Staphylococcus aureus pathogenicity in cystic fibrosis patients-results from an observational prospective multicenter study concerning virulence genes, phylogeny, and gene plasticity

Staphylococcus aureus and cystic fibrosis (CF) are closely interlinked. To date, however, the impact of S. aureus culture in CF airways on lung function and disease progression has only been elucidated to a limited degree. This analysis aims to identify bacterial factors associated to clinical deterioration. Data were collected during an observational prospective multi-center study following 195 patients from 17 centers. The average follow-up time was 80 weeks. S. aureus isolates (n = 3180) were scanned for the presence of 25 virulence genes and agr-types using single and multiplex PCR. The presence of specific virulence genes was not associated to clinical deterioration. For the agr-types 1 and 4, however, a link to the subjects' clinical status became evident. Furthermore, a significant longitudinal decrease in the virulence gene quantity was observed. Analyses of the plasticity of the virulence genes revealed significantly increased plasticity rates in the presence of environmental stress. The results suggest that the phylogenetic background defines S. aureus pathogenicity rather than specific virulence genes. The longitudinal loss of virulence genes most likely reflects the adaptation process directed towards a persistent and colonizing rather than infecting lifestyle

The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells

Background: Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Methods: Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. Results: HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Conclusion: Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.<br

Factors associated with worse lung function in cystic fibrosis patients with persistent staphylococcus aureus

Background Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. Methods Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors. Results 195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496). Conclusions In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Establishment of a Palliative Care Consultation Service (PCCS) in an Acute Hospital Setting

Background and study aims: Acute health service requires focused palliative care (PC). This study was performed to provide guidance for the establishment of a palliative care consultation service (PCCS). Patients and methods: This study was conceived as a retrospective single-center study for observing, analyzing and evaluating the initial setup of a PCCS from 1 May 2015 to 31 May 2018. Patients from Muenster University Hospital with advanced life-limiting diseases, identified to require PC, were included. Results: PCCS was requested from various departments, for between 20 and 80 patients per month, corresponding to a total of 2359 for the study period. Requests were highest in internal medicine (27.3%), gynecology (18.1%) and radiotherapy (17.6%). Time to referral was significantly shorter in departments with special PCCS ward rounds (6 ± 9 vs. 12 ± 22 days, p < 0.001). The most frequently reported symptoms were fatigue, pain and loss of appetite. Pain was frequently localized in the stomach (20.4%), back (17.1%), or in the head and neck area (14.9%). After the first PCCS consultation, 254 patients (90%) reported sufficient pain relief after 48 h. An introduction/modification of painkiller medication, which was recommended for 142 inpatients, was implemented in 57.0% of cases by the respective departments. Overall, the direct realization of PCCS recommendations reached only 50% on average. Conclusions: Besides an analysis of the ability to address the symptoms of the referred patients by the PCCS, this study highlights the importance of the interaction between PCCS and other departments. It further elucidates the role and possibilities of this service both in regular ward rounds and individual staff contacts

User Experience and Effects of an Individually Tailored Transdiagnostic Internet-Based and Mobile-Supported Intervention for Anxiety Disorders: Mixed-Methods Study

Background: Internet interventions have been shown to be effective in treating anxiety disorders. Most interventions to date focus on single disorders and disregard potential comorbidities. Objective: The aim of this mixed-methods study was to investigate feasibility, user experience, and effects of a newly developed individually tailored transdiagnostic guided internet intervention for anxiety disorders. Methods: This study is an uncontrolled, within-group, baseline, postintervention pilot trial with an embedded qualitative and quantitative process and effect evaluation. In total, 49 adults with anxiety disorders (generalized anxiety disorder n=20, social phobia n=19, agoraphobia without panic n=12, panic with agoraphobia n=6, panic without agoraphobia n=4, subclinical depression n=41) received access to the 7-session intervention. We examined motivation and expectations, intervention use, user experience, impact, and modification requests. Qualitative data were assessed using semistructured interviews and analyzed by qualitative content analysis. Quantitative outcomes included symptom severity of anxiety and depression (Hamilton Anxiety Rating Scale [HAM-A], Quick Item Inventory of Depressive Symptomatology clinician rating [QIDS-C]), diagnostic status in clinical interviews (Mini International Neuropsychiatric Interview [MINI]), and web-based self-reports (Generalized Anxiety Disorder-7 [GAD-7], Center for Epidemiological Studies Depression Scale [CES-D], Beck Anxiety Inventory [BAI], Panic and Agoraphobia Scale [PAS], Social Phobia Scale [SPS], Patient Health Questionnaire-9 [PHQ-9]) at baseline and postassessment. Quantitative data was analyzed by comparing within-group means expressed as Cohen d. Results: Anxiety symptom severity (HAM-A d=1.19) and depressive symptoms (QIDS-C d=0.42) improved significantly, and 54% (21/39) no longer were diagnosed as having any anxiety disorder. The main positive effects were the general improvement of disease burden and attentiveness to feelings and risk situations while the main negative effects experienced were lack of change in disease burden and symptom deterioration. The most prevalent reasons for participation were the advantages of online treatment, symptom burden, and openness toward online treatment. Helpful factors included support, psychoeducation and practicing strategies in daily life; the main hindering factors were too little individualization and being overwhelmed by the content and pace. Conclusions: The intervention was found to be feasible and results show preliminary data indicating potential efficacy for improving anxiety and depression. The next step should be the evaluation within a randomized controlled trial. Concerning intervention development, it was found that future interventions should emphasize individualization even more in order to further improve the fit to individual characteristics, preferences, and needs

Correlations of Host and Bacterial Characteristics with Clinical Parameters and Survival in Staphylococcus aureus Bacteremia

'Staphylococcus aureus' bacteremia (SAB) is a frequent, severe condition that occurs in patients of all age groups and affects clinical departments of all medical fields. It is associated with a high mortality rate of 20–30%. In this study, we analyzed patient mortality associated with SAB at our tertiary care university hospital, assessed the clinical management in terms of administered antimicrobial therapy, and determined which factors have an impact on the clinical course and outcome of patients with this disease. We collected clinical data and blood culture isolates of 178 patients diagnosed with SAB between May 2013 and July 2015. For this study, bacteria were cultured and analyzed concerning their phenotype, hemolysis activity, biofilm formation, nuclease activity, prevalence of toxin genes, 'spa' and 'agr' type. Overall mortality was 24.2% and 30-day mortality was 14.6%. Inadequate initial therapy was administered to 26.2% of patients and was associated with decreased survival (p = 0.041). Other factors associated with poor survival were patient age (p = 0.003), 'agr' type 4 (p ≤ 0.001) and pathological leukocyte counts (p = 0.029 if elevated and p = 0.003 if lowered). The type of infection focus, 'spa' clonal complex and enterotoxin genes 'seg' and 'sei' had an impact on severity of inflammation. Our results indicate that mortality and burden of disease posed by SAB are high at our university hospital

User Experience and Effects of an Individually Tailored Transdiagnostic Internet-Based and Mobile-Supported Intervention for Anxiety Disorders:Mixed-Methods Study

BACKGROUND: Internet interventions have been shown to be effective in treating anxiety disorders. Most interventions to date focus on single disorders and disregard potential comorbidities. OBJECTIVE: The aim of this mixed-methods study was to investigate feasibility, user experience, and effects of a newly developed individually tailored transdiagnostic guided internet intervention for anxiety disorders. METHODS: This study is an uncontrolled, within-group, baseline, postintervention pilot trial with an embedded qualitative and quantitative process and effect evaluation. In total, 49 adults with anxiety disorders (generalized anxiety disorder n=20, social phobia n=19, agoraphobia without panic n=12, panic with agoraphobia n=6, panic without agoraphobia n=4, subclinical depression n=41) received access to the 7-session intervention. We examined motivation and expectations, intervention use, user experience, impact, and modification requests. Qualitative data were assessed using semistructured interviews and analyzed by qualitative content analysis. Quantitative outcomes included symptom severity of anxiety and depression (Hamilton Anxiety Rating Scale [HAM-A], Quick Item Inventory of Depressive Symptomatology clinician rating [QIDS-C]), diagnostic status in clinical interviews (Mini International Neuropsychiatric Interview [MINI]), and web-based self-reports (Generalized Anxiety Disorder-7 [GAD-7], Center for Epidemiological Studies Depression Scale [CES-D], Beck Anxiety Inventory [BAI], Panic and Agoraphobia Scale [PAS], Social Phobia Scale [SPS], Patient Health Questionnaire-9 [PHQ-9]) at baseline and postassessment. Quantitative data was analyzed by comparing within-group means expressed as Cohen d. RESULTS: Anxiety symptom severity (HAM-A d=1.19) and depressive symptoms (QIDS-C d=0.42) improved significantly, and 54% (21/39) no longer were diagnosed as having any anxiety disorder. The main positive effects were the general improvement of disease burden and attentiveness to feelings and risk situations while the main negative effects experienced were lack of change in disease burden and symptom deterioration. The most prevalent reasons for participation were the advantages of online treatment, symptom burden, and openness toward online treatment. Helpful factors included support, psychoeducation and practicing strategies in daily life; the main hindering factors were too little individualization and being overwhelmed by the content and pace. CONCLUSIONS: The intervention was found to be feasible and results show preliminary data indicating potential efficacy for improving anxiety and depression. The next step should be the evaluation within a randomized controlled trial. Concerning intervention development, it was found that future interventions should emphasize individualization even more in order to further improve the fit to individual characteristics, preferences, and needs