Circadian Transcriptome Oscillations In Human Adipose Tissue Depend On Napping Status And Link To Metabolic And Inflammatory Pathways.

STUDY OBJECTIVES: Napping is a common habit in many countries. Nevertheless, studies about the chronic effects of napping on obesity are contradictory, and the molecular link between napping and metabolic alterations has yet to be studied. We aim to identify molecular mechanisms in adipose tissue (AT) that may connect napping and abdominal obesity. METHODS: In this cross-sectional study, we extracted the RNA repeatedly across 24h from cultured AT explants and performed RNA sequencing. Circadian rhythms were analyzed using 6 consecutive time points across 24 hours. We also assessed global gene expression in each group (nappers vs. non-nappers). RESULTS: With napping, there was a loss of rhythmicity in 88% of genes that showed circadian rhythmicity among non-nappers, a reduction in rhythm amplitudes of 29%, and significant phase changes from a coherent unimodal acrophase in non-nappers, towards a scattered and bimodal acrophase in nappers. Those genes that lost rhythmicity with napping were mainly involved in pathways of glucose and lipid metabolism, and of the circadian clock. Additionally, we found differential global gene expression between nappers and non-nappers with 34 genes down- and 32 genes up-regulated in nappers. The top up-regulated gene (IER3) and top down-regulated pseudogene (VDAC2P2) in nappers have been previously shown to be involved in inflammation. CONCLUSION: These new findings may have implications for our understanding of napping's effects on obesity and metabolic disorders.

Dynamic Adhesive Behavior and Biofilm Formation of Staphylococcus aureus on Polylactic Acid Surfaces in Diabetic Environments.

Interest in biodegradable implants has focused attention on the resorbable polymer polylactic acid. However, the risk of these materials promoting infection, especially in patients with existing pathologies, needs to be monitored. The enrichment of a bacterial adhesion medium with compounds that are associated with human pathologies can help in understanding how these components affect the development of infectious processes. Specifically, this work evaluates the influence of glucose and ketone bodies (in a diabetic context) on the adhesion dynamics of S. aureus to the biomaterial polylactic acid, employing different approaches and discussing the results based on the physical properties of the bacterial surface and its metabolic activity. The combination of ketoacidosis and hyperglycemia (GK2) appears to be the worst scenario: this system promotes a state of continuous bacterial colonization over time, suppressing the stationary phase of adhesion and strengthening the attachment of bacteria to the surface. In addition, these supplements cause a significant increase in the metabolic activity of the bacteria. Compared to non-enriched media, biofilm formation doubles under ketoacidosis conditions, while in the planktonic state, it is glucose that triggers metabolic activity, which is practically suppressed when only ketone components are present. Both information must be complementary to understand what can happen in a real system, where planktonic bacteria are the ones that initially colonize a surface, and, subsequently, these attached bacteria end up forming a biofilm. This information highlights the need for good monitoring of diabetic patients, especially if they use an implanted device made of PLA.

Sacha Inchi (Plukenetia volubilis L.) Protein Hydrolysate as a New Ingredient of Functional Foods.

Sacha inchi (Plukenetia volubilis L.) is an under-exploited crop with great potential due to its nutritional and medicinal characteristics. A Sacha inchi protein isolate (SII), obtained from defatted Sacha inchi flour (SIF), was hydrolyzed by Bioprotease LA 660 under specific conditions. The hydrolysates were characterized chemically, and their digestibility and antioxidant capacity were evaluated by in vitro cell-free experiments to select the hydrolysate with major antioxidant activity. Sacha inchi protein hydrolysate at 20 min (SIH20B) was selected, and the anti-inflammatory capacity was evaluated by RT-qPCR and ELISA techniques, using two different doses in monocytes THP-1 stimulated with lipopolysaccharide (LPS). The results obtained showed that the in vitro administration of SIH20B down-regulated the TNF-α gene and reduced the release of this cytokine, whereas the anti-inflammatory cytokines IL-10 and IL-4 were up-regulated in LPS-stimulated monocytes and co-administrated with SIH20B. The peptides contained in SIH20B were identified, and the 20 more relatively abundant peptides with a mass by 1 kDa were subjected to in silico analysis to hypothesize those that could be responsible for the bioactivity reported in the hydrolysate. From the identified peptides, the peptides AAGALKKFL and LGVKFKGGL, among others, are proposed as the most biologically actives. In conclusion, SIH20B is a novel, natural source of high-value-added biopeptides that could be used as an ingredient in formulations of food or nutraceutical compounds.

Synthesis and Properties of Hydrophilic and Hydrophobic Deep Eutectic Solvents via Heating-Stirring and Ultrasound.

Deep eutectic solvents (DESs) have emerged as a greener alternative to other more polluting traditional solvents and have attracted a lot of interest in the last two decades. The DESs are less toxic dissolvents and have a lower environmental footprint. This paper presents an alternative synthesis method to the classical heating-stirring method. The ultrasound method is one of the most promising synthesis methods for DESs in terms of yield and energy efficiency. Therefore, the ultrasound synthesis method was studied to obtain hydrophobic (Aliquat 336:L-Menthol (3:7); Lidocaine:Decanoic acid (1:2)) and hydrophilic DESs based on choline chloride, urea, ethylene glycol and oxalic acid. The physical characterization of DESs via comparison of Fourier transform infrared (FTIR) spectra showed no difference between the DESs obtained by heating-stirring and ultrasound synthesis methods. The study and comparison of all the prepared DESs were carried out via nuclear magnetic resonance spectroscopy (NMR). The density and viscosity properties of DESs were evaluated. The density values were similar for both synthesis methods. However, differences in viscosity values were detected due to the presence of some water in hygroscopic DESs.

Responses of fine particulate matter (PM2.5) air quality to future climate, land use, and emission changes: Insights from modeling across shared socioeconomic pathways.

Air pollution induced by fine particulate matter with diameter ≤ 2.5 µm (PM2.5) poses a significant challenge for global air quality management. Understanding how factors such as climate change, land use and land cover change (LULCC), and changing emissions interact to impact PM2.5 remains limited. To address this gap, we employed the Community Earth System Model and examined both the individual and combined effects of these factors on global surface PM2.5 in 2010 and projected scenarios for 2050 under different Shared Socioeconomic Pathways (SSPs). Our results reveal biomass-burning and anthropogenic emissions as the primary drivers of surface PM2.5 across all SSPs. Less polluted regions like the US and Europe are expected to experience substantial PM2.5 reduction in all future scenarios, reaching up to ~5 µg m-3 (70 %) in SSP1. However, heavily polluted regions like India and China may experience varied outcomes, with a potential decrease in SSP1 and increase under SSP3. Eastern China witness ~20 % rise in PM2.5 under SSP3, while northern India may experience ~70 % increase under same scenario. Depending on the region, climate change alone is expected to change PM2.5 up to ±5 µg m-3, while the influence of LULCC appears even weaker. The modest changes in PM2.5 attributable to LULCC and climate change are associated with aerosol chemistry and meteorological effects, including biogenic volatile organic compound emissions, SO2 oxidation, and NH4NO3 formation. Despite their comparatively minor role, LULCC and climate change can still significantly shape future air quality in specific regions, potentially counteracting the benefits of emission control initiatives. This study underscores the pivotal role of changes in anthropogenic emissions in shaping future PM2.5 across all SSP scenarios. Thus, addressing all contributing factors, with a primary focus on reducing anthropogenic emissions, is crucial for achieving sustainable reduction in surface PM2.5 levels and meeting sustainable pollution mitigation goals.

Viroporin-like activity of the hairpin transmembrane domain of African swine fever virus B169L protein.

African swine fever virus (ASFV) is the causative agent of a contagious disease affecting wild and domestic swine. The function of B169L protein, as a potential integral structural membrane protein, remains to be experimentally characterized. Using state-of-the-art bioinformatics tools, we confirm here earlier predictions indicating the presence of an integral membrane helical hairpin, and further suggest anchoring of this protein to the ER membrane, with both terminal ends facing the lumen of the organelle. Our evolutionary analysis confirmed the importance of purifying selection in the preservation of the identified domains during the evolution of B169L in nature. Also, we address the possible function of this hairpin transmembrane domain (HTMD) as a class IIA viroporin. Expression of GFP fusion proteins in the absence of a signal peptide supported B169L insertion into the ER as a Type III membrane protein and the formation of oligomers therein. Overlapping peptides that spanned the B169L HTMD were reconstituted into ER-like membranes and the adopted structures analyzed by infrared spectroscopy. Consistent with the predictions, B169L transmembrane sequences adopted α-helical conformations in lipid bilayers. Moreover, single vesicle permeability assays demonstrated the assembly of lytic pores in ER-like membranes by B169L transmembrane helices, a capacity confirmed by ion-channel activity measurements in planar bilayers. Emphasizing the relevance of these observations, pore-forming activities were not observed in the case of transmembrane helices derived from EP84R, another ASFV protein predicted to anchor to membranes through a α-helical HTMD. Overall, our results support predictions of viroporin-like function for the B169L HTMD.IMPORTANCEAfrican swine fever (ASF), a devastating disease affecting domestic swine, is widely spread in Eurasia, producing significant economic problems in the pork industry. Approaches to prevent/cure the disease are mainly restricted to the limited information concerning the role of most of the genes encoded by the large (160-170 kba) virus genome. In this report, we present the experimental data on the functional characterization of the African swine fever virus (ASFV) gene B169L. Data presented here indicates that the B169L gene encodes for an essential membrane-associated protein with a viroporin function.

Mild behavioral impairment domains are longitudinally associated with pTAU and metabolic biomarkers in dementia-free older adults.

BACKGROUND: The mechanisms linking mild behavioral impairment (MBI) and Alzheimer's disease (AD) have been insufficiently explored, with conflicting results regarding tau protein and few data on other metabolic markers. We aimed to evaluate the longitudinal association of the MBI domains and a spectrum of plasma biomarkers. METHODS: Our study is a secondary analysis of data from NOLAN. The longitudinal association of the MBI domains with plasma biomarkers, including pTau181, was tested using adjusted linear mixed-effects models. RESULTS: The sample comprised 359 participants (60% female, mean age: 78.3, standard deviation: 0.3 years). After 1 year, the MBI domain of abnormal perception was associated with steeper increases in plasma pTau181. Abnormal perception, decreased motivation, and impulse dyscontrol were associated with homocysteine or insulin dysregulation. DISCUSSION: Apart from the association with plasma pTau181, our results suggest that MBI might also represent metabolic dysregulation, probably contributing to dementia transition among older adults with subjective cognitive decline or mild cognitive impairment. HIGHLIGHTS: Mild behavioral impairment (MBI) psychosis was associated with steeper increases in plasma p. pTau could be a pharmacological target to treat agitation and psychosis symptoms. MBI domains were linked to metabolic dysregulation involving insulin and homocysteine.

Effects on Biochemical Parameters and Animal Welfare of Dusky Grouper (Epinephelus marginatus, Lowe 1834) by Feeding CTX Toxic Flesh.

Ciguatera is a foodborne disease caused by ciguatoxins (CTXs), produced by dinoflagellates (genera Gambierdiscus and Fukuyoa), which bioaccumulate in fish through the food web, causing poisoning in humans. Currently, the physiological mechanisms of the species with the highest amount of toxins in their adult stage of life that are capable of causing these poisonings are poorly understood. Dusky grouper (Epinephelus marginatus) is a relevant fishing species and is part of the CTX food chain in the Canary Islands. This study developed an experimental model of dietary exposure featuring adult dusky groupers with two diets of tissue naturally contaminated with CTXs (amberjack and moray eel flesh) with two different potential toxicities; both groups were studied at different stages of exposure (4, 6, 10, 12, and 18 weeks). The results showed that this species did not show changes in its behavior due to the provided feeding, but the changes were recorded in biochemical parameters (mainly lipid and hepatic metabolism) that may respond to liver damage and alterations in the homeostasis of the fish; more research is needed to understand histopathological and cytotoxic changes.

Sustainable agricultural practices influence s-metolachlor, foramsulfuron and thiencarbazone-methyl degradation and their metabolites formation.

The effect of sustainable agricultural practices, such as mulching or the application of straw residues as an organic amendment, on the degradation, dissipation and persistence in the soil of S-metolachlor (SMOC), foramsulfuron (FORAM) and thiencarbazone-methyl (TCM) is still unclear. The objective here was to conduct a laboratory experiment to evaluate the impact of milled wheat straw (WS) simulating its individual use as mulch or applied as an organic amendment to two agricultural soils: unamended and WS-amended soils on the degradation kinetics of the herbicides SMOC, FORAM and TCM, and on the formation of their major metabolites at two incubation temperatures (14 °C and 24 °C). The degradation rate of SMOC on WS was 6.9-16.7 times faster than that observed for FORAM and TCM at both temperatures. The half-life (DT50) values were 1.1-10.6 times lower for FORAM than for SMOC and TCM in the unamended and WS-amended soils at 14 °C and 24 °C. The application of WS to soils increased the DT50 values from 1.1 to 11.2 times for all the herbicides at both incubation temperatures due to their higher adsorption and lower bioavailability. The herbicides recorded a faster degradation at 24 °C (1.2-3.9 times) than at 14 °C, according to Q10 values >1. SMOC metabolites were more persistent in WS-amended soils than in unamended ones, in agreement with the DT50 values recorded for the parent compound. The results indicate that the effect of the mulch applied to soils as an organic amendment was different depending on the herbicide and incubation temperature. The outcomes of this research can give key suggestions for reducing the effects of residual herbicides following sustainable agricultural practices by avoiding soil and groundwater contamination, which is one of the challenges involved in the application of chemical inputs.

Predicting changes in brain metabolism and progression from mild cognitive impairment to dementia using multitask Deep Learning models and explainable AI.

BACKGROUND: The prediction of Alzheimer's disease (AD) progression from its early stages is a research priority. In this context, the use of Artificial Intelligence (AI) in AD has experienced a notable surge in recent years. However, existing investigations predominantly concentrate on distinguishing clinical phenotypes through cross-sectional approaches. This study aims to investigate the potential of modeling additional dimensions of the disease, such as variations in brain metabolism assessed via [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and utilize this information to identify patients with mild cognitive impairment (MCI) who will progress to dementia (pMCI). METHODS: We analyzed data from 1,617 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had undergone at least one FDG-PET scan. We identified the brain regions with the most significant hypometabolism in AD and used Deep Learning (DL) models to predict future changes in brain metabolism. The best-performing model was then adapted under a multi-task learning framework to identify pMCI individuals. Finally, this model underwent further analysis using eXplainable AI (XAI) techniques. RESULTS: Our results confirm a strong association between hypometabolism, disease progression, and cognitive decline. Furthermore, we demonstrated that integrating data on changes in brain metabolism during training enhanced the models' ability to detect pMCI individuals (sensitivity=88.4%, specificity=86.9%). Lastly, the application of XAI techniques enabled us to delve into the brain regions with the most significant impact on model predictions, highlighting the importance of the hippocampus, cingulate cortex, and some subcortical structures. CONCLUSION: This study introduces a novel dimension to predictive modeling in AD, emphasizing the importance of projecting variations in brain metabolism under a multi-task learning paradigm.

Effectiveness of repeated injections of botulinum toxin A on gait and fatigue in adults with spastic paraparesis secondary to multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is the most common neurologic disease in young adults. Spasticity is one of its most disabling symptoms, with botulinum toxin A type A (BoNT-A) being one of the treatments of choice for this symptom. OBJECTIVE: We assessed the response to abobotulinumtoxinA in improving walking ability and fatigue in patients with spastic paraparesis caused by MS. METHODS: We performed a real-world, multicenter, prospective, open-label low-intervention trial in 84 patients with MS and spastic paraparesis of the lower limbs infiltrated with abobotulinumtoxinA (LINITOX study). The response of spasticity, walking ability and fatigue is analyzed in 4 cycles of ultrasound-guided injection in the lower limbs. RESULTS: The patients improved their walking ability by an average of 11.34% meters measured with 6-Minute Walk Test (6MWT), and decreased the percentage of fatigue by 6.86% (4.66 percentage points less), in the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) 4 weeks after abobotulinumtoxinA injection, both values are statistically significant. This improvement seems to persist over time, throughout the cycles. CONCLUSION: We found improved walking ability and less fatigue in patients with MS-related spastic paresis of the lower limbs after injection of abobotulinumtoxinA.

Hyper-late major response after 5†years of nivolumab: role of treatment beyond progression in head and neck cancer.

Patients with recurrent/metastatic (R/M) platinum-refractory squamous cell carcinoma of the head and neck (SCCHN) have fewer treatment options and harbor an especially poor prognosis. Maintaining treatment with anti-PD1 agents beyond response evaluation criteria in solid tumors-defined disease progression (TBP) has been shown to be efficacious in several solid tumors, including head and neck cancer. We present the case of a platinum-refractory locally recurrent, PD-L1-negative hypopharyngeal carcinoma, that received second-line nivolumab which was then maintained beyond progression under the following criteria: no Eastern Cooperative Oncology Group performance status deterioration, no rapidly progressive disease, no severe toxicity, and evidence of overall treatment benefit. The patient achieved a partial response 8 months after starting second-line nivolumab, with progressive disease at 26 months, then followed by the first TBP with nivolumab lasting for 15 months due to a new tumor progression. A second TBP with nivolumab lasting for 7 months, was followed by a third TBP with nivolumab for 12 months and achieving a major tumor response. Treatment is still ongoing 60 months after starting nivolumab, with excellent tolerance to therapy. Maintaining anti-PD1 agents beyond progression is an efficacious treatment option for patients with R/M SCCHN, that may achieve very durable disease control and even late major responses.

BODYFAT: a new calculator to determine the risk of being overweight validated in Spanish children between 11 and 17 years of age.

The assessment of body fat of children in primary care requires consideration of the dynamic changes in height, weight, lean mass, and fat mass during childhood growth. To achieve this, we aim to develop a predictive equation based on anthropometric values, with optimal diagnostic utility. This is a cross-sectional observational study, involving schoolgoers aged 11-17 years in the Vigo metropolitan area. Out of 10,747 individuals, 577 were randomly recruited. VARIABLES: age, sex, ethnicity/country of origin, weight, height, 8 skinfolds, 3 diameters, 7 perimeters, and 85% percentile of body fat mass as the gold standard. Generalized additive regression was selected by cross-validation and compared using receiver operating characteristic curves (ROC curves). Sensitivity, specificity, positive and negative predictive values, true positive and true negative values, false positive and false negative values, accuracy, and positive and negative likelihood ratios were calculated. Two models were identified. The optimal model includes sex, weight, height, leg perimeter, and arm perimeter, with sensitivity of 0.93 (0.83-1.00), specificity of 0.91 (0.83-0.96), accuracy of 0.91 (0.84-0.96), and area under the curve (AUC) of 0.957 (0.928-0.986). The second model includes sex, age, and body mass index, with sensitivity of 0.93 (0.81-1.00), specificity of 0.90 (0.80-0.97), accuracy of 0.90 (0.82-0.96), and an AUC of 0.944 (0.903-0.984). CONCLUSION: Two predictive models, with the 85th percentile of fat mass as the gold standard, built with basic anthropometric measures, show very high diagnostic utility parameters. Their calculation is facilitated by a complementary online calculator. WHAT IS KNOWN: • In routine clinical practice, mainly in primary care, BMI is used to determine overweight and obesity. This index has its weaknesses in the assessment of children. WHAT IS NEW: • We provide a calculator whose validated algorithm, through the determination of fat mass by impedanciometry, makes it possible to determine the risk of overweight and obesity in the community setting, through anthropometric measurements, providing a new practical, accessible and reliable model that improves the classification of overweight and obesity in children with respect to that obtained by determining BMI.

The Association Between Food Security and Mammography Screening: Cross-Sectional Survey Results From the National Health Interview Survey.

OBJECTIVE: There are limited data about food insecurity within the cancer screening setting. To inform the potential need for food insecurity interventions, our study evaluated the association between food security and mammographic screening among eligible participants. METHODS: Female respondents aged 40 to 74 years in the 2019 National Health Interview Survey without history of breast cancer were included. Food insecurity was assessed using the Six-Item Food Security Scale developed by the National Center for Health Statistics. The proportion of patients who reported mammographic screening within the last year was estimated, stratified by food security. Multiple variable logistic regression analyses evaluated the association between food security and mammography screening, adjusted for potential confounders. All analyses were performed accounting for complex survey design features. RESULTS: In all, 8,956 weighted survey respondents met inclusion criteria; 90.1% were classified as having high or marginal food security, of whom 56.6% reported screening; 6.1% were classified with low food security, of whom 42.1% reported screening; and 3.8% were classified with very low food security, of whom 43.1% reported screening. In our unadjusted analyses, participants with low food security (P < .001) and very low food security (P < .001) were less likely to report screening within the last year. In our adjusted analyses, participants with food insecurity (P = .009) were less likely to report screening. DISCUSSION: In a nationally representative cross-sectional survey, participants with food insecurity were less likely to report mammography screening. Radiology practices should consider screening patients for food insecurity and social determinants of health. Evidence-based food insecurity interventions may increase adherence to mammography screening.

Predicted mechanistic impacts of human protein missense variants.

Genome sequencing efforts have led to the discovery of tens of millions of protein missense variants found in the human population with the majority of these having no annotated role and some likely contributing to trait variation and disease. Sequence-based artificial intelligence approaches have become highly accurate at predicting variants that are detrimental to the function of proteins but they do not inform on mechanisms of disruption. Here we combined sequence and structure-based methods to perform proteome-wide prediction of deleterious variants with information on their impact on protein stability, protein-protein interactions and small-molecule binding pockets. AlphaFold2 structures were used to predict approximately 100,000 small-molecule binding pockets and stability changes for over 200 million variants. To inform on protein-protein interfaces we used AlphaFold2 to predict structures for nearly 500,000 protein complexes. We illustrate the value of mechanism-aware variant effect predictions to study the relation between protein stability and abundance and the structural properties of interfaces underlying trans protein quantitative trait loci (pQTLs). We characterised the distribution of mechanistic impacts of protein variants found in patients and experimentally studied example disease linked variants in FGFR1.

Improved selection of canonical proteins for reference proteomes.

The 'canonical' protein sets distributed by UniProt are widely used for similarity searching, and functional and structural annotation. For many investigators, canonical sequences are the only version of a protein examined. However, higher eukaryotes often encode multiple isoforms of a protein from a single gene. For unreviewed (UniProtKB/TrEMBL) protein sequences, the longest sequence in a Gene-Centric group is chosen as canonical. This choice can create inconsistencies, selecting >95% identical orthologs with dramatically different lengths, which is biologically unlikely. We describe the ortho2tree pipeline, which examines Reference Proteome canonical and isoform sequences from sets of orthologous proteins, builds multiple alignments, constructs gap-distance trees, and identifies low-cost clades of isoforms with similar lengths. After examining 140 000 proteins from eight mammals in UniProtKB release 2022_05, ortho2tree proposed 7804 canonical changes for release 2023_01, while confirming 53 434 canonicals. Gap distributions for isoforms selected by ortho2tree are similar to those in bacterial and yeast alignments, organisms unaffected by isoform selection, suggesting ortho2tree canonicals more accurately reflect genuine biological variation. 82% of ortho2tree proposed-changes agreed with MANE; for confirmed canonicals, 92% agreed with MANE. Ortho2tree can improve canonical assignment among orthologous sequences that are >60% identical, a group that includes vertebrates and higher plants.

European survey on Paediatric Early Warning Systems, and other processes used to aid the recognition and response to children's deterioration on hospital wards.

BACKGROUND: Internationally, there is an increasing trend in using Rapid Response Systems (RRS) to stabilize in-patient deterioration. Despite a growing evidence base, there remains limited understanding of the processes in place to aid the early recognition and response to deteriorating children in hospitals across Europe. AIM/S: To describe the processes in place for early recognition and response to in-patient deterioration in children in European hospitals. STUDY DESIGN: A cross-sectional opportunistic multi-centre European study, of hospitals with paediatric in-patients, using a descriptive self-reported, web-based survey, was conducted between September 2021 and March 2022. The sampling method used chain referral through members of European and national societies, led by country leads. The survey instrument was an adaptation to the survey of Recognition and Response Systems in Australia. The study received ethics approval. Descriptive analysis and Chi-squared tests were performed to compare results in European regions. RESULTS: A total of 185 questionnaires from 21 European countries were received. The majority of respondents (n = 153, 83%) reported having written policies, protocols, or guidelines, regarding the measurement of physiological observations. Over half (n = 120, 65%) reported that their hospital uses a Paediatric Early Warning System (PEWS) and 75 (41%) reported having a Rapid Response Team (RRT). Approximately one-third (38%) reported that their hospital collects specific data about the effectiveness of their RRS, while 100 (54%) reported providing regular training and education to support it. European regional differences existed in PEWS utilization (North = 98%, Centre = 25%, South = 44%, p < .001) and process evaluation (North = 49%, Centre = 6%, South = 36%, p < .001). CONCLUSIONS: RRS practices in European hospitals are heterogeneous. Differences in the uptake of PEWS and RRS process evaluation emerged across Europe. RELEVANCE TO CLINICAL PRACTICE: It is important to scope practices for the safe monitoring and management of deteriorating children in hospital across Europe. To reduce variance in practice, a consensus statement endorsed by paediatric and intensive care societies could provide guidance and resources to support PEWS implementation and for the operational governance required for continuous quality improvement.

Primary Healthcare Case Management Nurses and Assistance Provided to Chronic Patients: A Narrative Review.

Population aging is causing increases in the numbers of chronic diseases, with the consequent need for changes in health systems to better assist patients with chronic conditions. A narrative review was conducted in this study with the objective of analysing the scientific evidence on the care and assistance provided by Case Management Nurses (CMNs) to chronic patients in primary healthcare. A total of 15 articles published in English, Spanish, and Portuguese were selected in the following databases: PubMed, Embase, Cochrane Library, Scopus, Dialnet, Cinahl, and Web of Science. In total, 46.6% of the studies showed the assistance provided by CMNs for chronic pathologies. Most of the articles selected (80%) considered that the assistance offered by case management nurses in relation to chronic diseases is effective, enabling cost reductions, which supposes benefits at the economic and political levels. It was concluded that CMNs have proven to be efficient in caring for people with chronic diseases, improving the quality of life of these people and their caregivers; therefore, they have a fundamental role in the PHC.

Tramadol intoxication in children: An emerging issue.

BACKGROUND: Prescribing tramadol in children raises safety concerns. In Europe, tramadol is still approved and licensed for use in children over 1-3 years of age, depending on the country. In this context, the authors report a case of a tramadol overdose in a 5-year-old-child with a medical history of homozygous sickle cell disease. METHODS: Tramadol and M1 were quantified using liquid chromatography with a diode array detection method. CYP2D6 genotype was determined using a next generation sequencing platform (MISeq, Illumina). RESULTS: Tramadol and M1 were quantified in blood respectively at 5.48 and 1.32µg/mL at admission, at 0.77 and 0.35µg/mL 12hours later, and at 0.32 and 0.18µg/mL 20hours later. The patient was predicted as a CYP2D6 normal metabolizer (*35/*29). CONCLUSION: One of the most important difficulties with the use of tramadol in children relates to its pharmacokinetic (PK) properties. Indeed, tramadol's PK is characterized by a great variability related to: (i) anatomical/physiological factors that impact the volume of distribution (Vd); (ii) CYP2D6 genetic polymorphisms. Considering such an issue is particularly relevant to prevent poisoning. In the reported case, the plasma elimination half-life was estimated at 6.3h, significantly more than those reported in 2-8 year-old children (about 3h). This discrepancy does not seem related to genetic polymorphisms but rather to the Vd. Indeed, the patient was predicted to be a CYP2D6 normal metabolizer (*35/*29). The case presented here highlights the risk associated with the tramadol use in children and emphasizes the importance of considering PK variability among this population. Such variability necessitates greater caution in prescribing tramadol in children and highlights the importance of therapeutic education for families of children treated with this painkiller.

Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer's disease.

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer's Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.