Soluble p75 neurotrophic receptor as a reliable biomarker in neurodegenerative diseases: what is the evidence?

Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve development and maturation.Its cleavable extracellular domain(ECD)is readily detectable in various biological fluids including plasma,serum and urine.There is evidence for increased p75NTR ECD levels in neurodegenerative diseases such as Alzheimer’s disease,amyotrophic lateral sclerosis,age-related dementia,schizophrenia,and diabetic neuropathy.Whether p75^(NTR) ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders,and whether it could potentially lead to the development of targeted therapies,remains an open question.In this review,we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases.We also highlight areas that require further investigation to better understand the role of p75^(NTR) ECD in the clinical diagnosis and management of neurodegenerative disorders.

Giant ultrafast dichroism and birefringence with active nonlocal metasurfaces

Switching of light polarization on the sub-picosecond timescale is a crucial functionality for applications in a variety of contexts,including telecommunications,biology and chemistry.The ability to control polarization at ultrafast speed would pave the way for the development of unprecedented free-space optical links and of novel techniques for probing dynamical processes in complex systems,as chiral molecules.Such high switching speeds can only be reached with an all-optical paradigm,i.e.,engineering active platforms capable of controlling light polarization via ultrashort laser pulses.Here we demonstrate giant modulation of dichroism and birefringence in an all-dielectric metasurface,achieved at low fluences of the optical control beam.This performance,which leverages the many degrees of freedom offered by all-dielectric active metasurfaces,is obtained by combining a high-quality factor nonlocal resonance with the giant third-order optical nonlinearity dictated by photogenerated hot carriers at the semiconductor band edge.

Dental impact of anti-fibroblast growth factor 23 therapy in X-linked hypophosphatemia

Elevated fibroblast growth factor 23(FGF23)in X-linked hypophosphatemia(XLH)results in rickets and phosphate wasting,manifesting by severe bone and dental abnormalities.Burosumab,a FGF23-neutralizing antibody,an alternative to conventional treatment(phosphorus and active vitamin D analogs),showed significant improvement in the long bone phenotype.Here,we examined whether FGF23 antibody(FGF23-mAb)also improved the dentoalveolar features associated with XLH.Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg−1 of FGF23-mAb for 2 months and compared to wild-type(WT)and vehicle(PBS)treated Hyp mice(n=3–7 mice).Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice,the higher concentration resulting in a rescue similar to WT levels.FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones.Histology revealed improved mineralization of the dentoalveolar tissues,with a decreased amount of osteoid,predentin and cementoid.Better periodontal ligament attachment was also observed,evidenced by restoration of the acellular cementum.These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features.Taken together,our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment,heralding its benefit in clinics for dental abnormalities.

Genetic identification and reiterated captures suggest that the Astyanax mexicanus El Pachón cavefish population is closed and declining

The sizes of Astyanax mexicanus blind cavefish populations of North-East Mexico are demographic parameters of great importance for investigating a variety of ecological,evolutionary,and conservation issues.However,few estimates have been obtained.For these mobile animals living in an environment difficult to explore as a whole,methods based on capture-mark-recapture are appropriate,but their feasibility and interpretation of results depend on several assumptions that must be carefully examined.Here,we provide evidence that minimally invasive genetic identification from captures at different time intervals(three days and three years)can give insights into cavefish population size dynamics as well as other important demographic parameters of interest.We also provide tools to calibrate sampling and genotyping efforts necessary to reach a given level of precision.Our results suggest that the El Pachón cave population is currently very small,of an order of magnitude of a few hundreds of individuals,and is distributed in a relatively isolated area.The probable decline in population size in the El Pachón cave since the last census in 1971 raises serious conservation issues.

Involvement of toll-like receptor 5 in mouse model of colonic hypersensitivity induced by neonatal maternal separation

BACKGROUND Chronic abdominal pain is the most common cause for gastroenterology consultation and is frequently associated with functional gastrointestinal disorders including irritable bowel syndrome and inflammatory bowel disease. These disorders present similar brain/gut/microbiota trialogue alterations, associated with abnormal intestinal permeability, intestinal dysbiosis and colonic hypersensitivity(CHS). Intestinal dysbiosis can alter colon homeostasis leading to abnormal activation of the innate immunity that promotes CHS, perhaps involving the toll-like receptors(TLRs), which play a central role in innate immunity.AIM To understand the mechanisms between early life event paradigm on intestinal permeability, fecal microbiota composition and CHS development in mice with TLRs expression in colonocytes.METHODS Maternal separation model(NMS) CHS model, which mimics deleterious events in childhood that can induce a wide range of chronic disorders during adulthood were used. Colonic sensitivity of NMS mice was evaluated by colorectal distension(CRD) coupled with intracolonic pressure variation(IPV) measurement. Fecal microbiota composition was analyzed by 16S rRNA sequencing from weaning to CRD periods. TLR mRNA expression was evaluated in colonocytes.Additionally, the effect of acute intrarectal instillation of the TLR5 agonist flagellin(FliC) on CHS in adult naive wildtype mice was analyzed.RESULTS Around 50% of NMS mice exhibited increased intestinal permeability and CHS associated with intestinal dysbiosis, characterized by a significant decrease of species richness, an alteration of the core fecal microbiota and a specific increased relative abundance of flagellated bacteria. Only TLR5mRNA expression was increased in colonocytes of NMS mice with CHS. Acute intrarectal instillation of FliC induced transient increase of IPV, reflecting transient CHS appearance.CONCLUSION Altogether, these data suggest a pathophysiological continuum between intestinal dysbiosis and CHS, with a role for TLR5.

Diabetes and pulmonary infection:how hyperglycaemia shapes the immune system

In a recent study published in Nature,Nobs and colleagues aimed to identify novel mechanisms that may explain why diabetes is associated with an increased susceptibility to viral respiratory infections.Their analyses revealed a central role of lung dendritic cells(DC)which exhibited several functional defects induced by hyperglycaemia and consequently result in impaired antiviral immune responses.

A level line of the Gaussian free field with measure-valued boundary conditions

In this article, we construct samples of Schramm-Loewner-evolution-like curves out of samples ofthe conformal loop ensemble and Poisson point processes of Brownian excursions. We show that the laws of thesecurves depend continuously on the intensity measure of the Brownian excursions. Using such a construction ofcurves, we extend the notion of level lines of the Gaussian free field to the case where the boundary conditionis measure-valued.

Advances in the engineering of the outer blood-retina barrier:From in-vitro modelling to cellular therapy

The outer blood-retina barrier(oBRB),crucial for the survival and the proper functioning of the overlying retinal layers,is disrupted in numerous diseases affecting the retina,leading to the loss of the photoreceptors and ultimately of vision.To study the oBRB and/or its degeneration,many in vitro oBRB models have been developed,notably to investigate potential therapeutic strategies against retinal diseases.Indeed,to this day,most of these pathologies are untreatable,especially once the first signs of degeneration are observed.To cure those patients,a current strategy is to cultivate in vitro a mature oBRB epithelium on a custom membrane that is further implanted to replace the damaged native tissue.After a description of the oBRB and the related diseases,this review presents an overview of the oBRB models,from the simplest to the most complex.Then,we propose a discussion over the used cell types,for their relevance to study or treat the oBRB.Models designed for in vitro applications are then examined,by paying particular attention to the design evolution in the last years,the development of pathological models and the benefits of co-culture models,including both the retinal pigment epithelium and the choroid.Lastly,this review focuses on the models developed for in vivo implantation,with special emphasis on the choice of the material,its processing and its characterization,before discussing the reported pre-clinical and clinical trials.

Recent advances in Fe-based bioresorbable stents:Materials design and biosafety

Fe-based materials have received more and more interests in recent years as candidates to fabricate bioresorbable stents due to their appropriate mechanical properties and biocompatibility.However,the low degradation rate of Fe is a serious limitation for such application.To overcome this critical issue,many efforts have been devoted to accelerate the corrosion rate of Fe-based stents,through the structural and surface modification of Fe matrix.As stents are implantable devices,the released corrosion products(Fe^(2+)ions)in vessels may alter the metabolism,by generating reactive oxygen species(ROS),which might in turn impact the biosafety of Fe-based stents.These considerations emphasize the importance of combining knowledge in both materials and biological science for the development of efficient and safe Fe-based stents,although there are still only limited numbers of reviews regarding this interdisciplinary field.This review aims to provide a concise overview of the main strategies developed so far to design Fe-based stents with accelerated degradation,highlighting the fundamental mechanisms of corrosion and the methods to study them as well as the reported approaches to accelerate the corrosion rates.These approaches will be divided into four main sections,focusing on(i)increased active surface areas,(ii)tailored microstructures,(iii)creation of galvanic reactions(by alloying,ion implantation or surface coating of noble metals)and(iv)decreased local pH induced by degradable surface organic layers.Recent advances in the evaluation of the in vitro biocompatibility of the final materials and ongoing in vivo tests are also provided.

Insights into the 2023 multidisciplinary surgical treatment guidelines for hepatocellular carcinoma:perspectives from Italian Professional Associations

The collaboration among various Italian scientific societies to establish recommendations for the surgical management of hepatocellular carcinoma(HCC),recently published in Digestive and Liver Disease(1),is a worthy effort.This multidisciplinary approach,which includes input from different disciplines such as surgery,hepatology,gastroenterology,oncology,pathology,radiology,and patient associations,underscores the commitment to placing patients at the center of care.Such a holistic and inclusive approach enhances the relevance and applicability of these guidelines in clinical practice.While several scientific associations have previously issued guidelines for managing HCC,the Italian colleagues have adopted a comprehensive methodology.

Lipid-derived radical-trapping antioxidants suppress ferroptosis

Ferroptosis,characterized by lipid peroxidation-mediated cell demise,is governed by a nuanced interplay of lipid species influencing its vulnerability.Two recent publications in Nature discovered 7-dehydrocholesterol,a cholesterol precursor,as a radical-trapping antioxidant that can suppress ferroptosis,thereby presenting a novel metabolic target to improve ferroptosis-related cancer therapy.

Protein-S-100-beta is increased in patients with decompensated cirrhosis admitted to ICU

Background Hepatic encephalopathy(HE)is highly prevalent in patients with liver diseases.The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation.However,some data suggest altered functioning of the blood–brain barrier(BBB).Assessing BBB function is challenging in clinical practice and at the bedside.Protein-S-100 Beta(PS100-Beta)could be a useful peripheral marker of BBB permeability in HE.This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit(ICU)with decompensated cirrhosis with and without overt HE.Methods We retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement.Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded.Overt HE was defined as West-Haven grades 2 to 4.The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes.After ICU discharge,the patients were followed for at least 3 months for the occurrence of overt HE.Adverse outcomes(liver transplantation or death)were collected.The ability of PS100-Beta–in combination with other factors–to predict overt HE was evaluated in a multivariate analysis using logistic regression.Likelihood ratios were used to determine the effects and calculate odds ratios(OR).Survival analysis was performed by using the Kaplan–Meier method and survival between groups was compared using a Log-rank test.Results A total of 194 ICU patients and 207 outpatients were included in the study.Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients([0.15±0.01]mg/L vs.[0.08±0]mg/L,P<0.001).ICU patients with overt HE had higher levels of PS100-Beta([0.19±0.03]mg/L)compared with the ICU patients without overt HE([0.13±0.01]mg/L)(P=0.003).PS100-Beta levels did not differ in outpatients with F 0–3 compared to F 4 fibrosis(P=0.670).PS100-Beta values were correlated with Child-Pugh score(P<0.001),Model for End-Stage Liver Disease(MELD)score(P=0.004),C-reactive protein(P<0.001),ammonemia(P<0.001),and chronic liver failure consortium(CLIF-C)organ failure(P<0.001)and CLIF-C acute-on-chronic(P=0.038)scores,but not with leukocytes(P=0.053),procalcitonin(PCT)(P=0.107),or the lymphocyte-to-neutrophil ratio in ICU patients(P=0.522).In a multivariate model including age,ammonemia,PS100-Beta,PCT,MELD,presence of transjugular portosystemic shunt,and sodium level,the diagnostic performance was 0.765 for the diagnosis of overt HE.Patients with a PS100-Beta level<0.12 mg/L had a better overall survival(P=0.019)and a better survival without liver transplantation(P=0.013).Conclusions Serum levels of PS100-Beta are elevated in ICU patients with decompensated cirrhosis,and even more so in those displaying overt HE,and the levels are correlated with outcome.This suggests an increase in the permeability of the BBB in these patients.

Targeted therapy for capillary-venous malformations

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK,an endothelial transmembrane receptor signaling through PIK3CA.Venous malformations are associated with pain,bleedings,thrombosis,pulmonary embolism,esthetic deformities and,in severe cases,life-threatening situations.No authorized medical treatment exists for patients with venous malformations.Here,we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes.We showed that these malformations only partially signal through AKT proteins.We compared the efficacy of different drugs,including rapamycin,a mTORC1 inhibitor,miransertib,an AKT inhibitor and alpelisib,a PI3Kαinhibitor at improving the lesions seen in the mouse model.We demonstrated the effectiveness of alpelisib in preventing vascular malformations’occurrence,improving the already established ones,and prolonging survival.Considering these findings,we were authorized to treat 25 patients with alpelisib,including 7 children displaying PIK3CA(n=16)or TEK(n=9)-related capillary venous malformations resistant to usual therapies including sirolimus,debulking surgical procedures or percutaneous sclerotherapies.We assessed the volume of vascular malformations using magnetic resonance imaging(MRI)for each patient.Alpelisib demonstrated improvement in all 25 patients.Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated.MRI showed a decrease of 33.4%and 27.8%in the median volume of PIK3CA and TEK malformations respectively,over 6 months on alpelisib.In conclusion,this study supports PI3Kαinhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.

Evidence for particle acceleration approaching PeV energies in the W51 complex

Theγ-ray emission from the W51 complex is widely acknowledged to be attributed to the interaction between the cosmic rays(CRs)accelerated by the shock of supernova remnant(SNR)W51C and the dense molecular clouds in the adjacent star-forming region,W51B.However,the maximum acceleration capability of W51C for CRs remains elusive.Based on observations conducted with the Large High Altitude Air Shower Observatory(LHAASO),we report a significant detection ofγrays emanating from the W51 complex,with energies from 2 to 200 TeV.The LHAASO measurements,for the first time,extend theγ-ray emission from the W51 complex beyond 100 TeV and reveal a significant spectrum bending at tens of TeV.By combining the"π^(0)-decay bump"featured data from Fermi-LAT,the broadbandγ-ray spectrum of the W51 region can be well-characterized by a simple pp-collision model.The observed spectral bending feature suggests an exponential cutoff at~400 TeV or a power-law break at~200 TeV in the CR proton spectrum,most likely providing the first evidence of SNRs serving as CR accelerators approaching the PeV regime.Additionally,two young star clusters within W51B could also be theoretically viable to produce the most energeticγrays observed by LHAASO.Our findings strongly support the presence of extreme CR accelerators within the W51 complex and provide new insights into the origin of Galactic CRs.

Expérience des parents faceàl’accompagnement pédiatrique en HAD:étude exploratoire qualitative Parents’Experience of Pediatric Home Care:A Qualitative Exploratory Study

Aim:To investigate parents’experience of home care for children in oncology in order to identify the benefits,expectations,and possible difficulties associated.Material and methods:A qualitative method was adopted,with non-directive interviews conducted with nine participants,then analyzed using thematic content analysis.Results:The main recurring themes in the discourse include:(1)relief,(2)positive representation of home,(3)positive representation of home care,and(4)negative representation of home care.For these parents,home care appears to be positive overall,even though the introduction of home care is often reported as a source of stress for them.Conclusion:These results must be interpreted with caution,but they do support previous research and highlight certain recommendations for further improving this experience,particularly for parents,but also for the sick child and the family.

Assessment of a Multimodal Strategy for Information and Collection of Advance Directives in a Comprehensive Cancer Center:Description of the Study Protocol

Background:Information on the possibility of drawing up Advance Directives(AD)is a necessity,and represents a major medical,ethical,and legal challenge.The difficulties are numerous,both organizational and cultural,and this is also true in the context of oncology,where ADs(and more broadly,advanced palliative care)are of critical importance.As an eminently sensitive subject,dealing with ADs(and therefore with end-of-life issues)requires both societal and medical/health-care acculturation.An institutional approach has therefore been developed,to deploy information tools,training professionals,and formalize the collection of AD.Such an approach cannot be implemented without an assessment not only of its objective results but also above all of its psychological effects,on both users(patients,family caregivers)and professionals.Methods:This longitudinal study,based on a mixed-method,interdisciplinary approach,will assess the impact of this information dissemination on AD,in terms of both potential positive and negative effects,using validated measurement methods.Thus,this study follows the 5 criteria of the RE-AIM model,designed to analyze the interest and impact of a device intended for users of the healthcare system;we will use a mixed methodology,relying on both a quantitative component(counting the number of people benefiting from the scheme,and those requesting support in drawing up their DA...,administering questionnaires),as well as a qualitative component(focus groups)which will enable us to study the subjective experiences of users,their relatives and the professionals involved in the scheme.Results:The results of this study will make it possible to determine the effects of this system of assistance in the drafting of ADs,which is currently being promoted by the legislator,but which is struggling to be implemented.

Mener des recherches pluridisciplinaires en SHS dans le domaine du cancer:quels leviers,quels freins?Conducting Multidisciplinary SHS Research in the Field of Cancer:Strengths and Barriers?

This paper summarizes the work held at the Cancéropôle Ile-de-France's annual SHS research seminar on the theme:Pluridisciplinarity and methods for SHS research in thefield of cancer.After clarifying the concepts of pluri-,inter-,and transdisciplinarité,it aimed to describe how this type of research is carried out in practice,addressing successively:the role of stakeholders and their respective positions,the need for a shared language,the various temporalities involved and task sharing,the interview and analysis methods as well as the implication of patient-researchers.It highlighted the personal qualities required to practice this type of research,such as psychologicalflexibility and adaptability,a strong desire for collaborative work,acceptance of risk,and a humble stance.

Mettre en dialogue disciplines et personnes concernées par le cancer pour améliorer le parcours des soins en oncologie Dialogue between Disciplines and People Affected by Cancer to Improve the Path of Care in Oncology

Interdisciplinarity and participatory research have become the guiding principles of cancer research.But what are the practical forms and methods?Based on the experience of 3 successive research projects aimed at improving cancer care pathways-PARCA1,PARCA2 and 4P-we present the encounters between researchers on the one hand,and between these same researchers and patients and health professionals on the other.Gradually,these meetings have led to the co-construction of projects and the shared conduct of research.The motivations behind the participatory approach are highlighted,as well as the‘step-by-step’approach needed to familiarize the people involved with the research process,and the limits of the approach:while everyone’s position tends to be adjusted as the projects progress,there is still an imbalance between the researchers and the people involved.

Health Democracy and Storytelling:A Synthesis of Knowledge

Aims:Health democracy requires tools and methodologies to involve non-scientific actors in the development and implementation of health policies.Storytelling could be one of the tools to make health democracy effective.Our aim is to describe how storytelling is used in relation to health democracy,the aims of its use,the methodology adopted and the results obtained.Procedure:We conducted a narrative review of the literature.Our search equation was composed by the keyword“narration”and its variations“récit de vie”,“histoire de vie”and“medécine narrative”and by the keyword“démocratie en santé”/“démocratie sanitaire”.Results:We obtained 135 results and included six articles,published between 2015 and 2022.The interest of storytelling in a health democracy approach concerns six main themes:a)the plurality of experiences;b)empowerment;c)the recognition of different types of knowledge;d)the involvement of all care actors in care;storytelling as a lever for change;e)in the care pathway;f)in health policies.Conclusion:The limited number of articles included in this literature review raises questions about the diffusion of the concept of health democracy associated with that of storytelling.Storytelling can contribute to the dissemination and effectiveness of health democracy:it is a complementary tool to quantitative tools for understanding the experiences of users of the health care system,and its use is particularly relevant to chronic diseases such as cancer.

Biliary tract viability assessment and sequential hypothermic-normothermic perfusion in liver transplantation

We read with great interest the study of Mergental et al.(1)reporting the 5-year outcomes of the VITTAL trial(2,3).VITTAL was a prospective,non-randomized,single-arm trial that tested end-ischemic oxygenated normothermic machine perfusion(NMP)with a“back-to-base”strategy to evaluate,and potentially transplant,liver grafts declined by all liver transplantation(LT)centers in the United Kingdom.For a liver to be considered viable,it had to metabolize perfusate lactate to a concentration of≤2.5 mmol/L within four hours from the start of perfusion,and meet at least two of the following criteria:bile production without a defined quantity;maintenance of perfusate pH above 7.3;glucose consumption in the perfusate;maintenance of stable arterial and portal flow above 150 and 500 mL/min,respectively;maintenance of graft suppleness and homogeneous perfusion(4).Thirty-one discarded human donor livers underwent viability testing by using end-ischemic NMP,of which 22(71%)livers were subsequently transplanted.The primary outcome of the trial was graft survival rate at 90 days and it was 100%.