Automated Measurements of Key Morphological Features of Human Embryos for IVF.

A major challenge in clinical In-Vitro Fertilization (IVF) is selecting the highest quality embryo to transfer to the patient in the hopes of achieving a pregnancy. Time-lapse microscopy provides clinicians with a wealth of information for selecting embryos. However, the resulting movies of embryos are currently analyzed manually, which is time consuming and subjective. Here, we automate feature extraction of time-lapse microscopy of human embryos with a machine-learning pipeline of five convolutional neural networks (CNNs). Our pipeline consists of (1) semantic segmentation of the regions of the embryo, (2) regression predictions of fragment severity, (3) classification of the developmental stage, and object instance segmentation of (4) cells and (5) pronuclei. Our approach greatly speeds up the measurement of quantitative, biologically relevant features that may aid in embryo selection.

Adjuvant non-bacteriolytic and anti-inflammatory combination therapy in pneumococcal meningitis: an investigation in a mouse model.

OBJECTIVES: Therapy with antibiotics, dexamethasone, and supportive intensive care has improved the prognosis of pneumococcal meningitis, but mortality remains high. Here, we investigated an adjunctive combination therapy of the non-bacteriolytic antibiotic daptomycin plus several anti-inflammatory agents to identify the currently most promising adjunctive combination therapy for pneumococcal meningitis. METHODS: C57BL/6 mice were infected by injection of pneumococci into the cisterna magna. Treatment was begun 21 h after infection, and consisted of ceftriaxone plus (a) dexamethasone, (b) dexamethasone plus daptomycin, (c) daptomycin, (d) daptomycin plus an anti-IL1 antibody, (e) daptomycin plus roscovitine, or (f) daptomycin plus an anti-C5 antibody. Animals were followed until 45 h after infection. Furthermore, adjunctive daptomycin plus anti-C5 antibodies were assessed in a long-term follow-up. RESULTS: Adjunctive treatment with daptomycin and an anti-C5 antibody was superior to adjunctive dexamethasone and reduced disease symptoms (clinical score 1.1 ± 1.1 versus 5.0 ± 2.7, p < 0.0083), improved explorative activity (open field test 17.8 ± 8.2 versus 7.4 ± 4.3 crossed fields/2 minutes, p < 0.0083), and reduced hearing impairment (thresholds for click stimulus 96.1 ± 14.7 versus 114.8 ± 9.3 dB SPL, p < 0.0083) in the acute stage. Furthermore, explorative activity (14.4 ± 7.3 crossed fields/2 minutes versus 6.3 ± 7.2, p < 0.05) and cognitive function (t-maze test, exploration time previously unknown alley 72.4 ± 14.3 versus 48.7 ± 25.6%, p < 0.05) was improved at 2 weeks after infection. Treatment with daptomycin plus an anti-IL-1ß antibody or roscovitine was not of significant benefit in comparison to adjunctive therapy with dexamethasone. CONCLUSIONS: An adjunctive combination of the non-lytic antibiotic daptomycin plus an anti-C5 antibody was superior to standard therapy with adjunctive dexamethasone in the treatment of pneumococcal meningitis.

Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis.

BACKGROUND: Pneumococcal meningitis remains a potentially lethal and debilitating disease, mainly due to brain damage from sustained inflammation. The release of danger-associated molecular patterns (DAMPs), like myeloid-related protein 14 (MRP14) and high mobility group box 1 protein (HMGB1), plays a major role in persistence of inflammation. In this study, we evaluated if paquinimod, an MRP14-inhibitor, and an anti-HMGB1 antibody can improve clinical outcome as adjunctive therapeutics in pneumococcal meningitis. METHODS: We tested the adjuvant administration of paquinimod and the anti-HMGB1 antibody in our pneumococcal meningitis mouse model assessing clinical (clinical score, open-field-test, temperature) and pathophysiological parameters (intracranial pressure, white blood cell count in CSF, bleeding area) as well as bacterial titers in blood and brain 24 h after administration and 48 h after infection. Furthermore, we explored the interactions of these two agents with dexamethasone, the standard adjuvant treatment in pneumococcal meningitis (PM), and daptomycin, a non-bacteriolytic antibiotic preventing pathogen-associated molecular pattern (PAMP) release. RESULTS: Adjunctive inhibition of MRP14 or HMGB1 reduced mortality in mice with PM. This effect was lost when the two anti-DAMP agents were given simultaneously, possibly due to excessive immunosuppression. Combining anti-PAMP (daptomycin) and anti-DAMP treatments did not produce synergistic results; instead, the anti-DAMP treatment alone was sufficient and superior. The combination of anti-HMGB1 with dexamethasone did not diminish the effect of the former. CONCLUSIONS: DAMP inhibition possesses good potential as an adjuvant treatment approach in PM, as it improves clinical outcome and can be given together with the standard adjuvant dexamethasone without drug effect loss in experimental PM.

Pathfinder: Visual Analysis of Paths in Graphs.

The analysis of paths in graphs is highly relevant in many domains. Typically, path-related tasks are performed in node-link layouts. Unfortunately, graph layouts often do not scale to the size of many real world networks. Also, many networks are multivariate, i.e., contain rich attribute sets associated with the nodes and edges. These attributes are often critical in judging paths, but directly visualizing attributes in a graph layout exacerbates the scalability problem. In this paper, we present visual analysis solutions dedicated to path-related tasks in large and highly multivariate graphs. We show that by focusing on paths, we can address the scalability problem of multivariate graph visualization, equipping analysts with a powerful tool to explore large graphs. We introduce Pathfinder (Figure 1), a technique that provides visual methods to query paths, while considering various constraints. The resulting set of paths is visualized in both a ranked list and as a node-link diagram. For the paths in the list, we display rich attribute data associated with nodes and edges, and the node-link diagram provides topological context. The paths can be ranked based on topological properties, such as path length or average node degree, and scores derived from attribute data. Pathfinder is designed to scale to graphs with tens of thousands of nodes and edges by employing strategies such as incremental query results. We demonstrate Pathfinder's fitness for use in scenarios with data from a coauthor network and biological pathways.

[Bacterial meningitis in adults in emergency and rescue services]. / Bakterielle Meningitis bei Erwachsenen im Notfall- und Rettungswesen.

The cardinal symptoms of bacterial meningitis are headache, fever, impaired consciousness and nuchal stiffness (meningism); however, the diagnosis of acute bacterial meningitis can only be confirmed or ruled out by investigation of cerebrospinal fluid. The recommended empirical antibiotic regimen for community-acquired acute bacterial meningitis in adults in Germany is a combination of ceftriaxone and ampicillin plus adjuvant dexamethasone. An important influenceable factor for treatment success of acute bacterial meningitis is a rapid induction of antibiotic therapy, which must be initiated directly after lumbar puncture. When this is delayed for any reason, e. g. because of the necessity of cerebral computed tomography imaging before lumbar puncture, antibiotics should be started even before acquisition of cerebrospinal fluid.

Spectrum and Prevalence of Pathological Intracranial Magnetic Resonance Imaging Findings in Acute Bacterial Meningitis.

PURPOSE: Aim of this study was to determine the spectrum and prevalence of pathological intracranial magnetic resonance imaging (MRI) findings in patients with acute bacterial meningitis. METHODS: We retrospectively identified all consecutive patients with cerebral spinal fluid proven bacterial meningitis who presented at our neurology department between 2007 and 2012. Pathogenic agents and clinical symptoms were noted. MR-examinations were evaluated regarding presence and localization of pathological signal alterations in the different sequences by two neuroradiologists in consensus. RESULTS: A total of 136 patients with purulent bacterial meningitis were identified. In 114 cases the bacterial pathogen agent was proven and in 75 patients an MRI was available. In 62 of the 75 (82.7 %) patients meningitis-associated pathologic imaging findings were evident on MRI. Overall, intraventricular signal alterations, i.e., signs of pyogenic ventriculitis, were present in 41 cases (54.7 %), while sulcal signal changes were found in 22 cases (29.3 %). Intraparenchymatous signal alterations affected the cortex in 15 cases (20 %), and the white matter in 20 patients (26.7 %). The diffusion-weighted imaging and fluid attenuated inversion recovery sequences were most sensitive in the detection of these changes and showed any pathologic findings in 67.6 and 79.6 %, respectively. Patients with streptococcal meningitis showed significantly more often (n = 29 of 34, 85.3 %) intraventricular and/or sulcal diffusion restrictions than patients with meningitis caused by other agents (n = 12 of 37, 32.4 %) (p< 0.0001). CONCLUSION: Pathological MR findings are frequently found in patients with acute bacterial meningitis. Intraventricular diffusion restrictions, i.e., signs of pyogenic ventriculitis, are more often found in patients with streptococcal, especially pneumococcal, infection.

Early identification of renal transplant recipients with high risk of polyomavirus-associated nephropathy.

Polyomavirus BK (BKPyV) is ubiquitous among humans. Following primary infection, the virus remains latent predominantly in the hosts' uroepithelial cells. Up to 10 % of renal transplant recipients show a viral reactivation that can lead to polyomavirus-associated nephropathy (PyVAN). In the absence of early treatments, the risk of graft loss is up to 80 %. Monitoring viral load in urine and plasma by real-time PCR after transplantation is the most common diagnostic tool to detect viral reactivation. In the present retrospective study, BKPyV-DNA loads in urine and plasma by quantitative real-time PCR were associated with clinical data, including HLA haplotype, blood parameters and viral genotype, of 40 renal transplant recipients at the University Clinics of Cologne. Seventeen out of 329 patients screened for BKPyV from January 2009 to October 2013 were detected BKPyV positive in urine only, whereas in 23 patients the virus became additionally detectable in plasma. Among these, ten patients progressed to PyVAN. Overall, the present study showed that the detection from the third month onwards after transplantation of a first viruric episode with a median viral load of 1 × 10(8) copies/mL, followed after few days by a first viremic episode with a median viral load of >1 × 10(4) copies/mL, was strongly associated with the development of PyVAN. In conclusion, the viral load and the temporal profile of the first viruric and viremic episode post-transplantation, in combination with specific features of the host immune response, should be considered as relevant clinical determinants of the risk of renal transplant recipients to progress to PyVAN.

Specific behaviour, mood and personality traits may contribute to obesity in patients with craniopharyngioma.

INTRODUCTION: Patients with craniopharyngioma (CP) often suffer from obesity, but the underlying causes are still not fully understood. We compared CP to patients with nonfunctioning pituitary adenoma (NFPA) and to a control group (CG) using standardized questionnaires to investigate whether behavioural, mood or personality traits contribute to obesity. METHODS: We compared 31 patients with CP (42% male, 53 ± 15·1 years) to 26 patients with NFPA (71% male, 63·2 ± 10·3 years) and to age- and gender-matched local CG (ratio 2:1). Normative data from the literature are included for reference. Patients were asked to complete eleven standardized questionnaires. Two questionnaires were used to evaluate eating disorders (FEV, EDE-Q), one depression (BDI), one anxiety (STAI), three health-related quality of life (SF-36, EuroQoL, QoL-AGHDA), one sleepiness (Epworth Sleepiness Scale), two personality (EPQ-RK, TPQ) and one body image (FKB-20). RESULTS: Patients with CP scored significantly higher in conscious hunger perception (FEV, CP 5·8 ± 3·2 scores, NFPA 3·6 ± 3·3 scores, CG 3·0 ± 2·5, P < 0·001). They had similar scores for BDI compared with NFPA, but higher scores to CG (P < 0·001, CP 10·6 ± 8·3, NFPA 7·5 ± 5·7, CG 4·96 ± 4·2). CP and NFPA scored higher than CG for anxiety and personality traits such as harm avoidance, fatigability and asthenia and slightly higher for neuroticism. No differences were seen for EDE-Q, quality of life, daytime sleepiness and body image between CP and NFPA. However, differences could be observed to normative data from the literature. CONCLUSION: Obesity in patients with CP might be influenced by eating disorders, negative mood alterations and increased anxiety-related personality traits.

[Lyme borreliosis]. / Lyme-Borreliose.

Lyme borreliosis is a multisystem infectious disease affecting mainly the skin, nervous system, joints and heart. It is caused by spirochetes of the Borrelia burgdorferi sensu lato complex which are transmitted by ticks. The diagnosis of Lyme borreliosis is based primarily on typical clinical symptoms and signs with serological confirmation. Antibiotic therapy is beneficial for all manifestations and treatment refractory cases are rare. The diagnosis "chronic Lyme borreliosis" is increasingly being misused for all conceivable medically unexplained symptoms.

Neuroinfectious diseases at a European neurological tertiary care center: one-third of patients require treatment in the neurological intensive care unit.

BACKGROUND AND PURPOSE: Studies on the impact of infectious diseases affecting the nervous system are sparse. METHODS: All patients with neuroinfectious diseases (NIDs) who were treated at our Department of Neurology from 2005 until 2009 were retrospectively analyzed. RESULTS: Patients with NIDs required treatment at the intensive care unit in 34.8%. The mortality rate of patients with NIDs was significantly higher than that of other inpatients with neurological diseases (5.1% vs. 3.0%, respectively, P = 0.018). CONCLUSION: In summary, this study shows that patients with NIDs are severely ill and mortality is high.

Anxious and non-anxious forms of major depression: familial, personality and symptom characteristics.

BACKGROUND: Earlier clinical studies have suggested consistent differences between anxious and non-anxious depression. The aim of this study was to compare parental pathology, personality and symptom characteristics in three groups of probands from the general population: depression with and without generalized anxiety disorder (GAD) and with other anxiety disorders. Because patients without GAD may have experienced anxious symptoms for up to 5 months, we also considered GAD with a duration of only 1 month to produce a group of depressions largely unaffected by anxiety. METHOD: Depressive and anxiety disorders were assessed in a 10-year prospective longitudinal community and family study using the DSM-IV/M-CIDI. Regression analyses were used to reveal associations between these variables and with personality using two durations of GAD: 6 months (GAD-6) and 1 month (GAD-1). RESULTS: Non-anxious depressives had fewer and less severe depressive symptoms, and higher odds for parents with depression alone, whereas those with anxious depression were associated with higher harm avoidance and had parents with a wider range of disorders, including mania. CONCLUSIONS: Anxious depression is a more severe form of depression than the non-anxious form; this is true even when the symptoms required for an anxiety diagnosis are ignored. Patients with non-anxious depression are different from those with anxious depression in terms of illness severity, family pathology and personality. The association between major depression and bipolar disorder is seen only in anxious forms of depression. Improved knowledge on different forms of depression may provide clues to their differential aetiology, and guide research into the types of treatment that are best suited to each form.

Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression.

The FK506 binding protein 51 or FKBP5 has been implicated in the regulation of glucocorticoid receptor (GR) sensitivity, and genetic variants in this gene have been associated with mood and anxiety disorders. GR resistance and associated stress hormone dysregulation are among the most robust biological findings in major depression, the extent of which may be moderated by FKBP5 polymorphisms. FKBP5 mRNA expression in peripheral blood cells (baseline and following in vivo GR stimulation with 1.5 mg dexamethasone p.o.) was analyzed together with plasma cortisol, ACTH, dexamethasone levels and the FKBP5 polymorphism rs1360780 in 68 depressed patients and 87 healthy controls. We observed a significant (P = 0.02) interaction between disease status and FKBP5 risk allele carrier status (minor allele T) on GR-stimulated FKBP5 mRNA expression. Patients carrying the risk T allele, but not the CC genotype, showed a reduced induction of FKBP5 mRNA. This FKBP5 polymorphism by disease status interaction was paralleled by the extent of plasma cortisol and ACTH suppression following dexamethasone administration, with a reduced suppression only observed in depressed patients carrying the T allele. Only depressed patients carrying the FKBP5 rs1360780 risk allele showed significant GR resistance compared with healthy controls, as measured by dexamethasone-induced FKBP5 mRNA induction in peripheral blood cells and suppression of plasma cortisol and ACTH concentrations. This finding suggests that endocrine alterations in depressed patients are determined by genetic variants and may allow identification of specific subgroups.

Increased prevalence of anxiety-associated personality traits in patients with Cushing's disease: a cross-sectional study.

BACKGROUND/AIMS: Chronic hypercortisolism in Cushing's disease (CD) has been suggested to contribute to an altered personality profile in these patients. We aimed to test this hypothesis and attempted to determine the effects of disease- and treatment-related factors that might moderate an altered personality in CD. METHODS: We assessed 50 patients with CD (74% biochemically controlled) and compared them to 60 patients with non-functioning pituitary adenomas (NFPA) and 100 age- and gender-matched mentally healthy controls. Personality was measured by two standardized personality questionnaires, TPQ (Cloninger personality questionnaire) and EPQ-RK (Eysenck personality questionnaire-RK). RESULTS: Compared to mentally healthy controls, CD patients reported significantly less novelty-seeking behaviour, including less exploratory excitability and less extravagance. On harm avoidant subscales, they presented with more anticipatory worries and pessimism, higher fear of uncertainty, shyness with strangers, fatigability and asthenia. Moreover, CD patients appeared to be less extraverted, more neurotic and socially desirable. CD patients differed from NFPA patients in terms of higher neuroticism scores, and NFPA patients did not show altered novelty-seeking behaviour or extraversion. In the subgroup analysis, CD patients with persistent hypercortisolism displayed significantly higher fear of uncertainty, fatigability and asthenia, indicating high harm avoidance in total, than those in biochemical remission. CONCLUSION: Patients with CD showed a distinct pattern of personality traits associated with high anxiety in combination with traits of low externalizing behaviour. Such personality changes should be taken into account in the diagnosis and treatment of CD patients, as they might interfere with the patient-physician communication and/or challenge the patients' social and psychological functioning.

Distinct dopaminergic personality patterns in patients with prolactinomas: a comparison with nonfunctioning pituitary adenoma patients and age- and gender-matched controls.

INTRODUCTION: Personality patterns such as extraversion and novelty seeking have been associated with an altered dopaminergic activity in healthy subjects. Patients with prolactinomas have been described as exhibiting an altered dopaminergic tone and are often treated with dopamine agonists. Little is known about the personality traits of this patient group. Hence, we aimed at examining whether patients with prolactinomas exhibit modified personality patterns compared to patients with nonfunctioning pituitary adenomas and healthy controls. SUBJECTS/METHODS: In this cross-sectional study, 86 patients with prolactinomas and 58 patients with nonfunctioning pituitary adenomas (NFPA) were compared with 172 mentally healthy age- and gender-matched controls. To assess personality traits, standardized personality questionnaires (Eysenck personality questionnaire-EPQ-RK and Tridimensional Personality Questionnaire devised by Cloninger-TPQ) were administered. RESULTS: Patients with either prolactinomas or NFPA showed a distinct personality profile compared to the normal population, characterized by increased neuroticism and they also answered in a socially desirable mode. On harm-avoidant total and subscales, they presented with a higher fear of uncertainty and also increased fatigability and asthenia. The prolactinoma patients, when contrasted with the 'clinical' control group of patients with NFPA and after post hoc tests for multiple comparisons following the Bonferroni-Holm procedure showed significantly reduced extraversion (p = 0.044) and increased shyness with strangers (p = 0.044), tending to be more neurotic and present lower scores in the novelty seeking subscale impulsiveness. CONCLUSION: This is, to our knowledge, the first study providing new evidence of an altered personality profile of prolactinoma patients which might affect the patient-doctor relationship, treatment and patient's quality of life.

Interactive Volume Exploration of Petascale Microscopy Data Streams Using a Visualization-Driven Virtual Memory Approach.

This paper presents the first volume visualization system that scales to petascale volumes imaged as a continuous stream of high-resolution electron microscopy images. Our architecture scales to dense, anisotropic petascale volumes because it: (1) decouples construction of the 3D multi-resolution representation required for visualization from data acquisition, and (2) decouples sample access time during ray-casting from the size of the multi-resolution hierarchy. Our system is designed around a scalable multi-resolution virtual memory architecture that handles missing data naturally, does not pre-compute any 3D multi-resolution representation such as an octree, and can accept a constant stream of 2D image tiles from the microscopes. A novelty of our system design is that it is visualization-driven: we restrict most computations to the visible volume data. Leveraging the virtual memory architecture, missing data are detected during volume ray-casting as cache misses, which are propagated backwards for on-demand out-of-core processing. 3D blocks of volume data are only constructed from 2D microscope image tiles when they have actually been accessed during ray-casting. We extensively evaluate our system design choices with respect to scalability and performance, compare to previous best-of-breed systems, and illustrate the effectiveness of our system for real microscopy data from neuroscience.

Cognitive function in acromegaly: description and brain volumetric correlates.

In acromegaly, we reported on increased rates of affective disorders such as dysthymia and depression, as well as structural brain changes. Objective of this study was to determine if cognitive impairments in patients with acromegaly exist and whether such impairments are associated with structural brain alterations defined by magnetic resonance imaging (MRI). In this cross-sectional study, 55 patients with biochemically confirmed acromegaly were enrolled. MRI data were compared with 87 control subjects. Main outcome measures were performance levels in 13 cognitive tests covering the domains of attention, memory and executive function, with performance below the cut-off level of the 16th percentile rated as impaired. In addition, individual global and hippocampal volume changes were defined for each patient in reference to a normative sample. We found that up to 33.3% of the patients were impaired in the attention, up to 24.1% in the memory, and up to 16.7% in the executive function domain. 67.3% of the patients failed to reach the cut-off level in at least one subtest. MRI demonstrated increased global, left and right hippocampal grey matter and white matter, particularly early in the disease course. Rather few positive than expected negative correlations could be established between the hippocampal grey matter gain and cognitive performance. Cognitive dysfunction, particularly attentional deficits, are common in acromegaly, rendering neuropsychological testing essential in the diagnostic work-up.

Factors associated with the seroprevalence of 26 cutaneous and two genital human papillomavirus types in organ transplant patients.

Viral skin infections are commonly present in organ transplant recipients (OTR). In this study, we aimed to identify factors associated with human papillomavirus (HPV) infections in OTR. Patients with solid-organ transplants were recruited from the outpatient nephrology and dermatology clinics in five European countries. Only patients with no current or past skin cancer were included in this analysis. Serum samples were analysed for antibodies to the L1 proteins of 26 cutaneous and two genital HPV types from five phylogenetic genera (α, ß, γ, µ and ν). The most consistent association was found between recreational sun exposure and the seroprevalence of all tested genera, except α. The antibody presence of any ß type was higher among people who had been transplanted at least 23 years prior to participation than in those who had been transplanted for less than 7 years. The prevalence of two γ-HPV types (60 and 65) and three ß-HPV types (15, 38 and 49) was associated with time since transplantation. The presence of a high number of warts was associated with the presence of any µ-PV or ν-PV types, and having greater than 50 keratotic skin lesions was almost significantly associated with the presence of antibodies to two or more γ-PV. Discrepancies in the results of the present study, as well as in previous reports, may depend on different methodologies and on geographical variations. Our results also indicate that further research with more standardized methods is needed to clarify the role of cutaneous HPV in OTR.