Hepatitis C prevalence and cascade of care among patients in the decentralised opioid agonist therapy programme of the canton of St Gallen, Switzerland: a cross-sectional study.

BACKGROUND: To eliminate chronic hepatitis C virus (HCV) infection by 2030, 90% of those infected must be diagnosed and 80% treated. In Switzerland, >40% of the estimated 32,000 infected people are still undiagnosed. In the canton of St Gallen, HCV prevalence and cascade of care have only been studied in the centralised opioid agonist therapy (OAT) setting (institutions), although about 80% of OAT patients are treated decentrally (general practitioner [GP] or pharmacy). AIM: To describe HCV prevalence and cascade of care among patients in the decentralised OAT programme of the canton of St Gallen, Switzerland, and compare it to contemporaneous data from the centralised setting. METHODS: For each patient receiving his/her OAT from a GP or pharmacy on 1 April 2021, the cantonal medical office sent a questionnaire to the prescribing GP. Patient characteristics, HCV antibody (Ab)/RNA screening uptake, HCV Ab/RNA prevalence and HCV treatment uptake were obtained and compared to those of patients of the Medizinisch-soziale Hilfsstelle 1 in St Gallen (centralised setting). RESULTS: Of the 563 OAT patients under the care of 127 GPs, 107 patients from 41 GPs could be analysed (median age: 48 years [IQR: 40-56]; ongoing intravenous drug use: 25%; OAT provider: 66% GP, 34% pharmacy). HCV Ab screening uptake was 68% (73/107) with an HCV Ab prevalence of 68% (50/73) among those tested. Of the HCV Ab-positive patients, 84% (42/50) were HCV RNA-tested, among whom 57% (24/42) were viraemic. HCV treatment uptake was 83% (20/24), with 95% (19/20) achieving a sustained virological response. Non-uptake of HCV screening and treatment tended to be higher among patients receiving OAT at the pharmacy vs at the GP's office: 37% vs 26% (p = 0.245) for screening and 30% vs 7% (p = 0.139) for treatment. The proportion never HCV Ab-tested and the proportion of HCV Ab-positives never HCV RNA-tested was significantly higher in the decentralised compared to the centralised setting: 32% vs 3% (p <0.001) never Ab-tested and 16% vs 0% (p = 0.002) never RNA-tested. In contrast, HCV treatment uptake (83% vs 78%), sustained virological response rate (95% vs 100%) and residual HCV RNA prevalence among the HCV Ab-positive (12% vs 14%) were comparable for both settings. CONCLUSION: In the decentralised OAT setting of the canton of St Gallen, HCV Ab prevalence is high. Since HCV Ab and RNA screening uptake are markedly lower than in the centralised setting, potentially >40% of patients with chronic HCV are not diagnosed yet. HCV screening in the decentralised setting needs improvement, e.g. by increasing awareness and simplifying testing. High HCV treatment uptake and cure rates are possible in centralised and decentralised settings.

External Mechanical Stability Regulates Hematoma Vascularization in Bone Healing Rather than Endothelial YAP/TAZ Mechanotransduction.

Bone fracture healing is regulated by mechanobiological cues. Both, extracellular matrix (ECM) deposition and microvascular assembly determine the dynamics of the regenerative processes. Mechanical instability as by inter-fragmentary shear or compression is known to influence early ECM formation and wound healing. However, it remains unclear how these external cues shape subsequent ECM and microvascular network assembly. As transcriptional coactivators, the mechanotransducers yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) translate physical cues into downstream signaling events, yet their role in sprouting angiogenesis into the hematoma after injury is unknown. Using bone healing as model system for scar-free regeneration, the role of endothelial YAP/TAZ in combination with tuning the extrinsic mechanical stability via fracture fixation is investigated. Extrinsically imposed shear across the gap delayed hematoma remodeling and shaped the morphology of early collagen fiber orientations and microvascular networks, suggesting that enhanced shear increased the nutrient exchange in the hematoma. In contrast, endothelial YAP/TAZ deletion has little impact on the overall vascularization of the fracture gap, yet slightly increases the collagen fiber deposition under semi-rigid fixation. Together, these data provide novel insights into the respective roles of endothelial YAP/TAZ and extrinsic mechanical cues in orchestrating the process of bone regeneration.

Molecular and Functional Characterization of Different BrainSphere Models for Use in Neurotoxicity Testing on Microelectrode Arrays.

The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differentiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction protocols yielded nearly 100% NESTIN-positive hiPSC-derived neural progenitor cells (hiNPCs), though with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed to apply such MEA-based spike sorting. These models are promising tools not only in toxicology but also for drug development and disease modeling.

20-year Results of a 3D Titanium Mesh Coating Stability of 31 Artificial Cups. / 20-Jahres-Ergebnisse der Verbundfestigkeit einer aufgesinterten 3-D-Titannetzbeschichtung von 31 Hüftpfannen.

BACKGROUND: The aim of this work was to demonstrate the bony bond strength and resilience of a three-dimensional titanium mesh coating of an artificial acetabulum produced using the diffusion bonding technique. Under the extreme conditions ranging from abrasion-related osteolysis to acetabular perforation, the degree of residual bone and the integrity of the coating were determined. The remaining zones of the (still) stable bone connection are inevitably exposed to a greater load of the layer adhesion between the titanium mesh and the core shell. The investigation was intended to provide information about the stages of damage according to Paprosky in which it was still justifiable to leave the implant in place and simply change the inlay from the purely material-technical point of view of a stable coating. The bond between bone and implant was examined with regard to a possible retention of the implant for its adaptive remodeling up to 27 years. MATERIALS AND METHODS: In a retrospective study, 31 explanted human acetabular cups of the Harris-Galante II type, with an average lifetime of 19.7 years (11-27 years), were examined by means of digital area measurement to determine both the bone areas remaining on the coating and the damaged areas of the titanium mesh. Periacetabular bone loss was recorded in a modified Paprosky (PAP) damage classification. Full hemispherical sections of 4 acetabular cups with a life time of 16, 20, 22 and 27 years were examined histopathologically using the diamond cut technique. RESULTS: The periacetabular bone loss resulted in damage class PAP I in 8 cases, PAP IIa in 7 cases, PAP IIb in 2 cases, PAP IIc in 9 cases, PAP IIIa in 3 cases and PAP IIIa in 2 cases PAP IIIb. The average amount of bone that was still firmly attached to the coating after explantation was 17% (0-70%) of the total cup surface. Paprosky I accounted for 44.1%, and PAP IIa and IIb stadiums together a total of 17.1%. The average bone fraction of the implants no longer anchored in the host bed at stages IIc, IIIa and IIIb was 2%. The average coating damage was 11% (0-100%) and was exclusively attributable to the unstable implants of stages IIc, IIIa and IIIb. The histopathological findings showed adaptive bone remodeling, that was detectable for up to 27 years through the titanium mesh down to the interface with the solid acetabular core. The titanium wire mesh was mostly surrounded by lamellar, mature bone. CONCLUSION: The results show that the connection between the Tivanium cup and the previously oldest and unchanged sintered coating - in the form of a three-dimensional titanium mesh applied in point and line contact - is very load-resistant even under the extreme loads of periacetabular osteolysis and cup perforations. Since there was no damage to the coating in periacetabular damage stages Paprosky I, IIa and IIb, it is justifiable in these damage stages to leave the implant in situ and to continue to use it with sole replacement of the inlay, but leaving the socket shell. The third-generation acetabular cup (Trilogy) with unchanged three-dimensional titanium mesh coating has been implanted in over 1.2 million cases for 26 years. After a long service life, an increasing number of wear and tear conditions can be expected in today's mostly elderly and vulnerable patient clientele. In view of the results presented here, the early detection of damage would make it possible to avoid costly and stressful explantation of the entire acetabular cup in favor of replacing the sole inlay in Paprosky stages I, IIa and IIb.

Reduced fractional anisotropy in bipolar disorder v. major depressive disorder independent of current symptoms.

BACKGROUND: Patients with bipolar disorder (BD) show reduced fractional anisotropy (FA) compared to patients with major depressive disorder (MDD). Little is known about whether these differences are mood state-independent or influenced by acute symptom severity. Therefore, the aim of this study was (1) to replicate abnormalities in white matter microstructure in BD v. MDD and (2) to investigate whether these vary across depressed, euthymic, and manic mood. METHODS: In this cross-sectional diffusion tensor imaging study, n = 136 patients with BD were compared to age- and sex-matched MDD patients and healthy controls (HC) (n = 136 each). Differences in FA were investigated using tract-based spatial statistics. Using interaction models, the influence of acute symptom severity and mood state on the differences between patient groups were tested. RESULTS: Analyses revealed a main effect of diagnosis on FA across all three groups (ptfce-FWE = 0.003). BD patients showed reduced FA compared to both MDD (ptfce-FWE = 0.005) and HC (ptfce-FWE < 0.001) in large bilateral clusters. These consisted of several white matter tracts previously described in the literature, including commissural, association, and projection tracts. There were no significant interaction effects between diagnosis and symptom severity or mood state (all ptfce-FWE > 0.704). CONCLUSIONS: Results indicated that the difference between BD and MDD was independent of depressive and manic symptom severity and mood state. Disruptions in white matter microstructure in BD might be a trait effect of the disorder. The potential of FA values to be used as a biomarker to differentiate BD from MDD should be further addressed in future studies using longitudinal designs.

Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro.

Adverse outcome pathways (AOPs) are organized sequences of key events (KEs) that are triggered by a xenobiotic-induced molecular initiating event (MIE) and summit in an adverse outcome (AO) relevant to human or ecological health. The AOP framework causally connects toxicological mechanistic information with apical endpoints for application in regulatory sciences. AOPs are very useful to link endophenotypic, cellular endpoints in vitro to adverse health effects in vivo. In the field of in vitro developmental neurotoxicity (DNT), such cellular endpoints can be assessed using the human "Neurosphere Assay," which depicts different endophenotypes for a broad variety of neurodevelopmental KEs. Combining this model with large-scale transcriptomics, we evaluated DNT hazards of two selected Chinese herbal medicines (CHMs) Lei Gong Teng (LGT) and Tian Ma (TM), and provided further insight into their modes-of-action (MoA). LGT disrupted hNPC migration eliciting an exceptional migration endophenotype. Time-lapse microscopy and intervention studies indicated that LGT disturbs laminin-dependent cell adhesion. TM impaired oligodendrocyte differentiation in human but not rat NPCs and activated a gene expression network related to oxidative stress. The LGT results supported a previously published AOP on radial glia cell adhesion due to interference with integrin-laminin binding, while the results of TM exposure were incorporated into a novel putative, stressor-based AOP. This study demonstrates that the combination of phenotypic and transcriptomic analyses is a powerful tool to elucidate compounds' MoA and incorporate the results into novel or existing AOPs for a better perception of the DNT hazard in a regulatory context.

Identifying Challenges, Enabling Practices, and Reviewing Existing Policies Regarding Digital Equity and Digital Divide Toward Smart and Healthy Cities: Protocol for an Integrative Review.

BACKGROUND: Digital equity denotes that all individuals and communities have equitable access to the information technology required to participate in digital life and can fully capitalize on this technology for their individual and community gain and benefits. Recent research highlighted that COVID-19 heightened the existing structural inequities and further exacerbated the technology-related social divide, especially for racialized communities, including new immigrants, refugees, and ethnic minorities. The intersection of challenges associated with racial identity (eg, racial discrimination and cultural differences), socioeconomic marginalization, and age- and gender-related barriers affects their access to health and social services, education, economic activity, and social life owing to digital inequity. OBJECTIVE: Our aim is to understand the current state of knowledge on digital equity and the digital divide (which is often considered a complex social-political challenge) among racialized communities in urban cities of high-income countries and how they impact the social interactions, economic activities, and mental well-being of racialized city dwellers. METHODS: We will conduct an integrative review adapting the Whittemore and Knafl methodology to summarize past empirical or theoretical literature describing digital equity issues pertaining to urban racialized communities. The context will be limited to studies on multicultural cities in high-income countries (eg, Calgary, Alberta) in the last 10 years. We will use a comprehensive search of 8 major databases across multiple disciplines and gray literature (eg, Google Scholar), using appropriate search terms related to digital "in/equity" and "divide." A 2-stage screening will be conducted, including single citation tracking and a hand search of reference lists. Results will be synthesized using thematic analysis guidelines. RESULTS: As of August 25, 2022, we have completed a systematic search of 8 major academic databases from multiple disciplines, gray literature, and citation or hand searching. After duplicate removal, we identified 8647 articles from all sources. Two independent reviewers are expected to complete the 2-step screening (title, abstract, and full-text screening) using Covidence followed by data extraction and analysis in 4 months (by December 2022). Data will be extracted regarding digital equity-related initiatives, programs, activities, research findings, issues, barriers, policies, recommendations, etc. Thematic analysis will reveal how barriers and facilitators of digital equity affect or benefit racialized population groups and what social, material, and systemic issues need to be addressed to establish digital equity for racialized communities in the context of a multicultural city. CONCLUSIONS: This project will inform public policy about digital inequity alongside conventional systemic inequities (eg, education and income levels); promote digital equity by exploring and examining the pattern, extent, and determinants and barriers of digital inequity across sociodemographic variables and groups; and analyze its interconnectedness with spatial dimensions and variations of the urban sphere (geographic differences). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40068.

Corrigendum to TBBPA Targets Converging Key Events of Human Oligodendrocyte Development Resulting in Two Novel AOPs.

In this manuscript, which appeared in ALTEX 38, 215-234 (doi:10.14573/altex.2007201), there was an error in Figure 4. The corrected Figure is available at 10.14573/altex.2203151.

Progenitor cells derived from gene-engineered human induced pluripotent stem cells as synthetic cancer cell alternatives for in vitro pharmacology.

Limitations in genetic stability and recapitulating accurate physiological disease properties challenge the utility of patient-derived (PD) cancer models for reproducible and translational research. A portfolio of isogenic human induced pluripotent stem cells (hiPSCs) with different pan-cancer relevant oncoprotein signatures followed by differentiation into lineage-committed progenitor cells was genetically engineered. Characterization on molecular and biological level validated successful stable genetic alterations in pluripotency state as well as upon differentiation to prove the functionality of our approach. Meanwhile proposing core molecular networks possibly involved in early dysregulation of stem cell homeostasis, the application of our cell systems in comparative substance testing indicates the potential for cancer research such as identification of augmented therapy resistance of stem cells in response to activation of distinct oncogenic signatures.

Scientific Validation of Human Neurosphere Assays for Developmental Neurotoxicity Evaluation.

There is a call for a paradigm shift in developmental neurotoxicity (DNT) evaluation, which demands the implementation of faster, more cost-efficient, and human-relevant test systems than current in vivo guideline studies. Under the umbrella of the Organisation for Economic Co-operation and Development (OECD), a guidance document is currently being prepared that instructs on the regulatory use of a DNT in vitro battery (DNT IVB) for fit-for-purpose applications. One crucial issue for OECD application of methods is validation, which for new approach methods (NAMs) requires novel approaches. Here, mechanistic information previously identified in vivo, as well as reported neurodevelopmental adversities in response to disturbances on the cellular and tissue level, are of central importance. In this study, we scientifically validate the Neurosphere Assay, which is based on human primary neural progenitor cells (hNPCs) and an integral part of the DNT IVB. It assesses neurodevelopmental key events (KEs) like NPC proliferation (NPC1ab), radial glia cell migration (NPC2a), neuronal differentiation (NPC3), neurite outgrowth (NPC4), oligodendrocyte differentiation (NPC5), and thyroid hormone-dependent oligodendrocyte maturation (NPC6). In addition, we extend our work from the hNPCs to human induced pluripotent stem cell-derived NPCs (hiNPCs) for the NPC proliferation (iNPC1ab) and radial glia assays (iNPC2a). The validation process we report for the endpoints studied with the Neurosphere Assays is based on 1) describing the relevance of the respective endpoints for brain development, 2) the confirmation of the cell type-specific morphologies observed in vitro, 3) expressions of cell type-specific markers consistent with those morphologies, 4) appropriate anticipated responses to physiological pertinent signaling stimuli and 5) alterations in specific in vitro endpoints upon challenges with confirmed DNT compounds. With these strong mechanistic underpinnings, we posit that the Neurosphere Assay as an integral part of the DNT in vitro screening battery is well poised for DNT evaluation for regulatory purposes.

Local slow-wave activity over the right prefrontal cortex reveals individual risk preferences.

In everyday life, we have to make decisions under varying degrees of risk. Even though previous research has shown that the manipulation of sleep affects risky decision-making, it remains unknown whether individual, temporally stable neural sleep characteristics relate to individual differences in risk preferences. Here, we collected sleep data under normal conditions in fifty-four healthy adults using a portable high-density EEG at participants' home. Whole-brain corrected for multiple testing, we found that lower slow-wave activity (SWA, an indicator of sleep depth) in a cluster of electrodes over the right prefrontal cortex (PFC) is associated with higher individual risk propensity. Importantly, the association between local sleep depth and risk preferences remained significant when controlling for total sleep time and for time spent in deep sleep, i.e., sleep stages N2 and N3. Moreover, the association between risk preferences and SWA over the right PFC was very similar in all sleep cycles. Because the right PFC plays a central role in cognitive control functions, we speculate that local sleep depth in this area, as reflected by SWA, might serve as a dispositional indicator of self-regulatory ability, which in turn reflects risk preferences.

Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery.

Due to their neurodevelopmental toxicity, flame retardants (FRs) like polybrominated diphenyl ethers are banned from the market and replaced by alternative FRs, like organophosphorus FRs, that have mostly unknown toxicological profiles. To study their neurodevelopmental toxicity, we evaluated the hazard of several FRs including phased-out polybrominated FRs and organophosphorus FRs: 2,2',4,4'-tetrabromodiphenylether (BDE-47), 2,2',4,4',5-pentabromodiphenylether (BDE-99), tetrabromobisphenol A, triphenyl phosphate, tris(2-butoxyethyl) phosphate and its metabolite bis-(2-butoxyethyl) phosphate, isodecyl diphenyl phosphate, triphenyl isopropylated phosphate, tricresyl phosphate, tris(1,3-dichloro-2-propyl) phosphate, tert-butylphenyl diphenyl phosphate, 2-ethylhexyl diphenyl phosphate, tris(1-chloroisopropyl) phosphate, and tris(2-chloroethyl) phosphate. Therefore, we used a human cell-based developmental neurotoxicity (DNT) in vitro battery covering a large variety of neurodevelopmental endpoints. Potency according to the respective most sensitive benchmark concentration (BMC) across the battery ranked from <1 µM (5 FRs), 1<10 µM (7 FRs) to the >10 µM range (3 FRs). Evaluation of the data with the ToxPi tool revealed a distinct ranking (a) than with the BMC and (b) compared to the ToxCast data, suggesting that DNT hazard of these FRs is not well predicted by ToxCast assays. Extrapolating the DNT in vitro battery BMCs to human FR exposure via breast milk suggests low risk for individual compounds. However, it raises a potential concern for real-life mixture exposure, especially when different compounds converge through diverse modes-of-action on common endpoints, like oligodendrocyte differentiation in this study. This case study using FRs suggests that human cell-based DNT in vitro battery is a promising approach for neurodevelopmental hazard assessment and compound prioritization in risk assessment.

Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs).

Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.

Different Behavioral Types of Distributional Preferences Are Characterized by Distinct Neural Signatures.

There are many situations where resources are distributed between two parties and where the deciding party has information about the initial distribution and can change its outcome, for example, the allocation of budget for funds or bonuses, where the deciding party might have self-interested motives. Although the neural underpinnings of distributional preferences of resources have been extensively studied, it remains unclear if there are different types of distributional preferences and if these types underlie different disposing neural signatures. We used source-localized resting EEG in combination with a data-driven clustering approach to participants' behavior in a distribution game in order to disentangle the neural sources of the different types of distributional preferences. Our findings revealed four behavioral types: Maximizing types always changed initial distributions to maximize their personal outcomes, and compliant types always left initial distributions unchanged. Disadvantage-averse types only changed initial distributions if they received less than the other party did, and equalizing types primarily changed initial distributions to fair distributions. These behavioral types differed regarding neural baseline activation in the right inferior frontal gyrus. Maximizing and compliant types showed the highest baseline activation, followed by disadvantage-averse types and equalizing types. Furthermore, maximizing types showed significantly higher baseline activation in the left orbitofrontal cortex compared to compliant types. Taken together, our findings show that different types of distributional preferences are characterized by distinct neural signatures, which further imply differences in underlying psychological processes in decision-making.

Age-related decline in murine heart and skeletal muscle performance is attenuated by reduced Ahnak1 expression.

BACKGROUND: Aging is associated with a progressive reduction in cellular function leading to poor health and loss of physical performance. Mitochondrial dysfunction is one of the hallmarks of aging; hence, interventions targeting mitochondrial dysfunction have the potential to provide preventive and therapeutic benefits to elderly individuals. Meta-analyses of age-related gene expression profiles showed that the expression of Ahnak1, a protein regulating several signal-transduction pathways including metabolic homeostasis, is increased with age, which is associated with low VO2MAX and poor muscle fitness. However, the role of Ahnak1 in the aging process remained unknown. Here, we investigated the age-related role of Ahnak1 in murine exercise capacity, mitochondrial function, and contractile function of cardiac and skeletal muscles. METHODS: We employed 15- to 16-month-old female and male Ahnak1-knockout (Ahnak1-KO) and wild-type (WT) mice and performed morphometric, biochemical, and bioenergetics assays to evaluate the effects of Ahnak1 on exercise capacity and mitochondrial morphology and function in cardiomyocytes and tibialis anterior (TA) muscle. A human left ventricular (LV) cardiomyocyte cell line (AC16) was used to investigate the direct role of Ahnak1 in cardiomyocytes. RESULTS: We found that the level of Ahnak1 protein is significantly up-regulated with age in the murine LV (1.9-fold) and TA (1.8-fold) tissues. The suppression of Ahnak1 was associated with improved exercise tolerance, as all aged adult Ahnak1-KO mice (100%) successfully completed the running programme, whereas approximately 31% male and 8% female WT mice could maintain the required running speed and distance. Transmission electron microscopic studies showed that LV and TA tissue specimens of aged adult Ahnak1-KO of both sexes have significantly more enlarged/elongated mitochondria and less small mitochondria compared with WT littermates (P < 0.01 and P < 0.001, respectively) at basal level. Further, we observed a shift in mitochondrial fission/fusion balance towards fusion in cardiomyocytes and TA muscle from aged adult Ahnak1-KO mice. The maximal and reserve respiratory capacities were significantly higher in cardiomyocytes from aged adult Ahnak1-KO mice compared with the WT counterparts (P < 0.05 and P < 0.01, respectively). Cardiomyocyte contractility and fatigue resistance of TA muscles were significantly increased in Ahnak1-KO mice of both sexes, compared with the WT groups. In vitro studies using AC16 cells have confirmed that the alteration of mitochondrial function is indeed a direct effect of Ahnak1. Finally, we presented Ahnak1 as a novel cardiac mitochondrial membrane-associated protein. CONCLUSIONS: Our data suggest that Ahnak1 is involved in age-related cardiac and skeletal muscle dysfunction and could therefore serve as a promising therapeutical target.

Advisory opinion of the AWMF Ad hoc Commission In-vitro Diagnostic Medical Devices regarding in-vitro diagnostic medical devices manufactured and used only within health institutions established in the Union according to Regulation (EU) 2017/746 (IVDR).

In view of the approaching application date of Regulation (EU) 2017/746 ("IVDR") and the resulting EU-wide, harmonized requirements for in-vitro diagnostic medical devices (IVD) manufactured and used within European health institutions, the Ad hoc Commission IVD of the German Association of the Scientific Medical Societies (AWMF) takes a national position on the details of the requirements and conditions related to the use of these IVD products. The Ad hoc Commission IVD emphasizes the relevance of examination procedures developed in medical laboratories, especially in the field of orphan diseases and new diagnostic markers. The IVDR sets an adequate regulatory framework for IVD manufactured and used within health institutions as long as these requirements are fulfilled with reliability and in accordance with the current state of the art in medical laboratory sciences. At the same time, the IVDR requirements have to be regarded under a pragmatic view and in accordance with the quality management systems approved within the different EU Member States. On the one hand, the mandatory requirements of the RiLiBÄK play an essential role in Germany. On the other hand, elements of voluntarily applicable international standards may support the fulfilment of product requirements for safety and performance according to Annex I of the IVDR. Both the complexity and possible solutions for the implementation of the IVDR requirements are discussed on the basis of examples such as the required documentation, performance evaluation and software validation. The Ad hoc Commission IVD recommends that, while aiming at a preferably EU-wide harmonized interpretation of the IVDR requirements, the flexibility in medical laboratory diagnostics necessary for patient care, including the use of IVD from in-house production, should be emphasized.

Academic application of Good Cell Culture Practice for induced pluripotent stem cells.

Human induced pluripotent stem cells (hiPSC) are a promising tool for replacing animal-based experiments. To warrant data reproducibility, quality-controlled research material is recommended. While the need for global harmonization of quality standards for stem cell banking centers, commercial providers, pre-clinical and clinical use of cells is well doc­umented, there are no recommendations available for quality control of hiPSC in an academic research environment to date. To fill this gap, we here give an example of a quality-controlled, two-tiered banking process producing a fully characterized master cell bank (MCB) and partially characterized respective working cell banks (WCB). Characteri­zation includes the study of morphology, mycoplasma contamination, cell line identity, karyotype stability, cell antigen expression and viability, gene expression, pluripotency, and post-thaw recovery. Costs of these procedures are cal­culated. We present the results of the proposed testing panel of two hiPSC MCBs and show that both fulfil the defined specifications regarding the above-mentioned characterization assays during and upon banking. In conclusion, we propose a panel of eight assays, which are practical and useful for an academic research laboratory working with hiPSCs. Meeting these proposed specifications ensures the quality of pluripotent stem cells throughout diverse experi­ments at moderate costs.

Effect of caffeine on alcohol drinking in mice.

Mixing alcohol (ethanol) with caffeinated beverages continues to be a common and risky practice. Energy drinks are one type of caffeinated beverage that may be especially problematic when used as mixers, due to their relatively high caffeine content in combination with their highly sweetened flavor profile. The present study used a mouse model of limited-access drinking and lickometer circuitry to examine the effects of an energy drink anid its caffeine content on ethanol consumption. Predictably, the highly sweetened energy drink significantly increased ethanol intake compared to a plain ethanol solution (6.34 ± 0.2 vs. 5.01 ± 0.3 g/kg; Cohen's d = 1.79). Interestingly, adulterating a plain ethanol solution with the same concentration of caffeine (without sweetener) found in the energy drink also increased ethanol intake (5.47 ± 0.3 vs. 4.11 ± 0.3 g/kg; Cohen's d = 1.4). A lower concentration of caffeine was without effect on ethanol drinking. Interestingly, plain caffeine solutions at both tested concentrations provoked high numbers of bottle contacts, indicating that the mice found the solution palatable. These findings suggest that altering the bitterness profile of an ethanol solution with the addition of caffeine can increase intake in a similar manner as sweetening the solution. Further, the findings underscore the importance of taste in motivating ethanol consumption and the potential role that caffeine can have in this process.