Demonstration of event position reconstruction based on diffusion in the NEXT-white detector.

Noble element time projection chambers are a leading technology for rare event detection in physics, such as for dark matter and neutrinoless double beta decay searches. Time projection chambers typically assign event position in the drift direction using the relative timing of prompt scintillation and delayed charge collection signals, allowing for reconstruction of an absolute position in the drift direction. In this paper, alternate methods for assigning event drift distance via quantification of electron diffusion in a pure high pressure xenon gas time projection chamber are explored. Data from the NEXT-White detector demonstrate the ability to achieve good position assignment accuracy for both high- and low-energy events. Using point-like energy deposits from 83mKr calibration electron captures (E∼45 keV), the position of origin of low-energy events is determined to 2 cm precision with bias <1mm. A convolutional neural network approach is then used to quantify diffusion for longer tracks (E≥1.5 MeV), from radiogenic electrons, yielding a precision of 3 cm on the event barycenter. The precision achieved with these methods indicates the feasibility energy calibrations of better than 1% FWHM at Qßß in pure xenon, as well as the potential for event fiducialization in large future detectors using an alternate method that does not rely on primary scintillation.

Principles for management of hip fracture for older adults taking direct oral anticoagulants: an international consensus statement.

Hip fracture is a common serious injury among older adults, yet the management of hip fractures for patients taking direct oral anticoagulants remains inconsistent worldwide. Drawing from a synthesis of available evidence and expert opinion, best practice approaches for managing patients with a hip fracture and who are taking direct oral anticoagulants pre-operatively were considered by a working group of the Fragility Fracture Network Hip Fracture Audit Special Interest Group. The literature and related clinical guidelines were reviewed and a two-round modified Delphi study was conducted with a panel of experts from 16 countries and involved seven clinical specialities. Four consensus statements were achieved: peripheral nerve blocks can reasonably be performed on presentation for patients with hip fracture who are receiving direct oral anticoagulants; hip fracture surgery can reasonably be performed for patients taking direct oral anticoagulants < 36 h from last dose; general anaesthesia could reasonably be administered for patients with hip fracture and who are taking direct oral anticoagulants < 36 h from last dose (assuming eGFR > 60 ml.min-1.1.73 m-2); and it is generally reasonable to consider recommencing direct oral anticoagulants (considering blood loss and haemoglobin) < 48 h after hip fracture surgery. No consensus was achieved regarding timing of spinal anaesthesia. The consensus statements were developed to aid clinicians in their decision-making and to reduce practice variations in the management of patients with hip fracture and who are taking direct oral anticoagulants. Each statement will need to be considered specific to each individual patient's treatment.

Machine learning to predict myocardial injury and death after non-cardiac surgery.

Myocardial injury due to ischaemia within 30 days of non-cardiac surgery is prognostically relevant. We aimed to determine the discrimination, calibration, accuracy, sensitivity and specificity of single-layer and multiple-layer neural networks for myocardial injury and death within 30 postoperative days. We analysed data from 24,589 participants in the Vascular Events in Non-cardiac Surgery Patients Cohort Evaluation study. Validation was performed on a randomly selected subset of the study population. Discrimination for myocardial injury by single-layer vs. multiple-layer models generated areas (95%CI) under the receiver operating characteristic curve of: 0.70 (0.69-0.72) vs. 0.71 (0.70-0.73) with variables available before surgical referral, p < 0.001; 0.73 (0.72-0.75) vs. 0.75 (0.74-0.76) with additional variables available on admission, but before surgery, p < 0.001; and 0.76 (0.75-0.77) vs. 0.77 (0.76-0.78) with the addition of subsequent variables, p < 0.001. Discrimination for death by single-layer vs. multiple-layer models generated areas (95%CI) under the receiver operating characteristic curve of: 0.71 (0.66-0.76) vs. 0.74 (0.71-0.77) with variables available before surgical referral, p = 0.04; 0.78 (0.73-0.82) vs. 0.83 (0.79-0.86) with additional variables available on admission but before surgery, p = 0.01; and 0.87 (0.83-0.89) vs. 0.87 (0.85-0.90) with the addition of subsequent variables, p = 0.52. The accuracy of the multiple-layer model for myocardial injury and death with all variables was 70% and 89%, respectively.

Intermittency properties in a temporal lobe epilepsy model.

Neuronal synchronization is important for communication between brain regions and plays a key role in learning. However, changes in connectivity can lead to hyper-synchronized states related to epileptic seizures that occur intermittently with asynchronous states. The activity-regulated cytoskeleton-associated protein (ARC) is related to synaptic alterations which can lead to epilepsy. Induction of status epilepticus in rodent models causes the appearance of intense ARC immunoreactive neurons (IAINs), which present a higher number of connections and conductance intensity than non-IAINs. This alteration might contribute to abnormal epileptic seizure activity. In this work, we investigated how IAINs connectivity influences the firing pattern and synchronization in neural networks. Firstly, we showed the appearance of synchronized burst patterns due to the emergence of IAINs. Second, we described how the increase of IAINs connectivity favors the appearance of intermittent up and down activities associated with synchronous bursts and asynchronous spikes, respectively. Once the intermittent activity was properly characterized, we applied the optogenetics control of the high synchronous activities in the intermittent regime. To do this, we considered that 1% of neurons were transfected and became photosensitive. We observed that optogenetics methods to control synchronized burst patterns are effective when IAINs are chosen as photosensitive, but not effective in non-IAINs. Therefore, our analyses suggest that IAINs play a pivotal role in both the generation and suppression of highly synchronized activities.

Renoprotective effect of N-acetylcysteine depends upon the severity of the ischemia reperfusion injury.

Acute kidney injury (AKI) is a common complication in seriously ill patients, while renal ischemia-reperfusion (I/R) injury is the most frequent event in this oxidative renal injury. N-acetylcysteine (NAC) is a small molecule containing a thiol group that has antioxidant properties, promoting detoxification and acting directly as a free radical scavenger. In this study, the protective effect of NAC was investigated in short-term (30 min) and long-term (45 min) ischemic AKI. This was achieved via clamping of the renal artery for 30 or 45 min in Wistar rats to induce I/R injury. AKI worsened with a longer period of ischemia (45 compared to 30 min) due to probable irreversible damage. Preconditioning with NAC in short-term ischemia improved renal blood flow and increased creatinine clearance by reducing oxidative metabolites and increasing antioxidant capacity. Otherwise, NAC did not change these parameters in the long-term ischemia. Therefore, this study demonstrated that the period of ischemia determines the severity of the AKI, and NAC presented antioxidant effects in short-term ischemia but not in long-term ischemia, confirming that there is a possible therapeutic window for its renoprotective effect.

Effects of cryolipolysis with adiposity plates located with the Crioplace concept in women.

BACKGROUND: Cryolipolysis with plates is a method of applying cooling without a vacuum system, which can be used in regions with less chance of forming a "crease." OBJECTIVE: To investigate the effects of cryolipolysis using a plate-shaped applicator (Crioplac) in the treatment of fat. MATERIALS AND METHODS: This is an experimental study in which women aged 25 to 45 years with adiposity located in the abdomen participated. Two applications of 75 min were made, using 04 plates in the abdomen regions, with -4 degree C being programmed as a temperature parameter. Anthropometric and ultrasound assessments were performed, and a satisfaction questionnaire on the validated treatment was conducted. The reassessments were performed 30 and 60 days after the first intervention. RESULTS: A reduction in adiposity was observed in the measurements of perimetry, plicometry and abdominal ultrasound (p<0.05). It was found that about 62.5% of the volunteers reported an improvement in water retention, about 62.5% reported the presence of loose clothing, and 31.3% reported satisfaction with the results obtained. It was observed that 18.5% of the volunteers reported that the treatment was excellent. CONCLUSION: The Crioplace method proved to be effective in reducing adiposity, with a high clinical satisfaction with the reduction in body measurements.

Renoprotective effect of N-acetylcysteine depends upon the severity of the ischemia reperfusion injury

Acute kidney injury (AKI) is a common complication in seriously ill patients, while renal ischemia-reperfusion (I/R) injury is the most frequent event in this oxidative renal injury. N-acetylcysteine (NAC) is a small molecule containing a thiol group that has antioxidant properties, promoting detoxification and acting directly as a free radical scavenger. In this study, the protective effect of NAC was investigated in short-term (30 min) and long-term (45 min) ischemic AKI. This was achieved via clamping of the renal artery for 30 or 45 min in Wistar rats to induce I/R injury. AKI worsened with a longer period of ischemia (45 compared to 30 min) due to probable irreversible damage. Preconditioning with NAC in short-term ischemia improved renal blood flow and increased creatinine clearance by reducing oxidative metabolites and increasing antioxidant capacity. Otherwise, NAC did not change these parameters in the long-term ischemia. Therefore, this study demonstrated that the period of ischemia determines the severity of the AKI, and NAC presented antioxidant effects in short-term ischemia but not in long-term ischemia, confirming that there is a possible therapeutic window for its renoprotective effect.

Effects of Cryolipolysis with Plates in Localized Adiposity with the CrioPlace Concept.

BACKGROUND: Plate cryolipolysis is a method of applying cooling without a vacuum system, which can be used in regions with less possibility of skin suction or fibrosis. OBJECTIVE: To investigate the effects of cryolipolysis with the use of plate-shaped applicators (CrioPlaceTM) for localized fat treatment. METHODS: The sample consisted of men aged 20 to 45 years with complaints of localized adiposity in the abdominal region and flanks. Two plates were positioned in the flank and abdomen regions, respectively. They received two 60-min applications in the temperature of -2°C. The anthropometric, thermographic and ultrasound assessments were performed, and a satisfaction questionnaire was applied after treatment. The re-evaluations occurred 30 and 60 days after the first intervention. RESULT: A reduction in adiposity was observed in flank region plicometry (p<0.05) and abdominal and flank ultrasound (p < 0.05). About 66.7% of the volunteers reported less water retention, about 41.7% reported that their clothes were looser, and 100% reported overall satisfaction. Fifty percent rated the treatment as excellent and 58.3% felt improvement in overall aesthetics. CONCLUSION: The CrioPlaceTM method was effective in reducing localized adiposity, with clinical satisfaction of measurement reduction, both in plicometry and ultrasound analyses, with highlights to the flank region results.

Creatine supplementation exacerbates ethanol-induced hepatic damage in mice.

OBJECTIVE: The aim of this study was to investigate the effects of creatine supplementation on early stages of ethanol-induced hepatic damage. METHODS: Male Swiss mice were divided into three groups (n = 12/group): control (C), ethanol (E), and ethanol supplemented with creatine (EC). The control group received a diet containing 15.8% of total calories from proteins, 46.3% from carbohydrates, and 37.9% from lipids. The ethanol and ethanol and creatine groups received diets containing 15.8% of total calories from proteins, 16.2% from carbohydrates, and 34.5% from lipids; the remaining calories were obtained from the addition of 5% of 95% ethanol. Creatine (1%; weight/vol) was added to the diet of EC mice. After 14 and 28 d, six animals from each group were sacrificed, generating subdivisions in each group: C14 and C28, E14 and E28, EC14 and EC28. After sacrifice, the liver was removed, weighed, and prepared for histologic, biochemical, and molecular analysis, and blood was collected. RESULTS: Ethanol intake induced mild cell degeneration, liver damage, oxidative lesions, and inflammation. Surprisingly, ethanol intake combined with creatine exacerbated cell degeneration and fat accumulation, hepatic expression of genes related to ethanol metabolism, oxidative stress and inflammation, and promoted oxidative stress and elevated plasma alanine aminotransferase (P < 0.05). CONCLUSION: Creatine supplementation associated with ethanol is able to interfere in the alcohol metabolism and oxidative stress and to exacerbate ethanol-induced hepatic damage. These new findings are opposite to those observed in several studies where protective effects of creatine in a wide variety of injury models, including non-alcoholic fatty liver disease, were described.

Fine-tuning the neuroprotective and blood-brain barrier permeability profile of multi-target agents designed to prevent progressive mitochondrial dysfunction.

Alzheimer's disease is an irreversible, complex and progressive neurodegenerative disorder associated with oxidative stress and mitochondrial dysfunction. Exogenous antioxidants can be beneficial for decreasing oxidative stress, as they are able to reward the lack of efficacy of the endogenous defense systems and raise the overall antioxidant response in a pathological condition. Along our overarching project related with the design and development of potent and safe multi-target mitochondriotropic antioxidants, based on dietary antioxidants, novel derivatives were obtained. Overall, mitochondriotropic antioxidants showed remarkable antioxidant and chelating properties, presenting low cytotoxic effects on human differentiated neuronal (SH-SY5Y) and hepatocarcinoma (HepG2) cells and exhibited neuroprotective properties on SH-SY5Y cells against 6-hydroxydopamine (6-OHDA) or hydrogen peroxide (H2O2) oxidative insults. Moreover, compounds 58, 59, 62, 63, 66 and 67 were able to permeate a layer of hCMEC/D3 cells in a time-dependent manner. Mitochondriotropic antioxidant 67 stands out by its remarkable iron chelating and neuroprotective properties toward both H2O2 and 6-OHDA-induced oxidative damage, drug-like properties and BBB permeability.

Food Matrix Design for Effective Lactic Acid Bacteria Delivery.

The range of foods featuring lactic acid bacteria (LAB) with potential associated health benefits has expanded over the years from traditional dairy products to meat, cereals, vegetables and fruits, chocolate, etc. All these new carriers need to be compared for their efficacy to protect, carry, and deliver LAB, but because of their profusion and the diversity of methods this remains difficult. This review points out the advantages and disadvantages of the main food matrix types, and an additional distinction between dairy and nondairy foods is made. The food matrix impact on LAB viability during food manufacturing, storage, and digestion is also discussed. The authors propose an ideal hypothetical food matrix that includes structural and physicochemical characteristics such as pH, water activity, and buffering capacities, all of which need to be taken into account when performing LAB food matrix design. Guidelines are finally provided to optimize food matrix design in terms of effective LAB delivery.

Multilocus sequence typing of Carnobacterium maltaromaticum strains associated with fish disease and dairy products.

AIMS: Carnobacterium maltaromaticum is a lactic acid bacterium of technological interest in the field of dairy ripening and food bioprotection and is generally recognized as safe in the United States. As it is associated with fish infections, the European Food Safety Agency did not include this species in the qualified presumption safety list of micro-organisms. This implies that the risk assessment for the species has to be performed at the strain level. METHODS AND RESULTS: Multilocus sequence typing (MLST) is a tool that (i) potentially allows to discriminate strains isolated from diseased fish from apathogenic strains and (ii) to assess the genetic relatedness between both groups of strains. In this study, we characterized by MLST 21 C. maltaromaticum strains including 16 strains isolated from diseased fish and 5 apathogenic dairy strains isolated from cheese. The resulting population structure was investigated by integrating these new data to the previously published population structure (available at http://pubmlst.org), which represents an overall of 71 strains. CONCLUSIONS: This analysis revealed that none of the strains isolated from diseased fish is assigned to a clonal complex containing cheese isolates, and that 11 strains exhibit singleton genotypes suggesting that the population of diseased fish isolates is not clonal. SIGNIFICANCE AND IMPACT OF THE STUDY: This study thus provides a population structure of C. maltaromaticum that could serve in the future as a reference that could contribute to the risk assessment of C. maltaromaticum strains intended to be used in the food chain.

Recurrence quantification analysis for the identification of burst phase synchronisation.

In this work, we apply the spatial recurrence quantification analysis (RQA) to identify chaotic burst phase synchronisation in networks. We consider one neural network with small-world topology and another one composed of small-world subnetworks. The neuron dynamics is described by the Rulkov map, which is a two-dimensional map that has been used to model chaotic bursting neurons. We show that with the use of spatial RQA, it is possible to identify groups of synchronised neurons and determine their size. For the single network, we obtain an analytical expression for the spatial recurrence rate using a Gaussian approximation. In clustered networks, the spatial RQA allows the identification of phase synchronisation among neurons within and between the subnetworks. Our results imply that RQA can serve as a useful tool for studying phase synchronisation even in networks of networks.

Synchronous behaviour in network model based on human cortico-cortical connections.

OBJECTIVE: We consider a network topology according to the cortico-cortical connection network of the human brain, where each cortical area is composed of a random network of adaptive exponential integrate-and-fire neurons. APPROACH: Depending on the parameters, this neuron model can exhibit spike or burst patterns. As a diagnostic tool to identify spike and burst patterns we utilise the coefficient of variation of the neuronal inter-spike interval. MAIN RESULTS: In our neuronal network, we verify the existence of spike and burst synchronisation in different cortical areas. SIGNIFICANCE: Our simulations show that the network arrangement, i.e. its rich-club organisation, plays an important role in the transition of the areas from desynchronous to synchronous behaviours.

Differential metallothionein expression in oral lichen planus and amalgam-associated oral lichenoid lesions.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease mediated by T cells, which manifests as reticular (white) or erosive (red) lesions, that are eventually painful. Oral lichenoid lesion (OLL) are distinguished from OLP by the presence of precipitating factors. The aim of this study was to evaluate whether the presence of metallothionein, which is involved in anti-apoptotic pathways and the anti-oxidative response, could serve as a differential diagnostic for OLP and OLL. MATERIAL AND METHODS: We evaluated the expression of metallothionein in 40 cases of OLP and 20 cases of OLL using immunohistochemistry. RESULTS AND CONCLUSIONS: White OLP has higher concentrations of metallothionein than red OLP in basal and parabasal layers. Moreover, metallothionein was more frequently observed in the cytoplasm and nuclei of basal cells in OLP patients compared to the same regions of OLL cases. Metallothionein levels are related to OLP severity and may contribute to a differential diagnosis between OLP and OLL.

Demonstration of Single-Barium-Ion Sensitivity for Neutrinoless Double-Beta Decay Using Single-Molecule Fluorescence Imaging.

A new method to tag the barium daughter in the double-beta decay of ^{136}Xe is reported. Using the technique of single molecule fluorescent imaging (SMFI), individual barium dication (Ba^{++}) resolution at a transparent scanning surface is demonstrated. A single-step photobleach confirms the single ion interpretation. Individual ions are localized with superresolution (∼2 nm), and detected with a statistical significance of 12.9σ over backgrounds. This lays the foundation for a new and potentially background-free neutrinoless double-beta decay technology, based on SMFI coupled to high pressure xenon gas time projection chambers.

Inference of topology and the nature of synapses, and the flow of information in neuronal networks.

The characterization of neuronal connectivity is one of the most important matters in neuroscience. In this work, we show that a recently proposed informational quantity, the causal mutual information, employed with an appropriate methodology, can be used not only to correctly infer the direction of the underlying physical synapses, but also to identify their excitatory or inhibitory nature, considering easy to handle and measure bivariate time series. The success of our approach relies on a surprising property found in neuronal networks by which nonadjacent neurons do "understand" each other (positive mutual information), however, this exchange of information is not capable of causing effect (zero transfer entropy). Remarkably, inhibitory connections, responsible for enhancing synchronization, transfer more information than excitatory connections, known to enhance entropy in the network. We also demonstrate that our methodology can be used to correctly infer directionality of synapses even in the presence of dynamic and observational Gaussian noise, and is also successful in providing the effective directionality of intermodular connectivity, when only mean fields can be measured.

Evaluation of peptides release using a natural rubber latex biomembrane as a carrier.

The biomembrane natural (NRL-Natural Rubber Latex), manipulated from the latex obtained from the rubber tree Hevea brasiliensis, has shown great potential for application in biomedicine and biomaterials. Reflecting the biocompatibility and low bounce rate of this material, NRL has been used as a physical barrier to infectious agents and for the controlled release of drugs and extracts. The aim of the present study was to evaluate the incorporation and release of peptides using a latex biomembrane carrier. After incorporation, the release of material from the membrane was observed using spectrophotometry. Analyses using HPLC and mass spectroscopy did not confirm the release of the antimicrobial peptide [W6]Hylin a1 after 24 h. In addition, analysis of the release solution showed new compounds, indicating the degradation of the peptide by enzymes contained in the latex. Additionally, the release of a peptide with a shorter sequence (Ac-WAAAA) was evaluated, and degradation was not observed. These results showed that the use of NRL as solid matrices as delivery systems of peptide are sequence dependent and could to be evaluated for each sequence.

Biological significance of 5-hydroxymethylcytosine in oral epithelial dysplasia and oral squamous cell carcinoma.

OBJECTIVES: The aim of this study was to determine the levels of 5-hydroxylmethylcytosine (5-hmC) in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) compared with those in benign, reactive inflammatory lesions and to explore whether DNA hydroxymethylation may serve as a novel biomarker for early diagnosis and prognosis of OSCC. STUDY DESIGN: The study included normal mucosa from uninvolved margins of 9 fibromas, 10 oral lichen planus, 15 OED, and 23 OSCC. Cultured human keratinocyte lines from benign oral mucosa, OED, and OSCC, as well as a murine model in which OSCC was induced with 4-nitroquinoline-1-oxide, were also evaluated. RESULTS: Progressive loss of 5-hmC from benign oral mucosal lesions to OED and OSCC was documented in patient samples. Decreased levels in 5-hmC that typify OED and OSCC were also detectable in human cell lines. Moreover, we characterized similar alterations in 5-hmC in an animal model of OED/OSCC. CONCLUSIONS: This study demonstrated that 5-hmC distinguishes OED and OSCC from benign lesions with high sensitivity and specificity. Consequently, loss of 5-hmC may be useful for the diagnosis of OED with potential implications for therapy of OSCC.

Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats

Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.