Refine
Year of publication
Document Type
- Article (364)
Language
- English (364) (remove)
Has Fulltext
- yes (364)
Is part of the Bibliography
- no (364)
Keywords
- - (304)
- stroke (12)
- proteomics (10)
- COVID-19 (8)
- depression (7)
- climate change (6)
- sepsis (6)
- Germany (5)
- biofilm (5)
- biomarker (5)
Institute
- Klinik und Poliklinik für Neurologie (38)
- Institut für Psychologie (34)
- Institut für Botanik und Landschaftsökologie & Botanischer Garten (20)
- Institut für Mikrobiologie - Abteilung für Genetik & Biochemie (20)
- Abteilung für Mikrobiologie und Molekularbiologie (18)
- Institut für Community Medicine (14)
- Interfakultäres Institut für Genetik und Funktionelle Genomforschung (MNF) (14)
- Institut für Biochemie (13)
- Institut für Erziehungswissenschaft (12)
- Klinik für Psychiatrie und Psychotherapie (12)
Publisher
- Frontiers Media S.A. (364) (remove)
Background: Stroke patients are at risk of acquiring secondary infections due to stroke-induced immune suppression (SIIS). Immunosuppressive cells comprise myeloid-derived suppressor cells (MDSCs) and immunosuppressive interleukin 10 (IL-10)-producing monocytes. MDSCs represent a small but heterogeneous population of monocytic, polymorphonuclear (or granulocytic), and early progenitor cells (“early” MDSC), which can expand extensively in pathophysiological conditions. MDSCs have been shown to exert strong immune-suppressive effects. The role of IL-10-producing immunosuppressive monocytes after stroke has not been investigated, but monocytes are impaired in oxidative burst and downregulate human leukocyte antigen—DR isotype (HLA-DR) on the cell surface.
Objectives: The objective of this work was to investigate the regulation and function of MDSCs as well as the immunosuppressive IL-10-producing monocytes in experimental and human stroke.
Methods: This longitudinal, monocentric, non-interventional prospective explorative study used multicolor flow cytometry to identify MDSC subpopulations and IL-10 expression in monocytes in the peripheral blood of 19 healthy controls and 27 patients on days 1, 3, and 5 post-stroke. Quantification of intracellular STAT3p and Arginase-1 by geometric mean fluorescence intensity was used to assess the functionality of MDSCs. In experimental stroke induced by electrocoagulation in middle-aged mice, monocytic (CD11b+Ly6G−Ly6Chigh) and polymorphonuclear (CD11b+Ly6G+Ly6Clow) MDSCs in the spleen were analyzed by flow cytometry.
Results: Compared to the controls, stroke patients showed a relative increase in monocytic MDSCs (percentage of CD11b+ cells) in whole blood without evidence for an altered function. The other MDSC subgroups did not differ from the control. Also, in experimental stroke, monocytic, and in addition, polymorphonuclear MDSCs were increased. The numbers of IL-10-positive monocytes did not differ between the patients and controls. However, we provide a new insight into monocytic function post-stroke since we can report that a differential regulation of HLA-DR and PD-L1 was found depending on the IL-10 production of monocytes. IL-10-positive monocytes are more activated post-stroke, as indicated by their increased HLA-DR expression.
Conclusions: MDSC and IL-10+ monocytes can induce immunosuppression within days after stroke.
Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.
Streptococcus pneumoniae has evolved versatile strategies to colonize the nasopharynx of humans. Colonization is facilitated by direct interactions with host cell receptors or via binding to components of the extracellular matrix. In addition, pneumococci hijack host-derived extracellular proteases such as the serine protease plasmin(ogen) for ECM and mucus degradation as well as colonization. S. pneumoniae expresses strain-dependent up to four serine proteases. In this study, we assessed the role of secreted or cell-bound serine proteases HtrA, PrtA, SFP, and CbpG, in adherence assays and in a mouse colonization model. We hypothesized that the redundancy of serine proteases compensates for the deficiency of a single enzyme. Therefore, double and triple mutants were generated in serotype 19F strain EF3030 and serotype 4 strain TIGR4. Strain EF3030 produces only three serine proteases and lacks the SFP encoding gene. In adherence studies using Detroit-562 epithelial cells, we demonstrated that both TIGR4Δcps and 19F mutants without serine proteases or expressing only CbpG, HtrA, or PrtA have a reduced ability to adhere to Detroit-562 cells. Consistent with these results, we show that the mutants of strain 19F, which preferentially colonizes mice, abrogate nasopharyngeal colonization in CD-1 mice after intranasal infection. The bacterial load in the nasopharynx was monitored for 14 days. Importantly, mutants showed significantly lower bacterial numbers in the nasopharynx two days after infection. Similarly, we detected a significantly reduced pneumococcal colonization on days 3, 7, and 14 post-inoculations. To assess the impact of pneumococcal serine proteases on acute infection, we infected mice intranasally with bioluminescent and invasive TIGR4 or isogenic triple mutants expressing only CbpG, HtrA, PrtA, or SFP. We imaged the acute lung infection in real-time and determined the survival of the mice. The TIGR4lux mutant expressing only PrtA showed a significant attenuation and was less virulent in the acute pneumonia model. In conclusion, our results showed that pneumococcal serine proteases contributed significantly to pneumococcal colonization but played only a minor role in pneumonia and invasive diseases. Because colonization is a prerequisite for invasive diseases and transmission, these enzymes could be promising candidates for the development of antimicrobials to reduce pneumococcal transmission.
The pathobiont Streptococcus pneumoniae causes life-threatening diseases, including pneumonia, sepsis, meningitis, or non-invasive infections such as otitis media. Serine proteases are enzymes that have been emerged during evolution as one of the most abundant and functionally diverse group of proteins in eukaryotic and prokaryotic organisms. S. pneumoniae expresses up to four extracellular serine proteases belonging to the category of trypsin-like or subtilisin-like family proteins: HtrA, SFP, PrtA, and CbpG. These serine proteases have recently received increasing attention because of their immunogenicity and pivotal role in the interaction with host proteins. This review is summarizing and focusing on the molecular and functional analysis of pneumococcal serine proteases, thereby discussing their contribution to pathogenesis.
This study explored the evidence of validity of internal structure of the 12-item Functional Assessment of Chronic Illness Therapy—Spiritual Wellbeing Scale (FACIT-Sp-12) in Brazilian adolescents with chronic health conditions. The study involved 301 Brazilian adolescents with cancer, type 1 diabetes mellitus, or cystic fibrosis. Exploratory Factor Analysis (EFA), Confirmatory Factor Analysis (CFA), and Item Response Theory (IRT) were used to test the internal structure. Reliability was determined with Cronbach’s Alpha and McDonald’s Omega. The EFA suggested a one-dimensional scale structure in contrast to the original 2-factor model or the 3-factor model which were not reproduced in the current CFA. All quality indicators for the EFA one-factor exceeded the required criteria (FDI = 0.97, EAP = 0.97, SR = 3.96 and EPTD = 0.96, latent GH = 0.90. and the observed GH = 0.85). The FACIT-Sp-12 for adolescents yielded strong evidence for a 1-factor model and with good reliability.
Human-driven peatland drainage has occurred in Europe for centuries, causing habitat degradation and leading to the emission of greenhouse gases. As such, in the last decades, there has been an increase in policies aiming at restoring these habitats through rewetting. Alder (Alnus glutinosa L.) is a widespread species in temperate forest peatlands with a seemingly high waterlogging tolerance. Yet, little is known about its specific response in growth and wood traits relevant for tree functioning when dealing with changing water table levels. In this study, we investigated the effects of rewetting and extreme flooding on alder growth and wood traits in a peatland forest in northern Germany. We took increment cores from several trees at a drained and a rewetted stand and analyzed changes in ring width, wood density, and xylem anatomical traits related to the hydraulic functioning, growth, and mechanical support for the period 1994–2018. This period included both the rewetting action and an extreme flooding event. We additionally used climate-growth and climate-density correlations to identify the stand-specific responses to climatic conditions. Our results showed that alder growth declined after an extreme flooding in the rewetted stand, whereas the opposite occurred in the drained stand. These changes were accompanied by changes in wood traits related to growth (i.e., number of vessels), but not in wood density and hydraulic-related traits. We found poor climate-growth and climate-density correlations, indicating that water table fluctuations have a stronger effect than climate on alder growth. Our results show detrimental effects on the growth of sudden water table changes leading to permanent waterlogging, but little implications for its wood density and hydraulic architecture. Rewetting actions should thus account for the loss of carbon allocation into wood and ensure suitable conditions for alder growth in temperate peatland forests.
Objective: The study aimed to test the reliability of a semi-structured telephone interview for the classification of headache disorders according to the ICHD-3.
Background: Questionnaire-based screening tools are often optimized for single primary headache diagnoses [e.g., migraine (MIG) and tension headache (TTH)] and therefore insufficiently represent the diagnostic precision of the ICHD-3, which limits epidemiological research of rare headache disorders. Brief semi-structured telephone interviews could be an effective alternative to improve classification.
Methods: A patient population representative of different primary and secondary headache disorders (n = 60) was recruited from the outpatient clinic (HSA) of a tertiary care headache center. These patients completed an established population-based questionnaire for the classification of MIG, TTH, or trigeminal autonomic cephalalgia (TAC). In addition, they received a semi-structured telephone interview call from three blinded headache specialists individually. The agreement of diagnoses made either using the questionnaires or interviews with the HSA diagnoses was evaluated.
Results: Of the 59 patients (n = 1 dropout), 24% had a second-order and 5% had a third-order headache disorder. The main diagnoses were as follows: frequent primary headaches with 61% MIG, 10% TAC, 9% TTH, and 5% rare primary and 16% secondary headaches. Second-order diagnosis was chronic migraine throughout, and third-order diagnoses were medication overuse headache and TTH. Agreement between main headaches from the HSA was significantly better for the telephone interview than for the questionnaire (questionnaire: κ = 0.330; interview: κ = 0.822; p < 0.001). Second-order diagnoses were not adequately captured by questionnaires, while there was a trend for good agreement with the telephone interview (κ = 0.433; p = 0.074). Headache frequency and psychiatric comorbidities were independent predictors of HSA and telephone interview agreement. Male sex, headache frequency, severity, and depressive disorders were independently predictive for agreement between the questionnaire and HSA. The telephone interview showed high sensitivity (≥71%) and specificity (≥92%) for all primary headache disorders, whereas the questionnaire was below 50% in either sensitivity or specificity.
Conclusion: The semi-structured telephone interview appears to be a more reliable tool for accurate diagnosis of headache disorders than self-report questionnaires. This offers the potential to improve epidemiological headache research and care even in underserved areas.
Bacillus subtilis has been extensively used as a microbial cell factory for industrial enzymes due to its excellent capacities for protein secretion and large-scale fermentation. This bacterium is also an attractive host for biopharmaceutical production. However, the secretion potential of this organism is not fully utilized yet, mostly due to a limited understanding of critical rearrangements in the membrane proteome upon high-level protein secretion. Recently, it was shown that bottlenecks in heterologous protein secretion can be resolved by genome minimization. Here, we present for the first time absolute membrane protein concentrations of a genome-reduced B. subtilis strain (“midiBacillus”) expressing the immunodominant Staphylococcus aureus antigen A (IsaA). We quantitatively characterize the membrane proteome adaptation of midiBacillus during production stress on the level of molecules per cell for more than 400 membrane proteins, including determination of protein concentrations for ∼61% of the predicted transporters. We demonstrate that ∼30% of proteins with unknown functions display a significant increase in abundance, confirming the crucial role of membrane proteins in vital biological processes. In addition, our results show an increase of proteins dedicated to translational processes in response to IsaA induction. For the first time reported, we provide accumulation rates of a heterologous protein, demonstrating that midiBacillus secretes 2.41 molecules of IsaA per minute. Despite the successful secretion of this protein, it was found that there is still some IsaA accumulation occurring in the cytosol and membrane fraction, leading to a severe secretion stress response, and a clear adjustment of the cell’s array of transporters. This quantitative dataset offers unprecedented insights into bioproduction stress responses in a synthetic microbial cell.
Species of the genus Wolffia are traditionally used as human food in some of the Asian countries. Therefore, all 11 species of this genus, identified by molecular barcoding, were investigated for ingredients relevant to human nutrition. The total protein content varied between 20 and 30% of the freeze-dry weight, the starch content between 10 and 20%, the fat content between 1 and 5%, and the fiber content was ~25%. The essential amino acid content was higher or close to the requirements of preschool-aged children according to standards of the World Health Organization. The fat content was low, but the fraction of polyunsaturated fatty acids was above 60% of total fat and the content of n-3 polyunsaturated fatty acids was higher than that of n-6 polyunsaturated fatty acids in most species. The content of macro- and microelements (minerals) not only depended on the cultivation conditions but also on the genetic background of the species. This holds true also for the content of tocopherols, several carotenoids and phytosterols in different species and even intraspecific, clonal differences were detected in Wolffia globosa and Wolffia arrhiza. Thus, the selection of suitable clones for further applications is important. Due to the very fast growth and the highest yield in most of the nutrients, Wolffia microscopica has a high potential for practical applications in human nutrition.
In summer 2017, the World Health Organization published 10 facts on asthma, which is known as a major non-communicable disease of high clinical and scientific importance with currently several hundred million people—with many children among them—suffering from air passages inflammation and narrowing. Importantly, the World Health Organization sees asthma as being underdiagnosed and undertreated. Consequently, much more efforts in clinical disease management and research need to be spent on reducing the asthma-related health burden. Particularly, for young approximately 6 months aged patients presenting recurrent bronchitic respiratory symptoms, many parents anxiously ask the doctors for risk prognosis for their children's future life. Therefore, we urgently need to reevaluate if the current diagnostic and treatment measures are in concordance with our yet incomplete knowledge of pathomechanisms on exacerbation. To contribute to this increasing concern worldwide, we established a multicentric pediatric exacerbation study network, still recruiting acute exacerbated asthmatics (children >6 years) and preschool asthmatics/wheezers (children <6 years) since winter 2018 in Germany. The current study that has a currently population comprising 176 study participants aims to discover novel holistic entry points for achieving a better understanding of the poorly understood plasticity of involved molecular pathways and to define biomarkers enabling improved diagnostics and therapeutics. With this study description, we want to present the study design, population, and few ongoing experiments for novel biomarker research.
Clinical Trial Registration: German Clinical Trials Register (Deutsches Register für Klinische Studien, DRKS): DRKS00015738.
Although the nose, as a gateway for organism–environment interactions, may have a key role in asthmatic exacerbation, the rhinobiome of exacerbated children with asthma was widely neglected to date. The aim of this study is to understand the microbiome, the microbial immunology, and the proteome of exacerbated children and adolescents with wheeze and asthma. Considering that a certain proportion of wheezers may show a progression to asthma, the comparison of both groups provides important information regarding clinical and phenotype stratification. Thus, deep nasopharyngeal swab specimens, nasal epithelial spheroid (NAEsp) cultures, and blood samples of acute exacerbated wheezers (WH), asthmatics (AB), and healthy controls (HC) were used for culture (n = 146), 16 S-rRNA gene amplicon sequencing (n = 64), and proteomic and cytokine analyses. Interestingly, Proteobacteria were over-represented in WH, whereas Firmicutes and Bacteroidetes were associated with AB. In contrast, Actinobacteria commonly colonized HCs. Moreover, Staphylococcaceae, Enterobacteriaceae, Burkholderiaceae, Xanthobacteraceae, and Sphingomonadaceae were significantly more abundant in AB compared to WH and HC. The α-diversity analyses demonstrated an increase of bacterial abundance levels in atopic AB and a decrease in WH samples. Microbiome profiles of atopic WH differed significantly from atopic AB, whereby atopic samples of WH were more homogeneous than those of non-atopic subjects. The NAEsp bacterial exposure experiments provided a disrupted epithelial cell integrity, a cytokine release, and cohort-specific proteomic differences especially for Moraxella catarrhalis cultures. This comprehensive dataset contributes to a deeper insight into the poorly understood plasticity of the nasal microbiota, and, in particular, may enforce our understanding in the pathogenesis of asthma exacerbation in childhood.
Self-regulated learning (SRL) is critical for learning across tasks, domains, and contexts. Despite its importance, research shows that not all learners are equally skilled at accurately and dynamically monitoring and regulating their self-regulatory processes. Therefore, learning technologies, such as intelligent tutoring systems (ITSs), have been designed to measure and foster SRL. This paper presents an overview of over 10 years of research on SRL with MetaTutor, a hypermedia-based ITS designed to scaffold college students’ SRL while they learn about the human circulatory system. MetaTutor’s architecture and instructional features are designed based on models of SRL, empirical evidence on human and computerized tutoring principles of multimedia learning, Artificial Intelligence (AI) in educational systems for metacognition and SRL, and research on SRL from our team and that of other researchers. We present MetaTutor followed by a synthesis of key research findings on the effectiveness of various versions of the system (e.g., adaptive scaffolding vs. no scaffolding of self-regulatory behavior) on learning outcomes. First, we focus on findings from self-reports, learning outcomes, and multimodal data (e.g., log files, eye tracking, facial expressions of emotion, screen recordings) and their contributions to our understanding of SRL with an ITS. Second, we elaborate on the role of embedded pedagogical agents (PAs) as external regulators designed to scaffold learners’ cognitive and metacognitive SRL strategy use. Third, we highlight and elaborate on the contributions of multimodal data in measuring and understanding the role of cognitive, affective, metacognitive, and motivational (CAMM) processes. Additionally, we unpack some of the challenges these data pose for designing real-time instructional interventions that scaffold SRL. Fourth, we present existing theoretical, methodological, and analytical challenges and briefly discuss lessons learned and open challenges.
Existing literature evidences the association between adolescents’ school self-concept and engagement, both concepts being related to students’ perception of teachers and peers as motivators. However, few longitudinal studies explore the interplay of these factors. The present study aims to close this gap, applying latent cross-lagged panel design to two-wave data from German adolescent students [1088 8th grade students at T1 (Mage = 13.7, SD = 0.53; 53.9% girls) and 845 9th grade students at T2 (Mage = 14.86; SD = 0.57; 55% girls) from the initial sample]. Besides direct effects, three cross-lagged over-time paths were found to be significant: students’ perception of peers as positive motivators (PPMs) at the beginning of 8th grade (T1) positively predicts their behavioral school engagement at the end of 9th grade (T2), as well as emotional school engagement at the beginning of 8th grade positively predicts students’ perception of PPMs 1.5 years later. Furthermore, behavioral school engagement at T1 functions as a predictor of a student’s school self-concept at T2.
Resource and cost constraints in hospitals demand thorough planning of operating room schedules. Ideally, exact start times and durations are known in advance for each case. However, aside from the first case’s start, most factors are hard to predict. While the role of the start of the first case for optimal room utilization has been shown before, data for to-follow cases are lacking. The present study therefore aimed to analyze all elective surgery cases of a university hospital within 1 year in search of visible patterns. A total of 14,014 cases scheduled on 254 regular working days at a university hospital between September 2015 and August 2016 underwent screening. After eliminating 112 emergencies during regular working hours, 13,547 elective daytime cases were analyzed, out of which 4,346 ranked first, 3,723 second, and 5,478 third or higher in the daily schedule. Also, 36% of cases changed start times from the day before to 7:00 a.m., with half of these (52%) resulting in a delay of more than 15 min. After 7:00 a.m., 87% of cases started more than 10 min off schedule, with 26% being early and 74% late. Timeliness was 15 ± 72 min (mean ± SD) for first, 21 ± 84 min for second, and 25 ± 93 min for all to-follow cases, compared to preoperative day planning, and 21 ± 45, 23 ± 61, and 19 ± 74 min compared to 7:00 a.m. status. Start time deviations were also related to procedure duration, with cases of 61–90 min duration being most reliable (deviation 9.8 ± 67 min compared to 7:00 a.m.), regardless of order. In consequence, cases following after 61–90 min long cases had the shortest deviations of incision time from schedule (16 ± 66 min). Taken together, start times for elective surgery cases deviate substantially from schedule, with first and second cases falling into the highest mean deviation category. Second cases had the largest deviations from scheduled times compared to first and all to-follow cases. While planned vs. actual start times differ among specialties, cases of 61–90 min duration had the most reliable start times, with neither shorter nor longer cases seeming to improve timeliness of start times.
Ductal Mucus Obstruction and Reduced Fluid Secretion Are Early Defects in Chronic Pancreatitis
(2018)
Objective: Defective mucus production in the pancreas may be an important factor in the initiation and progression of chronic pancreatitis (CP), therefore we aimed to (i) investigate the qualitative and quantitative changes of mucus both in human CP and in an experimental pancreatitis model and (ii) to correlate the mucus phenotype with epithelial ion transport function.
Design: Utilizing human tissue samples and a murine model of cerulein induced CP we measured pancreatic ductal mucus content by morphometric analysis and the relative expression of different mucins in health and disease. Pancreatic fluid secretion in CP model was measured in vivo by magnetic resonance cholangiopancreatography (MRCP) and in vitro on cultured pancreatic ducts. Time-changes of ductal secretory function were correlated to those of the mucin production.
Results: We demonstrate increased mucus content in the small pancreatic ducts in CP. Secretory mucins MUC6 and MUC5B were upregulated in human, Muc6 in mouse CP. In vivo and in vitro fluid secretion was decreased in cerulein-induced CP. Analysis of time-course changes showed that impaired ductal ion transport is paralleled by increased Muc6 expression.
Conclusion: Mucus accumulation in the small ducts is a combined effect of mucus hypersecretion and epithelial fluid secretion defect, which may lead to ductal obstruction. These results suggest that imbalance of mucus homeostasis may have an important role in the early-phase development of CP, which may have novel diagnostic and therapeutic implications.
Introduction
We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean dose optimized stereotactic body radiation therapy (SBRT) for primary and secondary lung tumors with and without robotic real-time motion compensation.
Materials and methods
Between 2011 and 2017, 208 patients were treated with SBRT for 111 primary lung tumors and 163 lung metastases with a median GTV of 8.2 cc (0.3–174.0 cc). Monte Carlo dose optimization was performed prioritizing GTV mean dose at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The median GTV mean biological effective dose (BED)10 was 162.0 Gy10 (34.2–253.6 Gy10) and the prescribed PTV BED10 ranged 23.6–151.2 Gy10 (median, 100.8 Gy10). Motion compensation was realized through direct tracking (44.9%), fiducial tracking (4.4%), and internal target volume (ITV) concepts with small (≤5 mm, 33.2%) or large (>5 mm, 17.5%) motion. The local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity were analyzed.
Results
Median follow-up was 14.5 months (1–72 months). The 2-year actuarial LC, PFS, and OS rates were 93.1, 43.2, and 62.4%, and the median PFS and OS were 18.0 and 39.8 months, respectively. In univariate analysis, prior local irradiation (hazard ratio (HR) 0.18, confidence interval (CI) 0.05–0.63, p = 0.01), GTV/PTV (HR 1.01–1.02, CI 1.01–1.04, p < 0.02), and PTV prescription, mean GTV, and maximum plan BED10 (HR 0.97–0.99, CI 0.96–0.99, p < 0.01) were predictive for LC while the tracking method was not (p = 0.97). For PFS and OS, multivariate analysis showed Karnofsky Index (p < 0.01) and tumor stage (p ≤ 0.02) to be significant factors for outcome prediction. Late radiation pneumonitis or chronic rip fractures grade 1–2 were observed in 5.3% of the patients. Grade ≥3 side effects did not occur.
Conclusion
Robotic SBRT is a safe and effective treatment for lung tumors. Reducing the PTV prescription and keeping high GTV mean doses allowed the reduction of toxicity while maintaining high local tumor control. The use of real-time motion compensation is strongly advised, however, well-performed ITV motion compensation may be used alternatively when direct tracking is not feasible.
Background
Few studies have assessed trajectories of alcohol use in the general population, and even fewer studies have assessed the impact of brief intervention on the trajectories. Especially for low-risk drinkers, it is unclear what trajectories occur, whether they benefit from intervention, and if so, when and how long. The aims were first, to identify alcohol use trajectories among at-risk and among low-risk drinkers, second, to explore potential effects of brief alcohol intervention and, third, to identify predictors of trajectories.
Methods
Adults aged 18-64 years were screened for alcohol use at a municipal registration office. Those with alcohol use in the past 12 months (N = 1646; participation rate: 67%) were randomized to assessment plus computer-generated individualized feedback letters or assessment only. Outcome was drinks/week assessed at months 3, 6, 12, and 36. Alcohol risk group (at-risk/low-risk) was determined using the Alcohol Use Disorders Identification Test–Consumption. Latent class growth models were estimated to identify alcohol use trajectories among each alcohol risk group. Sex, age, school education, employment status, self-reported health, and smoking status were tested as predictors.
Results
For at-risk drinkers, a light-stable class (46%), a medium-stable class (46%), and a high-decreasing class (8%) emerged. The light-stable class tended to benefit from intervention after 3 years (Incidence Rate Ratio, IRR=1.96; 95% Confidence Interval, CI: 1.14–3.37). Male sex, higher age, more years of school, and current smoking decreased the probability of belonging to the light-stable class (p-values<0.05). For low-risk drinkers, a very light-slightly increasing class (72%) and a light-increasing class (28%) emerged. The very light-slightly increasing class tended to benefit from intervention after 6 months (IRR=1.60; 95% CI: 1.12–2.28). Male sex and more years of school increased the probability of belonging to the light-increasing class (p-value < 0.05).
Conclusion
Most at-risk drinkers did not change, whereas the majority of low-risk drinkers increased alcohol use. There may be effects of alcohol feedback, with greater long-term benefits among persons with low drinking amounts. Our findings may help to identify refinements in the development of individualized interventions to reduce alcohol use.
The M protein of Streptococcus canis (SCM) is a virulence factor and serves as a surface-associated receptor with a particular affinity for mini-plasminogen, a cleavage product of the broad-spectrum serine protease plasmin. Here, we report that SCM has an additional high-affinity immunoglobulin G (IgG) binding activity. The ability of a particular S. canis isolate to bind to IgG significantly correlates with a scm-positive phenotype, suggesting a dominant role of SCM as an IgG receptor. Subsequent heterologous expression of SCM in non-IgG binding S. gordonii and Western Blot analysis with purified recombinant SCM proteins confirmed its IgG receptor function. As expected for a zoonotic agent, the SCM-IgG interaction is species-unspecific, with a particular affinity of SCM for IgGs derived from human, cats, dogs, horses, mice, and rabbits, but not from cows and goats. Similar to other streptococcal IgG-binding proteins, the interaction between SCM and IgG occurs via the conserved Fc domain and is, therefore, non-opsonic. Interestingly, the interaction between SCM and IgG-Fc on the bacterial surface specifically prevents opsonization by C1q, which might constitute another anti-phagocytic mechanism of SCM. Extensive binding analyses with a variety of different truncated SCM fragments defined a region of 52 amino acids located in the central part of the mature SCM protein which is important for IgG binding. This binding region is highly conserved among SCM proteins derived from different S. canis isolates but differs significantly from IgG-Fc receptors of S. pyogenes and S. dysgalactiae sub. equisimilis, respectively. In summary, we present an additional role of SCM in the pathogen-host interaction of S. canis. The detailed analysis of the SCM-IgG interaction should contribute to a better understanding of the complex roles of M proteins in streptococcal pathogenesis.