Background
Drug‐induced maculopapular exanthemas (MPEs) are mediated by Th1 CD4+ T cells. One of the mechanisms of control of Th1 cells in homeostasis is the interaction between the checkpoint ...inhibitor Tim3 and its physiological ligand galectin‐9 (Gal9). Disorders affecting this axis may be responsible for various autoimmune and immunological diseases. The aim of this study was to determinate the influence of the Tim3‐Gal9 axis on the development of MPE induced by drugs.
Methods
Frequencies of different cell subsets and the expression of Tim3 and Gal9 were measured in peripheral blood by flow cytometry and in skin biopsies by immunohistochemistry. Gal9 expression was assessed by RT‐qPCR; its release was measured by multiplex assay. The effects of blocking or enhancing the Tim3‐Gal9 axis on monocyte‐derived dendritic cell (moDC) maturation and T‐cell proliferation were determined by flow cytometry.
Results
The expression of Tim3 was significantly reduced in peripheral blood Th1 cells and in the skin of MPE patients vs controls. Gal9 expression and release were significantly reduced in patient peripheral blood and moDCs, respectively. The addition of exogenous Gal9 significantly reduced Tim3+ Th1 proliferation, although Treg proliferation increased.
Conclusion
This study showed the involvement of the Tim3‐Gal9 axis in MPE. The reduced expression of Tim3 in Th1 cells together with the impaired expression of Gal9 in PBMCs and DCs appears to have a role in the development of the disease. The potential of Gal9 to suppress Th1 and enhance Treg proliferation makes it a promising tool for treating these reactions.
The reduced level of the checkpoint molecule Tim3 in Th1 cells together with the impaired expression of Gal9 in PBMCs and dendritic cells hampers the control of Th1 cell numbers in patients with drug‐induced maculopapular exanthema (MPE). The reduced expression of Gal9 in patients with drug‐induced MPE could be responsible for the low frequencies of Treg cells in these patients. Exogenous administration of Gal9 could be a potential therapeutic tool able to suppress Th1 and enhance Treg differentiation in patients with drug‐induced MPE.
BACKGROUNDPassive immunotherapy with convalescent plasma (CP) is a potential treatment for COVID-19. Evidence from controlled clinical trials is inconclusive.METHODSWe conducted a randomized, ...open-label, controlled clinical trial at 27 hospitals in Spain. Patients had to be admitted for COVID-19 pneumonia within 7 days from symptom onset and not on mechanical ventilation or high-flow oxygen devices. Patients were randomized 1:1 to treatment with CP in addition to standard of care (SOC) or to the control arm receiving only SOC. The primary endpoint was the proportion of patients in categories 5 (noninvasive ventilation or high-flow oxygen), 6 (invasive mechanical ventilation or extracorporeal membrane oxygenation ECMO), or 7 (death) at 14 days. Primary analysis was performed in the intention-to-treat population.RESULTSBetween April 4, 2020, and February 5, 2021, 350 patients were randomly assigned to either CP (n = 179) or SOC (n = 171). At 14 days, proportion of patients in categories 5, 6, or 7 was 11.7% in the CP group versus 16.4% in the control group (P = 0.205). The difference was greater at 28 days, with 8.4% of patients in categories 5-7 in the CP group versus 17.0% in the control group (P = 0.021). The difference in overall survival did not reach statistical significance (HR 0.46, 95% CI 0.19-1.14, log-rank P = 0.087).CONCLUSIONCP showed a significant benefit in preventing progression to noninvasive ventilation or high-flow oxygen, invasive mechanical ventilation or ECMO, or death at 28 days. The effect on the predefined primary endpoint at 14 days and the effect on overall survival were not statistically significant.TRIAL REGISTRATIONClinicaltrials.gov, NCT04345523.FUNDINGGovernment of Spain, Instituto de Salud Carlos III.
The conversion of greenhouse gases, such as CO2 and CH4, to value chemicals is a major challenge, because of the high stability of both molecules. In this study, density functional theory (DFT) ...calculations with long-range corrections and ONIOM were used to analyze the reaction mechanism for the conversion of CO2 and CH4 to acetic acid with MFI zeolite exchanged with Be, Co, Cu, Mg, Mn, and Zn cations. Our results demonstrate that (a) the highest reaction barrier on the reaction mechanism is CH4 dissociation, and the transition state energy in that step is directly related to the energy of the lowest unoccupied molecular orbital and the electronegativity of the metal exchanged zeolites; (b) a charge transfer between CH4 and the metal cation occurs simultaneously to CH4 dissociation; (c) CO2 insertion has a low energy barrier, and the protonation of the acetate species is spontaneous; (d) dispersion interactions are the main contributions to CH4 adsorption energies, whereas, in the rest of the steps of the reaction mechanism, the contribution of dispersion to the energies of reaction is almost negligible; (e) desorption of acetic acid could be promoted by the coadsorption of water; and (f) CH4 dissociation on Cu-MFI has an apparent activation energy of 11.5 kcal/mol, and a forward rate constant of 1.1 s–1 at 398 K.
Even though Escherichia coli are common bacteria of the bovine vaginal microbiota, they represent an important pathogen that causes diseases in the reproductive tract and subfertility. However, the ...actual endometrial virulence profile of E. coli is poorly understood. The present study aims to characterize the phylogenetic structure and virulence potential of native vaginal populations of E. coli from healthy heifers (H), and cows with postpartum uterine diseases (PUD), such as metritis/endometritis (MT) or repeat breeder cows (RB). To this end, the virulence repertoire of 97 E. coli isolates was genotypically and phenotypically assessed. Most of them were assigned to phylogenetic group A (74%), followed by B1 (17%) and D (9%); RB strains were significantly (p < 0.05) more represented by B1. Seven of the 15 evaluated virulence genes (VFG) were detected and the most prevalent were fimH (87%), agn43 (41%) and csgA (35%); while traT (27%), fyuA (11%), hlyA (5%) and kpsMT II (5%) were observed in a lower proportion. Particularly, fyuA was significantly higher (p < 0.05) in MT cows whereas csgA showed the same behavior in PUD animals (p < 0.05). When comparing H and PUD strains, these last ones were associated to positive expression of biofilm, fimbriae curli/cellulose and motility; yet RB strains did not show motility. Vaginal B1 E. coli populations, that possess VFG (fyuA and csgA) as well as the expression of motility, curli fimbriae/cellulose and biofilm, may represent risk factors for endometrial disorders; specifically, those that also, have kpsMT II may have a pathogenic potential for causing the RB syndrome. Future research focusing on the detection of these strains in the vaginal microbiota of cows with postpartum uterine diseases should be done since the control of their presence in vagina could reduce the risk that they access the uterus during the postpartum period.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
New approaches on paediatric cancer treatment aim to maintain long-term health. As a result of radiotherapy, chemotherapy or surgery, paediatric cancer survivors tend to suffer from any chronic ...health condition. Endocrine dysfunction represents one of the most common issues and affects bone health. Exercise is key for bone mass accrual during growth, specifically plyometric jump training. The iBoneFIT study will investigate the effect of a 9-month online exercise programme on bone health in paediatric cancer survivors. This study will also examine the effect of the intervention on body composition, physical fitness, physical activity, calcium intake, vitamin D, blood samples quality of life and mental health.
A minimum of 116 participants aged 6 to 18 years will be randomized into an intervention (n = 58) or control group (n = 58). The intervention group will receive an online exercise programme and diet counselling on calcium and vitamin D. In addition, five behaviour change techniques and a gamification design will be implemented in order to increase the interest of this non-game programme. The control group will only receive diet counselling. Participants will be assessed on 3 occasions: 1) at baseline; 2) after the 9 months of the intervention; 3) 4 months following the intervention. The primary outcome will be determined by dual energy X-ray absorptiometry (DXA) and the hip structural analysis, trabecular bone score and 3D-DXA softwares. Secondary outcomes will include anthropometry, body composition, physical fitness, physical activity, calcium and vitamin D intake, blood samples, quality of life and mental health.
Whether a simple, feasible and short in duration exercise programme can improve bone health has not been examined in paediatric cancer survivors. This article describes the design, rationale and methods of a study intended to test the effect of a rigorous online exercise programme on bone health in paediatric cancer survivors. If successful, the iBoneFIT study will contribute to decrease chronic health conditions in this population and will have a positive impact in the society.
Prospectively registered in isrctn.com: isrctn61195625 . Registered 2 April 2020.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
One of the limitations of remote sensing is the low spatial resolution of the open-access multispectral sensors, generating a mixture of spatial information. The mixed pixels can be modelled as the ...linear combination of fundamental components, called endmember, with a weighted contribution or abundance. The development of linear unmixing algorithms considering spatial and spectral information has recently increased. Some unmixing methods have relied on segmentation to integrate spatial data, and one of the most used is superpixel-based segmentation. However, previous work in superpixel-based unmixing focuses on using superpixels as uniform regions. Commonly, linear unmixing is used on hyperspectral imagery, and limited literature is found with multispectral images. This paper aims to propose a new preprocessing approach for multispectral linear unmixing called Superpixel Linear Independent Preprocessing. The proposed approach generates a set of candidates to endmembers based on spatial-spectral information; these are the input of traditional endmember extraction methods for multispectral unmixing. Experimental results show that the proposed preprocessing improves the performance of endmember extraction.
Ischemic stroke continues to be one of the main causes of death worldwide. Inflammation accounts for a large part of damage in this pathology. The cannabinoid type 2 receptor (CB2R) has been proposed ...to have neuroprotective properties in neurological diseases. Therefore, our aim was to determine the effects of the activation of CB2R on infarct outcome and on ischemia-induced brain expression of classic and alternative markers of macrophage/microglial activation.
Swiss wild-type and CB2R knockout male mice were subjected to a permanent middle cerebral artery occlusion. Mice were treated with either a CB2R agonist (JWH-133), with or without a CB2R antagonist (SR144528) or vehicle. Infarct outcome was determined by measuring infarct volume and neurological outcome. An additional group of animals was used to assess mRNA and protein expression of CB2R, interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory peptide (MIP) -1α, RANTES, inducible nitric oxide synthase (iNOS), cyclooxygenase-2, IL-4, IL-10, transforming growth factor β (TGF-β), arginase I, and Ym1.
Administration of JWH-133 significantly improved infarct outcome, as shown by a reduction in brain infarction and neurological impairment. This effect was reversed by the CB2R antagonist and was absent in CB2R knockout mice. Concomitantly, administration of JWH-133 led to a lower intensity of Iba1+ microglia/macrophages and a decrease in middle cerebral artery occlusion-induced gene expression of both classic (IL-6, TNF-α, MCP-1, MIP-1α, RANTES, and iNOS) and alternative mediators/markers (IL-10, TGF-β, and Ym1) of microglial/macrophage activation after permanent middle cerebral artery occlusion.
The inhibitory effect of CB2R on the activation of different subpopulations of microglia/macrophages may account for the protective effect of the selective CB2R agonist JWH-133 after stroke.
Brazil hosts the largest expanse of tropical ecosystems within protected areas (PAs), which shelter biodiversity and support traditional human populations. We assessed the vulnerability to climate ...change of 993 terrestrial and coastal‐marine Brazilian PAs by combining indicators of climatic‐change hazard with indicators of PA resilience (size, native vegetation cover, and probability of climate‐driven vegetation transition). This combination of indicators allows the identification of broad climate‐change adaptation pathways. Seventeen PAs (20,611 km2) were highly vulnerable and located mainly in the Atlantic Forest (7 PAs), Cerrado (6), and the Amazon (4). Two hundred fifty‐eight PAs (756,569 km2), located primarily in Amazonia, had a medium vulnerability. In the Amazon and western Cerrado, the projected severe climatic change and probability of climate‐driven vegetation transition drove vulnerability up, despite the generally good conservation status of PAs. Over 80% of PAs of high or moderate vulnerability are managed by indigenous populations. Hence, besides the potential risks to biodiversity, the traditional knowledge and livelihoods of the people inhabiting these PAs may be threatened. In at least 870 PAs, primarily in the Atlantic Forest and Amazon, adaptation could happen with little or no intervention due to low climate‐change hazard, high resilience status, or both. At least 20 PAs in the Atlantic Forest, Cerrado, and Amazonia should be targeted for stronger interventions (e.g., improvement of ecological connectivity), given their low resilience status. Despite being a first attempt to link vulnerability and adaptation in Brazilian PAs, we suggest that some of the PAs identified as highly or moderately vulnerable should be prioritized for testing potential adaptation strategies in the near future.
Evaluación de la Vulnerabilidad y Adaptación al Cambio Climático de Áreas Protegidas en Brasil
Resumen
Brasil alberga la mayor extensión de ecosistemas tropicales dentro de áreas protegidas (AP), que protegen la biodiversidad y sustentan a poblaciones humanas tradicionales. Evaluamos la vulnerabilidad al cambio climático de 993 AP brasileñas terrestres y costeras‐marinas mediante la combinación de indicadores de riesgo de cambio climático con indicadores de la resiliencia de AP (tamaño, cobertura de vegetación nativa y la probabilidad de transición en la vegetación como consecuencia del cambio climático). Esta combinación de indicadores permite la identificación de amplias rutas de adaptación al cambio climático. Diecisiete AP (20,611 km2) fueron altamente vulnerables y se localizaron principalmente en el Bosque Atlántico (7 AP), El Cerrado (6) y la Amazonía (4). Doscientos cincuenta y ocho AP (756,569 km2), localizadas principalmente en la Amazonía, tuvieron vulnerabilidad media. En la Amazonía y el oeste de El Cerrado, el severo cambio climático proyectado y la probabilidad de transición de vegetación dirigida por el clima incrementó la vulnerabilidad, a pesar del estado de conservación generalmente bueno de las AP. Más de 80% de las AP con vulnerabilidad alta o media son manejadas por poblaciones indígenas. Por lo tanto, además de los riesgos potenciales para la biodiversidad, también hay amenazas para el conocimiento tradicional y las formas de vida de la gente que habita en esas AP. En por lo menos 870 AP, principalmente en el Bosque Atlántico y la Amazonía, la adaptación podría suceder con poca o ninguna intervención debido al bajo riesgo de cambio climático, estatus de resiliencia alta, o ambos. Por lo menos 20 AP en el Bosque Atlántico, El Cerrado y la Amazonía deberían ser objetivo de intervenciones mayores (e.g., mejoramiento de la conectividad ecológica), dada su estatus de resiliencia baja. A pesar de que es un primer intento para vincular vulnerabilidad y adaptación en AP brasileñas, sugerimos que algunas de las AP identificadas como alta o moderadamente vulnerables se deben priorizar para probar posibles estrategias de adaptación en un futuro próximo.
摘要
巴西是保护地体系中热带生态系统面积最大的国家, 这里的保护地支撑着生物多样性及当地的传统人群。我们结合气候变化灾害指标与保护地恢复力指标 (面积、原生植被覆盖、气候驱动植被转变的可能性), 评估了巴西 993 个陆地和近岸海域保护地对气候变化响应的脆弱性。这些指标的结合有助于确定广泛的气候变化适应机制。结果显示, 有十七个保护地 (20,611 平方公里) 被评为高度脆弱, 它们主要分布在大西洋森林 (7 个保护地) 、塞拉多 (6 个) 和亚马逊 (4 个); 两百五十八个主要位于亚马逊流域的保护地 (756,569 平方公里) 被评为中度脆弱。在亚马逊和塞拉多西部, 虽然保护地的保护情况总体良好, 但预测的气候变化严峻且气候驱动植被转变的可能性高, 这加剧了保护地的脆弱性。高度或中度脆弱的保护地中, 80%以上由原住民管理, 因此, 除了生物多样性的面临的潜在风险之外, 这些居住在保护地的人群的传统知识和生计也可能受到威胁。在主要位于大西洋森林和亚马逊地区的至少 870 个保护地中, 由于气候变化危害弱、保护地恢复力强或二者共同作用, 可能在很少或是没有干预的情况下产生适应。大西洋森林、塞拉多和亚马逊流域的至少二十个保护地由于恢复力较弱, 应得到更有力的干预 (如提高生态连通性) 。尽管这是第一个将巴西保护地的脆弱性和适应性联系起来的研究, 但我们建议一些被评为高度或中度脆弱的保护地应该在不久的将来优先实施可能的适应保护策略。【翻译: 胡怡思; 审校: 聂永刚】
Article impact statement: More than 25% of Brazilian protected areas are vulnerable to climate change and demand adaptation‐oriented management.
IMPORTANCE: Ivermectin is widely prescribed as a potential treatment for COVID-19 despite uncertainty about its clinical benefit. OBJECTIVE: To determine whether ivermectin is an efficacious ...treatment for mild COVID-19. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized trial conducted at a single site in Cali, Colombia. Potential study participants were identified by simple random sampling from the state’s health department electronic database of patients with symptomatic, laboratory-confirmed COVID-19 during the study period. A total of 476 adult patients with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between July 15 and November 30, 2020, and followed up through December 21, 2020. INTERVENTION: Patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200). MAIN OUTCOMES AND MEASURES: Primary outcome was time to resolution of symptoms within a 21-day follow-up period. Solicited adverse events and serious adverse events were also collected. RESULTS: Among 400 patients who were randomized in the primary analysis population (median age, 37 years interquartile range {IQR}, 29-48; 231 women 58%), 398 (99.5%) completed the trial. The median time to resolution of symptoms was 10 days (IQR, 9-13) in the ivermectin group compared with 12 days (IQR, 9-13) in the placebo group (hazard ratio for resolution of symptoms, 1.07 95% CI, 0.87 to 1.32; P = .53 by log-rank test). By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The most common solicited adverse event was headache, reported by 104 patients (52%) given ivermectin and 111 (56%) who received placebo. The most common serious adverse event was multiorgan failure, occurring in 4 patients (2 in each group). CONCLUSION AND RELEVANCE: Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04405843
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