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Background/objectiveThis study describes the impact of immunomodulatory and/or immunosuppressive (IM/IS) drugs in the outcomes of COVID-19 infection in a cohort of patients with immune-mediated inflammatory diseases (IMIDs).MethodsAdult patients with IMIDs with a confirmed SARS-CoV-2 infection were included. Data were reported by the treating physician between August 13, 2020 and July 31, 2021. Sociodemographic data, comorbidities, and DMARDs, as well as clinical characteristics, complications, and treatment of the SARS-CoV-2 infection, were recorded. Descriptive analysis and multivariable logistic regression models were carried out.ResultsA total of 1672 patients with IMIDs were included, of whom 1402 were treated with IM/IS drugs. The most frequent diseases were rheumatoid arthritis (47.7%) and systemic lupus erythematosus (18.4%). COVID-19 symptoms were present in 95.2% of the patients. A total of 461 (27.6%) patients were hospitalized, 8.2% were admitted to the intensive care unit, and 4.4% died due to COVID-19.Patients without IM/IS treatment used glucocorticoids less frequently but at higher doses, had higher levels of disease activity, were significantly older, were more frequently hospitalized, admitted to the intensive care unit, and died due to COVID-19. After adjusting for these factors, treatment with IM/IS drugs was not associated with a worse COVID-19 outcome (World Health Organization-Ordinal Scale ≥5) (odds ratio, 1.24; 95% confidence interval, 0.73-2.06).ConclusionsSAR-COVID is the first multicenter Argentine registry collecting data from patients with rheumatic diseases and SARS-CoV-2 infection. After adjusting for relevant covariates, treatment with IM/IS drugs was not associated with severe COVID-19 in patients with IMIDs.Study registrationThis study has been registered in ClinicalTrials.gov under the number NCT04568421.

Wines from grapes of Cabernet Sauvignon of the AOC Tarragona were elaborated with supplementation or not of two specific inactivated dry yeasts (Optired® and Optimum Red®; Lallemand Inc.) or with an experimental grape-skin extract. All the wines treated were significantly less astringent than the control wine because both inactivated dry yeast and the skin extract released polysaccharides which probably inhibit interactions between salivary proteins and tannins, and because their presence decrease the proportion of seed tannins and increase the proportion of skin tannins in the final wines.

The production of backyard chickens is an activity of great importance in the economy of rural families in Paraguay. The Rustipollos population was created through directed crosses between a commercial meat line and a local population belonging to non-specific breeds but phenotypically assimilated to Creole breeds. The aim of this study was to evaluate the genetic diversity, relationship, and structure of Rustipollos using 29 microsatellite markers. Analysis was performed on 50 Rustipollos animals and 926 other individuals as reference breeds/populations from Europe, Africa, South, and North America. A total of 318 alleles were detected, with a mean of 10.97 per locus. The polymorphic information content indicated that 80% of all loci were highly to moderately informative. Only two breeds/populations showed loci that did not deviate from the Hardy–Weinberg equilibrium. The results of genetic diversity indexes suggested moderate levels of genetic variability in Rustipollos population and low inbreeding level. The genetic differentiation index indicates a high genetic differentiation between populations. The results of the Neighbor-Net tree and STRUCTURE analyses indicate the existence of distinct gene pools, with some genetic relationships between Rustipollos, the commercial chicken strain, and south Spanish breeds. The Discriminant Analysis of Principal Components confirmed the observed genetic distances between breeds/populations. The results will be useful for sustainable use and official recognition of this population.

In this study, we show that pollutants of emerging concern are, by nature, prone to the emergence of epistemic uncertainty. We also show that the current uncertainty quantification methods used for pollutant modelling rely almost exclusively on parameter uncertainty, which is not adequate to tackle epistemic uncertainty affecting the model structure. We, therefore, suggest a paradigm shift in the current pollutant modelling approaches by adding a term explicitly accounting for epistemic uncertainties. In a proof-of-concept, we use this approach to investigate the impact of epistemic uncertainty in the fluctuation of pollutants during wet-weather discharge (input information) on the distribution of mass of pollutants (output distributions). We found that the range of variability negatively impacts the tail of output distributions. The fluctuation time, associated with high covariance between discharge and concentration, is a major driver for the output distributions. Adapting to different levels of epistemic uncertainty, our approach helps to identify critical unknown information in the fluctuation of pollutant concentration. Such information can be used in a risk management context and to design smart monitoring campaigns. HIGHLIGHTS Current modelling approaches are not suitable for the deep epistemic uncertainty associated with pollutants of emerging concern.; Variability and fluctuation of concentration and the concentration-discharge dependency can worsen the severity of an overflow event.; Through our method for the impact of epistemic uncertainty, we suggest a paradigm shift toward the design of smart stormwater quality monitoring campaigns.;

Relatively little attention has been paid to the underlying mechanisms determining the dominance of non-indigenous species (NIS) once established, despite being regarded as a proxy of invasion success and potential impacts in recipient communities. To bridge this knowledge gap, here we evaluate the potential direct and indirect effects of community filters on the dominance of two widespread NIS in the Baltic Sea: Marenzelleria spp. and the round goby (Neogobius melanostomus) within their corresponding communities. We applied a structural equation modelling approach to assess the direct and indirect effects amongst multiple abiotic and biotic variables on the relative biomass (as proxy of dominance) of NIS. The biotic variables represented the taxonomic- and functional diversity of the recipient communities, as well as the trait similarity between NIS and native species. We observed a comparable influence of abiotic and biotic drivers on the dominance of both NIS, with biotic variables having a somewhat stronger overall direct effect. Specifically, the dominance of both NIS was similarly affected negatively by the richness and positively by the evenness of the native communities. However, we also detected that both NIS might need different ecological strategies to become dominant in their recipient communities, which underwent similar assembly processes. Such strategies were partly highlighted by the different degrees of trait similarity between each NIS and their respective co-occurring native species. A better understanding of the underlying processes affecting NIS dominance is of high relevance to mitigate potential impacts of NIS once established. Furthermore, the provided approach could be further applied to unveil the potential strategies that NIS might follow in other regions and ecosystem types.

La Convención sobre los Derechos del Niño establece la participación infantil como un derecho fundamental. Esto significa que se debe permitir a los niños expresar sus puntos de vista, ser escuchados y que sus intereses sean considerados en las decisiones que tienen un impacto directo en ellos. Este principio es clave en el ámbito de los derechos del niño y la protección de la infancia. La presente investigación se centra en la integración de la infancia en los procesos de análisis y transformación arquitectónica de los espacios que ocupan. En particular, se analiza la transformación del espacio exterior del CEIP Son Basca en Sa Pobla, Mallorca, con el objetivo de fomentar un juego más diversificado, el aprendizaje, la inclusión, la coeducación, el confort ambiental y la naturalización. El estudio propone una metodología que implica la participación de toda la comunidad educativa, incluyendo a los niños, para garantizar una participación real y efectiva en la transformación final del patio. La experiencia se justifica por la necesidad de revisar la configuración tradicional de los patios escolares y por la aparición de nuevas metodologías para el diseño de estos espacios. Estas metodologías reconocen la importancia de la arquitectura en la creación de ambientes integrados, menos fragmentados y propicios para el aprendizaje significativo, e incorporan la participación de la infancia. Además de su objetivo principal de implementar la transformación de manera participativa, el estudio destaca el potencial del proceso de diseño colaborativo del patio para generar aprendizajes en varios niveles educativos del centro. Este enfoque participativo no solo mejora el entorno físico, sino que también contribuye al desarrollo educativo y s ocial de los alumnos.

Abstract Motorized spiral enteroscopy (MSE) enhances small bowel exploration, but the optimal target population for this technique is unknown. We aimed to identify the target population for MSE by evaluating its efficacy and safety, as well as detecting predictors of efficacy. A prospective multicenter observational study was conducted at 9 tertiary hospitals in Spain, enrolling patients between June 2020–2022. Analyzed data included demographics, indications for the procedure, exploration time, depth of maximum insertion (DMI), technical success, diagnostic yield, interventional yield, and adverse events (AE) up to 14 days from enteroscopy. Patients with prior gastrointestinal surgery, unsuccessful balloon enteroscopy and small bowel strictures were analyzed. A total of 326 enteroscopies (66.6% oral route) were performed in 294 patients (55.1% males, 65 years ± 21). Prior abdominal surgery was present in 50% of procedures (13.5% gastrointestinal surgery). Lower DMI (162 vs 275 cm, p = 0.037) and diagnostic yield (47.7 vs 67.5%, p = 0.016) were observed in patients with prior gastrointestinal surgery. MSE showed 92.2% technical success and 56.9% diagnostic yield after unsuccessful balloon enteroscopy (n = 51). In suspected small bowel strictures (n = 49), the finding was confirmed in 23 procedures (46.9%). The total AE rate was 10.7% (1.8% classified as major events) with no differences related to prior gastrointestinal/abdominal surgery, unsuccessful enteroscopy, or suspected small bowel strictures. The study demonstrates that MSE has a lower diagnostic yield and DMI in patients with prior gastrointestinal surgery but is feasible after unsuccessful balloon-enteroscopy and in suspected small bowel strictures without safety concerns.

Abstract Opioid withdrawal is a liability of chronic opioid use and misuse, impacting people who use prescription or illicit opioids. Hyperactive autonomic output underlies many of the aversive withdrawal symptoms that make it difficult to discontinue chronic opioid use. The locus coeruleus (LC) is an important autonomic centre within the brain with a poorly defined role in opioid withdrawal. We show here that pannexin-1 (Panx1) channels expressed on microglia critically modulate LC activity during opioid withdrawal. Within the LC, we found that spinally projecting tyrosine hydroxylase (TH)-positive neurons (LCspinal) are hyperexcitable during morphine withdrawal, elevating cerebrospinal fluid (CSF) levels of norepinephrine. Pharmacological and chemogenetic silencing of LCspinal neurons or genetic ablation of Panx1 in microglia blunted CSF NE release, reduced LC neuron hyperexcitability, and concomitantly decreased opioid withdrawal behaviours in mice. Using probenecid as an initial lead compound, we designed a compound (EG-2184) with greater potency in blocking Panx1. Treatment with EG-2184 significantly reduced both the physical signs and conditioned place aversion caused by opioid withdrawal in mice, as well as suppressed cue-induced reinstatement of opioid seeking in rats. Together, these findings demonstrate that microglial Panx1 channels modulate LC noradrenergic circuitry during opioid withdrawal and reinstatement. Blocking Panx1 to dampen LC hyperexcitability may therefore provide a therapeutic strategy for alleviating the physical and aversive components of opioid withdrawal.

Abstract Atopic dermatitis (AD), a prevalent chronic inflammatory disease with multifactorial etiology, features epidermal barrier defects and immune overactivation. Synthetic glucocorticoids (GCs) are widely prescribed for treating AD due to their anti-inflammatory actions; however, mechanisms are incompletely understood. Defective local GC signaling due to decreased production of endogenous ligand and/or GC receptor (GR) levels was reported in prevalent inflammatory skin disorders; whether this is a consequence or contributing factor to AD pathology is unclear. To identify the chromatin-bound cell-type-specific GR protein interactome in keratinocytes, we used rapid immunoprecipitation of endogenous proteins and mass spectrometry identifying 145 interactors that increased upon dexamethasone treatment. GR-interacting proteins were enriched in p53/p63 signaling, including epidermal transcription factors with critical roles in AD pathology. Previous analyses indicating mirrored AD-like phenotypes between P63 overexpression and GR loss in epidermis, and our data show an intricate relationship between these transcription factors in human keratinocytes, identifying TP63 as a direct GR target. Dexamethasone treatment counteracted transcriptional up-regulation of inflammatory markers by IL4/IL13, known to mimic AD, causing opposite shifts in GR and P63 genomic binding. Indeed, IL4/IL13 decreased GR and increased P63 levels in cultured keratinocytes and human epidermal equivalents (HEE), consistent with GR down-regulation and increased P63 expression in AD lesions vs normal skin. Moreover, GR knockdown (GRKD) resulted in constitutive increases in P63, phospho-P38 and S100A9, IL6, and IL33. Also, GRKD culture supernatants showed increased autocrine production of TH2-/TH1-/TH17-TH22-associated factors including IL4, CXCL10, CXCL11, and CXCL8. GRKD HEEs showed AD-like features including hyperplasia and abnormal differentiation, resembling phenotypes observed with GR antagonist or IL4/IL13 treatment. The simultaneous GR/P63 knockdown partially reversed constitutive up-regulation of inflammatory genes in GRKD. In summary, our data support a causative role for GR loss in AD pathogenesis via functional interactions with P63 and autocrine signaling in epidermal keratinocytes.

Climate change is a global challenge with multiple far-reaching consequences, including the intensification and increased frequency of many extreme-weather events. In response to this pressing issue, we present ClimaMeter, a platform designed to assess and contextualize extreme-weather events relative to climate change. The platform offers near-real-time insights into the dynamics of extreme events, serving as a resource for researchers and policymakers while also being a science dissemination tool for the general public. ClimaMeter currently analyses heatwaves, cold spells, heavy precipitation, and windstorms. This paper elucidates the methodology, data sources, and analytical techniques on which ClimaMeter relies, providing a comprehensive overview of its scientific foundation. We further present two case studies: the late 2023 French heatwave and the July 2023 Storm Poly. We use two distinct datasets for each case study, namely Multi-Source Weather (MSWX) data, which serve as the reference for our rapid-attribution protocol, and the ERA5 dataset, widely regarded as the leading global climate reanalysis. These examples highlight both the strengths and limitations of ClimaMeter in expounding the link between climate change and the dynamics of extreme-weather events.

Abstract Rehabilitation technologies offer promising opportunities for interventions for patients with motor disabilities. However, their use in routine care remains limited due to their high cost and persistent doubts about their cost-effectiveness. Providing solid evidence of the economic efficiency of rehabilitation technologies would help dispel these doubts in order to better take advantage of these technologies. In this context, this systematic review aimed to examine the cost-effectiveness of rehabilitation interventions based on the use of digital technologies. In total, 660 articles published between 2011 and 2021 were identified, of which eleven studies met all the inclusion criteria. Of these eleven studies, seven proved to be cost-effective, while four were not. Four studies used cost-utility analyses (CUAs) and seven used cost-minimization analyses (CMAs). The majority (ten studies) focused on the rehabilitation of the upper and/or lower limbs after a stroke, while only one study examined the rehabilitation of the lower limbs after knee arthroplasty. Regarding the evaluated devices, seven studies analyzed the cost-effectiveness of robotic rehabilitation and four analyzed rehabilitation with virtual reality.The assessment of the quality of the included studies using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) suggested that the quality was related to the economic analysis method: all studies that adopted a cost-utility analysis obtained a high quality score (above 80%), while the quality scores of the cost-minimization analyses were average, with the highest score obtained by a CMA being 72%. The average quality score of all the articles was 75%, ranging between 52 and 100. Of the four studies with a considering score, two concluded that there was equivalence between the intervention and conventional care in terms of cost-effectiveness, one concluded that the intervention dominated, while the last one concluded that usual care dominated. This suggests that even considering the quality of the included studies, rehabilitation interventions based on digital technologies remain cost-effective, they improved health outcomes and quality of life for patients with motor disorders while also allowing cost savings.

Context: Comprehensive medication management service provides comprehensive pharmaceutical care to patients to meet their pharmacotherapeutic needs and improve their quality of life in terms of health. Aims: To describe the results of the pilot implementation of the comprehensive medication management service provided to inpatients with cardiovascular diseases. Methods: Longitudinal, prospective and intervention study was carried out, with qualitative research elements. The sample included patients with cardiovascular diseases and more than five days from the Cardiology Service of the “Saturnino Lora” Provincial Hospital in Santiago de Cuba. The care process was developed according to the OFIL's Guide for the implementation of Comprehensive Medication Management. The patients’ medication experiences were evaluated according to Ramalho de Oliveira et al. The evaluation of drug-related problems and the clinical outcomes was carried out according to the Pharmacotherapy Work-up Method. Results: Twenty patients were included, 65% male. The mean age was 66.2 ± 13.1 years. Eighty percent of the patients had hypertension. One hundred percent received antihypertensive and antithrombotic drugs. Forty percent reported body as a pharmacotherapeutic experience. One hundred and thirty-three drug-related problems were detected and 45.1% corresponded to safety problems. One hundred and fifty-five pharmaceutical interventions were performed and 89% were accepted. Ninety percent of the patients achieved positive clinical outcomes. Conclusions: The pilot implementation of the comprehensive medication management service contributed to the resolution of drug-related problems and showed positive clinical outcomes in patients with cardiovascular diseases.

Objetives. Bacterial resistance to antibiotics is a public health problem, however, few studies are performed in natural water ecosystems in middle-low-income countries. The objective of this study was to evaluate the presence and sensitivity to antimicrobials of Escherichia coli strains isolated from 24 irrigation water samples from the Rimac River in eastern Lima. Materials and methods. E.coli were identified by PCR. Antibiotic susceptibility was determined by disk diffusion method. The extended-spectrum beta-lactamase (ESBL), quinolones and virulence involved genes were determined by PCR. Results. All samples exceeded the permissible limits established in the Environmental Quality Standards for vegetable irrigation. Of the 94 strains, 72.3% showed resistance to at least one antibiotic, 24.5% were multidrug-resistant (MDR), and 2.1% were extremely drug resistant. The highest percentages of resistance were observed against nalidixic acid (50%), trimethoprim-sulfamethoxazole (35.5%) and ciprofloxacin (20.4%). Among the isolates, 3.2% presented ESBL phenotype related to blaCTX-M-15 gene. The transferable mechanisms of resistance to quinolones, qnrB were more frequent (20.4%), and 2.04% had the qnrS. It was determined that 5.3% were diarrheagenic E. coli and of these, 60% were enterotoxigenic E. coli, 20% were enteropathogenic E. coli and 20% were enteroaggregative E. coli. Conclusions. Our results show the existence diarrheagenic pathotypes in water used to irrigate fresh produce and highlights the presence of ESBL-producers and MDR E. coli, demonstrating the role that irrigation water plays in disseminating resistance genes in Peru.

Abstract Background Severe trauma is associated with systemic inflammation and organ dysfunction. Preclinical rodent trauma models are the mainstay of postinjury research but have been criticized for not fully replicating severe human trauma. The aim of this study was to create a rat model of multicompartmental injury which recreates profound traumatic injury. Methods Male Sprague–Dawley rats were subjected to unilateral lung contusion and hemorrhagic shock (LCHS), multicompartmental polytrauma (PT) (unilateral lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofracture), or naïve controls. Weight, plasma toll‐like receptor 4 (TLR4), hemoglobin, spleen to body weight ratio, bone marrow (BM) erythroid progenitor (CFU‐GEMM, BFU‐E, and CFU‐E) growth, plasma granulocyte colony‐stimulating factor (G‐CSF) and right lung histologic injury were assessed on day 7, with significance defined as p values