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Im April 2004 wurde im Rahmen des DFG-Forschungsprojektes „Kokainkonsum in Frankfurt am Main“ eine Repräsentativbefragung in der erwachsenen Wohnbevölkerung in Frankfurt a.M. durchgeführt. Da neben Kokain auch andere illegale und legale Drogen Thema der Befragung waren, eröffnet dies die Möglichkeit, einen Blick auf den Konsum psychoaktiver Substanzen in Frankfurt am Main zu werfen. Insgesamt 1.011 18-59-jährige Frankfurterinnen und Frankfurter beteiligten sich an der postalischen Erhebung. Die Ergebnisse der in diesem Bericht vorgelegte Sonderauswertung können mit ähnlich konzipierten Befragungen für Hamburg und das Bundesgebiet verglichen werden. Tabak 35,9% der Befragten sind aktuelle Raucher/innen, weitere 25,4% haben früher einmal geraucht. Insgesamt 10,3% rauchen täglich mindestens 20 Zigaretten. Etwas mehr Männer als Frauen rauchen aktuell. Bei den Altersgruppen zeigt sich lediglich unter 18-24-jährigen eine Überrepräsentation der Raucher/innen. Der Anteil aktueller Raucher/innen in Frankfurt ist etwa mit denen in Hamburg und dem gesamten Bundesgebiet vergleichbar, allerdings zeigt sich insbesondere im Vergleich zu Hamburg, dass in Frankfurt die Quote starker Raucher/innen relativ gering ist. Alkohol Einen Alkoholkonsum in den letzten 24 Stunden geben 38,4% der Befragten an, darunter deutlich mehr Männer als Frauen; zudem steigt dieser Anteil mit zunehmendem Alter. Demgegenüber geben jüngere Befragte häufiger an, in den letzten 30 Tagen betrunken gewesen zu sein (Gesamt: 15,1%). Die 30-39-jährigen sind die Altersgruppe, die durchschnittlich am frühesten in einen regelmäßigen Alkoholkonsum eingestiegen ist. 10,5% der Befragten sind aufgrund der Intensität ihres Gebrauchsmusters als mindestens „riskante“ Konsumenten einzustufen. Der Alkoholkonsum in Frankfurt unterscheidet sich nur geringfügig von dem in Hamburg bzw. dem im Bundesgebiet. Medikamente 16% der Stichprobe haben in den zurückliegenden 30 Tagen mindestens einmal pro Woche Medikamente eingenommen, dabei dominieren mit 11,8% die Schmerzmittel. Ein deutlicher Schwerpunkt des Medikamentengebrauchs ist bei älteren Befragten auszumachen. Im Unterschied zu den beiden Vergleichsbefragungen konsumieren Frauen in Frankfurt nur etwas häufiger als Männer regelmäßig Medikamente. Cannabis Auch in Frankfurt stellt Cannabis die mit Abstand meistkonsumierte illegale Droge dar; 41,3% verfügen über Erfahrungen mit der Substanz, darunter mehr Männer als Frauen. Dieser geschlechtsspezifische Unterschied zeigt sich in verstärktem Maße bei der 12-Monats- (insgesamt 10,6%) und 30-Tages-Prävalenz (5,0%). Deutliche Schwerpunkte des aktuellen Konsums zeigen sich in den jüngeren Altersgruppen. Etwa der Hälfte der Befragten wurde Cannabis schon einmal angeboten, etwas weniger halten die Droge für leicht beschaffbar und 5,5% der Drogenunerfahrenen würden die Droge bei entsprechendem Angebot möglicherweise probieren. Diese Probierbereitschaft fällt im Vergleich zu Hamburg etwas niedriger aus, wogegen die Beschaffbarkeit in Frankfurt höher eingeschätzt wird. Die Cannabis-Prävalenzraten entsprechen in etwa denen von Hamburg, liegen aber deutlich über den gesamtdeutschen Prävalenzraten (Lebenszeit: Ffm 41,3%, HH 42,4%, D 24,5%). Die Werte für das Einstiegsalter liegen in Frankfurt unter den bundesweit ermittelten, aber über denen aus Hamburg. Andere illegale Drogen 14,0% der Befragten haben schon einmal mindestens eine illegale Droge außer Cannabis konsumiert; 2,2% haben eine derartige Substanz auch in den letzten 12 Monaten und 1% in den letzten 30 Tagen konsumiert. Kokain liegt hier mit einer Lebenszeitprävalenz von 7,5% an erster Stelle, gefolgt von LSD, psychoaktiven Pilzen, Ecstasy und Amphetaminen mit jeweils rund 5%. Auch hier verfügen Männer deutlich häufiger über Konsumerfahrungen als Frauen, aktueller Konsum dieser Substanzen ist unter 25-29-jährigen am stärksten verbreitet. Die Probierbereitschaft für ‚harte Drogen’ ist unter Unerfahrenen ausgesprochen gering, wogegen 11,2% der drogenerfahrenen Personen Kokain und 5,7% Ecstasy bei entsprechendem Angebot konsumieren würden. Je etwa 20% geben an, eine dieser Substanzen leicht beschaffen zu können. In Frankfurt verfügen mehr Personen als in Hamburg und im Bundesdurchschnitt über Erfahrungen mit illegalen Drogen (außer Cannabis), Frankfurt fällt aber hinsichtlich des aktuellen Konsums hinter Hamburg zurück und rangiert hier etwa gleichauf mit dem Bundesdurchschnitt. In der Hansestadt haben im Unterschied zu Frankfurt nahezu so viele Frauen wie Männer Erfahrungen mit ‚harten Drogen’, beim aktuellen Konsum übertreffen sie sogar die Werte für die männlichen Befragten, wogegen in Frankfurt und bundesweit hier die Männer deutlich überwiegen. Freizeitaktivitäten und politische Einstellung Die Befragten in der vorliegenden Stichprobe stufen sich selbst im Schnitt leicht „links“ der politischen „Mitte“ ein. Jüngere Personen weisen eine höhere Ausgehhäufigkeit auf als ältere Befragte. Eine hohe Ausgehhäufigkeit wiederum geht oftmals mit einer höheren Prävalenz des Konsums legaler und illegaler Drogen einher. Konsum psychoaktiver Substanzen unter Frankfurter Jugendlichen und Erwachsenen im Vergleich Im Hinblick auf die Verbreitung im Bekanntenkreis zeigt sich bei den legalen Drogen ein leicht, bei den illegalen ein deutlich erhöhter Wert unter den Frankfurter Schüler/innen. Besonders eindeutig fällt dieser Unterschied bei Cannabis, synthetischen Drogen und psychoaktiven Pilzen aus. Letzteres schlägt sich auch in der Rangliste der Konsumprävalenzen nieder, wo Ecstasy, Amphetamine und Pilze bei den Jugendlichen im Unterschied zu den Erwachsenen vor Kokain rangieren. Eine noch deutlichere Differenz zeigt sich bei den Schnüffelstoffen, die bei den Erwachsenen nahezu gar keine, bei den Schüler/innen hingegen eine vergleichsweise hohe Verbreitung finden. Fazit Die Einwohner/innen von Frankfurt am Main unterscheiden sich im Hinblick auf den Gebrauch legaler Drogen nur unwesentlich von der deutschen Allgemeinbevölkerung wie auch von der in Hamburg. Hinsichtlich der illegalen Drogen sind sowohl in Frankfurt als auch in Hamburg im Vergleich zum Bundesdurchschnitt bezogen auf die Lebenszeit höhere Erfahrungswerte zu beobachten. Bezüglich des aktuellen Konsums rangiert Hamburg leicht vor Frankfurt, und was den aktuellen Konsum ‚harter Drogen’ betrifft, liegt Frankfurt gleichauf mit dem Bundesdurchschnitt.
Der vorliegende Bericht beschreibt die Situation in der „offenen Drogenszene“ in Frankfurt am Main unter zwei Aspekten: zum einen im Hinblick auf die Veränderungen, die sich in zentralen Inhaltsbereichen wie der sozialen und gesundheitlichen Situation, dem Substanzkonsum und der Inanspruchnahme des Hilfesystems in den letzten Jahren gezeigt haben, zum zweiten im Hinblick auf die aktuelle Situation, wie sie sich in der „offenen Drogenszene“ Mitte des Jahres 2004 auf Grundlage der hier vorliegenden Daten darstellt.
OBJECTIVE: To compare efficacy, safety, and tolerability of an oral enzyme combination (OEC) containing proteolytic enzymes and bioflavonoid vs diclofenac (DIC), a nonselective nonsteroidal anti-inflammatory drug in the treatment of osteoarthritis of the knee.
MATERIALS AND METHODS: This was an individual patient-level pooled reanalysis of patient-reported data from prospective, randomized, double-blind, parallel-group studies in adult patients with moderate-to-severe osteoarthritis of the knee treated for at least 3 weeks with OEC or DIC. Appropriate trials were identified with a systemic literature and database search. Data were extracted from the original case-report forms and reanalyzed by a blinded evaluation committee. The primary end point was the improvement of the Lequesne algofunctional index (LAFI) score at study end vs baseline. Secondary end points addressed LAFI response rates, treatment-related pain-intensity changes, adverse events, and laboratory parameters.
RESULTS: Six trials were identified that enrolled in total 774 patients, of whom 759 had post-baseline data for safety analysis, 697 (n=348/349 with OEC/DIC) for intent to treat, 524 for per protocol efficacy analysis, and 500 for laboratory evaluation. LAFI scores - the primary efficacy end point - decreased comparably with both treatments and improved with both treatments significantly vs baseline (OEC 12.6±2.4 to 9.1±3.9, DIC 12.7±2.4 to 9.1±4.2, effect size 0.9/0.88; P<0.001 for each). In parallel, movement-related 11-point numeric rating-scale pain intensity improved significantly (P<0.001) and comparably with both treatments from baseline (6.4±1.9/6.6±1.8) to study end (3.8±2.7/3.9±2.5). Overall, 55/81 OEC/DIC patients of the safety-analysis population (14.7%/21.1%, P=0.022) reported 90/133 treatment-emergent adverse events, followed by premature treatment discontinuations in 22/39 patients (5.9%/10.2%, P=0.030). Changes in laboratory parameters were significantly less with OEC vs DIC: on average 18.8% vs 86.3% of patients presented a decrease with respect to hemoglobin, hematocrit, or erythrocyte count (P<0.001), and 28.2% vs 72.6% showed an increase in AST, ALT, or GGT (P<0.001).
CONCLUSION: When compared with DIC, OEC showed comparable efficacy and a superior tolerability/safety profile associated with a significantly lower risk of treatment-emergent adverse events, related study discontinuations, and changes in laboratory parameters.
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
Comprehensive analysis of tumour sub-volumes for radiomic risk modelling in locally advanced HNSCC
(2020)
Simple Summary: Radiomic risk models are usually based on imaging features, which are extracted from the entire gross tumour volume (GTV entire ). This approach does not explicitly consider the complex biological structure of the tumours. Therefore, in this retrospective study, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma who were treated with primary radio-chemotherapy. The GTV entire was cropped by different margins to define the rim and corresponding core sub-volumes of the tumour. Furthermore, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. As a result, the models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed an improved performance compared to models based on the corresponding tumour core. This indicates that the consideration of tumour sub-volumes may help to improve radiomic risk models.
Abstract: Imaging features for radiomic analyses are commonly calculated from the entire gross tumour volume (GTVentire). However, tumours are biologically complex and the consideration of different tumour regions in radiomic models may lead to an improved outcome prediction. Therefore, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma. The GTVentire was cropped by different margins to define the rim and the corresponding core sub-volumes of the tumour. Subsequently, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. Radiomic risk models were developed and validated using a retrospective cohort consisting of 291 patients in one of the six Partner Sites of the German Cancer Consortium Radiation Oncology Group treated between 2005 and 2013. The validation concordance index (C-index) averaged over all applied learning algorithms and feature selection methods using the GTVentire achieved a moderate prognostic performance for loco-regional tumour control (C-index: 0.61 ± 0.04 (mean ± std)). The models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed higher median performances (C-index: 0.65 ± 0.02 and 0.64 ± 0.05, respectively), while models based on the corresponding tumour core volumes performed less (C-index: 0.59 ± 0.01). The difference in C-index between the 5 mm tumour rim and the corresponding core volume showed a statistical trend (p = 0.10). After additional prospective validation, the consideration of tumour sub-volumes may be a promising way to improve prognostic radiomic risk models.
Purpose: To develop and validate a CT-based radiomics signature for the prognosis of loco-regional tumour control (LRC) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated by primary radiochemotherapy (RCTx) based on retrospective data from 6 partner sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG).
Material and methods: Pre-treatment CT images of 318 patients with locally advanced HNSCC were collected. Four-hundred forty-six features were extracted from each primary tumour volume and then filtered through stability analysis and clustering. First, a baseline signature was developed from demographic and tumour-associated clinical parameters. This signature was then supplemented by CT imaging features. A final signature was derived using repeated 3-fold cross-validation on the discovery cohort. Performance in external validation was assessed by the concordance index (C-Index). Furthermore, calibration and patient stratification in groups with low and high risk for loco-regional recurrence were analysed.
Results: For the clinical baseline signature, only the primary tumour volume was selected. The final signature combined the tumour volume with two independent radiomics features. It achieved moderately good discriminatory performance (C-Index [95% confidence interval]: 0.66 [0.55–0.75]) on the validation cohort along with significant patient stratification (p = 0.005) and good calibration.
Conclusion: We identified and validated a clinical-radiomics signature for LRC of locally advanced HNSCC using a multi-centric retrospective dataset. Prospective validation will be performed on the primary cohort of the HNprädBio trial of the DKTK-ROG once follow-up is completed.
The biological effects of energetic heavy ions are attracting increasing interest for their applications in cancer therapy and protection against space radiation. The cascade of events leading to cell death or late effects starts from stochastic energy deposition on the nanometer scale and the corresponding lesions in biological molecules, primarily DNA. We have developed experimental techniques to visualize DNA nanolesions induced by heavy ions. Nanolesions appear in cells as “streaks” which can be visualized by using different DNA repair markers. We have studied the kinetics of repair of these “streaks” also with respect to the chromatin conformation. Initial steps in the modeling of the energy deposition patterns at the micrometer and nanometer scale were made with MCHIT and TRAX models, respectively.
Background: Radiochemotherapy (RCT) has been shown to induce changes in immune cell homeostasis which might affect antitumor immune responses. In the present study, we aimed to compare the composition and kinetics of major lymphocyte subsets in the periphery of patients with non-locoregional recurrent (n = 23) and locoregional recurrent (n = 9) squamous cell carcinoma of the head and neck (SCCHN) upon primary RCT. Methods: EDTA-blood of non-locoregional recurrent SCCHN patients was collected before (t0), after application of 20–30 Gy (t1), in the follow-up period 3 (t2) and 6 months (t3) after RCT. In patients with locoregional recurrence blood samples were taken at t0, t1, t2 and at the time of recurrence (t5). EDTA-blood of age-related, healthy volunteers (n = 22) served as a control (Ctrl). Major lymphocyte subpopulations were phenotyped by multiparameter flow cytometry. Results: Patients with non-recurrent SCCHN had significantly lower proportions of CD19+ B cells compared to healthy individuals before start of any therapy (t0) that dropped further until 3 months after RCT (t2), but reached initial levels 6 months after RCT (t3). The proportion of CD3+ T and CD3+/CD4+ T helper cells continuously decreased between t0 and t3, whereas that of CD8+ cytotoxic T cells and CD3+/CD56+ NK-like T cells (NKT) gradually increased in the same period of time in non-recurrent patients. The percentage of CD4+/CD25+/FoxP3+ regulatory T cells (Tregs) decreased directly after RCT, but increased above initial levels in the follow-up period 3 (t2) and 6 (t3) months after RCT. Patients with locoregional recurrence showed similar trends with respect to B, T cells and Tregs between t0 and t5. CD4+ T helper cells remained stably low between t0 and t5 in patients with locoregional recurrence compared to Ctrl. NKT/NK cell subsets (CD56+/CD69+, CD3−/CD56+, CD3−/CD94+, CD3−/NKG2D+, CD3−/NKp30+, CD3−/NKp46+) increased continuously up to 6 months after RCT (t0-t3) in patients without locoregional recurrence, whereas in patients with locoregional recurrence, these subsets remained stably low until time of recurrence (t5). Conclusion: Monitoring the kinetics of lymphocyte subpopulations especially activatory NK cells before and after RCT might provide a clue with respect to the development of an early locoregional recurrence in patients with SCCHN. However, studies with larger patient cohorts are needed. Trial registration: Observational Study on Biomarkers in Head and Neck Cancer (HNprädBio), NCT02059668. Registered on 11 February 2014, https://clinicaltrials.gov/ct2/show/NCT02059668.
Filamentous enzymes have been found in all domains of life, but the advantage of filamentation is often elusive1. Some anaerobic, autotrophic bacteria have an unusual filamentous enzyme for CO2 fixation—hydrogen-dependent CO2 reductase (HDCR)2,3—which directly converts H2 and CO2 into formic acid. HDCR reduces CO2 with a higher activity than any other known biological or chemical catalyst4,5, and it has therefore gained considerable interest in two areas of global relevance: hydrogen storage and combating climate change by capturing atmospheric CO2. However, the mechanistic basis of the high catalytic turnover rate of HDCR has remained unknown. Here we use cryo-electron microscopy to reveal the structure of a short HDCR filament from the acetogenic bacterium Thermoanaerobacter kivui. The minimum repeating unit is a hexamer that consists of a formate dehydrogenase (FdhF) and two hydrogenases (HydA2) bound around a central core of hydrogenase Fe-S subunits, one HycB3 and two HycB4. These small bacterial polyferredoxin-like proteins oligomerize through their C-terminal helices to form the backbone of the filament. By combining structure-directed mutagenesis with enzymatic analysis, we show that filamentation and rapid electron transfer through the filament enhance the activity of HDCR. To investigate the structure of HDCR in situ, we imaged T. kivui cells with cryo-electron tomography and found that HDCR filaments bundle into large ring-shaped superstructures attached to the plasma membrane. This supramolecular organization may further enhance the stability and connectivity of HDCR to form a specialized metabolic subcompartment within the cell.
This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, |GE | and |GM|, using the ¯pp → μ+μ− reaction at PANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at PANDA, using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is ¯pp → π+π−,due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distribuations of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented.