The human tickle response and mechanisms of self-tickle suppression.

A tickle is a complex sensation: it occurs in response to touch but not unequivocally so, and makes us laugh albeit not when we self-tickle. We quantified human ticklishness by means of physiological, visual and acoustic measures alongside subjective reports, and assessed mechanisms of self-tickle suppression. Tickle responses arose faster than previously reported as changes in thoracic circumference and joyous facial expressions co-emerge approximately 300 ms after tickle onset and are followed by vocalizations starting after an additional 200 ms. The timing and acoustic properties of vocalizations tightly correlated with subjective reports: the faster, louder and higher-pitched participants laughed, the stronger they rated the experienced ticklishness. Externally evoked ticklishness is reduced by simultaneous self-tickling, whereby self-touch evokes stronger suppression than sole self-tickle movement without touch. We suggest that self-tickle suppression can be understood as broad attenuation of sensory temporally coincident inputs. Our study provides new insight on the nature of human ticklishness and the attenuating effects of self-tickling. This article is part of the theme issue 'Cracking the laugh code: laughter through the lens of biology, psychology and neuroscience'.

Recommendations on compiling test datasets for evaluating artificial intelligence solutions in pathology.

Artificial intelligence (AI) solutions that automatically extract information from digital histology images have shown great promise for improving pathological diagnosis. Prior to routine use, it is important to evaluate their predictive performance and obtain regulatory approval. This assessment requires appropriate test datasets. However, compiling such datasets is challenging and specific recommendations are missing. A committee of various stakeholders, including commercial AI developers, pathologists, and researchers, discussed key aspects and conducted extensive literature reviews on test datasets in pathology. Here, we summarize the results and derive general recommendations on compiling test datasets. We address several questions: Which and how many images are needed? How to deal with low-prevalence subsets? How can potential bias be detected? How should datasets be reported? What are the regulatory requirements in different countries? The recommendations are intended to help AI developers demonstrate the utility of their products and to help pathologists and regulatory agencies verify reported performance measures. Further research is needed to formulate criteria for sufficiently representative test datasets so that AI solutions can operate with less user intervention and better support diagnostic workflows in the future.

Efficiency of a 15-Week Weight-Loss Program, Including a Low-Calorie Formula Diet, on Glycemic Control in Patients with Type 2 Diabetes Mellitus and Overweight or Obesity.

INTRODUCTION: Patients who are overweight or obese have an increased risk of developing type 2 diabetes mellitus (T2DM). Weight loss can have a positive effect on glycemic control. OBJECTIVE: We aimed to investigate glycemic control in patients with T2DM and overweight or obesity during a structured weight-loss program. METHODS: This was a prospective, interventional study. We recruited 36 patients (14 men and 22 women) with a median age of 58.5 years and median body mass index (BMI) of 34.1, to a 15-week structured weight-loss program with a low-calorie (800 kcal) formula diet for 6 weeks. The primary end point, HbA1c level, and secondary end points, anthropometric data, medication, and safety, were assessed weekly. Laboratory values and quality of life were assessed at baseline and after 15 weeks. RESULTS: HbA1c decreased from 7.3% at baseline to 6.5% at 15 weeks (p < 0.001), median body weight by 11.9 kg (p < 0.001), median BMI by 4.3 (p < 0.001) and median waist circumference by 11.0 cm (p < 0.001). Two participants discontinued insulin therapy, 4 could reduce their dosage of oral antidiabetic agents, and 6 completely discontinued their antidiabetic medication. Insulin dose decreased from 0.63 (0.38-0.89) to 0.39 (0.15-0.70) units/kg body weight (p < 0.001). No patient experienced hypoglycemic episodes or hospital emergency visits. Triglycerides and total cholesterol decreased as well as surrogate markers of liver function. However, the levels of high-density and low-density lipoprotein cholesterol (HDL-C and LDL-C) as well as uric acid remain unchanged. Regarding quality of life, the median physical health score increased from 44.5 (39.7-51.4) at baseline to 48.0 (43.1-55.3; p = 0.007), and the median mental health score decreased from 42.1 (36.1-46.7) to 37.4 (30.3-43.7; p = 0.004). CONCLUSIONS: A structured weight-loss program is effective in the short term in reducing HbA1c, weight, and antidiabetic medication in patients with T2DM who are overweight or obese. Levels of HDL-C and LDL-C were not affected by short-term weight loss. The decline in mental health and the long-term effects of improved glycemic control require further trials.

Suppress Me if You Can: Neurofeedback of the Readiness Potential.

Voluntary movements are usually preceded by a slow, negative-going brain signal over motor areas, the so-called readiness potential (RP). To date, the exact nature and causal role of the RP in movement preparation have remained heavily debated. Although the RP is influenced by several motorical and cognitive factors, it has remained unclear whether people can learn to exert mental control over their RP, for example, by deliberately suppressing it. If people were able to initiate spontaneous movements without eliciting an RP, this would challenge the idea that the RP is a necessary stage of the causal chain leading up to a voluntary movement. We tested the ability of participants to control the magnitude of their RP in a neurofeedback experiment. Participants performed self-initiated movements, and after every movement, they were provided with immediate feedback about the magnitude of their RP. They were asked to find a strategy to perform voluntary movements such that the RPs were as small as possible. We found no evidence that participants were able to to willfully modulate or suppress their RPs while still eliciting voluntary movements. This suggests that the RP might be an involuntary component of voluntary action over which people cannot exert conscious control.

Preparation and execution of voluntary action both contribute to awareness of intention.

How and when motor intentions form has long been controversial. In particular, the extent to which motor preparation and action-related processes produce a conscious experience of intention remains unknown. Here, we used a brain-computer interface (BCI) while participants performed a self-paced movement task to trigger cues upon the detection of a readiness potential (a well-characterized brain signal that precedes movement) or in its absence. The BCI-triggered cues instructed participants either to move or not to move. Following this instruction, participants reported whether they felt they were about to move at the time the cue was presented. Participants were more likely to report an intention (i) when the cue was triggered by the presence of a readiness potential than when the same cue was triggered by its absence, and (ii) when they had just made an action than when they had not. We further describe a time-dependent integration of these two factors: the probability of reporting an intention was maximal when cues were triggered in the presence of a readiness potential, and when participants also executed an action shortly afterwards. Our results provide a first systematic investigation of how prospective and retrospective components are integrated in forming a conscious intention to move.

Differential Expression of Serum MicroRNAs Supports CD4⁺ T Cell Differentiation into Th2/Th17 Cells in Severe Equine Asthma.

MicroRNAs (miRNAs) regulate post-transcriptional gene expression and may be exported from cells via exosomes or in partnership with RNA-binding proteins. MiRNAs in body fluids can act in a hormone-like manner and play important roles in disease initiation and progression. Hence, miRNAs are promising candidates as biomarkers. To identify serum miRNA biomarkers in the equine model of asthma we investigated small RNA derived from the serum of 34 control and 37 asthmatic horses. These samples were used for next generation sequencing, novel miRNA identification and differential miRNA expression analysis. We identified 11 significantly differentially expressed miRNAs between case and control horses: eca-miR-128, eca-miR-744, eca-miR-197, eca-miR-103, eca-miR-107a, eca-miR-30d, eca-miR-140-3p, eca-miR-7, eca-miR-361-3p, eca-miR-148b-3p and eca-miR-215. Pathway enrichment using experimentally validated target genes of the human homologous miRNAs showed a significant enrichment in the regulation of epithelial-to-mesenchymal transition (key player in airway remodeling in asthma) and the phosphatidylinositol (3,4,5)-triphosphate (PIP3) signaling pathway (modulator of CD4⁺ T cell maturation and function). Downregulated miR-128 and miR-744 supports a Th2/Th17 type immune response in severe equine asthma.

Two Sets of Piwi Proteins Are Involved in Distinct sRNA Pathways Leading to Elimination of Germline-Specific DNA.

Piwi proteins and piRNAs protect eukaryotic germlines against the spread of transposons. During development in the ciliate Paramecium, two Piwi-dependent sRNA classes are involved in the elimination of transposons and transposon-derived DNA: scan RNAs (scnRNAs), associated with Ptiwi01 and Ptiwi09, and iesRNAs, whose binding partners we now identify as Ptiwi10 and Ptiwi11. scnRNAs derive from the maternal genome and initiate DNA elimination during development, whereas iesRNAs continue DNA targeting until the removal process is complete. Here, we show that scnRNAs and iesRNAs are processed by distinct Dicer-like proteins and bind Piwi proteins in a mutually exclusive manner, suggesting separate biogenesis pathways. We also demonstrate that the PTIWI10 gene is transcribed from the developing nucleus and that its transcription depends on prior DNA excision, suggesting a mechanism of gene expression control triggered by the removal of short DNA segments interrupting the gene.

Effective treatment of benign biliary strictures with a removable, fully covered, self-expandable metal stent: A prospective, multicenter European study.

BACKGROUND: Temporary placement of removable, fully covered, self-expandable metal stents (fcSEMS) for treatment of benign biliary strictures (BBS) has been reported to be effective. However, the optimal extraction time point remains unclear and stent migration has been a major concern. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of this treatment modality using an fcSEMS with a special antimigration design and prolonged stent indwell time. METHODS: We performed a prospective, single-arm study at six tertiary care centers in Europe. Patients with BBS underwent endoscopic or percutaneous implantation of an fcSEMS (GORE® VIABIL® Biliary Endoprosthesis, W.L. Gore & Associates, Flagstaff, AZ, USA). The devices were scheduled to be removed nine months later, and patients were to return for follow-up for an additional 15 months. RESULTS: Forty-three patients were enrolled in the study. Stricture etiology was chronic pancreatitis in the majority of patients (57.5%). All fcSEMS were placed successfully, either endoscopically (76.7%) or percutaneously (23.3%). Stent migration was observed in two patients (5.2%). Primary patency of the SEMS prior to removal was 73.0%. All attempted stent removals were successful. At removal, stricture was resolved or significantly improved without need for further therapy in 78.9% of patients. Stricture recurrence during a follow-up of two years post-implant was observed in two patients. CONCLUSIONS: Temporary placement of the fcSEMS is a feasible, safe and effective treatment for BBS. The design of the device used in this study accounts for very low migration rates and facilitates easy stent retrieval, even after it has been in place for up to 11 months.

Evaluation of a non-invasive multisensor accelerometer for calculating energy expenditure in ventilated intensive care patients compared to indirect calorimetry and predictive equations.

Continuous measurement of resting energy expenditure (REE) in critically ill patients remains challenging but is required to prevent malnutrition. SenseWear Pro 3 Armband (SWA) is a research grade accelerometer for assessment of REE with the advantage of easy handling. In a prospective study we compared SWA with indirect calorimetry (IC) and predictive equations in critically ill, ventilated patients. REE was measured by SWA, IC and calculated by predictive formulas. Potential confounding factors that influence REE were also recorded. Results of SenseWear Armband and indirect calorimetry were compared using the Bland-Altman method. 34 ICU patients were investigated. SWA underestimated resting energy expenditure compared to IC with a mean bias of ΔREE = -253.6 ± 333.2 kcal, equivalent to -11.7 % (p = 0.025). This underestimation was seen in both, medical (-14.9 %) and surgical (-12.9 %) patients and the bias was greater in patients with fever (-19.0 %), tachycardia (-18.7 %) or tachypnea (-26.2 %). Differences were also noted when SWA was compared to predictive formulas. At present, SWA cannot be regarded as an alternative to indirect calorimetry. Individual measurements are often inaccurate and should be used with caution until improved algorithms, based on the results of this study, have been implemented.

Geriatric nutritional risk index correlates with length of hospital stay and inflammatory markers in older inpatients.

BACKGROUND & AIMS: Malnutrition is a prevalent condition in older inpatients and has been shown to increase morbidity and direct medical costs. A number of established tools to assess malnutrition are available but malnourished patients rarely receive adequate nutritional assessment and treatment. The medical and economic consequences of malnutrition in hospitalized patients are therefore often underestimated. This study investigates whether the Geriatric Nutritional Risk Index (GNRI) predicts hospital mortality, correlates with length of hospital stay (LOS) and inflammatory markers in older inpatients. METHODS: We conducted a prospective monocentric study in 500 hospital patients over 65 years of age (female: 248; male: 252; age: 76.3 ± 0.31 years). GNRI was correlated to C-reactive protein (CRP), lymphocyte count, LOS and all-cause mortality, adjusted for potential confounders. RESULTS: The median body mass index was 24.1 (25th percentile: 21.1; 75th percentile: 27.8) kg/m2 and the mean GNRI 82.2 ± 0.56. A higher risk GNRI was associated with increased CRP levels (p < 0.05) and low lymphocyte counts (p < 0.05) after multivariable adjustment. Moreover, we found positive correlation between a higher risk GNRI and length of hospital stay, whereas, the association with in-hospital mortality was not significant. CONCLUSIONS: The GNRI correlates well with indicators of inflammation and the length of hospital stay. The routine implementation of the GNRI for the nutritional assessment of older patients could have a significant medical and socio-economic impact.

The Berlin Brain-Computer Interface: Progress Beyond Communication and Control.

The combined effect of fundamental results about neurocognitive processes and advancements in decoding mental states from ongoing brain signals has brought forth a whole range of potential neurotechnological applications. In this article, we review our developments in this area and put them into perspective. These examples cover a wide range of maturity levels with respect to their applicability. While we assume we are still a long way away from integrating Brain-Computer Interface (BCI) technology in general interaction with computers, or from implementing neurotechnological measures in safety-critical workplaces, results have already now been obtained involving a BCI as research tool. In this article, we discuss the reasons why, in some of the prospective application domains, considerable effort is still required to make the systems ready to deal with the full complexity of the real world.

Early Parenteral Nutrition in Patients with Biliopancreatic Mass Lesions, a Prospective, Randomized Intervention Trial.

PURPOSE: Patients with biliopancreatic tumors frequently suffer from weight loss and cachexia. The in-hospital work-up to differentiate between benign and malignant biliopancreatic lesions requires repeated pre-interventional fasting periods that can aggravate this problem. We conducted a randomized intervention study to test whether routine in-hospital peripheral intravenous nutrition on fasting days (1000 ml/24 h, 700 kcal) has a beneficial effect on body weight and body composition. MATERIAL AND METHODS: 168 patients were screened and 100 enrolled in the trial, all undergoing in-hospital work-up for biliopancreatic mass lesions and randomized to either intravenous nutrition or control. Primary endpoint was weight loss at time of hospital discharge; secondary endpoints were parameters determined by bioelectric impedance analysis and quality of life recorded by the EORTC questionnaire. RESULTS: Within three months prior to hospital admission patients had a median self-reported loss of 4.0 kg (25*th: -10.0 kg and 75*th* percentile: 0.0kg) of body weight. On a multivariate analysis nutritional intervention increased body weight by 1.7 kg (95% CI: 0.204; 3.210, p = 0.027), particularly in patients with malignant lesions (2.7 kg (95% CI: 0.71; 4.76, p < 0.01). CONCLUSIONS: In a hospital setting, patients with suspected biliopancreatic mass lesions stabilized their body weight when receiving parenteral nutrition in fasting periods even when no total parenteral nutrition was required. Analysis showed that this effect was greatest in patients with malignant tumors. Further studies will be necessary to see whether patient outcome is affected as well. TRIAL REGISTRATION: ClinicalTrials.gov NCT02670265.

Transformation Optics: A Time- and Frequency-Domain Analysis of Electron-Energy Loss Spectroscopy.

Electron energy loss spectroscopy (EELS) and cathodoluminescence (CL) play a pivotal role in many of the cutting edge experiments in plasmonics. EELS and CL experiments are usually supported by numerical simulations, which-though accurate-may not provide as much physical insight as analytical calculations do. Fully analytical solutions to EELS and CL systems in plasmonics are rare and difficult to obtain. This paper aims to narrow this gap by introducing a new method based on transformation optics that allows to calculate the quasistatic frequency- and time-domain response of plasmonic particles under electron beam excitation. We study a nonconcentric annulus (and ellipse in the Supporting Information ) as an example.

Unsupervised classification of operator workload from brain signals.

OBJECTIVE: In this study we aimed for the classification of operator workload as it is expected in many real-life workplace environments. We explored brain-signal based workload predictors that differ with respect to the level of label information required for training, including entirely unsupervised approaches. APPROACH: Subjects executed a task on a touch screen that required continuous effort of visual and motor processing with alternating difficulty. We first employed classical approaches for workload state classification that operate on the sensor space of EEG and compared those to the performance of three state-of-the-art spatial filtering methods: common spatial patterns (CSPs) analysis, which requires binary label information; source power co-modulation (SPoC) analysis, which uses the subjects' error rate as a target function; and canonical SPoC (cSPoC) analysis, which solely makes use of cross-frequency power correlations induced by different states of workload and thus represents an unsupervised approach. Finally, we investigated the effects of fusing brain signals and peripheral physiological measures (PPMs) and examined the added value for improving classification performance. MAIN RESULTS: Mean classification accuracies of 94%, 92% and 82% were achieved with CSP, SPoC, cSPoC, respectively. These methods outperformed the approaches that did not use spatial filtering and they extracted physiologically plausible components. The performance of the unsupervised cSPoC is significantly increased by augmenting it with PPM features. SIGNIFICANCE: Our analyses ensured that the signal sources used for classification were of cortical origin and not contaminated with artifacts. Our findings show that workload states can be successfully differentiated from brain signals, even when less and less information from the experimental paradigm is used, thus paving the way for real-world applications in which label information may be noisy or entirely unavailable.

Graphene as a Tunable Anisotropic or Isotropic Plasmonic Metasurface.

We demonstrate a tunable plasmonic metasurface by considering a graphene sheet subject to a periodically patterned doping level. The unique optical properties of graphene result in electrically tunable plasmons that allow for extreme confinement of electromagnetic energy in the technologically significant regime of THz frequencies. Here, we add an extra degree of freedom by using graphene as a metasurface, proposing to dope it with an electrical gate patterned in the micron or submicron scale. By extracting the effective conductivity of the sheet, we characterize metasurfaces periodically modulated along one or two directions. In the first case, and making use of the analytical insight provided by transformation optics, we show an efficient control of THz radiation for one polarization. In the second case, we demonstrate a metasurface with an isotropic response that is independent of wave polarization and orientation.

The point of no return in vetoing self-initiated movements.

In humans, spontaneous movements are often preceded by early brain signals. One such signal is the readiness potential (RP) that gradually arises within the last second preceding a movement. An important question is whether people are able to cancel movements after the elicitation of such RPs, and if so until which point in time. Here, subjects played a game where they tried to press a button to earn points in a challenge with a brain-computer interface (BCI) that had been trained to detect their RPs in real time and to emit stop signals. Our data suggest that subjects can still veto a movement even after the onset of the RP. Cancellation of movements was possible if stop signals occurred earlier than 200 ms before movement onset, thus constituting a point of no return.

Quality control of parenteral nutrition in hospitalized patients.

OBJECTIVE: For hospitalized patients requiring parenteral nutrition (PN), adequate nutritional support has a profound effect on hospital length of stay, morbidity, mortality, and complication rates. Inappropriate or inadequate nutritional therapy may worsen clinical outcome. The aim of this study was to investigate the compliance with nutritional guidelines for PN in a university hospital setting. METHODS: Over a 6-mo period, this monocentric study prospectively recruited 107 (41 women, 66 men) hospitalized medical and surgical patients requiring PN. Data on nutritional support were collected before nutritional counseling. Nutritional requirements were estimated on the basis of the European Society for Clinical Nutrition and Metabolism (ESPEN) Guidelines for Adult Parenteral Nutrition (2009). RESULTS: The mean patient age was 65 ± 1.4 y and the mean body mass index was 23.2 ± 0.5 kg/m². Only 75% of the caloric requirement was met. Multivitamin supplementation was adequate in only 37%, and for vitamin K in only 6% of cases. Trace element supplementation was adequate in only 35%. PN in complete agreement with the ESPEN guidelines was achieved in none of the patients. CONCLUSIONS: In routine hospital practice, PN is generally not provided in compliance with established guidelines. To improve the quality of nutritional therapy, a nutritional support team should be established. Furthermore, there should be periodical training sessions in nutrition for medical and nursing staff, as well as in standard operating procedures.