Pelvic floor muscle function in a general female population in relation with age and parity and the relation between voluntary and involuntary contractions of the pelvic floor musculature

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Topographic staging of tau positron emission tomography images

Introduction: It has been proposed that the signal distribution on tau positron emission tomography (PET) images could be used to define pathologic stages similar to those seen in neuropathology. Methods: Three topographic staging schemes for tau PET, two sampling the temporal and occipital subregions only and one sampling cortical gray matter across the major brain lobes, were evaluated on flortaucipir F 18 PET images in a test-retest scenario and from Alzheimer's Disease Neuroimaging Initiative 2. Results: All three schemes estimated stages that were significantly associated with amyloid status and when dichotomized to tau positive or negative were 90% to 94% concordant in the populations identified. However, the schemes with fewer regions and simpler decision rules yielded more robust performance in terms of fewer unclassified scans and increased test-retest reproducibility of assigned stage. Discussion: Tau PET staging schemes could be useful tools to concisely index the regional involvement of tau pathology in living subjects. Simpler schemes may be more robust

Prediction models for development of retinopathy in people with type 2 diabetes:systematic review and external validation in a Dutch primary care setting

Aims/hypothesis: The aims of this study were to identify all published prognostic models predicting retinopathy risk applicable to people with type 2 diabetes, to assess their quality and accuracy, and to validate their predictive accuracy in a head-to-head comparison using an independent type 2 diabetes cohort. Methods: A systematic search was performed in PubMed and Embase in December 2019. Studies that met the following criteria were included: (1) the model was applicable in type 2 diabetes; (2) the outcome was retinopathy; and (3) follow-up was more than 1 year. Screening, data extraction (using the checklist for critical appraisal and data extraction for systemic reviews of prediction modelling studies [CHARMS]) and risk of bias assessment (by prediction model risk of bias assessment tool [PROBAST]) were performed independently by two reviewers. Selected models were externally validated in the large Hoorn Diabetes Care System (DCS) cohort in the Netherlands. Retinopathy risk was calculated using baseline data and compared with retinopathy incidence over 5 years. Calibration after intercept adjustment and discrimination (Harrell’s C statistic) were assessed. Results: Twelve studies were included in the systematic review, reporting on 16 models. Outcomes ranged from referable retinopathy to blindness. Discrimination was reported in seven studies with C statistics ranging from 0.55 (95% CI 0.54, 0.56) to 0.84 (95% CI 0.78, 0.88). Five studies reported on calibration. Eight models could be compared head-to-head in the DCS cohort (N = 10,715). Most of the models underestimated retinopathy risk. Validating the models against different severities of retinopathy, C statistics ranged from 0.51 (95% CI 0.49, 0.53) to 0.89 (95% CI 0.88, 0.91). Conclusions/interpretation: Several prognostic models can accurately predict retinopathy risk in a population-based type 2 diabetes cohort. Most of the models include easy-to-measure predictors enhancing their applicability. Tailoring retinopathy screening frequency based on accurate risk predictions may increase the efficiency and cost-effectiveness of diabetic retinopathy care. Registration: PROSPERO registration ID CRD42018089122

Performance of prediction models for nephropathy in people with type 2 diabetes:systematic review and external validation study

OBJECTIVES To identify and assess the quality and accuracy of prognostic models for nephropathy and to validate these models in external cohorts of people with type 2 diabetes. DESIGN Systematic review and external validation. DATA SOURCES PubMed and Embase. ELIGIBILITY CRITERIA Studies describing the development of a model to predict the risk of nephropathy, applicable to people with type 2 diabetes. METHODS Screening, data extraction, and risk of bias assessment were done in duplicate. Eligible models were externally validated in the Hoorn Diabetes Care System (DCS) cohort (n=11 450) for the same outcomes for which they were developed. Risks of nephropathy were calculated and compared with observed risk over 2, 5, and 10 years of follow-up. Model performance was assessed based on intercept adjusted calibration and discrimination (Harrell's C statistic). RESULTS 41 studies included in the systematic review reported 64 models, 46 of which were developed in a population with diabetes and 18 in the general population including diabetes as a predictor. The predicted outcomes included albuminuria, diabetic kidney disease, chronic kidney disease (general population), and end stage renal disease. The reported apparent discrimination of the 46 models varied considerably across the different predicted outcomes, from 0.60 (95% confidence interval 0.56 to 0.64) to 0.99 (not available) for the models developed in a diabetes population and from 0.59 (not available) to 0.96 (0.95 to 0.97) for the models developed in the general population. Calibration was reported in 31 of the 41 studies, and the models were generally well calibrated. 21 of the 64 retrieved models were externally validated in the Hoorn DCS cohort for predicting risk of albuminuria, diabetic kidney disease, and chronic kidney disease, with considerable variation in performance across prediction horizons and models. For all three outcomes, however, at least two models had C statistics >0.8, indicating excellent discrimination. In a secondary external validation in GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland), models developed for diabetic kidney disease outperformed those for chronic kidney disease. Models were generally well calibrated across all three prediction horizons. CONCLUSIONS This study identified multiple prediction models to predict albuminuria, diabetic kidney disease, chronic kidney disease, and end stage renal disease. In the external validation, discrimination and calibration for albuminuria, diabetic kidney disease, and chronic kidney disease varied considerably across prediction horizons and models. For each outcome, however, specific models showed good discrimination and calibration across the three prediction horizons, with clinically accessible predictors, making them applicable in a clinical setting. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42020192831.Molecular Epidemiolog

Intestinal Obstruction Syndromes in Cystic Fibrosis: Meconium Ileus, Distal Intestinal Obstruction Syndrome, and Constipation

Meconium ileus at birth, distal intestinal obstruction syndrome (DIOS), and constipation are an interrelated group of intestinal obstruction syndromes with a variable severity of obstruction that occurs in cystic fibrosis patients. Long-term follow-up studies show that today meconium ileus is not a risk factor for impaired nutritional status, pulmonary function, or survival. DIOS and constipation are frequently seen in cystic fibrosis patients, especially later in life; genetic, dietary, and other associations have been explored. Diagnosis of DIOS is based on suggestive symptoms, with a right lower quadrant mass confirmed on abdominal radiography, whereas symptoms of constipation are milder and of longer standing. In DIOS, early aggressive laxative treatment with oral laxatives (polyethylene glycol) or intestinal lavage with balanced osmotic electrolyte solution and rehydration is required, which now makes the need for surgical interventions rare. Constipation can generally be well controlled with polyethylene glycol maintenance treatment

The prevalence of pelvic organ prolapse symptoms and signs and their relation with bladder and bowel disorders in a general female population

Contains fulltext : 81191.pdf (publisher's version ) (Closed access)INTRODUCTION AND HYPOTHESIS: In selected populations, pelvic organ prolapse (POP) was associated with bladder/bowel symptoms, but data on the general female population are lacking. Our aim was to obtain normative data on the prevalence of POP and pelvic floor dysfunction (PFD) symptoms and signs and to identify associations. METHODS: Validated questionnaires on POP and PFD (urogenital distress inventory, (UDI) and defaecation distress inventory (DDI)) were sent to a general population of 2,979 women (aged 45-85 years). Data were analysed using the Kruskal-Wallis test, chi square test and Spearman's rank correlation coefficient. RESULTS: Response rate was 62.7%. Associations between POP stage and parity (0.002) and vaginal bulging (<0.001) are significant. Anatomical locations of POP and PFD symptoms correlated significantly with incontinence of flatus, feeling anal prolapse, manual evacuation of stool, vaginal bulging, constipation and pain during faecal urge (p < or = 0.005). CONCLUSIONS: Strategies should be developed to alleviate obstructive bowel disorders associated with POP

Differences in bioactivity between human insulin and insulin analogues approved for therapeutic use- compilation of reports from the past 20 years

In order to provide comprehensive information on the differences in bioactivity between human insulin and insulin analogues, published in vitro comparisons of human insulin and the rapid acting analogues insulin lispro (Humalog®), insulin aspart ( NovoRapid®), insulin glulisine (Apidra®), and the slow acting analogues insulin glargine (Lantus®), and insulin detemir (Levemir®) were gathered from the past 20 years (except for receptor binding studies). A total of 50 reports were retrieved, with great heterogeneity among study methodology. However, various differences in bioactivity compared to human insulin were obvious (e.g. differences in effects on metabolism, mitogenesis, apoptosis, intracellular signalling, thrombocyte function, protein degradation). Whether or not these differences have clinical bearings (and among which patient populations) remains to be determined

Lovastatin Inhibits VEGFR and AKT Activation: Synergistic Cytotoxicity in Combination with VEGFR Inhibitors

BACKGROUND: In a recent study, we demonstrated the ability of lovastatin, a potent inhibitor of mevalonate synthesis, to inhibit the function of the epidermal growth factor receptor (EGFR). Lovastatin attenuated ligand-induced receptor activation and downstream signaling through the PI3K/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in a variety of tumor derived cell lines. The vascular endothelial growth factor receptor (VEGFR) and EGFR share similar activation, internalization and downstream signaling characteristics. METHODOLOGY/PRINCIPAL FINDINGS: The VEGFRs, particularly VEGFR-2 (KDR, Flt-1), play important roles in regulating tumor angiogenesis by promoting endothelial cell proliferation, survival and migration. Certain tumors, such as malignant mesothelioma (MM), also express both the VEGF ligand and VEGFRs that act in an autocrine loop to directly stimulate tumor cell growth and survival. In this study, we have shown that lovastatin inhibits ligand-induced VEGFR-2 activation through inhibition of receptor internalization and also inhibits VEGF activation of AKT in human umbilical vein endothelial cells (HUVEC) and H28 MM cells employing immunofluorescence and Western blotting. Combinations of lovastatin and a VEGFR-2 inhibitor showed more robust AKT inhibition than either agent alone in the H28 MM cell line. Furthermore, combining 5 µM lovastatin treatment, a therapeutically relevant dose, with two different VEGFR-2 inhibitors in HUVEC and the H28 and H2052 mesothelioma derived cell lines demonstrated synergistic cytotoxicity as demonstrated by MTT cell viability and flow cytometric analyses. CONCLUSIONS/SIGNIFICANCE: These results highlight a novel mechanism by which lovastatin can regulate VEGFR-2 function and a potential therapeutic approach for MM through combining statins with VEGFR-2 inhibitors

Vaginal noise: prevalence, bother and risk factors in a general female population aged 45–85 years

Item does not contain fulltextINTRODUCTION AND HYPOTHESIS: Vaginal noise (VN) is a symptom of pelvic floor (PF) dysfunction and has been described in a few studies. No other risk factors have been described besides parity and pelvic organ prolapse (POP). Underlying mechanisms of VN are unclear. Aims of this study were to describe prevalence, bother and relation between VN and PF (muscle)(dys)function. METHODS: A cross-sectional study was performed on a general population of 2,921 women (aged 45-85 years). Questionnaires were filled in by 1,397 women, and 800 were selected at random to undergo vaginal examination for POP Quantification and PF muscle function assessment. Chi-square tests, Student's t test and multivariate logistic regression were performed (P < 0.05). RESULTS: Response rate was 62.7%. Prevalence of VN was 12.8%; 72.1% reported only a little bother. Odds ratios for parity and solid stool were high. CONCLUSIONS: VN was strongly related to many symptoms of pelvic floor dysfunction, but it was only causing a little bother

Additive Anti-Tumor Effects of Lovastatin and Everolimus In Vitro through Simultaneous Inhibition of Signaling Pathways

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThis work was supported by a research grant from the Ludwig-Maximilians University of Munich (Förderprogramm für Forschung und Lehre [FöFoLe], grant number 865/829)