Complications of Resection Arthroplasty in Two-Stage Revision for the Treatment of Periprosthetic Hip Joint Infection

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

Endotheliale Anreicherung: Konzept, Mechanismen und Potential für Tumor-Targeting mithilfe von Antikörpern und Nanopartikeln

Fragestellung Die vorliegende Arbeit geht der Fragestellung nach, anhand welcher Mechanismen eine zielgerichtete, lokale Substanzanreicherung mithilfe von endothelspezifischen Antikörpern und Antikörper-beschichteten Nanopartikeln am Endothel der Leber sowie in experimentellen Lebertumoren erfolgt. Ergebnisse Endothelspezifische Antikörper werden durch eine unterschiedliche Dynamik der Endothelbindung charakterisiert. Anti-CD31-, anti-CD146- sowie anti-CD49e-Antikörper konnten als schnell bindende Antikörper im Mausmodell selektioniert werden. Dabei ist die quantitative Dynamik der Antikörperbindung unabhängig vom Gewebetyp, kann jedoch durch Konjugation des Antikörpers stark beeinträchtigt werden. Es konnte eine nahezu vollständige Retention dieser schnell bindenden Antikörper bei der ersten intravaskulären Passage ex vivo gezeigt werden. Die Effizienz der endothelialen Anreicherung ist zwar Antikörperdosis-unabhängig, wird jedoch durch die Perfusionsgeschwindigkeit beeinflusst und durch wiederholte oder Langzeitinjektion beeinträchtigt. Bei dem Prinzip der endothelialen Anreicherung besteht außerdem ein negativer Zusammenhang zwischen der Masse des perfundierten Gewebes und lokaler Antikörperkonzentration. Lokoregionale Applikation in vivo begünstigt zusätzlich eine hohe intratumorale Antikörperakkumulierung. Die Bindung der mit endothelspezifischen Antikörpern beschichteten magnetischen Nanopartikel und Liposomen am Endothel ist spezifisch, jedoch substantiell schlechter als die Antikörperbindung und wird zusätzlich durch Scherkräfte beeinträchtigt. Der zytotoxische Einfluss Doxorubicin-haltiger CD49e-Immunoliposomen auf murine Tumorzellen ist, trotz spezifischer Bindung und effizienter Anreicherung, nur bei hoher Konzentration nachweisbar. Die Perfusionsgeschwindigkeits-abhängige endotheliale Anreicherung, der negative Zusammenhang zwischen der Masse des perfundierten Gewebes und lokaler Anreicherung sowie der Vorteil lokoregionaler Applikation für die Tumorendothel-anreicherung in vivo konnte auch für Immunoliposomen gezeigt werden. Diskussion Alle hier getroffenen Aussagen sind nur für die untersuchten Antikörperklone sichergestellt. Das stärkste Translationspotential haben dabei die untersuchten anti-CD49e-Antikörper. Mit Tumorendothel-Targeting können klassische physiologische Barrieren des Tumorzell-Targetings umgangen werden. Klinik-übliche, hohe Dosierung sowie Nichtbeachtung des Injektionsregimes von Antikörper(-Arzneimittel-Konjugate)n verschleiert die Effizienz der endothelialen Anreicherung. Die Berechnung der halbmaximalen effektiven Konzentration der Antikörperbindung am histologischen Schnitt könnte als Parameter für die Antikörperselektion zur Anwendung der endothelialen Anreicherung verwendet werden. Die Auswahl optimaler Eigenschaften für eine effiziente endotheliale Anreicherung Antikörper-beschichteter Nanopartikel ist komplex, da diese von multiplen Parametern beeinflusst wird. Zudem darf die unspezifische Eliminierung der Partikel durch das Mononukleäre Phagozytensystem oder den Effekt erhöhter Permeabilität und Retention in vivo nicht vernachlässigt werden. Die geringe zytotoxische Wirkung des hier verwendeten liposomalen Doxorubicins ist womöglich durch suboptimale Wahl der Dosis und des Messzeitpunkts sowie die Komplexität des beteiligten Endozytosemechanismus zu erklären. Schlussfolgerungen Das Prinzip der endothelialen Anreicherung ist ein vielversprechender Ansatz, um einen endothelspezifischen, schnell bindenden Antikörper nach lokoregionaler Applikation effizient am Tumorendothel anzureichern und dessen Eintritt in die systemische Zirkulation erheblich zu reduzieren. Dies ist insbesondere für das Tumor-Targeting mit Radioimmunkonjugaten von Bedeutung und stellt sowohl für Diagnose als auch möglicherweise für die gezielte Therapie lokoregional zugänglicher Tumoren, wie das Hepatozelluläre Karzinom, eine Chance dar. Neben CD49e sollten weitere gegen humane Tumorendothelmarker gerichtete, schnell bindende Antikörper selektioniert werden. Durch die Optimierung der Immunoliposomen bezüglich Größe, Doxorubicingehalt und Avidität scheint eine Therapiestudie im murinen Modell des Hepatozellulären Karzinoms möglich. Beim Einsatz beschichteter Nanopartikel in der Klinik ist das Ziel der Anwendung hinsichtlich der Wahl optimaler Eigenschaften entscheidend, da die ausschließliche endotheliale Anreicherung vom therapeutischen Anspruch mit Nanopartikel-Internalisierung und -Degradierung zu unterscheiden ist

Frequency, stability and differentiation of self-reported school fear and truancy in a community sample

BACKGROUND: Surprisingly little is known about the frequency, stability, and correlates of school fear and truancy based on self-reported data of adolescents. METHODS: Self-reported school fear and truancy were studied in a total of N = 834 subjects of the community-based Zurich Adolescent Psychology and Psychopathology Study (ZAPPS) at two times with an average age of thirteen and sixteen years. Group definitions were based on two behavioural items of the Youth Self-Report (YSR). Comparisons included a control group without indicators of school fear or truancy. The three groups were compared across questionnaires measuring emotional and behavioural problems, life-events, self-related cognitions, perceived parental behaviour, and perceived school environment. RESULTS: The frequency of self-reported school fear decreased over time (6.9 vs. 3.6%) whereas there was an increase in truancy (5.0 vs. 18.4%). Subjects with school fear displayed a pattern of associated internalizing problems and truants were characterized by associated delinquent behaviour. Among other associated psychosocial features, the distress coming from the perceived school environment in students with school fear is most noteworthy. CONCLUSION: These findings from a community study show that school fear and truancy are frequent and display different developmental trajectories. Furthermore, previous results are corroborated which are based on smaller and selected clinical samples indicating that the two groups display distinct types of school-related behaviour

B‐GATA factors are required to repress high‐light stress responses in Marchantia polymorpha and Arabidopsis thaliana

GATAs are evolutionarily conserved zinc-finger transcription factors from eukaryotes. In plants, GATAs can be subdivided into four classes, A–D, based on their DNA-binding domain, and into further subclasses based on additional protein motifs. B-GATAs with a so-called leucine-leucine-methionine (LLM)-domain can already be found in algae. In angiosperms, the B-GATA family is expanded and can be subdivided in to LLM- or HAN-domain B-GATAs. Both, the LLM- and the HAN-domain are conserved domains of unknown biochemical function. Interestingly, the B-GATA family in the liverwort Marchantia polymorpha and the moss Physcomitrium patens is restricted to one and four family members, respectively. And, in contrast to vascular plants, the bryophyte B-GATAs contain a HAN- as well as an LLM-domain. Here, we characterise mutants of the single B-GATA from Marchantia polymorpha. We reveal that this mutant has defects in thallus growth and in gemma formation. Transcriptomic studies uncover that the B-GATA mutant displays a constitutive high-light (HL) stress response, a phenotype that we then also confirm in mutants of Arabidopsis thaliana LLM-domain B-GATAs, suggesting that the B-GATAs have a protective role towards HL stress.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Peer Reviewe

Attitudes towards psychopharmacology and psychotherapy in psychiatric patients with and without migration background

Background: Sociodemographic factors, attitude towards treatment and acculturation may be important factors influencing the decision of immigrants to seek and maintain psychiatric treatment. A better understanding of these factors may significantly improve treatment adherence and outcome in these patients. Therefore, we investigated factors associated the attitude towards psychotherapy and medication in a sample of psychiatric outpatients with and without migration background. Methods: N = 381 patients in a psychiatric outpatient unit offering specialized treatment for migrants were included in this study. Attitude towards psychotherapy was assessed using the Questionnaire on Attitudes Toward Psychotherapeutic Treatment, attitude towards medication with the Drug Attitude Inventory-10. Acculturation, symptom load and sociodemographic variables were assessed in a general questionnaire. Statistical analyses included analyses of covariance and hierarchical regression. Results: Patients of Turkish and Eastern European origin reported a significantly more positive attitude towards medication than patients without migration background. When controlling for sociodemographic and clinical variables, we did not observe any significant differences in attitude towards psychotherapy. Acculturation neither influenced the attitude towards psychotherapy nor towards medication. Conclusion: Our study indicates that sociodemographic and clinical factors may be more relevant for patients´ attitudes towards treatment than acculturation. Considering these factors in psychiatric treatment of patients with migration background may improve treatment outcome and adherence

Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome

Transposable elements (TEs) have no longer been totally considered as “junk DNA” for quite a time since the continual discoveries of their multifunctional roles in eukaryote genomes. As one of the most important and abundant TEs that still active in human genome, Alu, a SINE family, has demonstrated its indispensable regulatory functions at sequence level, but its spatial roles are still unclear. Technologies based on 3C(chromosomeconformation capture) have revealed the mysterious three-dimensional structure of chromatin, and make it possible to study the distal chromatin interaction in the genome. To find the role TE playing in distal regulation in human genome, we compiled the new released Hi-C data, TE annotation, histone marker annotations, and the genome-wide methylation data to operate correlation analysis, and found that the density of Alu elements showed a strong positive correlation with the level of chromatin interactions (hESC: r=0.9, P<2.2×1016; IMR90 fibroblasts: r = 0.94, P < 2.2 × 1016) and also have a significant positive correlation withsomeremote functional DNA elements like enhancers and promoters (Enhancer: hESC: r=0.997, P=2.3×10−4; IMR90: r=0.934, P=2×10−2; Promoter: hESC: r = 0.995, P = 3.8 × 10−4; IMR90: r = 0.996, P = 3.2 × 10−4). Further investigation involving GC content and methylation status showed the GC content of Alu covered sequences shared a similar pattern with that of the overall sequence, suggesting that Alu elements also function as the GC nucleotide and CpG site provider. In all, our results suggest that the Alu elements may act as an alternative parameter to evaluate the Hi-C data, which is confirmed by the correlation analysis of Alu elements and histone markers. Moreover, the GC-rich Alu sequence can bring high GC content and methylation flexibility to the regions with more distal chromatin contact, regulating the transcription of tissue-specific genes

Multi-Ancestry Sleep-by-SNP Interaction Analysis in 126,926 Individuals Reveals Lipid Loci Stratified by Sleep Duration

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure

OBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction &lt; 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.</p