The high incidence of bacterial genes that confer resistance to last-resort antibiotics, such as colistin, caused by mobilized colistin resistance (mcr) genes, poses an unprecedented threat to human ...health. Understanding the spread, evolution, and distribution of such genes among human populations will help in the development of strategies to diminish their occurrence. To tackle this problem, we investigated the distribution and prevalence of potential mcr genes in the human gut microbiome using a set of bioinformatics tools to screen the Unified Human Gastrointestinal Genome (UHGG) collection for the presence, synteny and phylogeny of putative mcr genes, and co-located antibiotic resistance genes.
A total of 2079 antibiotic resistance genes (ARGs) were classified as mcr genes in 2046 metagenome assembled genomes (MAGs), distributed across 1596 individuals from 41 countries, of which 215 were identified in plasmidial contigs. The genera that presented the largest number of mcr-like genes were Suterella and Parasuterella. Other potential pathogens carrying mcr genes belonged to the genus Vibrio, Escherichia and Campylobacter. Finally, we identified a total of 22,746 ARGs belonging to 21 different classes in the same 2046 MAGs, suggesting multi-resistance potential in the corresponding bacterial strains, increasing the concern of ARGs impact in the clinical settings.
This study uncovers the diversity of mcr-like genes in the human gut microbiome. We demonstrated the cosmopolitan distribution of these genes in individuals worldwide and the co-presence of other antibiotic resistance genes, including Extended-spectrum Beta-Lactamases (ESBL). Also, we described mcr-like genes fused to a PAP2-like domain in S. wadsworthensis. These novel sequences increase our knowledge about the diversity and evolution of mcr-like genes. Future research should focus on activity, genetic mobility and a potential colistin resistance in the corresponding strains to experimentally validate those findings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
With the advent of cryptocurrencies and blockchain, the growth and adaptation of cryptographic features and capabilities were quickly extended to new and underexplored areas, such as healthcare. ...Currently, blockchain is being implemented mainly as a mechanism to secure Electronic Health Records (EHRs). However, new studies have shown that this technology can be a powerful tool in empowering patients to control their own health data, as well for enabling a fool-proof health data history and establishing medical responsibility. Additionally, with the proliferation of mobile health (m-Health) sustained on service-oriented architectures, the adaptation of blockchain mechanisms into m-Health applications creates the possibility for a more decentralized and available healthcare service. Hence, this paper presents a review of the current security best practices for m-Health and the most used and widely known implementations of the blockchain protocol, including blockchain technologies in m-Health. The main goal of this comprehensive review is to further discuss and elaborate on identified open-issues and potential use cases regarding the uses of blockchain in this area. Finally, the paper presents the major findings, challenges and advantages on future blockchain implementations for m-Health services and applications.
IMPORTANCE: The efficacy of vitamin D3 supplementation in coronavirus disease 2019 (COVID-19) remains unclear. OBJECTIVE: To investigate the effect of a single high dose of vitamin D3 on hospital ...length of stay in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, double-blind, randomized, placebo-controlled trial conducted in 2 sites in Sao Paulo, Brazil. The study included 240 hospitalized patients with COVID-19 who were moderately to severely ill at the time of enrollment from June 2, 2020, to August 27, 2020. The final follow-up was on October 7, 2020. INTERVENTIONS: Patients were randomly assigned to receive a single oral dose of 200 000 IU of vitamin D3 (n = 120) or placebo (n = 120). MAIN OUTCOMES AND MEASURES: The primary outcome was length of stay, defined as the time from the date of randomization to hospital discharge. Prespecified secondary outcomes included mortality during hospitalization; the number of patients admitted to the intensive care unit; the number of patients who required mechanical ventilation and the duration of mechanical ventilation; and serum levels of 25-hydroxyvitamin D, total calcium, creatinine, and C-reactive protein. RESULTS: Of 240 randomized patients, 237 were included in the primary analysis (mean SD age, 56.2 14.4 years; 104 43.9% women; mean SD baseline 25-hydroxyvitamin D level, 20.9 9.2 ng/mL). Median (interquartile range) length of stay was not significantly different between the vitamin D3 (7.0 4.0-10.0 days) and placebo groups (7.0 5.0-13.0 days) (log-rank P = .59; unadjusted hazard ratio for hospital discharge, 1.07 95% CI, 0.82-1.39; P = .62). The difference between the vitamin D3 group and the placebo group was not significant for in-hospital mortality (7.6% vs 5.1%; difference, 2.5% 95% CI, –4.1% to 9.2%; P = .43), admission to the intensive care unit (16.0% vs 21.2%; difference, –5.2% 95% CI, –15.1% to 4.7%; P = .30), or need for mechanical ventilation (7.6% vs 14.4%; difference, –6.8% 95% CI, –15.1% to 1.2%; P = .09). Mean serum levels of 25-hydroxyvitamin D significantly increased after a single dose of vitamin D3 vs placebo (44.4 ng/mL vs 19.8 ng/mL; difference, 24.1 ng/mL 95% CI, 19.5-28.7; P < .001). There were no adverse events, but an episode of vomiting was associated with the intervention. CONCLUSIONS AND RELEVANCE: Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D3 for treatment of moderate to severe COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04449718
Elesclomol (ELC) is an anticancer drug inducing mitochondria cytotoxicity through reactive oxygen species. Here, for the first time, we encapsulate the poorly water soluble ELC in monoolein-based ...cubosomes stabilized with Pluronic F127. Cellular uptake and nanocarrier accumulation close to the mitochondria with sub-micrometer distance is identified via three-dimensional (3D) confocal microscopy and edge-to-edge compartment analysis. To monitor the therapeutic effect of the ELC nanocarrier, we apply for the first time, label-free time-lapse multi-photon fluorescence lifetime imaging microscopy (MP-FLIM) to track NAD(P)H cofactors with sub-cellular resolution on live cells exposed to an anticancer nanocarrier. Improved
in vitro
cytotoxicity is verified when loading the pre-complexed ELC with copper (ELC-Cu). Importantly, for equivalent copper concentration, cubosomes loaded with ELC-Cu show higher cytotoxicity compared to the free drug. The novel nanocarrier shows promising features for systemic ELC-Cu administration, and furthermore we establish the MP-FLIM technique for the assessment of anticancer drug delivery systems.
We sought to assess whether the effects of mesenchymal stromal cells (MSC) on lung inflammation and remodeling in experimental emphysema would differ according to MSC source and administration route. ...Emphysema was induced in C57BL/6 mice by intratracheal (IT) administration of porcine pancreatic elastase (0.1 UI) weekly for 1 month. After the last elastase instillation, saline or MSCs (1×105), isolated from either mouse bone marrow (BM), adipose tissue (AD) or lung tissue (L), were administered intravenously (IV) or IT. After 1 week, mice were euthanized. Regardless of administration route, MSCs from each source yielded: 1) decreased mean linear intercept, neutrophil infiltration, and cell apoptosis; 2) increased elastic fiber content; 3) reduced alveolar epithelial and endothelial cell damage; and 4) decreased keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8) and transforming growth factor-β levels in lung tissue. In contrast with IV, IT MSC administration further reduced alveolar hyperinflation (BM-MSC) and collagen fiber content (BM-MSC and L-MSC). Intravenous administration of BM- and AD-MSCs reduced the number of M1 macrophages and pulmonary hypertension on echocardiography, while increasing vascular endothelial growth factor. Only BM-MSCs (IV > IT) increased the number of M2 macrophages. In conclusion, different MSC sources and administration routes variably reduced elastase-induced lung damage, but IV administration of BM-MSCs resulted in better cardiovascular function and change of the macrophage phenotype from M1 to M2.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•A careful biological in vitro and in vivo of PBAT containning two different nHAp loads were investigated.•The incorporation of nHAp increased the hydrophilicity and controlled the in ...vitro osteogenesis.•nHAp at 3% and 5wt% led enhanced the bone volume after 6 weeks of implantation.•nHAp at 5wt% positively influenced the flexural mode of bone neoformation.
Combining polyester scaffolds with synthetic nanohydroxyapatite (nHAp), which is bioactive and osteoconductive, is a plausible strategy to improve bone regeneration. Here, we propose the combination of PBAT poly(butylene-adipate-co-terephthalate) and synthetic nHAp (at 3 and 5wt%). PBAT is a relatively a new polymer with low crystallinity and attractive biodegradability and mechanical properties for orthopedic applications, however, with a still underexplored potential for in vivo applications. Then, we performed a careful biological in vitro and in vivo set of experiments to evaluate the influence of PBAT containing two different nHAp loads. For in vitro assays, osteoblast-like MG63 cells were used and the bioactivity and gene expression related to osteogenesis were evaluated by qRT-PCR. For in vivo experiments, twenty-four male rats were used and a tibial defect model was applied to insert the scaffolds. Micro-computed tomography (Micro-CT) and histological analysis were used to assess e bone neoformation after 6 weeks of implantation. Three point flexural tests measured the mechanical properties of the neoformed bone. All scaffolds showed promising in vitro properties, since they were not cytotoxic against MG-63 cells and promoted high cell proliferation and formation of mineralized nodules. From a mechanistic point-of-view, nHAp loading increased hydrophilicity, which in turn allowed for a better adsorption of proteins and consequent changes in the phenotypic expression of osteoblasts. nHAp induced better cellular responses on/in the scaffolds, which was mainly attributed to its osteoconductive and osteoinductive properties. Micro-CT images showed that nHAp at 3% and 5wt% led to more effective bone formation, presenting the highest bone volume after 6 weeks of implantation. Considering the three point flexural tests, 5wt% of nHAp positively influenced the flexural mode of the neoformed bone, but the stiffiness was similar between the 3% and 5wt% groups. In summary, this investigation demonstrated great potential for the application of these novel scaffolds towards bone regeneration and, thus, should be further studied.
The monotypic Fuscous Flycatcher, Cnemotriccus fuscatus (Wied, 1831) (Tyrannidae), is widely distributed in South America eastern, with seven diagnosable subspecies. This is a common, but ...inconspicuous passerine which occurs in a variety of habitats, often close to water, including the undergrowth of dry and humid forests, gallery forests, and secondary woodlands, where they silently forage for insects. While nest and egg descriptions are available for different subspecies and/or localities, other reproductive aspects of C. fuscatus remain poorly documented. Here, Bruno et al provide further reproductive data for C. f. bimaculatus from São Paulo state, southeastern Brazil.
...while it has been some months since the original article was published, we would like to bring to your attention a new point to consider: In the Results section, the authors state: “…opioids use ...was significantly higher in patients affected by NSCLC Non-Small Cell Lung Cancer (p < 0.0001), in patients with a worse ECOG PS Eastern Cooperative Oncology Group Performance Status (p < 0.0001), in second-line setting subgroup (p = 0.009), in patients taking corticosteroids (p < 0.0001), and in patients with a high tumor burden (p = 0.006)” 1. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Drilon A, Wolchok JD, Carvajal RD, McHenry MB, Hosein F, Harbison CT, Grosso JF, Sznol M. Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
We examined gene expression, germline variant, and somatic mutation features associated with pathologic response to neoadjuvant durvalumab plus chemotherapy in basal-like triple-negative breast ...cancer (bTNBC).
Germline and somatic whole-exome DNA and RNA sequencing, programmed death ligand 1 (PD-L1) IHC, and stromal tumor-infiltrating lymphocyte scoring were performed on 57 patients. We validated our results using 162 patients from the GeparNuevo randomized trial.
Gene set enrichment analysis showed that pathways involved in immunity (adaptive, humoral, innate), JAK-STAT signaling, cancer drivers, cell cycle, apoptosis, and DNA repair were enriched in cases with pathologic complete response (pCR), whereas epithelial-mesenchymal transition, extracellular matrix, and TGFβ pathways were enriched in cases with residual disease (RD). Immune-rich bTNBC with RD was enriched in CCL-3, -4, -5, -8, -23, CXCL-1, -3, -6, -10, and IL1, -23, -27, -34, and had higher expression of macrophage markers compared with immune-rich cancers with pCR that were enriched in IFNγ, IL2, -12, -21, chemokines CXCL-9, -13, CXCR5, and activated T- and B-cell markers (GZMB, CD79A). In the validation cohort, an immune-rich five-gene signature showed higher expression in pCR cases in the durvalumab arm (P = 0.040) but not in the placebo arm (P = 0.923) or in immune-poor cancers. Independent of immune markers, tumor mutation burden was higher, and PI3K, DNA damage repair, MAPK, and WNT/β-catenin signaling pathways were enriched in germline and somatic mutations in cases with pCR.
The TGFβ pathway is associated with immune-poor phenotype and RD in bTNBC. Among immune-rich bTNBC RD, macrophage/neutrophil chemoattractants dominate the cytokine milieu, and IFNγ and activated B cells and T cells dominate immune-rich cancers with pCR.
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