Abstract
Early restoration of oxygen delivery to end organs in paediatric patients experiencing shock states is critical to optimizing outcomes. However, obtaining central access in paediatric ...patients may be challenging in non-intensive care settings. There is limited literature on the use of peripheral vasoactive infusions in the initial resuscitation of paediatric patients in the emergency department. The aims of this study were to report the associated complications of peripheral vasoactive infusions and describe our local experience on its use. This was a single-centre, retrospective study on all paediatric patients who received peripheral vasoactive infusions at our paediatric emergency department from 2009 to 2016. 65 patients were included in this study. No patients had any local or regional complications. The mean patient age was 8.29 years old (± 5.99). The most frequent diagnosis was septic shock (45, 69.2%). Dopamine was the most used peripheral vasoactive agent (71.2%). The median time to central agents was 2 h (IQR 1–4). 16(24.2%) received multiple peripheral infusions. We reported no complications of peripheral vasoactive infusions. Its use could serve as a bridge till central access is obtained. Considerations on the use of multiple peripheral vasoactive infusions in the emergency department setting needs further research.
In late 2019, a novel human coronavirus – severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) – emerged in Wuhan, China. This virus has caused a global pandemic involving more than 200 ...countries. SARS-CoV-2 is highly adapted to humans and readily transmits from person-to-person.
To investigate the infectivity of SARS-CoV-2 under various environmental and pH conditions. The efficacies of various laboratory virus inactivation methods and home disinfectants against SARS-CoV-2 were investigated.
The residual virus in dried form or in solution was titrated on to Vero E6 cells on days 0, 1, 3, 5 and 7 after incubation at different temperatures. Viral viability was determined after treatment with various disinfectants and pH solutions at room temperature (20–25oC).
SARS-CoV-2 was able to retain viability for 3–5 days in dried form or 7 days in solution at room temperature. SARS-CoV-2 could be detected under a wide range of pH conditions from pH 4 to pH 11 for several days, and for 1–2 days in stool at room temperature but lost 5 logs of infectivity. A variety of commonly used disinfectants and laboratory inactivation procedures were found to reduce viral viability effectively.
This study demonstrated the stability of SARS-CoV-2 on environmental surfaces, and raises the possibility of faecal–oral transmission. Commonly used fixatives, nucleic acid extraction methods and heat inactivation were found to reduce viral infectivity significantly, which could ensure hospital and laboratory safety during the SARS-CoV-2 pandemic.
DNA methylation has pivotal regulatory roles in mammalian development, retrotransposon silencing, genomic imprinting, X-chromosome inactivation, and cancer. Cancer cells display highly dysregulated ...DNA methylation profiles, characterized by global hypomethylation in conjunction with hypermethylation of promoter CpG islands; these changes are often correlated with promoter hypermethylation, leading to decreased expression of tumor suppressor genes, as well as with genome instability, leading to amplification and aberrant expression of oncogenes. Ten-eleven-translocation (TET) proteins are α-ketoglutarate (α-KG)–dependent dioxygenases that oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and the additional oxidation products 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC); together, these oxidized methylcytosines are intermediates in DNA demethylation. TET2 is frequently mutated in diverse lymphoid and myeloid cancers, and TET loss of function is often observed in the absence of coding region mutations in TET genes. Despite our understanding of the biochemical activities of TET proteins, how TET loss of function promotes the onset and progression of hematopoietic malignancies is largely unknown. Here, we review recent advances in our understanding of the role of TET enzymes in lymphoid and myeloid neoplasms and highlight the importance of metabolic alterations that decrease TET activity in cancer initiation and progression.
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Abstract
We present a blind time-delay strong lensing (TDSL) cosmographic analysis of the doubly imaged quasar SDSS 1206+4332 . We combine the relative time delay between the quasar images, Hubble ...Space Telescope imaging, the Keck stellar velocity dispersion of the lensing galaxy, and wide-field photometric and spectroscopic data of the field to constrain two angular diameter distance relations. The combined analysis is performed by forward modelling the individual data sets through a Bayesian hierarchical framework, and it is kept blind until the very end to prevent experimenter bias. After unblinding, the inferred distances imply a Hubble constant H0 = 68.8$^{+5.4}_{-5.1}$ km s−1 Mpc−1, assuming a flat Λ cold dark matter cosmology with uniform prior on Ωm in 0.05, 0.5. The precision of our cosmographic measurement with the doubly imaged quasar SDSS 1206+4332 is comparable with those of quadruply imaged quasars and opens the path to perform on selected doubles the same analysis as anticipated for quads. Our analysis is based on a completely independent lensing code than our previous three H0LiCOW systems and the new measurement is fully consistent with those. We provide the analysis scripts paired with the publicly available software to facilitate independent analysis (footnote with link to www.h0licow.org). The consistency between blind measurements with independent codes provides an important sanity check on lens modelling systematics. By combining the likelihoods of the four systems under the same prior, we obtain H0 = 72.5$^{+2.1}_{-2.3}$ km s−1 Mpc−1. This measurement is independent of the distance ladder and other cosmological probes.
While injectable hydrogels have several advantages in the context of biomedical use, their generally weak mechanical properties often limit their applications. Herein, we describe in situ-gelling ...nanocomposite hydrogels based on poly(oligoethylene glycol methacrylate) (POEGMA) and rigid rod-like cellulose nanocrystals (CNCs) that can overcome this challenge. By physically incorporating CNCs into hydrazone cross-linked POEGMA hydrogels, macroscopic properties including gelation rate, swelling kinetics, mechanical properties, and hydrogel stability can be readily tailored. Strong adsorption of aldehyde- and hydrazide-modified POEGMA precursor polymers onto the surface of CNCs promotes uniform dispersion of CNCs within the hydrogel, imparts physical cross-links throughout the network, and significantly improves mechanical strength overall, as demonstrated by quartz crystal microbalance gravimetry and rheometry. When POEGMA hydrogels containing mixtures of long and short ethylene oxide side chain precursor polymers were prepared, transmission electron microscopy reveals that phase segregation occurs with CNCs hypothesized to preferentially locate within the stronger adsorbing short side chain polymer domains. Incorporating as little as 5 wt % CNCs results in dramatic enhancements in mechanical properties (up to 35-fold increases in storage modulus) coupled with faster gelation rates, decreased swelling ratios, and increased stability versus hydrolysis. Furthermore, cell viability can be maintained within 3D culture using these hydrogels independent of the CNC content. These properties collectively make POEGMA–CNC nanocomposite hydrogels of potential interest for various biomedical applications including tissue engineering scaffolds for stiffer tissues or platforms for cell growth.
TET enzymes oxidize 5-methylcytosine to 5-hydroxymethylcytosine and other oxidized methylcytosines in DNA. Here we examine the role of TET proteins in regulatory T (Treg) cells. Tet2/3
Foxp3
mice ...lacking Tet2 and Tet3 in Treg cells develop inflammatory disease, and Treg cells from these mice show altered expression of Treg signature genes and upregulation of genes involved in cell cycle, DNA damage and cancer. In littermate mice with severe inflammation, both CD4
Foxp3
and CD4
Foxp3
cells show strong skewing towards Tfh/Th17 phenotypes. Wild-type Treg cells in mixed bone marrow chimeras and in Tet2/3
Foxp3
heterozygous female mice are unable to rescue the aberrant properties of Tet2/3
Foxp3
Treg cells. Treg cells from Tet2/3
Foxp3
mice tend to lose Foxp3 expression, and transfer of total CD4
T cells isolated from Tet2/3
Foxp3
mice could elicit inflammatory disease in fully immunocompetent mice. Together, these data indicate that Tet2 and Tet3 are guardians of Treg cell stability and immune homeostasis.
DNA methylation is an abundant and stable epigenetic modification that allows inheritance of information from parental to daughter cells. At active genomic regions, DNA methylation can be reversed by ...TET (Ten-eleven translocation) enzymes, which are responsible for fine-tuning methylation patterns. TET enzymes oxidize the methyl group of 5-methylcytosine (5mC) to yield 5-hydroxymethylcytosine (5hmC) and other oxidized methylcytosines, facilitating both passive and active demethylation. Increasing evidence has demonstrated the essential functions of TET enzymes in regulating gene expression, promoting cell differentiation, and suppressing tumor formation. In this review, we will focus on recent discoveries of the functions of TET enzymes in the development and function of lymphoid and myeloid cells. How TET activity can be modulated by metabolites, including vitamin C and 2-hydroxyglutarate, and its potential application in shaping the course of immune response will be discussed.
The transcription factors nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1; Fos-Jun) cooperate to promote the effector functions of T cells, but NFAT in the absence of AP-1 ...imposes a negative feedback program of T cell hyporesponsiveness (exhaustion). Here, we show that basic leucine zipper ATF-like transcription factor (BATF) and interferon regulatory factor 4 (IRF4) cooperate to counter T cell exhaustion in mouse tumor models. Overexpression of BATF in CD8
T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumor-infiltrating CAR T cells, increased the production of effector cytokines, decreased the expression of inhibitory receptors and the exhaustion-associated transcription factor TOX and supported the generation of long-lived memory T cells that controlled tumor recurrence. These responses were dependent on BATF-IRF interaction, since cells expressing a BATF variant unable to interact with IRF4 did not survive in tumors and did not effectively delay tumor growth. BATF may improve the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.
The contribution of thymic antigen-presenting-cell (APC) subsets in selecting a self-tolerant T cell population remains unclear. We show that bone marrow (BM) APCs and medullary thymic epithelial ...cells (mTECs) played nonoverlapping roles in shaping the T cell receptor (TCR) repertoire by deletion and regulatory T (Treg) cell selection of distinct TCRs. Aire, which induces tissue-specific antigen expression in mTECs, affected the TCR repertoire in a manner distinct from mTEC presentation. Approximately half of Aire-dependent deletion or Treg cell selection utilized a pathway dependent on antigen presentation by BM APCs. Batf3-dependent CD8α+ dendritic cells (DCs) were the crucial BM APCs for Treg cell selection via this pathway, showing enhanced ability to present antigens from stromal cells. These results demonstrate the division of function between thymic APCs in shaping the self-tolerant TCR repertoire and reveal an unappreciated cooperation between mTECs and CD8α+ DCs for presentation of Aire-induced self-antigens to developing thymocytes.
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•BM APCs and mTECs have nonredundant roles in deletion and Treg cell selection•Aire is involved in both Treg cell selection and deletion•Aire-dependent Treg cell selection is equally mediated by mTECs and BM APCs•Batf3-dependent CD8α+ DCs mediate Treg cell selection to Aire-dependent antigens
The contribution of thymic antigen-presenting cell subsets in selecting a self-tolerant T cell population remains unclear. Hsieh and colleagues demonstrate that medullary thymic epithelial cells, dendritic cells, and Aire play nonredundant roles in the deletion and regulatory T cell selection of distinct TCR repertoires.
Aims/hypothesis
The renal and cardiovascular protective effects of angiotensin receptor blocker (ARB) remain controversial in type 2 diabetic patients treated with a contemporary regimen including an ...angiotensin converting enzyme inhibitor (ACEI).
Methods
We examined the effects of olmesartan, an ARB, on primary composite outcome of doubling of serum creatinine, endstage renal disease and death in type 2 diabetic patients with overt nephropathy. Secondary outcome included composite cardiovascular outcomes, changes in renal function and proteinuria. Randomisation and allocation to trial group were carried out by a central computer system. Participants, caregivers, the people carrying out examinations and people assessing the outcomes were blinded to group assignment.
Results
Five hundred and seventy-seven (377 Japanese, 200 Chinese) patients treated with antihypertensive therapy (73.5%
n
= 424 received concomitant ACEI), were given either once-daily olmesartan (10–40 mg) (
n
= 288) or placebo (
n
= 289) over 3.2 ± 0.6 years (mean±SD). In the olmesartan group, 116 developed the primary outcome (41.1%) compared with 129 (45.4%) in the placebo group (HR 0.97, 95% CI 0.75, 1.24;
p
= 0.791). Olmesartan significantly decreased blood pressure, proteinuria and rate of change of reciprocal serum creatinine. Cardiovascular death was higher in the olmesartan group than the placebo group (ten vs three cases), whereas major adverse cardiovascular events (cardiovascular death plus non-fatal stroke and myocardial infarction) and all-cause death were similar between the two groups (major adverse cardiovascular events 18 vs 21 cases, all-cause deaths; 19 vs 20 cases). Hyperkalaemia was more frequent in the olmesartan group than the placebo group (9.2% vs 5.3%).
Conclusions/interpretation
Olmesartan was well tolerated but did not improve renal outcome on top of ACEI.
Trial registration:
ClinicalTrials.gov NCT00141453
Funding:
The ORIENT study was supported by a research grant from Daiichi Sankyo.
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