E.R. van den Heuvel

Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

ABSTRACT Voriconazole (VCZ) exhibits great inter- and intrapatient variability. The latter variation cannot exclusively be explained by concomitant medications, liver disease or dysfunction, and genetic polymorphisms in cytochrome P450 2C19 (CYP2C19). We hypothesized that inflammatory response in patients under VCZ medication might also influence this fluctuation in concentrations. In this study, we explored the association between inflammation, reflected by the C-reactive protein (CRP) concentration, and VCZ trough concentrations over time. A retrospective analysis of data was performed for patients with more than one steady-state VCZ trough concentration and a CRP concentration measured on the same day. A longitudinal analysis was used for series of observations obtained from many study participants over time. The approach involved inclusion of random effects and autocorrelation in linear models to reflect within-person cross-time correlation. A total of 50 patients were eligible for the study, resulting in 139 observations (paired VCZ and CRP concentrations) for the analysis, ranging from 2 to 6 observations per study participant. Inflammation, marked by the CRP concentration, had a significant association with VCZ trough concentrations (P < 0.001). Covariates such as age and interacting comedication ([es]omeprazole), also showed a significant correlation between VCZ and CRP concentrations (P < 0.05). The intrapatient variation of trough concentrations of VCZ was 1.401 (confidence interval [CI], 0.881 to 2.567), and the interpatient variation was 1.756 (CI, 0.934 to 4.440). The autocorrelation between VCZ trough concentrations at two sequential time points was calculated at 0.71 (CI, 0.51 to 0.92). The inflammatory response appears to play a significant role in the largely unpredictable pharmacokinetics of VCZ, especially in patients with high inflammatory response, as reflected by high CRP concentrations.

Age of onset of recurrent respiratory papillomatosis: a distribution analysis

Distribution of age of onset of recurrent respiratory papillomatosis (RRP) is generally described to be bimodal, with peaks at approximately 5 years and 30 years. This assumption has never been scientifically confirmed, and authors tend to refer to an article that does not describe distribution. Knowledge of the distribution of age of onset is important for virological and epidemiological comprehension. The objective of this study was to determine the distribution of age of onset of RRP in a large international sample.

Influence of inflammation on voriconazole metabolism

ABSTRACT Voriconazole pharmacokinetics shows a large inter- and intrapatient variability. Inflammation is associated with changes in the expression of CYP isoenzymes. Here, we evaluated the influence of inflammation, marked by C-reactive protein (CRP) levels in blood, on the metabolism of voriconazole. Observational data showed an association between CRP level and the ratio of voriconazole N-oxide to voriconazole.

Determinants of perceived sleep quality in normal sleepers

ABSTRACT Objective: This study aimed to establish the determinants of perceived sleep quality over a longer period of time, taking into account the separate contributions of actigraphy-based sleep measures and self-reported sleep indices. Methods: Fifty participants (52 ± 6.6 years; 27 females) completed two consecutive weeks of home monitoring, during which they kept a sleep–wake diary while their sleep was monitored using a wrist-worn actigraph. The diary included questions on perceived sleep quality, sleep–wake information, and additional factors such as well-being and stress. The data were analyzed using multilevel models to compare a model that included only actigraphy-based sleep measures (model Acti) to a model that included only self-reported sleep measures to explain perceived sleep quality (model Self). In addition, a model based on the self-reported sleep measures and extended with nonsleep-related factors was analyzed to find the most significant determinants of perceived sleep quality (model Extended). Results: Self-reported sleep measures (model Self) explained 61% of the total variance, while actigraphy-based sleep measures (model Acti) only accounted for 41% of the perceived sleep quality. The main predictors in the self-reported model were number of awakenings during the night, sleep onset latency, and wake time after sleep onset. In the extended model, the number of awakenings during the night and total sleep time of the previous night were the strongest determinants of perceived sleep quality, with 64% of the variance explained. Conclusion: In our cohort, perceived sleep quality was mainly determined by self-reported sleep measures and less by actigraphy-based sleep indices. These data further stress the importance of taking multiple nights into account when trying to understand perceived sleep quality.

The relation of vitamin D, metabolic risk and negative symptom severity in people with psychotic disorders

People with psychotic disorders have an increased metabolic risk and their mean life expectancy is reduced with circa 28 years (Olfson et al., 2015).Predictors of this increased metabolic risk are genetic predisposition (Liu et al., 2013), lifestyle factors such as unhealthy diet, physical inactivity and smoking (Bobes et al., 2010), and the side effects of antipsychotic medication (Werner and Covenas, 2014;Chadda et al., 2013). Low vitamin D status might also contribute to an increased metabolic risk (Ginde et al., 2009;Kendrick et al., 2009;Kilkkinen et al., 2009;Ford et al., 2009) and all-cause mortality by promoting atherosclerosis, hypertension, inflammation and activation of the renin-angiotensin system (Wang et al., 2012;Garland et al., 2014;Lee et al., 2008). Also, one review demonstrated cardiovascular mortality rates in the general population were higher during winter than in summer (Zittermann et al., 2005). Vitamin D interacts with dopaminergic, cholinergic and noradrenergic neurotransmitter systems, which have all been implicated in Schizophrenia Research 195 (2018) 513–518 ⁎ Corresponding author at: University Medical Center Groningen, University Center for Psychiatry, Rob Giel Research center, P.O. Box 30.001 (CC72), 9700 RB Groningen, The Netherlands. E-mail addresses: j.bruins@lentis.nl (J. Bruins), f.jorg@umcg.nl (F. Jorg), e.r.v.d.heuvel@tue.nl (E.R. van den Heuvel), a.a.bartels@umcg.nl (A.A. Bartels-Velthuis), e.corpeleijn@umcg.nl (E. Corpeleijn), f.a.j.muskiet@umcg.nl (F.A.J. Muskiet), g.h.m.pijnenborg@rug.nl (G.H.M. Pijnenborg), r.bruggeman@umcg.nl (R. Bruggeman). experiencing psychotic symptoms (Eyles et al., 2013). When vitamin D is low, dopamine signalling in the brain appears to decrease (Eyles et al., 2013;Cui et al., 2015;Cui et al., 2013;Groves et al., 2014), which in its turn could lead to more severe negative symptoms of psychosis (Buchanan et al., 2007). Indeed, several studies found that vitamin D insufficiency was strongly associated with negative symptoms of psychosis (Graham et al., 2015;Yuksel et al., 2014;Cieslak et al., 2014;Ottesen Berg et al., 2010). Vitamin D is thus associated with both metabolic risk and negative symptom severity. Negative symptoms have also been shown to interfere with patients ability to be physically active and make healthy lifestyle choices, which can increase their metabolic risk (Bergqvist et al., 2013). Negative symptom severity may therefore mediate the association between low vitamin D and increased metabolic risk in people with a psychotic disorder. Vitamin D is mostly produced in the skin by exposure to ultravioletB radiation in sunlight (Brown et al., 1999;Holick, 2007). Absorption of vitamin D and levels of circulation differ among individuals and can be influenced by determinants such as latitude, season, time of day, skin color (Holick et al., 2011), bodyweight, age, calcium intake (Zittermann et al., 2014), diet and genetics (Mazahery and von Hurst, 2015). Vitamin D shows a natural fluctuation throughout the year, with vitamin D insufficiency more likely to occur during winter than in summer (Rosecrans and Dohnal, 2014). A recent study suggests seasonality may also affect clinical symptoms of schizophrenia, although the underlying mechanism is unknown (Byrne et al., 2015). In this study we aim to investigate whether vitamin D levels are associated with metabolic risk in people with psychotic disorders and whether this effect was mediated by negative symptoms. We hypothesize that vitamin D levels may influence the severity of metabolic disturbances and negative symptoms. As vitamin D levels naturally fluctuate throughout the seasons (Rosecrans and Dohnal, 2014), we examine whether metabolic risk and negative symptom severity follow a similar seasonal fluctuation pattern. Furthermore, we investigate whether the http://dx.doi.org/10.1016/j.schres.2017.08.059 0920-9964/© 2017 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres severity of metabolic risk and negative symptoms differ between patients using and patients not using vitamin D supplementation. In this cross-sectional study, seasonal patterns and differences with regard to supplementation may indicate an interdependent and potentially causal connection between vitamin D, metabolic risk and negative symptom severity

Adult periodontitis treated with a new device for subgingival lavage-a randomized controlled clinical trial using a split-mouth design

OBJECTIVESnTo evaluate in patients with untreated adult periodontitis, the effect of treatment with a novel pocket irrigator/evacuator device (IED) compared to conventional subgingival debridement (CPT), both provided during the initial phase of active periodontal therapy.nnnMETHODSnThis study was an examiner-blind, randomized controlled clinical trial using a split-mouth design. Systemically healthy patients with adult periodontitis were selected. Full-mouth probing pocket depth (PPD), gingival bleeding on pocket probing scores (BOPP), gingival recession (REC) and dental plaque (PI) were assessed at baseline. All participants received oral hygiene instructions and supragingival prophylaxis including polishing. In 2 randomly assigned contra-lateral quadrants, approximal sites were irrigated with the IED, whereas in the other quadrants, CPT was provided. The CPT consisted of subgingival debridement using ultrasonic devices followed by the use of hand instruments. At 3xa0months post-treatment, the clinical parameters were re-assessed.nnnRESULTSnTwenty-five patients met the inclusion criteria and were willing to participate. At 3xa0months post-treatment, the PPD and BOPP had significantly improved for both treatment modalities. Pockets of ≥5xa0mm reduced by 0.64xa0mm in the IED group (Pxa0<xa0.001), compared to a reduction of 0.82xa0mm for the CPT group (Pxa0<xa0.001). With respect to the primary outcome parameter (PPD) and BI, the results with the IED were less pronounced. Between the test and control groups, no significant differences were observed for REC and PI.nnnCONCLUSIONSnOral hygiene instructions, supragingival prophylaxis and subgingival lavage with the IED resulted in a significant reduction in PPD and BOPP. However, the effect does not reach the results of CPT which included the subgingival use of ultrasonic and hand instruments.

Long-term cognitive trajectories and heterogeneity in patients with schizophrenia and their unaffected siblings

This study aimed to assess the heterogeneity and stability of cognition in patients with a non‐affective psychotic disorder and their unaffected siblings. In addition, we aimed to predict the cognitive subtypes of siblings by their probands.

Familial liability to psychosis is a risk factor for multimorbidity in people with psychotic disorders and their unaffected siblings

BACKGROUNDnMultimorbidity may impose an overwhelming burden on patients with psychosis and is affected by gender and age. Our aim is to study the independent role of familial liability to psychosis as a risk factor for multimorbidity.nnnMETHODSnWe performed the study within the framework of the Genetic Risk and Outcome of Psychosis (GROUP) project. Overall, we compared 1024 psychotic patients, 994 unaffected siblings and 566 controls on the prevalence of 125 lifetime diseases, and 19 self-reported somatic complaints. Multimorbidity was defined as the presence of two or more complaints/diseases in the same individual. Generalized linear mixed model (GLMM) were used to investigate the effects of gender, age (adolescent, young, older) and familial liability (patients, siblings, controls) and their interactions on multimorbidity.nnnRESULTSnFamilial liability had a significant effect on multimorbidity of either complaints or diseases. Patients had a higher prevalence of multimorbidity of complaints compared to siblings (OR 2.20, 95% CI 1.79-2.69, P<0.001) and to controls (3.05, 2.35-3.96, P<0.001). In physical health multimorbidity, patients (OR 1.36, 95% CI 1.05-1.75, P=0.018), but not siblings, had significantly higher prevalence than controls. Similar finding were observed for multimorbidity of lifetime diseases, including psychiatric diseases. Significant results were observed for complaints and disease multimorbidity across gender and age groups.nnnCONCLUSIONnMultimorbidity is a common burden, significantly more prevalent in patients and their unaffected siblings. Familial liability to psychosis showed an independent effect on multimorbidity; gender and age are also important factors determining multimorbidity.