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Objective: The present study aims to elucidate the state of gender equality in high-quality dermatological research by analysing the representation of female authorships from January 2008 to May 2017.
Design: Retrospective, descriptive study.
Setting: 113 189 male and female authorships from 23 373 research articles published in 23 dermatological Q1 journals were analysed with the aid of the Gendermetrics Platform.
Results: 43.0% of all authorships and 50.2% of the firstauthorships, 43.7% of the coauthorships and 33.1% of the last authorships are held by women. The corresponding female-to-male ORs are 1.41 (95% CI 1.37 to 1.45) for first authorships, 1.07 (95% CI 1.04 to 1.10) for coauthorships and 0.60 (95% CI 0.58 to 0.62) for last authorships. The annual growth rates are 1.74% overall and 1.45% for first authorships, 1.53% for coauthorships and 2.97% for last authorships. Women are slightly under-represented at prestigious authorships compared with men (Prestige Index=−0.11). The under-representation remains stable in highly competitive articles attracting the highest citation rates, namely, articles with many authors and articles that were published in highest-impact journals. Multiauthor articles with male key authors are only slightly more frequently cited than those with female key authors. Women publish slightly fewer papers compared with men (47.2% women hold 43.0% of the authorships). At the level of individual journals, there is a high degree of uniformity in gender-specific authorship odds. By contrast, distinct differences at country level were revealed. The prognosis for the next decades forecasts a consecutive harmonisation of authorship odds between the two genders.
Conclusions: In high-quality dermatological research, the integration of female scholars is advanced as compared with other medical disciplines. A gender gap consists mainly in the form of a career dichotomy, with many female early career researchers and few women in academic leadership positions. However, this gender gap has been narrowed in the last decade and will likely be further reduced in the future.
In the context of limited donor pool in cardiothoracic transplantation, utilization of organs from high risk donors, such as suicidal hanging donors, while ensuring safety, is under consideration. We sought to evaluate the outcomes of lung transplantations (LTx) that use organs from this group.
Between January 2011 and December 2015, 265 LTx were performed at our center. Twenty-two recipients received lungs from donors after suicidal hanging (group 1). The remaining 243 transplantations were used as a control (group 2). Analysis of recipient and donor characteristics as well as outcomes was performed.
No statistically significant difference was found in the donor characteristics between analyzed groups, except for higher incidence of cardiac arrest, younger age and smoking history of hanging donors (P < .001, P = .022 and P = .0042, respectively). Recipient preoperative and perioperative characteristics were comparable. Postoperatively in group 1 there was a higher incidence of extracorporeal life support (27.3 vs 9.1%, P = .019). There were no significant differences in chronic lung allograft dysfunction-free survival between group 1 and 2: 92.3 vs 94% at 1 year and 65.9 vs 75.5% at 3 years (P = .99). The estimated cumulative survival rate was also similar between groups: 68.2 vs 83.2% at 1 year and 68.2% versus 72% at 3 years (P = .3758).
Hanging as a donor cause of death is not associated with poor mid-term survival or chronic lung allograft dysfunction following transplantation. These results encourage assessment of lungs from hanging donors, and their consideration for transplantation.
We aimed to prospectively assess changes in chronic stress among young adults transitioning from high school to university or working life. A population-based cohort in Munich and Dresden (Germany) was followed from age 16–18 (2002–2003) to age 20–23 (2007–2009) (n = 1688). Using the Trier Inventory for the Assessment of Chronic Stress, two dimensions of stress at university or work were assessed: work overload and work discontent. In the multiple ordinal generalized estimating equations, socio-demographics, stress outside the workplace, and job history were additionally considered. At follow-up, 52% of the population were university students. Work overload increased statistically significantly from first to second follow-up, while work discontent remained constant at the population level. Students, compared to employees, reported a larger increase in work overload (adjusted odds ratio (OR): 1.33; 95% confidence interval (95% CI): 1.07, 1.67), while work discontent did not differ between the groups. In conclusion, work overload increases when young adults transition from school to university/job life, with university students experiencing the largest increase.
Marine nematodes of the genus Anisakis are common parasites of a wide range of aquatic organisms. Public interest is primarily based on their importance as zoonotic agents of the human Anisakiasis, a severe infection of the gastro-intestinal tract as result of consuming live larvae in insufficiently cooked fish dishes. The diverse nature of external impacts unequally influencing larval and adult stages of marine endohelminth parasites requires the consideration of both abiotic and biotic factors. Whereas abiotic factors are generally more relevant for early life stages and might also be linked to intermediate hosts, definitive hosts are indispensable for a parasite’s reproduction. In order to better understand the uneven occurrence of parasites in fish species, we here use the maximum entropy approach (Maxent) to model the habitat suitability for nine Anisakis species accounting for abiotic parameters as well as biotic data (definitive hosts). The modelled habitat suitability reflects the observed distribution quite well for all Anisakis species, however, in some cases, habitat suitability exceeded the known geographical distribution, suggesting a wider distribution than presently recorded. We suggest that integrative modelling combining abiotic and biotic parameters is a valid approach for habitat suitability assessments of Anisakis, and potentially other marine parasite species.
Cellular informational and metabolic processes are propagated with specific membrane fusions governed by soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNARE). SNARE protein Ykt6 is highly expressed in brain neurons and plays a critical role in the membrane-trafficking process. Studies suggested that Ykt6 undergoes a conformational change at the interface between its longin domain and the SNARE core. In this work, we study the conformational state distributions and dynamics of rat Ykt6 by means of single-molecule Förster Resonance Energy Transfer (smFRET) and Fluorescence Cross-Correlation Spectroscopy (FCCS). We observed that intramolecular conformational dynamics between longin domain and SNARE core occurred at the timescale ~200 μs. Furthermore, this dynamics can be regulated and even eliminated by the presence of lipid dodecylphoshpocholine (DPC). Our molecular dynamic (MD) simulations have shown that, the SNARE core exhibits a flexible structure while the longin domain retains relatively stable in apo state. Combining single molecule experiments and theoretical MD simulations, we are the first to provide a quantitative dynamics of Ykt6 and explain the functional conformational change from a qualitative point of view.
This study aimed to appraise two quantitative magnetic resonance imaging techniques, T2* imaging and diffusion-weighted imaging (DWI), for the diagnosis of the intervertebral disc degeneration of the cervico-thoracic junction. Influence of specific factors and diagnostic accuracy of both techniques were particularly explored. Sixty-one volunteers with neck and upper back pain were recruited and evaluated with both T2* imaging and DWI. The Pfirrmann grade, T2* relaxation time and apparent diffusion coefficient (ADC) value of each disc between C7 and T3 were recorded. Stratified analyses were performed for different anatomic levels, genders, age ranges and Pfirrmann grades. The diagnostic accuracy of both techniques was investigated using the receiver operating characteristic (ROC) curves. No statistically significant difference of either T2* relaxation time or ADC value was detected between males and females. Both parameters decreased with the increasing age and Pfirrmann grade. The ROC curves showed the higher sensitivity and specificity for T2* imaging than DWI to quantitatively identify the disc degeneration. Particularly, T2* imaging allowed for a quantitative distinguishing the normal, mild and moderate disc degeneration from the severe degeneration, which was unable to accomplish with DWI. In conclusion, we demonstrated that T2* imaging possess a better accuracy than DWI to quantitatively diagnose the intervertebral disc degeneration at the cervico-thoracic junction.
Perception, particularly in the visual domain, is drastically influenced by rhythmic changes in ambient lighting conditions. Anticipation of daylight changes by the circadian system is critical for survival. However, the neural bases of time-of-day-dependent modulation in human perception are not yet understood. We used fMRI to study brain dynamics during resting-state and close-to-threshold visual perception repeatedly at six times of the day. Here we report that resting-state signal variance drops endogenously at times coinciding with dawn and dusk, notably in sensory cortices only. In parallel, perception-related signal variance in visual cortices decreases and correlates negatively with detection performance, identifying an anticipatory mechanism that compensates for the deteriorated visual signal quality at dawn and dusk. Generally, our findings imply that decreases in spontaneous neural activity improve close-to-threshold perception.
Reconstructing the evolution of baleen whales (Mysticeti) has been problematic because morphological and genetic analyses have produced different scenarios. This might be caused by genomic admixture that may have taken place among some rorquals. We present the genomes of six whales, including the blue whale (Balaenoptera musculus), to reconstruct a species tree of baleen whales and to identify phylogenetic conflicts. Evolutionary multilocus analyses of 34,192 genome fragments reveal a fast radiation of rorquals at 10.5 to 7.5 million years ago coinciding with oceanic circulation shifts. The evolutionarily enigmatic gray whale (Eschrichtius robustus) is placed among rorquals, and the blue whale genome shows a high degree of heterozygosity. The nearly equal frequency of conflicting gene trees suggests that speciation of rorqual evolution occurred under gene flow, which is best depicted by evolutionary networks. Especially in marine environments, sympatric speciation might be common; our results raise questions about how genetic divergence can be established.
Biosynthetic human insulin and insulin analogues are the mainstay of insulin therapy for both type 1 and type 2 diabetes although access to human insulin at affordable prices remains a global issue. The world is experiencing an exponential rise in the prevalence of diabetes presenting an urgent need to establish effective diabetes therapy in countries burdened by inadequate health care budgets, malnutrition and infectious diseases. Recombinant human insulin has replaced animal insulins and animal-based semisynthetic human insulin thereby available in sufficient quantities and at affordable prices able to provide global access to insulin therapy. In many patients, analog insulins can offer additional clinical benefit, although at a considerably higher price thus severely restricting availability in low income countries. The approval process for recombinant human insulins (i.e. biosimilars) and analogue insulins is highly variable in the developing countries in contrast to Europe and in North America, where it is well established within a strict regulatory framework. This review aims to discuss the future access to human insulin therapy in a global context with an ever increasing burden of diabetes and significant economic implications.
Diagnostic approaches for invasive aspergillosis—specific considerations in the pediatric population
(2018)
Invasive aspergillosis (IA) is a major cause of morbidity and mortality in children with hematological malignancies and those undergoing hematopoietic stem cell transplantation. Similar to immunocompromised adults, clinical signs, and symptoms of IA are unspecific in the pediatric patient population. As early diagnosis and prompt treatment of IA is associated with better outcome, imaging and non-invasive antigen-based such as galactomannan or ß-D-glucan and molecular biomarkers in peripheral blood may facilitate institution and choice of antifungal compounds and guide duration of therapy. In patients in whom imaging studies suggest IA or another mold infection, invasive diagnostics such as bronchoalveolar lavage and/or bioptic procedures should be considered. Here we review the current data of diagnostic approaches for IA in the pediatric setting and highlight the major differences of performance and clinical utility of the tests between children and adults.
Background: Anger and aggression belong to the core symptoms of borderline personality disorder. Although an early and specific treatment of BPD is highly relevant to prevent chronification, still little is known about anger and aggression and their neural underpinnings in adolescents with BPD.
Method: Twenty female adolescents with BPD (age 15–17 years) and 20 female healthy adolescents (age 15–17 years) took part in this functional magnetic resonance imaging (fMRI) study. A script-driven imagery paradigm was used to induce rejection-based feelings of anger, which was followed by descriptions of self-directed and other-directed aggressive reactions. To investigate the specificity of the neural activation patterns for adolescent patients, results were compared with data from 34 female adults with BPD (age 18–50 years) and 32 female healthy adults (age 18–50 years).
Results: Adolescents with BPD showed increased activations in the left posterior insula and left dorsal striatum as well as in the left inferior frontal cortex and parts of the mentalizing network during the rejection-based anger induction and the imagination of aggressive reactions compared to healthy adolescents. For the other-directed aggression phase, a significant diagnosis by age interaction confirmed that these results were specific for adolescents.
Discussion: The results of this very first fMRI study on anger and aggression in adolescents with BPD suggest an enhanced emotional reactivity to and higher effort in controlling anger and aggression evoked by social rejection at an early developmental stage of the disorder. Since emotion dysregulation is a known mediator for aggression in BPD, the results point to the need of appropriate early interventions for adolescents with BPD.
Necroptosis contributes to the pathophysiology of several inflammatory, infectious and degenerative disorders. TNF-induced necroptosis involves activation of the receptor-interacting protein kinases 1 and 3 (RIPK1/3) in a necrosome complex, eventually leading to the phosphorylation and relocation of mixed lineage kinase domain like protein (MLKL). Using a high-content screening of small compounds and FDA-approved drug libraries, we identified the anti-cancer drug Sorafenib tosylate as a potent inhibitor of TNF-dependent necroptosis. Interestingly, Sorafenib has a dual activity spectrum depending on its concentration. In murine and human cell lines it induces cell death, while at lower concentrations it inhibits necroptosis, without affecting NF-κB activation. Pull down experiments with biotinylated Sorafenib show that it binds independently RIPK1, RIPK3 and MLKL. Moreover, it inhibits RIPK1 and RIPK3 kinase activity. In vivo Sorafenib protects against TNF-induced systemic inflammatory response syndrome (SIRS) and renal ischemia–reperfusion injury (IRI). Altogether, we show that Sorafenib can, next to the reported Braf/Mek/Erk and VEGFR pathways, also target the necroptotic pathway and that it can protect in an acute inflammatory RIPK1/3-mediated pathology.
Rho GTPases control fundamental cellular processes and Cdc42 is a well-studied member of the family that controls filopodia formation and cell migration. Although the regulation of Cdc42 activity by nucleotide binding is well documented, the mechanisms driving its proteostasis are not clear. Here, we demonstrate that the highly conserved, RING domain containing E3 ubiquitin ligase XIAP controls the protein stability of Cdc42. XIAP binds to Cdc42 and directly conjugates poly ubiquitin chains to the Lysine 166 of Cdc42 targeting it for proteasomal degradation. Depletion of XIAP led to an increased protein stability and activity of Cdc42 in normal and tumor cells. Consistently, loss of XIAP enhances filopodia formation in a Cdc42-dependent manner and this phenomenon phenocopies EGF stimulation. Further, XIAP depletion promotes lung colonization of tumor cells in mice in a Cdc42-dependent manner. These observations shed molecular insights into ubiquitin-dependent regulation of Cdc42 and that of actin cytoskeleton.
Chemotherapy-induced thrombocytopenia is a common bleeding risk in cancer patients and limits chemotherapy dose and frequency. Recent data from mouse and human platelets revealed that activation of protein kinase A/G (PKA/PKG) not only inhibited thrombin/convulxin-induced platelet activation but also prevented the platelet pro-coagulant state. Here we investigated whether or not PKA/PKG activation could attenuate caspase-dependent apoptosis induced by the anti-cancer drugs ABT-737 (the precursor of navitoclax) and thymoquinone (TQ), thereby potentially limiting chemotherapy-induced thrombocytopenia. This is particularly relevant as activation of cyclic nucleotide signalling in combination chemotherapy is an emerging strategy in cancer treatment. However, PKA/PKG-activation, as monitored by phosphorylation of Vasodilator-stimulated phosphoprotein (VASP), did not block caspase-3-dependent platelet apoptosis induced by the compounds. In contrast, both substances induced PKA activation themselves and PKA activation correlated with platelet inhibition and apoptosis. Surprisingly, ABT-737- and TQ-induced VASP-phosphorylation was independent of cAMP levels and neither cyclases nor phosphatases were affected by the drugs. In contrast, however, ABT-737- and TQ-induced PKA activation was blocked by caspase-3 inhibitors. In conclusion, we show that ABT-737 and TQ activate PKA in a caspase-3-dependent manner, which correlates with platelet inhibition and apoptosis and therefore potentially contributes to the bleeding risk in chemotherapy patients.
Summary: This retrospective database study assessed 2-year persistence with bisphosphonates or denosumab in a large German cohort of women with a first-time prescription for osteoporosis treatment. Compared with intravenous or oral bisphosphonates, 2-year persistence was 1.5–2 times higher and risk of discontinuation was significantly lower (P < 0.0001) with denosumab.
Introduction: Persistence with osteoporosis therapies is critical for fracture risk reduction. Detailed data on long-term persistence (≥2 years) with bisphosphonates and denosumab are sparse.
Methods: From the German IMS® database, we included women aged 40 years or older with a first-time prescription for bisphosphonates or denosumab between July 2010 and August 2014; patients were followed up until December 2014. The main outcome was treatment discontinuation, with a 60-day permissible gap between filled prescriptions. Two-year persistence was estimated using Kaplan–Meier survival curves, with treatment discontinuation as the failure event. Denosumab was compared with intravenous (i.v.) and oral bisphosphonates separately. Cox proportional hazard ratios (HRs) for the 2-year risk of discontinuation were calculated, with adjustment for age, physician specialty, health insurance status, and previous medication use.
Results: Two-year persistence with denosumab was significantly higher than with i.v. or oral bisphosphonates (39.8 % [n = 21,154] vs 20.9 % [i.v. ibandronate; n = 20,472] and 24.8 % [i.v. zoledronic acid; n = 3966] and 16.7–17.5 % [oral bisphosphonates; n = 114,401]; all P < 0.001). Patients receiving i.v. ibandronate, i.v. zoledronic acid, or oral bisphosphonates had a significantly increased risk of treatment discontinuation than did those receiving denosumab (HR = 1.65, 1.28, and 1.96–2.02, respectively; all P < 0.0001).
Conclusions: Two-year persistence with denosumab was 1.5–2 times higher than with i.v. or oral bisphosphonates, and risk of discontinuation was significantly lower with denosumab than with bisphosphonates. A more detailed understanding of factors affecting medication-taking behavior may improve persistence and thereby reduce rates of fracture.
Biomaterials are widely used in guided bone regeneration (GBR) and guided tissue regeneration (GTR). After application, there is an interaction between the host immune system and the implanted biomaterial, leading to a biomaterial-specific cellular reaction. The present review focuses on cellular reactions to numerous biomaterials in vivo with consideration of different implantation models and microenvironments in different species, such as subcutaneous implantation in mice and rats, a muscle model in goats and a femur model in rabbits. Additionally, cellular reactions to different biomaterials in various clinical indications within the oro-maxillofacial surgical field were considered. Two types of cellular reactions were observed. There was a physiological reaction with the induction of only mononuclear cells and a pathological reaction with the induction of multinucleated giant cells (MNGCs). Attention was directed to the frequently observed MNGCs and consequences of their appearance within the implantation region. MNGCs have different subtypes. Therefore, the present review addresses the different morphological phenotypes observed within the biomaterial implantation bed and discusses the critical role of MNGCs, their subtypes and their precursors as well as comparing the characteristics and differences between biomaterial-related MNGCs and osteoclasts. Polymeric biomaterials that only induced mononuclear cells underwent integration and maintained their integrity, while polymeric biomaterials that induced MNGCs underwent disintegration with material breakdown and loss of integrity. Hence, there is a question regarding whether our attention should be directed to alternative biological concepts, in combination with biomaterials that induce a physiological mononuclear cellular reaction to optimize biomaterial-based tissue regeneration.
Die folgende Darstellung argumentiert nicht mit Blick auf eine Metahistorik im Koselleck'schen Sinn, sondern beschränkt sich auf die Nachzeichnung einer kurzen Debatte, die unmittelbar an der Wende zum 19. Jahrhundert über die Bedeutung und den angemessenen Gebrauch von 'ahnen' und 'ahnden' geführt wurde. Genauer in den Blick genommen werden drei Fußnoten, in denen Johann Gottfried Herder und Immanuel Kant ihre Einschätzungen zur Gleichheit oder Ungleichheit der Wörter austauschten. Die Passagen entstammen Texten der Jahre 1797 bis 1799 - zweien von Herder, einem vom Kant - die auch sonst einschlägige Positionsbestimmungen zu Problemen der Zukunftserkenntnis vornehmen.
Die Frage ist, ob Blumenbergs explizite Überlegungen zum Phänomen der Epochenschwelle - vor allem in der 'Legitimität der Neuzeit' - sich auch in seinen anderen begriffs- und metapherngeschichtlichen Studien niederschlagen bzw. in welchem Verhältnis beide Theorieelemente zueinander stehen. Dieser Frage widmen sich die folgenden Anmerkungen. Sie versuchen beide Bereiche in Blumenbergs Denken aufeinander zu beziehen, ihre Kohärenz zu untersuchen und sie in eine produktive Spannung miteinander zu bringen.
Die folgenden Ausführungen am Beispiel von Zukunft und Zukünftigkeit setzen in dem Areal an, von dem Blumenberg eine ganze Reihe von Begrifflichkeiten und Denkfiguren entlehnt und historisch seinen Ausgang genommen hat, der Phänomenologie Husserls. Im Mittelpunkt steht dabei die für sämtliche Diskussionen um Zukunft und Zukünftigkeit zentrale Denkfigur der Protention. Sie wird in ihren begrifflichen Zusammenhängen, Problemen und Dimensionen entwickelt (1-4). Sodann wird Blumenbergs Kritik der Futurologie dargestellt (5). Mit dem Konzept der Prävention soll schließlich der von der Protention abgeleitete Modus thematisiert werden, in dem metaphorologische und anthropologische Aspekte zusammengeschlossen sind (6). Abschließend wird die Konzeption der Prävention in den Kontext der philosophischen Anthropologie Gehlens und der Existenzialanalyse Heideggers gestellt (7).