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In neurocritical care, the gold standard method is intracranial pressure (ICP) monitoring for the patient's lifesaving. Since it is an invasive method, it is desirable to use an alternative, noninvasive technique. The computerized real-time invasive cerebral blood flow (CBF) autoregulation (AR) monitoring calculates the status of CBF AR, called the pressure reactivity index (PRx). Studies documented that the electrical impedance of the head (Rheoencephalography – REG) can detect the status of CBF AR (REGx) and ICP noninvasively. We aimed to test REG to reflect ICP and CBF AR.

The significant drop in estrogen levels during menopause increases the cardiovascular risks, one of which is cerebrovascular atherosclerosis. Research on rheoencephalography (REG) parameters for the early diagnosis of cerebrovascular atherosclerotic lesions is of great interest to scientists because of its ease of implementation, low cost, and non-invasiveness. The objectives of study are to evaluate the vascular tone, cerebral circulation flow in each hemisphere of the brain of menopausal women, and some associated factors through waveform characteristics and parameters in REG. A controlled cross-sectional descriptive study was conducted on a group of patients including 80 menopausal women and a control group of 46 menstruating women. All patients were measured REG in the frontal-occipital leads by VasoScreen 5000 impedance REG meter. In menopausal women, the percentage of sharp waves, the percentage of clear side waves, and the average REG were all lower than in the control group (p

Highlights • Serum biomarkers can help to distinguish benign from malignant pelvic masses • We evaluated the diagnostic value of adding HE4, CA125 and ROMA to ultrasound for detecting ovarian cancer • In stage III and IV ovarian cancer all three biomarkers showed excellent performance • ROMA and HE4 performed better than CA125 in the differential diagnosis of ovarian cancer and endometriosis

Objective The prognosis for ovarian cancer patients remains poor. A key to maximizing survival rates is early detection and treatment. This requires an accurate prediction of malignancy. Our study seeks to improve the accuracy of prediction by focusing on early subjective assessment of malignancy. We therefore investigated the assessment of patients themselves in comparison to the assessment of physicians. Methods One thousand three hundred and thirty patients participated in a prospective and multicenter study in six hospitals in Berlin. Using univariate analysis and multivariate logistic regression models, we measured the accuracy of the early subjective assessment in comparison to the final histological outcome. Moreover, we investigated factors related to the assessment of patients and physicians. Results The patients’ assessment of malignancy is remarkably accurate. With a positive predictive value of 58%, the majority of patients correctly assessed a pelvic mass as malignant. With more information available, physicians achieved only a slightly more accurate prediction of 63%. Conclusions For the first time, our study considered subjective factors in the diagnostic process of pelvic masses. This paper demonstrates that the patients’ personal assessment should be taken seriously as it can provide a significant contribution to earlier diagnosis and thus improved therapy and overall prognosis.

Ordinary differential equation (ODE) models are widely used to understand multiple processes. Here the authors show how the concept of mini-batch optimization can be transferred from the field of Deep Learning to ODE modelling.

Extracellular vesicles such as exosomes are small-sized, bilayered extracellular biovesicles generated by almost every cell and released into the surrounding body fluids upon the fusion of multivesicular bodies and the plasma membrane. Based on their origin, they are enriched with a variety of biologically active components including proteins, lipids, nucleic acids, cellular metabolites, and many other constituents. They can either attach or fuse with the membrane of a target cell, or alternatively be taking up via endocytosis by a recipient cell. In particular, milk exosomes have been recently shown to be a fundamental factor supporting infant growth, health, and development. In addition, exosomes derived from different cell types have been shown to possess regenerative, immunomodulatory, and anti-inflammatory properties, suggesting that they are a potential therapeutic tool in modulating the pathogenesis of diverse diseases. Therefore, efficient protocols for the isolation of milk exosomes in a high quantity and purity are the basis for establishing clinical applications. Here, we present an easy-to-follow protocol for exosome isolation from bovine and human milk. Electron microscopic analysis and nanoparticle tracking analysis reveal that the protocols allow the isolation of highly enriched fractions of exosomes. The purified exosomes express the typical exosomal protein markers, CD81 and ALIX.

Positive end-expiratory pressure (PEEP) is a respiratory/ventilation procedure that is used to maintain or improve breathing in clinical and experimental cases that exhibit impaired lung function. Body fluid shift movement is not monitored during PEEP application in intensive care units (ICU), which would be interesting specifically in hypotensive patients. Brain injured and hypotensive patients are known to have compromised cerebral blood flow (CBF) autoregulation (AR) but currently, there is no non-invasive way to assess the risk of implementing a hypotensive resuscitation strategy and PEEP use in these patients.

The clustering of platelet glycoprotein receptors with cytosolic YxxL and YxxM motifs, including GPVI, CLEC-2 and PEAR1, triggers activation via phosphorylation of the conserved tyrosine residues and recruitment of the tandem SH2 (Src homology 2) domain effector proteins, Syk and PI 3-kinase. We have modelled the clustering of these receptors with monovalent, divalent and tetravalent soluble ligands and with transmembrane ligands based on the law of mass action using ordinary differential equations and agent-based modelling. The models were experimentally evaluated in platelets and transfected cell lines using monovalent and multivalent ligands, including novel nanobody-based divalent and tetravalent ligands, by fluorescence correlation spectroscopy. Ligand valency, receptor number, receptor dimerisation, receptor phosphorylation and a cytosolic tandem SH2 domain protein act in synergy to drive receptor clustering. Threshold concentrations of a CLEC-2-blocking antibody and Syk inhibitor act in synergy to block platelet aggregation. This offers a strategy for countering the effect of avidity of multivalent ligands and in limiting off-target effects.

This paper describes a new combined impedance plethysmographic (IPG) and electrical bioimpedance spectroscopic (BIS) instrument and software that will allow noninvasive real-time measurement of segmental blood flow, intracellular, interstitial, and intravascular volume changes during various fluid management procedures. The impedance device can be operated either as a fixed frequency IPG for the quantification of segmental blood flow and hemodynamics or as a multi-frequency BIS for the recording of intracellular and extracellular resistances at 40 discrete input frequencies. The extracellular volume is then deconvoluted to obtain its intravascular and interstitial component volumes as functions of elapsed time. The purpose of this paper is to describe this instrumentation and to demonstrate the information that can be obtained by using it to monitor segmental compartment volume responses of a pig model during simulated hemorrhage and resuscitation. Such information may prove valuable in the diagnosis and management of rapid changes in the body fluid balance and various clinical treatments.

Neuromonitoring is performed to prevent further (secondary) brain damage by detecting low brain blood flow following a head injury, stroke or neurosurgery. This comparative neuromonitoring study is part of an ongoing investigation of brain bioimpedance (rheoencephalography-REG) as a measuring modality for use in both civilian and military medical settings, such as patient transport, emergency care and neurosurgery intensive care. In a previous animal study, we validated that REG detects cerebral blood flow autoregulation (CBF AR), the body’s physiological mechanism that protects the brain from adverse effects of low brain blood flow (hypoxia/ischemia). In the current descriptive pig study, the primary goal was to compare measurements of CBF AR made with REG to measurements made with other neuromonitoring modalities: laser Doppler flow (LDF); intracranial pressure (ICP); absolute CBF; carotid flow (CF); and systemic arterial pressure (SAP). Challenges administered to anesthetized pigs were severe induced hemorrhage (bleeding) and resuscitation; CO2 inhalation; and positive end expiratory pressure (PEEP). Data were stored on a computer and processed offline. After hemorrhage, the loss of CBF AR was detected by REG, ICP, and CF, all of which passively followed systemic arterial SAP after bleeding. Loss of CBF AR was the earliest indicator of low brain blood flow: loss of CBF AR occurred before a decrease in cardiac output, which is the cardiovascular response to hemorrhage. A secondary goal of this study was to validate the usefulness of new automated data processing software developed to detect the status of CBF AR. Both the new automated software and the traditional (observational) evaluation indicated the status of CBF AR. REG indicates the earliest breakdown of CBF AR; cessation of EEG for 2 seconds and respiration would be used as additional indicators of loss of CBF AR. The clinical significance of this animal study is that REG shows potential for use as a noninvasive, continuous and non-operator dependent neuromonitor of CBF AR in both civilian and military medical settings. Human validation studies of neuromonitoring with REG are currently in progress.

In neurosurgery intensive care units, cerebrovascular reactivity tests for neuromonitoring are used to evaluate the status of cerebral blood flow autoregulation; lack of autoregulation indicates a poor patient outcome. The goal of neuromonitoring is to prevent secondary injuries following a primary central nervous system injury, when the brain is vulnerable to further compromise due to hypoxia, ischemia and disturbances in cerebral blood flow and intracranial pressure. Ideally, neuromonitoring would be noninvasive and continuous. This study compares cerebrovascular reactivity monitored by rheoencephalography, a noninvasive continuous monitoring modality, to cerebrovascular reactivity measured by currently used neuromonitoring modalities: transcranial Doppler, near infrared spectroscopy and laser Doppler flowmetry. Fourteen healthy volunteer subjects were measured. The tests used for comparison of cerebrovascular reactivity were breath-holding, hyperventilation, CO2 inhalation, the Valsalva maneuver, and the Trendelenburg and reverse Trendelenburg positions. Data for all modalities measured were recorded by computers and processed off line. All measured modalities reflected cerebrovascular reactivity with variabilities. Breath-holding, CO2 inhalation, and the Valsalva maneuver caused CO2 increase and consequent brain vasodilatation; hyperventilation caused CO2 decrease and brain vasoconstriction. The Trendelenburg and reverse Trendelenburg positions caused extracranial blood volume changes, which masked intracranial cerebrovascular reactivity. The hyperventilation test proved ineffective for measuring cerebrovascular reactivity with rheoencephalography due to respiratory artifacts. Some discrepancies among the

This article analyses the violence that broke out at a 1965 Rolling Stones concert in West Berlin. In a close reading of records from the Berlin Police archives, it understands the events at the concert as the combined result of a lack of experience with new cultural forms of expression, old-fashioned ideas of ‘order’ deeply rooted in German history, and logistical failures. Analysing the aftermath of the concert, the article demonstrates how not only the event itself, but also the effects of rock music in general and the state of post-war youth, were discussed extensively in the media and even in a political debate at the Berlin city parliament. As a result, police reforms and new safety standards for concert halls and arenas were developed and internationally debated. Therefore, the article suggests considering the mid-sixties as a watershed (‘Schwellenzeit’) in the process establishing a new rock and pop culture.

Measuring brain electrical impedance (rheoencephalography) is a potential technique for noninvasive, continuous neuro-monitoring of cerebral blood flow autoregulation in humans. In the present rat study, we compared changes in cerebral blood flow autoregulation during CO2 inhalation measured by rheoencephalography to changes measured by laser Doppler flowmetry, an invasive continuous monitoring modality. Our hypothesis was that both modalities would reflect cerebral blood flow autoregulation.

The article analyses the violence that broke out at a concert of the Rolling Stones in 1965 West-Berlin. In a close reading of records from the Berlin Police archives the article understands the actions at the concert as a result of lacking experience with new cultural forms of expression, old-fashioned ideas of “order” rooting deep in German history as well as logistical failures. Analyzing the aftermath of the concert, the article demonstrates how not only the event itself, but also the effects of rock music in general and the state of post-war youth was discussed extensively in the media and even in a political debate at the Berlin city parliament. As a result, police reforms and new safety standards for concert halls and arenas were developed and internationally debated. Therefore, the article suggests to regard the mid-sixties as a watershed (« Schwellenzeit ») in the process of the establishment of a new rock and pop culture.

Science advances through rich, scholarly discussion. More than ever before, digital tools allow us to take that dialogue online. To chart a new future for open publishing, we must consider alternatives to the core features of the legacy print publishing system, such as an access paywall and editorial selection before publication. Although journals have their strengths, the traditional approach of selecting articles before publication ("curate first, publish second") forces a focus on "getting into the right journals," which can delay dissemination of scientific work, create opportunity costs for pushing science forward, and promote undesirable behaviors among scientists and the institutions that evaluate them. We believe that a "publish first, curate second" approach with the following features would be a strong alternative: authors decide when and what to publish; peer review reports are published, either anonymously or with attribution; and curation occurs after publication, incorporating community feedback and expert judgment to select articles for target audiences and to evaluate whether scientific work has stood the test of time. These proposed changes could optimize publishing practices for the digital age, emphasizing transparency, peer-mediated improvement, and post-publication appraisal of scientific articles.

Every patient and every disease is different. Each patient therefore requires a personalized treatment approach. For technical reasons, a personalized approach is feasible for treatment strategies such as surgery, but not for drug-based therapy or drug development. The development of individual mechanistic models of the disease process in every patient offers the possibility of attaining truly personalized drug-based therapy and prevention. The concept of virtual clinical trials and the integrated use of in silico, in vitro, and in vivo models in preclinical development could lead to significant gains in efficiency and order of magnitude increases in the cost effectiveness of drug development and approval. We have developed mechanistic computational models of large-scale cellular signal transduction networks for prediction of drug effects and functional responses, based on patient-specific multi-level omics profiles. However, a major barrier to the use of such models in a clinical and developmental context is the reliability of predictions. Here we detail how the approach of using “models of models” has the potential to impact cancer treatment and drug development. We describe the iterative refinement process that leverages the flexibility of experimental systems to generate highly dimensional data, which can be used to train and validate computational model parameters and improve model predictions. In this way, highly optimized computational models with robust predictive capacity can be generated. Such models open up a number of opportunities for cancer drug treatment and development, from enhancing the design of experimental studies, reducing costs, and improving animal welfare, to increasing the translational value of results generated.

During the past decade, piezo-resistive cantilever type silicon microprobes for high-speed roughness measurements inside high-aspect-ratio microstructures, like injection nozzles or critical gas nozzles have been developed. This article summarizes their metrological properties for fast roughness and shape measurements including noise, damping, tip form, tip wear, and probing forces and presents the first results on the measurement of mechanical surface parameters. Due to the small mass of the cantilever microprobes, roughness measurements at very high traverse speeds up to 15 mm/s are possible. At these high scanning speeds, considerable wear of the integrated silicon tips was observed in the past. In this paper, a new tip-testing artefact with rectangular grooves of different width was used to measure this wear and to measure the tip shape, which is needed for morphological filtering of the measured profiles and, thus, for accurate form measurements. To reduce tip wear, the integrated silicon tips were replaced by low-wear spherical diamond tips of a 2 µm radius. Currently, a compact microprobe device with an integrated feed-unit is being developed for high-speed roughness measurements on manufacturing machines. First measurements on sinusoidal artefacts were carried out successfully. Moreover, the first measurements of the elastic modulus of a polymer surface applying the contact resonance measurement principle are presented, which indicates the high potential of these microprobes for simultaneous high-speed roughness and mechanical parameter measurements.

This article presents an overview of rheoencephalography (REG) – electrical impedance measurements of the brain – and summarizes past and ongoing research to develop medical applications of REG for neuro-critical care and for primary prevention of stroke and cardiovascular disease. The availability of advanced electronics and computation has opened up the potential for use of REG technology as a noninvasive, continuous and inexpensive brain monitor for military and civilian applications. The clinical background information presented here introduces physiological and clinical environments where REG has potential for use in research and clinical settings.

Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction.

Despite a growing body of knowledge on the mechanisms underlying the onset and progression of cancer, treatment success rates in oncology are at best modest. Current approaches use statistical methods that fail to embrace the inherent and expansive complexity of the tumor/patient/drug interaction. Computational modeling, in particular mechanistic modeling, has the power to resolve this complexity. Using fundamental knowledge on the interactions occurring between the components of a complex biological system, large-scale in silico models with predictive capabilities can be generated. Here, we describe how mechanistic virtual patient models, based on systematic molecular characterization of patients and their diseases, have the potential to shift the theranostic paradigm for oncology, both in the fields of personalized medicine and targeted drug development. In particular, we highlight the mechanistic modeling platform ModCell™ for individualized prediction of patient responses to treatment, emphasizing modeling techniques and avenues of application.

The k-means method is the method of choice for clustering large-scale data sets and it performs exceedingly well in practice despite its exponential worst-case running-time. To narrow the gap between theory and practice, k-means has been studied in the semi-random input model of smoothed analysis, which often leads to more realistic conclusions than mere worst-case analysis. For the case that n data points in Rd are perturbed by Gaussian noise with standard deviation σ, it has been shown that the expected running-time is bounded by a polynomial in n and 1/σ. This result assumes that squared Euclidean distances are used as the distance measure.In many applications, however, data is to be clustered with respect to Bregman divergences rather than squared Euclidean distances. A prominent example is the Kullback-Leibler divergence (a.k.a. relative entropy) that is commonly used to cluster web pages. To broaden the knowledge about this important class of distance measures, we analyze the running-time of the k-means method for Bregman divergences. We first give a smoothed analysis of k-means with (almost) arbitrary Bregman divergences, and we show bounds of poly(n√k, 1/σ) and kkd·poly(n, 1/σ). The latter yields a polynomial bound if k and d are small compared to n. On the other hand, we show that the exponential lower bound carries over to a huge class of Bregman divergences.