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.

Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer's Disease and Parkinson's Dementia: Systematic Review and Meta-Analysis.

BACKGROUND: The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. OBJECTIVES: While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. METHODS: We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia. RESULTS: A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. CONCLUSIONS: Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. CLINICAL TRIAL REGISTRATION: The study was pre-registered on PROSPERO (CRD42021258376).

Adoption, Fostering, and Parental Absence in Vanuatu.

Alloparenting, wherein people provide care to children who are not their biological offspring, is a key aspect of human child-rearing. In the Pacific, many children are adopted or fostered by custodial alloparents even when both biological parents are still alive. From a behavioral ecology perspective, such behaviors are puzzling: why parent someone else's child at your expense? Furthermore, little is known about how these arrangements are made in Pacific Islander societies today, who provides care, and what kinds of outcomes fostered children experience. A better understanding of these proximate factors may help reveal the ultimate drivers behind custodial alloparenting. Here, we report findings from a survey carried out with the caregivers of 282 children in rural areas of Vanuatu, an island nation in Melanesia. Most fostered and adopted children lived with relatives such as aunts, uncles, and grandparents (87.5%) rather than unrelated caregivers, with a strong preference for maternal kin. The most common reasons for these arrangements were that the parents had separated (16.7%), were engaging in labor migration (27.1%), or a combination of both (27.1%). Results for investment in children's education and their educational outcomes were mixed, although children removed from crisis situations did more poorly than children removed for aspirational reasons. Our findings suggest that custodial alloparenting helps families adapt to socioeconomic transitions and changing marriage practices. Outcomes may depend on a range of factors, such as the reason children were transferred out of the natal home to begin with.

The cultural evolution of teaching.

Teaching is an important process of cultural transmission. Some have argued that human teaching is a cognitive instinct - a form of 'natural cognition' centred on mindreading, shaped by genetic evolution for the education of juveniles, and with a normative developmental trajectory driven by the unfolding of a genetically inherited predisposition to teach. Here, we argue instead that human teaching is a culturally evolved trait that exhibits characteristics of a cognitive gadget. Children learn to teach by participating in teaching interactions with socialising agents, which shape their own teaching practices. This process hijacks psychological mechanisms involved in prosociality and a range of domain-general cognitive abilities, such as reinforcement learning and executive function, but not a suite of cognitive adaptations specifically for teaching. Four lines of evidence converge on this hypothesis. The first, based on psychological experiments in industrialised societies, indicates that domain-general cognitive processes are important for teaching. The second and third lines, based on naturalistic and experimental research in small-scale societies, indicate marked cross-cultural variation in mature teaching practice and in the ontogeny of teaching among children. The fourth line indicates that teaching has been subject to cumulative cultural evolution, i.e. the gradual accumulation of functional changes across generations.

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.

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.

[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.

Trail Making Test Error Analysis in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Dementia With and Without Depression.

OBJECTIVE: Standard evaluation of the Trail Making Test (TMT) only incorporates completion times. However, the analysis of different error types may provide more insight into underlying cognitive processes and could also increase diagnostic accuracy. This cross-sectional observational study compared three different TMT error types and assessed their diagnostic utility in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's dementia (AD) with or without depression. METHOD: We evaluated 618 outpatients of a memory clinic with SCD (N = 190), MCI (N = 210), or AD (N = 218). Of these, 157 had comorbid depression. TMT completion times, total error rates, and the three error types "sequencing error," "perseverative error," and "proximity error" were examined. RESULTS: Results indicated that patients with MCI or AD committed more errors on TMT B, and specifically more perseverative errors than patients with SCD (p < 0.001). Depression was not associated with any TMT error type. Including TMT errors in models predicting diagnosis group by TMT completion times did not increase predictive accuracy, measured by areas under the curve. CONCLUSIONS: The findings do not indicate any impact of comorbid depression on TMT errors. Moreover, TMT error analysis does not seem to provide additional diagnostic utility for SCD, MCI, and AD diagnoses.

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.

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.

Assessing the Accuracy of Sales Forecasts Submitted by Pharmaceutical Companies Applying for Reimbursement in Austria.

Objectives: Reimbursement decisions on new medicines require an assessment of their value. In Austria, when applying for reimbursement of new medicines, pharmaceutical companies are also obliged to submit forecasts of future sales. We systematically examined the accuracy of these pharmaceutical sales forecasts and hence the usefulness of these forecasts for reimbursement evaluations. Methods: We retrospectively analyzed reimbursement applications of 102 new drugs submitted between 2005 and 2014, which were accepted for reimbursement outside of hospitals, and for which actual reimbursed sales were available for at least 3 years. The main outcome variable was the accuracy ratio, defined as the ratio of forecasted sales submitted by pharmaceutical companies when applying for reimbursement to actual sales from reimbursement data. Results: The median accuracy ratio [95% confidence interval] was 1.33 [1.03; 1.74, range 0.15-37.5], corresponding to a median overestimation of actual sales by 33%. Forecasts of actual sales for 55.9% of all examined products either overestimated actual sales by more than 100% or underestimated them by more than 50%. The accuracy of sales forecasts did not show systematic change over the analyzed decade nor was it discernibly influenced by reimbursement status (restricted or unrestricted), the degree of therapeutic benefit, or the therapeutic area of the pharmaceutical product. Sales forecasts of drugs with a higher degree of innovation and those within a dynamic market tended to be slightly more accurate. Conclusions: The majority of sales forecasts provided by applicants for reimbursement evaluations in Austria were highly inaccurate and were on average too optimistic. This is in line with published results for other jurisdictions and highlights the need for caution when using such forecasts for reimbursement procedures.

The Differential Impact of Lockdown Measures Upon Migrant and Female Psychiatric Patients - A Cross-Sectional Survey in a Psychiatric Hospital in Berlin, Germany.

The COVID-19 pandemic could have major effects on already vulnerable individuals with psychiatric disorders. It is important to assess how different patient groups respond to stress related to the pandemic, and what additional factors influence it, including family-related stress, migration background, and sex. We conducted a survey in a sample of 294 psychiatric patients in a large outpatient clinic in Berlin, measuring level of distress in relation to COVID-19 lockdown as well as family-related distress. We also measured potential influencing factors such as media consumption and medical support. In the migration background group, we found that women had more lockdown related psychological distress than men. This was not apparent in those patients with a German background. We found that females were more strongly affected by family-related distress, particularly those with a migration background. People with PTSD were most strongly affected by family-related distress, whereas people with psychotic disorders and addiction reported the least distress. There were no effects of media consumption. There were no differences in ability to abide by the lockdown related restrictions across diagnoses. Our results support earlier findings on differential vulnerability of diagnostic groups to these stressors. Thus, clinicians can optimize treatment by taking family-related stressors into account particularly for females and people with a migrant background.

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.

How evolutionary behavioural sciences can help us understand behaviour in a pandemic.

The COVID-19 pandemic has brought science into the public eye and to the attention of governments more than ever before. Much of this attention is on work in epidemiology, virology and public health, with most behavioural advice in public health focusing squarely on 'proximate' determinants of behaviour. While epidemiological models are powerful tools to predict the spread of disease when human behaviour is stable, most do not incorporate behavioural change. The evolutionary basis of our preferences and the cultural evolutionary dynamics of our beliefs drive behavioural change, so understanding these evolutionary processes can help inform individual and government decision-making in the face of a pandemic. Lay summary: The COVID-19 pandemic has brought behavioural sciences into the public eye: Without vaccinations, stopping the spread of the virus must rely on behaviour change by limiting contact between people. On the face of it, "stop seeing people" sounds simple. In practice, this is hard. Here we outline how an evolutionary perspective on behaviour change can provide additional insights. Evolutionary theory postulates that our psychology and behaviour did not evolve to maximize our health or that of others. Instead, individuals are expected to act to maximise their inclusive fitness (i.e, spreading our genes) - which can lead to a conflict between behaviours that are in the best interests for the individual, and behaviours that stop the spread of the virus. By examining the ultimate explanations of behaviour related to pandemic-management (such as behavioural compliance and social distancing), we conclude that "good of the group" arguments and "one size fits all" policies are unlikely to encourage behaviour change over the long-term. Sustained behaviour change to keep pandemics at bay is much more likely to emerge from environmental change, so governments and policy makers may need to facilitate significant social change - such as improving life experiences for disadvantaged groups.

Association between the -2548G/A polymorphism of the leptin gene and antipsychotic-induced weight gain: Analysis of the CATIE sample and meta-analysis.

BACKGROUND: Antipsychotics, especially most of the second-generation antipsychotics, have a high risk for metabolic syndrome and antipsychotic-induced weight gain (AIWG). A promoter variant of the leptin (LEP) gene, -2548G/A (rs7799039), has been associated with AIWG in several studies. The aim of this study was to evaluate this association in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) sample, followed by meta-analysis. METHODS: We investigated the association between rs7799039 and AIWG in a sub-sample of European (N = 164) individuals from the CATIE study. Body mass index (BMI) change and weight gain (presence or absence) was analyzed using ANCOVA and logistic regression, respectively. For the meta-analysis, a literature search was conducted using MEDLINE, Embase, and PsycINFO up to October 2019. The pooled odds ratio was calculated for presence or absence of weight gain (≥7% weight change) using a random effects model. RESULTS: We did not detect an association between rs7799039 and BMI change or weight gain (presence or absence) in the CATIE sample. As for the meta-analysis, we included 12 studies. No significant associations between the LEP rs7799039 polymorphism and AIWG were observed under the allelic genetic model (allele A vs. allele G) (OR = 1.10 [0.71, 1.70], p = .68). In the subgroup analyses of first-episode schizophrenia patients, a significant association between the A-allele and weight gain was observed, respectively (OR = 2.32 [1.41, 3.82], p = .0009). CONCLUSIONS: The present meta-analysis showed no significant effect of rs7799039 on AIWG. However, this variant may influence AIWG in first-episode schizophrenia patients. Further investigation of a larger and more homogenous sample is required to elucidate the role of the LEP gene in AIWG.

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.

Alcohol and Dementia - What is the Link? A Systematic Review.

BACKGROUND: Dementia is a globally increasing health issue and since no cure is currently available, prevention is crucial. The consumption of alcohol is a controversially discussed risk factor for dementia. While many previously published epidemiological studies reported a risk reduction by light to moderate alcohol consumption, there is no persuasive model of an underlying biochemical mechanism. The purpose of this article is to review current models on alcohol neurotoxicity and dementia and to analyze and compare studies focusing on the epidemiological link between alcohol consumption and the risk of dementia. METHODS: The electronic database Pubmed was searched for studies published between 1994 and 2019 concerning the topic. RESULTS: Available epidemiological studies are not sufficient to verify a protective effect of alcohol on dementia development.