A monocentric, randomized, double-blind, controlled crossover trial of nasturtium (Tropaeolum majus) on the lipid regulator prostaglandin E2.

Scope: As prostaglandin E2 (PGE2) has important roles in physiological and inflammatory functions, a double-blind randomized controlled crossover study to investigate the potential of nasturtium (Tropaeolum majus) for modulating PGE2 was conducted, aiming at clarifying the role of benzyl isothiocyanate (BITC). As secondary parameters leukotriene 4 (LTB4), and cytokine release (tumor necrosis factor alpha, TNF-α; interleukins IL-1ß, IL-10, and IL-12) were quantified. Methods and results: Thirty-four healthy female participants consumed 1.5 g nasturtium containing BITC, (verum) or no BITC (control) twice a day for 2 weeks each. Nasturtium intervention resulted in an increase in mean PGE2 levels in serum samples (verum: 1.76-fold, p ≤ 0.05; control: 1.78-fold, p ≤ 0.01), and ex vivo stimulated peripheral blood mononuclear cells (PBMC) (verum: 1.71-fold, p ≤ 0.01; control: 1.43-fold). Using a pre-to-post responder analysis approach, 18 of 34 subjects showed a > 25% PGE2 increase in serum, while it was >25% decreased for 9 subjects (stimulated PBMC: 14 and 8 of 28, respectively). Under the selected conditions, the BITC content of nasturtium did not affect the observed changes in PGE2. Verum intervention also increased mean LTB4 serum level (1.24-fold, p ≤ 0.01), but not in LPS stimulated PBMC, and significantly increased TNF-α release in stimulated PBMC after 3 h (verum: 1.65-fold, p = 0.0032; control: 1.22-fold, p = 0.7818). No change was seen in the anti-inflammatory cytokine IL-10, or the pro-inflammatory cytokines IL-1ß, and IL-12. Conclusion: In contrast to the previously reported in vitro results, on average, LPS activated PBMC and serum from both groups showed increased PGE2 levels. Further analyses suggest that PGE2 release after intervention could possibly depend on the baseline PGE2 level. Identification of phenotypes that respond differently to the nasturtium intervention could be useful to establish personalized approaches for dosing phytopharmaceuticals medicines.

Over- and under-prescribing, and their association with functional disability in older patients at risk of further decline in Germany - a cross-sectional survey conducted as part of a randomised comparative effectiveness trial.

BACKGROUND: Older patients at risk of functional decline are frequently affected by polypharmacy. This is associated with a further loss of independence. However, a relationship between functional disability and medications, such as 'Potentially Inappropriate Medications' (PIMs) and 'Potential Prescribing Omissions' (PPOs), as itemised for (de) prescribing in practice-orientated medication lists, has yet to be established. METHODS: As part of a randomised comparative effectiveness trial, LoChro, we conducted a cross-sectional analysis of the association between PIMs and PPOs measured using the 'Screening Tool of Older Persons' Prescription Criteria / Screening Tool To Alert to Right Treatment' (STOPP/START) Version 2, with functional disability assessed using the 'World Health Organization Disability Assessment Schedule 2.0' (WHODAS). Individuals aged 65 and older at risk of loss of independence were recruited from the inpatient and outpatient departments of the local university hospital. Multiple linear regression analysis was used to model the potential prediction of functional disability using the numbers of PIMs and PPOs, adjusted for confounders including multimorbidity. RESULTS: Out of 461 patients, both the number of PIMs and the number of PPOs were significantly associated with an increase in WHODAS-score (Regression coefficients B 2.7 [95% confidence interval: 1.5-3.8] and 1.5 [95% confidence interval: 0.2-2.7], respectively). In WHODAS-score prediction modelling the contribution of the number of PIMs exceeded the one of multimorbidity (standardised coefficients beta: PIM 0.20; multimorbidity 0.13; PPO 0.10), whereas no significant association between the WHODAS-score and the number of medications was seen. 73.5 % (339) of the participants presented with at least one PIM, and 95.2% (439) with at least one PPO. The most common PIMs were proton pump inhibitors and analgesic medication, with frequent PPOs being pneumococcal and influenza vaccinations, as well as osteoporosis prophylaxis. CONCLUSIONS: The results indicate a relationship between inappropriate prescribing, both PIMs and PPOs, and functional disability, in older patients at risk of further decline. Long-term analysis may help clarify whether these patients benefit from interventions to reduce PIMs and PPOs.

Similarity of competing risks models with constant intensities in an application to clinical healthcare pathways involving prostate cancer surgery.

The recent availability of routine medical data, especially in a university-clinical context, may enable the discovery of typical healthcare pathways, that is, typical temporal sequences of clinical interventions or hospital readmissions. However, such pathways are heterogeneous in a large provider such as a university hospital, and it is important to identify similar care pathways that can still be considered typical pathways. We understand the pathway as a temporal process with possible transitions from a single initial treatment state to hospital readmission of different types, which constitutes a competing risks setting. In this article, we propose a multi-state model-based approach to uncover pathway similarity between two groups of individuals. We describe a new bootstrap procedure for testing the similarity of constant transition intensities from two competing risk models. In a large simulation study, we investigate the performance of our similarity approach with respect to different sample sizes and different similarity thresholds. The studies are motivated by an application from urological clinical routine and we show how the results can be transferred to the application example.

Data Mining in Urology: Understanding Real-world Treatment Pathways for Lower Urinary Tract Systems via Exploration of Big Data.

With an increasing number of novel therapeutic options for lower urinary tract symptoms (LUTS), the spectrum of potential treatment pathways resulting from different combinations of treatment decisions is expanding and evolving. Treatment decisions are frequently made with little or no evidence from randomized controlled trials (RCTs) and thus require evidence from other data sources. Clinical routine data reflect real-world treatment pathways. However, evidence for LUTS from routine data means that heterogeneous pathways need to be simultaneously analyzed for compiling evidence in the absence of RCTs. Statistical multi-state model approaches can provide a powerful framework for achieving this goal. More extensive statistical and methodological efforts in the area of similarity of small data are needed to enable the valid pooling of pathways towards joining evidence. PATIENT SUMMARY: Treatment decisions should rely primarily on evidence from clinical trials. When treatment for which there is limited trial evidence needs to be provided, analysis of results from routine clinical practice can represent valuable complementary evidence, but this requires integration of data from heterogeneous treatment pathways.

Comprehensive analysis of complications after transperineal prostate biopsy without antibiotic prophylaxis: results of a multicenter trial with 30 days' follow-up.

BACKGROUND: To investigate infectious and non-infectious complications after transperineal prostate biopsy (TPB) without antibiotic prophylaxis in a multicenter cohort. Secondly, to identify whether increasing the number of cores was predictive for the occurrence of complications. Thirdly, to examine the relation between TPB and erectile dysfunction. METHODS: We analyzed a retrospective multicenter cohort of 550 patients from three different urological centers undergoing TPB without antibiotic prophylaxis. The median number of cores was 26. Demographic and clinical data were extracted by reviewing patients' electronic medical records and follow-up data such as postoperative complications obtained by structured phone interviews. To investigate the influence of the number of cores taken on the occurrence of complications, we performed univariate and multivariate mixed effects logistic regression models. RESULTS: There was no case of sepsis reported. Overall, 6.0% of patients (33/550) presented with any complication besides mild macrohematuria. In all, 46/47 (98%) complications were ≤Grade 2 according to Clavien-Dindo. In multivariate regression analyses, an increased number of cores was associated with overall complications (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.02-1.14, P = 0.01) and specifically bleeding complications (OR 1.28, 95% CI 1.11-1.50, P = 0.01) but not with infectious complications (OR 1.03, 95% CI 0.97-1.10, P = 0.67). A total of 14.4% of patients referred impairment of erectile function after TPB. Of note, 98% of these men were diagnosed with prostate cancer. CONCLUSIONS: This is the first multicenter trial to investigate complications after TPB without antibiotic prophylaxis. In our study, we found no case of sepsis. This underlines the safety advantage of TPB even without antibiotic prophylaxis and supports the ongoing initiative to abandon TRB of the prostate. A higher number of cores were associated with an increase in overall complications specifically bleeding complications, but not with infectious complications. Post-biopsy erectile dysfunction was mainly present in patients diagnosed with PCa.

Evaluation of the Ginsburg Scheme: Where Is Significant Prostate Cancer Missed?

BACKGROUND: Systematic biopsy (SB) according to the Ginsburg scheme (GBS) is widely used to complement MRI-targeted biopsy (MR-TB) for optimizing the diagnosis of clinically significant prostate cancer (sPCa). Knowledge of the GBS's blind sectors where sPCa is missed is crucial to improve biopsy strategies. METHODS: We analyzed cancer detection rates in 1084 patients that underwent MR-TB and SB. Cancerous lesions that were missed or underestimated by GBS were re-localized onto a prostate map encompassing Ginsburg sectors and blind-sectors (anterior, central, basodorsal and basoventral). Logistic regression analysis (LRA) and prostatic configuration analysis were applied to identify predictors for missing sPCa with the GBS. RESULTS: GBS missed sPCa in 39 patients (39/1084, 3.6%). In 27 cases (27/39, 69.2%), sPCa was missed within a blind sector, with 17/39 lesions localized in the anterior region (43.6%). Neither LRA nor prostatic configuration analysis identified predictors for missing sPCa with the GBS. CONCLUSIONS: This is the first study to analyze the distribution of sPCa missed by the GBS. GBS misses sPCa in few men only, with the majority localized in the anterior region. Adding blind sectors to GBS defined a new sector map of the prostate suited for reporting histopathological biopsy results.

Comprehensive infectious disease screening in a cohort of unaccompanied refugee minors in Germany from 2016 to 2017: A cross-sectional study.

BACKGROUND: Information regarding the prevalence of infectious diseases (IDs) in child and adolescent refugees in Europe is scarce. Here, we evaluate a standardized ID screening protocol in a cohort of unaccompanied refugee minors (URMs) in a municipal region of southwest Germany. METHODS AND FINDINGS: From January 2016 to December 2017, we employed a structured questionnaire to screen a cohort of 890 URMs. Collecting sociodemographic information and medical history, we also performed a standardized diagnostics panel, including complete blood count, urine status, microbial stool testing, tuberculosis (TB) screening, and serologies for hepatitis B virus (HBV) and human immunodeficiency virus (HIV). The mean age was 16.2 years; 94.0% were male, and 93.6% originated from an African country. The most common health complaints were dental problems (66.0%). The single most frequent ID was scabies (14.2%). Of the 776 URMs originating from high-prevalence countries, 7.7% and 0.4% tested positive for HBV and HIV, respectively. Nineteen pathogens were detected in a total of 119 stool samples (16.0% positivity), with intestinal schistosomiasis being the most frequent pathogen (6.7%). Blood eosinophilia proved to be a nonspecific criterion for the detection of parasitic infections. Active pulmonary TB was identified in 1.7% of URMs screened. Of note, clinical warning symptoms (fever, cough >2 weeks, and weight loss) were insensitive parameters for the identification of patients with active TB. Study limitations include the possibility of an incomplete eosinophilia workup (as no parasite serologies or malaria diagnostics were performed), as well as the inherent selection bias in our cohort because refugee populations differ across Europe. CONCLUSIONS: Our study found that standardized ID screening in a URM cohort was practicable and helped collection of relevant patient data in a thorough and time-effective manner. However, screening practices need to be ameliorated, especially in relation to testing for parasitic infections. Most importantly, we found that only a minority of infections were able to be detected clinically. This underscores the importance of active surveillance of IDs among refugees.

Urinary excretion of sex steroid hormone metabolites after consumption of cow milk: a randomized crossover intervention trial.

Background: Current cow milk production practices introduce considerable levels of pregnancy hormones into the milk. Humans are exposed to these hormones when cow milk is consumed, and this may explain the observed association between cow milk consumption and several hormone-sensitive cancers. Objectives: The aim of the study was to evaluate whether cow milk consumption is associated with an increase in urinary excretion of sex steroid hormones and their metabolites in humans. Methods: We conducted a randomized crossover intervention feeding experiment. A total of 109 postmenopausal women consumed 1 L of semiskimmed milk (1.5% fat) per day for 4 d and 1 L of whole milk (3.5% fat) per day for 4 d, intersected by 4-d wash-out periods. Sex steroid hormone levels were measured in 24-h urine samples collected at the end of each intervention and wash-out period. Results: Estrogens, androgens, and progesterone were detected in the examined milk samples used for our intervention. Although a very high proportion of the estrogens were conjugated, only small proportions of the androgens and progesterone were conjugated. Milk consumption resulted in a significant increase in urinary estrone (E1) excretion, whereas estradiol (E2), estriol (E3), and 16ketoE2 excretion only increased after semiskimmed milk consumption. Urinary pregnanediol glucuronide excretion was not significantly affected. Conclusion: Cow milk consumption increases urinary excretion of E1 in humans. Ingestion of semiskimmed milk appears also to raise E2, E3, and 16ketoE2 excretion, but future studies need to confirm these associations. This trial was registered at https://www.drks.de as DRKS00003377.

Are Raw Brassica Vegetables Healthier Than Cooked Ones? A Randomized, Controlled Crossover Intervention Trial on the Health-Promoting Potential of Ethiopian Kale.

The present human intervention trial investigated the health-promoting potential of B. carinata, with a focus on effects of thermal processing on bioactivity. Twenty-two healthy subjects consumed a B. carinata preparation from raw (allyl isothiocyanate-containing) or cooked (no allyl isothiocyanate) leaves for five days in a randomized crossover design. Peripheral blood mononuclear cells were exposed to aflatoxin B1 (AFB1), with or without metabolic activation using human S9 mix, and subsequently analyzed for DNA damage using the comet assay. Plasma was analyzed for total antioxidant capacity and prostaglandin E2 (PGE2) levels. Cooked B. carinata significantly reduced DNA damage induced by AFB1 as compared to baseline levels (+S9 mix: 35%, -S9 mix: 33%, p ≤ 0.01, respectively). Raw B. carinata only reduced DNA damage by S9-activated AFB1 by 21% (p = 0.08). PGE2 plasma levels were significantly reduced in subjects after consuming raw B. carinata. No changes in plasma antioxidant capacity were detectable. A balanced diet, including raw and cooked Brassica vegetables, might be suited to fully exploit the health-promoting potential. These results also advocate the promotion of B. carinata cultivation in Eastern Africa as a measure to combat effects of unavoidable aflatoxin exposure.

Guidance in author instructions of hematology and oncology journals: A cross sectional and longitudinal study.

BACKGROUND: The debate about the value of biomedical publications led to recommendations for improving reporting quality. It is unclear to what extent these recommendations have been endorsed by journals. We analyzed whether specific recommendations were included in author instructions, which journal characteristics were associated with their endorsement, how endorsement of the domains changed and whether endorsement was associated with change of impact factor between 2010 and 2015. METHODS: We considered two study samples consisting of "Hematology" and "Oncology" journals of the Journal Citation Report 2008 and 2014, respectively. We extracted information regarding endorsement of the (1) recommendations of the International Committee of Medical Journal Editors, of (2) reporting guidelines, (3) requirement for trial registration and (4) disclosure of conflicts of interest. Data extraction was done by reading the author instructions before conducting a text search with keywords. We calculated a global generalized linear mixed effects model for endorsement of each of the four domains followed by separate multivariable logistic regression models and a longitudinal analysis. We defined endorsement as the author instructions saying that they approve the use of the recommendations. RESULTS: In 2015, the ICMJE recommendations were mentioned in author instructions of 156 journals (67.5%). CONSORT was referred to by 77 journals (33.3%); MOOSE, PRISMA, STARD and STROBE were referred to by less than 15% of journals. There were 99 journals (42.9%) that recommended or required trial registration, 211 (91.3%) required authors to disclose conflicts of interest. Journal impact factor, journal start year and geographical region were positively associated with endorsement of any of the four domains. The overall endorsement of all domains increased between 2010 and 2015. The endorsement of any domain in 2010 seemed to be associated with an increased impact factor in 2014. CONCLUSION: Hematology and oncology journals endorse major recommendations to various degrees. Endorsement is increasing slowly over time and might be positively associated with the journals' impact factor.

Pseudo-observations for competing risks with covariate dependent censoring.

Regression analysis for competing risks data can be based on generalized estimating equations. For the case with right censored data, pseudo-values were proposed to solve the estimating equations. In this article we investigate robustness of the pseudo-values against violation of the assumption that the probability of not being lost to follow-up (un-censored) is independent of the covariates. Modified pseudo-values are proposed which rely on a correctly specified regression model for the censoring times. Bias and efficiency of these methods are compared in a simulation study. Further illustration of the differences is obtained in an application to bone marrow transplantation data and a corresponding sensitivity analysis.

A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes.

Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder of immune regulation caused by defects in lymphocyte cytotoxicity. Rapid differentiation of primary, genetic forms from secondary forms of hemophagocytic lymphohistiocytosis (HLH) is crucial for treatment decisions. We prospectively evaluated the performance of degranulation assays based on surface up-regulation of CD107a on natural killer (NK) cells and cytotoxic T lymphocytes in a cohort of 494 patients referred for evaluation for suspected HLH. Seventy-five of 77 patients (97%) with FHL3-5 and 11 of 13 patients (85%) with Griscelli syndrome type 2 or Chediak-Higashi syndrome had abnormal resting NK-cell degranulation. In contrast, NK-cell degranulation was normal in 14 of 16 patients (88%) with X-linked lymphoproliferative disease and in 8 of 14 patients (57%) with FHL2, who were identified by diminished intracellular SLAM-associated protein (SAP), X-linked inhibitor of apoptosis protein (XIAP), and perforin expression, respectively. Among 66 patients with a clinical diagnosis of secondary HLH, 13 of 59 (22%) had abnormal resting NK-cell degranulation, whereas 0 of 43 had abnormal degranulation using IL-2-activated NK cells. Active disease or immunosuppressive therapy did not impair the assay performance. Overall, resting NK-cell degranulation below 5% provided a 96% sensitivity for a genetic degranulation disorder and a specificity of 88%. Therefore, degranulation assays allow a rapid and reliable classification of patients, benefiting treatment decisions.