OBJECTIVE: To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients.

DESIGN: Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies.

DATA SOURCES: Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators.

ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups.

RESULTS: Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)).

CONCLUSIONS: In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients.

SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42012002780.

Drug nanosuspensions/nanocrystals have been recognized as one useful and successful approach for drug delivery. Drug nanocrystals could be further decorated to possess extended functions (such as controlled release) and designed for special in vivo applications (such as drug tracking), which make best use of the advantages of drug nanocrystals. A lot of novel and advanced size reduction methods have been invented recently for special drug deliveries. In addition, some novel downstream processes have been combined with nanosuspensions, which have highly broadened its application areas (such as targeting) besides traditional routes. A large number of recent research publication regarding as nanocrystals focuses on above mentioned aspects, which have widely attracted attention. This review will focus on the recent development of nanocrystals and give an overview of regarding modification of nanocrystal by some new approaches for tailor-made drug delivery.

Glycan microarrays have become a powerful technology to study biological processes, such as cell–cell interaction, inflammation, and infections. Yet, several challenges, especially in multivalent display, remain. In this introductory lecture we discuss the state-of-the-art glycan microarray technology, with emphasis on novel approaches to access collections of pure glycans and their immobilization on surfaces. Future directions to mimic the natural glycan presentation on an array format, as well as in situ generation of combinatorial glycan collections, are discussed.

This open access book provides an exhaustive picture of the role that annulment conflicts play in the EU multilevel system. Based on a rich dataset of annulment actions since the 1960s and a number of in-depth case studies, it explores the political dimension of annulment litigation, which has become an increasingly relevant judicial tool in the struggle over policy content and decision-making competences. The book covers the motivations of actors to turn policy conflicts into annulment actions, the emergence of multilevel actors’ litigant configurations, the impact of actors’ constellations on success in court, as well as the impact of annulment actions on the multilevel policy conflicts they originate from.

Viruses of the genus Roseolovirus belong to the subfamily Betaherpesvirinae, family Herpesviridae. Roseoloviruses have been studied in humans, mice and pigs, but they are likely also present in other species. This is the first comparative analysis of roseoloviruses in humans and animals. The human roseoloviruses human herpesvirus 6A (HHV-6A), 6B (HHV-6B), and 7 (HHV-7) are relatively well characterized. In contrast, little is known about the murine roseolovirus (MRV), also known as murine thymic virus (MTV) or murine thymic lymphotrophic virus (MTLV), and the porcine roseolovirus (PRV), initially incorrectly named porcine cytomegalovirus (PCMV). Human roseoloviruses have gained attention because they can cause severe diseases including encephalitis in immunocompromised transplant and AIDS patients and febrile seizures in infants. They have been linked to a number of neurological diseases in the immunocompetent including multiple sclerosis (MS) and Alzheimer’s. However, to prove the causality in the latter disease associations is challenging due to the high prevalence of these viruses in the human population. PCMV/PRV has attracted attention because it may be transmitted and pose a risk in xenotransplantation, e.g., the transplantation of pig organs into humans. Most importantly, all roseoloviruses are immunosuppressive, the humoral and cellular immune responses against these viruses are not well studied and vaccines as well as effective antivirals are not available.

In this work, we study the d-Hitting Set and Feedback Vertex Set problems through the paradigm of finding diverse collections of r solutions of size at most k each, which has recently been introduced to the field of parameterized complexity. This paradigm is aimed at addressing the loss of important side information which typically occurs during the abstraction process that models real-world problems as computational problems. We use two measures for the diversity of such a collection: the sum of all pairwise Hamming distances, and the minimum pairwise Hamming distance. We show that both problems are fixed-parameter tractable in k+r for both diversity measures. A key ingredient in our algorithms is a (problem independent) network flow formulation that, given a set of ‘base’ solutions, computes a maximally diverse collection of solutions. We believe that this could be of independent interest.

The notion of the waggle dance simulating a flight towards a goal in a walking pattern has been proposed in the context of evolutionary considerations. Behavioral components, like its arousing effect on the social community, the attention of hive mates induced by this behavior, the direction of the waggle run relative to the sun azimuth or to gravity, as well as the number of waggles per run, have been tentatively related to peculiar behavioral patterns in both solitary and social insect species and are thought to reflect phylogenetic pre-adaptations. Here, I ask whether these thoughts can be substantiated from a functional perspective. Communication in the waggle dance is a group phenomenon involving the dancer and the followers that perform partially overlapping movements encoding and decoding the message respectively. It is thus assumed that the dancer and follower perform close cognitive processes. This provides us with access to these cognitive processes during dance communication because the follower can be tested in its flight performance when it becomes a recruit. I argue that the dance message and the landscape experience are processed in the same navigational memory, allowing the bee to fly novel direct routes, a property understood as an indication of a cognitive map.

Brucellosis is a highly contagious zoonosis worldwide with economic and public health impacts. The aim of the present study was to identify Brucella (B.) spp. isolated from animal populations located in different districts of Egypt and to determine their antimicrobial resistance. In total, 34-suspected Brucella isolates were recovered from lymph nodes, milk, and fetal abomasal contents of infected cattle, buffaloes, sheep, and goats from nine districts in Egypt. The isolates were identified by microbiological methods and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Differentiation and genotyping were confirmed using multiplex PCR for B. abortus, Brucella melitensis, Brucella ovis, and Brucella suis (AMOS) and Bruce-ladder PCR. Antimicrobial susceptibility testing against clinically used antimicrobial agents (chloramphenicol, ciprofloxacin, erythromycin, gentamicin, imipenem, rifampicin, streptomycin, and tetracycline) was performed using E-Test. The antimicrobial resistance-associated genes and mutations in Brucella isolates were confirmed using molecular tools. In total, 29 Brucella isolates (eight B. abortus biovar 1 and 21 B. melitensis biovar 3) were identified and typed. The resistance of B. melitensis to ciprofloxacin, erythromycin, imipenem, rifampicin, and streptomycin were 76.2%, 19.0%, 76.2%, 66.7%, and 4.8%, respectively. Whereas, 25.0%, 87.5%, 25.0%, and 37.5% of B. abortus were resistant to ciprofloxacin, erythromycin, imipenem, and rifampicin, respectively. Mutations in the rpoB gene associated with rifampicin resistance were identified in all phenotypically resistant isolates. Mutations in gyrA and gyrB genes associated with ciprofloxacin resistance were identified in four phenotypically resistant isolates of B. melitensis. This is the first study highlighting the antimicrobial resistance in Brucella isolated from different animal species in Egypt. Mutations detected in genes associated with antimicrobial resistance unravel the molecular mechanisms of resistance in Brucella isolates from Egypt. The mutations in the rpoB gene in phenotypically resistant B. abortus isolates in this study were reported for the first time in Egypt.

Background: Early life stress (ELS) affects facial emotion recognition (FER), as well as the underlying brain network. However, there is considerable inter-individual variability in these ELS-caused alterations. As the hypothalamic-pituitary-adrenal (HPA) axis is assumed to mediate neural and behavioural sequelae of ELS, the genetic disposition towards HPA axis reactivity might explain differential vulnerabilities. Methods: An additive genetic profile score (GPS) of HPA axis reactivity was built from 6 SNPs in 3 HPA axisrelated genes (FKBP5, CRHR1, NR3C1). We studied two independent samples. As a proof of concept, GPS was tested as a predictor of cortisol increase to a psychosocial challenge (MIST) in a healthy community sample of n=40. For the main study, a sample of n=170 completed a video-based FER task and retrospectively reported ELS experiences in the Childhood Trauma Questionnaire (CTQ). Results: GPS positively predicted cortisol increase in the stress challenge over and above covariates. CTQ and genetic profile scores interacted to predict facial emotion recognition, such that ELS had a detrimental effect on emotion processing only in individuals with higher GPS. Post-hoc moderation analyses revealed that, while a less stress-responsive genetic profile was protective against ELS effects, individuals carrying a moderate to high GPS were affected by ELS in their ability to infer emotion from facial expressions. Discussion: These results suggest that a biologically informed genetic profile score can capture the genetic disposition to HPA axis reactivity and moderates the influence of early environmental factors on facial emotion recognition. Further research should investigate the neural mechanisms underlying this moderation. The GPS used here might prove a powerful tool for studying inter-individual differences in vulnerability to early life stress.

Owing to the increase in freely available software and data for cheminformatics and structural bioinformatics, research for computer-aided drug design (CADD) is more and more built on modular, reproducible, and easy-to-share pipelines. While documentation for such tools is available, there are only a few freely accessible examples that teach the underlying concepts focused on CADD, especially addressing users new to the field. Here, we present TeachOpenCADD, a teaching platform developed by students for students, using open source compound and protein data as well as basic and CADD-related Python packages. We provide interactive Jupyter notebooks for central CADD topics, integrating theoretical background and practical code. TeachOpenCADD is freely available on GitHub: https://github.com/volkamerlab/TeachOpenCADD

OBJECTIVES:

Patients with acute symptoms present not only to general practitioners (GPs), but also frequently to emergency departments (EDs). Patients' decision processes leading up to an ED self-referral are complex and supposed to result from a multitude of determinants. While they are key providers in primary care, little is known about GPs' perception of such patients. This qualitative study explores the GPs' view regarding motives and competences of patients self-referring to EDs, and also GPs' rationale for or against physician-initiated ED referrals.

DESIGN:

Qualitative study with semi-structured, face-to-face interviews; qualitative content analysis.

SETTING:

GP practices in Berlin, Germany.

PARTICIPANTS:

15 GPs (female/male: 9/6; mean age 53.6 years).

RESULTS:

The interviewed GPs related a wide spectrum of factors potentially influencing their patients' decision to visit an ED, and also their own decision-making in potential referrals. Considerations go beyond medical urgency. Statements concerning patients' surmised rationale corresponded to GPs' reasoning in a variety of important areas. For one thing, the timely availability of an extended spectrum of diagnostic and therapeutic options may make ED services attractive to both. Access difficulties in the ambulatory setting were mentioned as additional triggers for an ED visit initiated by a patient or a GP. Key patient factors like severity of symptoms and anxiety also play a major role; a desire for reassurance may lead to both self-referred and physician-initiated ED visits. Patients' health competence was prevailingly depicted as limited, with the internet as an important influencing factor. Counselling efforts by GP were described as crucial for improving health literacy.

CONCLUSIONS:

Health education could hold promise when aiming to reduce non-urgent ED consultations. Primary care providers are in a key position here. Amelioration of organisational shortages in ambulatory care, for example, limited consultation hours, might also make an important impact, as these trigger both self-referrals and GP-initiated ED referrals.

TRIAL REGISTRATION NUMBER:

DRKS00011930.

Various gait parameters can be used to assess the risk of falling in older adults. However, the state-of-the-art systems used to quantify gait parameters often come with high costs as well as training and space requirements. Gait analysis systems, which use mobile and commercially available cameras, can be an easily available, marker-free alternative. In a study with 44 participants (age ≥ 65 years), gait patterns were analyzed with three different systems: a pressure sensitive walkway system (GAITRite-System, GS) as gold standard, Motognosis Labs Software using a Microsoft Kinect Sensor (MKS), and a smartphone camera-based application (SCA). Intertrial repeatability showed moderate to excellent results for MKS (ICC(1,1) 0.574 to 0.962) for almost all measured gait parameters and moderate reliability in SCA measures for gait speed (ICC(1,1) 0.526 to 0.535). All gait parameters of MKS showed a high level of agreement with GS (ICC(2,k) 0.811 to 0.981). Gait parameters extracted with SCA showed poor reliability. The tested gait analysis systems based on different camera systems are currently only partially able to capture valid gait parameters. If the underlying algorithms are adapted and camera technology is advancing, it is conceivable that these comparatively simple methods could be used for gait analysis.

Little data is available regarding complications associated with resection arthroplasty in the treatment of hip periprosthetic joint infection (PJI). We assessed complications during and after two-stage revision using resection arthroplasty. In this retrospective study, 93 patients undergoing resection arthroplasty for hip PJI were included. Patients were assigned to a prosthesis-free interval of ≤10 weeks (group 1; 49 patients) or >10 weeks (group 2; 44 patients). The complication rates between groups were compared using the chi-squared test. The revision-free and infection-free survival was estimated using a Kaplan-Meier survival analysis. Seventy-one patients (76%) experienced at least one local complication (overall 146 complications). Common complications were blood loss during reimplantation (n = 25) or during explantation (n = 23), persistent infection (n = 16), leg length discrepancy (n = 13) and reinfection (n = 9). Patients in group 1 experienced less complications after reimplantation (p = 0.012). With increasing severity of acetabular bone defects, higher incidence of complications (p = 0.008), periprosthetic bone fractures (p = 0.05) and blood loss (p = 0.039) was observed. The infection-free survival rate at 24 months was 93.9% in group 1 and 85.9% in group 2. The indication for resection arthroplasty needs to be evaluated carefully, considering the high rate of complications and reduced mobility, particularly if longer prosthesis-free intervals are used.

Cells release extracellular vesicles (EVs) to communicate in a paracrine manner with other cells, and thereby influence processes, such as angiogenesis. The conditioned medium of human cardiac-derived adherent proliferating (CardAP) cells was recently shown to enhance angiogenesis. To elucidate whether their released EVs are involved, we isolated them by differential centrifugation from the conditioned medium derived either in the presence or absence of a pro-inflammatory cytokine cocktail. Murine recipient cells internalized CardAP-EVs as determined by an intracellular detection of human proteins, such as CD63, by a novel flow cytometry method for studying EV-cell interaction. Moreover, endothelial cells treated for 24 h with either unstimulated or cytokine stimulated CardAP-EVs exhibited a higher tube formation capability on Matrigel. Interestingly, unstimulated CardAP-EVs caused endothelial cells to release significantly more vascular endothelial growth factor and interleukin (IL)-6, while cytokine stimulated CardAP-EVs significantly enhanced the release of IL-6 and IL-8. By nCounter® miRNA expression assay (NanoString Technologies) we identified microRNA 302d-3p to be enhanced in unstimulated CardAP-EVs compared to their cytokine stimulated counterparts, which was verified by quantitative polymerase chain reaction. This study demonstrates that both CardAP-EVs are pro-angiogenic by inducing different factors from endothelial cells. This would allow to select potent targets for a safe and efficient therapeutic application.

Cardiovascular diseases are a major cause of morbidity and mortality, and there are significant sex differences therein. However, the underlying mechanisms are poorly understood. The steroid hormone 17β-estradiol (E2) is thought to play a major role in cardiovascular sex differences and to be protective, but this may not hold true for males. We aimed at assessing whether the zebrafish is an appropriate model for the study of E2 effects in the heart. We hypothesized that E2 regulates the cardiac contractility of adult zebrafish in a sex-specific manner. Male and female zebrafish were treated with vehicle (control) or E2 and the cardiac contractility was measured 0, 4, 7 and 14 days after treatment initiation using echocardiography. There was no significant effect on the heart rate by E2. Notably, there was a significant decrease in the ejection fraction of male zebrafish treated with E2 compared with controls. By contrast, there was no major difference in the ejection fraction between the two female groups. The dramatic effect in male zebrafish occurred as early as 4 days post treatment initiation. Although there was no significant difference in stroke volume and cardiac output between the two male groups, these were significantly higher in female zebrafish treated with E2 compared with controls. Gene expression analysis revealed that the levels of estrogen receptors were comparable among all groups. In conclusion, our data demonstrate that the adult zebrafish heart robustly responds to E2 and this occurs in a sex-specific manner. Given the benefits of using zebrafish as a model, new targets may be identified for the development of novel cardiovascular therapies for male and female patients. This would contribute towards the realization of personalized medicine.

The cardiac-specific overexpression of the adenine nucleotide translocase 1 (ANT1) has cardioprotective effects in various experimental heart disease models. Here, we analyzed the link between ANT1 expression and heat shock protein 27 (HSP27)-mediated toll-like receptor 4 (TLR4) signaling, which represents a novel communication pathway between mitochondria and the extracellular environment. The interaction between ANT1 and HSP27 was identified by co-immunoprecipitation from neonatal rat cardiomyocytes. ANT1 transgenic (ANT1-TG) cardiomyocytes demonstrated elevated HSP27 expression levels. Increased levels of HSP27 were released from the ANT1-TG cardiomyocytes under both normoxic and hypoxic conditions. Extracellular HSP27 stimulated TLR4 signaling via protein kinase B (AKT). The HSP27-mediated activation of the TLR4 pathway was more pronounced in ANT1-TG cardiomyocytes than in wild-type (WT) cardiomyocytes. HSP27-specific antibodies inhibited TLR4 activation and the expression of HSP27. Inhibition of the HSP27-mediated TLR4 signaling pathway with the TLR4 inhibitor oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) reduced the mitochondrial membrane potential (∆ψm) and increased caspase 3/7 activity, which are both markers for cell stress. Conversely, treating cardiomyocytes with recombinant HSP27 protein stimulated TLR4 signaling, induced HSP27 and ANT1 expression, and stabilized the mitochondrial membrane potential. The activation of HSP27 signaling was verified in ischemic ANT1-TG heart tissue, where it correlated with ANT1 expression and the tightness of the inner mitochondrial membrane. Our study shows a new mechanism by which ANT1 is part of the cardioprotective HSP27-mediated TLR4 signaling.

Die FU-Dokumentation ist die umfangreichste Quellensammlung zur Studentenbewegung und zur hochschulpolitischen Thematik in dieser Zeit. Und sie hat -dies sei aus der Erfahrung von 30 Jahren gesagt -sowohl als Quellenwerk wie aufgrund ihres detaillierten Chronikteils (zumindest an bundesdeutschen Forschungsinstitutionen) die Funktion eines unentbehrlichen Orientierungs- und Nachschlagewerkes für den gesamten Forschungszweig übernommen, dies nach übereinstimmender Beurteilung aller Rezensenten.

OBJECTIVES: In Germany, healthcare for people lacking legal residency status and European Union citizens without health insurance is often provided by non-governmental organisations. Scientific studies assessing the situation of the patients with chronic diseases in this context are scarce. We aimed to characterise medical care for chronically ill migrants without health insurance and outline its possibilities and limitations from the treating physicians' perspective.

DESIGN: Qualitative semi-structured interviews; qualitative content analysis.

SETTING: Organisations and facilities providing healthcare for uninsured migrants: free clinics, medical practices and public health services.

PARTICIPANTS: 14 physicians working regularly in healthcare for uninsured migrants.

RESULTS: Delayed contact to the healthcare system was frequently addressed in the interviews. Care was described as constrained by a scarcity of resources that often impedes adequate treatment for many conditions, most pronounced in the case of oncological diseases or chronic viral infections (HIV, hepatitis). For other chronic conditions such as cardiovascular diseases or diabetes, some diagnostics and basic medications were described as partially available, while management of complications or rehabilitative measures are frequently unfeasible. For the patients with mental health problems, attainability of psychotherapeutic treatment is reported as severely limited. Care is predominantly described as fragmented with limitations to information flow and continuity. Which level of care a patient receives appears to depend markedly on the respective non-governmental organisation and the individual commitment, subjective decisions and personal connections of the treating physician.

CONCLUSIONS: Restrictions in medical care for uninsured migrants have even more impact on chronically ill patients. Volunteer-based care often constitutes an inadequate compensation for regular access to the healthcare system, as it is strongly influenced by the limitation of its resources and its arbitrariness.

Brucellosis is considered as endemic disease of animals and humans since thousands of years in Egypt. However, brucellosis in pigs has never been reported in Egypt. Thus, serological and molecular assays were applied to detect anti-Brucella antibodies and DNA in serum samples collected from pigs. In total 331 blood samples collected from male and female pigs at slaughterhouses of Cairo and Giza governorates were investigated using Brucella c- and i-ELISA and Brucella real-time PCR. Anti-Brucella antibodies were detected in 16 (4.83%) and 36 (10.8%) sera by i-ELISA and c-ELISA, respectively. Brucella DNA was detected in 10 (3.02%) seropositive samples and identified as Brucella melitensis (7/10) and Brucella suis (3/10). A higher prevelance was found in boars. This is the first study investigating pig brucellosis in Egypt. The results of this study will raise awareness for brucellosis in these farm animals and will help to develop effective control strategies.

Marek’s disease virus (MDV) is an alphaherpesvirus that causes Marek’s disease, a malignant lymphoproliferative disease of domestic chickens. While MDV vaccines protect animals from clinical disease, they do not provide sterilizing immunity and allow field strains to circulate and evolve in vaccinated flocks. Therefore, there is a need for improved vaccines and for a better understanding of innate and adaptive immune responses against MDV infections. Interferons (IFNs) play important roles in the innate immune defenses against viruses and induce upregulation of a cellular antiviral state. In this report, we quantified the potent antiviral effect of IFNα and IFNγ against MDV infections in vitro. Moreover, we demonstrate that both cytokines can delay Marek’s disease onset and progression in vivo. Additionally, blocking of endogenous IFNα using a specific monoclonal antibody, in turn, accelerated disease. In summary, our data reveal the effects of IFNα and IFNγ on MDV infection and improve our understanding of innate immune responses against this oncogenic virus.