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Objective: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES.Methods: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided.Results: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity.Conclusions: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases. Significance: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials. (C) 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Inorganic nanomaterials are often depicted as rigid structures whose shape is permanent. However, forces that are ordinarily considered weak can exert sufficient stress at the nanoscale to drive mechanical deformation. Here, we leverage van der Waals (VdW) interactions to mechanically reshape inorganic nanostructures from planar to curvilinear. Modified plate deformation theory shows that high aspect ratio 2D particles can be plastically deformed via VdW forces. Informed by this finding, silver nanoplates were deformed over spherical iron oxide template particles, resulting in distinctive bend contour patterns in bright field (BF) transmission electron microscopy (TEM) images. High resolution (HR) TEM images of deformed areas reveal the presence of highly strained bonds in the material. Finally, we show the distance between two nearby template particles allows for the engineering of several distinct curvilinear morphologies. This work challenges the traditional view of nanoparticles as static objects and introduces methods for post-synthetic mechanical shape control.

Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided. Device appraisal showed moderate digitalization readiness, with high safety and the possibility of trial implementation, but low connectivity. Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; although they reached no consensus about aspects regarding methodological biases. We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials.Graphical Abstract. Consensus Roadmap(A) Recruitment process. The study procedure started with defining the components of the research problem by the core research team. After defining the problems, two different sets of participants (the steering committee (SC) including key leaders of the field identified by the core team and the expert panel (EP) as a more diverse group of experts identified based on the number of publications based on a systematic review) were identified and were invited to participate in a Delphi study. The study facilitators (first and last authors) led the communications with the SC to design the initial questionnaire through an iterative approach. (B) Evidence synthesis: To collect the available evidence, companies producing portable tES (ptES) devices were contacted, based on the companies suggested by the SC and EP to provide details about the available devices. For mapping methodological processes of digitizing tES trials, two distinct strategies were performed and embedded into the questionnaire, namely SIPOC (Suppliers, Inputs, Process, Outputs, and Customer) and SWOT (Strengths, Weaknesses, Opportunities, and Threats) assessment were performed and embedded into the questionnaire. (C) Consensus development: In the next phase, the questionnaire was validated and finalized via collecting and summarizing opinions. Afterward, the SC and EP responded to the final questionnaire, and results were analyzed providing a list of recommendations for running tES digital trials based on a pre-registered consensus threshold.

Inorganic nanomaterials are often depicted as rigid structures whose shape is permanent. However, forces that are ordinarily considered weak can exert sufficient stress at the nanoscale to drive mechanical deformation. Here, we leverage van der Waals (VdW) interactions to mechanically reshape inorganic nanostructures from planar to curvilinear. Modified plate deformation theory shows that high aspect ratio 2D particles can be plastically deformed via VdW forces. Informed by this finding, silver nanoplates were deformed over spherical iron oxide template particles, resulting in distinctive bend contour patterns in bright field (BF) transmission electron microscopy (TEM) images. High resolution (HR) TEM images of deformed areas reveal the presence of highly strained bonds in the material. Finally, we show the distance between two nearby template particles allows for the engineering of several distinct curvilinear morphologies. This work challenges the traditional view of nanoparticles as static objects and introduces methods for post-synthetic mechanical shape control.

Liquid-phase transmission electron microscopy (LP-TEM) is a powerful characterization tool for probing the dynamics of nanometer-scale systems in a solvated environment. When the energetic electron beam (80–300 kV) interacts with the solvent, radiolysis occurs, generating highly reactive species that interact with the sample. While these species are often considered harmful and great efforts are taken to mitigate their influence, many of these radiolytic products, such as hydroxyl radicals and solvated electrons, are crucially relevant to several areas of energy research. In this Perspective, we propose a paradigm shift wherein solvent-derived, reactive radiolytic species generated by the electron beam are viewed as a tool for rational chemical perturbation of a material system rather than as a source of error to minimize. With an increased understanding of and control over the chemical kinetics governing the distribution of radiolytic species, LP-TEM is poised to allow for direct imaging of chemically dr...

The current management of severely injured patients includes damage control resuscitation strategies that minimise the use of crystalloids and emphasise earlier transfusion of red blood cells (RBC) to prevent coagulopathy. In 2012, London's air ambulance (LAA) became the first UK civilian pre-hospital service to routinely carry RBC to the trauma scene.To investigate the effect of pre-hospital RBC transfusion (phRTx) on overall blood product consumption.A retrospective trauma database study compares before implementation with after implementation of phRTx in exsanguinating trauma patients transported directly to one major trauma centre. Pre-hospital deaths were excluded. Univariate and multivariate Poisson regression analyses on data subject to multiple imputation were conducted.We included 137 and 128 patients in the before and after the implementation of phRTx groups, respectively. LAA transfused 304 RBC units (median 2, inter quartile range 1-3). We found a significant reduction in total RBC usage and reduced early use of platelets and fresh-frozen plasma (FFP) after the implementation of phRTx in both univariate (P 0·001) and multivariate analyses (P 0·001). No immediate adverse transfusion reactions were identified.Pre-hospital trauma transfusion practice is feasible and associated with overall reduced RBC, platelets and FFP consumption.

Bei der Therapie des Endometriumkarzinoms steht heute der operative Weg im Vordergrund und ermoglicht den stadiengerechten Einsatz zusatzlicher adjuvanter Masnahmen. Die Aufgabe der Diagnostik besteht darin, das operative Vorgehen moglichst individuell festzulegen. Der transvaginale Ultraschall ist eine kostengunstige, zumeist schmerz- und komplikationslose Methode in der Diagnostik des Endometriumkarzinoms. Sonographisch beurteilt werden Endometriumdicke, Echostruktur und Endometriumbegrenzung sowie – falls vorhanden – eine intrakavitare Flussigkeitsansammlung. Neben der konventionellen transvaginalen Sonographie (TVS) besteht die Moglichkeit einer Dignitatsbeurteilung mittels Farb- und Pulsdopplersonographie, z. B unter Verwendung von Pulsatility-Index und Resistance-Index. Bei der praoperativen Stadieneinteilung stellt die MRT bezuglich der Myometriuminfiltration und des zervikalen Befalls im Vergleich zu TVS und CT die praziseste Methode dar.

Significant placental insufficiency, indicated by Doppler ultrasound findings of absent or reverse end-diastolic flow velocities (AREDV), is associated with increased morbidity and mortality. Analysis of blood flow in the ductus venosus should assist in early intrauterine recognition of threatened foetuses. 58 high-risk pregnancies with umbilical AREDV were repeatedly examined (n=364). Doppler findings were correlated with neonatal signs of deterioration (ratio of normoblasts to leukocytes, pH, base excess, Apgar score), as well as short-term morbidity [need for intubation, duration of assisted respiration, evidence of respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC), intraventricular haemorrhage (IVH grade III+IV)] against the analysis of the blood flow findings (normal or increased pulsitility, absence or reverse end-diastolic flow) in the umbilical arteries (AU), the middle cerebral arteries (ACM) and ductus venosus (DV) relating these to birth weight and the duration of the pregnancy. The median period of observation was 12.8 days, 48% of the foetuses showed an abnormal ductus venosus flow and 26% an absent venous or reverse end-diastolic flow. The median date of delivery was 30 weeks, with a mean birth weight of 816 g. 93% were live births with 12% dying postnatally. Although the criteria for postnatal morbidity (BPD, NEC, IVH III+IV) and mortality did not correlate with changes in arterial and venous Doppler parameters in our group, there was a significant relationship between the normoblast count, known to be a marker of chronic hypoxia. The Apgar 10 minte score, umbilical arterial pH and base excess were correlated with changes in the DV flow curves. Healthy survival started, irrespective of arterial or venous blood flow criteria, from 27+0 weeks of pregnancy. If born between 27.0 and 30+6 weeks, the infants were more likely to be healthy the less the blood flow had been compromised. A birth weight of 590 g (sensitivity 62.5%; specificity 93.5%) and gestational age of 28+5 weeks (sensitivity 87.5%; specificity 90.3%) were shown to be cut-off points between healthy survival and survival with serious neonatal complications.

The effects of carbocyclic thromboxane A(2) (cTXA(2); 10(-6) mol L(-1)) on membrane potential and cytosolic Ca(2+) concentration were measured with the whole-cell patch-clamp or the fura-2 method, respectively, at rat myenteric ganglia. cTXA(2) caused a hyperpolarization of myenteric neurones from -19.3 +/- 2.5 to -29.3 +/- 2.3 mV. In addition, the eicosanoid potentiated the carbachol-induced depolarization from 4.2 +/- 1.0 mV under control conditions to 11.1 +/- 1.1 mV in the presence of the cTXA(2) (n = 9). The hyperpolarization was abolished by internal application of CsCl (140 mmol L(-1)), a non-selective blocker of K(+) channels, or EGTA (11 mmol L(-1)in the pipette solution), a chelator of intracellular Ca(2+). A similar inhibition was observed in the presence of charybdotoxin (10(-7) mol L(-1)). Fura-2 imaging experiments revealed a cTXA(2)-evoked increase in the intracellular Ca(2+) concentration as indicated by a rise in the fura-2 ratio signal. This response was mediated by a release of Ca(2+) from intracellular stores as sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase blockade with cyclopiazonic acid (5 x 10(-5) mol L(-1)) completely abolished the response to cTXA(2). A similar inhibition was observed after blockade of phospholipase C with U-73122 (10(-5) mol L(-1)). These results suggest an activation of Ca(2+)-activated K(+) channels by cTXA(2) after stimulation of phospholipase C.

Short-chain fatty acids produced by the bacterial fermentation of carbohydrates are present in high concentrations within the colonic lumen and have been shown to alter the excitability of enteric neurones. The present study was designed to investigate the mechanisms of butyrate-induced changes in membrane potential of myenteric neurones. Myenteric neurones from 4-10-day-old rats were isolated from the small and large intestine by an enzymatic digestion with collagenase and kept in culture. Membrane potential was measured with the whole-cell patch-clamp technique and the intracellular Ca2+ concentration was measured with the fura-2 method. The short-chain fatty acid butyrate (10-100 mmol L(-1)) induced a reversible and concentration-dependent hyperpolarization of the membrane with a half-maximal effect at 30 mmol L(-1). The hyperpolarization evoked by butyrate (50 mmol L(-1)) was strongly inhibited by charybdotoxin (10(-7) mol L(-1)), a specific blocker of Ca2+ -dependent K+ channels. The butyrate-induced hyperpolarization was resistant against blockade of phospholipase C by U-73122 (10(-5) mol L(-1)), and resistant against inclusion of heparin (6 x 10(-6) mol L(-1)), an inositol-1,4,5-trisphosphate receptor antagonist, in the patch-pipette. In contrast, ruthenium red (3 x 10(-5) mol L(-1)), an inhibitor of ryanodine receptors, significantly reduced both the hyperpolarization of the membrane as well as the increase in the intracellular Ca2+ concentration evoked by butyrate. Even in neurones permeabilized with saponin (10 mg L(-1)), butyrate was able to stimulate a release of stored intracellular Ca2+ suggesting a direct action of the short-chain fatty acid at the stores without mediation of a soluble intracellular second messenger.

Aims Tumour necrosis factor-alpha (TNF-alpha) plays a central role in the pathophysiology of inflammatory bowel disease. The present experiments were designed to characterize the action of this cytokine on enteric neurones. Methods Myenteric ganglia from newborn rats were treated for 20 h with TNF-alpha (100 ng mL(-1)) and studied with the patch-clamp technique. Results Control neurones showed a membrane potential of -34.6 +/- 2.2 mV (n = 22), whereas TNF-alpha-treated cells exhibited a membrane potential of -50.8 +/- 3.5 mV (n = 25). The depolarization evoked by carbachol (50 microm) was potentiated from 5.2 +/- 0.7 mV (n = 6) in control neurones to 27.5 +/- 2.0 mV (n = 10) in TNF-alpha-treated cells. This effect was mimicked by 1,1-dimethyl-4-phenylpiperazinium iodide, but not by bethanechol. The changes in basal membrane potential and in the nicotinic receptor response were suppressed by the non-selective cyclooxygenase (COX) inhibitor indomethacin (10 microm), and the COX II-specific inhibitor, nimesulide (100 microm), whereas the COX-I selective inhibitor SC-560 (5 microm) and the proteintyrosinekinase inhibitor genistein (50 microm) only partially inhibited the action of TNF-alpha. Staining of the ganglionic cells with an antibody against the transcription factor STAT5 revealed that TNF-alpha induced a nuclear translocation of STAT5 in non-neuronal cells. Conclusion TNF-alpha changes the electrophysiological properties of myenteric neurones via cyclooxygenase metabolites and protein tyrosine phosphorylation; the cells primarily responding to the cytokine seem to be non-neuronal cells in the ganglion culture, which respond with a nuclear STAT5 translocation suggesting an action on gene transcription.

Hierarchical temporal memory (HTM) is a biologically inspired framework that can be used to learn invariant representations of patterns in a wide range of applications. Classical HTM learning is mainly unsupervised, and once training is completed, the network structure is frozen, thus making further training (i.e., incremental learning) quite critical. In this letter, we develop a novel technique for HTM (incremental) supervised learning based on gradient descent error minimization. We prove that error backpropagation can be naturally and elegantly implemented through native HTM message passing based on belief propagation. Our experimental results demonstrate that a two-stage training approach composed of unsupervised pretraining and supervised refinement is very effective (both accurate and efficient). This is in line with recent findings on other deep architectures.

Genital findings in sexually abused prepubertal girls. Childhood sexual abuse is defined as the involvement of dependent, developmentally immature children and adolescents in sexual activities that they do not fully comprehend, to which they are unable to give informed consent or that violate the social taboos of family roles. Essential to the diagnosis of sexual abuse is an awareness of the problem and acknowledgement of its manifestations. The evaluation of the sexually abused girl usually is performed in a pediatric and adolescent gynecology outpatient department. Thus, the gynecologist will be part of a multidisciplinary approach to the problem and will need to be competent in the basic skills of history taking, physical examination, selection of laboratory tests und differential diagnosis. Findings secondary to sexual abuse are often subtle. Acute tears or bruisings are rare, because force is seldom part of sexual acts committed against a child. A vaginal opening of greater than 5 mm is not common and may indicate vaginal penetration. An intact hymen not necessarily exclude vaginal intercourse. Lack of physical evidence never rules out abuse because sexual acts may leave no physical findings. Language: de

To overcome the limitations of the state-of-the-art influenza surveillance systems in Europe, we established in 2008 a European-wide consortium aimed at introducing an innovative information and communication technology approach for a web-based surveillance system across different European countries, called Influenzanet. The system, based on earlier efforts in The Netherlands and Portugal, works with the participation of the population in each country to collect real-time information on the distribution of influenza-like illness cases through web surveys administered to volunteers reporting their symptoms (or lack of symptoms) every week during the influenza season. Such a large European-wide web-based monitoring infrastructure is intended to rapidly identify public health emergencies, contribute to understanding global trends, inform data-driven forecast models to assess the impact on the population, optimize the allocation of resources, and help in devising mitigation and containment measures. In this article, we describe the scientific and technological issues faced during the development and deployment of a flexible and readily deployable web tool capable of coping with the requirements of different countries for data collection, during either a public health emergency or an ordinary influenza season. Even though the system is based on previous successful experience, the implementation in each new country represented a separate scientific challenge. Only after more than 5 years of development are the existing platforms based on a plug-and-play tool that can be promptly deployed in any country wishing to be part of the Influenzanet network, now composed of The Netherlands, Belgium, Portugal, Italy, the UK, France, Sweden, Spain, Ireland, and Denmark.

We present the case of a female infant born prematurely at 34 weeks of gestation. Prenatally a midsized ventricular septal defect was diagnosed. Due to marked respiratory distress intubation was attempted but failed, since the tube could not be placed beyond the glottis. Oxygenation could be improved by nasopharyngeal bag ventilation. The clinical course as well as radiographic imaging was suggestive for a complete tracheal agenesis with broncho-oesophageal fistula which was confirmed at autopsy. Tracheal agenesis (TA) is a rare differential diagnosis of postnatal respiratory distress and the obstetrician or neonatologist will regularly be surprised by this malformation. Partial or complete absence of the trachea without associated malformations will be rarely diagnosed antenatally. In the case of the absence of an oesophageal fistula to the remaining airway a congenital high airway obstruction syndrome (CHAOS) ensues, leading to enlarged hyperechogenic lungs, dilated and fluid-filled trachea and bronchi and an absent tracheal flow during foetal breathing. Aetiology of TA is unknown, therapeutic options are limited thus making TA a usually fatal disorder.

Trisomy 22 is a common trisomy in spontaneous abortions. In contrast, live-born trisomy 22 is rarely seen due to severe organ malformations associated with this condition. Here, we report on a male infant with complete, non-mosaic trisomy 22 born at 35 + 5 weeks via caesarean section. Peripheral blood lymphocytes and fibroblasts showed an additional chromosome 22 in all metaphases analyzed (47,XY,+22). In addition, array CGH confirmed complete trisomy 22. The patient’s clinical features included dolichocephalus, hypertelorism, flattened nasal bridge, dysplastic ears with preauricular sinuses and tags, medial cleft palate, anal atresia, and coronary hypospadias with scrotum bipartitum. Essential treatment was implemented in close coordination with the parents. The child died 29 days after birth due to respiratory insufficiency and deterioration of renal function. Our patient’s history complements other reports illustrating that children with complete trisomy 22 may survive until birth and beyond.

From 1982 to 1993 67 diabetic women attended the University Women's Hospital obstetric clinic at Wurzburg. These women were separated into two groups: group 1 (inpatient group) delivered between 1/82 and 7/87, group 2 (outpatient group) delivered between 8/87 and 4/93. Between 1982 and 1987 we used extensive inpatient care. But did not so after 1987. The fetus was monitored by ultrasound scans, cardiotocography, oxytocin stress test and doppler measurements. Nearly all patients used home blood glucose monitoring. We compared blood glucose levels, mode of delivery and fetal outcome for the two groups. There was no significant difference in the average blood glucose levels between the two groups. Cesarean section rates (37%) and gestational age at delivery (37 weeks) were similar in both groups. Fetal macrosomia (birth weight > 4000 g) occured more frequently in the outpatient group (group l: 4%, group 2: 25%,P

The perinatal morbidity and mortality risk in monochorionic twin pregnancies are 3-5-fold increased compared to those of dichorionic twin pregnancies. Partially, this is due to the higher rate of preterm delivery but also to the twin-to-twin transfusion syndrome (TTTS). Caused by unidirectional blood flow via placental anastomoses, the TTTS leads to weight differences of more than 20% between monochorial twins. The blood donor often shows oligohydramnios, whereas the recipient shows polyhydramnios. Lewi et al. demonstrated, in a study with 202 monochorionic twin pregnancies, a 9% rate of severe TTTS. The mortality of this complication is about 90% when untreated. In contrast to the chronic TTTS, little is known about the acute intrapartal one, which is characterised by anaemia and hypovolaemia of the donor and polyglobulia of the recipient without significant weight differences between the two. In most cases, anaemia occurred after normal delivery of the first twin. Still, there are no means or signs for early detection. We describe the case of a 30-year-old primigravida with a monochorionic diamniotic twin pregnancy. During pregnancy, no evidence of TTTS could be detected. At 37 + 1 weeks gestation labour was induced with prostaglandin-containing gel. Both foetuses showed cephalic presentation. The CTG of the first twin showed a conspicuous heart rate. After labour the first twin presented with anaemia and hypovolaemic shock, the APGAR was 2/7/8. The infant's haemoglobin was 13.7 g/dL. After delivery, the second twin with APGAR 10/10/10 showed a haemoglobin of 19.6 g/dL, which is in the upper normal range. Their birth weights differed by merely 10.4%. Acute TTTS is frequently characterised by anaemia and hypovolaemia of the second twin. In our case of a monochorionic twin delivery with acute TTTS the donor was born first. Early diagnosis and neonatal intervention is essential for reducing postnatal morbidity and mortality.

Malformations of the central nervous system are among the most frequent congenital anomalies. At best, a qualified and standardised screening of the foetal brain is possible between the 18th and the 22nd week. The newly decided modification of the maternity directives envisages an extended screening upon request. This extended screening refers to the central nervous system and the representation of the ventricles, the evaluation of the head shape and the cerebellum and the back. The examination of the foetal brain should be carried out in a structured way. Three axial planes, the transventricular, the transthalamic and the transcerebellar planes, suffice to represent and measure all structures which are of importance for the screening. In case of ventricular anomalies, anomalies of the head shape, anomalies of the cerebellum and irregularities of the dorsal skin outlined in the second screening a further diagnostic procedure should be initiated. This diagnostic work-up should include a detailed neurosonography, a diagnostic evaluation of the organs and eventually further examination in the form of a caryotyping, determination of the infectology or a foetal MRI. The present article offers an overview of possible CNS abnormalities which could be recognised during the second screening according to the extended maternity directives and describes which differential diagnostics should be considered. In detail, anomalies of the head size (microcephaly, macrocephaly), of the head size (brachycephaly, dolichocephaly, cavities of the cranium, banana sign, etc.,), ventricular abnormalities, anomalies of the cerebellum (cerebellum hypoplasia, abnormal cerebellum shape) and abnormalities of the intermediate line and the intracerebral space requirements are discussed.

The current study investigates if an inductive method for the generation of ethical principles can be applied to the crucial moral question if late interruption of pregnancy due to fetal disease is ethically adequate.This method originates from the US American philosopher John Rawls and puts a group of so-called competent moral investigators in the beginning of the decision process. These competent moral investigators should be objective, tolerant and sensitive. Thus, real cases which lead to an intuitive, unanimous and clear decision of the competent moral investigators are analysed for the underlying ethical principles. The ethical principles thus detected are then applied to more complicated cases which could not be assessed clearly.In the current study, the case of foetal trisomy 18 and foetal palate cleft could be clearly judged with a yes and a no, respectively, with regard to an approval of late interruption of pregnancy. The underlying ethical principle leading to these decisions is the utilitaristic principle of minimising harm for mother and fetus.We then tried to apply this principle to a case of foetal trisomy 21, however, no clear decision for an approval or a disapproval of the interruption of pregnancy could be found as it was not possible to assess foetal interests.