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The Gleason grading system remains the most powerful prognostic predictor for patients with prostate cancer since the 1960s. Its application requires highly-trained pathologists, is tedious and yet suffers from limited inter-pathologist reproducibility, especially for the intermediate Gleason score 7. Automated annotation procedures constitute a viable solution to remedy these limitations. In this study, we present a deep learning approach for automated Gleason grading of prostate cancer tissue microarrays with Hematoxylin and Eosin (H&E) staining. Our system was trained using detailed Gleason annotations on a discovery cohort of 641 patients and was then evaluated on an independent test cohort of 245 patients annotated by two pathologists. On the test cohort, the inter-annotator agreements between the model and each pathologist, quantified via Cohen’s quadratic kappa statistic, were 0.75 and 0.71 respectively, comparable with the inter-pathologist agreement (kappa = 0.71). Furthermore, the model’s Gleason score assignments achieved pathology expert-level stratification of patients into prognostically distinct groups, on the basis of disease-specific survival data available for the test cohort. Overall, our study shows promising results regarding the applicability of deep learning-based solutions towards more objective and reproducible prostate cancer grading, especially for cases with heterogeneous Gleason patterns.
Background: The present study aims to elucidate the state of gender equality in high-quality research by analyzing the representation of female authorships in the last decade (from 2008 to 2016).
Methods: Based on the Gendermetrics platform, 293,557 research articles from 54 journals listed in the Nature Index were considered covering the categories Life Science, Multidisciplinary, Earth & Environmental and Chemistry. The core method was the combined analysis of the proportion of female authorships and the female-to-male odds ratio for first, co- and last authorships. The distribution of prestigious authorships was measured by the Prestige Index.
Results: 29.8% of all authorships and 33.1% of the first, 31.8% of the co- and 18.1% of the last authorships were held by women. The corresponding female-to-male odds ratio is 1.19 (CI: 1.18–1.20) for first, 1.35 (CI: 1.34–1.36) for co- and 0.47 (CI: 0.46–0.48) for last authorships. Women are underrepresented at prestigious authorships compared to men (Prestige Index = -0.42). The underrepresentation accentuates in highly competitive articles attracting the highest citation rates, namely, articles with many authors and articles that were published in highest-impact journals. More specifically, a large negative correlation between the 5-Year-Impact-Factor of a journal and the female representation at prestigious authorships was revealed (r(52) = -.63, P < .001). Women publish fewer articles compared to men (39.0% female authors are responsible for 29.8% of all authorships) and are underrepresented at productivity levels of more than 2 articles per author. Articles with female key authors are less frequently cited than articles with male key authors. The gender-specific differences in citation rates increase the more authors contribute to an article. Distinct differences at the journal, journal category, continent and country level were revealed. The prognosis for the next decades forecast a very slow harmonization of authorships odds between the two genders.
The Education Against Tobacco (EAT) network delivers smoking prevention advice in secondary schools, typically using the mirroring approach (i.e., a "selfie" altered with a face-aging app and shared with a class). In November 2017, however, the German assembly of EAT opted to expand its remit to include nursing students. To assess the transferability of the existing approach, we implemented it with the self-developed face-aging app "Smokerface" (=mixed − methods approach) in six nursing schools. Anonymous questionnaires were used to assess the perceptions of 197 students (age 18–40 years; 83.8% female; 26.4% smokers; 23.3% daily smokers) collecting qualitative and quantitative data for our cross-sectional study. Most students perceived the intervention to be fun (73.3%), but a minority disagreed that their own animated selfie (25.9%) or the reaction of their peers (29.5%) had motivated them to stop smoking. The impact on motivation not to smoke was considerably lower than experienced with seventh graders (63.2% vs. 42.0%; notably, more smokers also disagreed (45.1%) than agreed (23.5%) with this statement. Agreement rates on the motivation not to smoke item were higher in females than in males and in year 2–3 than in year 1 students. Potential improvements included greater focus on pathology (29%) and discussing external factors (26%). Overall, the intervention seemed to be appealing for nursing students
Selective BRAF inhibitors such as vemurafenib have become a treatment option in patients with Langerhans cell Histiocytosis (LCH). To date, only 14 patients receiving vemurafenib for LCH have been reported. Although vemurafenib can stabilize the clinical condition of these patients, it does not seem to cure the patients, and it is unknown, when and how to stop vemurafenib treatment. We present a girl with severe multisystem LCH who responded only to vemurafenib. After 8 months of treatment, vemurafenib was tapered and replaced by prednisone and vinblastine, a strategy which has not been described to date. Despite chemotherapy, early relapse occurred, but remission was achieved by re-institution of vemurafenib. Further investigation needs to address the optimal duration of vemurafenib therapy in LCH and whether and which chemotherapeutic regimen may prevent disease relapse after cessation of vemurafenib.
Background: Despite the numerous associations of vitamin D with health and disease, vitamin D deficiency is still common from a global perspective. While basic research, clinical and preventive activities grow constantly in vitamin D research, there is no in-depth analysis of the related global scientific productivity available so far.
Methods: Density equalizing mapping procedures (DEMP) were combined with socioeconomic benchmarks using the NewQIS platform.
Results: A total of 25,992 vitamin D-related research articles were identified between 1900 to 2014 with a significant increase (r2 = .6541) from 1900 to 2014. Authors located in Northern America – especially in the USA – distributed the majority of global vitamin D research, followed by their Western European counterparts. DEMP-analysis illustrates that Africa and South America exhibit only minor scientific productivity. Among high-income group countries, Scandinavian nations such as Denmark or Finland (2147.9 and 1607.7 vitamin D articles per GDP in 1000 billion USD) were highly active with regard to socioeconomic figures.
Conclusion: Networks dedicated to vitamin D research are present around the world. Overall, the Northern American and Western European nations occupy prominent positions. However, South American, African and Asian countries apart from Japan only play a minor role in the global research production related to vitamin D. Since vitamin D deficiency is currently increasing in the Americas, Europe and parts of the Middle East, research in these regions may need to be encouraged.
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.
Background: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.
Methods: In a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.
Findings: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46–11·60; p<0·0001), antiplatelet use (1·68, 1·06–2·66; p=0·026), and anticoagulant use (3·48, 1·96–6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75–0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95–6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03–0·07).
Interpretation: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.
Funding: UK Medical Research Council and British Heart Foundation.
Background: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day–night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co-morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD.
Methods: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 – < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of α = 0.10 (two-sided) and the power of 1-β = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up.
Discussion: This is the first pilot RCT on the use of BLT and EI in combination with mobile health-based monitoring and reinforcement targeting the prevention of co-morbid depression and obesity in adolescents and young adults with ADHD. If at least medium effects can be established with regard to the prevention of depressive symptoms and obesity, a larger scale confirmatory phase-III trial may be warranted.
Trial registration: German Clinical Trials Register, DRKS00011666. Registered on 9 February 2017. ClinicalTrials.gov, NCT03371810. Registered on 13 December 2017.
The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory diseases.