An Update Based on the SCORE-Deutschland Risk Charts

Estimation of absolute risk of cardiovascular disease (CVD), preferably with population-specific risk charts, has become a cornerstone of CVD primary prevention. Regular recalibration of risk charts may be necessary due to decreasing CVD rates and CVD risk factor levels. The SCORE risk charts for fatal CVD risk assessment were first calibrated for Germany with 1998 risk factor level data and 1999 mortality statistics. We present an update of these risk charts based on the SCORE methodology including estimates of relative risks from SCORE, risk factor levels from the German Health Interview and Examination Survey for Adults 2008–11 (DEGS1) and official mortality statistics from 2012. Competing risks methods were applied and estimates were independently validated. Updated risk charts were calculated based on cholesterol, smoking, systolic blood pressure risk factor levels, sex and 5-year age-groups. The absolute 10-year risk estimates of fatal CVD were lower according to the updated risk charts compared to the first calibration for Germany. In a nationwide sample of 3062 adults aged 40–65 years free of major CVD from DEGS1, the mean 10-year risk of fatal CVD estimated by the updated charts was lower by 29% and the estimated proportion of high risk people (10-year risk > = 5%) by 50% compared to the older risk charts. This recalibration shows a need for regular updates of risk charts according to changes in mortality and risk factor levels in order to sustain the identification of people with a high CVD risk

Perioperative changes in osteopontin and TGFβ1 plasma levels and their prognostic impact for radiotherapy in head and neck cancer

Background: In head and neck cancer little is known about the kinetics of osteopontin (OPN) expression after tumor resection. In this study we evaluated the time course of OPN plasma levels before and after surgery. Methods: Between 2011 and 2013 41 consecutive head and neck cancer patients were enrolled in a prospective study (group A). At different time points plasma samples were collected: T0) before, T1) 1 day, T2) 1 week and T3) 4 weeks after surgery. Osteopontin and TGFβ1 plasma concentrations were measured with a commercial ELISA system. Data were compared to 131 head and neck cancer patients treated with primary (n = 42) or postoperative radiotherapy (n = 89; group B1 and B2). Results: A significant OPN increase was seen as early as 1 day after surgery (T0 to T1, p < 0.01). OPN levels decreased to base line 3-4 weeks after surgery. OPN values were correlated with postoperative TGFβ1 expression suggesting a relation to wound healing. Survival analysis showed a significant benefit for patients with lower OPN levels both in the primary and postoperative radiotherapy group (B1: 33 vs 11.5 months, p = 0.017, B2: median not reached vs 33.4, p = 0.031). TGFβ1 was also of prognostic significance in group B1 (33.0 vs 10.7 months, p = 0.003). Conclusions: Patients with head and neck cancer showed an increase in osteopontin plasma levels directly after surgery. Four weeks later OPN concentration decreased to pre-surgery levels. This long lasting increase was presumably associated to wound healing. Both pretherapeutic osteopontin and TGFβ1 had prognostic impact

Clinical Characterization of Symptomatic Microangiopathic Brain Lesions

Background: Microangiopathic brain lesions can be separated in diffuse lesions – leukoaraiosis – and focal lesions – lacunes. Leukoaraiosis and lacunes are caused by common cerebrovascular risk factors, but whether they represent a common entity is not sufficiently investigated. The present study aimed to determine the clinical profiles associated with the extent of leukoaraiosis and lacunes. Methods: Sixty-four consecutive patients with acute microangiopathic stroke were studied. Leukoaraiosis and lacunes were stratified according to their MRI-based extent. Standardized clinical assessment included clinical syndromes, cerebrovascular risk factors, cognitive performance, retinal imaging, ultrasonography, blood, and urine parameters. Results: Different clinical profiles for leukoaraiosis and lacunes were found. Regarding leukoaraiosis, the cognitive scores (SISCO, mini mental score examination, mental examination) and the presence of hyperlipidemia decreased as the severity of leukoaraiosis increased. Univariate and multivariate analysis revealed that these cognitive score values as well as the presence of hyperlipidemia correlated significantly with no or only mild leukoaraiosis. Regarding lacunes, the percentage of migraine, previous stroke events, hydrocephalus, left ventricular hypertrophy, and a higher National Institutes of Health Stroke Scale increased as the number of lacunar lesions increased. Statistical analysis revealed that these parameters correlated not significantly with the number of lacunes. Conclusions: The findings suggests that leukoaraiosis and lacunes are different microangiopathic entities potentially requiering different treatment concepts

Serious Adverse Drug Reactions in Children and Adolescents Treated On- and Off-Label with Antidepressants and Antipsychotics in Clinical Practice

Introduction: Despite the growing evidence base for psychotropic drug treatment in pediatric patients, knowledge about the benefit-risk ratio in clinical practice remains limited. The 'Therapeutic Drug Monitoring (TDM)-VIGIL' study aimed to evaluate serious adverse drug reactions (ADRs) in children and adolescents treated with antidepressants and/or antipsychotics in approved ('on-label'), and off-label use in clinical practice. Methods: Psychiatric pediatric patients aged 6-18 years treated with antidepressants and/or antipsychotics either on-label or off-label were prospectively followed between October 2014 and December 2018 within a multicenter trial. Follow-up included standardized assessments of response, serious ADRs and therapeutic drug monitoring. Results: 710 youth (age=14.6±2.2 years, female=66.6%) were observed for 5.5 months on average; 76.3% received antidepressants, 47.5% antipsychotics, and 25.2% both. Altogether, 55.2% of the treatment episodes with antidepressants and 80.7% with antipsychotics were off-label. Serious ADRs occurred in 8.3% (95%CI=6.4-10.6%) of patients, mainly being psychiatric adverse reactions (77.4%), predominantly suicidal ideation and behavior. The risk of serious ADRs was not significantly different between patients using psychotropics off-label and on-label (antidepressants: 8.1% vs. 11.3%, p=0.16; antipsychotics: 8.7% vs 7.5%, p=0.67). Serious ADRs occurred in 16.6% of patients who were suicidal at enrollment versus 5.6% of patients who were not suicidal (relative risk 3.0, 95%CI=1.9-4.9). Conclusion: Off-label use of antidepressants and antipsychotics in youth was not a risk factor for the occurrence of serious ADRs in a closely monitored clinical setting. Results from large naturalistic trials like ours can contribute to bridging the gap between knowledge from randomized controlled trials and real-world clinical settings

Therapeutic drug monitoring of sertraline in children and adolescents: A naturalistic study with insights into the clinical response and treatment of obsessive-compulsive disorder.

BACKGROUND Sertraline is a selective serotonin reuptake inhibitor with specific indications in child and adolescent psychiatry. Notwithstanding its frequent use and clinical benefits, the relationship between pharmacokinetics, pharmacodynamics, efficacy, and tolerability of sertraline across indications, particularly in non-adult patients, is not fully understood. METHOD This naturalistic therapeutic drug monitoring (TDM) study was conducted in a transdiagnostic sample of children and adolescents treated with sertraline (n = 78; mean age, 14.22 ± 2.39; range, 7-18 years) within the prospective multicenter "TDM-VIGIL" project. Associations between dose, serum concentration, and medication-specific therapeutic and side effects based on the Clinical Global Impression scale were examined. Tolerability was measured qualitatively with the 56-item Pediatric Adverse Event Rating Scale. RESULTS A strong linear positive dose-serum concentration relationship (with dose explaining 45% of the variance in concentration) and significant effects of weight and co-medication were found. Neither dose nor serum concentration were associated with side effects. An overall mild-to-moderate tolerability profile of sertraline was observed. In contrast with the transdiagnostic analysis that did not indicate an effect of concentration, when split into depression (MDD) and obsessive-compulsive disorder (OCD) diagnoses, the probability of clinical improvement significantly increased as both dose and concentration increased for OCD, but not for MDD. CONCLUSIONS This TDM-flexible-dose study revealed a significant diagnosis-specific effect between sertraline serum concentration and clinical efficacy for pediatric OCD. While TDM already guides clinical decision-making regarding compliance, dose calibration, and drug-drug interactions, combining TDM with other methods, such as pharmacogenetics, may facilitate a personalized medicine approach in psychiatry

Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial

Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial (“TDM-VIGIL”), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7–18 years; 24.6% males) was treated with fluoxetine (10–40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208–328 ng/mL (transdiagnostically) and 201.5–306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose–serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults

Environmental factors in early childhood are associated with multiple sclerosis: a case-control study

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with increasing incidence mainly in high-income countries. One explanation of this phenomenon may be a higher prevalence of allergic and autoimmune diseases in industrialized countries as a consequence of otherwise beneficial advances in sanitation (hygiene hypothesis). We investigated environmental factors in early childhood associated with MS.</p> <p>Methods</p> <p>A case-control study was performed of 245 MS patients and 296 population-based controls in Berlin. The study participants completed a standardized questionnaire on environmental factors in childhood and youth, including aspects of personal and community hygiene. Multivariable logistic regression analysis was performed to investigate factors in childhood and youth associated with the occurrence of MS.</p> <p>Results</p> <p>Mean age was 46 years (range, 20-80) in the MS group and 42 years (range 18-80) in the control group, of which 73.9% in the MS and 61.5% in the control group were female. The multivariable analysis showed that having at least two older siblings (OR 0.54; p = 0.05, for individuals with two older siblings compared to individuals without older siblings), attending a day-care center (OR 0.5; p = 0.004) and growing up in an urban center with more than 100, 000 inhabitants (OR 0.43; p = 0.009) were factors independently associated with a lower chance for MS.</p> <p>Conclusions</p> <p>The hygiene hypothesis may play a role in the occurrence of MS and could explain disease distribution and increasing incidence.</p

FGF-21 levels in polyuria-polydipsia syndrome

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

Influence of Ocean Acidification on a Natural Winter-to-Summer Plankton Succession : First Insights from a Long-Term Mesocosm Study Draw Attention to Periods of Low Nutrient Concentrations

Every year, the oceans absorb about 30% of anthropogenic carbon dioxide (CO2) leading to a re-equilibration of the marine carbonate system and decreasing seawater pH. Today, there is increasing awareness that these changes-summarized by the term ocean acidification (OA)-could differentially affect the competitive ability of marine organisms, thereby provoking a restructuring of marine ecosystems and biogeochemical element cycles. In winter 2013, we deployed ten pelagic mesocosms in the Gullmar Fjord at the Swedish west coast in order to study the effect of OA on plankton ecology and biogeochemistry under close to natural conditions. Five of the ten mesocosms were left unperturbed and served as controls (similar to 380 mu atm pCO(2)), whereas the others were enriched with CO2-saturated water to simulate realistic end-of-the-century carbonate chemistry conditions (mu 760 mu atm pCO(2)). We ran the experiment for 113 days which allowed us to study the influence of high CO2 on an entire winter-to-summer plankton succession and to investigate the potential of some plankton organisms for evolutionary adaptation to OA in their natural environment. This paper is the first in a PLOS collection and provides a detailed overview on the experimental design, important events, and the key complexities of such a "long-term mesocosm" approach. Furthermore, we analyzed whether simulated end-of-the-century carbonate chemistry conditions could lead to a significant restructuring of the plankton community in the course of the succession. At the level of detail analyzed in this overview paper we found that CO2-induced differences in plankton community composition were non-detectable during most of the succession except for a period where a phytoplankton bloom was fueled by remineralized nutrients. These results indicate: (1) Long-term studies with pelagic ecosystems are necessary to uncover OA-sensitive stages of succession. (2) Plankton communities fueled by regenerated nutrients may be more responsive to changing carbonate chemistry than those having access to high inorganic nutrient concentrations and may deserve particular attention in future studies.Peer reviewe