[Neurogenetics of schizophrenia: findings from studies based on data sharing and global partnerships]. / Neurogenetik der Schizophrenie: Erkenntnisse aus Studien basierend auf Datenaustausch und globalen Partnerschaften.

Schizophrenic psychoses are the result of a multifactorial process in which not only environmental influences but also genetic factors play an important role. These factors are based on a complex mode of inheritance that involves a large number of genetic variants. In the last three decades, biological psychiatric research has focused closely on molecular genetic aspects of the hereditary basis of schizophrenic psychoses. In particular, international consortia are combining cohorts from individual researchers, creating continuously increasing sample sizes and thus increased statistical power. As part of the Psychiatric Genomics Consortium (PGC), genome-wide association studies with tens of thousands of patients and controls have for the first time found robustly replicable markers for schizophrenic psychoses. Through intensive phenotyping, first approaches to a transdiagnostic clinical reclassification of severe mental illnesses have been established in the longitudinal PsyCourse study of the UMG Göttingen and the LMU Munich, allowing new biologically validated disease subgroups with prognostic value to be identified. For the first time environmental factors could even be examined in an African cohort that contribute to the development of the psychosis. In the coming years, the enormous technical progress in the area of genomic high-throughput technologies (next-generation sequencing) is expected to provide new knowledge not only about the influence of frequently occurring single nucleotide polymorphisms but also about rare variants. For the successful use of this technological revolution an exchange of data between research groups is essential.

Can network analysis shed light on predictors of lithium response in bipolar I disorder?

OBJECTIVE: To undertake a large-scale clinical study of predictors of lithium (Li) response in bipolar I disorder (BD-I) and apply contemporary multivariate approaches to account for inter-relationships between putative predictors. METHODS: We used network analysis to estimate the number and strength of connections between potential predictors of good Li response (measured by a new scoring algorithm for the Retrospective Assessment of Response to Lithium Scale) in 900 individuals with BD-I recruited to the Consortium of Lithium Genetics. RESULTS: After accounting for co-associations between potential predictors, the most important factors associated with the good Li response phenotype were panic disorder, manic predominant polarity, manic first episode, age at onset between 15-32 years and family history of BD. Factors most strongly linked to poor outcome were comorbid obsessive-compulsive disorder, alcohol and/or substance misuse, and/or psychosis (symptoms or syndromes). CONCLUSIONS: Network analysis can offer important additional insights to prospective studies of predictors of Li treatment outcomes. It appears to especially help in further clarifying the role of family history of BD (i.e. its direct and indirect associations) and highlighting the positive and negative associations of different subtypes of anxiety disorders with Li response, particularly the little-known negative association between Li response and obsessive-compulsive disorder.

Comparison of a 3D head-mounted display (HMS-3000MT) and 3D passive polarizing display with 2D technique for first laparoscopic inguinal hernia repair by novice surgeons.

BACKGROUND: Three-dimensional (3D) laparoscopy improves the surgical skills of novice surgeons and positively affects the learning curve in experimental settings. This study aimed to investigate the effect of a 3D passive polarizing display (3DPPD) and a novel 3D head-mounted display (3DHMD; HMS-3000MT) on the performance of the first laparoscopic inguinal hernia repair by novices and compare both systems with standard high-definition 2D (HD2D) laparoscopy. METHODS: Patients with symptomatic inguinal hernia underwent transabdominal preperitoneal (TAPP) approach hernia repair using 3DHMD, 3DPPD, or a conventional HD2D laparoscopic system. All surgeries were performed for the first time by three laparoscopically novice surgeons. Operative performance was compared in terms of the time taken for mesh placement and peritoneal suturing under standardized conditions. Additionally, visual perception parameters and adverse effects were assessed. RESULTS: The use of both 3D techniques shortened the time required for mesh placement and peritoneal suturing compared with the conventional HD2D approach. Generally, 3D laparoscopy was superior to HD2D laparoscopy in terms of visual perception parameters such as depth perception, sharpness, ghosting, and contrast. However, compared with the use of HD2D laparoscopy, the use of 3DHMD significantly impaired a surgeon's comfort, with the greatest impairment caused by ear discomfort, headaches, and facial and physical discomforts. CONCLUSIONS: The 3DHMD and 3DPPD systems showed clear improvement in first hernia repair laparoscopy by novice surgeons in terms of surgical performance, as well as visual perception; however, the 3DHMD system was not superior to the 3DPPD system. The reduction in training time for new surgeons is obviously advantageous. In this respect, the 3D equipment may be a worthwhile investment.

A comparison of non-absorbable polymeric clips and staplers for laparoscopic appendiceal stump closure: analysis of 618 adult patients.

PURPOSE: The aim of this long-term study was the comparison of appendiceal stump closure with polymeric clips or staplers with respect to perioperative costs and surgical outcome under routine conditions in a university centre. METHODS: For this retrospective chart review, a total of 618 patients undergoing laparoscopic appendectomy for suspected acute appendicitis between 2010 and 2017 were reviewed: 410 patients in the stapler group and 208 patients in the clip group. The database contained demographic data, operation time, inflammation parameters, closure method of the stump, surgeon status, length of hospital stay, and complications as well as histology reports. The costs were also compared. RESULTS: Clip application was more likely among younger patients (mean age 33.6 years vs. 41.7 years). Histopathological evidence for appendiceal pathology was found in 96.6% of patients in the clip group and 99.5% of patients in the stapler group. Laparoscopic appendectomy in the clip group was more frequently performed by resident physicians (69.2%) than in the stapler group (57.8%). The mean postoperative stay was 2.9 days in the clip group and 3.7 days in the stapler group. The use of the polymeric clip resulted in considerable cost savings (19.94€ vs. 348.70€). CONCLUSIONS: The use of polymeric clips for appendiceal stump closure during appendectomy is safe and effective. The base of the appendix is amenable to clipping in 32% of appendectomies in adult patients. This study supports the use of polymeric clips over staplers to decrease cost and environmental impact.

An adaptable two-lens high-resolution objective for single-site resolved imaging of atoms in optical lattices.

In this paper, we present a high-resolution, simple, and versatile imaging system for single-site resolved imaging of atoms in optical lattices. The system, which relies on an adaptable infinite conjugate two-lens design, has a numerical aperture of 0.52, which can in the ideal case be further extended to 0.57. It is optimized for imaging on the sodium D2-line but allows us to tune the objective's diffraction limited performance between 400 nm and 1000 nm by changing the distance between the two lenses. Furthermore, the objective is designed to be integrated into a typical atomic physics vacuum apparatus where the operating distance can be large (>20 mm) and diffraction limited performance still needs to be achieved when imaging through thick vacuum windows (6 mm to 10 mm). Imaging gold nanoparticles, using a wavelength of 589 nm which corresponds to the D2-line of sodium atoms, we measure diffraction limited performance and a resolution corresponding to an Airy radius of less than 0.7 µm, enabling potential single-site resolution in the commonly used 532 nm optical lattice spacing.

Association between completed suicide and bipolar disorder: A systematic review of the literature.

BACKGROUND: Completed suicide is a major cause of death in bipolar disorder (BD) patients. OBJECTIVE: The aim of this paper is to provide an overall review of the existing literature of completed suicide in BD patients, including clinical and genetic data DATA SOURCES: We performed a systematic review of English and non-English articles published on MEDLINE/PubMed, PsycInfo and Cochrane database (1970-2017). Additional studies were identified by contacting clinical experts, searching bibliographies, major textbooks and website of World Health Organization. Initially we did a broad search for the association of bipolar disorder and suicide and we were narrowing the search in terms included "bipolar disorder" and "completed suicide". STUDY SELECTION: Inclusion criteria were articles about completed suicide in patients with BD. Articles exclusively focusing on suicide attempts and suicidal behaviour have been excluded. We used PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) consensus for drafting this systematic review. RESULTS: The initial search generated 2806 articles and a total of 61 meeting our inclusion criteria. We reviewed epidemiological data, genetic factors, risk factors and treatment of completed suicide in BD. Suicide rates in BD vary between studies but our analyses show that they are approximately 20-30-fold greater than in general population. The highest risk of successful suicide was observed in BD-II subjects. The heritability of completed suicide is about 40% and some genes related to major neurotransmitter systems have been associated with suicide. Lithium is the only treatment that has shown anti-suicide potential. LIMITATIONS: The most important limitation of the present review is the limited existing literature on completed suicide in BD. CONCLUSIONS: BD patients are at high risk for suicide. It is possible to identify some factors related to completed suicide, such as early onset, family history of suicide among first-degree relatives, previous attempted suicides, comorbidities and treatment. However it is necessary to promote research on this serious health problem.

Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii.

Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivo efficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50's comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype.

[Pharmacogenetics in psychiatry: state of the art]. / Pharmakogenetik in der Psychiatrie: eine Standortbestimmung.

In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine. The main obstacle for a broad application of pharmacogenetic tests in psychiatry remains the lack of large prospective studies, for both single gene-drug pair and cobinatorial pharmacogenetic tests, to evaluate the benefits of genetic testing. Psychiatrists, geneticists and funding agencies are encouraged to increase their efforts for the future benefit of psychiatric patients.

The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.

Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.

Novel Toxoplasma gondii inhibitor chemotypes.

We profiled three novel T. gondii inhibitors identified from an antimalarial phenotypic high throughput screen (HTS) campaign: styryl 4-oxo-1,3-benzoxazin-4-one KG3, tetrahydrobenzo[b]pyran KG7, and benzoquinone hydrazone KG8. These compounds inhibit T. gondii in vitro with IC50 values ranging from 0.3 to 2µM, comparable to that of 0.25 to 1.5µM for the control drug pyrimethamine. KG3 had no measurable cytotoxicity against five mammalian cell lines, whereas KG7 and KG8 inhibited the growth of 2 of 5 cell lines with KG8 being the least selective for T. gondii. None of the compounds were mutagenic in an Ames assay. Experimental gLogD7.4 and calculated PSA values for the three compounds were well within the ranges predicted to be favorable for good ADME, even though each compound had relatively low aqueous solubility. All three compounds were metabolically unstable, especially KG3 and KG7. Multiple IP doses of 5mg/kg KG7 and KG8 increased survival in a T. gondii mouse model. Despite their liabilities, we suggest that these compounds are useful starting points for chemical prospecting, scaffold-hopping, and optimization.

[Healthcare models for traumatized refugees in Germany]. / Versorgungsmodelle für traumatisierte Flüchtlinge in Deutschland.

People with a migration background are a risk group for psychiatric disorders. Innovative, transnational and sustainable projects are necessary to ensure adequate care for refugees and asylum seekers. Selected projects of the University of Munich, the Charité Berlin and the University of Konstanz show promising approaches in addition to other initiatives.

[Psychiatric care of refugees in Africa and the Middle East : Challenges and solutions]. / Psychiatrische Versorgung von Flüchtlingen in Afrika und dem Nahen Osten : Herausforderungen und Lösungsansätze.

Violence, flight, famine, and natural disasters as well as the absence of a psychosocial healthcare system are major psychological burdens for refugees. The level of provision of mental healthcare is particularly low in developing countries. Internally displaced people and refugees place high demands on the healthcare system because they often suffer from psychiatric disorders, such as depression, posttraumatic stress disorder, and substance use disorders. We present first initiatives to improve psychiatric care in refugee camps in Ethiopia, Kenya, and Sudan. Moreover, we provide first insights into a project based in Northern Iraq and Germany aimed at the treatment of people who were severely traumatized by the terror regime of the so-called Islamic State (IS).

[Genetics of bipolar disorder]. / Genetische Grundlagen der bipolaren Störung.

Bipolar disorder (BD) has a multifactorial etiology. Its development is influenced by genetic as well as environmental factors. Large genome-wide association studies (GWAS), in which genetic risk allelic variants for the disorder could be replicated for the first time, marked the breakthrough in the identification of the responsible risk genes. In addition to these common genetic variants with moderate effects identified by GWAS, rare variants with a higher penetrance are expected to play a role in disease development. The results of recent studies suggest that copy number variants might contribute to BD development, although to a lesser extent than in other psychiatric disorders, such as schizophrenia or autism. Results from the initial next generation sequencing studies indicate an enrichment of rare variants in pathways and genes that were previously found to be associated with BD. In the field of pharmacogenetics, a risk gene that influences the individual variance in the response to lithium treatment was identified for the first time in a recent large international GWAS. Currently the reported risk alleles do not sufficiently explain the phenotypic variance to be used for individual prediction of disease risk, disease course or response to medication. Future genetic research will provide important insights into the biological basis of BD by the identification of additional genes associated with BD. This knowledge of genetics will help identify potential etiological subgroups as well as cross-diagnostic disease mechanisms.

Pharmacogenomic aspects of bipolar disorder: An update.

The hopes for readily implementable precision medicine are high. For many complex disorders, such as bipolar disorder, these hopes critically hinge on tangible successes in pharmacogenetics of treatment response or susceptibility to adverse events. In this article, we review the current state of pharmacogenomics of bipolar disorder including latest results from candidate genes and genome-wide association studies. The majority of studies focus on response to lithium treatment. Although a host of genes has been studied, hardly any replicated findings have emerged so far. Very small samples sizes and heterogeneous phenotype definition may be considered the major impediments to success in this field. Drawing from current experiences and successes in studies on diagnostic psychiatric phenotypes, we suggest several approaches for our way forward.

Co-location of passive gear fisheries in offshore wind farms in the German EEZ of the North Sea: A first socio-economic scoping.

Worldwide the renewable energy sector is expanding at sea to address increasing demands. Recently the race for space in heavily used areas such as the North Sea triggered the proposal of co-locating other activities such as aquaculture or fisheries with passive gears in offshore wind farms (OWFs). Our interdisciplinary approach combined a quantification of spatial overlap of activities by using Vessel Monitoring System and logbook data with a stakeholder consultation to conclude and verify on the actual feasibility of co-location. In the German Exclusive Economic Zone (EEZ) of the North Sea up to 90% of Danish and 40% of German annual gillnet fleet landings of plaice overlapped with areas where OWFs are developed. Our results indicated further that the international gillnet fishery could lose up to 50% in landings within the North Sea German EEZ when OWF areas are closed entirely for fisheries. No spatial overlap was found for UK potters targeting brown crab in the German EEZ. We further identified a number of key issues and obstacles that to date hinder an actual implementation of co-location as a measure in the marine spatial planning process: defining the legal base; implementation of safety regulations; delineation of minimum requirements for fishing vessels such as capacities, quotas, technical equipment; implementation of a licensing process; and scoping for financial subsidies to set up business. The stakeholder consultation verified the scientific findings and highlighted that all those points need to be addressed in a planning process. In the German EEZ we have shown that the socio-economic importance of spatial overlap varies within planning boundaries. Therefore we recommend an interdisciplinary bottom-up approach when scoping for suitable areas of co-location. Hence, an informed marine spatial planning process requires comprehensive and spatial explicit socio-economic viability studies factoring in also ecological effects of OWFs on target species.

[The German research network for mental disorders]. / Das deutsche Forschungsnetz zu psychischen Erkrankungen.

Mental disorders are among the greatest medical and social challenges facing us. They can occur at all stages of life and are among the most important commonly occurring diseases. In Germany 28 % of the population suffer from a mental disorder every year, while the lifetime risk of suffering from a mental disorder is almost 50 %. Mental disorders cause great suffering for those affected and their social network. Quantitatively speaking, they can be considered to be among those diseases creating the greatest burden for society due to reduced productivity, absence from work and premature retirement. The Federal Ministry of Education and Research is funding a new research network from 2015 to 2019 with up to 35 million euros to investigate mental disorders in order to devise and develop better therapeutic measures and strategies for this population by means of basic and translational clinical research. This is the result of a competitive call for research proposals entitled research network for mental diseases. It is a nationwide network of nine consortia with up to ten psychiatric and clinical psychology partner institutions from largely university-based research facilities for adults and/or children and adolescents. Furthermore, three cross-consortia platform projects will seek to identify shared causes of diseases and new diagnostic modalities for anxiety disorders, attention deficit hyperactivity disorders (ADHS), autism, bipolar disorders, depression, schizophrenia and psychotic disorders as well as substance-related and addictive disorders. The spectrum of therapeutic approaches to be examined ranges from innovative pharmacological and psychotherapeutic treatment to novel brain stimulation procedures. In light of the enormous burden such diseases represent for society as a whole, a sustainable improvement in the financial support for those researching mental disorders seems essential. This network aims to become a nucleus for long overdue and sustained support for a German center for mental disorders.