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Summary: Some HIV controllers experience immunologic progression with CD4+ T cell decline. We aimed to identify genetic factors associated with CD4+ T cell lost in HIV controllers. A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p = 0.005; OR = 1.70], rs59440261 [p = 0.003; OR = 1.78]), MICA (rs112243036 [p = 0.011; OR = 1.45]), and PSORS1C1 loci (rs3815087 [p = 0.017; OR = 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype.

Summary: Background: Plasmacytoid dendritic cells (pDCs) sense viral and bacterial products through Toll-like receptor (TLR)-7 and -9 and translate this sensing into Interferon-α (IFN-α) production and T-cell activation. The understanding of the mechanisms involved in pDCs stimulation may contribute to HIV-cure immunotherapeutic strategies. The objective of the present study was to characterize the immunomodulatory effects of TLR agonist stimulations in several HIV-1 disease progression phenotypes and in non HIV-1 infected donors. Methods: pDCs, CD4 and CD8 T-cells were isolated from 450 ml of whole blood from non HIV-1 infected donors, immune responders (IR), immune non responders (INR), viremic (VIR) and elite controller (EC) participants. pDCs were stimulated overnight with AT-2, CpG-A, CpG-C and GS-9620 or no stimuli. After that, pDCs were co-cultured with autologous CD4 or CD8 T-cells and with/without HIV-1 (Gag peptide pool) or SEB (Staphylococcal Enterotoxin B). Cytokine array, gene expression and deep immunophenotyping were assayed. Findings: pDCs showed an increase of activation markers levels, interferon related genes, HIV-1 restriction factors and cytokines levels after TLR stimulation in the different HIV-disease progression phenotypes. This pDC activation was prominent with CpG-C and GS-9620 and induced an increase of HIV-specific T-cell response even in VIR and INR comparable with EC. This HIV-1 specific T-cell response was associated with the upregulation of HIV-1 restriction factors and IFN-α production by pDC. Interpretation: These results shed light on the mechanisms associated with TLR-specific pDCs stimulation associated with the induction of a T-cell mediated antiviral response which is essential for HIV-1 eradication strategies. Funding: This work was supported by Gilead fellowship program, the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, FEDER, “a way to make Europe”) and the Red Temática de Investigación Cooperativa en SIDA and by the Spanish National Research Council (CSIC).

Amazonian countries have historically sourced the international wildlife trade. However, little is known about their domestic trade, which is often overlooked in estimates of trafficking. Peruvian law prohibits the unauthorized trade and possession of wildlife, but illegal sales are common in urban markets. To describe the dynamics, diversity, and composition of this illegal trade, we surveyed live wildlife for sale in urban markets in 16 Peruvian departments from 2007 to 2012. We identified the main hotspots of market trafficking, detected 193 species being sold alive, and estimate that 0.35–1.25 million animals were trafficked in this period. Iquitos, Lima, Pucallpa, and Tumbes were the most active and diverse trafficking nodes. Amazonian cities trafficked mostly local species, whereas in other cities the proportion of local species varied significantly (39–67%). Species dissimilarity across cities was high and correlated with their distance along trafficking routes. To assess if the market-based trade was representative of the national trade, we compared species richness in markets with that of country-wide confiscations. At least 430 species were confiscated in Peru between 2001 and 2019, but only 50% of species overlapped with markets in the same cities and period of our surveys. Our data suggest that urban markets are connected in a structured network that provides consumers with a diverse selection of species from across the country. Authorities should consider organizational aspects of trafficking networks to ensure success. Failure to eradicate wildlife trafficking in markets constitutes a serious threat to wildlife conservation and One Health in Peru and beyond.

Exudate absorption is a key parameter for proper wound dressing performance. Unlike standardized tests that consider exudate viscosity close to that of water, patients' exudates vary greatly in composition and, therefore, viscosity. This work aimed to investigate the effects of exudate viscosity and pore size of hydrogel-like dressings on the exudate absorption rate to establish rational criteria for the design of dressings that can meet the personalized needs of wound treatment. Computer-aided design (CAD) was used for Digital Light Processing (DLP) 3D printing of hydrogels with 0%, 30% and 60% porosity. The hydrogels were characterized in detail, and the absorption of two simulated exudate fluids (SEFs) was video-recorded. The same CAD files were used to develop in silico models to simulate exudate uptake rate. Both in vitro data and in silico modeling revealed that low-viscosity SEF penetrates faster through relatively small hydrogel pores (approx. 400 μm) compared to larger pores (approx. 1100 μm) due to capillary forces. However, in vitro vertical uptake took longer than when simulated using CAD design due to lateral fluid absorption through the pore walls in the hydrogel bulk. Distortions of hydrogel channels (micro-CT images) and lateral fluid absorption should be both considered for in silico simulation of SEF penetration. Overall, the results evidenced that porous hydrogel dressings allow rapid penetration (within a few seconds) and hosting of exudates, especially for pore size

Background: Appendicitis in children is associated with diagnostic complexity leading to delayed diagnosis. Such delays risk progression to complicated appendicitis. This study investigates the potential of cellular indices, including neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), to differentiate uncomplicated (UA) from complicated appendicitis (CA). Methods: Diagnostic study of pediatric patients with acute appendicitis admitted to our hospital from 2021 to 2022. NLR, dNLR, PLR and MLR were compared between groups. Results: A total of 182 patients were enrolled: 116 cases with CA (63 % male, age 9.6 ± 5.5 years) and 66 patients with UA (67 % male, age 10.6 ± 2.7 years). All blood cell indices were significantly higher in the CA group than in the UA group (p=

Background: No evidence-based therapy has yet been established for Takotsubo syndrome (TTS). Given the putative harmful effects of catecholamines in patients with TTS, beta-blockers may potentially decrease the intensity of the detrimental cardiac effects in those patients. Objective: The purpose of this study was to assess the impact of beta-blocker therapy on long-term mortality and TTS recurrence. Methods: The cohort study used the national Spanish Registry on TakoTsubo Syndrome (RETAKO). A total of 970 TTS post-discharge survivors, without pheochromocytoma, left ventricular outflow tract obstruction, sustained ventricular arrhythmias, and significant bradyarrhythmias, between January 1, 2003, and July 31, 2018, were assessed. Cox regression analysis and inverse probability weighting (IPW) propensity score analysis were used to evaluate the association between beta-blocker therapy and survival free of TTS recurrence. Results: From 970 TTS patients, 582 (60.0%) received beta-blockers. During a mean follow-up of 2.5 ± 3.3 years, there were 87 deaths (3.6 per 100 patients/year) and 29 TTS recurrences (1.2 per 100 patient/year). There was no significant difference in follow-up mortality or TTS recurrence in unadjusted and adjusted Cox analysis (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.59–1.27, and 0.95, 95% CI 0.57–1.13, respectively). After weighting and adjusting by IPW, differences in one-year survival free of TTS recurrence between patients treated and untreated with beta-blockers were not found (average treatment effect −0.01, 95% CI −0.07 to 0.04; p=0.621). Conclusions: In this observational nationwide study from Spain, there was no significant association between beta-blocker therapy and follow-up survival free of TTS recurrence. Resumo: Introdução: Ainda não foi estabelecido um tratamento baseado na evidência para a síndrome de Takotsubo (STT). Dados os efeitos supostamente nocivos das catecolaminas em doentes com STT, os betabloqueantes podem potencialmente diminuir a intensidade dos seus efeitos prejudiciais nesses doentes. Objetivo: Avaliar o impacto da terapêutica com betabloqueantes na mortalidade a longo prazo e na recidiva da STT. Métodos: O estudo coorte utilizou o registo nacional espanhol da síndrome de Takotsubo (RETAKO). Foram avaliados 970 sobreviventes de STT após a alta, sem feocromocitoma, sem obstrução do trato de saída do ventrículo esquerdo, sem arritmias ventriculares mantidas e sem bradiarritmias significativas, entre 1 de janeiro de 2003 e 31 de julho de 2018. A análise de regressão de Cox e a análise da ponderação de probabilidade inversa (PPI) foram utilizadas para avaliar a associação entre a terapia com betabloqueantes e a sobrevivência sem recidiva de STT. Resultados: Dos 970 doentes com STT, 582 (60,0%) foram tratados com betabloqueantes. Durante um seguimento médio de 2,5 ± 3,3 anos, houve 87 mortes (3,6 por 100 doentes/ano) e 29 recidivas de STT (1,2 por 100 doentes/ano). Não se verificaram diferenças significativas na mortalidade durante o seguimento, nem na recidiva de STT na análise Cox não ajustada e ajustada (Hazard Ratio [HR] 0,86, Intervalo de Confiança [IC] 95%, 0,59-1,27 e IC 95%−0,57-1,13, respetivamente). Após ponderação e ajuste por PPI, não foram também encontradas diferenças na sobrevivência a um ano e na recidiva de STT entre doentes tratados e não tratados com betabloqueantes (efeito médio do tratamento −0,01, IC 95% −0,07 a 0,04; p=0,621). Conclusão: Neste estudo observacional de âmbito nacional em Espanha, não houve associação significativa entre a terapêutica com betabloqueantes e a sobrevivência ou recidivas de STT.

Synucleinopathies are a group of neurodegenerative diseases without effective treatment characterized by the abnormal aggregation of alpha-synuclein (aSyn) protein. Changes in levels or in the amino acid sequence of aSyn (by duplication/triplication of the aSyn gene or point mutations in the encoding region) cause familial cases of synucleinopathies. However, the specific molecular mechanisms of aSyn-dependent toxicity remain unclear. Increased aSyn protein levels or pathological mutations may favor abnormal protein-protein interactions (PPIs) that could either promote neuronal death or belong to a coping response program against neurotoxicity. Therefore, the identification and modulation of aSyn-dependent PPIs can provide new therapeutic targets for these diseases. To identify aSyn-dependent PPIs we performed a proximity biotinylation assay based on the promiscuous biotinylase BioID2. When expressed as a fusion protein, BioID2 biotinylates by proximity stable and transient interacting partners, allowing their identification by streptavidin affinity purification and mass spectrometry. The aSyn interactome was analyzed using BioID2-tagged wild-type (WT) and pathological mutant E46K aSyn versions in HEK293 cells. We found the 14-3-3 epsilon isoform as a common protein interactor for WT and E46K aSyn. 14‐3-3 epsilon correlates with aSyn protein levels in brain regions of a transgenic mouse model overexpressing WT human aSyn. Using a neuronal model in which aSyn cell-autonomous toxicity is quantitatively scored by longitudinal survival analysis, we found that stabilization of 14‐3-3 protein-proteins interactions with Fusicoccin-A (FC-A) decreases aSyn-dependent toxicity. Furthermore, FC-A treatment protects dopaminergic neuronal somas in the substantia nigra of a Parkinson's disease mouse model. Based on these results, we propose that the stabilization of 14‐3-3 epsilon interaction with aSyn might reduce aSyn toxicity, and highlight FC-A as a potential therapeutic compound for synucleinopathies.

Background: Bloodstream infections (BSIs) are the most frequent nosocomial infections in neonatal intensive care units (NICUs), especially in very low birth weight (VLBW) infants (birth weight ≤ 1500 g). An epidemiologic surveillance system may contribute to the prevention of infection by continuous monitoring of its frequency and associated risk factors. The aim of this article was to describe the implementation of the NeoKissEs surveillance system for BSIs in VLBW newborns in a group of Spanish NICUs. Methods: We assessed the clinical cohort consisting of all VLBW newborns aged less than 28 days admitted to the participating units. In the pilot phase, 2 NICUs translated and adapted materials from the original German NEO-KISS system. During implementation, 210 health care professionals attended one of 8 educational workshops. A web-based system was created that allows entering data regarding patients and BSI episodes, data monitoring, benchmarking and providing feedback to the units. At each NICU, one neonatologist was responsible for the implementation of the system and reporting the difficulties perceived throughout the process. Results: Out of the 50 units that agreed to participate, 45 successfully started using the surveillance platform during the implementation phase, recording 1108 episodes of catheter-associated BSI (CABSI) in 3638 newborns, and finding an overall rate of CABSI of 18.4 (95% CI, 17.8-19.1) per 1000 catheter days. Conclusions: The NeoKissEs surveillance system constitutes a helpful source of information for the purpose of benchmarking the performance of neonatal units, assessing factors associated with BSI in VLBW infants and measuring the impact of future preventive interventions in NICUs. Resumen: Antecedentes: Las sepsis son las infecciones nosocomiales más frecuentes en las Unidades de Cuidados Intensivos Neonatales (UCIN), afectando especialmente a los recién nacidos de muy bajo peso al nacer (RNMBP, ≤ 1.500 g). Un sistema de vigilancia epidemiológica puede contribuir a su prevención mediante una evaluación continua de su frecuencia y factores de riesgo asociados. El objetivo de este artículo es describir la implementación del sistema de vigilancia de las sepsis nosocomiales en RNMBP (NeoKissEs) en un grupo de UCIN españolas. Métodos: Estudio de cohorte de RNMBP con < 28 días de edad ingresados en las UCIN participantes. Dos UCIN tradujeron y adaptaron materiales a partir del sistema original alemán NEO-KISS. Durante la implementación, se desarrollaron 8 talleres formativos, con participación de 210 profesionales. Se creó un sistema web para la introducción de datos de pacientes y episodios de sepsis, su monitorización, análisis comparativo y retroalimentación a las unidades. En cada UCIN, un neonatólogo fue responsable de la implementación, recogiendo información sobre las dificultades percibidas durante el proceso. Resultados: De 50 unidades que aceptaron participar, 45 utilizaron NeoKissEs durante la fase de implementación, registrando 1.108 episodios de sepsis asociados a catéter vascular en 3.638 neonatos, con una tasa de 18,4 episodios por 1.000 pacientes-día con catéter (IC del 95%: 17,8-19,1). Conclusiones: El sistema de vigilancia epidemiológica NeoKissEs representa una fuente útil de información para la comparación estandarizada de la incidencia de sepsis de las UCIN, evaluar factores de riesgo y facilitar la evaluación del efecto de futuras intervenciones preventivas.

Overactivation of subtype P2X7 receptors can induce excitotoxic neuronal death by calcium (Ca2+) overload. In this study, we characterize the functional properties of P2X7 receptors using electrophysiology and Ca2+ monitoring in primary cortical neuron cultures and in brain slices. Both electrical responses and Ca2+ influx induced by ATP and benzoyl-ATP were reduced by Brilliant Blue G (BBG) at concentrations which specifically inhibit P2X7 receptors. In turn, oxygen-glucose deprivation (OGD) caused neuronal death that was reduced with BBG application. OGD in neuron cultures and brain slices generated an inward current, which was delayed and reduced by BBG. To assess the relevance of these in vitro findings, we used middle cerebral artery occlusion in rats as a model of transient focal cerebral ischemia to study the neuroprotective effect of BBG in vivo. Treatment with BBG (twice per day, 30 mg/kg) produced a 60% reduction in the extent of brain damage compared to treatment with vehicle alone. These results show that P2X7 purinergic receptors mediate tissue damage after OGD in neurons and following transient brain ischemia. Therefore, these receptors are a relevant molecular target for the development of new treatments to attenuate brain damage following stroke.

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPPwt) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ42) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ42 were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ-independent pathogenic pathways in Alzheimer's disease.

Introducción: Identificar los factores asociados a un mayor riesgo de estancias inadecuadas. Material y método: Se calcularon las tasas crudas y ajustadas de inadecuación mediante regresión binomial negativa, obteniéndose los riesgos relativos para distintas variables. La recogida de datos se realizó mediante el Appropriateness Evaluation Protocol. Resultados: El 34,17% (intervalo de confianza del 95%, 33,28-35,08) de las estancias fueron inadecuadas. Las mujeres, los mayores de 65 años, los ingresos programados y las estancias en servicios médicos tuvieron más riesgo de inadecuación. La ausencia en la historia clínica de un seguimiento continuado del paciente incrementa el riesgo de inadecuación un 36%. Conclusiones: La ausencia de un registro continuado de la evolución clínica del paciente es un factor que incrementa el riesgo de estancias inadecuadas. La utilización de la binomial negativa es una alternativa válida y sencilla para el análisis de este tipo de fenómenos.Background: To identify the factors associated with a higher risk of inappropriate days of stay. Material and method: Crude and adjusted inappropriateness rates were calculated using negative binomial regression to obtain information about the relative risk of each variable. The Appropriateness Evaluation Protocol (AEP) was applied to collect information about patients' hospital stays. Results: A total of 34.17% (95%CI, 33.28-35.08) of the stays were inappropriate. Women, age older than 65 years, elective admission, and stays in medical services showed the highest inappropriateness risk. Lack of correct patient follow-up in the medical record increased the risk of inappropriateness to 36%. Conclusions: Lack of continual registration of the patient's clinical course increased the risk of inappropriate days of stay in the hospital. The use of the negative binomial is a valid and simple option for analysis of this type of phenomenon.

Even though the idea that amyloid β peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of β-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between β-amyloid and tau alterations may take place in vivo.