Symptoms of pelvic floor dysfunction are poorly correlated with findings on clinical examination and dynamic MR imaging of the pelvic floor

Contains fulltext : 81433.pdf (publisher's version ) (Closed access)INTRODUCTION AND HYPOTHESIS: The aim of the study was to determine whether patients' symptoms agree with findings on clinical examination and dynamic MR imaging of the pelvic floor. METHODS: Symptoms of pelvic organ dysfunction were measured with the use of three validated questionnaires. The domain scores were compared with POP-Q and dynamic MR imaging measurements. The Spearman's rank correlation coefficient (r(s)) was used to assess agreement. RESULTS: Only the domain score genital prolapse was significantly correlated in the positive direction with the degree of pelvic organ prolapse as assessed by POP-Q and dynamic MR imaging (r(s) = 0.64 and 0.27, respectively), whereas the domain score urinary incontinence was inversely correlated (r(s) = -0.32 and -0.35, respectively). CONCLUSIONS: The sensation or visualization of a bulge in the vagina was the only symptom which correlated positively with the degree of pelvic organ prolapse, and clinical examination and dynamic MR imaging showed similar correlation in this respect

Development and psychometric evaluation of the Decision Tool Anxiety Disorders, OCD and PTSD (DTAOP):Facilitating the early detection of patients in need of highly specialized care

Background: Early identification of patients with an anxiety disorder, obsessive-compulsive disorder (OCD), or post-traumatic stress disorder (PTSD) in need of highly specialized care could facilitate the selection of the optimal initial treatment in these patients. This paper describes the development and psychometric evaluation of the Decision Tool Anxiety Disorders, OCD and PTSD (DTAOP), which aims to aid clinicians in the early identification of patients with an anxiety disorder, OCD, or PTSD in need of highly specialized mental healthcare. Methods: A systematic literature review and a concept mapping procedure were carried out to inform the development of the DTAOP. To evaluate the psychometric properties of the DTAOP, a cross-sectional study in 454 patients with a DSM-IV-TR anxiety disorder was carried out. Feasibility was evaluated by the completion time and the content clarity of the DTAOP. Inter-rater reliability was assessed in a subsample of 87 patients. Spearman’s rank correlation coefficients between the DTAOP and EuroQol five-dimensional questionnaire (EQ-5D-5L) scores were computed to examine the convergent validity. Criterion validity was assessed against independent clinical judgments made by clinicians. Results: The average time required to complete the eight-item DTAOP was 4.6 min and the total DTAOP was evaluated as clear in the majority (93%) of the evaluations. Krippendorff’s alpha estimates ranged from 0.427 to 0.839. Based on the qualitative feedback, item wording and instructions were improved. As hypothesized, the DTAOP correlated negatively with EQ-5D-5L scores. The area under the curve was 0.826 and the cut-off score of >= 4 optimized sensitivity (70%) and specificity (71%). Conclusions: The DTAOP demonstrated excellent feasibility and good validity, but weak inter-rater reliability. Based on the qualitative feedback and reliability estimates, revisions and refinements of the wording and instructions were made, resulting in the final version of the DTAOP

International Paediatric Mitochondrial Disease Scale

Objective: There is an urgent need for reliable and universally applicable outcome measures for children with mitochondrial diseases. In this study, we aimed to adapt the currently available Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to the International Paediatric Mitochondrial Disease Scale (IPMDS) during a Delphi-based process with input from international collaborators, patients and caretakers, as well as a pilot reliability study in eight patients. Subsequently, we aimed to test the feasibility, construct validity and reliability of the IPMDS in a multicentre study. Methods: A clinically, biochemically and genetically heterogeneous group of 17 patients (age 1.6–16 years) from five different expert centres from four different continents were evaluated in this study. Results: The feasibility of the IPMDS was good, as indicated by a low number of missing items (4 %) and the positive evaluation of patients, parents and users. Principal component analysis of our small sample identified three factors, which explained 57.9 % of the variance. Good construct validity was found using hypothesis testing. The overall interrater reliability was good [median intraclass correlation coefficient for agreement between raters (ICCagreement) 0.85; range 0.23–0.99). Conclusion: In conclusion, we suggest using the IPMDS for assessing natural history in children with mitochondrial diseases. These data should be used to further explore construct validity of the IPMDS and to set age limits. In parallel, responsiveness and the minimal clinically important difference should be studied to facilitate sample size calculations in future clinical trials

Nuclear positioning rather than contraction controls ordered rearrangements of immunoglobulin loci

Progenitor-B cells recombine their immunoglobulin (Ig) loci to create unique antigen receptors. Despite a common recombination machinery, the Ig heavy and Ig light chain loci rearrange in a stepwise manner. We studied pre-pro-B cells and Rag-/- progenitor-B cells to determine whether Ig locus contraction or nuclear positioning is decisive for stepwise rearrangements. We found that both Ig loci were contracted in pro-B and pre-B cells. Igh relocated from the nuclear lamina to central domains only at the pro-B cell stage, whereas, Igê remained sequestered at the lamina, and only at the pre-B cell stage located to central nuclear domains. Finally, in vitro induced re-positioning of Ig alleles away from the nuclear periphery increased germline transcription of Ig loci in pre-pro-B cells. Thus, Ig locus contraction juxtaposes genomically distant elements to mediate efficient recombination, however, sequential positioning of Ig loci away from the nuclear periphery determines stage-specific accessibility of Ig loci

Evaluation of Staphylococcus aureus Nasal Carriage Screening before Vascular Surgery

INTRODUCTION: Staphylococcus aureus is the most important pathogen in the development of surgical site infections (SSI). Patients who carry S. aureus in the nose are at increased risk for the development of SSI in cardiothoracic and orthopedic surgery. In these populations it has been shown that the risk for SSI can be substantially reduced by eradicating S. aureus carriage. For vascular surgery the relation between nasal carriage and surgical site infections has not been clearly investigated. For this reason we performed this study to analyze the relation between S. aureus nasal carriage and SSI in our vascular surgery population. METHODS: A prospective cohort study was undertaken, including all patients undergoing vascular surgery between January first 2010 and December 31th 2010. Before surgery patients were screened for S. aureus nasal carriage using a PCR technique. The presence of SSI was recorded based on criteria of the CDC. RESULTS: Screening was performed in 224. Of those, 55 (24.5%) were positive, 159 (71.0%) were negative and 10 (4.5%) were inconclusive. In the screened vascular population 4 S. aureus SSI occurred in the 55 carriers compared with 6 in 159 non-carriers (p=0.24). A stratified analysis revealed a 10-fold increased risk in nasal carriers undergoing central reconstruction surgery (3 S. aureus SSI in 20 procedures versus 1 in 65 procedures in non-carriers, p=0.039). DISCUSSION: In patients undergoing central reconstruction surgery nasals carriers are at increased risk for the development of S. aureus SSI. These patients will probably benefit from perioperative treatment to eradicate nasal carriage

Pelvic organ prolapse symptoms in relation to POPQ, ordinal stages and ultrasound prolapse assessment

Adequate staging of pelvic organ prolapse is important in clinical practice and research. The ability of the POPQ, ordinal stages and ultrasound prolapse assessment were evaluated for their ability to discriminate between women with and without prolapse symptoms. The leading edge of the predominant compartment in the three assessment systems was used for the calculation of receiver operating characteristics curves. Two hundred and sixty five (265) consecutive women were evaluated. The area under the receiver operating characteristics curve for the three staging systems ranged from 0.715 to 0.783. POPQ staging and ordinal staging performed equally well in the prediction of prolapse symptoms (p = 0.780), and both performed better as compared with ultrasound prolapse assessment (p = 0.048 and p = 0.015, respectively). Prolapse staging can equally be performed by the POPQ and ordinal stages systems as far as the discrimination between women with and without prolapse symptoms is concerned. The ultrasound prolapse assessment does not perform better as compared with these two systems

Modelling the impact of toxic and disturbance stress on white-tailed eagle (Haliaeetus albicilla) populations

Several studies have related breeding success and survival of sea eagles to toxic or non-toxic stress separately. In the present investigation, we analysed single and combined impacts of both toxic and disturbance stress on populations of white-tailed eagle (Haliaeetus albicilla), using an analytical single-species model. Chemical and eco(toxico)logical data reported from laboratory and field studies were used to parameterise and validate the model. The model was applied to assess the impact of ∑PCB, DDE and disturbance stress on the white-tailed eagle population in The Netherlands. Disturbance stress was incorporated through a 1.6% reduction in survival and a 10–50% reduction in reproduction. ∑PCB contamination from 1950 up to 1987 was found to be too high to allow the return of white-tailed eagle as a breeding species in that period. ∑PCB and population trends simulated for 2006–2050 suggest that future population growth is still reduced. Disturbance stress resulted in a reduced population development. The combination of both toxic and disturbance stress varied from a slower population development to a catastrophical reduction in population size, where the main cause was attributed to the reduction in reproduction of 50%. Application of the model was restricted by the current lack of quantitative dose–response relationships between non-toxic stress and survival and reproduction. Nevertheless, the model provides a first step towards integrating and quantifying the impacts of multiple stressors on white-tailed eagle populations

Central role of dendritic cells in pulmonary arterial hypertension in human and mice

The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3(DNGR1-KO) mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNF alpha-induced protein-3 (Tnfaip3) gene, encoding the NF-kappa B regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s). Here, we studied the involvement of dendritic cells (DCs) in PH in more detail. We found various immune cells, including DCs, in the hearts of Tnfaip3(DNGR1-KO) mice, particularly in the right ventricle (RV). Secondly, in young Tnfaip3(DNGR1-KO) mice, innate immune activation through airway exposure to toll-like receptor ligands essentially did not result in elevated RV pressures, although we did observe significant RV hypertrophy. Thirdly, PH symptoms in Tnfaip3(DNGR1-KO) mice were not enhanced by concomitant mutation of bone morphogenetic protein receptor type 2 (Bmpr2), which is the most affected gene in PAH patients. Finally, in human IPAH lung tissue we found co-localization of DCs and CD8+ T cells, representing the main cell type activated by cDC1s. Taken together, these findings support a unique role of cDC1s in PAH pathogenesis, independent of general immune activation or a mutation in the Bmpr2 gene

Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease

Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI