Carrier-frequency specific omission-related neural activity in ordered sound sequences is independent of omission-predictability.

Regularities in our surroundings lead to predictions about upcoming events. Previous research has shown that omitted sounds during otherwise regular tone sequences elicit frequency-specific neural activity related to the upcoming but omitted tone. We tested whether this neural response is depending on the unpredictability of the omission. Therefore, we recorded magnetencephalography (MEG) data while participants listened to ordered or random tone sequences with omissions occurring either ordered or randomly. Using multivariate pattern analysis shows that the frequency-specific neural pattern during omission within ordered tone sequences occurs independent of the regularity of the omissions. These results suggest that the auditory predictions based on sensory experiences are not immediately updated by violations of those expectations.

Replacing concurrent controls with virtual control groups in rat toxicity studies.

Virtual control groups (VCGs) in nonclinical toxicity represent the concept of using appropriate historical control data for replacing concurrent control group animals. Historical control data collected from standardized studies can serve as base for constructing VCGs and legacy study reports can be used as a benchmark to evaluate the VCG performance. Replacing concurrent controls of legacy studies with VCGs should ideally reproduce the results of these studies. Based on three four-week rat oral toxicity legacy studies with varying degrees of toxicity findings we developed a concept to evaluate VCG performance on different levels: the ability of VCGs to (i) reproduce statistically significant deviations from the concurrent control, (ii) reproduce test substance-related effects, and (iii) reproduce the conclusion of the toxicity study in terms of threshold dose, target organs, toxicological biomarkers (clinical pathology) and reversibility. Although VCGs have shown a low to moderate ability to reproduce statistical results, the general study conclusions remained unchanged. Our results provide a first indication that carefully selected historical control data can be used to replace concurrent control without impairing the general study conclusion. Additionally, the developed procedures and workflows lay the foundation for the future validation of virtual controls for a use in regulatory toxicology.

Points to consider regarding the use and implementation of virtual controls in nonclinical general toxicology studies.

The replacement of a proportion of concurrent controls by virtual controls in nonclinical safety studies has gained traction over the last few years. This is supported by foundational work, encouraged by regulators, and aligned with societal expectations regarding the use of animals in research. This paper provides an overview of the points to consider for any institution on the verge of implementing this concept, with emphasis given on database creation, risks, and discipline-specific perspectives.

Direct Cochlear Recordings in Humans Show a Theta Rhythmic Modulation of Auditory Nerve Activity by Selective Attention.

The architecture of the efferent auditory system enables prioritization of strongly overlapping spatiotemporal cochlear activation patterns elicited by relevant and irrelevant inputs. So far, attempts at finding such attentional modulations of cochlear activity delivered indirect insights in humans or required direct recordings in animals. The extent to which spiral ganglion cells forming the human auditory nerve are sensitive to selective attention remains largely unknown. We investigated this question by testing the effects of attending to either the auditory or visual modality in human cochlear implant (CI) users (3 female, 13 male). Auditory nerve activity was directly recorded with standard CIs during a silent (anticipatory) cue-target interval. When attending the upcoming auditory input, ongoing auditory nerve activity within the theta range (5-8 Hz) was enhanced. Crucially, using the broadband signal (4-25 Hz), a classifier was even able to decode the attended modality from single-trial data. Follow-up analysis showed that the effect was not driven by a narrow frequency in particular. Using direct cochlear recordings from deaf individuals, our findings suggest that cochlear spiral ganglion cells are sensitive to top-down attentional modulations. Given the putatively broad hair-cell degeneration of these individuals, the effects are likely mediated by alternative efferent pathways compared with previous studies using otoacoustic emissions. Successful classification of single-trial data could additionally have a significant impact on future closed-loop CI developments that incorporate real-time optimization of CI parameters based on the current mental state of the user.SIGNIFICANCE STATEMENT The efferent auditory system in principle allows top-down modulation of auditory nerve activity; however, evidence for this is lacking in humans. Using cochlear recordings in participants performing an audiovisual attention task, we show that ongoing auditory nerve activity in the silent cue-target period is directly modulated by selective attention. Specifically, ongoing auditory nerve activity is enhanced within the theta range when attending upcoming auditory input. Furthermore, over a broader frequency range, the attended modality can be decoded from single-trial data. Demonstrating this direct top-down influence on auditory nerve activity substantially extends previous works that focus on outer hair cell activity. Generally, our work could promote the use of standard cochlear implant electrodes to study cognitive neuroscientific questions.

Can Historical Control Group Data Be Used to Replace Concurrent Controls in Animal Studies?

The availability of large amounts of high-quality control data from tightly controlled regulated animal safety data has created the idea to re-use these data beyond its classical applications of quality control, identification of treatment-related effects and assessing effect-size relevance for building virtual control groups (VCGs). While the ethical and cost-saving aspects of such a concept are immediately evident, the potential challenges need to be carefully considered to avoid any effect which could lower the sensitivity of an animal study to detect adverse events, safety thresholds, target organs, or biomarkers. In our brief communication, we summarize the current discussion regarding VCGs and propose a path forward how the replacement of concurrent control with VCGs resulting from historical data could be systematically assessed and to come to conclusions regarding the scientific value of the concept.

Radiologic image sharing among U.S. children's hospitals.

BACKGROUND: There is no streamlined approach for sharing radiologic images among medical institutions. Common methods to transfer imaging between facilities include electronic image-sharing platforms and physical media, such as compact discs (CDs). The prompt and secure transfer of imaging is vital for patient safety as demand for imaging increases. OBJECTIVE: Use a survey-based study to outline the methods and difficulties of image sharing among U.S. children's hospitals. MATERIALS AND METHODS: A multi-question survey regarding radiologic image sharing was distributed to children's hospital department chairs in the United States in August 2021. Descriptive statistical analyses of the results were performed. RESULTS: Our results reveal 78% of responding U.S. children's hospitals have an electronic image-sharing platform. Twenty-seven percent of surveyed institutions experience daily difficulties with radiologic image sharing. Most of the difficulties are with CDs (67%) and a lack of interoperability among electronic image-sharing platforms (51%). CONCLUSION: Our study identified the various methods used by U.S. children's hospitals for radiologic image sharing and quantified the ongoing challenges with these systems.

Decoding across sensory modalities reveals common supramodal signatures of conscious perception.

An increasing number of studies highlight common brain regions and processes in mediating conscious sensory experience. While most studies have been performed in the visual modality, it is implicitly assumed that similar processes are involved in other sensory modalities. However, the existence of supramodal neural processes related to conscious perception has not been convincingly shown so far. Here, we aim to directly address this issue by investigating whether neural correlates of conscious perception in one modality can predict conscious perception in a different modality. In two separate experiments, we presented participants with successive blocks of near-threshold tasks involving subjective reports of tactile, visual, or auditory stimuli during the same magnetoencephalography (MEG) acquisition. Using decoding analysis in the poststimulus period between sensory modalities, our first experiment uncovered supramodal spatiotemporal neural activity patterns predicting conscious perception of the feeble stimulation. Strikingly, these supramodal patterns included activity in primary sensory regions not directly relevant to the task (e.g., neural activity in visual cortex predicting conscious perception of auditory near-threshold stimulation). We carefully replicate our results in a control experiment that furthermore show that the relevant patterns are independent of the type of report (i.e., whether conscious perception was reported by pressing or withholding a button press). Using standard paradigms for probing neural correlates of conscious perception, our findings reveal a common signature of conscious access across sensory modalities and illustrate the temporally late and widespread broadcasting of neural representations, even into task-unrelated primary sensory processing regions.

Patient Understanding of Provider Credentials and Selection of Plastic Surgery Providers.

BACKGROUND: Many physicians who are not board-certified plastic surgeons have started performing aesthetic procedures, leading to unsafe practices that jeopardize patients' health. METHODS: Patients of a cosmetic and reconstructive private plastic surgery practice were asked to complete a survey that assessed their understanding of plastic surgeon credentials and advertising practices, and what influences their choice of a plastic surgeon. RESULTS: Eighty-five patients completed the survey, with 37.2% reporting prior aesthetic surgery; 84.9% were unaware of the lack of legal regulations governing the advertising practices of physicians. When asked if a doctor can perform surgery to improve their appearance without being a board-certified plastic surgeon, 22.1% responded "yes," 50% responded "no," and 27.9% responded "I don't know;" 98.8% reported a sense of comfort knowing their provider is board-certified in plastic surgery. When asked what factors help them decide if a surgeon is knowledgeable and trustworthy, the overwhelming majority reported referral from patients and providers as the most important factor, followed by online ratings and reviews. When deciding whether to recommend a plastic surgeon, personal experience was the most important factor. When deciding who should perform their cosmetic procedure, the most important factor was experience, followed by plastic surgery board certification. DISCUSSION: Current physician advertising practices lack strict guidelines and are often misleading. Patients would benefit from more thorough education on these practices. Of the various plastic surgeon assessment factors, most patients rely heavily on feedback obtained from patients and providers.

Identifying barriers for nature-based solutions in flood risk management: An interdisciplinary overview using expert community approach.

The major event that hit Europe in summer 2021 reminds society that floods are recurrent and among the costliest and deadliest natural hazards. The long-term flood risk management (FRM) efforts preferring sole technical measures to prevent and mitigate floods have shown to be not sufficiently effective and sensitive to the environment. Nature-Based Solutions (NBS) mark a recent paradigm shift of FRM towards solutions that use nature-derived features, processes and management options to improve water retention and mitigate floods. Yet, the empirical evidence on the effects of NBS across various settings remains fragmented and their implementation faces a series of institutional barriers. In this paper, we adopt a community expert perspective drawing upon LAND4FLOOD Natural flood retention on private land network (https://www.land4flood.eu) in order to identify a set of barriers and their cascading and compound interactions relevant to individual NBS. The experts identified a comprehensive set of 17 barriers affecting the implementation of 12 groups of NBS in both urban and rural settings in five European regional environmental domains (i.e., Boreal, Atlantic, Continental, Alpine-Carpathian, and Mediterranean). Based on the results, we define avenues for further research, connecting hydrology and soil science, on the one hand, and land use planning, social geography and economics, on the other. Our suggestions ultimately call for a transdisciplinary turn in the research of NBS in FRM.

New ideas for non-animal approaches to predict repeated-dose systemic toxicity: Report from an EPAA Blue Sky Workshop.

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a 'Blue Sky Workshop' on new ideas for non-animal approaches to predict repeated-dose systemic toxicity. The aim of the Workshop was to formulate strategic ideas to improve and increase the applicability, implementation and acceptance of modern non-animal methods to determine systemic toxicity. The Workshop concluded that good progress is being made to assess repeated dose toxicity without animals taking advantage of existing knowledge in toxicology, thresholds of toxicological concern, adverse outcome pathways and read-across workflows. These approaches can be supported by New Approach Methodologies (NAMs) utilising modern molecular technologies and computational methods. Recommendations from the Workshop were based around the needs for better chemical safety assessment: how to strengthen the evidence base for decision making; to develop, standardise and harmonise NAMs for human toxicity; and the improvement in the applicability and acceptance of novel techniques. "Disruptive thinking" is required to reconsider chemical legislation, validation of NAMs and the opportunities to move away from reliance on animal tests. Case study practices and data sharing, ensuring reproducibility of NAMs, were viewed as crucial to the improvement of non-animal test approaches for systemic toxicity.

Auditory cortical generators of the Frequency Following Response are modulated by intermodal attention.

The efferent auditory system suggests that brainstem auditory regions could also be sensitive to top-down processes. In electrophysiology, the Frequency Following Response (FFR) to speech stimuli has been used extensively to study brainstem areas. Despite seemingly straight-forward in addressing the issue of attentional modulations of brainstem regions by means of the FFR, the existing results are inconsistent. Moreover, the notion that the FFR exclusively represents subcortical generators has been challenged. We aimed to gain a more differentiated perspective on how the generators of the FFR are modulated by either attending to the visual or auditory input while neural activity was recorded using magnetoencephalography (MEG). In a first step our results confirm the strong contribution of also cortical regions to the FFR. Interestingly, of all regions exhibiting a measurable FFR response, only the right primary auditory cortex was significantly affected by intermodal attention. By showing a clear cortical contribution to the attentional FFR effect, our work significantly extends previous reports that focus on surface level recordings only. It underlines the importance of making a greater effort to disentangle the different contributing sources of the FFR and serves as a clear precaution of simplistically interpreting the FFR as brainstem response.

Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentrations.

Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (Cmax) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC10) yielded better metrics than higher toxicity thresholds (EC50); (2) compound incubation for 48 h was better than 24 h, with no further improvement of TSI after 7 days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of Cmax were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC10 and Cmax as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and the corresponding oral doses were obtained by reverse modeling. Application of this in vitro/in silico method to the rat hepatotoxicant pulegone resulted in an ADI that was similar to values previously established based on animal experiments. In conclusion, the proposed method links oral doses and blood concentrations of test compounds to the probability of hepatotoxicity.

[Which medications are safe while breastfeeding? : A synopsis for the anesthetist, obstetrician and pediatrician]. / Welche Medikamente sind in der Stillzeit erlaubt? : Eine Übersicht für den Anästhesisten, Geburtshelfer und Kinderarzt.

Pharmacokinetic data on drug administration during lactation are often inconsistent or missing. For legal reasons medicinal drug product information generally advises to interrupt breastfeeding for 24 h after medication intake. However this is not standard of care in clinical practice as the mother should be instructed to initiate breastfeeding as soon as possible after giving birth. At the same time the medication exposure over the breast milk for the newborn should be minimized. Aim of this article is to summarize pharmacokinetic data and to give important clinical information on medications frequently administered during the lactation period. As a general rule a mother can start breastfeeding following anesthesia as soon as she is able to get her baby latched on her breast.

A big data approach to the concordance of the toxicity of pharmaceuticals in animals and humans.

Although lack of efficacy is an important cause of late stage attrition in drug development the shortcomings in the translation of toxicities observed during the preclinical development to observations in clinical trials or post-approval is an ongoing topic of research. The concordance between preclinical and clinical safety observations has been analyzed only on relatively small data sets, mostly over short time periods of drug approvals. We therefore explored the feasibility of a big-data analysis on a set of 3,290 approved drugs and formulations for which 1,637,449 adverse events were reported for both humans animal species in regulatory submissions over a period of more than 70 years. The events reported in five species - rat, dog, mouse, rabbit, and cynomolgus monkey - were treated as diagnostic tests for human events and the diagnostic power was computed for each event/species pair using likelihood ratios. The animal-human translation of many key observations is confirmed as being predictive, such as QT prolongation and arrhythmias in dog. Our study confirmed the general predictivity of animal safety observations for humans, but also identified issues of such automated analyses which are on the one hand related to data curation and controlled vocabularies, on the other hand to methodological changes over the course of time.

Making reliable negative predictions of human skin sensitisation using an in silico fragmentation approach.

A previously published fragmentation method for making reliable negative in silico predictions has been applied to the problem of predicting skin sensitisation in humans, making use of a dataset of over 2750 chemicals with publicly available skin sensitisation data from 18 in vivo assays. An assay hierarchy was designed to enable the classification of chemicals within this dataset as either sensitisers or non-sensitisers where data from more than one in vivo test was available. The negative prediction approach was validated internally, using a 5-fold cross-validation, and externally, against a proprietary dataset of approximately 1000 chemicals with in vivo reference data shared by members of the pharmaceutical, nutritional, and personal care industries. The negative predictivity for this proprietary dataset was high in all cases (>75%), and the model was also able to identify structural features that resulted in a lower accuracy or a higher uncertainty in the negative prediction, termed misclassified and unclassified features respectively. These features could serve as an aid for further expert assessment of the negative in silico prediction.

Pitfalls of cannulation for extracorporeal life support: review of the literature and illustrative case presentation.

Extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) are an increasingly established advanced therapy for emerging severe lung and/or cardiocirculatory dysfunction or failure. Several reports have provided evidence for a potential benefit in prognosis by ECLS in cases of cardiogenic shock including cardiopulmonary resuscitation. Routine use in specialized centers reduces the incidence of negative side effects (e.g., vascular/ischemic, embolic, hemorrhagic, hemolytic and, furthermore, septic). Vascular complications like not only limb ischemia but also hypoxia proximal to the cannulation site up to complete sectorial hypoxia called "harlequin phenomenon" could refer to be a major adverse event in ECLS which, therefore, should be limited primarily to cardiocirculatory indications. Here we report on a case with "harlequin phenomenon" after ECLS implementation as a relevant complication of the mode of cannulation and review benefits and risks of commonly used variants of vascular access.

Travelling without a helmet: tourists' vulnerabilities and responses to disasters in Indonesia.

Tourists are particularly vulnerable when natural disasters occur in regions that they are visiting. It is assumed that they lack awareness and understanding of the actions that they need to take in such circumstances. This study examines the responses of tourists in times of disaster, building on empirical data collected through large-scale surveys conducted in Bali and Yogyakarta, Indonesia, in 2015. Both are important tourist destinations in the country that have suffered major disasters in recent years. The different types of responses to these events are framed using a grid/group analysis stemming from cultural theory. The study resulted in three key findings: (i) current disaster management planning largely follows a single rationale; (ii) tourists are not a homogeneous group, but rather a complex, diverse, and dynamic body of stakeholders; and (iii) the focus of disaster management planning should shift from a single rationale to a polyrational methodology. Disaster managers need to consider, therefore, these different aspects in the context of preparedness.

A quantitative in silico model for predicting skin sensitization using a nearest neighbours approach within expert-derived structure-activity alert spaces.

Dermal contact with chemicals may lead to an inflammatory reaction known as allergic contact dermatitis. Consequently, it is important to assess new and existing chemicals for their skin sensitizing potential and to mitigate exposure accordingly. There is an urgent need to develop quantitative non-animal methods to better predict the potency of potential sensitizers, driven largely by European Union (EU) Regulation 1223/2009, which forbids the use of animal tests for cosmetic ingredients sold in the EU. A Nearest Neighbours in silico model was developed using an in-house dataset of 1096 murine local lymph node (LLNA) studies. The EC3 value (the effective concentration of the test substance producing a threefold increase in the stimulation index compared to controls) of a given chemical was predicted using the weighted average of EC3 values of up to 10 most similar compounds within the same mechanistic space (as defined by activating the same Derek skin sensitization alert). The model was validated using previously unseen internal (n = 45) and external (n = 103) data and accuracy of predictions assessed using a threefold error, fivefold error, European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) and Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classifications. In particular, the model predicts the GHS skin sensitization category of compounds well, predicting 64% of chemicals in an external test set within the correct category. Of the remaining chemicals in the previously unseen dataset, 25% were over-predicted (GHS 1A predicted: GHS 1B experimentally) and 11% were under-predicted (GHS 1B predicted: GHS 1A experimentally). Copyright © 2017 John Wiley & Sons, Ltd.

Inhibition of Cullin-RING E3 ubiquitin ligase 7 by simian virus 40 large T antigen.

Simian virus 40 (SV40) large tumor antigen (LT) triggers oncogenic transformation by inhibition of key tumor suppressor proteins, including p53 and members of the retinoblastoma family. In addition, SV40 transformation requires binding of LT to Cullin 7 (CUL7), a core component of Cullin-RING E3 ubiquitin ligase 7 (CRL7). However, the pathomechanistic effects of LT-CUL7 interaction are mostly unknown. Here we report both in vitro and in vivo experimental evidence that SV40 LT suppresses the ubiquitin ligase function of CRL7. We show that SV40 LT, but not a CUL7 binding-deficient mutant (LT(Δ69-83)), impaired 26S proteasome-dependent proteolysis of the CRL7 target protein insulin receptor substrate 1 (IRS1), a component of the insulin and insulin-like growth factor 1 signaling pathway. SV40 LT expression resulted in the accumulation and prolonged half-life of IRS1. In vitro, purified SV40 LT reduced CRL7-dependent IRS1 ubiquitination in a concentration-dependent manner. Expression of SV40 LT, or depletion of CUL7 by RNA interference, resulted in the enhanced activation of IRS1 downstream signaling pathways phosphatidylinositol-3-kinase/AKT and Erk mitogen-activated pathway kinase, as well as up-regulation of the downstream target gene c-fos. Finally, SV40 LT-positive carcinoma of carcinoembryonic antigen 424/SV40 LT transgenic mice displayed elevated IRS1 protein levels and activation of downstream signaling. Taken together, these data suggest that SV40 LT protects IRS1 from CRL7-mediated degradation, thereby sustaining high levels of promitogenic IRS1 downstream signaling pathways.

[Education and Training in Public Health - Results of the Working Group 9 of the Forum Future Public Health, Berlin 2016]. / Lehre, Fort- und Weiterbildung in Public Health.

The need for a qualified public health workforce can only be met by appropriate provision of a wide spectrum of basic, advanced and continuing education and training programs on public health that meet international standards. At the same time, efforts must be made to offer young academics attractive career opportunities. Training in public health competences must also be provided for allied professionals in health care and for professions with influence on the determinants of health such as urban planning or agricultural science. This report from a working group meeting at the 'Public Health Zukunftsforum 2016' in Berlin presents ideas for the further development of training in public health in Germany.