Leptomeningeal collaterals regulate reperfusion in ischemic stroke and rescue the brain from futile recanalization.

Recanalization is the mainstay of ischemic stroke treatment. However, even with timely clot removal, many stroke patients recover poorly. Leptomeningeal collaterals (LMCs) are pial anastomotic vessels with yet-unknown functions. We applied laser speckle imaging, ultrafast ultrasound, and two-photon microscopy in a thrombin-based mouse model of stroke and fibrinolytic treatment to show that LMCs maintain cerebral autoregulation and allow for gradual reperfusion, resulting in small infarcts. In mice with poor LMCs, distal arterial segments collapse, and deleterious hyperemia causes hemorrhage and mortality after recanalization. In silico analyses confirm the relevance of LMCs for preserving perfusion in the ischemic region. Accordingly, in stroke patients with poor collaterals undergoing thrombectomy, rapid reperfusion resulted in hemorrhagic transformation and unfavorable recovery. Thus, we identify LMCs as key components regulating reperfusion and preventing futile recanalization after stroke. Future therapeutic interventions should aim to enhance collateral function, allowing for beneficial reperfusion after stroke.

The role of leptomeningeal collaterals in redistributing blood flow during stroke.

Leptomeningeal collaterals (LMCs) connect the main cerebral arteries and provide alternative pathways for blood flow during ischaemic stroke. This is beneficial for reducing infarct size and reperfusion success after treatment. However, a better understanding of how LMCs affect blood flow distribution is indispensable to improve therapeutic strategies. Here, we present a novel in silico approach that incorporates case-specific in vivo data into a computational model to simulate blood flow in large semi-realistic microvascular networks from two different mouse strains, characterised by having many and almost no LMCs between middle and anterior cerebral artery (MCA, ACA) territories. This framework is unique because our simulations are directly aligned with in vivo data. Moreover, it allows us to analyse perfusion characteristics quantitatively across all vessel types and for networks with no, few and many LMCs. We show that the occlusion of the MCA directly caused a redistribution of blood that was characterised by increased flow in LMCs. Interestingly, the improved perfusion of MCA-sided microvessels after dilating LMCs came at the cost of a reduced blood supply in other brain areas. This effect was enhanced in regions close to the watershed line and when the number of LMCs was increased. Additional dilations of surface and penetrating arteries after stroke improved perfusion across the entire vasculature and partially recovered flow in the obstructed region, especially in networks with many LMCs, which further underlines the role of LMCs during stroke.

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.

Centre for Statistical and Methodological Excellence (CESAME): A Consortium Initiative for Improving Methodology in Randomised Clinical Trials.

When conducting randomised clinical trials, the choice of methodology and statistical analyses will influence the results. If the planned methodology is not of optimal quality and predefined in detail, there is a risk of biased trial results and interpretation. Even though clinical trial methodology is already at a very high standard, there are many trials that deliver biased results due to the implementation of inadequate methodology, poor data quality and erroneous or biased analyses. To increase the internal and external validity of randomised clinical trial results, several international institutions within clinical intervention research have formed The Centre for Statistical and Methodological Excellence (CESAME). Based on international consensus, the CESAME initiative will develop recommendations for the proper methodological planning, conduct and analysis of clinical intervention research. CESAME aims to increase the validity of randomised clinical trial results which will ultimately benefit patients worldwide across medical specialities. The work of CESAME will be performed within 3 closely interconnected pillars: (1) planning randomised clinical trials; (2) conducting randomised clinical trials; and (3) analysing randomised clinical trials.

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.

Vascular Response to Spreading Depolarization Predicts Stroke Outcome.

BACKGROUND: Cortical spreading depolarization (CSD) is a massive neuro-glial depolarization wave, which propagates across the cerebral cortex. In stroke, CSD is a necessary and ubiquitous mechanism for the development of neuronal lesions that initiates in the ischemic core and propagates through the penumbra extending the tissue injury. Although CSD propagation induces dramatic changes in cerebral blood flow, the vascular responses in different ischemic regions and their consequences on reperfusion and recovery remain to be defined. METHODS: Ischemia was performed using the thrombin model of stroke and reperfusion was induced by r-tPA (recombinant tissue-type plasminogen activator) administration in mice. We used in vivo electrophysiology and laser speckle contrast imaging simultaneously to assess both electrophysiological and hemodynamic characteristics of CSD after ischemia onset. Neurological deficits were assessed on day 1, 3, and 7. Furthermore, infarct sizes were quantified using 2,3,5-triphenyltetrazolium chloride on day 7. RESULTS: After ischemia, CSDs were evidenced by the characteristic propagating DC shift extending far beyond the ischemic area. On the vascular level, we observed 2 types of responses: some mice showed spreading hyperemia confined to the penumbra area (penumbral spreading hyperemia) while other showed spreading hyperemia propagating in the full hemisphere (full hemisphere spreading hyperemia). Penumbral spreading hyperemia was associated with severe stroke-induced damage, while full hemisphere spreading hyperemia indicated beneficial infarct outcome and potential viability of the infarct core. In all animals, thrombolysis with r-tPA modified the shape of the vascular response to CSD and reduced lesion volume. CONCLUSIONS: Our results show that different types of spreading hyperemia occur spontaneously after the onset of ischemia. Depending on their shape and distribution, they predict severity of injury and outcome. Furthermore, our data show that modulating the hemodynamic response to CSD may be a promising therapeutic strategy to attenuate stroke outcome.

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.

[Learning from coding data-surgical treatment of benign prostatic syndrome : Big data for BPS]. / Lernen aus Kodierungsdaten ­ chirurgische Behandlung des benignen Prostatasyndroms : Big Data bei N40-Diagnose.

Benign prostatic syndrome (BPS) is one of the most common urological diseases. Currently, there are numerous surgical methods to treat BPS. The digitalisation of medicine enables new study approaches in healthcare research using digital data from individual treatment pathways. In the present work, BPS-specific longitudinal trend analyses were performed. Treatment-related figures, both with regard to the therapy methods and predefined patient cohorts, could be examined after validating the datasets. This meant that information on relevant characteristics of surgical BPS treatment could be read and calculations made that reflect the overall impact of these processes. In the future, it is expected that increasingly comprehensive, higher-quality digital datasets on different clinical pictures will be available for analytical purposes. Intensification of research projects in this field is desirable. The results thus obtained enable further optimisation steps of certain treatment actions and provide important key figures for the strategy development of a medical facility.

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.

Assessing mediating effects of high-dimensional microbiome measurements in dietary intervention studies.

Habitual diet can influence health-related outcomes directly, but such effects may also be modulated indirectly by gut microbiota. We consider randomized trials and the question to what extent the effect of diet on an outcome of interest is mediated through the gut microbiome or whether there is a diet-microbiome interaction identifying subgroups of individuals who are more susceptible to specific dietary effects. The baseline microbiome by itself may be a modifier of the effects of diet on health. Yet, the high dimensionality of microbiome data requires innovative statistical approaches to identify potential mediating or moderating effects. To motivate our proposal for an appropriate analysis workflow, we consider a randomized trial that investigates the effect of a 4-week vegan diet on the diversity of gut microbiota and branched-chain amino acid metabolism in healthy omnivorous volunteers. To address the challenge of compositional microbiome data, we consider an adaptation of the lasso for penalized estimation of multivariable regression models with a large number of microbiotic taxa. This is plugged into a classical regression mediation effect analysis strategy. The interaction effects are obtained via an approach that can directly estimate them without having to deal with main effects. As a result we obtain signatures comprised of microbiotic taxa with potential mediating and moderating effects. Some taxa no longer show up as mediating, when taking moderating effects into account. Thus, the proposed analysis strategy allows to identify specific mediating effects, while avoiding potential erroneous conclusions, where moderating effects might have believed to be mediating effects.

Changes in Gut Microbiota after a Four-Week Intervention with Vegan vs. Meat-Rich Diets in Healthy Participants: A Randomized Controlled Trial.

An essential role of the gut microbiota in health and disease is strongly suggested by recent research. The composition of the gut microbiota is modified by multiple internal and external factors, such as diet. A vegan diet is known to show beneficial health effects, yet the role of the gut microbiota is unclear. Within a 4-week, monocentric, randomized, controlled trial with a parallel group design (vegan (VD) vs. meat-rich (MD)) with 53 healthy, omnivore, normal-weight participants (62% female, mean 31 years of age), fecal samples were collected at the beginning and at the end of the trial and were analyzed using 16S rRNA gene amplicon sequencing (Clinical Trial register: DRKS00011963). Alpha diversity as well as beta diversity did not differ significantly between MD and VD. Plotting of baseline and end samples emphasized a highly intra-individual microbial composition. Overall, the gut microbiota was not remarkably altered between VD and MD after the trial. Coprococcus was found to be increased in VD while being decreased in MD. Roseburia and Faecalibacterium were increased in MD while being decreased in VD. Importantly, changes in genera Coprococcus, Roseburia and Faecalibacterium should be subjected to intense investigation as markers for physical and mental health.

Use of GRADE in evidence syntheses published in high-impact-factor nutrition journals: A methodological survey.

OBJECTIVE: To identify and describe the use of the GRADE approach for rating the certainty of evidence in nutrition systematic reviews (SRs). STUDY DESIGN AND SETTING: We systematically searched for SRs using GRADE that were published between 2015 and 2019 in the 10 "nutrition" journals with the highest impact factor according to the JCR 2018. RESULTS: Out of 800 SRs, 55 SRs of randomized control trials (RCTs) and/or nonrandomized studies (NRSs) used GRADE. Forty-seven SRs (5.9%) rated the outcome specific certainty of evidence (n = 36 in 2018/2019). We identified a total of 465 certainty of evidence outcome ratings (n = 335 RCT ratings), ranging from very-low (28.8%) to low (41%), moderate (26.5%), and high (3.7%). Very-low and high certainty of evidence ratings accounted for 61.4% and 0.8% of ratings in SRs of NRSs, compared to 16.1% and 4.8% in SRs of RCTs. Certainty of evidence was downgraded mostly for risk of bias (37.8%) and imprecision (33%) in SRs of RCTs and for imprecision (32.7%), risk of bias (29.4%) and inconsistency (29%) in SRs of NRSs. CONCLUSION: Our study suggests a need for directing more attention toward strengthening acceptance of GRADE as well as building knowledge of the GRADE methodology in nutrition evidence synthesis.

Neutrophils Obstructing Brain Capillaries Are a Major Cause of No-Reflow in Ischemic Stroke.

Despite successful clot retrieval in large vessel occlusion stroke, ∼50% of patients have an unfavorable clinical outcome. The mechanisms underlying this functional reperfusion failure remain unknown, and therapeutic options are lacking. In the thrombin-model of middle cerebral artery (MCA) stroke in mice, we show that, despite successful thrombolytic recanalization of the proximal MCA, cortical blood flow does not fully recover. Using in vivo two-photon imaging, we demonstrate that this is due to microvascular obstruction of ∼20%-30% of capillaries in the infarct core and penumbra by neutrophils adhering to distal capillary segments. Depletion of circulating neutrophils using an anti-Ly6G antibody restores microvascular perfusion without increasing the rate of hemorrhagic complications. Strikingly, infarct size and functional deficits are smaller in mice treated with anti-Ly6G. Thus, we propose neutrophil stalling of brain capillaries to contribute to reperfusion failure, which offers promising therapeutic avenues for ischemic stroke.

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.

A multi-state model analysis of the time from ethical approval to publication of clinical research studies.

BACKGROUND: Results of medical research should be made publicly available in a timely manner to enable patients and health professionals to make informed decisions about health issues. We aimed to apply a multi-state model to analyze the overall time needed to publish study results, and to examine predictors of the timing of transitions within the research process from study initiation through completion/discontinuation to eventual publication. METHODS: Using a newly developed multi-state model approach, we analysed the effect of different study-related factors on each of the transitions from study approval to eventual publication, using a data set of clinical studies approved by a German research ethics committee between 2000 and 2002. RESULTS: Of 917 approved studies, 806 were included in our analyses. About half of the clinical studies which began were subsequently published as full articles, and the median time from study approval to publication was 10 years. Differences across model states were apparent; several factors were predictive of the transition from study approval to completion, while funding source and collaboration were predictive of the transition from completion to publication. CONCLUSIONS: The proposed multi-state model approach permits a more comprehensive analysis of time to publication than a simple examination of the transition from approval to publication, and thus the findings represent an advance on previous studies of this aspect of the research process.

A multi-state model based reanalysis of the Framingham Heart Study: Is dementia incidence really declining?

Recent research by Satizabal and colleagues using data from the Framingham Heart Study demonstrated a linear decline in dementia incidence since the 1970s. The aim of this study is to re-examine these findings, given concerns that bias resulted from failure to account for the probability of acquiring dementia between the last dementia-free observation and death. This analysis included 5118 persons 60+ years of age, and determined the 5-year dementia incidence during four non-overlapping epochs. In addition to a replication using Cox proportional hazards, we applied separate Cox models (given unequal hazards across epochs) and a Spline-based penalized likelihood approach based on the illness-death multi-state model. In addition, we present a simulation study demonstrating the bias associated with the use of standard survival models. The simulation showed that estimates of disease incidence derived from the multi-state model-based approach were consistent with the true disease incidence, whereas Cox regression 'censoring' observations at death or at last observation consistently underestimated it. Using the Framingham data, the 5-year age- and sex-adjusted cumulative hazard rates for dementia as derived from the multi-state model-based approach were 3.84, 2.66, 3.29 and 3.13 per 100 persons in epochs 1, 2, 3 and 4 respectively. The findings do not support the conclusion that dementia incidence has declined in the Framingham Heart Study over the given time period. Previous findings of a decline may have been an artefact resulting from improper treatment of those cases in which death precluded the observation of dementia onset.

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.