On the treatment effect heterogeneity of antidepressants in major depression: A Bayesian meta-analysis and simulation study

Background: The average treatment effect of antidepressants in major depression was found to be about 2 points on the 17-item Hamilton Depression Rating Scale, which lies below clinical relevance. Here, we searched for evidence of a relevant treatment effect heterogeneity that could justify the usage of antidepressants despite their low average treatment effect. Methods: Bayesian meta-analysis of 169 randomized, controlled trials including 58,687 patients. We considered the effect sizes log variability ratio (lnVR) and log coefficient of variation ratio (lnCVR) to analyze the difference in variability of active and placebo response. We used Bayesian random-effects meta-analyses (REMA) for lnVR and lnCVR and fitted a random-effects meta-regression (REMR) model to estimate the treatment effect variability between antidepressants and placebo. Results: The variability ratio was found to be very close to 1 in the best fitting models (REMR: 95% highest density interval (HDI) [0.98, 1.02], REMA: 95% HDI [1.00, 1.02]). The between-study standard deviation tau under the REMA with respect to lnVR was found to be low (95% HDI [0.00, 0.02]). Simulations showed that a large treatment effect heterogeneity is only compatible with the data if a strong correlation between placebo response and individual treatment effect is assumed. Conclusions: The published data from RCTs on antidepressants for the treatment of major depression is compatible with a near-constant treatment effect. Although it is impossible to rule out a substantial treatment effect heterogeneity, its existence seems rather unlikely. Since the average treatment effect of antidepressants falls short of clinical relevance, the current prescribing practice should be re-evaluated

A Reference Model for Common Understanding of Capabilities and Skills in Manufacturing

In manufacturing, many use cases of Industry 4.0 require vendor-neutral and machine-readable information models to describe, implement and execute resource functions. Such models have been researched under the terms capabilities and skills. Standardization of such models is required, but currently not available. This paper presents a reference model developed jointly by members of various organizations in a working group of the Plattform Industrie 4.0. This model covers definitions of most important aspects of capabilities and skills. It can be seen as a basis for further standardization efforts

Konfigurierung von Oligonukleotid-Bibliotheken für nukleinsäurebasierte Nachweisverfahren

Zur Verbesserung der Einsetzbarkeit und zur Vereinfachung der Interpretation der Messergebnisse werden im Umfeld der Biosensorik intelligente bioinformatische Systeme benötigt. Am Beispiel der Konfigurierung von Sensoren für die Nukleinsäureanalytik wird die Notwendigkeit und der Nutzen von Bioinformatiksystemen gezeigt. Es wird vorgestellt wie Entwicklungszeiten reduziert, die Qualität der Sensoren verbessert und die Erstellung von Varianten vereinfacht werden kann. Mit nukleinsäureanalytischen Verfahren wie der DNA-Mikroarray-Technologie oder Mikrobead-basierten Methoden können genetische Informationen hoch spezifisch nachgewiesen werden. Die nukleinsäure-analytischen Nachweisverfahren können für folgende Aufgabenstellungen eingesetzt werden: · Genotypisierung (Nachweis von Krankheitserregern in Körperflüssigkeiten und -geweben zur medizinischen Diagnostik und zur Qualitätssicherung bei Lebensmitteln, Nachweis gentechnisch veränderter Lebensmittel, Nachweis von Stoffen biologischen Ursprungs in Lebens-, Futter- und Genussmitteln, forensische Anwendungen) · Genexpressionsanalytik (Erkennung von Expressionsmustern beispielsweise in der Pharmakogenomik) Mit der Konfigurierungssoftware wurden bisher verschiedene Oligonukleotid-Bibliotheken unter anderem für den Nachweis von Hepatitis-C Viren und für den Nachweis von menschlichen Genen mit alternativen Spleiß-Varianten erstellt. Dabei konnte nachgewiesen werden, dass die automatischen Bibliotheken bessere Eigenschaften hinsichtlich der aufgrund von Datenbankabfragen bestimmten Spezifität und Sensitivität haben als die auf konventionellem Weg erstellten Bibliotheken [2,4]. Inzwischen wurde ein Internet-Interface entwickelt, über das die Konfigurierung von Bibliotheken als elektronische Dienstleistung angeboten wird. Die Qualität der automatisch erstellten Bibliotheken hinsichtlich der Hybridisierungssignale wird zur Zeit mit Partnern aus der Forschung und der Industrie evaluiert

A signature of circulating microRNAs differentiates takotsubo cardiomyopathy from acute myocardial infarction

Aims Takotsubo cardiomyopathy (TTC) remains a potentially life-threatening disease, which is clinically indistinguishable from acute myocardial infarction (MI). Today, no established biomarkers are available for the early diagnosis of TTC and differentiation from MI. MicroRNAs (miRNAs/miRs) emerge as promising sensitive and specific biomarkers for cardiovascular disease. Thus, we sought to identify circulating miRNAs suitable for diagnosis of acute TTC and for distinguishing TTC from acute MI. Methods and results After miRNA profiling, eight miRNAs were selected for verification by real-time quantitative reverse transcription polymerase chain reaction in patients with TTC (n = 36), ST-segment elevation acute myocardial infarction (STEMI, n = 27), and healthy controls (n = 28). We quantitatively confirmed up-regulation of miR-16 and miR-26a in patients with TTC compared with healthy subjects (both, P < 0.001), and up-regulation of miR-16, miR-26a, and let-7f compared with STEMI patients (P < 0.0001, P < 0.05, and P < 0.05, respectively). Consistent with previous publications, cardiac specific miR-1 and miR-133a were up-regulated in STEMI patients compared with healthy controls (both, P < 0.0001). Moreover, miR-133a was substantially increased in patients with STEMI compared with TTC (P < 0.05). A unique signature comprising miR-1, miR-16, miR-26a, and miR-133a differentiated TTC from healthy subjects [area under the curve (AUC) 0.835, 95% CI 0.733-0.937, P < 0.0001] and from STEMI patients (AUC 0.881, 95% CI 0.793-0.968, P < 0.0001). This signature yielded a sensitivity of 74.19% and a specificity of 78.57% for TTC vs. healthy subjects, and a sensitivity of 96.77% and a specificity of 70.37% for TTC vs. STEMI patients. Additionally, we noticed a decrease of the endothelin-1 (ET-1)-regulating miRNA-125a-5p in parallel with a robust increase of ET-1 plasma levels in TTC compared with healthy subjects (P < 0.05). Conclusion The present study for the first time describes a signature of four circulating miRNAs as a robust biomarker to distinguish TTC from STEMI patients. The significant up-regulation of these stress- and depression-related miRNAs suggests a close connection of TTC with neuropsychiatric disorders. Moreover, decreased levels of miRNA125a-5p as well as increased plasma levels of its target ET-1 are in line with the microvascular spasm hypothesis of the TTC pathomechanis

Effect of nintedanib in patients with systemic sclerosis-associated interstitial lung disease and risk factors for rapid progression

OBJECTIVE: To investigate the rate of decline in forced vital capacity (FVC), and the effect of nintedanib on the rate of decline in FVC, in subjects with systemic sclerosis-associated interstitial lung disease (SSc-ILD) who had risk factors for rapid decline in FVC. METHODS: The SENSCIS trial enrolled subjects with SSc and fibrotic ILD of ≥10% extent on high-resolution CT. The rate of decline in FVC over 52 weeks was analysed in all subjects and in those with early SSc (<18 months since first non-Raynaud symptom), elevated inflammatory markers (C reactive protein ≥6 mg/L and/or platelets ≥330×109/L) or significant skin fibrosis (modified Rodnan skin score (mRSS) 15-40 or mRSS ≥18) at baseline. RESULTS: In the placebo group, the rate of decline in FVC was numerically greater in subjects with <18 months since first non-Raynaud symptom (-167.8 mL/year), elevated inflammatory markers (-100.7 mL/year), mRSS 15-40 (-121.7 mL/year) or mRSS ≥18 (-131.7 mL/year) than in all subjects (-93.3 mL/year). Nintedanib reduced the rate of FVC decline across subgroups, with a numerically greater effect in patients with these risk factors for rapid FVC decline. CONCLUSION: In the SENSCIS trial, subjects with SSc-ILD who had early SSc, elevated inflammatory markers or extensive skin fibrosis had a more rapid decline in FVC over 52 weeks than the overall trial population. Nintedanib had a numerically greater effect in patients with these risk factors for rapid ILD progression

Financial phantasmagoria: corporate image-work in times of crisis

Our purpose in this article is to relate the real movements in the economy during 2008 to the ?image-work? of financial institutions. Over the period January?December 2008 we collected 241 separate advertisements from 61 financial institutions published in the Financial Times. Reading across the ensemble of advertisements for themes and evocative images provides an impression of the financial imaginaries created by these organizations as the global financial crisis unfolded. In using the term ?phantasmagoria? we move beyond its colloquial sense of a set of strange images designed to dazzle towards the more technical connotation used by Ranci�re (2004) who suggested that words and images can offer a trace of an overall determining set-up if they are torn from their obviousness so they become phantasmagoric figures. The key phantasmagoric figure we identify here is that of the financial institution as timeless, immortal and unchanging; a coherent and autonomous entity amongst other actors. This notion of uniqueness belies the commonality of thinking which precipitated the global financial crisis as well as the limited capacity for control of financial institutions in relation to market events. It also functions as a powerful naturalizing force, making it hard to question certain aspects of the recent period of ?capitalism in crisis?

Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy

The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment; 1-3; . These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver-a frequent site of metastasis; 4; that is often associated with a poor prognosis; 5; . Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-γ signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth

Atlantic Water advection versus sea-ice advances in the eastern Fram Strait during the last 9 ka - multiproxy evidence for a two-phase Holocene

A sediment core from the West Spitsbergen continental margin was studied to reconstruct climate and paleoceanographic variability during the last ~9 ka in the eastern Fram Strait. Our multiproxy evidence suggests that the establishment of the modern oceanographic configuration in the eastern Fram Strait occurred stepwise, in response to the postglacial sea-level rise and the related onset of modern sea-ice production on the shallow Siberian shelves. The late Early and Mid Holocene interval (9 to 5 ka) was generally characterized by relatively unstable conditions. High abundance of the subpolar planktic foraminifer species Turborotalita quinqueloba implies strong intensity of Atlantic Water (AW) inflow with high productivity and/or high AW temperatures, resulting in a strong heat flux to the Arctic. A series of short-lived cooling events (8.2, 6.9. and 6.1 ka) occurred superimposed on the warm late Early and Mid Holocene conditions. Our proxy data imply that simultaneous to the complete postglacial flooding of Arctic shallow shelves and the initiation of modern sea-ice production, strong advance of polar waters initiated modern oceanographic conditions in the eastern Fram Strait at ~5.2 ka. The Late Holocene was marked by the dominance of the polar planktic foraminifer species Neogloboquadrina pachyderma, a significant expansion of sea ice/icebergs, and strong stratification of the water column. Although planktic foraminiferal assemblages as well as sea surface and subsurface temperatures suggest a return of slightly strengthened advection of subsurface Atlantic Water after 3 ka, a relatively stable cold-water layer prevailed at the sea surface and the study site was probably located within the seasonally fluctuating marginal ice zone during the Neoglacial period