200 pg/mL (95%CI − 334 to − 66; p = 0.004). No effect was detectable after longer-term treatment (between-group difference: − 8.8 pg/mL (95%CI − 130.9 to 113.3; p = 0.89). Acute treatment with dexamethasone was associated with reductions of FGF21 by -175 pg/mL (95%CI − 236 to − 113; p

Arginine vasopressin (AVP) was suggested to contribute to cardiovascular risk and type 2 diabetes in patients with metabolic syndrome. The proinflammatory cytokine interleukin (IL)-1 is able to induce AVP secretion and plays a causal role in cardiovascular mortality and type 2 diabetes. We investigated in two studies whether copeptin levels – the surrogate marker for AVP – are regulated by IL-1-mediated chronic inflammation in patients with metabolic syndrome. Study A was a prospective, interventional, single-arm study (2014–2016). Study B was a randomized, placebo-controlled, double-blind study (2016–2017). n = 73 (Study A) and n = 66 (Study B) adult patients with metabolic syndrome were treated with 100 mg anakinra or placebo (only in study B) twice daily for 1 day (study A) and 28 days (study B). Fasting blood samples were drawn at day 1, 7, and 28 of treatment for measurement of serum copeptin. Patients with chronic low-grade inflammation (C-reactive protein levels ≥2 mg/L) and BMI >35 kg/m2 had higher baseline copeptin levels (7.7 (IQR 4.9–11.9) vs 5.8 (IQR 3.9–9.3) pmol/L, Pinflamm = 0.009; 7.8 (IQR 5.4–11.7) vs 4.9 (IQR 3.7–9.8) pmol/L, PBMI = 0.008). Copeptin levels did not change either in the anakinra or in the placebo group and remained stable throughout the treatment (P = 0.44). Subgroup analyses did not reveal effect modifications. Therefore, we conclude that, although IL-1-mediated inflammation is associated with increased circulating copeptin levels, antagonizing IL-1 does not significantly alter copeptin levels in patients with metabolic syndrome.

Objective: The syndrome of inappropriate antidiuresis (SIAD) is a common condition in hospitalized patients. It is crucial to establish the cause of SIAD, especially in order to exclude underlying malignancy. As malignant SIAD may be due to a paraneoplastic synthesis of arginine vasopressin, we hypothesized that its stable surrogate marker copeptin can be used as a diagnostic tool to differentiate betwe en malignant and non-malignant SIAD. Methods: Prospective observational study. We analyzed data from 146 SIAD patients of two different cohorts from Switzerland and Germany. Patients were included while presenting at the emergency department and underwent a standardized diagnostic assessment including the measurement of copeptin levels. Results: Thirty-nine patients (median age: 63 years, 51% female) were diagnosed with cancer-related SIAD and 107 (median age: 73 years, 68% female) with non-malignant SIAD. Serum sodium levels were higher in cancer-related versus non-malignant SIAD: median (IQR) 124 mmol/l (120; 127) versus 120 mmol/l (117; 123) (P

Background Latent class analysis (LCA) has identified subgroups with meaningful treatment implications in acute respiratory distress syndrome. We performed a secondary analysis of three studies to assess whether LCA can identify clinically distinct subgroups in community-acquired pneumonia (CAP) and whether the treatment effect of adjunctive corticosteroids differs between subgroups. Methods LCA was performed on baseline clinical and biomarker data from the Ovidius trial (n=304) and the Steroids in Pneumonia (STEP) trial (n=727), both randomised controlled trials investigating adjunctive corticosteroid treatment in CAP, and the observational TripleP cohort (n=201). Analyses were conducted independently in two cohorts (Ovidius–TripleP combined and the STEP trial). In both cohorts, differences in clinical outcomes and response to adjunctive corticosteroid treatment were examined between subgroups identified through LCA. Results A two-class model fitted both cohorts best. Class 2 patients had more signs of systemic inflammation compared to class 1. In both cohorts, length of stay was longer and in-hospital mortality rate was higher in class 2. In the Ovidius trial, corticosteroids reduced the median length of stay in class 2 (6.5 versus 9.5 days) but not in class 1 (p-value for interaction=0.02). In the STEP trial, there was no significant interaction for length of stay. We found no significant interaction between class assignment and adjunctive corticosteroid treatment for secondary outcomes. Conclusions In two independent cohorts, LCA identified two classes of CAP patients with different clinical characteristics and outcomes. Given the different response to adjunctive corticosteroids in the Ovidius trial, LCA might provide a useful basis to improve patient selection for future trials.

Background: Hyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. In contrast to acute hyponatremia where the need for immediate treatment is well-recognized, chronic hyponatremia is often considered not clinically relevant. This is illustrated by reports showing that appropriate laboratory tests are ordered in

Osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters, such as interle ukin-8 (IL-8) and tumor necrosis factor-α (TNF-α), increase in parallel in the central nervous system and bronc hial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in hum ans is unknown. We therefore investigated the influence of osmotic stimulus on c irculatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium ≥150 mmol/L) by hypertonic saline infusion. Copeptin – a marker indicating vasopressin act ivity – serum sodium and osmolality, plasma IL-8 and TNF-α were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/L (136, 147) to 151 mmol/L (145, 154) (P < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 0.01). Median (range) copeptin increased from 4.3 pg/L (1.1, 21.4) to 28.8 pg/L (19.9, 43.4) (P < 0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/mL (0.37, 1.6) to 0.7 pg/mL (0.4 , 1.9) (P < 0.09) and TNF-α levels decreased from 0.53 pg/mL (0.11, 1.1) to 0.45 pg/mL (0.1 2, 0.97) (P < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation.

Background: Anti-inflammatory treatment with interleukin-1 (IL-1) antagonism decreases both cortisol and adrenocorticotropin hormone (ACTH) levels in individuals with obesity in short term. However, it remains unknown whether these effects persist upon prolonged treatment. Methods: In this double-blind, parallel-group trial involving patients with features of the metabolic syndrome, 33 patients were randomly assigned to receive 100 mg of anakinra (recombinant human IL-1 receptor antagonist) subcutaneously twice-daily and 34 patients to receive placebo for 4 weeks. For this analysis, change in cortisol and ACTH levels from baseline to 4 weeks were predefined end points of the trial. Results: The mean age was 54 years, baseline cortisol levels were 314 nmol/L (IQR 241–385) and C-reactive protein (CRP) levels were 3.4 mg/L (IQR 1.7–4.8). Treatment with anakinra led to a significant decrease in cortisol levels a t day 1 when compared to placebo with an adjusted between-group difference of 28 nmol/L (95% CI, −7 to −43; P = 0.03). After 4 weeks, the cortisol-lowering effect of anakinra was attenuated and overall was statistically not significant (P = 0.72). Injection-site reactions occurred in 21 patients receiving anakinra and were associated with higher CRP and cortisol levels. Conclusions: IL-1 antagonism decreases cortisol levels in male patients with obesity and chronic low-grade inflammation on the short term. After prolonged treatment, this effect is attenuated, probably due to injection-site reactions (ClinicalTrials.gov, NCT02672592).

Abstract Background Adrenal hormone metabolite levels are altered in acute illnesses such as community-acquired pneumonia (CAP). Our aim was to investigate associations of sex and mineralocorticoid hormone metabolites with short- and long-term mortality and severity of CAP in male and female patients. Methods We prospectively followed 285 patients (60.4% male, mean age 71 years) with CAP from a previous multicenter trial. At baseline, levels of different metabolites of sex hormones and mineralocorticoids were measured by liquid chromatography coupled to tandem mass spectrometry. We calculated Cox regression models adjusted for age and comorbidities. Results All-cause mortality was 5.3% after 30 days and increased to 47.4% after 6 years. In males, high levels of dihydrotestosterone were associated with higher 6-year mortality (adjusted HR 2.84, 95%CI 1.15–6.99, p = 0.023), whereas high levels of 17-OH-progesterone were associated with lower 6-year mortality (adjusted HR 0.72, 95%CI 0.54–0.97, p = 0.029). Testosterone levels in males correlated inversely with inflammatory markers (CRP rho = − 0.39, p

The pathomechanism of primary polydipsia is poorly understood. Recent animal data reported a connection between fibroblast growth factor 21 (FGF-21) and elevated fluid intake independently of hormonal control by the hormone arginine-vasopressin (AVP) and osmotic stimulation. We therefore compared circulating FGF-21 levels in patients with primary polydipsia to patients with AVP deficiency (central diabetes insipidus) and healthy volunteers. In this prospective cohort study, we analyzed FGF-21 levels of 20 patients with primary polydipsia, 20 patients with central diabetes insipidus and 20 healthy volunteers before and after stimulation with hypertonic saline infusion targeting a plasma sodium level ≥150 mmol/L. The primary outcome was the difference in FGF-21 levels between the three groups. Baseline characteristics were similar between the groups except for patients with central diabetes insipidus being heavier. There was no difference in baseline FGF-21 levels between patients with primary polydipsia and healthy volunteers (122 pg/mL (52,277) vs 193 pg/mL (48,301), but higher levels in patients with central diabetes insipidus were observed (306 pg/mL (114,484); P = 0.037). However, this was not confirmed in a multivariate linear regression analysis after adjusting for age, sex, BMI and smoking status. Osmotic stimulation did not affect FGF-21 levels in either group (difference to baseline: primary polydipsia −23 pg/mL (−43, 22); central diabetes insipidus 17 pg/mL (−76, 88); healthy volunteers −6 pg/mL (−68, 22); P = 0.45). To conclude, FGF-21 levels are not increased in patients with primary polydipsia as compared to central diabetes insipidus or healthy volunteers. FGF-21 therefore does not seem to be causal of elevated fluid intake in these patients.

Background and Aims: Endothelins have shown to play a role in the pathophysiology of ischemic stroke. We aimed at evaluating the incremental prognostic value of C-terminal-pro-endothelin-1 (CT-pro-ET-1) in a well-described cohort of acute stroke patients.Methods: We performed serial measurements of CT-pro-ET-1 in 361 consecutively enrolled ischemic stroke patients and assessed functional outcome and mortality after 90 days. As we found peak levels of CT-pro-ET-1 and the most prominent association with mortality on day 1 after admission (n = 312), we focused on this time point for further outcome analyses. We calculated logistic regression and cox proportional hazards models to estimate the association of CT-pro-ET-1 with our outcome measures after adjusting for demographic and clinical risk factors. To evaluate the incremental value of CT-pro-ET-1, we calculated the area under the receiver operating characteristics (AUC) curve and the continuous net reclassification index (cNRI) comparing the model with and without the biomarker CT-pro-ET-1.Results: In the univariate analysis CT-pro-ET-1 with a peak on day 1 after admission was associated with unfavorable outcome with an OR of 1.32 (95% CI, 1.16–1.51, p < 0.001) and with mortality with a HR of 1.45 (95% CI, 1.29–1.63, p < 0.001). After adjusting, CT-pro-ET-1 remained an independent predictor of mortality with an adjusted HR of 1.50 (95% CI, 1.29–1.74, p < 0.001), but not for functional outcome. Adding CT-pro-ET-1 to the cox-regression model for mortality, the discriminatory accuracy improved from 0.89 (95% CI, 0.84–0.94) to 0.92 (95% CI, 0.88–0.96) p < 0.001, and the cNRI was 0.72 (95% CI, 0.17–1.13).Conclusion: CT-pro-ET-1 with a peak level on day 1 was an independent predictor of mortality adding incremental prognostic value beyond traditional risk factors.

Polyuria-polydipsia syndrome consists of the three main entities: central or nephrogenic diabetes insipidus and primary polydipsia. Reliable distinction between these diagnoses is essential as treatment differs substantially, with the wrong treatment potentially leading to serious complications. Past diagnostic measures using the classical water deprivation test had several pitfalls and clinicians were often left with uncertainity concerning the diagnosis. With the establishment of copeptin, a stable and reliable surrogate marker for arginine vasopressin, diagnosis of the polyuria-polydipsia syndrome has been newly evaluated. Whereas unstimulated basal copeptin measurement reliably diagnoses nephrogenic diabetes insipidus, two new tests using stimulated copeptin cutoff levels showed a high diagnostic accuracy in differentiating central diabetes insipidus from primary polydipsia. For the hypertonic saline infusion test, osmotic stimulation via the induction of hypernatraemia is used. This makes the test highly reliable and superior to the classical water deprivation test, but also requires close supervision and the availability of rapid sodium measurements to guarantee the safety of the test. Alternatively, arginine infusion can be used to stimulate copeptin release, opening the doors for an even shorter and safer diagnostic test. The test protocols of the two tests are provided and a new copeptin-based diagnostic algorithm is proposed to reliably differentiate between the different entities. Furthermore, the role of copeptin as a predictive marker for the development of diabetes insipidus following surgical procedures in the sellar region is described.

Objective: The aim of this study was to confirm previous observations that proenkephalin A (PENK-A) may serve as prognostic marker in the setting of acute ischemic stroke in a large stroke cohort. Methods: The plasma concentration of PENK-A was measured within 72 hours of symptom onset in 320 consecutively enrolled patients with stroke. The primary outcome measures were unfavorable functional outcome (modified Rankin Scale score 0-2 vs 3-6) and mortality within 90 days. Logistic and cox proportional regression analyses were fitted to estimate odds ratios (ORs), hazard ratios (HRs) and 95% confidence intervals (CIs), respectively, for the association between PENK-A and the primary outcome measures. Results: After adjusting for demographic and vascular risk factors, PENK-A was neither independently associated with functional outcome (OR: 1.29, 95% CI: 0.16-10.35) nor mortality (HR: 1.02, 95% CI: 0.14-7.33). Conclusion: Among patients with acute stroke, PENK-A does not serve as an independent prognostic marker in this external validation cohort.

Abstract Background Oxidative stress is a modifiable risk-factor in infection causing damage to human cells. As an adaptive response, cells catabolize Tyrosine to 3-Nitrotyrosine (Tyr-NO2) by nitrosylation. We investigated whether a more efficient reduction in oxidative stress, mirrored by a lowering of Tyrosine, and an increase in Tyr-NO2 and the Tyrosine/Tyr-NO2 ratio was associated with better clinical outcomes in patients with community-acquired pneumonia (CAP). Methods We measured Tyrosine and Tyr-NO2 in CAP patients from a previous randomized Swiss multicenter trial. The primary endpoint was adverse outcome defined as death or ICU admission within 30-days; the secondary endpoint was 6-year mortality. Results Of 278 included CAP patients, 10.4% experienced an adverse outcome within 30 days and 45.0% died within 6 years. After adjusting for the pneumonia Severity Index [PSI], BMI and comorbidities, Tyrosine nitrosylation was associated with a lower risk for short-term adverse outcome and an adjusted OR of 0.44 (95% CI 0.20 to 0.96, p = 0.039) for Tyr-NO2 and 0.98 (95% CI 0.98 to 0.99, p = 0.043) for the Tyrosine/Tyr-NO2 ratio. There were no significant associations for long-term mortality over six-years for Tyr-NO2 levels (adjusted hazard ratio 0.81, 95% CI 0.60 to 1.11, p = 0.181) and Tyrosine/Tyr-NO2 ratio (adjusted hazard ratio 1.00, 95% CI 0.99 to 1.00, p = 0.216). Conclusions Tyrosine nitrosylation in our cohort was associated with better clinical outcomes of CAP patients at short-term, but not at long term. Whether therapeutic modulation of the Tyrosine/Tyr-NO2 pathway has beneficial effects should be evaluated in future studies. Trial registration ISRCTN95122877. Registered 31 July 2006.

Abstract Background Hypernatraemia is common in inpatients and is associated with substantial morbidity. Its differential diagnosis is challenging, and delayed treatment may have devastating consequences. The most important hormone for the regulation of water homeostasis is arginine vasopressin, and copeptin, the C-terminal portion of the precursor peptide of arginine vasopressin, might be a reliable new parameter with which to assess the underlying cause of hypernatraemia. Methods In this prospective, multicentre, observational study conducted in two tertiary referral centres in Switzerland, 92 patients with severe hyperosmolar hypernatraemia (Na+ > 155 mmol/L) were included. After a standardised diagnostic evaluation, the underlying cause of hypernatraemia was identified and copeptin levels were measured. Results The most common aetiology of hypernatraemia was dehydration (DH) (n = 65 [71%]), followed by salt overload (SO) (n = 20 [22%]), central diabetes insipidus (CDI) (n = 5 [5%]) and nephrogenic diabetes insipidus (NDI) (n = 2 [2%]). Low urine osmolality was indicative for patients with CDI and NDI (P

Background and Purpose Micro ribonucleic acid-150-5p (miR-150-5p) regulates proinflammatory cytokines as well as vessel integrity. We evaluated the incremental prognostic value of logarithm (log) of miR-150-5p plasma levels after ischemic stroke. Methods In a prospective cohort study, levels of miR-150-5p were measured within 72 hours of symptom onset in 329 ischemic stroke patients. The outcome measures were unfavorable functional outcome (assessed by the modified Rankin Scale score >2) and mortality within 90 days. Logistic regression and Cox proportional hazards models were fitted to estimate odds ratio (OR), respectively hazard ratio (HR) and 95% confidence interval (CI) for the association between log-miR-150-5p and the outcome measures. The discriminatory accuracy was assessed with the area under the receiver-operating-characteristic curve (AUC) and the incremental prognostic value was estimated with the net reclassification index. Results After adjusting for demographic and vascular risk factors, lower log-miR-150-5p levels were independently associated with mortality (HR 0.21 [95% CI, 0.08–0.51], P=0.001) but not functional outcome (OR 1.10 [95% CI, 0.54–2.25], P=0.79). Adding log-miR-150-5p improved the discriminatory accuracy of the best multivariate model to predict mortality from an AUC of 0.91 (95% CI, 0.88–0.95) to 0.92 (95% CI, 0.88–0.96 Likelihood-ratio test-P

Abstract Background Several studies found mid-regional pro-adrenomedullin (ProADM), the prohormone of the cardiovascular protein adrenomedullin, to be strongly associated with short-term mortality, mostly in the inpatient setting. We evaluated associations of ProADM levels with 10-year mortality in community-dwelling primary care patients with respiratory tract infections. Methods This is a post-hoc analysis using clinical and biomarker data of 134 primary care patients with respiratory tract infections. ProADM was measured on admission and after 7 days in batch-analysis. 10-year follow-up data was collected by GP, patient and relative tracing through phone interviews. We calculated Cox regression models and area under the receiver operating characteristics curves to assess associations of ProADM with 10-year all-cause mortality. Results During the 10-year follow-up 6% of included patients died. Median baseline ProADM blood levels (nmol/l) were significantly higher in non-survivors compared to survivors (0.5, IQR 0.4–1.3; vs. 0.2, IQR 0.1–0.5; p = 0.02) and showed a significant association with 10-year all-cause mortality in an age-adjusted cox regression model (HR: 2.5, 95%-CI: 1.0–6.1, p = 0.04). ProADM levels on day 7 showed similar results. Conclusions This posthoc analysis found an association of elevated ProADM blood levels and 10-year all-cause mortality in a primary care cohort with respiratory tract infections. Due to the methodological limitations including incomplete data regarding follow-up information and biomarker measurement, this study warrants validation in future larger studies. Trial registration Current Controlled Trials, SRCTN73182671

AIM OF THE STUDY The internal validity of double blinding in randomised placebo-controlled trials (RCTs) has become a target of criticism. The goal of this study was to investigate (a) how accurately the patients and their treating physicians were able to guess their assigned treatment, and (b) predictors for an accurate guess. METHODS Data on treatment estimation from patients (n = 382) and their physicians (n = 358 guesses) in an RCT investigating the role of adjunct prednisone for community-acquired pneumonia in a tertiary care setting were analysed. At discharge, patients and their physicians had to guess whether they had been assigned to the prednisone or to the placebo group. The alternative possibility was “uncertain”. Percentages and confidence intervals (CIs) were calculated for the proportion of patients guessing correctly. Chance finding was defined as having 50% or less correct guesses. To test for predictors for prednisone treatment guess, a mixed effects logistic regression model was performed. RESULTS In the prednisone group, 28.9% (55/190; 95% CI 22.6–36.0%) of the patients made a correct guess and the majority (61.6%, 117/190) was uncertain. In the placebo group, 13.0% (25/192; 95% CI 8.8–18.8%) guessed correctly, with the majority being uncertain (69.8%, 134/192). Physicians guessed correctly in 48.3% (87/180, 95% CI 40.8–55.9%) of cases in the prednisone group and in 66.3% (118/178, 95% CI 58.8–73.2%) of cases in the placebo group, which was above chance for the placebo group. The physicians were uncertain in 21.7% (39/180) of cases in the prednisone group, and in 15.2% (27/178) of cases in the placebo group. Significant predictors for guessing prednisone were the occurrence of hyperglycaemia (odds ratio [OR] 3.77, 95% CI 2.39–5.95; p

Abstract Background Increasing evidence points to beta‐cell regeneration in individuals with type 1 diabetes mellitus (type 1 DM) at all stages of the disease. Exercise and glucagon‐like peptide‐1 (GLP‐1) independently improve beta‐cell function and glucose homeostasis in animal studies and in clinical trials in individuals with type 2 diabetes mellitus (type 2 DM). Whether a combination of both, exercise and GLP‐1, induces a similar effect in individuals with long‐lasting type 1 DM remains to be investigated. Methods In an open‐label study, participants with long‐standing type 1 DM were randomly assigned to oral sitagliptin 100 mg daily for 12 weeks in combination with or without an exercise intervention. The primary end‐point was change in the area under the concentration‐time curve of C‐peptide during a mixed meal tolerance test before and after 12 weeks of intervention. Results A total of 24 participants were included in the study and treated with sitagliptin, 12 participants were allocated to a 12‐week exercise intervention. After 12 weeks, there was no difference in the change of AUC C‐peptide between groups (exercise: 0 [−1424 to 1870], no exercise: 2091 [283‐17 434]; P = 0.09). HDL improved in the exercise intervention group compared to the group with sitagliptin only (exercise: 0.11 [−0.09 to 0.27]; no exercise: −0.18 [−0.24 to 0.01]; P = 0.04). AUC glucose was numerically slightly lower in the exercise intervention group but this did not translate into changes in HbA1c. Conclusion The combination of exercise and sitagliptin had no effect on beta‐cell function in individuals with long‐lasting type 1 DM.

ObjectiveStudies have suggested that arginine vasopressin (AVP) and its surrogate marker copeptin increase during exercise, independently of serum sodium and/or osmolality. In extreme cases, this can lead to runners-induced hyponatremia. Interleukin-1 (IL-1) increases during exercise and induces AVP in animal models. We here therefore investigate whether copeptin (a surrogate marker for AVP) increases upon exercise in young and healthy males, and whether this increase is regulated by IL-1.DesignIn a randomized, placebo-controlled, double-blind, crossover trial in 17 healthy male volunteers, the effect of the IL-1 receptor antagonist anakinra on exercise-induced copeptin was compared with placebo.MethodsParticipants exercised for one hour at 75% of VO2max and were not allowed to drink/eat 6 hours before and during the study. Participants received either 100 mg of anakinra or placebo 1h before exercise. Blood was drawn at certain time intervals.ResultsIn both groups, copeptin levels were induced by 2.5-fold upon exercise (pConclusionsExercise induces a continuous rise of plasma copeptin levels in healthy male volunteers independently of sodium levels and fluid intake. This increase is not regulated by the IL-1 pathway.

Primary polydipsia (PP) has been defined as excessive intake of fluids. However, the pathogenesis of PP remains unexplored. Different theories include a dysfunction in the thirst mechanism, involvement of the hippocampus, stress-reducing behaviour and lesion occurrences in specific areas of the brain. Most studies have been performed in the psychiatric setting, indicating that PP coincides with schizophrenia, anxiety disorder and depression. However, an increasing number of case reports emphasise the incidence of PP in non-psychiatric patients. As often recommended by healthcare professions and in life-style programmes, the phenomenon of excessive fluid intake appears to be growing, especially in health-conscious and active people. PP is part of the polyuria-polydipsia syndrome, so the differential diagnosis diabetes insipidus (central or nephrogenic) must be excluded. The gold standard when differentiating between these disorders has been the water deprivation test. However, new options for distinguishing between these entities have been proposed e.g., measurement of copeptin, a reliable surrogate marker of the hormone arginine vasopressin (AVP). The major risk of excessive drinking is the development of hyponatraemia and the ensuing complications. In patients with PP, factors reducing the renal excretory capacity of the kidney such as acute illness, medications or low solute intake may accumulate in hyponatraemia. Treatment options for PP remain scarce. Different medication and behavioural therapy have been investigated, but never on a large scale and rarely in non-psychiatric patients. This review provides an overview of the pathophysiology, characteristics, complications, and outcomes of patients with PP in the medical and psychiatric patient.

Objective. Syndrome of inappropriate antidiuresis (SIADH) is the predominant cause of hyponatremia, but treatment options are unsatisfying. SGLT2 inhibitors increase urinary glucose excretion with concomitant osmotic diuresis. We therefore hypothesized SGLT2-inhibitors as a novel treatment for SIADH. Design. Double-blind placebo-controlled randomised crossover study in 14 healthy volunteers. Methods. We induced an artificial SIADH model by administration of desmopressin and overhydration. Afterwards, empagliflozin 25 mg or placebo was given in random order. The main outcomes were total urinary excretion, glucosuria, and the area under the curve (AUC) of serum sodium concentration. Outcome measures were obtained 2–8 hours after administration of study drug. Results. 14 participants (64% males), BMI 23 kg/m2 (±2.4), aged 28.6 years (±9), completed the study. Empagliflozin led to significantly increased total urinary excretion (579.3 ml (±194.8) versus 367.3 ml (±158.8); treatment effect 158 ml (CI 48.29, 267.74), p=0.017) due to glucosuria (74.18 mmol (±22.3) versus 0.12 mmol (±0.04); treatment effect (log scale) 2.85 (CI 2.75, 2.96), p

PRINCIPLES: In-hospital care of patients with community-acquired pneumonia (CAP) varies across hospitals. Understanding of the underlying factors is the basis for tailored quality improvements. Using data from a randomised controlled Swiss-wide multicentre trial, we compared length of stay (LOS) and other patient outcomes according to (A) the use of a procalcitonin (PCT)-based antibiotic stewardship protocol, (B) institution type (university vs non-university), and (C) historical time period in relation to the introduction of Diagnosis Related Group (DRG) reimbursement (2012). METHODS: We included 784 patients hospitalised with CAP from six institutions into this secondary analysis. We used multivariable regression models adjusted for age, comorbidities and disease severity to determine the influence of institution characteristics on LOS and patient outcomes. FINDINGS: LOS was significantly shorter in the institution using a PCT-based antibiotic stewardship protocol (9.2 vs 5.3 days; adjusted mean difference 3.92 days; 95% confidence interval [CI] 5.16–2.68) with shorter antibiotic treatment. There was no difference in LOS in university vs non-university hospitals, but antibiotic courses in university-type hospitals were longer (11.0 vs 8.3 days; adjusted mean difference 2.59 days; 95% CI, 1.69–3.49). No significant difference in LOS was found when comparing the time period before and after the introduction of the DRG system in Switzerland. CONCLUSIONS: We found differences in LOS associated with theuse of a PCT-based antibiotic stewardship protocol, which remained robust after multivariable adjustment. Importantly, the type of institution and model of reimbursement did not influence LOS in our CAP cohort. More health services research studies are needed to establish causal effects.

BackgroundCopeptin, a surrogate marker for arginin vasopressin production, is evaluated as an osmo-dependent stress and inflammatory biomarker in different diseases. We investigated copeptin during the menstrual cycle and its relationship to sex hormones, markers of subclinical inflammation and estimates of body fluid.MethodsIn 15 healthy women with regular menstrual cycles, blood was drawn on fifteen defined days of their menstrual cycle and was assayed for copeptin, progesterone, estradiol, luteinizing hormone, high-sensitive C-reactive protein, tumor necrosis factor-alpha and procalcitonin. Symptoms of fluid retention were assessed on each visit, and bio impedance analysis was measured thrice to estimate body fluid changes. Mixed linear model analysis was performed to assess the changes of copeptin across the menstrual cycle and the relationship of sex hormones, markers of subclinical inflammation and estimates of body fluid with copeptin.ResultsCopeptin levels did not significantly change during the menstrual cycle (p = 0.16). Throughout the menstrual cycle, changes in estradiol (p = 0.002) and in the physical premenstrual symptom score (p = 0.01) were positively related to copeptin, but changes in other sex hormones, in markers of subclinical inflammation or in bio impedance analysis-estimated body fluid were not (all p = ns).ConclusionAlthough changes in estradiol and the physical premenstrual symptom score appear to be related to copeptin changes, copeptin does not significantly change during the menstrual cycle.

IntroductionRapid and accurate risk stratification in patients with community-acquired pneumonia (CAP) is an unmet clinical need. Cortisol to dehydroepiandrosterone (DHEA) ratio was put forward as a prognostic marker in sepsis. We herein validated the prognostic value of the adrenal hormones DHEA, DHEA-Sulfate (DHEAS), cortisol/DHEA-, cortisol/DHEAS- and DHEA/DHEAS-ratios in patients with CAP.MethodsWe assessed severity of illness using the pneumonia severity index (PSI) and measured adrenal hormone concentrations in 179 serum samples of prospectively recruited patients hospitalized with CAP. We calculated spearman rank correlation, logistic regression analysis and Kaplan Meier curves to study associations of adrenal hormones and outcomes.ResultsThere was a significant correlation between PSI score and total cortisol (r = 0.24, p = 0.001), DHEAS (r = -0.23, p = 0.002), cortisol/DHEA (r = 0.23, p = 0.003), cortisol/DHEAS (r = 0.32, p = ConclusionCortisol, DHEAS and their ratios correlate with CAP severity, and cortisol and DHEA predict mortality. Adrenal function in severe pneumonia may be an important factor for CAP outcomes.

We analyzed the prognostic value of b-type natriuretic peptide (BNP) and sensitive cardiac Troponin (s-cTnI) in patients with ischemic stroke or transient ischemic attack (TIA) and their significance in predicting stroke aetiology.In a prospectively enrolled cohort we measured BNP and s-cTnI levels upon admission. Primary endpoints were mortality, unfavorable functional outcome and stroke recurrence after 90 days and after 12 months. Secondary endpoint was cardioembolic aetiology.In 441 patients BNP but not s-cTnI remained an independent predictor for death with an adjusted HR of 1.2 (95% CI 1.1-1.4) after 90 days and 1.2 (95% CI 1.0-1.3) after one year. The comparison of the Area under Receiver Operating Characteristic (AUROC) of model A (age, NIHSS) and model B (age, NIHSS, BNP) showed an improvement in the prediction of mortality (0.85 (95% CI 0.79-0.90) vs. 0.86 (95% CI 0.81-0.92), Log Rank p = 0.004). Furthermore the category free net reclassification improvement (cfNRI) when adding BNP to the multivariate model was 57.5%, p

In this study, we assessed the relationship of insular strokes and plasma MR-proANP levels with newly diagnosed atrial fibrillation (NDAF).This study is based on a prospective acute stroke cohort (http://www.clinicaltrials.gov, NCT00390962). Patient eligibility was dependent on the diagnosis of acute ischemic stroke, absence of previous stroke based on past medical history and MRI, no history of AF and congestive heart failure (cohort A) and, additionally, no stroke lesion size ≥ 20 mL (sub-cohort A*). AF, the primary endpoint, was detected on 24-hour electrocardiography and/or echocardiography. Involvement of the insula was assessed by two experienced readers on MRI blinded to clinical data. MR-proANP levels were obtained through a novel sandwich immunoassay. Logistic-regression-models were fitted to estimate odds ratios for the association of insular strokes and MR-proANP with NDAF. The discriminatory accuracy of insular strokes and MR-proANP was assessed by a model-wise comparison of the area under the receiver-operating-characteristics-curve (AUC) with known predictors of AF.104 (cohort A) and 83 (cohort A*) patients fulfilled above-mentioned criteria. Patients with isolated insular strokes had a 10.7-fold higher odds of NDAF than patients with a small ischemic stroke at any other location. The AUC of multivariate logistic regression models for the prediction of NDAF improved significantly when adding stroke location and MR-proANP levels. Moreover, MR-proANP levels remained significantly elevated throughout the acute hospitalization period in patients with NDAF compared to those without.Isolated insular strokes and plasma MR-proANP levels on admission are independent predictors of NDAF and significantly improve the prediction accuracy of identifying patients with NDAF compared to known predictors including age, the NIHSS and lesion size. To accelerate accurate diagnosis and enhance secondary prevention in acute stroke, higher levels of MR-proANP and insular strokes may represent easily accessible indicators of AF if confirmed in an independent validation cohort.

Acute stroke has a high morbidity and mortality. We evaluated the predictive value of adrenal function testing in acute ischemic stroke.In a cohort of 231 acute ischemic stroke patients, we measured dehydroepiandrosterone (DHEA), DHEA-Sulfate (DHEAS), cortisol at baseline and 30 minutes after stimulation with 1 ug ACTH. Delta cortisol, the amount of rise in the 1 ug ACTH-test, was calculated. Primary endpoint was poor functional outcome defined as modified Rankin scale 3-6 after 1 year. Secondary endpoint was nonsurvival after 1 year.Logistic regression analysis showed that DHEAS (OR 1.21, 95% CI 1.01-1.49), but not DHEA (OR 1.01, 95% CI 0.99-1.04), was predictive for adverse functional outcome. Neither DHEA (OR 0.99, 95% CI 0.96-1.03) nor DHEAS (OR 1.10, 95% CI 0.82-1.44) were associated with mortality. Baseline and stimulated cortisol were predictive for mortality (OR 1.41, 95% CI 1.20-1.71; 1.35, 95% CI 1.15-1.60), but only basal cortisol for functional outcome (OR 1.20, 95% CI 1.04-1.38). Delta cortisol was not predictive for functional outcome (OR 0.86, 95% CI 0.71-1.05) or mortality (OR 0.92, 95% CI 0.72-1.17). The ratios cortisol/DHEA and cortisol/DHEAS discriminated between favorable outcome and nonsurvival (both p

Copeptin, a marker for stress mirroring vasopressin concentrations, has been shown to increase upon insulin-induced hypoglycaemia in patients after transsphenoidal surgery of pituitary adenomas. Patients with type 1 diabetes mellitus are prone to hypoglycaemia, but no data about copeptin levels upon hypoglycaemia are available. Furthermore, the perception of hypoglycaemia can vary from total unawareness to disabling episodes. The aim of this study was to investigate whether copeptin increases upon hypoglycaemia in patients with type 1 diabetes mellitus and is associated with the degree of hypoglycaemia awareness.In this prospective observational study, 17 patients with type 1 diabetes underwent a standardized insulin infusion test. Blood sampling for glucose and copeptin was performed at baseline and after 60 minutes (min). To assess hypoglycaemia associated symptoms the Mood and Symptom Questionnaire (MSQ) was conducted at baseline and after 60 min.During insulin infusion, blood glucose decreased from 5.1 (SD±0.2) to 3.0 (±0.5) mmol/L at 60 min (p

The definition of late onset hypogonadism in the aging male is controversially debated, and according to the latest literature consists of at least three especially sexual symptoms such as loss of morning erection, low sexual desire and erectile dysfunction as well as a total testosterone

Early predictors for the development of stroke-associated infection may identify patients at high risk and reduce post-stroke infection and mortality.In 383 prospectively enrolled acute stroke patients we assessed time point and type of post-stroke infections (i.e. pneumonia, urinary tract infection (UTI) other infection (OI)). Blood samples were collected on admission, and days 1, and 3 to assess white blood cells (WBC), monocytes, C-reactive protein (CRP), procalcitonin (PCT), and copeptin. To determine the magnitude of association with the development of infections, odds ratios (OR) were calculated for each prognostic blood marker. The discriminatory ability of different predictors was assessed, by calculating area under the receiver operating characteristic curves (AUC). Prognostic models including the three parameters with the best performance were identified.Of 383 patients, 66 (17.2%) developed an infection after onset of stroke. WBC, CRP, copeptin and PCT were all independent predictors of any infection, pneumonia and UTI developed at least 24 hours after measurements. The combination of the biomarkers WBC, CRP and copeptin (AUC: 0.92) and WBC, CRP and PCT (AUC: 0.90) showed a better predictive accuracy concerning the development of pneumonia during hospitalization compared to each marker by itself (p-Wald