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Effective pharmacologic treatments for psychiatric disorders are available, but their effect is limited due to patients’ genetic heterogeneity and low compliance-related to frequent adverse events. Only one third of patients respond to treatment and experience remission. Pharmacogenetics is a relatively young field which focusses on genetic analyses in the context of the metabolism and outcome of drug treatment. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Recently, a clinical guideline was authorized by the Dutch Clinical Psychiatric Association (NVvP) on the clinical use of pharmacogenetics in psychiatry. The main goal was to provide guidance, based on current evidence, on how to best use genotyping in clinical psychiatric practice. A systematic literature search was performed, and available publications were assessed using the GRADE methodology. General recommendations for psychiatric clinical practice were provided, and specific recommendations per medication were made available. This clinical guideline for caregivers prescribing psychotropic drugs is the product of a broad collaboration of professionals from different disciplines, making use of the information available at the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) so far. We summarize the relevant literature and all recommendations in this article. General recommendations are provided and also detailed recommendations per medication. In summary we advise to consider genotyping, when there are side effects or inefficacy for CYP2C19 and CYP2D6. When genotype information is available use this to select the right drug in the right dose for the right patient.

This is a proposal to add three Greek characters to the international character encoding standard Unicode, needed to represent text on papyri. The characters were published in Unicode Standard version 7.0 in June 2014.

Background Maternal psychopathology during pregnancy is associated with negative outcomes in offspring. Increased placental transfer of maternal cortisol may contribute to mediate this association. Hair cortisol concentrations (HCCs) appear to be a good biomarker of long-term prenatal stress exposure. Little is known about the associations between severe maternal psychopathology and perinatal infant HCCs. Aims We assessed HCCs in the perinatal period in mother–infant dyads with and without severe psychiatric disorders. Method We examined group differences in HCCs of mother–infant dyads (n = 18) subjected to severe maternal psychiatric disorders versus healthy control dyads (n = 27). We assessed the correlation of HCCs between mother and infant within both groups, and the association between current maternal symptoms and HCCs in patient dyads. Results Median (interquartile range) and distribution of HCC differed in patients compared with control mothers (U = 468.5, P = 0.03). HCCs in infants of patients did not differ from control infants (U = 250.0, P = 0.67). Subsequently, we found that HCCs within healthy control dyads were correlated (n = 27, r 0.55 (0.14), P = 0.003), but were not within patient dyads (n = 18, r 0.082 (0.13), P = 0.746). HCCs in infants of patients showed a positive correlation with maternal symptoms (n = 16, r = 0.63 (0.06), P = 0.008). Conclusions These preliminary findings suggest that infant HCC reflect perinatal stress exposure. In infants, these early differences could influence lifetime hypothalamic–pituitary–adrenal axis functioning, which might be associated with increased susceptibility to later disease.

Abstract Background To examine the mortality risk of current and life-time depressive as well as anxiety disorders, whether this risk is moderated by sex or age, and whether this risk can be explained by lifestyle and/or somatic health status. Methods A cohort study (Lifelines) including 141,377 participants (18–93 years) which were followed-up regarding mortality for 8.6 years (range 3.0–13.7). Baseline depressive and anxiety disorders according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria were assessed with the Mini International Neuropsychiatric Interview and lifetime diagnoses by self-report. All-cause mortality was retrieved from Statistics Netherlands. Cox-regression was applied to calculate proportional hazard ratios, adjusted for lifestyle (physical activity, alcohol use, smoking, and body mass index) and somatic health status (multimorbidity and frailty) in different models. Results The mortality rate of depressive and anxiety disorders was conditional upon age but not on sex. Only in people below 60 years, current depressive and anxiety disorders were associated with mortality. Only depressive disorder and panic disorder independently predicted mortality when all mental disorders were included simultaneously in one overall model (hazard ratio [HR] = 2.18 [95% confidence intervals (CI): 1.56–3.05], p

The extent of non-coding RNA alterations in patients with sepsis and their relationship to clinical characteristics, soluble mediators of the host response to infection, as well as an advocated in vivo model of acute systemic inflammation is unknown. Here we obtained whole blood from 156 patients with sepsis and 82 healthy subjects among whom eight were challenged with lipopolysaccharide in a clinically controlled setting (human endotoxemia). Via next-generation microarray analysis of leukocyte RNA we found that long non-coding RNA and, to a lesser extent, small non-coding RNA were significantly altered in sepsis relative to health. Long non-coding RNA expression, but not small non-coding RNA, was largely recapitulated in human endotoxemia. Integrating RNA profiles and plasma protein levels revealed known as well as previously unobserved pathways, including non-sensory olfactory receptor activity. We provide a benchmark dissection of the blood leukocyte ‘regulome’ that can facilitate prioritization of future functional studies.

Objectives:. Previous studies demonstrated that extensive fluid loading and consequently positive fluid balances during sepsis resuscitation are associated with adverse outcome. Yet, the association between fluid balance and mortality after reversal of shock, that is, during deresuscitation, is largely unappreciated. Our objective was to investigate the effects of fluid balance on mortality in the days after septic shock reversal. Design:. Retrospective observational cohort study. Setting:. ICUs of two university-affiliated hospitals in The Netherlands. Patients:. Adult patients admitted with septic shock followed by shock reversal. Reversal of septic shock was defined based on Sepsis-3 criteria as the first day that serum lactate was less than or equal to 2 mmol/L without vasopressor requirement. Interventions:. None. Measurements and Main Results:. Reversal of septic shock occurred in 636 patients, of whom 20% died in the ICU. Mixed-effects logistic regression modeling, adjusted for possible confounders, showed that fluid balance in the days after reversal of septic shock (until discharge or death) was an independent predictor of ICU mortality: odds ratio 3.18 (1.90–5.32) per 10 mL/kg increase in daily fluid balance. Similar results were found for 30-day, 90-day, hospital, and 1-year mortality: odds ratios 2.09 (1.64–2.67); 1.79 (1.38–2.32); 1.70 (1.40–2.07); and 1.53 (1.17–2.01), respectively. Positive cumulative fluid balances vs. neutral or negative fluid balances on the final day in the ICU were associated with increased ICU, hospital, 30-day, and 90-day mortality: odds ratios 3.46 (2.29–5.23); 3.39 (2.35–4.9); 5.33 (3.51–8.08); and 3.57 (2.49–5.12), respectively. Using restricted cubic splines, we found a dose-response relationship between cumulative fluid balance after shock reversal and ICU mortality. Conclusions:. A higher fluid balance in the days after septic shock reversal was associated with increased mortality. This stresses the importance of implementing restrictive and deresuscitative fluid management strategies after initial hemodynamic resuscitation. Prospective interventional studies are needed to confirm our results.

Objectives Approximately 11%–13% of pregnant women suffer from depression. Bright light therapy (BLT) is a promising treatment, combining direct availability, sufficient efficacy, low costs and high safety for both mother and child. Here, we examined the effects of BLT on depression during pregnancy.Design Randomised, double-blind controlled trial.Setting Primary and secondary care in The Netherlands, from November 2016 to March 2019.Participants 67 pregnant women (12–32 weeks gestational age) with a DSM-5 diagnosis of depressive disorder (Diagnostic and Statistical Manual of Mental Disorders).Interventions Participants were randomly allocated to treatment with either BLT (9000 lux, 5000 K) or dim red light therapy (DRLT, 100 lux, 2700 K), which is considered placebo. For 6 weeks, both groups were treated daily at home for 30 min on awakening. Follow-up took place weekly during the intervention, after 6 weeks of therapy, 3 and 10 weeks after treatment and 2 months postpartum.Primary and secondary outcome measures Depressive symptoms were measured primarily with the Structured Interview Guide for the Hamilton Depression Scale—Seasonal Affective Disorder. Secondary measures were the Hamilton Rating Scale for Depression and the Edinburgh Postnatal Depression Scale. Changes in rating scale scores of these questionnaires over time were analysed using generalised linear mixed models.Results Median depression scores decreased by 40.6%–53.1% in the BLT group and by 50.9%–66.7% in the DRLT group. We found no statistically significant difference in symptom change scores between BLT and DRLT. Sensitivity and post-hoc analyses did not change our findings.Conclusions Depressive symptoms of pregnant women with depression improved in both treatment arms. More research is necessary to determine whether these responses represent true treatment effects, non-specific treatment responses, placebo effects or a combination hereof.Trial registration number NTR5476.

In the complex with von Willebrand factor (VWF) factor VIII (FVIII) is protected from rapid clearance from circulation. Although it has been established that the FVIII binding site resides in the N-terminal D’-D3 domains of VWF, detailed information about the amino acid regions that contribute to FVIII binding is still lacking. In the present study, hydrogen-deuterium exchange mass spectrometry was employed to gain insight into the FVIII binding region on VWF. To this end, time-dependent deuterium incorporation was assessed in D’-D3 and the FVIII-D’-D3 complex. Data showed reduced deuterium incorporation in the D’ region Arg782-Cys799 in the FVIII-D’-D3 complex compared to D’-D3. This implies that this region interacts with FVIII. Site-directed mutagenesis of the six charged amino acids in Arg782-Cys799 into alanine residues followed by surface plasmon resonance analysis and solid phase binding studies revealed that replacement of Asp796 affected FVIII binding. A marked decrease in FVIII binding was observed for the D’-D3 Glu787Ala variant. The same was observed for D’-D3 variants in which Asp796 and Glu787 were replaced by Asn796 and Gln787. Site-directed mutagenesis of Leu786, which together with Glu787 and Cys789 forms a short helical region in the crystal structure of D’-D3, also had a marked impact on FVIII binding. The combined results show that the amino acid region Arg782-Cys799 is part of a FVIII binding surface. Our study provides new insight into FVIII-VWF complex formation and defects therein that may be associated with bleeding caused by markedly reduced levels of FVIII.

Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia. Despite the high prevalence, the cause of PVCs remains elusive in most patients. A better understanding of the underlying pathophysiological mechanism may help to steer future research. This review aims to provide an overview of the potential pathophysiological mechanisms of PVCs and their differentiation.

Hypoxia is associated with increased erythropoietin (EPO) release to drive erythropoiesis. At high altitude, EPO levels first increase and then decrease, although erythropoiesis remains elevated at a stable level. The roles of hypoxia and related EPO adjustments are not fully understood, which has contributed to the formulation of the theory of neocytolysis. We aimed to evaluate the role of oxygen exclusively on erythropoiesis, comparing in vitro erythroid differentiation performed at atmospheric oxygen, a lower oxygen concentration (three percent oxygen) and with cultures of erythroid precursors isolated from peripheral blood after a 19-day sojourn at high altitude (3450 m). Results highlight an accelerated erythroid maturation at low oxygen and more concave morphology of reticulocytes. No differences in deformability were observed in the formed reticulocytes in the tested conditions. Moreover, hematopoietic stem and progenitor cells isolated from blood affected by hypoxia at high altitude did not result in different erythroid development, suggesting no retention of a high-altitude signature but rather an immediate adaptation to oxygen concentration. This adaptation was observed during in vitro erythropoiesis at three percent oxygen by a significantly increased glycolytic metabolic profile. These hypoxia-induced effects on in vitro erythropoiesis fail to provide an intrinsic explanation of the concept of neocytolysis.

Background: Among people living with frailty, adherence to a healthy lifestyle may be a low-cost and effective strategy to decrease frailty-induced health risks across different social environments. Methods: We included 15 594 frail participants at baseline from the UK Biobank study. We used four lifestyle factors to create a composite healthy lifestyle score and 17 social factors to construct a polysocial score. We classified the lifestyle score into two levels (unhealthy and healthy) and the polysocial score into three levels (low, intermediate and high). We used Cox regression to determine the association of each lifestyle factor and lifestyle score with all-cause mortality, respectively. We also examined the associations across polysocial score categories. We evaluated the joint association of the lifestyle score and the categorical polysocial score with all-cause mortality. Results: During up to 14.41 follow-up years, we documented 3098 all-cause deaths. After multivariable adjustment, we found a significant association between not smoking and adequate physical activity with all-cause mortality across polysocial score categories, respectively. We also found a significant association between a healthy diet and all-cause mortality among frail participants living in an intermediate social environment. A healthy lifestyle was associated with a lower all-cause mortality risk across polysocial score categories, especially among those with a low polysocial score. Conclusions: Adherence to a healthy lifestyle, particularly not smoking, adequate physical activity and a healthy diet, may provide a feasible solution to decreasing mortality risk among frail adults across different social environments, especially for those in the socially disadvantaged group. [ABSTRACT FROM AUTHOR]

Background: Impaired intestinal barrier function can enable passage of enteric microorganisms into the bloodstream and lead to nosocomial bloodstream infections during critical illness. We aimed to determine the relative importance of gut translocation as a source for ICU-acquired enterococcal bacteremia of unknown origin. Methods: We conducted a nested case–control study in two mixed medical-surgical tertiary ICUs in the Netherlands among patients enrolled between 2011 and 2018. We selected 72 cases with ICU-acquired bacteremia due to enterococci (which are known gastrointestinal tract commensals) and 137 matched controls with bacteremia due to coagulase-negative staphylococci (CoNS) (which are of non-intestinal origin). We measured intestinal fatty acid-binding protein, trefoil factor-3, and citrulline 48 h before bacteremia onset. A composite measure for Gut Barrier Injury (GBI) was calculated as the sum of standardized z-scores for each biomarker plus a clinical gastrointestinal failure score. Results: No single biomarker yielded statistically significant differences between cases and controls. Median composite GBI was higher in cases than in controls (0.58, IQR − 0.36–1.69 vs. 0.32, IQR − 0.53–1.57, p = 0.33) and higher composite measures of GBI correlated with higher disease severity and ICU mortality (p < 0.001). In multivariable analysis, higher composite GBI was not significantly associated with increased occurrence of enterococcal bacteremia relative to CoNS bacteremia (adjusted OR 1.12 95% CI 0.93–1.34, p = 0.22). Conclusions: We could not demonstrate an association between biomarkers of gastrointestinal barrier dysfunction and an increased occurrence of bacteremia due to gut compared to skin flora during critical illness, suggesting against bacterial translocation as a major vector for acquisition of nosocomial bloodstream infections in the ICU. [ABSTRACT FROM AUTHOR]

Malocclusion is a common finding in both companion animals and humans due to dental or maxillofacial discrepancies. Treatment depends on the complications and the species it presents in. In humans, orthognathic surgery is commonly performed to address skeletal malocclusions. A male chimpanzee born in 2002 and orphaned due to the bush meat pet trade was rescued in 2010 by Chimp Eden, a chimpanzee sanctuary. In 2017, it presented with inappetence and weight loss of 6‐month duration. After a computed tomography scan was performed and full mouth impressions were made, a diagnosis of asymmetry of the mandible with the left side markedly shorter and rotated along its long axis was made (malocclusion class IV in a side‐to‐side direction). A bilateral sagittal split operation was performed to correct the malocclusion and improve its feeding. At the time of writing this report, it was eating freely and no complications were seen on multiple post‐operative radiographs. [ABSTRACT FROM AUTHOR]

Introduction Frailty is associated with adverse outcomes among patients attending emergency departments (EDs). While multiple frailty screens are available, little is known about which variables are important to incorporate and how best to facilitate accurate, yet prompt ED screening. To understand the core requirements of frailty screening in ED, we conducted an international, modified, electronic two-round Delphi consensus study. Methods A two-round electronic Delphi involving 37 participants from 10 countries was undertaken. Statements were generated from a prior systematic review examining frailty screening instruments in ED (logistic, psychometric and clinimetric properties). Reflexive thematic analysis generated a list of 56 statements for Round 1 (August–September 2021). Four main themes identified were: (i) principles of frailty screening, (ii) practicalities and logistics, (iii) frailty domains and (iv) frailty risk factors. Results In Round 1, 13/56 statements (23%) were accepted. Following feedback, 22 new statements were created and 35 were re-circulated in Round 2 (October 2021). Of these, 19 (54%) were finally accepted. It was agreed that ideal frailty screens should be short (<5 min), multidimensional and well-calibrated across the spectrum of frailty, reflecting baseline status 2–4 weeks before presentation. Screening should ideally be routine, prompt (<4 h after arrival) and completed at first contact in ED. Functional ability, mobility, cognition, medication use and social factors were identified as the most important variables to include. Conclusions Although a clear consensus was reached on important requirements of frailty screening in ED, and variables to include in an ideal screen, more research is required to operationalise screening in clinical practice. [ABSTRACT FROM AUTHOR]

Background Consistent and reproducible estimates of the underlying true level of frailty are essential for risk stratification and monitoring of health changes. The purpose of this study is to examine the reliability of the frailty index (FI). Methods A total of 426 community-dwelling older adults from the FRequent health Assessment In Later life (FRAIL70+) study in Austria were interviewed biweekly up to 7 times. Two versions of the FI, one with 49 deficits (baseline), and another with 44 (follow-up) were created. Internal consistency was assessed using confirmatory factor analysis and coefficient omega. Test–retest reliability was assessed with Pearson correlation coefficients and the intraclass correlation coefficient. Measurement error was assessed with the standard error of measurement, limits of agreement, and smallest detectable change. Results Participants (64.6% women) were on average 77.2 (±5.4) years old with mean FI49 at a baseline of 0.19 (±0.14). Internal consistency (coefficient omega) was 0.81. Correlations between biweekly FI44 assessments ranged between 0.86 and 0.94 and reliability (intraclass correlation coefficient) was 0.88. The standard error of measurement was 0.05, and the smallest detectable change and upper limits of agreement were 0.13; the latter is larger than previously reported minimal clinically meaningful changes. Conclusions Both internal consistency and reliability of the FI were good, that is, the FI differentiates well between community-dwelling older adults, which is an important requirement for risk stratification for both group-level oriented research and patient-level clinical purposes. Measurement error, however, was large, suggesting that individual health deteriorations or improvements, cannot be reliably detected for FI changes smaller than 0.13. [ABSTRACT FROM AUTHOR]

Abstract Background Statins can exert pleiotropic anti-inflammatory, vascular protective and anticoagulant effects, which in theory could improve the dysregulated host response during sepsis. We aimed to determine the association between prior statin use and host response characteristics in critically ill patients with sepsis. Methods We performed a prospective observational study in 1060 patients admitted with sepsis to the mixed intensive care units (ICUs) of two hospitals in the Netherlands between January 2011 and July 2013. Of these, 351 patients (33%) were on statin therapy before admission. The host response was evaluated by measuring 23 biomarkers providing insight into key pathways implicated in sepsis pathogenesis and by analyzing whole-blood leukocyte transcriptomes in samples obtained within 24 h after ICU admission. To account for indication bias, a propensity score-matched cohort was created (N = 194 in both groups for protein biomarkers and N = 95 in both groups for gene expression analysis). Results Prior statin use was not associated with an altered mortality up to 90 days after admission (38.0 vs. 39.7% in the non-statin users in the propensity-matched analysis). Statin use did not modify systemic inflammatory responses, activation of the vascular endothelium or the coagulation system. The blood leukocyte genomic response, characterized by over-expression of genes involved in inflammatory and innate immune signaling pathways as well as under-expression of genes associated to T cell function, was not different between patients with and without prior statin use. Conclusions Statin therapy is not associated with a modified host response in sepsis patients on admission to the ICU.

Abstract Major Depression is a prevalent mental disorder that is characterized by negative mood and reduced motivation, and frequently results in social withdrawal and memory-related deficits. Repeated stressors, such as adverse life events, increase the risk for development of the disorder. Consequently, individual variability in stress response greatly weighs on depression-vulnerability and -resilience. Here, we employed the social defeat-induced persistent stress (SDPS) paradigm to identify depression-prone individuals and to examine the temporal development of depression in the months following exposure to brief defeat stress. Male Wistar rats were socially defeated (5 defeat episodes) and single-housed for a prolonged period of time (~24 weeks). We assessed the emergence of a sustained depressive-like state by repeatedly evaluating social motivation (social approach avoidance) and spatial memory (object place recognition) in SDPS rats during the isolation period. Individual variability in the effects of SDPS yielded two extreme subpopulations: an SDPS-prone group that showed gradual affective and cognitive deterioration in terms of social approach and memory retention, and a SDPS-resilient group that did not develop this phenotype. Notably, in SDPS-prone individuals, the affective deficits preceded later cognitive impairments, providing a novel temporal profile of the development of pathology in this preclinical model of sustained depression.