The cross-sectional area of the median nerve: An independent prognostic biomarker in amyotrophic lateral sclerosis.

INTRODUCTION: Ultrasound changes in the cross-sectional area of the median nerve (CSAmn) could be of interest as biomarkers in patients with amyotrophic lateral sclerosis (ALS). METHODS: Eighty-four ALS patients (51 men [60.7%]; mean 62.0 [SD 11.46] years old) and forty-six controls (27 men [58.7%]; mean 59.9 [SD 8.08] years old) of two different cohorts were recruited between September 2013 and February 2018. The CSAmn was measured bilaterally in each cohort, by two different examiners with two different ultrasound machines (one in each cohort). Its association with clinical variables (disease duration, muscle strength, disability, progression rate and tracheostomy-free survival) was assessed. RESULTS: The CSAmn was smaller in patients than in controls, and the study cohort did not influence its values. A mild correlation between the strength of the wrist flexor and the CSAmn was found. In the multivariable analysis, the probability of this association being true was 90%. In the cox regression, both a faster progression rate and a larger CSAmn independently predicted poor survival (HR=4.29, [Cr.I95%: 2.71-6.80], p<0.001; and HR=1.14, [Cr.I95%: 1.03-1.25], p=0.01), after adjusting by age, body mass index, bulbar onset, and diagnostic delay. CONCLUSIONS: The CSAmn is an easy to assess biomarker that seems reliable and reproducible. Our data also suggest that it could act as a progression and prognostic biomarker in ALS patients. Longitudinal studies with repeated measures are warranted to confirm its usefulness in the clinical practice.

Thermosensitive chitosan-based hydrogel: A vehicle for overcoming the limitations of nose-to-brain cell therapy.

Cell therapy is a promising strategy for treating neurological pathologies but requires invasive methods to bypass the blood-brain barrier restrictions. The nose-to-brain route has been presented as a direct and less invasive alternative to access the brain. The primary limitations of this route are low retention in the olfactory epithelium and poor cell survival in the harsh conditions of the nasal cavity. Thus, using chitosan-based hydrogel as a vehicle is proposed in this work to overcome the limitations of nose-to-brain cell administration. The hydrogel's design was driven to achieve gelification in response to body temperature and a mucosa-interacting chemical structure biocompatible with cells. The hydrogel showed a < 30 min gelation time at 37 °C and >95 % biocompatibility with 2D and 3D cultures of mesenchymal stromal cells. Additionally, the viability, stability, and migration capacity of oligodendrocyte precursor cells (OPCs) within the hydrogel were maintained in vitro for up to 72 h. After the intranasal administration of the OPCs-containing hydrogel, histological analysis showed the presence of viable cells in the nasal cavity for up to 72 h post-administration in healthy athymic mice. These results demonstrate the hydrogel's capacity to increase the residence time in the nasal cavity while providing the cells with a favorable environment for their viability. This study presents for the first time the use of thermosensitive hydrogels in nose-to-brain cell therapy, opening the possibility of increasing the delivery efficiency in future approaches in translational medicine. STATEMENT OF SIGNIFICANCE: This work highlights the potential of biomaterials, specifically hydrogels, in improving the effectiveness of cell therapy administered through the nose. The nose-to-brain route has been suggested as a non-invasive way to directly access the brain. However, delivering stem cells through this route poses a challenge since their viability must be preserved and cells can be swept away by nasal mucus. Earlier attempts at intranasal cell therapy have shown low efficiency, but still hold promise to the future. The hydrogels designed for this study can provide stem cells with a biocompatible environment and adhesion to the nasal atrium, easing the successful migration of viable cells to the brain.

Nonlinear response of very high frequency contour mode resonators.

We explore the source of nonlinearities in Aluminum Nitride (AlN) Contour Mode Resonators (CMRs) operating in the Very High Frequency (VHF) range. We demonstrate that the red-shift of the resonance frequency found in VHF CMRs when the input RF power increases is due to nonlinear stiffness appearing from self-heating, and variable damping due to geometric nonlinearities. Moreover, we find a linear relationship between the variable damping coefficient and the resonator quality factor (Q). Such nonlinear mechanisms are modeled using a spring-mass-damper physical system and, in the electrical domain, a modified Butterworth-Van Dyke (MBVD) circuit where the nonlinear stiffness and variable damping are captured by a charge-dependent motional capacitor and a charge-dependent motional resistor, respectively. Detailed guidelines are provided to accurately analyze nonlinear CMRs using full-wave numerical simulations based on a finite-element method. Such simulations allow us to isolate the influence of each independent nonlinear mechanism and establish a relation between variable damping and geometric nonlinearities. Circuit and full-wave numerical simulations are in good agreement with measured data from fabricated 225 MHz CMRs exhibiting different Q. Finally, we exploit nonlinearities in high-Q CMRs to generate frequency combs at the MHz range opening the door to new exciting applications in telecommunication and sensing.

Outcomes of people with TB reported to the WHO Global Clinical Platform of COVID-19.

BACKGROUND: TB is a leading infectious cause of death worldwide. The COVID-19 pandemic raised concerns that the burden of TB disease and death would increase due to the synergy between the two conditions. METHODS: We used individual-level data submitted to the WHO Global Clinical Platform for COVID-19 on hospitalised patients to explore associations of TB with mortality using multivariable logistic regression. RESULTS: Data were available from 453,233 persons with COVID-19 and known TB status and mortality outcomes from 62 countries (96% SARS-CoV-2 test-positive). Of these, 48% were male, and the median age was 53 years (IQR 38-67). There were 8,214 cases with current TB reported by 46 countries, mainly from Africa. Of people with current TB, 31.4% were admitted with severe illness, and 24.5% died. Current TB was independently associated with higher mortality when adjusted for age, sex, HIV status, illness severity at hospital admission, and underlying conditions (adjusted RR 1.47, 95% CI 1.35-1.61). CONCLUSION: Current or past TB were independent risk factors for in-hospital mortality regardless of illness severity at admission. Caveats for interpretation include changes during the data collection period (viral variation, vaccination coverage) and opportunistic sampling. However, the platform exemplifies how timely, coordinated global reporting can inform our understanding of health emergencies and the vulnerable populations affected.

CONTEXTE: La TB est l'une des principales causes infectieuses de décès dans le monde. La pandémie de COVID-19 a fait craindre que le fardeau de la TB et des décès n'augmente en raison de la synergie entre les deux maladies. MÉTHODES: Nous avons utilisé les données individuelles soumises à la Plateforme clinique mondiale de l'OMS pour la COVID-19 sur les patients hospitalisés pour explorer les associations entre la TB et la mortalité à l'aide d'une régression logistique multivariée. RÉSULTATS: Des données étaient disponibles sur 453 233 personnes atteintes de COVID-19 et connues pour le statut de TB et les résultats de mortalité dans 62 pays (96% de tests positifs au SRAS-CoV-2). Parmi eux, 48% étaient des hommes et l'âge médian était de 53 ans (IQR 38­67). Un total de 8 214 cas de TB ont été signalés par 46 pays, principalement en Afrique. Parmi les personnes atteintes de TB actuelle, 31,4% ont été admises avec une maladie grave et 24,5% sont décédées. La TB actuelle était indépendamment associée à une mortalité plus élevée lorsqu'elle était ajustée en fonction de l'âge, du sexe, du statut VIH, de la gravité de la maladie à l'admission à l'hôpital et des affections sous-jacentes (RR ajusté 1,47 ; IC à 95% 1,35­1,61). CONCLUSION: La TB actuelle ou passée était un facteur de risque indépendant de mortalité à l'hôpital, quelle que soit la gravité de la maladie à l'admission. Les mises en garde concernant l'interprétation comprennent les changements au cours de la période de collecte des données (variation virale, couverture vaccinale) et l'échantillonnage opportuniste. Cependant, la plateforme illustre comment des rapports mondiaux opportuns et coordonnés peuvent éclairer notre compréhension des urgences sanitaires et des populations vulnérables touchées.

Life cycle and economic assessment of tidal energy farms in early design phases: Application to a second-generation tidal device.

Ocean currents are emerging as key contributors to renewable energy generation. However, technologies for harvesting tidal current energy are still in the early stages of development. In this context, environmental and economic studies on tidal energy converters (TECs) are crucial to further advance tidal technology and facilitate its entry into the market. This article presents a life cycle and economic assessment of a 34.5 MW tidal farm project comprising 23 second-generation tidal devices, each with a rated power of 1.5 MW. The tidal system was simulated using primary data from the full-scale floating platform Atir. The Atir is a pre-commercial tidal device designed with a steel trimaran and a submerged section for TEC installation. An assessment of 18 environmental impact categories was conducted using the ReCiPe 2016 MidPoint method, with process flow systems modelled using SimaPro v9.2.0.1 software. The environmental assessment indicates emissions of 42.11 g CO2eq per kWh, primarily stemming from manufacturing processes that demand substantial amounts of steel. The economic analysis reveals a Levelized Cost of Electricity (LCOE) of 0.125 EUR/kWh, consistent with European Commission projections. Although the platform structure represents a high initial investment, the lower maintenance costs of the Atir device provide long-term savings and, overall, result in a competitive LCOE. The study also introduces a methodological framework for harmonised environmental and economic assessments in tidal energy projects, proving crucial in supporting decision-making processes.

Acute liver failure: Management update and prognosis.

Acute liver failure is a rare but serious syndrome, with an incidence of approximately 2,000 to 3,000 cases per year in North America. Its pathophysiology and clinical course vary, depending on the cause of the primary liver injury, and can lead to high morbidity and mortality or the need for liver transplantation, despite available therapies. This syndrome involves excessive activation of the immune system, with damage in other organs, contributing to its high mortality rate. The most accepted definition includes liver injury with hepatic encephalopathy and coagulopathy within the past 26 weeks in a patient with no previous liver disease. The main causes are paracetamol poisoning, viral hepatitis, and drug-induced liver injury, among others. Identifying the cause is crucial, given that it influences prognosis and treatment. Survival has improved with supportive measures, intensive therapy, complication prevention, and the use of medications, such as N-acetylcysteine. Liver transplantation is a curative option for nonresponders to medical treatment, but adequate evaluation of transplantation timing is vital for improving results. Factors such as patient age, underlying cause, and severity of organ failure influence the post-transplant outcomes and survival.

How heatwaves affect short-term emergency hospital admissions due to bacterial foodborne diseases.

The coming decades are likely to see of extreme weather events becoming more intense and frequent across Europe as a whole and around the Mediterranean in particular. The reproduction rate of some microorganisms, including the bacteria that cause foodborne diseases, will also be affected by these events. The aim of this study was thus to ascertain whether there might be a statistically significant relationship between emergency hospital admissions due to the principal bacterial foodborne diseases (BFDs) and the various meteorological variables, including heatwaves. We conducted a time-series study, with daily observations of both the dependent variable (emergency hospital admissions due to BFDs) and the independent variables (meteorological variables and control variables of chemical air pollution) across the period 2013-2018 in the Madrid Region (Spain), using Generalised Linear Models with Poisson regression, in which control and lag variables were included for the purpose of fitting the models. We calculated the threshold value of the maximum daily temperature above which such admissions increased statistically significantly, analysed data for the whole year and for the summer months alone, and estimated the relative and attributable risks. The estimated attributable risk was 3.6 % for every one-degree rise in the maximum daily temperature above 12 °C throughout the year, and 12.21 % for every one degree rise in temperature above the threshold heatwave definition temperature (34 °C) in summer. Furthermore, different meteorological variables displayed a statistically significant association. Whereas hours of sunlight and mean wind speed proved significant in the analyses of both the whole year and summer, the variables "rain" and "relative humidity", only showed a significant relationship in the analysis for the whole year. High ambient temperature is a risk factor that favours the increase in emergency hospitalisations attributable to the principal BFDs, with a greater impact being observed on days coinciding with heatwave periods. The results yielded by this study could serve as a basis for implementing BFD prevention strategies, especially on heatwave days.

Short-term effects of fine particulate matter from biomass combustion and Saharan dust intrusions on emergency hospital admissions due to mental and behavioural disorders, anxiety and depression in Spain.

Climate change is affecting both the frequency and scale of wildfires, as well as the increase in the number of days with Saharan dust intrusions. Traditionally, studies have focused on the extent to which the increase in fine particulate matter (PM) has had an impact on cardio-respiratory diseases, but (apart from PM) not on how the meteorological and pollution conditions in these situations affect other diseases, such as those linked to mental health. This study therefore sought to ascertain how daily mean PM10, PM 2.5, NO2, O3 concentrations and daily maximum temperature in heat waves influence daily emergency hospital admissions in Spain caused by mental and behavioural disorders, depression and anxiety on days with PM from biomass combustion and/or Saharan dust intrusions, as compared to days without such conditions, across the period 2009-2018. Our results indicate that on days on which there is biomass combustion, PM concentrations have a statistically significant effect on emergency admissions due to mental disorders, probably related with the toxicity of these particles. Yet on days with intrusions of Saharan dust rather than PM, it is the other variables considered in the analysis that are most closely linked to these types of admissions. The results of this study thus point to the need to implement public health prevention plans which take into account the joint effect of various environmental risk factors that act synergistically in given situations.

Unraveling metabolic stress response in dairy cows: genetic control of plasma biomarkers throughout lactation and the transition period.

Breeding animals able to effectively respond to stress could be a long-term, sustainable, and affordable strategy to improve resilience and welfare in livestock systems. In the present study, the concentrations of 29 plasma biomarkers were used as candidate endophenotypes for metabolic stress response in single-SNP, gene- and haplotype-based GWAS using 739 healthy lactating Italian Holstein cows and 88,271 variants. Significant genetic associations were found in all the 3 GWAS approaches for plasma γ-glutamyl transferase concentration on BTA17, for paraoxonase on BTA4, and for alkaline phosphatase and zinc on BTA2. On these chromosomes, single-SNP and gene-based chromosome-wide association studies were performed, confirming GWAS findings. The signals identified for paraoxonase, γ-glutamyl transferase, and alkaline phosphatase were in proximity of the genes coding for them. The heritability of these 4 biomarkers ranged from moderate to high (from 0.39 to 0.54). Plasma biomarkers are known to undergo large changes in concentration during metabolic stress in the transition period, with an inter-individual variability in the rate of change and recovery time. Genetics may account in part for these differences. To assess this, we studied a subset of 139 periparturient cows homozygous at 3 SNPs known to be respectively associated with concentration of plasma ceruloplasmin, paraoxonase and γ-glutamyl transferase. We compared the immune-metabolic profile measured in plasma at -7, +5 and +30 d relative to calving between groups of opposite homozygotes. A significant effect of the genotype was found on paraoxonase and γ-glutamyl transferase plasma concentration at all the 3 time points. No evidence for genotype effect was detected for ceruloplasmin. Understanding the genetic control underlying metabolic stress response may suggest new approaches to foster resilience in dairy cows.

Development of Potent Microtubule Targeting Agent by Structural Simplification of Natural Diazonamide.

The marine metabolite diazonamide A exerts low nanomolar cytotoxicity against a range of tumor cell lines; however, its highly complex molecular architecture undermines the therapeutic potential of the natural product. We demonstrate that truncation of heteroaromatic macrocycle in natural diazonamide A, combined with the replacement of the challenging-to-synthesize tetracyclic hemiaminal subunit by oxindole moiety leads to considerably less complex analogues with improved drug-like properties and nanomolar antiproliferative potency. The structurally simplified macrocycles are accessible in 12 steps from readily available indolin-2-one and tert-leucine with excellent diastereoselectivity (99:1 dr) in the key macrocyclization step. The most potent macrocycle acts as a tubulin assembly inhibitor and exerts similar effects on A2058 cell cycle progression and induction of apoptosis as does marketed microtubule-targeting agent vinorelbine.