Die Metalloprotease Meprin beta ist eine Sheddase des triggering receptor expressed on myeloid cells type 2 (TREM2)

Diese Arbeit demonstriert, dass die Metalloprotease Meprin beta in der Lage ist den Zelloberflächenrezeptor TREM2 proteolytisch zu spalten. TREM2 wird vor allem von Monozyten/Makrophagen exprimiert und kann über Bindung von anionischen Liganden, oder nach Stimulation durch benachbarte Rezeptoren, die Immunantwort modulieren. Mikroglia, welche die Repräsentanten des Mononukleären-Phagozytären Sytems (MPS) im Zentralnervensystem sind, zeigen eine hohe Expression des TREM2. So erregte der Rezeptor Aufsehen im Kontext neurodegenerativer Erkrankungen. In der Tat konnten diverse Korrelationen zwischen Mutationen des TREM2 und neurodegenerativen Erkrankungen hergestellt werden. Die prominenteste unter diesen Erkrankungen ist die Alzheimer-Erkrankung, in welcher der Funktionsverlust des TREM2 gleich mit mehreren Prozessen der Pathogenese in Verbindung gebracht wird. In unseren Experimenten demonstrierten wir die proteolytische Spaltung des TREM2 durch Meprin beta in mehreren Zellsystemen. Ein Mausmodell, mit einem Gen-Knockout für Meprin beta, wies erhöhte Mengen an TREM2 auf monozytären Zellen auf. Um die Reduktion des TREM2 auf der Zelloberfläche auch qualitativ beurteilen zu können, bedienten wir uns des regulatorischen Einflusses des TREM2 auf die Phagozytose. Der Rezeptor ist in der Lage über Bindung extrazellulärer Liganden eine intrazelluläre Signalkaskade in Gang zu setzen, welche einen steigernden Einfluss auf die Phagozytose der Zelle hat. Die Abspaltung des TREM2 von der Zelloberfläche durch Meprin beta führte experimentell in mehreren Zellsystemen zu einer Reduktion der Phagozytoseleistung. Aus dem Knochenmark gewonnene Makrophagen der Meprin beta k.o. Mäuse veranschaulichten neben erhöhten Mengen an TREM2 ein gesteigertes Maß ihrer Phagozytoseleistung. Dies verdeutlicht, dass Meprin beta diesen Rezeptor so prozessiert, dass er seine Funktionsfähigkeit verliert. TREM2 kann neben seiner membrangebundenen Form auch als lösliches Signalmolekül vorliegen. Diese freie Form wird auch als soluble TREM2 (sTREM2) bezeichnet und entsteht entweder nach Abspaltung von der Zellmembran oder wird nach alternativem Splicing von der Zelle sekretiert. Auch Meprin beta kann von der Zelloberfläche abgespalten werden und als freie Protease im Extrazellularraum agieren. So konnten wir ebenfalls belegen, dass das sTREM2 sowohl von membrangebundenem Meprin beta, als auch von der löslichen Variante weiter gespalten werden kann. Mäuse mit einer Defizienz für Meprin beta weisen neben erhöhten Mengen des TREM2 an der Zelloberfläche höhere Mengen an sTREM2 im Extrazellularraum auf

The Professional Peer Membership of School Counselors and the Resources Used Within Their Decision-Making

Abstract The purpose of this study was to describe the demographic identity of a national sample of professional school counselors who were members of the American School Counselor Association (ASCA), understand the manner in which they conceptualized their professional peer membership, and explore what sources they use to make professional and ethical decisions. Consistent with previous research, the majority of participants were white woman, across all four regions in the sample; however, when compared to previous studies, there were a slightly higher percentage of non-white school counselors. Results suggest that there is still a significant gap between the demographics of school counselors and the students they serve. The results of this study indicate that professional school counselors hold a wide range of opinions concerning who they view are their professional peers. There were also significant differences on what resources participants’ used to make professional and ethical decisions. Implications and future directions for research are discussed

A Systematic Review of Prognostic Factors in Patients with Cancer Receiving Palliative Radiotherapy: Evidence-Based Recommendations

: (1) Background: Prognostication in patients with cancer receiving palliative radiotherapy remains a challenge. To improve the process, we aim to identify prognostic factors in this population from the literature and offer evidence-based recommendations on prognostication in patients undergoing palliative radiotherapy for non-curable or advanced cancers. (2) Methods: A systematic review was performed on the medical literature from 2005 to 2023 to extract papers on the prognosis of palliative radiotherapy patients with advanced cancer. The initial selection was performed by at least two authors to determine study relevance to the target area. Studies were then classified based on type and evidence quality to determine final recommendations. (3) Results: The literature search returned 57 papers to be evaluated. Clinical and biological prognostic factors were identified from these papers to improve clinical decision making or construct prognostic models. Twenty prognostic models were identified for clinical use. There is moderate evidence supporting (i) evidence-based factors (patient, clinical, disease, and lab) in guiding decision making around palliative radiation; (ii) that certain biological factors are of importance; (iii) prognostication models in patients with advanced cancer; and that (iv) SBRT or re-irradiation use can be guided by predictions of survival by prognostic scores or clinicians. Patients with more favorable prognoses are generally better suited to SBRT or re-irradiation, and the use of prognostic models can aid in this decision making. (4) Conclusions: This evaluation has identified several factors or tools to aid in prognosis and clinical decision making. Future studies should aim to further validate these tools and factors in a clinical setting, including the leveraging of electronic medical records for data availability. To increase our understanding of how causal factors interact with palliative radiotherapy, future studies should also examine and include prediction of response to radiation as an outcome

MicroRNAs Associated with Metastatic Prostate Cancer

Metastasis is the most common cause of death of prostate cancer patients. Identification of specific metastasis biomarkers and novel therapeutic targets is considered essential for improved prognosis and management of the disease. MicroRNAs (miRNAs) form a class of non-coding small RNA molecules considered to be key regulators of gene expression. Their dysregulation has been shown to play a role in cancer onset, progression and metastasis, and miRNAs represent a promising new class of cancer biomarkers. The objective of this study was to identify down- and up-regulated miRNAs in prostate cancer that could provide potential biomarkers and/or therapeutic targets for prostate cancer metastasis. into NOD/SCID mice, a methodology that tends to preserve properties of the original cancers (e.g., tumor heterogeneity, genetic profiles).Differentially expressed known miRNAs, isomiRs and 36 novel miRNAs were identified. A number of these miRNAs (21/104) have previously been reported to show similar down- or up-regulation in prostate cancers relative to normal prostate tissue, and some of them (e.g., miR-16, miR-34a, miR-126*, miR-145, miR-205) have been linked to prostate cancer metastasis, supporting the validity of the analytical approach.The use of metastatic and non-metastatic prostate cancer subrenal capsule xenografts derived from one patient's cancer makes it likely that the differentially expressed miRNAs identified in this study include potential biomarkers and/or therapeutic targets for human prostate cancer metastasis

Patterns of Pain and Functional Improvement in Patients with Bone Metastases after Conventional External Beam Radiotherapy and a Telephone Validation Study

Patients experiencing lower body pain resulting from bone metastases have greater levels of functional interference than those with upper body pain. The purpose of this study was to assess the levels of interference caused by pain after treatment with conventional radiotherapy using the Brief Pain Inventory (BPI) and to validate this tool for telephone use. After radiotherapy, a total of 159, 129, and 106 patients completed the BPI over the telephone at months 1, 2, and 3, respectively. Cronbach's alpha, confirmatory factor analysis, and discriminant validity tests were performed to assess the validity of the BPI. One-way ANOVA was used to compare BPI scores. There was no statistically significant difference in functional interference among patients after treatment. Internal consistency of the BPI was high. Functional interference may be inherently higher in patients with pain in the lower body. Telephone use of the BPI is reliable and recommended in this population

Radiotherapy for Metastatic Epidural Spinal Cord Compression with Increased Doses: Final Results of the RAMSES-01 Trial

Simple Summary Patients with MESCC and favorable survival prognoses assigned to radiotherapy alone may benefit from increased doses. In a multi-center phase 2 trial, patients receiving 15 x 2.633 Gy or 18 x 2.333 Gy were evaluated and subsequently compared to a historical control group receiving 10 x 3.0 Gy. The phase 2 cohort, including 50 (of 62 planned) evaluable patients, showed promising results regarding 12-month local progression-free survival (LPFS), 12-month overall survival (OS), improvement of motor and sensory functions, post-radiotherapy ambulatory status, and relief of pain and distress. Radiotherapy with 15 x 2.633 Gy or 18 x 2.333 Gy was well tolerated and appeared more effective than 10 x 3.0 Gy with respect to LPFS and improvement of motor function.Abstract Patients with metastatic epidural spinal cord compression (MESCC) and favorable survival prognoses may benefit from radiation doses exceeding 10 x 3.0 Gy. In a multi-center phase 2 trial, patients receiving 15 x 2.633 Gy (41.6 Gy10) or 18 x 2.333 Gy (43.2 Gy10) were evaluated for local progression-free survival (LPFS), motor/sensory functions, ambulatory status, pain, distress, toxicity, and overall survival (OS). They were compared (propensity score-adjusted Cox regression) to a historical control group (n = 266) receiving 10 x 3.0 Gy (32.5 Gy10). In the phase 2 cohort, 50 (of 62 planned) patients were evaluated for LPFS. Twelve-month rates of LPFS and OS were 96.8% and 69.9%, respectively. Motor and sensory functions improved in 56% and 57.1% of patients, and 94.0% were ambulatory following radiotherapy. Pain and distress decreased in 84.4% and 78.0% of patients. Ten and two patients experienced grade 2 and 3 toxicities, respectively. Phase 2 patients showed significantly better LPFS than the control group (p = 0.039) and a trend for improved motor function (p = 0.057). Ambulatory and OS rates were not significantly different. Radiotherapy with 15 x 2.633 Gy or 18 x 2.333 Gy was well tolerated and appeared superior to 10 x 3.0 Gy

Statistical Learning Methods to Identify Nonwear Periods From Accelerometer Data

Background: Accelerometers are used to objectively measure movement in free-living individuals. Distinguishing nonwear from sleep and sedentary behavior is important to derive accurate measures of physical activity, sedentary behavior, and sleep. We applied statistical learning approaches to examine their promise in detecting nonwear time and compared the results with commonly used wear time (WT) algorithms. Methods: Fifteen children, aged 4–17, wore an ActiGraph wGT3X- BT monitor on their hip during overnight polysomnography. We applied Hidden Markov Models (HMM) and Gaussian Mixture Models (GMM) to classify states of nonwear and wear in triaxial acceleration data. Performance of methods was compared with WT algorithms across two conditions with differing amounts of consecutive nonwear. Clinical scoring of polysomnography served as the gold standard. Results: When the length of nonwear was less than or equal to WT algorithms’ predefined thresholds for consecutive nonwear time, GMM methods yielded improved classification error, specificity, positive predictive value, and negative predictive value over commonly used algorithms. HMM was superior to one algorithm for sensitivity and negative predictive value. When the length of nonwear was longer, results were mixed, with the commonly used algorithms performing better on some parameters but GMM with the greatest specificity. However, all approached the upper limits of performance for almost all metrics. Conclusions: GMM and HMM demonstrated robust, consistently strong performance across multiple conditions, surpassing or remaining competitive with commonly used WT algorithms which had marked inaccuracy when nonwear time periods were shorter. Of the two statistical learning algorithms, GMM was superior to HMM

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings: In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

The long term vaccine-induced anti-SARS-CoV-2 immune response is impaired in quantity and quality under TNFα blockade

The humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in patients with chronic inflammatory disease (CID) declines more rapidly with tumor necrosis factor-α (TNF-α) inhibition. Furthermore, the efficacy of current vaccines against Omicron variants of concern (VOC) including BA.2 is limited. Alterations within immune cell populations, changes in IgG affinity, and the ability to neutralize a pre-VOC strain and the BA.2 virus were investigated in these at-risk patients. Serum levels of anti-SARS-CoV-2 IgG, IgG avidity, and neutralizing antibodies (NA) were determined in anti-TNF-α patients (n = 10) and controls (n = 24 healthy individuals; n = 12 patients under other disease-modifying antirheumatic drugs, oDMARD) before and after the second and third vaccination by ELISA, immunoblot and live virus neutralization assay. SARS-CoV-2-specific B- and T cell subsets were analysed by multicolor flow cytometry. Six months after the second vaccination, anti-SARS-CoV-2 IgG levels, IgG avidity and anti-pre-VOC NA titres were significantly reduced in anti-TNF-α recipients compared to controls (healthy individuals: avidity: p ≤ 0.0001; NA: p = 0.0347; oDMARDs: avidity: p = 0.0012; NA: p = 0.0293). The number of plasma cells was increased in anti-TNF-α patients (Healthy individuals: p = 0.0344; oDMARDs: p = 0.0254), while the absolute number of SARS-CoV-2-specific plasma cells 7 days after 2nd vaccination were comparable. Even after a third vaccination, these patients had lower anti-BA.2 NA titres compared to both other groups. We show a reduced SARS-CoV-2 neutralizing capacity in patients under TNF-α blockade. While these effects were observable after the first two vaccinations and with older VOC, the differences in responses to BA.2 were enhanced

Quantifiable Assessment of SWNT Dispersion in Polymer Composites

NASA LaRC has established a new protocol for visualizing the nanomaterials in structural polymer matrix resins. Using this new technique and reconstructing the 3D distribution of the nanomaterials allows us to compare this distribution against a theoretically perfect distribution. Additional tertiary structural information can now be obtained and quantified with the electron tomography studies. These tools will be necessary to establish the structural-functional relationships between the nano and the bulk. This will also help define the critical length scales needed for functional properties. Field ready tool development and calibration can begin by using these same samples and comparing the response. i.e. gold standards of good and bad dispersion