Dynamics of the intratumoral immune response during progression of high-grade serous ovarian cancer

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have an established impact on the prognosis of high-grade serous ovarian carcinoma (HGSOC), however, their role in recurrent ovarian cancer is largely unknown. We therefore systematically investigated TIL densities and MHC class I and II (MHC1, 2) expression in the progression of HGSOC. EXPERIMENTAL DESIGN: CD3+, CD4+, CD8+ TILs and MHC1, 2 expression were evaluated by immunohistochemistry on tissue microarrays in 113 paired primary and recurrent HGSOC. TILs were quantified by image analysis. All patients had been included to the EU-funded OCTIPS FP7 project. RESULTS: CD3+, CD4+, CD8+ TILs and MHC1 and MHC2 expression showed significant correlations between primary and recurrent tumor levels (Spearman rho 0.427, 0.533, 0.361, 0.456, 0.526 respectively; P<.0001 each). Paired testing revealed higher CD4+ densities and MHC1 expression in recurrent tumors (Wilcoxon P=.034 and P=.018). There was also a shift towards higher CD3+ TILs levels in recurrent carcinomas when analyzing platinum-sensitive tumors only (Wilcoxon P=.026) and in pairs with recurrent tumor tissue from first relapse only (Wilcoxon P=.031). High MHC2 expression was the only parameter to be significantly linked to prolonged progression-free survival after first relapse (PFS2, log-rank P=.012). CONCLUSIONS: This is the first study that analyzed the development of TILs density and MHC expression in paired primary and recurrent HGSOC. The level of the antitumoral immune response in recurrent tumors was clearly dependent on the one in the primary tumor. Our data contribute to the understanding of temporal heterogeneity of HGSOC immune microenvironment and have implications for selection of samples for biomarker testing in the setting of immune-targeting therapeutics

Spatial models of cell distribution in human lumbar dorsal root ganglia

Dorsal root ganglia (DRG), which contain the somata of primary sensory neurons, have increasingly been considered as novel targets for clinical neural interfaces, both for neuroprosthetic and pain applications. Effective use of either neural recording or stimulation technologies requires an appropriate spatial position relative to the target neural element, whether axon or cell body. However, the internal three- dimensional spatial organization of human DRG neural fibers and somata has not been quantitatively described. In this study, we analyzed 202 cross- sectional images across the length of 31 human L4 and L5 DRG from 10 donors. We used a custom semi- automated graphical user interface to identify the locations of neural elements in the images and normalize the output to a consistent spatial reference for direct comparison by spinal level. By applying a recursive partitioning algorithm, we found that the highest density of cell bodies at both spinal levels could be found in the inner 85% of DRG length, the outer- most 25- 30% radially, and the dorsal- most 69- 76%. While axonal density was fairly homogeneous across the DRG length, there was a distinct low density region in the outer 7- 11% radially. These findings are consistent with previous qualitative reports of neural distribution in DRG. The quantitative measurements we provide will enable improved targeting of future neural interface technologies and DRG- focused pharmaceutical therapies, and provide a rigorous anatomical description of the bridge between the central and peripheral nervous systems.Dorsal root ganglia (DRG) are novel targets for neural interface technologies that treat neurological disorders, such as chronic pain and spinal cord injury. The three- dimensional cellular anatomy of DRG are not well- mapped, particularly in humans, limiting the effectiveness of neurotechnology. We developed a semi- automated algorithm to quantify the three- dimensional distribution of neural elements in histologically- processed tissue. We applied this algorithm to sequential NF200- stained histology slices obtained from human lumbar DRG and demonstrated that cell bodies typically congregate around the dorsal edge of the ganglia. These results are crucial to the development of safe and effective clinical neural interface technologies.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155471/1/cne24848_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155471/2/cne24848.pd

Application of conflictology methods for evaluating physical protection systems effectiveness

At present, physical protection of nuclear material and nuclear facilities is actual. For the implementation of physical protection, Physical Protection System (PPS) is created at nuclear facilities. We all know that the most important characteristic is effectiveness of physical protection systems. PPS effectiveness value is determined by the probability that reaction forces can stop and intercept the intruder. There are many methods to assess the effectiveness of PPS. However, not all methods can provide an accurate quantitative assessment of the effectiveness of security systems. This work presents an approach for assessing the resistance of PPS to emerging threat (that is, the intruder to act against items of physical protection).Based on the fact that different processes are subject to universal physical laws and principles of development, a parallel between the concepts of Conflictology field was established to describe the interaction in the system "intruder against PPS"

Understanding psychiatric institutionalization: a conceptual review

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Communication and patient safety in gynecology and obstetrics - study protocol of an intervention study.

BACKGROUND: Patient safety is a key target in public health, health services and medicine. Communication between all parties involved in gynecology and obstetrics (clinical staff/professionals, expectant mothers/patients and their partners, close relatives or friends providing social support) should be improved to ensure patient safety, including the avoidance of preventable adverse events (pAEs). Therefore, interventions including an app will be developed in this project through a participatory approach integrating two theoretical models. The interventions will be designed to support participants in their communication with each other and to overcome difficulties in everyday hospital life. The aim is to foster effective communication in order to reduce the frequency of pAEs. If communication is improved, clinical staff should show an increase in work satisfaction and patients should show an increase in patient satisfaction. METHODS: The study will take place in two maternity clinics in Germany. In line with previous studies of complex interventions, it is divided into three interdependent phases. Each phase provides its own methods and data. Phase 1: Needs assessment and a training for staff (n = 140) tested in a pre-experimental study with a pre/post-design. Phase 2: Assessment of communication training for patients and their social support providers (n = 423) in a randomized controlled study. Phase 3: Assessment of an app supporting the communication between staff, patients, and their social support providers (n = 423) in a case-control study. The primary outcome is improvement of communication competencies. A range of other implementation outcomes will also be assessed (i.e. pAEs, patient/treatment satisfaction, work satisfaction, safety culture, training-related outcomes). DISCUSSION: This is the first large intervention study on communication and patient safety in gynecology and obstetrics integrating two theoretical models that have not been applied to this setting. It is expected that the interventions, including the app, will improve communication practice which is linked to a lower probability of pAEs. The app will offer an effective and inexpensive way to promote effective communication independent of users' motivation. Insights gained from this study can inform other patient safety interventions and health policy developments. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03855735; date of registration: February 27, 2019

Evolution of the geomagnetic daily variation at Tatuoca, Brazil, from 1957 to 2019: a transition from Sq to EEJ

The magnetic equator in the Brazilian region has moved over 1,100 km northward since 1957, passing the geomagnetic observatory Tatuoca (TTB), in northern Brazil, around 2013. We recovered and processed TTB hourly mean values of the geomagnetic field horizontal (H) component from 1957 until 2019, allowing the investigation of long‐term changes in the daily variation due to the influence of secular variation, solar activity, season, and lunar phase. The H day‐to‐day variability and the occurrence of the counter electrojet at TTB were also investigated. Until the 1990s, ionospheric solar quiet currents dominated the quiet‐time daily variation at TTB. After 2000, the magnitude of the daily variation became appreciably greater due to the equatorial electrojet (EEJ) contribution. The H seasonal and day‐to‐day variability increased as the magnetic equator approached, but their amplitudes normalized to the average daily variation remained at similar levels. Meanwhile, the amplitude of the lunar variation, normalized in the same way, increased from 5% to 12%. Within the EEJ region, the occurrence rate of the morning counter electrojet (MCEJ) increased with proximity to the magnetic equator, while the afternoon counter electrojet (ACEJ) did not. EEJ currents derived from CHAMP and Swarm satellite data revealed that the MCEJ rate varies with magnetic latitude within the EEJ region while the ACEJ rate is largely constant. Simulations with the Thermosphere‐Ionosphere‐Electrodynamics General Circulation Model based on different geomagnetic main field configurations suggest that long‐term changes in the geomagnetic daily variation at TTB can be attributed to the main field secular variation

Virtual slides in peer reviewed, open access medical publication

<p>Abstract</p> <p>Background</p> <p>Application of virtual slides (VS), the digitalization of complete glass slides, is in its infancy to be implemented in routine diagnostic surgical pathology and to issues that are related to tissue-based diagnosis, such as education and scientific publication.</p> <p>Approach</p> <p>Electronic publication in Pathology offers new features of scientific communication in pathology that cannot be obtained by conventional paper based journals. Most of these features are based upon completely open or partly directed interaction between the reader and the system that distributes the article. One of these interactions can be applied to microscopic images allowing the reader to navigate and magnify the presented images. VS and interactive Virtual Microscopy (VM) are a tool to increase the scientific value of microscopic images.</p> <p>Technology and Performance</p> <p>The open access journal Diagnostic Pathology <url>http://www.diagnosticpathology.org</url> has existed for about five years. It is a peer reviewed journal that publishes all types of scientific contributions, including original scientific work, case reports and review articles. In addition to digitized still images the authors of appropriate articles are requested to submit the underlying glass slides to an institution (DiagnomX.eu, and Leica.com) for digitalization and documentation. The images are stored in a separate image data bank which is adequately linked to the article. The normal review process is not involved. Both processes (peer review and VS acquisition) are performed contemporaneously in order to minimize a potential publication delay. VS are not provided with a DOI index (digital object identifier). The first articles that include VS were published in March 2011.</p> <p>Results and Perspectives</p> <p>Several logistic constraints had to be overcome until the first articles including VS could be published. Step by step an automated acquisition and distribution system had to be implemented to the corresponding article. The acceptance of VS by the reader is high as well as by the authors. Of specific value are the increased confidence to and reputation of authors as well as the presented information to the reader. Additional associated functions such as access to author-owned related image collections, reader-controlled automated image measurements and image transformations are in preparation.</p> <p>Virtual Slides</p> <p>The virtual slide(s) for this article can be found here: <url>http://www.diagnosticpathology.diagnomx.eu/vs/1232133347629819</url>.</p

Levels of different subtypes of tumour-infiltrating lymphocytes correlate with each other, with matched circulating lymphocytes, and with survival in breast cancer

Purpose: Breast cancer tumour-infiltrating lymphocytes associate with clinico-pathological factors, including survival, although the literature includes many conflicting findings. Our aim was to assess these associations for key lymphocyte subtypes and in different tumour compartments, to determine whether these provide differential correlations and could, therefore, explain published inconsistencies. Uniquely, we also examine whether infiltrating levels merely reflect systemic lymphocyte levels or whether local factors are predominant in recruitment. Methods: Immunohistochemistry was used to detect tumour-infiltrating CD20+ (B), CD4+ (helper T), CD8+ (cytotoxic T) and FoxP3+ (regulatory T) cells in breast cancers from 62 patients, with quantification in tumour stroma, tumour cell nests, and tumour margins. Levels were analysed with respect to clinico-pathological characteristics and matched circulating levels (determined by flow-cytometry). Results: CD4+ lymphocytes were the most prevalent subtype in tumour stroma and at tumour edge and CD8+ lymphocytes were most prevalent in tumour nests; FoxP3+ lymphocytes were rarest in all compartments. High grade or hormone receptor negative tumours generally had significantly increased lymphocytes, especially in tumour stroma. Only intra-tumoural levels of CD8+ lymphocytes correlated significantly with matched circulating levels (p < 0.03), suggesting that recruitment is mainly unrelated to systemic activity. High levels of stromal CD4+ and CD20+ cells associated with improved survival in hormone receptor negative cases (p < 0.04), while tumour nest CD8+ and FoxP3+ cells associated with poor survival in hormone receptor positives (p < 0.005). Conclusions: Lymphocyte subtype and location define differential impacts on tumour biology, therefore, roles of tumour-infiltrating lymphocytes will only be unravelled through thorough analyses that take this into account