Linguistic and (micro)cultural differences in the global debate about re-naming 'schizophrenia': A mixed-methods survey from Switzerland.

BACKGROUND AND HYPOTHESIS: This survey explores Swiss mental health professionals', users', and relatives' opinions on re-naming schizophrenia exploiting Switzerland's specific multilingualism to examine possible effects of linguistic and microcultural differences on the issue. STUDY DESIGN: Opinions on 'schizophrenia' were collected using a self-rated online questionnaire incl. Freetext answers available in the three main Swiss languages, German, French and Italian. It was distributed to the main professional and self-help organizations in Switzerland between June and October 2021. STUDY RESULTS: Overall, 449 persons completed the questionnaire, 263 in German, 172 in French and 14 in Italian. Of the total sample, 339 identified as mental health professionals, 81 as relatives and 29 as users. Considering the whole sample, almost half favored a name-change with a significant difference between stakeholder- and between language groups. Also, the name 'schizophrenia' was evaluated more critically than the diagnostic concept. Qualitative analysis of freetext answers showed a highly heterogenous argumentation, but no difference between language groups. CONCLUSIONS: Our results suggest the attitude towards re-naming might itself be subject to (micro)cultural difference, and they highlight the nature of 'schizophrenia' as not only a scientific, but also a linguistic and cultural object. Such local factors ought to be taken into consideration in the global debate.

Exploring secretory proteome and cytokine kinetic of human peripheral blood mononuclear cells exposed to methicillin-resistant Staphylococcus aureus biofilms and planktonic bacteria.

Staphylococcus aureus is a highly successful pathogen infecting various body parts and forming biofilms on natural and artificial surfaces resulting in difficult-to-treat and chronic infections. We investigated the secreted cytokines and proteomes of isolated peripheral blood mononuclear cells (PBMCs) from healthy volunteers exposed to methicillin-resistant S. aureus (MRSA) biofilms or planktonic bacteria. Additionally, the cytokine profiles in sera from patients with community-acquired pneumonia (CAP) caused by S. aureus were investigated. The aim was to gain insights into the immune response involved and differentiate between the planktonic and sessile MRSA forms. We identified 321 and 298 targets that were significantly differently expressed in PBMCs when exposed to planktonic or biofilm-embedded bacteria, respectively. PBMCs exposed to planktonic MRSA cells secreted increased levels of TNF-α, while IL-18 was elevated when exposed to the biofilm. The machine-learning analyses of the cytokine profiles obtained for the in vitro PBMCs and CAP sera distinguished between the two types of bacteria forms based on cytokines IL-18, IL12, and IL-17, and with a lower importance IL-6. Particularly, IL-18 which has not been correlated with S. aureus biofilms so far might represent a suitable marker for monitoring chronification during MRSA infection to individualize the therapy, but this hypothesis must be proved in clinical trials.

Predictors for early and long-term readmission in involuntarily admitted patients.

BACKGROUND: It is a common aim to reduce psychiatric readmissions. Although risk factors for readmissions were described, specific data in the group of patients with potentially aversively experienced involuntary admissions are lacking. To better understand underlying mechanisms, it is important to identify factors that are linked to readmissions in this specific patient group, which is the purpose of the current paper. METHODS: A four-year cohort of N = 3575 involuntary admissions (IA) was followed-up for subsequent re-hospitalization. Demographic, administrative and clinical factors associated with short- (within 30 days) or long-term (> 30 days) readmissions were examined using logistic regression modelling. RESULTS: Almost half of all IA cases were readmitted within the observation period, whereof every fifth readmission was within the first month after discharge from the involuntary index hospitalization. Adjusted regression modelling revealed problematic substance use at admission and assisted living or homelessness as risk factors for readmission, while high functioning at discharge, anxiety disorders, no subsequent treatment after discharge or IA due to danger to others were negatively associated with readmission. Factors specifically linked to short-term readmission were substance use and personality disorders, abscondence or discharge by initiation of the clinic, as well as being discharged to any place except the patient's home. There were no specific risk-factors for long-term readmission. CONCLUSIONS: To prevent readmissions after IA, especially for patients at risk, the aim of treatment strategies should be to focus on intensive discharge planning, enable continuous treatment in the outpatient setting, and provide social support.

Feasibility, Adherence, and Effectiveness of Blended Psychotherapy for Severe Mental Illnesses: Scoping Review.

BACKGROUND: Blended psychotherapy (bPT) combines face-to-face psychotherapy with digital interventions to enhance the effectiveness of mental health treatment. The feasibility and effectiveness of bPT have been demonstrated for various mental health issues, although primarily for patients with higher levels of functioning. OBJECTIVE: This scoping review aims to investigate the feasibility, adherence, and effectiveness of bPT for the treatment of patients with severe mental illnesses (SMIs). METHODS: Following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines, we conducted searches in PubMed, MEDLINE, Embase, PsycINFO, and PsycArticles for studies published until March 23, 2023. RESULTS: Out of 587 screened papers, we incorporated 25 studies encompassing 23 bPT interventions, involving a total of 2554 patients with SMI. The intervention formats and research designs exhibited significant variation. Our findings offer preliminary evidence supporting the feasibility of bPT for SMI, although there is limited research on adherence. Nevertheless, the summarized studies indicated promising attrition rates, spanning from 0% to 37%, implying a potential beneficial impact of bPT on adherence to SMI treatment. The quantity of evidence on the effects of bPT for SMI was limited and challenging to generalize. Among the 15 controlled trials, 4 concluded that bPT interventions were effective compared with controls. However, it is noteworthy that 2 of these studies used the same study population, and the control groups exhibited significant variations. CONCLUSIONS: Overall, our review suggests that while bPT appears promising as a treatment method, further research is necessary to establish its effectiveness for SMI. We discuss considerations for clinical implementation, directions, and future research.

Differential Transcriptional Responses of Human Granulocytes to Fungal Infection with Candida albicans and Aspergillus fumigatus.

Neutrophils are critical phagocytic cells in innate immunity, playing a significant role in defending against invasive fungal pathogens. This study aimed to explore the transcriptional activation of human neutrophils in response to different fungal pathogens, including Candida albicans and Aspergillus fumigatus, compared to the bacterial pathogen Escherichia coli. We identified distinct transcriptional profiles and stress-related pathways in neutrophils during fungal infections, highlighting their functional diversity and adaptability. The transcriptional response was largely redundant across all pathogens in immune-relevant categories and cytokine pathway activation. However, differences in the magnitude of differentially expressed genes (DEGs) were observed, with A. fumigatus inducing a lower transcriptional effect compared to C. albicans and E. coli. Notably, specific gene signatures associated with cell death were differentially regulated by fungal pathogens, potentially increasing neutrophil susceptibility to autophagy, pyroptosis, and neutrophil extracellular trap (NET) formation. These findings provide valuable insights into the complex immunological responses of neutrophils during fungal infections, offering new avenues for diagnostic and therapeutic strategies, particularly in the management of invasive fungal diseases.

Mismatch negativity generation in subjects at risk for psychosis: source analysis is more sensitive than surface electrodes in risk prediction.

Background: Deficits of mismatch negativity (MMN) in patients with schizophrenia have been demonstrated many times and there is growing evidence that alterations of MMN already exist in individuals at risk for psychosis. The present study examines differences in MMN between subjects fulfilling ultra-high risk (UHR) or only basic symptoms criteria and it addresses the question, if MMN source analysis can improve prediction of transition to psychosis. Methods: The MMN to duration, frequency, and intensity deviants was recorded in 50 healthy controls and 161 individuals at risk for psychosis classified into three subgroups: only basic symptoms (n = 74), only ultra-high risk (n = 13) and persons who fulfill both risk criteria (n = 74). Based on a three-source model of MMN generation, we conducted an MMN source analysis and compared the amplitudes of surface electrodes and sources among the three groups. Results: Significant differences in MMN generation among the four groups were revealed at surface electrodes Cz and C4 (p < 0.05) and at the frontal source (p < 0.001) for duration deviant stimuli. The 15 subjects from the risk groups who subsequently developed a manifest psychosis had a significantly lower MMN amplitude at frontal source (p = 0.019) without showing significant differences at surface electrodes. Low activity at frontal MMN source increased the risk of transition to manifest disease by the factor 3.12 in UHR subjects. Conclusion: MMN activity differed significantly between subjects presenting only basic symptoms and subjects which additionally meet UHR criteria. The largest differences between groups as well as between individuals with and without transition were observed at the frontal source. The present results suggest that source analysis is more sensitive than surface electrodes in psychosis risk prediction by MMN.

The role of pneumococcal extracellular vesicles on the pathophysiology of the kidney disease hemolytic uremic syndrome.

Streptococcus pneumoniae-induced hemolytic uremic syndrome (Sp-HUS) is a kidney disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. This disease is frequently underdiagnosed and its pathophysiology is poorly understood. In this work, we compared clinical strains, isolated from infant Sp-HUS patients, with a reference pathogenic strain D39, for host cytotoxicity and further explored the role of Sp-derived extracellular vesicles (EVs) in the pathogenesis of an HUS infection. In comparison with the wild-type strain, pneumococcal HUS strains caused significant lysis of human erythrocytes and increased the release of hydrogen peroxide. Isolated Sp-HUS EVs were characterized by performing dynamic light-scattering microscopy and proteomic analysis. Sp-HUS strain released EVs at a constant concentration during growth, yet the size of the EVs varied and several subpopulations emerged at later time points. The cargo of the Sp-HUS EVs included several virulence factors at high abundance, i.e., the ribosomal subunit assembly factor BipA, the pneumococcal surface protein A, the lytic enzyme LytC, several sugar utilization, and fatty acid synthesis proteins. Sp-HUS EVs strongly downregulated the expression of the endothelial surface marker platelet endothelial cell adhesion molecule-1 and were internalized by human endothelial cells. Sp-HUS EVs elicited the release of pro-inflammatory cytokines (interleukin [IL]-1ß, IL-6) and chemokines (CCL2, CCL3, CXCL1) by human monocytes. These findings shed new light on the overall function of Sp-EVs, in the scope of infection-mediated HUS, and suggest new avenues of research for exploring the usefulness of Sp-EVs as therapeutic and diagnostic targets. IMPORTANCE Streptococcus pneumoniae-associated hemolytic uremic syndrome (Sp-HUS) is a serious and underdiagnosed deadly complication of invasive pneumococcal disease. Despite the introduction of the pneumococcal vaccine, cases of Sp-HUS continue to emerge, especially in children under the age of 2. While a lot has been studied regarding pneumococcal proteins and their role on Sp-HUS pathophysiology, little is known about the role of extracellular vesicles (EVs). In our work, we isolate and initially characterize EVs from a reference pathogenic strain (D39) and a strain isolated from a 2-year-old patient suffering from Sp-HUS. We demonstrate that despite lacking cytotoxicity toward human cells, Sp-HUS EVs are highly internalized by endothelial cells and can trigger cytokine and chemokine production in monocytes. In addition, this work specifically highlights the distinct morphological characteristics of Sp-HUS EVs and their unique cargo. Overall, this work sheds new light into potentially relevant players contained in EVs that might elucidate about pneumococcal EVs biogenesis or pose as interesting candidates for vaccine design.

Staphylococcus aureus induces tolerance in human monocytes accompanied with expression changes of cell surface markers.

Exposure of human monocytes to lipopolysaccharide (LPS) or other pathogen-associated molecular pattern (PAMPs) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance (ET), associated with the pathogenesis of sepsis. In this study, we aimed to characterize the cellular state of human monocytes from healthy donors stimulated with Staphylococcus aureus in comparison to TLR2-specific ligands. We analyzed S. aureus induced gene expression changes after 2 and 24 hours by amplicon sequencing (RNA-AmpliSeq) and compared the pro-inflammatory response after 2 hours with the response in re-stimulation experiments. In parallel, glycoprotein expression changes in human monocytes after 24 hours of S. aureus stimulation were analyzed by proteomics and compared to stimulation experiments with TLR2 ligands Malp-2 and Pam3Cys and TLR4 ligand LPS. Finally, we analyzed peripheral blood monocytes of patients with S. aureus bloodstream infection for their ex vivo inflammatory responses towards S. aureus stimulation and their glycoprotein expression profiles. Our results demonstrate that monocytes from healthy donors stimulated with S. aureus and TLR ligands of Gram-positive bacteria entered the tolerant cell state after activation similar to LPS treatment. In particular reduced gene expression of pro-inflammatory cytokines (TNF, IL1ß) and chemokines (CCL20, CCL3, CCL4, CXCL2, CXCL3 and CXCL8) could be demonstrated. Glycoprotein expression changes in monocytes tolerized by the different TLR agonists were highly similar while S. aureus-stimulated monocytes shared some of the PAMP-induced changes but also exhibited a distinct expression profile. 11 glycoproteins (CD44, CD274, DSC2, ICAM1, LAMP3, LILRB1, PTGS2, SLC1A3, CR1, FGL2, and HP) were similarly up- or downregulated in all four comparisons in the tolerant cell state. Monocytes from patients with S. aureus bacteremia revealed preserved pro-inflammatory responsiveness to S. aureus stimulation ex vivo, expressed increased CD44 mRNA but no other glycoprotein of the tolerance signature was differentially expressed.

[Relevant biomarkers in infectiology]. / Relevante Biomarker in der Infektiologie.

A biomarker in infectiology should ideally be able to identify infectious agents, monitor clinical response and determine the duration of treatment. This article answers the question to what extent C-reactive protein and procalcitonin meet these requirements and reports on the search for further biomarkers - e.g. with the help of "omics"-based technologies and the integration of artificial intelligence.

Predicting coercion during the course of psychiatric hospitalizations.

BACKGROUND: Coercive measures (such as seclusion, mechanical restraint, and forced medication) during psychiatric inpatient treatment should be avoided whenever possible. Different interventions were already developed to reduce coercion, but for their effective application, it is crucial to know the risk factors of individuals and clinical situations that might be associated with coercion. Since the results of previous studies differ considerably the current study aims to fill this gap by evaluating the course of the exertion of coercion in detail. METHODS: In this study, we analyzed clinical, procedural, and sociodemographic data from patients (n = 16,607 cases) who were treated as inpatients in Switzerland's largest psychiatric institution with 320 beds during the years 2017 to 2020. We used regression models to identify predictors for the exertion of coercion, the number of coercive measures during a treatment episode and time until exertion of the first and last coercive measure. RESULTS: Coercive measures are mostly used during the first days of treatment. We identified clinical parameters such as manic or psychotic episodes to be the most relevant predictors for the exertion of coercion. Cases with those disorders also received coercion more often and earlier in their treatment course than other diagnostic groups. Other promoting factors for frequency and early application of coercion were involuntary admission and factors of chronicity and clinical severity. CONCLUSIONS: Knowing the risk factors may help to target preventive strategies for those at highest risk. In particular, interventions should focus on the critical timeframe at the beginning of treatment.

Fit for Work and Life-an eight-week program for improvement of functionality and quality of life : A two-stage study.

BACKGROUND: The current two-stage study focused on work integration and quality of life of patients in an acute psychiatric day care unit. There is evidence that a longer absence from work due to illness negatively affects job retention, life satisfaction and clinical prognosis. Furthermore, there are individual supportive methods that proved to be effective in work integration. We therefore developed a specific group program Fit for Work and Life (FWL) for patients in an acute psychiatric day care unit focusing on work integration in the first labor market (in contrast to work in institutions for people with disabilities/second labor market). METHODS: Between 2018 and 2020, 62 patients (intervention group; IG) were enrolled in an 8­week prospective job integration program and compared to 74 patients (control group; CG) who received treatment as usual (partly retrospective survey). Patients of both groups held a job when entering treatment. Main outcome was defined as their working status 4 weeks after the end of treatment as well as self-reported life satisfaction. RESULTS: At the end of treatment (i.e. the week prior to discharge), the IG participants reported higher overall life satisfaction as well as higher health-, self- and living condition-related satisfaction than controls. Functional and clinical improvement during treatment was linked to subsequently returning to work. Functional improvement was further linked to higher life satisfaction. Mediational analysis revealed an indirect path from functional improvement on life satisfaction via working status, i.e. the higher functional improvement during treatment, the higher the chance of successfully returning to work, which in turn increased life satisfaction. CONCLUSION: Our findings suggest that programs such as FWL are useful interventions for employed patients to improve reintegration into work and life and to help to increase life satisfaction.

Antibody ligation of CEACAM1, CEACAM3, and CEACAM6, differentially enhance the cytokine release of human neutrophils in responses to Candida albicans.

Invasive candidiasis is a healthcare-associated fungal infection with a high mortality rate. Neutrophils, the first line of defense during fungal infections, express the immunoregulatory Candida albicans receptors CEACAM1, CEACAM3, and CEACAM6. We analyzed the effects of specific antibodies on C. albicans-induced neutrophil responses. CEACAM6 ligation by 1H7-4B and to some extent CEACAM1 ligation by B3-17, but not CEACAM3 ligation by 308/3-3, resulted in the immediate release of stored CXCL8 and altered transcriptional responses of the C. albicans-stimulated neutrophils. Integrated network analyses and dynamic simulations of signaling cascades predicted alterations in apoptosis and cytokine secretion. We verified that CEACAM6 ligation enhanced Candida-induced neutrophil apoptosis and increased long-term IL-1ß/IL-6 release in responses to C. albicans. CEACAM3 ligation, but not CEACAM1 ligation, increased the long-term release of pro-inflammatory IL-1ß/IL-6. Taken together, we demonstrated for the first time that ligation of CEACAM receptors differentially affects the regulation of C. albicans-induced immune functions in human neutrophils.

Childhood adversity patterns differentially cluster with mental disorders and socioeconomic indicators in a large Swiss community sample.

BACKGROUND: Exposure to childhood adversities (CHAD) has been found to be strongly associated with individuals' mental health and social development. Recently, it has been suggested that certain CHAD patterns exist in the population, which are more closely related to individuals' later mental health than the simple summation of adversities. The current study aims 1) to establish CHAD patterns based on self-reported child abuse and family dysfunction and 2) to assess their associations with mental disorders and sociodemographic indicators reported in adulthood. METHODS: Data used in this cross-sectional study were derived from the representative CoLaus/PsyCoLaus population-based cohort (N = 5111, 35 to 88 years). Latent class analysis was conducted for the identification of CHAD patterns, while their associations with mental disorders and socioeconomic achievements (e. g. education and income) were investigated using correspondence analysis. RESULTS: Four CHAD patterns emerged. While the majority (70.7%) of the sample showed an overall low adversity pattern (c1), 13.6% had not been raised by both of their biological parents due to divorce or being placed in foster home (c2), 11.0% had been raised by conflictive / dysfunctional / abusive parents (c3), and 4.7% showed high overall adversities (c4). Patterns c3 and c4 were most strongly associated with various mental disorders, especially c3 with internalizing anxiety disorders, while c2 was closely related to lower educational achievement. CONCLUSIONS: Four CHAD patterns characterised by varying levels of child abuse and family dysfunction existed in this community sample. They yielded distinct associations with mental disorders and socioeconomic indicators.

Starve to Sustain-An Ancient Syrian Landrace of Sorghum as Tool for Phosphorous Bio-Economy?

Phosphorus (P) is an essential macronutrient, playing a role in developmental and metabolic processes in plants. To understand the local and systemic responses of sorghum to inorganic phosphorus (Pi) starvation and the potential of straw and ash for reutilisation in agriculture, we compared two grain (Razinieh) and sweet (Della) sorghum varieties with respect to their morpho-physiological and molecular responses. We found that Pi starvation increased the elongation of primary roots, the formation of lateral roots, and the accumulation of anthocyanin. In Razinieh, lateral roots were promoted to a higher extent, correlated with a higher expression of SbPht1 phosphate transporters. Infrared spectra of straw from mature plants raised to maturity showed two prominent bands at 1371 and 2337 cm-1, which could be assigned to P-H(H2) stretching vibration in phosphine acid and phosphinothious acid, and their derivates, whose abundance correlated with phosphate uptake of the source plant and genotype (with a higher intensity in Razinieh). The ash generated from these straws stimulated the shoot elongation and root development of the rice seedlings, especially for the material derived from Razinieh raised under Pi starvation. In conclusion, sorghum growing on marginal lands has potential as a bio-economy alternative for mineral phosphorus recycling.

Developing a short-term prediction model for asthma exacerbations from Swedish primary care patients' data using machine learning - Based on the ARCTIC study.

OBJECTIVE: The ability to predict impending asthma exacerbations may allow better utilization of healthcare resources, prevention of hospitalization and improve patient outcomes. We aimed to develop models using machine learning to predict risk of exacerbations. METHODS: Data from 29,396 asthma patients was collected from electronic medical records and national registers covering clinical and epidemiological factors (e.g. comorbidities, health care contacts), between 2000 and 2013. Machine-learning classifiers were used to create models to predict exacerbations within the next 15 days. Model selection was done using the mean cross validation score of area under precision-recall curve (AUPRC). RESULTS: The most important predictors of exacerbation were comorbidity burden and previous exacerbations. Model validation on test data yielded an AUPRC = 0.007 (95% CI: ± 0.0002), indicating that historic clinical information alone may not be sufficient to predict a near future risk of asthma exacerbation. CONCLUSIONS: Supplementation with additional data on environmental triggers, (e.g. weather, pollen count, air quality) and from wearables, might be necessary to improve performance of the short-term predictive model to develop a more clinically useful tool.

Multimodule Web-Based COVID-19 Anxiety and Stress Resilience Training (COAST): Single-Cohort Feasibility Study With First Responders.

BACKGROUND: Since the emergence of COVID-19, health care workers and first responders have been at a high risk for mental health symptoms owing to their exposure to the virus and increased work stress during the pandemic. Although interventions exist to address mental health issues following exposure to disasters, emergencies, and humanitarian crises, considerably less is known about web-based unguided interventions to help mitigate the negative impacts of such events. Additionally, in contexts in which emergencies reduce access to in-person care, remote forms of support are critical, yet there are limited studies on the use of such interventions. Evidence-based, easy-to-use, scalable interventions are direly needed for this population. OBJECTIVE: This study aimed to develop and test the feasibility of an unguided electronic mental health program, COVID-19 Anxiety and Stress Resilience Training (COAST), tailored to first responders and health care personnel, based on scientific evidence and empirically based techniques. METHODS: We developed COVID-19-specific training modules focusing on several domains that are previously reported as key to resilience and stress recovery: self-efficacy, mindfulness, sleep quality, and positive thinking. The program was made available to 702 first responders between May and August 2020, during the COVID-19 pandemic. Sociodemographic, work-, and COVID-19-related information was collected, and psychometric questionnaires were completed. We examined user acceptance and user activity, including module choice and participant feedback. RESULTS: In total, 52 of 702 (7%) first responders to whom we reached out used the program at least once. COAST use was independent of age, sex, or baseline levels of self-efficacy, mindful awareness, sleep quality, and positive thinking (for all, P>.39). First responders who had tested positive and those who had been quarantined were more likely to engage in the program. A click count analysis per module showed that participants used the self-efficacy and mindfulness modules most often, with 382 and 122 clicks, respectively, over 15 weeks. Overall, first responders expressed satisfaction with the program. CONCLUSIONS: Engagement of first responders in the multimodule web-based COAST program was feasible and the first responder cohort expressed overall satisfaction with the program. Those in more difficult circumstances, including those in quarantine and those who tested positive, may be more likely to engage in such programs. Further controlled studies could pave the way for efficacy studies and the development of additional modules, including just-in-time interventions or blended interventions combining individual use of an unguided self-help intervention, such as COAST, with subsequent individual psychotherapy for those who continue to experience stress and psychological symptoms.

Predicting Hospitalization Due to COPD Exacerbations in Swedish Primary Care Patients Using Machine Learning - Based on the ARCTIC Study.

PURPOSE: Chronic obstructive pulmonary disease (COPD) exacerbations can negatively impact disease severity, progression, mortality and lead to hospitalizations. We aimed to develop a model that predicts a patient's risk of hospitalization due to severe exacerbations (defined as COPD-related hospitalizations) of COPD, using Swedish patient level data. PATIENTS AND METHODS: Patient level data for 7823 Swedish patients with COPD was collected from electronic medical records (EMRs) and national registries covering healthcare contacts, diagnoses, prescriptions, lab tests, hospitalizations and socioeconomic factors between 2000 and 2013. Models were created using machine-learning methods to predict risk of imminent exacerbation causing patient hospitalization due to COPD within the next 10 days. Exacerbations occurring within this period were considered as one event. Model performance was assessed using the Area under the Precision-Recall Curve (AUPRC). To compare performance with previous similar studies, the Area Under Receiver Operating Curve (AUROC) was also reported. The model with the highest mean cross validation AUPRC was selected as the final model and was in a final step trained on the entire training dataset. RESULTS: The most important factors for predicting severe exacerbations were exacerbations in the previous six months and in whole history, number of COPD-related healthcare contacts and comorbidity burden. Validation on test data yielded an AUROC of 0.86 and AUPRC of 0.08, which was high in comparison to previously published attempts to predict COPD exacerbation. CONCLUSION: Our work suggests that clinically available information on patient history collected via automated retrieval from EMRs and national registries or directly during patient consultation can form the basis for future clinical tools to predict risk of severe COPD exacerbations.

Retrospectively assessed trajectories of PTSD symptoms and their subsequent comorbidities.

BACKGROUND: Dynamic trajectories of psychopathology, such as post-traumatic stress disorder (PTSD) provide a key to understanding human adjustment processes after trauma exposure. Recent studies have suggested more heterogeneous mental health outcomes than the initially identified four adjustment trajectories. To explore this heterogeneity, we investigated the after-trauma adjustment patterns of psychopathology based on retrospective lifetime data. This was first carried out on the PTSD symptoms (PTSS, including no symptoms, few symptoms, partial and full PTSD), and secondly together with their post-trauma comorbidities. METHODS: Data of trauma and the post-trauma mental disorders were collected for a large and randomly selected community sample, resulting in a N = 960 trauma-exposed subsample. Pattern recognition as carried out by latent class analysis (LCA) was implemented on this subsample. LCA was first exploited to identify the potential trajectory patterns of PTSS and next to explore the patterns of mental adjustments when additional post-trauma comorbid disorders, such as anxiety, mood and substance use disorders, were assessed. RESULTS: Four PTSS trajectory patterns were found, namely resilient, chronic, recovered, and delayed onset, consistent with findings from longitudinal PTSD studies. When post-trauma comorbidities were evaluated, other than the trajectory pattern of delayed onset which retained a low comorbidity profile, the other three split respectively and paired up with either low, moderate or high comorbidity profile. CONCLUSIONS: Mental health outcomes after trauma exposure were considerably more complex than the four previously established adjustment trajectories. Here, we uncovered additional and more heterogeneous adjustment patterns comprised of PTSS trajectories and post-trauma comorbidity profiles.

Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis.

The interaction and crosstalk of Toll-like receptors (TLRs) is an established pathway in which the innate immune system recognises and fights pathogens. In a single nucleotide polymorphisms (SNP) analysis of an Indian cohort, we found evidence for both TLR4-399T and TRL8-1A conveying increased susceptibility towards tuberculosis (TB) in an interdependent manner, even though there is no established TLR4 ligand present in Mycobacterium tuberculosis (Mtb), which is the causative pathogen of TB. Docking studies revealed that TLR4 and TLR8 can build a heterodimer, allowing interaction with TLR8 ligands. The conformational change of TLR4-399T might impair this interaction. With immunoprecipitation and mass spectrometry, we precipitated TLR4 with TLR8-targeted antibodies, indicating heterodimerisation. Confocal microscopy confirmed a high co-localisation frequency of TLR4 and TLR8 that further increased upon TLR8 stimulation. The heterodimerisation of TLR4 and TLR8 led to an induction of IL12p40, NF-κB, and IRF3. TLR4-399T in interaction with TLR8 induced an increased NF-κB response as compared to TLR4-399C, which was potentially caused by an alteration of subsequent immunological pathways involving type I IFNs. In summary, we present evidence that the heterodimerisation of TLR4 and TLR8 at the endosome is involved in Mtb recognition via TLR8 ligands, such as microbial RNA, which induces a Th1 response. These findings may lead to novel targets for therapeutic interventions and vaccine development regarding TB.

Raloxifene inhibits pancreatic adenocarcinoma growth by interfering with ERß and IL-6/gp130/STAT3 signaling.

PURPOSE: Currently, the exact role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we showed that expression of phosphorylated ERß correlates with a poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here, we hypothesized that raloxifene, a FDA-approved selective ER modulator (SERM), may suppress PDAC tumor growth by interfering with ERß signaling. To test this hypothesis, we studied the impact of raloxifene on interleukin-6/glycoprotein-130/signal transducer and activator of transcription-3 (IL-6/gp130/STAT3) signaling. METHODS: Human PDAC cell lines were exposed to raloxifene after which growth inhibition was assessed using a BrdU assay. ER knockdown was performed using siRNAs specific for ERα and ERß. The effects of raloxifene on IL-6 expression and STAT3 phosphorylation in PDAC cells were assessed by ELISA and Western blotting, respectively. In addition, raloxifene was administered to an orthotopic PDAC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry was performed. RESULTS: Raloxifene inhibited the in vitro growth of PDAC cells, and this effect was reversed by siRNA-mediated knockdown of ERß, but not of ERα, indicating ER isotype-specific signaling. We also found that treatment with raloxifene inhibited the release of IL-6 and suppressed the phosphorylation of STAT3Y705 in PDAC cells. In vivo, we found that orthotopic PDAC tumor growth, lymph node and liver metastases as well as Ki-67 expression were reduced in mice treated with raloxifene. CONCLUSIONS: Inhibition of ERß and the IL-6/gp130/STAT3 signaling pathway by raloxifene leads to potent reduction of PDAC growth in vitro and in vivo. Our results suggest that ERß signaling and IL-6/gp130 interaction may serve as promising drug targets for pancreatic cancer and that raloxifene may serve as an attractive therapeutic option for PDAC patients expressing the ERß isotype.