BackgroundFor virtually every patient with colorectal cancer (CRC), hematoxylin–eosin (HE)–stained tissue slides are available. These images contain quantitative information, which is not routinely used to objectively extract prognostic biomarkers. In the present study, we investigated whether deep convolutional neural networks (CNNs) can extract prognosticators directly from these widely available images.Methods and findingsWe hand-delineated single-tissue regions in 86 CRC tissue slides, yielding more than 100,000 HE image patches, and used these to train a CNN by transfer learning, reaching a nine-class accuracy of >94% in an independent data set of 7,180 images from 25 CRC patients. With this tool, we performed automated tissue decomposition of representative multitissue HE images from 862 HE slides in 500 stage I–IV CRC patients in the The Cancer Genome Atlas (TCGA) cohort, a large international multicenter collection of CRC tissue. Based on the output neuron activations in the CNN, we calculated a “deep stroma score,” which was an independent prognostic factor for overall survival (OS) in a multivariable Cox proportional hazard model (hazard ratio [HR] with 95% confidence interval [CI]: 1.99 [1.27–3.12], p = 0.0028), while in the same cohort, manual quantification of stromal areas and a gene expression signature of cancer-associated fibroblasts (CAFs) were only prognostic in specific tumor stages. We validated these findings in an independent cohort of 409 stage I–IV CRC patients from the “Darmkrebs: Chancen der Verhütung durch Screening” (DACHS) study who were recruited between 2003 and 2007 in multiple institutions in Germany. Again, the score was an independent prognostic factor for OS (HR 1.63 [1.14–2.33], p = 0.008), CRC-specific OS (HR 2.29 [1.5–3.48], p = 0.0004), and relapse-free survival (RFS; HR 1.92 [1.34–2.76], p = 0.0004). A prospective validation is required before this biomarker can be implemented in clinical workflows.ConclusionsIn our retrospective study, we show that a CNN can assess the human tumor microenvironment and predict prognosis directly from histopathological images.

Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n ¼ 20) including tumor cells, lymphocytes, stroma, and necrosis to generate a multiagent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n ¼ 37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyteenriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n ¼ 261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, P ¼ 0.0219) as compared with high stroma and high lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in preestablished tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions, which target the colorectal cancer microenvironment.

BackgroundOne of the most widely used self-reporting tools assessing diabetes self-management in English is the Summary of Diabetes Self-Care Activities (SDSCA) measure. To date there is no psychometric validated instrument in German to assess self-management in patients with diabetes mellitus. Therefore, this study aimed to translate the SDSCA into German and examine its psychometric properties.MethodsThe English version of the SDSCA was translated into German following the guidelines for cultural adaptation. The German version of the SDSCA (SDSCA-G) was administered to a random sample of 315 patients with diabetes mellitus type 2. Reliability was analyzed using Cronbach’s alpha coefficient and item characteristics were assessed. Exploratory and confirmatory factor analysis (EFA and CFA) were carried out to explore the construct validity. A multivariable linear regression model was used to identify the influence of predictor variables on the SDSCA-G sum score.ResultsThe Cronbach’s alpha for the SDSCA-G (all items) was α = 0.618 and an acceptable correlation between the SDSCA-G and Self-management Diabetes Mellitus-Questionnaire (SDQ) (ρ = 0.664) was identified. The EFA suggested a four factor construct as did the postulated model. The CFA showed the goodness of fit of the SDSCA-G. However, item 4 was found to be problematic regarding the analysis of psychometric properties. The omission of item 4 yielded an increase in Cronbach’s alpha (α = 0.631) and improvements of the factor structure and model fit. No statistically significant influences of predictor variables on the SDSCA-G sum score were observed.ConclusionThe revised German version of the SDSCA (SDSCA-G) is a reliable and valid tool assessing self-management in adults with type 2 diabetes in Germany.Electronic supplementary materialThe online version of this article (doi:10.1186/s12955-014-0185-1) contains supplementary material, which is available to authorized users.

The COVID-19 pandemic has led to an unprecedented response in terms of clinical research activity. An important part of this research has been focused on randomized controlled clinical trials to evaluate potential therapies for COVID-19. The results from this research need to be obtained as rapidly as possible. This presents a number of challenges associated with considerable uncertainty over the natural history of the disease and the number and characteristics of patients affected, and the emergence of new potential therapies. These challenges make adaptive designs for clinical trials a particularly attractive option. Such designs allow a trial to be modified on the basis of interim analysis data or stopped as soon as sufficiently strong evidence has been observed to answer the research question, without compromising the trial's scientific validity or integrity. In this article, we describe some of the adaptive design approaches that are available and discuss particular issues and challenges associated with their use in the pandemic setting. Our discussion is illustrated by details of four ongoing COVID-19 trials that have used adaptive designs.

Periodontally compromised splinted teeth show a high survival-rate and periodontal stability during SPT.

Background War in Yemen started three years ago, and continues unabated with a steadily rising number of direct and indirect victims thus leaving the majority of Yemen’s population in dire need of humanitarian assistance. The conflict adversely affects basic socioeconomic and health conditions across the country. Methods This study analyzed the recent ongoing diphtheria outbreak in Yemen and in particular, the health system’s failure to ensure immunization coverage and respond to this outbreak. Data from the weekly bulletins of the national electronic Disease Early Warning System’s (eDEWS) daily diphtheria reports and district immunization coverage were analyzed. The number of diphtheria cases and deaths, and immunization coverage (DPT) were reviewed by district including the degree to which a district was affected by conflict using a simple scoring system. A logistic regression and bivariate correlation were applied using the annual immunization coverage per district to determine if there was an association between diphtheria, immunization coverage and conflict. Results The study results confirm the association between the increasing cases of diphtheria, immunization coverage and ongoing conflict. A total of 1294 probable cases of diphtheria were reported from 177 districts with an overall case fatality rate of 5.6%. Approximately 65% of the patients were children under 15 years, and 46% of the cases had never been vaccinated against diphtheria. The risk of an outbreak increased by 11-fold if the district was experiencing ongoing conflict p < 0.05. In the presence of conflict (whether past or ongoing), the risk of an outbreak decreased by 0.98 if immunization coverage was high p > 0.05. Conclusion The conflict is continuously devastating the health system in Yemen with serious consequences on morbidity and mortality. Therefore, the humanitarian response should focus on strengthening health services including routine immunization procedures to avoid further outbreaks of life-threatening infectious diseases, such as diphtheria.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an often deadly complication of IPF. No focussed international guidelines for the management of AE-IPF exist. The aim of this international survey was to assess the global variability in prevention, diagnostic and treatment strategies for AE-IPF.Pulmonologists with ILD expertise were invited to participate in a survey designed by an international expert panel.509 pulmonologists from 66 countries responded. Significant geographical variability in approaches to manage AE-IPF was found. Common preventive measures included antifibrotic drugs and vaccination. Diagnostic differences were most pronounced regarding use of Krebs von den Lungen-6 and viral testing, while high-resolution computed tomography, brain natriuretic peptide and D-dimer are generally applied. High-dose steroids are widely administered (94%); the use of other immunosuppressant and treatment strategies is highly variable. Very few (4%) responders never use immunosuppression. Antifibrotic treatments are initiated during AE-IPF by 67%. Invasive ventilation or extracorporeal membrane oxygenation are mainly used as a bridge to transplantation. Most physicians educate patients comprehensively on the severity of AE-IPF (82%) and consider palliative care (64%).Approaches to the prevention, diagnosis and treatment of AE-IPF vary worldwide. Global trials and guidelines to improve the prognosis of AE-IPF are needed.

Within the limitations of an in vitro study, IR can be recommended as the initial imaging method for evaluating peri-implant bone defects at zirconia implants. CBCT provides higher diagnostic accuracy of defect classification at the expense of higher cost and radiation dose. Dental MRI may be a promising imaging method for evaluating peri-implant bone defects at zirconia implants in the future.