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Los peregrinajes han sido una de las tantas formas en que las personas se han relacionado con aspectos claves de su cosmología a lo largo de la historia. En este trabajo analizaremos un circuito de peregrinaje de altura en la ladera oriental del Nevado de Cachi (Salta, Argentina) a través de datos generados con relevamientos intensivos, excavaciones sistemáticas, imágenes aéreas y satelitales, bases de datos georreferenciadas, y asistidos por herramientas CAD, GIS y de realidad aumentada. Específicamente, discutiremos cómo la topografía, la arquitectura y 3 km de camino inca expusieron y ocultaron intencional y secuencialmente las características fundamentales de este paisaje. Argumentaremos que las transformaciones incaicas alteraron estratégicamente la forma en que se experimentaba este paisaje, reensamblando sus jerarquías humanas y no humanas a través de un nuevo circuito de peregrinaje que presentaba a las comitivas incaicas como mediadoras especialmente entrenadas para interactuar con las principales entidades, fuerzas y sustancias procreativas de la montaña.

Abstract Conventional immunosuppressants are ineffective for the management of EGPA-related asthma. Tezepelumab is a human monoclonal antibody that inhibits thymic stromal lymphopoietin (TLSP) that has proven efficacy in several phase 3 studies for the treatment of asthma. We treated with off-label tezepelumab the first two patients with severe refractory EPGA-related asthma. These preliminary findings suggest that targeting upstream signaling of the T2 inflammatory pathway can improve symptoms, reduce BVAS and increase Asthma Control Test scores, even in patients with refractory asthma who have failed several previous lines of treatment. Nevertheless, by analogy with dupilumab-induced IL-4/13 blockade, the persistence of sputum eosinophilia (reported in both patients) raises questions as to whether TSLP inhibition could lead to a rebound of eosinophilia and potentially to eosinophil-related symptoms in patients with EGPA.

Triple negative breast cancer, TNBC, is a difficult disease to treat due to relapse and resistance to known therapies. Epidermal growth factor receptor (EGFR), a tyrosine kinase responsible for downstream signaling leading to cell growth and survival, is typically overexpressed in TNBC. Our previous work has detailed the synthesis of triazole-estradiol derivatives as inhibitors of EGFR and downstream receptors, and this work continues that discussion by evaluating them in EGFR-dependent TNBC cell models MDA-MB-231 and MDA-MB-468. Compound Fz25 was cytotoxic against both MDA-MB-231 and MDA-MB-468 cell lines, yielding IC50 values of 8.12 ± 0.85 and 25.43 ± 3.68 µM, respectively. However, compounds Fz57 and Fz200 were potent against only MDA-MB-231 cells, generating IC50 values of 21.18 ± 0.23 and 10.86 ± 0.69 µM, respectively. Pathway analyses revealed that Fz25, Fz57 and Fz200 arrested the G0/G1 phase of the cell cycle and concomitantly suppressed cell cycle regulators, cyclin D1, cyclin E and Dyrk1B in MDA-MB-231 cells. Additionally, all compounds inhibited EGFR and its downstream signaling pathways—extracellular receptor kinase (ERK) and the mammalian target of rapamycin (mTOR)—in a dose-dependent manner. Furthermore, Fz25, Fz57 and Fz200 induced apoptosis in MDA-MB-231 cells by modulating morphological changes, including chromatin condensation, and attenuating the levels of cytochrome c, APAF1, caspases-3 and -9 as well as cleaved PARP. Of these compounds, only Fz25 showed overall satisfactory ADMET properties in silico. Similarly, Fz25 showed suitable binding parameters explored using molecular dynamic simulations in silico. These findings suggest that Fz25 warrants further preclinical and clinical investigations as a new generation of triazole congeners with significant potency in EFGR-dependent TNBC.

Purpose To better characterise the effects of corticosteroids on the course of pure idiopathic orbital inflammation syndrome (pIOIS).Methods This was a national, multicentre, prospective, non-interventional cohort study (SIOI). Among the 35 patients with histologically proven orbital inflammation who had previously been studied for their IgG4 immunostaining status, we selected those with a negative IgG4 status (ie, pIOIS) who received corticosteroids as single first-line treatment. Clinical, morphological and pathological findings at diagnosis and during follow-up from treatment initiation to study completion were analysed. Patients were assessed for their response to prednisone after the 24-month prospective phase in terms of remission (≤10 mg/d) or failure (>10 mg/d). Daily standard doses of prednisone (DSDP) were calculated at different time-points and compared between response groups.Results Of the 17 patients with pIOIS included in the final analysis, two-thirds received corticosteroids only. DSDP (mg/kg-day) were significantly higher at the time of failure in eight patients (47%) than in nine (53%) remitting at M24 (0.16 vs 0.045; p: 0.03). Notably, patients with pIOIS with a cellular pattern or orbital fat involvement tended to receive higher daily corticosteroid doses in the event of failure than remission (0.16 vs 0.045 and 0.12 vs 0.042, respectively). During treatment, maximal DSDP was 0.52 in failed patients.Conclusion The highest corticosteroid doses were insufficient to prevent failure in patients with pIOIS, particularly in those with a cellular pattern or orbital fat involvement. Large-scale interventional studies are now necessary to clarify prognostic factors and optimise corticosteroid management in patients with pIOIS.

The Chilean meagre, Cilus gilberti, emerges as a novel species to South American aquaculture. Nevertheless, the successful establishment of its cultivation necessitates careful consideration of productive parameters and tolerance to abiotic stressors. To address these challenges, the identifications of biomarkers emerges as a promising approach. Indeed, leptin stands out as a potential biomarker, given its multifaceted role. This study focuses on characterizing leptin in C. gilberti (cgLep) and assessing its gene expression in juveniles exposed to different culture and feeding conditions. The results indicated that cgLep coding sequence yields a 137-amino acid prohormone, preserving high relevant cysteine residues for maintaining its structural integrity. Basal cgLep gene expression profiles reveal its expression mainly in the liver, followed by white muscle. Conversely, its receptor (cgLepR) exhibits higher levels in white muscle. Additionally, it was observed that juveniles in a postprandial state exhibited an upregulation of hepatic cgLep. Simultaneously, the cgLepR showed a significant increase at brain level during the preprandial stage. The exposure to acute hypoxia revealed a notable upregulation of cgLep after two hours of low oxygen availability and returned to normoxia baseline after six hours post-hypoxia. Notably, when subjected to a prolonged daily hypoxia regimen, no significant differences in leptin mRNA expression were observed. This suggests a dynamic adaptive response of the C. gilberti leptin system to hypoxia. Finally, juvenile Chilean meagre cultivated at 15 Kg/m3 showcase significant individual variability in hepatic leptin expression levels when compared to those cultured at 25 or 35 kg/m3. These observations highlight that leptin primarily expresses in the liver and its expression is notably influenced by fasting periods and chronic stress induced by low stock density. This variability in leptin expression could potentially impact food intake, emphasizing the importance of considering these factors in the design and implementation of aquaculture practices for Chilean meagre.

This paper presents the design process and resulting technical concept for an integrated hyperloop system, aimed at realizing efficient high-speed ground transportation. This study integrates various functions into a coherent and technically feasible solution, with key design decisions that optimize performance and cost-efficiency. An iterative design process with domain-specific experts, regular reviews, and a dataset with a single source of truth were employed to ensure continuous and collective progress. The proposed hyperloop system features a maximum speed of 600 kmh and a capacity of 21 passengers per pod (vehicle). It employs air docks for efficient boarding, electromagnetic suspension (EMS) combined with electrodynamic suspension (EDS) for high-speed lane switching, and short stator motor technology for propulsion. Cooling is managed through water evaporation at an operating pressure of 10 mbar, while a 300 kW inductive power supply (IPS) provides onboard power. The design includes a safety system that avoids emergency exits along the track and utilizes separated safety-critical and high-bandwidth communication. With prefabricated concrete parts used for the tube, construction costs can be reduced and scalability improved. A dimensioned cross-sectional drawing, as well as a preliminary pod mass budget and station layout, are provided, highlighting critical technical systems and their interactions. Calculations of energy consumption per passenger kilometer, accounting for all functions, demonstrate a distinct advantage over existing modes of transportation, achieving greater efficiency even at high speeds and with smaller vehicle sizes. This work demonstrates the potential of a well-integrated hyperloop system to significantly enhance transportation efficiency and sustainability, positioning it as a promising extension to existing modes of travel. The findings offer a solid framework for future hyperloop development, encouraging further research, standardization efforts, and public dissemination for continued advancements.

In vitro cell culture systems serve as instrumental platforms for probing biological phenomena and elucidating intricate cellular mechanisms. These systems afford researchers the opportunity to scrutinize cellular responses within a regulated environment, thereby circumventing the ethical and logistical challenges associated with in vivo experimentation. Three-dimensional (3D) cell cultures have emerged as a viable alternative to mimic in vivo environments. Within this context, spheroids are recognized as one of the most straightforward and efficacious models, presenting a promising substitute for conventional monolayer cultures. The application of 3D cultures of fish cells remains limited, focusing mainly on physiological and morphological characterization studies. However, given the capacity of spheroids to emulate in vivo conditions, researchers are exploring diverse applications of these 3D cultures. These include eco-toxicology, immunology, drug screening, endocrinology, and metabolism studies, employing a variety of cell types such as fibroblasts, hepatocytes, embryonic cells, gonadal cells, gastrointestinal cells, and pituitary cells. This review provides a succinct overview, concentrating on the most frequently employed methods for generating fish cell spheroids and their applications to date. The aim is to compile and highlight the significant contributions of these methods to the field and their potential for future research.

The salmonid industry faces challenges due to the susceptibility of fish to opportunistic pathogens, particularly in early developmental stages. Understanding the immunological capacity during these stages is crucial for developing effective disease control strategies. IL-8R, a member of the G-protein-coupled receptor family, acts as a receptor for Interleukin 8 (IL-8). The binding of IL-8 to IL-8R plays a major role in the pathophysiology of a wide spectrum of inflammatory conditions. This study focused on the immune response capacity of rainbow trout (Oncorhynchus mykiss) larvae by analyzing IL-8/CXCR1 response to lipopolysaccharide (LPS) from Pseudomonas aeruginosa. Previous research demonstrated that LPS from P. aeruginosa acts as a potent immunostimulant in teleost, enhancing pro-inflammatory cytokines. The methodology included in silico analysis and the synthesis and characterization of an omCXCR1-derived epitope peptide, which was used to produce omCXCR1-specific anti98 serum in mice. The research revealed that rainbow trout larvae 19 days post-hatching (dph) exhibited pronounced immune responses post-stimulation with 1 µg/mL of LPS. This was evidenced by the upregulated protein expression of IL-8 and omCXCR1 in trout larvae 2 and 8 h after LPS challenge, as analyzed by ELISA and immunohistochemistry. Furthermore, fluorescence microscopy successfully revealed the colocalization of IL-8 and its receptor in cells from mucosal tissues after LPS challenge in larvae 19 dph. These findings underscore the efficacy of LPS immersion as a method to activate the innate immune system in trout larvae. Furthermore, we propose IL-8 and its receptor as molecular markers for evaluating immunostimulation in the early developmental stages of salmonids.

Optimizing growth and feed conversion ratios by improving gut function and health is critial to ensuring cost-effective production in aquaculture, especially in the current context of low fishmeal and low fish oil-based diets. However, the use of practical diets based on high levels of plant-based raw materials as an alternative to traditional marine ingredients has been associated with negative effects on fish performance, feed utilization, and health. Organic acids and their salts have been widely used as functional ingredients not only for their antimicrobial and immunomodulatory properties, but also for their potential to promote animal digestive capacity and gut health. The aim of the present study was to evaluate the effects of a mixture of formic acid and sodium formate (Amasil NA®, BASF, Germany- AMA diet) at a dietary level of 0.3%, on key performance indicators, gut morphology and disease resistance to Vibrio anguillarum in juvenile gilthead sea bream (Sparus aurata). The results of the present study showed that fish fed the AMA diet for 8 weeks, performed similar to fish fed the control diet in terms of growth but presented an optimization of 8% in the utilization of a low in fishmeal and high in plant proteins based diet. The AMA-diet also increased the folds length of gilthead sea bream anterior gut, increasing intestinal absorption area, and decreasing the submucosa width and goblet cell size in the posterior gut when included in a high dietary plant protein content diet. Furthermore, dietary supplementation with Amasil NA® at 0.3% increased gilthead sea bream disease resistance against V. anguillarum compared with fish fed the unsupplemented diet. These results highlight the potential of this combination of formic acid and sodium formate based product as a feed efficiency enhancer, and as a gut health promoter in gilthead sea bream plant protein-based diets.

Comprehending the immune defense mechanisms of new aquaculture species, such as the Chilean meagre (Cilus gilberti), is essential for sustaining large-scale production. Two bioassays were conducted to assess the impact of acute and intermittent hypoxia on the antibacterial activity of juvenile Chilean meagre epidermal mucus against the potential pathogens Vibrio anguillarum and Vibrio ordalii. Lysozyme and peroxidase activities were also measured. In general, fish exposed to hypoxia showed a 9–30% reduction in mucus antibacterial activity at the end of hypoxic periods and after stimulation with lipopolysaccharide. However, following water reoxygenation, the activity of non-stimulated fish was comparable to that of fish in normoxic conditions, inhibiting bacterial growth by 35–52%. In the case of fish exposed to chronic hypoxia, the response against V. anguillarum increased by an additional 19.8% after 6 days of control inoculation. Lysozyme exhibited a similar pattern, while no modulation of peroxidase activity was detected post-hypoxia. These results highlight the resilience of C. gilberti to dissolved oxygen fluctuations and contribute to understanding the potential of mucus in maintaining the health of cultured fish and the development of future control strategies.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

En los humedales con influencia marina de la vertiente sur de la Sierra Maestra se refieren sintáxones pertenecientes a cuatro clases, seis órdenes, ocho alianzas y 20 asociaciones aplicando la metodología de Braun Blanquet, de las cuales uno, uno, dos y nueve respectivamente son descritas por primera vez y están contenidas en cinco formaciones vegetales, de las cuales la más prolífica son los manglares.

The objective of this study was to determine if selected fish genotypes could benefit from the use of functional additives in novel aqua feed formulations to improve growth performance, gut microbiota, immune response, and disease resistance in fish. Two batches of juvenile European sea bass selected for high growth (HG; selected sires x selected dams), and wild types (WT; wild sires x selected females) were fed a “future diet” coated with three different functional additives for 12 weeks as follows: (i) 2 weeks with a high dose, followed by (ii) 10 weeks with a low dose. The functional additives tested were a mixture of probiotics (PROB), organic acids (ORG), and phytogens (PHYTO). A pathogen challenge test (Vibrio anguillarum) and a stress condition (overcrowding) were performed after each dose. At the end of the feeding experiment, fish from the HG group performed better than fish from the WT group in terms of body weight, relative growth, SGR, and DGI. The results of the two challenge tests performed after two weeks of high dose and ten weeks of low dose showed a significant effect of diet on fish survival. GALT-associated gene expression analysis revealed an interaction between the genotype and diet for il-1β in the distal gut. Finally, regarding the gut microbiota, discriminant analysis showed no clear separation between fish fed the future diet and those fed the same diet with experimental additives. Nevertheless, the relative abundance of certain taxa varied between experimental groups. For example, fish fed the ORG diet had higher relative abundance of Streptococcus in both genotypes, whereas fish fed the PHYTO diet had higher abundance of Lactobacillales. In contrast, fish fed PROB had lower abundance of Pseudomonas and Acinetobacter.

Amid growing concerns about antibiotic resistance, innovative strategies are imperative in addressing bacterial infections in aquaculture. Quorum quenching (QQ), the enzymatic inhibition of quorum sensing (QS), has emerged as a promising solution. This study delves into the QQ capabilities of the probiotic strain Bacillus velezensis D-18 and its products, particularly in Vibrio anguillarum 507 communication and biofilm formation. Chromobacterium violaceum MK was used as a biomarker in this study, and the results confirmed that B. velezensis D-18 effectively inhibits QS. Further exploration into the QQ mechanism revealed the presence of lactonase activity by B. velezensis D-18 that degraded both long- and short-chain acyl homoserine lactones (AHLs). PCR analysis demonstrated the presence of a homologous lactonase-producing gene, ytnP, in the genome of B. velezensis D-18. The study evaluated the impact of B. velezensis D-18 on V. anguillarum 507 growth and biofilm formation. The probiotic not only controls the biofilm formation of V. anguillarum but also significantly restrains pathogen growth. Therefore, B. velezensis D-18 demonstrates substantial potential for preventing V. anguillarum diseases in aquaculture through its QQ capacity. The ability to disrupt bacterial communication and control biofilm formation positions B. velezensis D-18 as a promising eco-friendly alternative to conventional antibiotics in managing bacterial diseases in aquaculture.

Abstract Background The Headache Impact Test (HIT-6) and the Chronic Headache Questionnaire (CH-QLQ) measure headache-related quality of life but are not preference-based and therefore cannot be used to generate health utilities for cost-effectiveness analyses. There are currently no established algorithms for mapping between the HIT-6 or CH-QLQ and preference-based health-related quality-of-life measures for chronic headache population. Methods We developed algorithms for generating EQ-5D-5L and SF-6D utilities from the HIT-6 and the CHQLQ using both direct and response mapping approaches. A multi-stage model selection process was used to assess the predictive accuracy of the models. The estimated mapping algorithms were derived to generate UK tariffs and was validated using the Chronic Headache Education and Self-management Study (CHESS) trial dataset. Results Several models were developed that reasonably accurately predict health utilities in this context. The best performing model for predicting EQ-5D-5L utility scores from the HIT-6 scores was a Censored Least Absolute Deviations (CLAD) (1) model that only included the HIT-6 score as the covariate (mean squared error (MSE) 0.0550). The selected model for CH-QLQ to EQ-5D-5L was the CLAD (3) model that included CH-QLQ summary scores, age, and gender, squared terms and interaction terms as covariates (MSE 0.0583). The best performing model for predicting SF-6D utility scores from the HIT-6 scores was the CLAD (2) model that included the HIT-6 score and age and gender as covariates (MSE 0.0102). The selected model for CH-QLQ to SF-6D was the OLS (2) model that included CH-QLQ summary scores, age, and gender as covariates (MSE 0.0086). Conclusion The developed algorithms enable the estimation of EQ-5D-5L and SF-6D utilities from two headache-specific questionnaires where preference-based health-related quality of life data are missing. However, further work is needed to help define the best approach to measuring health utilities in headache studies.

This paper explores the importance of equitable global health research collaborations that prioritize human dignity. It addresses the need for Global North partners to increase their efforts in raising awareness among all actors in global health. The aim is to bridge the gap in research collaborations and promote equitable practices that uphold the principles of human dignity and equity. A comprehensive review of existing literature and case studies was conducted to examine current practices and challenges in global health research collaborations. The review focused on the role of Global North partners in promoting equitable collaborations, capacity building efforts, and the impact of colonial legacies on research dynamics. The findings highlight the need for deliberate actions by Global North partners to raise awareness and promote equitable research collaborations. Initiatives such as Principal Investigator positions to partners from low- and middle-income countries (LMICs) during grant applications have been observed. Assigning first/last authorship positions to LMIC members is gaining momentum. However, further efforts are necessary to enhance the inclusivity of global health research collaborations. We emphasize the need for standardized definitions of global health that encompass human dignity and equity. Urgent action is required to ensure that all actors in global health research collaborations embrace human dignity. By deploying new techniques and tools where they are most needed, we can effectively promote equitable research collaborations that contribute to improving the health of individuals worldwide.

Introduction Aseptic abscess (AA) syndrome is a rare disease whose pathophysiology is unknown. It is often associated with inflammatory bowel disease and characterised by sterile inflammation with collections of neutrophils affecting several organs, especially the spleen. Microbiota are known to influence local and systemic immune responses, and both gut and oral microbiota perturbations have been reported in diseases associated with AA syndrome. However, interactions between these factors have never been studied in AA syndrome. The purpose of this translational case-control study (ABSCESSBIOT) is to investigate gut and/or oral microbiota in patients with AA syndrome compared with healthy controls. Moreover, microbiota associated metabolites quantification and Treg/Th17 balance characterisation will give a mechanistic insight on how microbiota may be involved in the pathophysiology of AA syndrome.Methods and analysis This French multicentre case-control study including 30 French centres (University hospital or regional hospital) aims to prospectively enrol 30 patients with AA syndrome with 30 matched controls and to analyse microbiota profiling (in stools and saliva), microbial metabolites quantification in stools and circulating CD4+ T cell populations.Ethics and dissemination This study protocol was reviewed and approved by an independent French regional review board (n° 2017-A03499-44, Comité de Protection des Personnes Ile de France 1) on 10 October 2022, and declared to the competent French authority (Agence Nationale de Sécurité du Médicament et des produits de santé, France). Oral and written informed consent will be obtained from each included patient and the control participant. Study results will be reported to the scientific community at conferences and in peer-reviewed scientific journals.Trial registration number Clinical Trials web-based platform (NCT05537909).

In the Sierra Maestra the rainforests occupied mountains territories between 800 and 1 500 meters above sea level (mosl). By using the Zurich Montpellier school methodology one new order are described, Clethro cubensis- Cyrilletalia silvae with two alliances and two associations that the late and mature succesional communities are.

Siendo necesario conocer las características de las pluvisilvas sobre ofiolitas en la Altiplanicie de Nipe, el objetivo del trabajo fue estudiar las fitocenosis mediante el método de Braun Blanquet. Se describen por primera vez una alianza y dos asociaciones, así como sus condiciones fisionómicas, ecológicas y fitosociológicas, lo que tiene gran impacto para analizar sus relaciones florísticas y comunitarias.

Abstract Background Schistosomiasis remains an important public health problem, also among adults, and infected individuals not treated serve as a reservoir for continued transmission. Despite this fact, evidence on the epidemiology of schistosomiasis in adults in Côte d’Ivoire is scanty. This study aimed to determine the prevalence and risk factors of Schistosoma infection and co-infection with other helminth species and Plasmodium among adults in the Taabo region in the south-central part of Côte d’Ivoire. Methods A cross-sectional survey was carried out in April and May 2017 in the frame of the “Côte d’Ivoire Dual Burden of Disease Study” (CoDuBu). A total of 901 randomly selected individuals, aged 18–90 years, provided blood, stool and urine samples for the diagnosis of malaria and helminth infections. Stool samples were subjected to the Kato-Katz technique for detection of Schistosoma mansoni and soil-transmitted helminth eggs, while urine samples were examined for eggs of Schistosoma haematobium and circulating cathodic antigen of S. mansoni. Risk factors and morbidity profiles were assessed using health examination and questionnaires. Multinomial logistic regressions were employed to identify risk factors and morbidity patterns associated with S. mansoni mono- and co-infections. Results The prevalence of S. mansoni and S. haematobium was 23.2% and 1.0%, respectively. Most S. mansoni were mono-infections (81.3%). Independent determinants of S. mansoni infection were young age, low socioeconomic status (mono- and co-infection) and poor hygiene practices (co-infection) (P

Despite successes in malaria control interventions over the past two decades, malaria remains a major public health concern. Over 125 million women live in endemic areas and experience adverse pregnancy outcomes due to malaria. Understanding health workers' perspectives on malaria identification and management is important to informing policy changes on the control and eradication of the disease. This study explored the perspectives of health workers on malaria case identification and management among pregnant women in Savelugu Municipality, Ghana. A qualitative study with a phenomenology design was conducted among participants. Participants were purposively selected and interviewed using a semi-structured interview guide. Thematic analysis was performed and the results were presented as themes and sub-themes. Four themes and eight sub-themes regarding case identification and management of malaria in pregnancy were identified including malaria case identification training (trained and untrained), identification approach (signs/symptoms and routine laboratory test), diagnostic tools (rapid diagnostic test and microscopy) and management options. It revealed that attending malaria training programs was generally optional. Some of the participants had not undergone any refresher training for malaria identification after their formal training at health institutions. Participants identified malaria by its signs and symptoms. However, they often referred clients for routine laboratory tests for confirmation. When malaria is confirmed in pregnancy, quinine is used for first trimester treatment, while Artemisinin-based Combination Therapies are prescribed after the first trimester. Clindamycin was not used in the first trimester treatment. This study found that training programs were optional for health workers. Some participants have not received refresher training after graduating from health institutions. Treatment of confirmed cases did not include clindamycin for first trimester malaria infections. Malaria refresher training programs should be made mandatory for health workers. Every suspected case should be confirmed using Rapid Diagnostic Test or microscopy before treatment.

Con vistas a conocer las características de las pluvisilvas sobre ofiolitas en la Sierra del Cristal y en la parte noroeste de las Alturas de Moa, el objetivo del trabajo fue estudiar las fitocenosis mediante el método de Braun Blanquet. Se describen por primera vez una alianza y dos asociaciones, así como sus condiciones fisionómicas, ecológicas y fitosociológicas, lo que tiene gran impacto para analizar el posterior uso de sus propiedades comunitarias.

Functional ingredients have profiled as suitable candidates for reinforcing the fish antioxidant response and stress tolerance. In addition, selective breeding strategies have also demonstrated a correlation between fish growth performance and susceptibility to stressful culture conditions as a key component in species domestication processes. The aim of the present study is to evaluate the ability of a selected high-growth genotype of 300 days post-hatch European sea bass (Dicentrarchus labrax) juveniles to use different functional additives as endogenous antioxidant capacity and stress resistance boosters when supplemented in low fish meal (FM) and fish oil (FO) diets. Three isoenergetic and isonitrogenous diets (10% FM/6% FO) were supplemented with 200 ppm of a blend of garlic and Labiatae plant oils (PHYTO0.02), 1000 ppm of a mixture of citrus flavonoids and Asteraceae and Labiatae plant essential oils (PHYTO0.1) or 5000 ppm of galactomannan-oligosaccharides (GMOS0.5). A reference diet was void of supplementation. The fish were fed the experimental diets for 72 days and subjected to a H2O2 exposure oxidative stress challenge. The fish stress response was evaluated through measuring the circulating plasma cortisol levels and the fish gill antioxidant response by the relative gene expression analysis of nfΚβ2, il-1b, hif-1a, nd5, cyb, cox, sod, cat, gpx, tnf-1α and caspase 9. After the oxidative stress challenge, the genotype origin determined the capacity of the recovery of basal cortisol levels after an acute stress response, presenting GS fish with a better pattern of recovery. All functional diets induced a significant upregulation of cat gill gene expression levels compared to fish fed the control diet, regardless of the fish genotype. Altogether, suggesting an increased capacity of the growth selected European sea bass genotype to cope with the potential negative side-effects associated to an H2O2 bath exposure.

European sea bass production has increased in recent decades. This increase is associated with an annually rising demand for sea bass, which encourages the aquaculture industries to increase their production to meet that demand. However, this intensification has repercussions on the animals, causing stress that is usually accompanied by dysbiosis, low feed-conversion rates, and immunodepression, among other factors. Therefore, the appearance of pathogenic diseases is common in these industries after immunodepression. Seeking to enhance animal welfare, researchers have focused on alternative approaches such as probiotic application. The use of probiotics in European sea bass production is presented as an ecological, safe, and viable alternative in addition to enhancing different host parameters such as growth performance, feed utilization, immunity, disease resistance, and fish survival against different pathogens through inclusion in fish diets through vectors and/or in water columns. Accordingly, the aim of this review is to present recent research findings on the application of probiotics in European sea bass aquaculture and their effect on growth performance, microbial diversity, enzyme production, immunity, disease resistance, and survival in order to help future research.

Abstract Background Community disaster resilience is comprised of a multitude of factors, including the capacity of citizens to psychologically recover. There is growing recognition of the need for public health departments to prioritize a communitywide mental health response strategy to facilitate access to behavioral health services and reduce potential psychological impacts. Due to the US Department of Veterans Affairs’ (VA) extensive experience providing trauma-informed behavioral healthcare to its Veterans, and the fact that VA Medical Centers (VAMCs) are located throughout the United States, the VA is well situated to be a key partner in local communities’ response plans. In this study we examined the role the VA can play in a community’s behavioral health response using case studies from three disasters. Methods This study investigated experiences of VA employees in critical emergency response positions (N = 17) in communities where disasters occurred between 2017 and 2019. All respondents were interviewed March–July 2019. Data were collected via semi-structured interviews exploring participants’ experiences and knowledge about VA activities provided to communities following the regional disasters. Data were analyzed using thematic and grounded theory coding methods. Results Respondents underscored VA’s primary mission after a disaster was to maintain continuity of care to Veterans. The majority also described the VA supporting community recovery. Specifically, three recent events provided key examples of VA’s involvement in disaster behavioral health response. Each event showed VA’s integration into local response structures was facilitated by pre-existing emergency management and clinical relationships as well as prioritization from VA leadership to engage in humanitarian missions. The behavioral health interventions were provided by behavioral health teams integrated into disaster assistance centers and non-VA hospitals, VA mobile units deployed into the community, and VA telehealth services. Conclusions Recent disasters have revealed that coordinated efforts between multidisciplinary agencies can strengthen communities’ capacity to respond to mental health needs, thereby fostering resilience. Building relationships with local VAMCs can help expedite how VA can be incorporated into emergency management strategies. In considering the strengths community partners can bring to bear, a coordinated disaster mental health response would benefit from involving VA as a partner during planning.

A multisystem inflammatory syndrome mimicking Kawasaki disease has been increasingly reported, mainly in children, in the context of coronavirus disease-2019 (COVID-19). We report on the first case of coronary aneurysm resolution after treatment with steroids and intravenous immunoglobulins in an adult patient with multisystem inflammatory syndrome temporally associated with COVID-19. (Level of Difficulty: Beginner.)

Introduction: This study sought to identify the availability of automated external defibrillators (AEDs) in schools in the region served by West Midlands Ambulance Service University NHS Trust (WMAS), United Kingdom, and the number of out-of-hospital cardiac arrests (OHCA) that occurred at or near to schools. A secondary aim was to explore the cost effectiveness of school-based defibrillators. Methods: This observational study used data from the national registry for OHCA (University of Warwick) to identify cases occurring at or near schools between January 2014 and December 2016 in WMAS region (n = 11,399). A school survey (n = 2,453) was carried out in September 2017 to determine the presence of AEDs and their registration status with WMAS. Geographical Information System mapping software identified OHCAs occurring within a 300-metre radius of a school. An economic analysis calculated the cost effectiveness of school-based AEDs. Results: A total of 39 (0.34%) of all OHCAs occurred in schools, although 4,250 (37.3%) of OHCAs in the region were estimated to have occurred within 300 metres of a school. Of 323 school survey responses, 184 (57%) had an AED present, of which 24 (13.0%) were available 24 h/day. Economic modelling of a school-based AED programme showed additional quality-adjusted life years (QALY) of 0.26 over the lifetime of cardiac arrest survivors compared with no AED programme. The incremental cost-effectiveness ratio (ICER) was £8,916 per QALY gained. Conclusion: Cardiac arrests in schools are rare. Registering AEDs with local Emergency Medical Services and improving their accessibility within their local community would increase their utility.

ABSTRACT: This single-centre observational study demonstrated that lower cycle threshold (Ct) values (indicating higher viral loads) on admission to hospital were associated with poorer outcomes in unvaccinated, hospitalized patients with coronavirus disease 2019 (COVID-19). Demographic and outcome data were collected prospectively for all adult patients who tested positive for severe acute respiratory syndrome coronavirus-2 on admission to the University Hospitals North Midlands NHS Trust between 1 February and 1 July 2020. Nasopharyngeal swab samples were obtained, and a valid Ct value was determined for all patients using the Viasure reverse transcription polymerase chain reaction assay, validated by Public Health England, on admission to hospital. Multi-variable logistic regression results based on data from 618 individuals demonstrated a significant inverse relationship between the odds of death and Ct values (adjusted odds ratio 0.95, 95% confidence interval 0.92–0.98, P=0.001). The association remained highly significant after adjusting for known clinical risk factors for COVID-19

Abstract Eosinophils have widespread procoagulant effects. Eosinophilic cardiovascular toxicity mostly consists of endomyocardial damage or eosinophilic vasculitis, while reported cases of venous thrombosis (VT) are scarce. We aimed to report on the clinical features and treatment outcomes of patients with unexplained VT and eosinophilia, and to identify predictors of relapse. This retrospective, multicenter, observational study included patients aged over 15 years with VT, concomitant blood eosinophilia ≥ 1G/L and without any other moderate-to-strong contributing factors for VT. Fifty-four patients were included. VT was the initial manifestation of eosinophil-related disease in 29 (54%) patients and included pulmonary embolism (52%), deep venous thrombosis (37%), hepatic (11%) and portal vein (9%) thromboses. The median [IQR] absolute eosinophil count at VT onset was 3.3G/L [1.6–7.4]. Underlying eosinophil-related diseases included FIP1L1-PDGFRA-associated chronic myeloid neoplasm (n = 4), Eosinophilic Granulomatosis with Polyangiitis (n = 9), lymphocytic (n = 1) and idiopathic (n = 29) variants of hypereosinophilic syndrome. After a median [IQR] follow-up of 24 [10–62] months, 7 (13%) patients had a recurrence of VT. In multivariate analysis, persistent eosinophilia was the sole variable associated with a shorter time to VT relapse (HR 7.48; CI95% [1.94–29.47]; p = 0.015). Long-term normalization of eosinophil count could prevent the recurrence of VT in a subset of patients with unexplained VT and eosinophilia ≥ 1G/L.

Abstract The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient’s plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.

Abstract Background The ‘Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration In Cardiac Arrest’ (PARAMEDIC2) trial showed that adrenaline improves overall survival, but not neurological outcomes. We sought to determine the within-trial and lifetime health and social care costs and benefits associated with adrenaline, including secondary benefits from organ donation. Methods We estimated the costs, benefits (quality-adjusted life years (QALYs)) and incremental cost-effectiveness ratios (ICERs) associated with adrenaline during the 6-month trial follow-up. Model-based analyses explored how results altered when the time horizon was extended beyond 6 months and the scope extended to include recipients of donated organs. Results The within-trial (6 months) and lifetime horizon economic evaluations focussed on the trial population produced ICERs of £1,693,003 (€1,946,953) and £81,070 (€93,231) per QALY gained in 2017 prices, respectively, reflecting significantly higher mean costs and only marginally higher mean QALYs in the adrenaline group. The probability that adrenaline is cost-effective was less than 1% across a range of cost-effectiveness thresholds. Combined direct economic effects over the lifetimes of survivors and indirect economic effects in organ recipients produced an ICER of £16,086 (€18,499) per QALY gained for adrenaline with the probability that adrenaline is cost-effective increasing to 90% at a £30,000 (€34,500) per QALY cost-effectiveness threshold. Conclusions Adrenaline was not cost-effective when only directly related costs and consequences are considered. However, incorporating the indirect economic effects associated with transplanted organs substantially alters cost-effectiveness, suggesting decision-makers should consider the complexity of direct and indirect economic impacts of adrenaline. Trial registration ISRCTN73485024 . Registered on 13 March 2014.

Abstract Background Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients. Methods HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ

Abstract Background Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been increasingly used over the last decade in patients with refractory cardiogenic shock. ECMO weaning can, however, be challenging and lead to circulatory failure and death. Recent data suggest a potential benefit of levosimendan for ECMO weaning. We sought to further investigate whether the use of levosimendan could decrease the rate of ECMO weaning failure in adult patients with refractory cardiogenic shock. Methods We performed an observational single-center cohort study. All patients undergoing VA-ECMO from January 2012 to December 2018 were eligible and divided into two groups: group levosimendan and group control (without levosimendan). The primary endpoint was VA-ECMO weaning failure defined as death during VA-ECMO treatment or within 24 h after VA-ECMO removal. Secondary outcomes were mortality at day 28 and at 6 months. The two groups were compared after propensity score matching. P

Summary: Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42–1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19–20–0151, PHRC COVID-19–20–0029], Fondation de l'Assistance Publique – Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale” (FRM). Tocilizumab was provided by Roche.

Background: Femoroacetabular impingement syndrome is an important cause of hip pain in young adults. It can be treated by arthroscopic hip surgery or with physiotherapist-led conservative care. Objective: To compare the clinical effectiveness and cost-effectiveness of hip arthroscopy with best conservative care. Design: The UK FASHIoN (full trial of arthroscopic surgery for hip impingement compared with non-operative care) trial was a pragmatic, multicentre, randomised controlled trial that was carried out at 23 NHS hospitals. Participants: Participants were included if they had femoroacetabular impingement, were aged ≥ 16 years old, had hip pain with radiographic features of cam or pincer morphology (but no osteoarthritis) and were believed to be likely to benefit from hip arthroscopy. Intervention: Participants were randomly allocated (1 : 1) to receive hip arthroscopy followed by postoperative physiotherapy, or personalised hip therapy (i.e. an individualised physiotherapist-led programme of conservative care). Randomisation was stratified by impingement type and recruiting centre using a central telephone randomisation service. Outcome assessment and analysis were masked. Main outcome measure: The primary outcome was hip-related quality of life, measured by the patient-reported International Hip Outcome Tool (iHOT-33) 12 months after randomisation, and analysed by intention to treat. Results: Between July 2012 and July 2016, 648 eligible patients were identified and 348 participants were recruited. In total, 171 participants were allocated to receive hip arthroscopy and 177 participants were allocated to receive personalised hip therapy. Three further patients were excluded from the trial after randomisation because they did not meet the eligibility criteria. Follow-up at the primary outcome assessment was 92% (N = 319; hip arthroscopy, n = 157; personalised hip therapy, n = 162). At 12 months, mean International Hip Outcome Tool (iHOT-33) score had improved from 39.2 (standard deviation 20.9) points to 58.8 (standard deviation 27.2) points for participants in the hip arthroscopy group, and from 35.6 (standard deviation 18.2) points to 49.7 (standard deviation 25.5) points for participants in personalised hip therapy group. In the primary analysis, the mean difference in International Hip Outcome Tool scores, adjusted for impingement type, sex, baseline International Hip Outcome Tool score and centre, was 6.8 (95% confidence interval 1.7 to 12.0) points in favour of hip arthroscopy (p = 0.0093). This estimate of treatment effect exceeded the minimum clinically important difference (6.1 points). Five (83%) of six serious adverse events in the hip arthroscopy group were related to treatment and one serious adverse event in the personalised hip therapy group was not. Thirty-eight (24%) personalised hip therapy patients chose to have hip arthroscopy between 1 and 3 years after randomisation. Nineteen (12%) hip arthroscopy patients had a revision arthroscopy. Eleven (7%) personalised hip therapy patients and three (2%) hip arthroscopy patients had a hip replacement within 3 years. Limitations: Study participants and treating clinicians were not blinded to the intervention arm. Delays were encountered in participants accessing treatment, particularly surgery. Follow-up lasted for 3 years. Conclusion: Hip arthroscopy and personalised hip therapy both improved hip-related quality of life for patients with femoroacetabular impingement syndrome. Hip arthroscopy led to a greater improvement in quality of life than personalised hip therapy, and this difference was clinically significant at 12 months. This study does not demonstrate cost-effectiveness of hip arthroscopy compared with personalised hip therapy within the first 12 months. Further follow-up will reveal whether or not the clinical benefits of hip arthroscopy are maintained and whether or not it is cost-effective in the long term. Trial registration: Current Controlled Trials ISRCTN64081839. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 16. See the NIHR Journals Library website for further project information.

SeptiCyte® RAPID is a gene expression assay measuring the relative expression levels of host response genes PLA2G7 and PLAC8, indicative of a dysregulated immune response during sepsis. As severe forms of COVID-19 may be considered viral sepsis, we evaluated SeptiCyte RAPID in a series of 94 patients admitted to Foch Hospital (Suresnes, France) with proven SARS-CoV-2 infection. EDTA blood was collected in the emergency department (ED) in 67 cases, in the intensive care unit (ICU) in 23 cases and in conventional units in 4 cases. SeptiScore (0–15 scale) increased with COVID-19 severity. Patients in ICU had the highest SeptiScores, producing values comparable to 8 patients with culture-confirmed bacterial sepsis. Receiver operating characteristic (ROC) curve analysis had an area under the curve (AUC) of 0.81 for discriminating patients requiring ICU admission from patients who were immediately discharged or from patients requiring hospitalization in conventional units. SeptiScores increased with the extent of the lung injury. For 68 patients, a chest computed tomography (CT) scan was performed within 24 h of COVID-19 diagnosis. SeptiScore >7 suggested lung injury ≥50% (AUC = 0.86). SeptiCyte RAPID was compared to other biomarkers for discriminating Critical + Severe COVID-19 in ICU, versus Moderate + Mild COVID-19 not in ICU. The mean AUC for SeptiCyte RAPID was superior to that of any individual biomarker or combination thereof. In contrast to C-reactive protein (CRP), correlation of SeptiScore with lung injury was not impacted by treatment with anti-inflammatory agents. SeptiCyte RAPID can be a useful tool to identify patients with severe forms of COVID-19 in ED, as well as during follow-up.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Spatial weight matrices play a key role in econometrics to capture spatial effects. However, these constructs are prone to clustering and can be challenging to analyse in common statistical packages such as STATA. Multiple observations of survey participants in the same location (or cluster) have traditionally not been dealt with appropriately by statistical packages. It is common that participants are assigned Geographic Information System (GIS) data at a regional or district level rather than at a small area level. For example, the Demographic Health Survey (DHS) generates GIS data at a cluster level, such as a regional or district level, rather than providing coordinates for each participant. Moreover, current statistical packages are not suitable for estimating large matrices such as 20,000 × 20,000 (reflective of data within large health surveys) since the statistical package limits the N to a smaller number. In addition, in many cases, GIS information is offered at an aggregated level of geographical areas. To alleviate this problem, this paper proposes a bootstrap approach that generates an inverse distance spatial weight matrix for application in econometric analyses of health survey data. The new approach is illustrated using DHS data on uptake of HIV testing in low and middle income countries.

The aim of the present study is to evaluate the potential of two functional additives as gill endogenous antioxidant capacity boosters in European sea-bass juveniles fed low-FM/FO diets when challenged against physical and biological stressors. For that purpose, two isoenergetic and isonitrogenous diets with low FM (10%) and FO (6%) contents were supplemented with 5000 ppm plant-derived galactomannan–oligosaccharides (GMOS) or 200 ppm of a mixture of garlic and labiate plant essential oils (PHYTO). A control diet was void from supplementation. Fish were fed the experimental diet for nine weeks and subjected to a confinement stress challenge (C challenge) or a confinement stress challenge combined with an exposure to the pathogen Vibrio anguillarum (CI challenge). Both GMOS and PHYTO diets attenuated fish stress response, inducing lower circulating plasma cortisol and down-regulating nfκβ2 and gr relative gene-expression levels in the gill. This attenuated stress response was associated with a minor energetic metabolism response in relation to the down-regulation of nd5 and coxi gene expression.

An effective replacement for fish meal (FM) and fish oil (FO) based on plant-based raw materials in the feed of marine fish species is necessary for the sustainability of the aquaculture sector. However, the use of plant-based raw materials to replace FM and FO has been associated with several negative health effects, some of which are related to oxidative stress processes that can induce functional and morphological alterations in mucosal tissues. This study aimed to evaluate the effects of dietary oligosaccharides of plant origin (5,000 ppm; galactomannan oligosaccharides, GMOS) and a phytogenic feed additive (200 ppm; garlic oil and labiatae plant extract mixture, PHYTO) on the oxidative stress status and mucosal health of the gills of juvenile European sea bass (Dicentrarchus labrax). The experimental diets, low FM and FO diets (10%FM/6%FO) were supplemented with GMOS from plant origin and PHYTO for 63 days. GMOS and PHYTO did not significantly affect feed utilization, fish growth, and survival. GMOS and PHYTO downregulated the expression of β-act, sod, gpx, cat, and gr in the gills of the fish compared with that in fish fed the control diet. The expression of hsp70 and ocln was upregulated and downregulated, respectively, in the GMOS group compared with that in the control group, whereas the expression of zo-1 was downregulated in the PHYTO group compared with that in the GMOS group. The morphological, histopathological, immunohistochemical, and biochemical parameters of the fish gills were mostly unaffected by GMOS and PHYTO. However, the PHYTO group had lower incidence of lamellar fusion than did the control group after 63 days. Although the tissular distribution of goblet cells was unaffected by GMOS and PHYTO, goblet cell size showed a decreasing trend (−11%) in the GMOS group. GMOS and PHYTO significantly reduced the concentration of PCNA+ in the epithelium of the gills. The above findings indicated that GMOS and PHYTO in low FM/FO-based diets protected the gill epithelia of D. labrax from oxidative stress by modulating the expression of oxidative enzyme-related genes and reducing the density of PCNA+ cells in the gills of the fish.

Background: Adrenaline has been used as a treatment for cardiac arrest for many years, despite uncertainty about its effects on long-term outcomes and concerns that it may cause worse neurological outcomes. Objectives: The objectives were to evaluate the effects of adrenaline on survival and neurological outcomes, and to assess the cost-effectiveness of adrenaline use. Design: This was a pragmatic, randomised, allocation-concealed, placebo-controlled, parallel-group superiority trial and economic evaluation. Costs are expressed in Great British pounds and reported in 2016/17 prices. Setting: This trial was set in five NHS ambulance services in England and Wales. Participants: Adults treated for an out-of-hospital cardiac arrest were included. Patients were ineligible if they were pregnant, if they were aged

Background: Sore throat is a common condition caused by an infection of the airway. Most cases are of a viral nature; however, a number of these infections may be caused by the group A Streptococcus bacterium. Most viral and bacterial sore throat infections resolve spontaneously within a few weeks. Point-of-care testing in primary care has been recognised as an emerging technology for aiding targeted antibiotic prescribing for sore throat in cases that do not spontaneously resolve. Objective: Systematically review the evidence for 21 point-of-care tests for detecting group A Streptococcus bacteria and develop a de novo economic model to compare the cost-effectiveness of point-of-care tests alongside clinical scoring tools with the cost-effectiveness of clinical scoring tools alone for patients managed in primary care and hospital settings. Data sources: Multiple electronic databases were searched from inception to March 2019. The following databases were searched in November and December 2018 and searches were updated in March 2019: MEDLINE [via OvidSP (Health First, Rockledge, FL, USA)], MEDLINE In-Process & Other Non-Indexed Citations (via OvidSP), MEDLINE Epub Ahead of Print (via OvidSP), MEDLINE Daily Update (via OvidSP), EMBASE (via OvidSP), Cochrane Database of Systematic Reviews [via Wiley Online Library (John Wiley & Sons, Inc., Hoboken, NJ, USA)], Cochrane Central Register of Controlled Trials (CENTRAL) (via Wiley Online Library), Database of Abstracts of Reviews of Effects (DARE) (via Centre for Reviews and Dissemination), Health Technology Assessment database (via the Centre for Reviews and Dissemination), Science Citation Index and Conference Proceedings [via the Web of Science™ (Clarivate Analytics, Philadelphia, PA, USA)] and the PROSPERO International Prospective Register of Systematic Reviews (via the Centre for Reviews and Dissemination). Review methods: Eligible studies included those of people aged ≥ 5 years presenting with sore throat symptoms, studies comparing point-of-care testing with antibiotic-prescribing decisions, studies of test accuracy and studies of cost-effectiveness. Quality assessment of eligible studies was undertaken. Meta-analysis of sensitivity and specificity was carried out for tests with sufficient data. A decision tree model estimated costs and quality-adjusted life-years from an NHS and Personal Social Services perspective. Results: The searches identified 38 studies of clinical effectiveness and three studies of cost-effectiveness. Twenty-six full-text articles and abstracts reported on the test accuracy of point-of-care tests and/or clinical scores with biological culture as a reference standard. In the population of interest (patients with Centor/McIsaac scores of ≥ 3 points or FeverPAIN scores of ≥ 4 points), point estimates were 0.829 to 0.946 for sensitivity and 0.849 to 0.991 for specificity. There was considerable heterogeneity, even for studies using the same point-of-care test, suggesting that is unlikely that any single study will have accurately captured a test’s true performance. There is some randomised controlled trial evidence to suggest that the use of rapid antigen detection tests may help to reduce antibiotic-prescribing rates. Sensitivity and specificity estimates for each test in each age group and care setting combination were obtained using meta-analyses where appropriate. Any apparent differences in test accuracy may not be attributable to the tests, and may have been caused by known differences in the studies, latent characteristics or chance. Fourteen of the 21 tests reviewed were included in the economic modelling, and these tests were not cost-effective within the current National Institute for Health and Care Excellence’s cost-effectiveness thresholds. Uncertainties in the cost-effectiveness estimates included model parameter inputs and assumptions that increase the cost of testing, and the penalty for antibiotic overprescriptions. Limitations: No information was identified for the elderly population or pharmacy setting. It was not possible to identify which test is the most accurate owing to the paucity of evidence. Conclusions: The systematic review and the cost-effectiveness models identified uncertainties around the adoption of point-of-care tests in primary and secondary care settings. Although sensitivity and specificity estimates are promising, we have little information to establish the most accurate point-of-care test. Further research is needed to understand the test accuracy of point-of-care tests in the proposed NHS pathway and in comparable settings and patient groups. Study registration: The protocol of the review is registered as PROSPERO CRD42018118653. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 31. See the NIHR Journals Library website for further project information.

Introduction Chronic headaches are poorly diagnosed and managed and can be exacerbated by medication overuse. There is insufficient evidence on the non-pharmacological approaches to helping people living with chronic headaches.Methods and analysis Chronic Headache Education and Self-management Study is a pragmatic randomised controlled trial to test the effectiveness and cost-effectiveness of a self-management education support programme on top of usual care for patients with chronic headaches against a control of usual care and relaxation. The intervention is a 2-day group course based on education, personal reflection and a cognitive behavioural approach, plus a nurse-led one-to-one consultation and follow-up over 8 weeks. We aim to recruit 689 participants (356 to the intervention arm and 333 to the control) from primary care and self-referral in London and the Midlands. The trial is powered to show a difference of 2.0 points on the Headache Impact Test, a patient-reported outcome measure at 12 months post randomisation. Secondary outcomes include health related quality of life, self-efficacy, social activation and engagement, anxiety and depression and healthcare utilisation. Outcomes are being measured at 4, 8 and 12 months. Cost-effectiveness will be expressed in terms of incremental cost per quality-adjusted life year gained.Ethics and dissemination This trial will provide data on effectiveness and cost-effectiveness of a self-management support programme for chronic headaches. The results will inform commissioning of services and clinical practice. North West – Greater Manchester East Research Ethics Committee have approved the trial. The current protocol version is 3.6 date 7 March 2019.Trial registration number ISRCTN79708100.

Antimicrobial peptides (AMP) play an essential role in the innate immune system, modulating the defense response. In a previous study, we demonstrated the antimicrobial activity of synthetic hepcidin (hep20) from rainbow trout (Oncorhynchus mykiss), and its protective effect in European sea bass (Dicentrarchus labrax) challenged with Vibrio anguillarum. Additionally, we described the uptake and distribution of hep20 in different tissues and leukocyte cells. Interestingly, various AMPs characterized in high vertebrates, called host defense peptides (HDPs), also possess immunomodulation activity. For that reason, the present study explores the immunomodulatory abilities of hep20 through in vitro and in vivo studies. First, a monocyte/macrophage RTS-11 cell line from rainbow trout was used to evaluate hep20 effects on pro- and anti-inflammatory cytokines in fish leukocyte cells. Next, the European sea bass juveniles were used to determine if hep20 can regulate the expression of cytokines in fish immune tissues. The results show that hep20 was uptake inner to RTS-11 cells and was able to induce the expression of IL-10, IL-1β, and TNFα at transcriptional and protein levels. Then, the European sea bass juveniles were given intraperitoneal injections of the peptide. At 1, 3, 7, 14, and 21 days post-injection (dpi), IL-10, IL -1β, and TNFα mRNA were quantified in the anterior gut, spleen, and head kidney. The hep20 was able to up-regulate cytokine gene expression in these tissues, mainly in the head kidney. Furthermore, the evaluated cytokines showed a cyclical tendency of higher to lesser expression. Finally, a bioinformatics analysis showed that the structure adopted by hep20 is similar to the γ-core domain described for cysteine-stabilized AMP, defined as immunomodulatory and antimicrobial, which could explain the ability of hep20 to regulate the cytokine expression. This study provides new insights into immunomodulatory function complementary to the previously established antimicrobial activity of hep20, suggesting a role as an HDP in teleost fish. These facts are likely to be associated with molecular functions underpinning the protective effect of fish hepcidin against pathogens.

Dog-assisted interventions (DAI) are those that include specially trained dogs in human health services. Often, the training methods employed to train animals for DAI are transmitted between trainers, so the latest scientific research on dog learning and cognition is not always taken into account. The present work aims to evaluate the impact that the main theories on the evolution of the dog have had both in promoting different training methods and in the relevance of behavior in the evolution of the skills of actual dogs. Then, an integrative method for the training of dogs is presented. This method takes into account the research on dog learning mechanisms and cognition processes, and effectively promotes the development of desirable behaviors for DAI during the dog’s ontogeny.

Abstract Acinetobacter baumannii is a common cause of health care associated infections worldwide. A. pittii is an opportunistic pathogen also frequently isolated from Acinetobacter infections other than those from A. baumannii. Knowledge of Acinetobacter virulence factors and their role in pathogenesis is scarce. Also, there are no detailed published reports on the interactions between A. pittii and human phagocytic cells. Using confocal laser and scanning electron microscopy, immunofluorescence, and live-cell imaging, our study shows that immediately after bacteria-cell contact, neutrophils rapidly and continuously engulf and kill bacteria during at least 4 hours of infection in vitro. After 3 h of infection, neutrophils start to release neutrophil extracellular traps (NETs) against Acinetobacter. DNA in NETs colocalizes well with human histone H3 and with the specific neutrophil elastase. We have observed that human neutrophils use large filopodia as cellular tentacles to sense local environment but also to detect and retain bacteria during phagocytosis. Furthermore, co-cultivation of neutrophils with human differentiated macrophages before infections shows that human neutrophils, but not macrophages, are key immune cells to control Acinetobacter. Although macrophages were largely activated by both bacterial species, they lack the phagocytic activity demonstrated by neutrophils.

Active travel can have health and environmental benefits. This study evaluated the impact of a month-long (October 2015) campaign encouraging primary school children in Victoria, Australia to engage in active school travel. With support from local councils, schools participated in the campaign by monitoring active school travel and delivering promotional activities. A longitudinal study evaluated campaign impact. Carers (n = 715) of Victorian primary school children were recruited via social media and completed online surveys at baseline (T1; 0 wk) and during (T2; +2 wks) and after the campaign (T3; +6 wks). Carers reported their child's travel behaviour over the last five school days, and whether their child and/or their child's school participated in the campaign. Separate generalised linear models were used for T2 and T3 outcomes adjusting for T1 values and potential confounders. A greater proportion of children who participated in the campaign engaged in any active school travel at T2 (OR = 2.49, 95% CI = 1.63, 3.79) and T3 (1.62, 95% CI = 1.06, 2.46) compared with non-participating children. Similarly, these children had a higher frequency of active school travel at T2 (IRR = 1.60, 95% CI = 1.29, 1.97) and T3 (IRR = 1.45, 95% CI = 1.16, 1.80). Campaign participation resulted in small, short-term increases in active school travel. Keywords: Walking, Cycling, Active travel, Young people, Intervention, School