Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells.

ABSTRACT: Hematopoietic stem cells (HSCs) are characterized by the ability to self-renew and to replenish the hematopoietic system. The cell-cycle kinase cyclin-dependent kinase 6 (CDK6) regulates transcription, whereby it has both kinase-dependent and kinase-independent functions. Herein, we describe the complex role of CDK6, balancing quiescence, proliferation, self-renewal, and differentiation in activated HSCs. Mouse HSCs expressing kinase-inactivated CDK6 show enhanced long-term repopulation and homing, whereas HSCs lacking CDK6 have impaired functionality. The transcriptomes of basal and serially transplanted HSCs expressing kinase-inactivated CDK6 exhibit an expression pattern dominated by HSC quiescence and self-renewal, supporting a concept, in which myc-associated zinc finger protein (MAZ) and nuclear transcription factor Y subunit alpha (NFY-A) are critical CDK6 interactors. Pharmacologic kinase inhibition with a clinically used CDK4/6 inhibitor in murine and human HSCs validated our findings and resulted in increased repopulation capability and enhanced stemness. Our findings highlight a kinase-independent role of CDK6 in long-term HSC functionality. CDK6 kinase inhibition represents a possible strategy to improve HSC fitness.

Feasibility of using virtual reality in geriatric psychiatry.

OBJECTIVES: Virtual Reality-based interventions have become an important element of digital mental health, offering accessible and scalable treatment options. However, studies on VR-based approaches in elderly patients are scarce. This explorative study examined the feasibility of using Virtual Reality (VR) for elderly patients with psychiatric illness, focusing on the sense of presence as the primary outcome. METHODS: The study included N = 30 patients between the ages of 59-92 years who were currently in geriatric psychiatric inpatient and day clinic treatment. Participants were assessed before, during and after a relaxing ten-minute VR experience. Attitude towards digital media and VR, subjective digital competence, and previous experience were examined using questionnaires. Motion sickness was measured repeatedly during the VR experience using the Fast Motion Sickness Scale (FMS). Patients rated their motion sickness and their general well-being in the virtual environment. Sense of presence in the virtual environment was quantified with the Igroup Presence Questionnaire (IPQ). RESULTS: Participants reported a notable sense of presence (M = 0.41 ± 1.4) in the virtual environment, particularly in terms of spatial presence. Motion sickness was reported by a minority of patients. Three patients terminated the VR application before it was finished. The average well-being during the VR experience was reported as high (70/100). Sense of presence and motion sickness showed a significant negative correlation. Presence, motion sickness and well-being were not significantly correlated with age, nor did they differ significantly between groups. CONCLUSIONS: This study underscores the potential of VR-based experiences in the treatment of elderly psychiatric patients and highlights their willingness and ability to engage with VR technology. While the results are promising, future research should explore more interactive VR scenarios and assess their safety and feasibility in elderly populations.

Polygenic risk scores analyses of psychiatric and metabolic traits with antipsychotic-induced weight gain in schizophrenia: an exploratory study.

Given the polygenic nature of antipsychotic-induced weight gain (AIWG), we investigated whether polygenic risk scores (PRS) for various psychiatric and metabolic traits were associated with AIWG. We included individuals with schizophrenia (SCZ) of European ancestry from two cohorts (N = 151, age = 40.3 ± 11.8 and N = 138, age = 36.5 ± 10.8). We investigated associations of AIWG defined as binary and continuous variables with PRS calculated from genome-wide association studies of body mass index (BMI), coronary artery disease (CAD), fasting glucose, fasting insulin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, type 1 and 2 diabetes mellitus, and SCZ, using regression models. We observed nominal associations (uncorrected p < 0.05) between PRSs for BMI, CAD, and LDL-C, type 1 diabetes, and SCZ with AIWG. While results became non-significant after correction for multiple testing, these preliminary results suggest that PRS analyses might contribute to identifying risk factors of AIWG and might help to elucidate mechanisms at play in AIWG.

Development of teaching in ni-Vanuatu children.

Teaching is an important mechanism of social learning. In industrialized societies, 3-year-olds tend to teach through demonstrations and short commands, while 5-year-olds use more verbal communication and abstract explanations. However, it remains unclear whether this generalizes to other cultures. This study presents results from a peer teaching game with 55 Melanesian children (4.7-11.4 years, 24 female) conducted in Vanuatu in 2019. Up to age 8, most participants taught through a participatory approach, emphasizing learning-by-doing, demonstrations, and short commands (57.1% of children aged 4-6 and 57.9% of children aged 7-8). Contrary to Western findings, abstract verbal communication only became common in children aged 9-11 (63.6%), suggesting that the ontogeny of teaching is shaped by the socio-cultural environment.

[Utilization of a Specialized Outpatient Service for Parents with Mental Disorders]. / Inanspruchnahme einer Spezialsprechstunde für psychisch kranke Eltern.

BACKGROUND: Patients with mental disorders have a high need for support during the peripartum period. Only few outpatient services have specialized on parents with mental disorders. This study assesses a newly established outpatient unit. METHODS: We analyzed the population utilizing the outpatient service for parents with psychiatric disorders (N=279) at the psychiatric university hospital of Charité at St. Hedwig-hospital in Berlin, Germany, from June 2017 until December 2021. RESULTS: The service was mainly utilized by individuals with affective disorders, a higher education and good compliance. Patients with migration background started psychotherapy less often. DISCUSSION: The data indicate a good acceptance of a specialized outpatient unit for parents with psychiatric disorders; however, it was mainly utilized by individuals with a higher socioeconomic status and less commonly by individuals with severe mental illness. More specialized treatment units for parents would be desirable.

Structured Interventions to Optimize Polypharmacy in Psychiatric Treatment and Nursing Homes: A Systematic Review.

BACKGROUND: Polypharmacy is a common clinical issue. It increases in prevalence with older age and comorbidities of patients and has been recognized as a major cause for treatment complications. In psychiatry, polypharmacy is also commonly seen in younger patients and can lead to reduced treatment satisfaction and incompliance. A variety of structured polypharmacy interventions have been investigated. This systematic review provides a comprehensive overview of the field and identifies research gaps. METHODS: We conducted a systematic review on structured interventions aimed at optimizing polypharmacy of psychotropic and somatic medication in psychiatric inpatient and outpatient settings as well as nursing homes. A search protocol was registered with PROSPERO (CRD42020187304). Data were synthesized narratively. RESULTS: Fifty-eight studies with a total of 30,554 participants met the inclusion criteria. Interventions were most commonly guided by self-developed or national guidelines, drug assessment scores, and lists of potentially inappropriate medications. Tools to identify underprescribing were less commonly used. Most frequently reported outcomes were quantitative drug-related measures; clinical outcomes such as falls, hospital admission, cognitive status, and neuropsychiatric symptom severity were reported less commonly. Reduction of polypharmacy and improvement of medication appropriateness were shown by most studies. CONCLUSIONS: Improvement of drug-related outcomes can be achieved by interventions such as individualized medication review and educational approaches in psychiatric settings and nursing homes. Changes in clinical outcomes, however, are often nonsubstantial and generally underreported. Patient selection and intervention procedures are highly heterogeneous. Future investigations should establish standards in intervention procedures, identify and assess patient-relevant outcome measures, and consider long-term follow-up assessments.

Loneliness in Elderly Inpatients.

PURPOSE: Loneliness among the elderly is a widespread phenomenon and is connected to various negative health outcomes. Nevertheless, loneliness among elderly inpatients, especially those with a psychiatric diagnosis, has hardly been examined. Our study assessed loneliness in elderly inpatients, identified predictors, and compared levels of loneliness between inpatients on psychiatric and somatic wards. METHODS: N = 100 elderly inpatients of a somatic and psychiatric ward were included. Levels of loneliness were assessed, as were potential predictors such as depression, psychological resilience, severity of mental illness, well-being, daily functioning, and psychiatric diagnosis. Analyses of group differences and hierarchical multiple regression analysis were conducted. RESULTS: 37% of all inpatients reported elevated levels of loneliness. Significant predictor variables were self-reported depressive symptoms, well-being, severity of mental illness, being single and living with a caregiver. Hierarchical multiple regression analysis revealed that the full model explained 58% of variance in loneliness. Psychiatric inpatients' loneliness was significantly higher than loneliness in somatic inpatients. When analyzing group differences between inpatients with different main psychiatric diagnoses, highest levels were found in patients with an affective disorder, followed by those treated for organic mental disorder. Since the study took place during the COVID-19 pandemic, potential influence of different measurement points (lockdown vs. no lockdown) were analyzed: Differences in loneliness depending on the phase of the pandemic were non-significant. CONCLUSION: Elderly inpatients experience high levels of loneliness, especially those with a mental disorder. Interventions to reduce loneliness in this population should address predictors of loneliness, preferably through multiprofessional interventions.

Cortical Surfaces Mediate the Relationship Between Polygenic Scores for Intelligence and General Intelligence.

Recent large-scale, genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with general intelligence. The cumulative influence of these loci on brain structure is unknown. We examined if cortical morphology mediates the relationship between GWAS-derived polygenic scores for intelligence (PSi) and g-factor. Using the effect sizes from one of the largest GWAS meta-analysis on general intelligence to date, PSi were calculated among 10 P value thresholds. PSi were assessed for the association with g-factor performance, cortical thickness (CT), and surface area (SA) in two large imaging-genetics samples (IMAGEN N = 1651; IntegraMooDS N = 742). PSi explained up to 5.1% of the variance of g-factor in IMAGEN (F1,1640 = 12.2-94.3; P < 0.005), and up to 3.0% in IntegraMooDS (F1,725 = 10.0-21.0; P < 0.005). The association between polygenic scores and g-factor was partially mediated by SA and CT in prefrontal, anterior cingulate, insula, and medial temporal cortices in both samples (PFWER-corrected < 0.005). The variance explained by mediation was up to 0.75% in IMAGEN and 0.77% in IntegraMooDS. Our results provide evidence that cumulative genetic load influences g-factor via cortical structure. The consistency of our results across samples suggests that cortex morphology could be a novel potential biomarker for neurocognitive dysfunction that is among the most intractable psychiatric symptoms.

Quantitative historical analysis uncovers a single dimension of complexity that structures global variation in human social organization.

Do human societies from around the world exhibit similarities in the way that they are structured, and show commonalities in the ways that they have evolved? These are long-standing questions that have proven difficult to answer. To test between competing hypotheses, we constructed a massive repository of historical and archaeological information known as "Seshat: Global History Databank." We systematically coded data on 414 societies from 30 regions around the world spanning the last 10,000 years. We were able to capture information on 51 variables reflecting nine characteristics of human societies, such as social scale, economy, features of governance, and information systems. Our analyses revealed that these different characteristics show strong relationships with each other and that a single principal component captures around three-quarters of the observed variation. Furthermore, we found that different characteristics of social complexity are highly predictable across different world regions. These results suggest that key aspects of social organization are functionally related and do indeed coevolve in predictable ways. Our findings highlight the power of the sciences and humanities working together to rigorously test hypotheses about general rules that may have shaped human history.

Psychosocial Impact of COVID-19 Pandemic in Elderly Psychiatric Patients: a Longitudinal Study.

The study was designed to investigate the impact of the Coronavirus Disease 2019 (COVID-19) pandemic on mental health and perceived psychosocial support for elderly psychiatric patients in a longitudinal design. n = 32 patients with affective or anxiety disorders aged ≥60 years were included. Telephone interviews were conducted in April/May 2020 (T1) and August 2020 (T2). The psychosocial impact (PSI) of the pandemic and psychopathology were measured. Changes between T1 and T2 were examined. Patients' psychosocial support system six months before the pandemic and at T1/T2 was assessed. We found a significant positive correlation between general PSI and depression as well as severity of illness. General PSI differed significantly depending on social contact. Neither general PSI nor psychopathology changed significantly between T1 and T2. At T1, patients' psychosocial support systems were reduced as compared to six months before. Patients reported an increase in psychosocial support between T1 and T2 and high demand for additional support (sports, arts/occupational therapy, physiotherapy, psychotherapy). Elderly psychiatric patients show a negative PSI of the pandemic. They are likely to suffer from an impaired psychosocial situation, emphasizing the importance of developing concepts for sufficient psychosocial support during a pandemic.

Attitudes towards psychopharmacology and psychotherapy in psychiatric patients with and without migration background.

BACKGROUND: Sociodemographic factors, attitude towards treatment and acculturation may be important factors influencing the decision of immigrants to seek and maintain psychiatric treatment. A better understanding of these factors may significantly improve treatment adherence and outcome in these patients. Therefore, we investigated factors associated the attitude towards psychotherapy and medication in a sample of psychiatric outpatients with and without migration background. METHODS: N = 381 patients in a psychiatric outpatient unit offering specialized treatment for migrants were included in this study. Attitude towards psychotherapy was assessed using the Questionnaire on Attitudes Toward Psychotherapeutic Treatment, attitude towards medication with the Drug Attitude Inventory-10. Acculturation, symptom load and sociodemographic variables were assessed in a general questionnaire. Statistical analyses included analyses of covariance and hierarchical regression. RESULTS: Patients of Turkish and Eastern European origin reported a significantly more positive attitude towards medication than patients without migration background. When controlling for sociodemographic and clinical variables, we did not observe any significant differences in attitude towards psychotherapy. Acculturation neither influenced the attitude towards psychotherapy nor towards medication. CONCLUSION: Our study indicates that sociodemographic and clinical factors may be more relevant for patients´ attitudes towards treatment than acculturation. Considering these factors in psychiatric treatment of patients with migration background may improve treatment outcome and adherence.

[Cultural Influence on Attitude towards Psychotherapy - A Comparison of Individuals of Turkish Origin with Individuals without Migration Background]. / Kulturabhängigkeit der Einstellung gegenüber psychotherapeutischer Behandlung bei Türkeistämmigen und Personen ohne Migrationshintergrund.

AIM: The present study compares the attitude towards psychotherapy of persons living in Germany with or without Turkish background. In this context, gender-related, disorder-specific and sociodemographic differences in openness towards psychotherapy are taken into account. METHODS: Individuals of Turkish origin (n=129) and individuals without migration background (n=129) were interviewed with the Questionnaire on Attitudes towards Psychotherapeutic Treatment, the Social Support Questionnaire, a short version of the Symptom-Checklist with the subscales anxiety, depression and somatization, and a sociodemographic questionnaire. RESULTS: The attitude towards psychotherapy is less positive in Turkish migrants than in people without migration background. Females, depressive individuals, persons with high social support, with children and a high level of education are more open towards psychotherapy. DISCUSSION: The attitude towards psychotherapy is influenced by gender, socio-demographic and disorder-specific factors and in particular by cultural factors. CONCLUSION: These results elucidate the need for better information about psychotherapy and the development of intercultural consulting services for migrants in Germany.

The impact of parallel regulatory-health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations.

AIMS: The parallel regulatory-health technology assessment scientific advice (PSA) procedure allows manufacturers to receive simultaneous feedback from both EU regulators and health technology assessment (HTA) bodies on development plans for new medicines. The primary objective of the present study is to investigate whether PSA is integrated in the clinical development programmes for which advice was sought. METHODS: Contents of PSA provided by regulators and HTA bodies for each procedure between 2010 and 2015 were analysed. The development of all clinical studies for which PSA had been sought was tracked using three different databases. The rate of uptake of the advice provided by regulators and HTA bodies was assessed on two key variables: comparator/s and primary endpoint. RESULTS: In terms of uptake of comparator recommendations at the time of PSA in the actual development, our analysis showed that manufacturers implemented comparators to address both the needs of regulators and of at least one HTA body in 12 of 21 studies. For primary endpoints, in all included studies manufacturers addressed both the needs of the regulators and at least one HTA body. CONCLUSIONS: One of the key findings of this analysis is that manufacturers tend to implement changes to the development programme based on both regulatory and HTA advice with regards to the choice of primary endpoint and comparator. It also confirms the challenging choice of the study comparator, for which manufacturers seem to be more inclined to satisfy the regulatory advice. Continuous research efforts in this area are of paramount importance from a public health perspective.

Weather conditions influence the number of psychiatric emergency room patients.

The specific impact of weather factors on psychiatric disorders has been investigated only in few studies with inconsistent results. We hypothesized that meteorological conditions influence the number of cases presenting in a psychiatric emergency room as a measure of mental health conditions. We analyzed the number of patients consulting the emergency room (ER) of a psychiatric hospital in Berlin, Germany, between January 1, 2008, and December 31, 2014. A total of N = 22,672 cases were treated in the ER over the study period. Meteorological data were obtained from a publicly available data base. Due to collinearity among the meteorological variables, we performed a principal component (PC) analysis. Association of PCs with the daily number of patients was analyzed with autoregressive integrated moving average model. Delayed effects were investigated using Granger causal modeling. Daily number of patients in the ER was significantly higher in spring and summer compared to fall and winter (p < 0.001). Three PCs explained 76.8% percent of the variance with PC1 loading mostly on temperature, PC2 on cloudiness and low pressure, and PC3 on windiness. PC1 and PC2 showed strong association with number of patients in the emergency room (p < 0.010) indicating higher patient numbers on warmer and on cloudy days. Further, PC1, PC2, and PC3 predicted the number of patients presenting in the emergency room for up to 7 days (p < 0.050). A secondary analysis revealed that the effect of temperature on number of patients was mostly due to lower patient numbers on cold days. Although replication of our findings is required, our results suggest that weather influences the number of psychiatric patients consulting the emergency room. In particular, our data indicate lower patient numbers during very cold temperatures.

Cortical surface-based threshold-free cluster enhancement and cortexwise mediation.

Threshold-free cluster enhancement (TFCE) is a sensitive means to incorporate spatial neighborhood information in neuroimaging studies without using arbitrary thresholds. The majority of methods have applied TFCE to voxelwise data. The need to understand the relationship among multiple variables and imaging modalities has become critical. We propose a new method of applying TFCE to vertexwise statistical images as well as cortexwise (either voxel- or vertexwise) mediation analysis. Here we present TFCE_mediation, a toolbox that can be used for cortexwise multiple regression analysis with TFCE, and additionally cortexwise mediation using TFCE. The toolbox is open source and publicly available (https://github.com/trislett/TFCE_mediation). We validated TFCE_mediation in healthy controls from two independent multimodal neuroimaging samples (N = 199 and N = 183). We found a consistent structure-function relationship between surface area and the first independent component (IC1) of the N-back task, that white matter fractional anisotropy is strongly associated with IC1 N-back, and that our voxel-based results are essentially identical to FSL randomise using TFCE (all PFWE <0.05). Using cortexwise mediation, we showed that the relationship between white matter FA and IC1 N-back is mediated by surface area in the right superior frontal cortex (PFWE  < 0.05). We also demonstrated that the same mediation model is present using vertexwise mediation (PFWE  < 0.05). In conclusion, cortexwise analysis with TFCE provides an effective analysis of multimodal neuroimaging data. Furthermore, cortexwise mediation analysis may identify or explain a mechanism that underlies an observed relationship among a predictor, intermediary, and dependent variables in which one of these variables is assessed at a whole-brain scale. Hum Brain Mapp 38:2795-2807, 2017. © 2017 Wiley Periodicals, Inc.

Modulation of the heart's electrical properties by the anticonvulsant drug retigabine.

Retigabine, currently used as antiepileptic drug, has a wide range of potential medical uses. Administration of the drug in patients can lead to QT interval prolongation in the electrocardiogram and to cardiac arrhythmias in rare cases. This suggests that the drug may perturb the electrical properties of the heart, and the underlying mechanisms were investigated here. Effects of retigabine on currents through human cardiac ion channels, heterologously expressed in tsA-201 cells, were studied in whole-cell patch-clamp experiments. In addition, the drug's impact on the cardiac action potential was tested. This was done using ventricular cardiomyocytes isolated from Langendorff-perfused guinea pig hearts and cardiomyocytes derived from human induced pluripotent stem cells. Further, to unravel potential indirect effects of retigabine on the heart which might involve the autonomic nervous system, membrane potential and noradrenaline release from sympathetic ganglionic neurons were measured in the absence and presence of the drug. Retigabine significantly inhibited currents through hKv11.1 potassium, hNav1.5 sodium, as well as hCav1.2 calcium channels, but only in supra-therapeutic concentrations. In a similar concentration range, the drug shortened the action potential in both guinea pig and human cardiomyocytes. Therapeutic concentrations of retigabine, on the other hand, were sufficient to inhibit the activity of sympathetic ganglionic neurons. We conclude that retigabine- induced QT interval prolongation, and the reported cases of cardiac arrhythmias after application of the drug in a typical daily dose range, cannot be explained by a direct modulatory effect on cardiac ion channels. They are rather mediated by indirect actions at the level of the autonomic nervous system.

Association study between the neurexin-1 gene and tardive dyskinesia.

OBJECTIVE: Tardive dyskinesia (TD) is a motor side effect that may develop after long-term antipsychotic treatment. Schizophrenia has recently been associated with the Neurexin-1 (NRXN1) gene that codes for a cell adhesion molecule in synaptic communication. METHODS: This study examined five NRXN1 single-nucleotide polymorphisms (SNPs) for possible association with the occurrence and severity of TD in 178 schizophrenia patients of European ancestry. RESULTS: We did not find these SNPs to be significantly associated with TD. CONCLUSIONS: More research is needed with additional SNPs and in bigger samples before we can completely rule out the role of NRXN1 in TD.

Repurposing Treprostinil for Enhancing Hematopoietic Progenitor Cell Transplantation.

Activation of Gs-coupled receptors enhances engraftment of hematopoietic stem and progenitor cells (HSPCs). We tested the hypothesis that treprostinil, a prostacyclin analog approved for the treatment of pulmonary hypertension, can be repurposed to improve hematopoietic stem cell transplantation. Murine and human HSPCs were isolated from bone marrow and umbilical cord blood, respectively. Prostanoid receptor agonists and the combination thereof with forskolin were tested for their capacity to stimulate [(3)H]cAMP accumulation in HSPCs. Three independent approaches were employed to verify the ability of agonist-activated HSPCs to reconstitute the bone marrow in lethally irradiated recipient mice. The underlying mechanism was explored in cellular migration assays and by blocking C-X-C motif chemokine receptor 4 (CXCR4). Among several prostanoid agonists tested in combination with forskolin, treprostinil was most efficacious in raising intracellular cAMP levels in murine and human HPSCs. Injection of murine and human HSPCs, which had been pretreated with treprostinil and forskolin, enhanced survival of lethally irradiated recipient mice. Survival was further improved if recipient mice were subcutaneously administered treprostinil (0.15 mg kg(-1) 8 h(-1)) for 10 days. This regimen also reduced the number of HSPCs required to rescue lethally irradiated mice. Enhanced survival of recipient mice was causally related to treprostinil-enhanced CXCR4-dependent migration of HSPCs. Treprostinil stimulates the engraftment of human and murine hematopoietic stem cells without impairing their capacity for self-renewal. The investigated dose range corresponds to the dose approved for human use. Hence, these findings may be readily translated into a clinical application.

Association of Dystrobrevin-Binding Protein 1 Polymorphisms with Sustained Attention and Set-Shifting in Schizophrenia Patients.

BACKGROUND: Despite extensive research in the past decades, the influence of genetics on cognitive functions in schizophrenia remains unclear. Dystrobrevin-binding protein 1 (DTNBP1) is one of the most promising candidate genes in schizophrenia. An association of DTNBP1 with cognitive dysfunction, particularly memory impairment, has been reported in a number of studies. However, the results remain inconsistent. The aim of this study was to measure the association between DTNBP1 polymorphisms and cognitive domains in a well-characterized sample. METHODS: Ninety-one clinically stable schizophrenia outpatients underwent a battery of cognitive tests. Six single nucleotide polymorphisms (SNPs) of DTNBP1 were genotyped in all participants. Statistical and multivariate analyses were performed. RESULTS: Factor analysis revealed 4 factors corresponding to distinct cognitive domains, namely sustained attention, set-shifting, executive functioning, and memory. We found a significant association of the rs909706 polymorphism with attention (p = 0.030) and a nonsignificant trend for set-shifting (p = 0.060). The other SNPs and haplotypes were not associated with cognitive function. DISCUSSION: Replication of this finding in a larger sample is needed in order to confirm the importance of this particular polymorphism in the genetics of schizophrenia, particularly the distinct cognitive domains. In conclusion, the present study supports the involvement of DTNBP1 in the regulation of cognitive processes and demonstrates association in particular with sustained attention and set-shifting in schizophrenia patients.