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AIMS: Circulating levels of sphingosine 1-phosphate (S1P), an HDL-associated ligand for endothelial cell (EC) protective S1P receptor-1 (S1PR1), are reduced in disease states associated with endothelial dysfunction. Yet as S1PR1 has high affinity for S1P and can be activated by ligand-independent mechanisms and EC-autonomous S1P production, it is unclear if relative reductions in circulating S1P impact endothelial function. It is also unclear how EC S1PR1 insufficiency, whether induced by ligand deficiency or by S1PR1-directed immunosuppressive therapy, affects different vascular subsets. METHODS AND RESULTS: We here fine-map the zonation of S1PR1 signalling in the murine blood and lymphatic vasculature, superimpose cell type-specific and relative deficiencies in S1P production to define ligand source- and dose-dependence, and correlate receptor engagement to essential functions. In naïve blood vessels, despite broad expression, EC S1PR1 engagement was restricted to resistance-size arteries, lung capillaries and high-endothelial venules (HEV). Similar zonation was observed for albumin extravasation in EC S1PR1 deficient mice, and brain extravasation was reproduced with arterial EC-selective S1pr1 deletion. In lymphatic EC, S1PR1 engagement was high in collecting vessels and lymph nodes and low in terminal capillaries that drain tissue fluids. While EC S1P production sustained S1PR1 signaling in lymphatics and HEV, hematopoietic cells provided â¼90% of plasma S1P and sustained signaling in resistance arteries and lung capillaries. S1PR1 signaling and endothelial function were both surprisingly sensitive to reductions in plasma S1P with apparent saturation around 50% of normal levels. S1PR1 engagement did not depend on sex or age, but modestly increased in arteries in hypertension and diabetes. Sphingosine kinase (Sphk)-2 deficiency also increased S1PR1 engagement selectively in arteries, which could be attributed to Sphk1-dependent S1P release from perivascular macrophages. CONCLUSIONS: This study highlights vessel subtype-specific S1PR1 functions and mechanisms of engagement and supports the relevance of S1P as circulating biomarker for endothelial function.
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INTRODUCTION: On 1 January 2020, Vietnam introduced a new law with harsher fines and penalties for driving under the influence of alcohol. Reports of empty beer restaurants following this implementation suggested the new law has the potential to reduce population-level alcohol consumption. This pilot study aims to quantify short-term changes in alcohol consumption levels after the implementation of the new law and assess whether it could lead to a reduction in total alcohol consumption in the population. METHODS: Wastewater samples were collected from two sites along a sewage canal in Hanoi during two periods: Period 1 (15 December 2018 to 14 January 2019) and Period 2 (15 December 2019 to 14 January 2020). Ethyl sulfate, a specific metabolite of alcohol, was quantified to monitor the trend of alcohol consumption. Both interrupted time series and controlled interrupted time series approaches were utilised, with Period 1 and Period 2 serving as the control and intervention periods, respectively. RESULTS: Our analysis indicated that the implementation of the new law did not result in an immediate and significant reduction in alcohol consumption at the population level. Meanwhile, there was no significant difference in alcohol consumption between weekdays and weekends both before and after the implementation of the new law. DISCUSSION AND CONCLUSIONS: Long-term monitoring is needed to assess the impact of stricter DUI policy on alcohol consumption in the urban areas of Vietnam.
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BACKGROUND: Ten-eleven-translocation (TET) 2 is a member of the TET family of proteins (TET1-3). DNMT1 gene deletion confers resistance to DNA methyltransferase (DNMT) inhibitors in colorectal, breast, and ovarian cancer cells. Currently, the effect of DNMT1 gene status on TET2 phenotype following DNMT inhibitor treatment is unclear in human malignancies. METHODS: Human colorectal carcinoma HCT116 cells (DNMT+/+) and their isogenic DNMT1 knockout (DNMT1-/-) counterpart were treated with DNMT inhibitors. Expression of TET2 and tumor suppressor (p16ink4A and p15ink4B) proteins were examined by Western blot. Apoptosis and CDKN2A promoter demethylation following drug treatment were detected by Annexin-V apoptosis assay and methylation-specific PCR. RESULTS: TET2 expression was robustly increased in DNMT1-/- cells by 0.5 µM and 5 µM decitabine and azacitidine treatment. Augmentation of TET2 expression was accompanied by re-expression of p16ink4A and p15ink4B proteins and CDKN2A promoter demethylation. TET2 upregulation and tumor suppressor re-expression were associated with resistance conferred by DNMT1 deletion. Treatment with 5-aza-4'-thio-2'-deoxycytidine at a low 0.5 µM dose only upregulated TET2 and reduced CDKN2A promoter methylation, and re-expression of p16ink4A in DNMT1-/- cells. DNMT inhibitors showed minimal effects on TET2 upregulation and re-expression of tumor suppressor proteins in cells with intact DNMT1. CONCLUSIONS: DNMT1 gene deletion made cancer cells prone to TET2 upregulation and activation of tumor suppressor expression upon DNMT inhibitor challenge. TET2 augmentation is concomitant with resistance to DNMT inhibitors in a DNMT1-deleted state.
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Reaction of lithium 1,3-diamidopropane Li2(TripNCN) (TripNCN=[{(Trip)NCH2}2CH2]2-, Trip=2,4,6-triisopropylphenyl) with BeBr2(OEt2)2 gave the diamido beryllium complex, [(TripNCN)Be(OEt2)]. Deprotonation reactions between the bulkier 1,3-diaminopropane (TCHPNCN)H2 (TCHPNCN=[{(TCHP)NCH2}2CH2]2-, TCHP=2,4,6-tricyclohexylphenyl) and magnesium alkyls afforded the adduct complexes [(TCHPNCN)Mg(OEt2)] and [(TCHPNCN)Mg(THF)2], depending on the reaction conditions employed. Treating [(TCHPNCN)Mg(THF)2] with the N-heterocyclic carbene :C{(MeNCMe)2} (TMC) gave [(TCHPNCN)Mg(TMC)2] via substitution of the THF ligands. Reactions of (ArNCN)H2 (Ar=Trip or TCHP) with Mg{CH2(SiMe3)}2, in the absence of Lewis bases, yielded the N-bridged dimers [{(ArNCN)Mg}2]. Salt metathesis reactions between alkali metal salts M2(TCHPNCN) (M=Li or K) and CaI2 or SrI2 led to the THF adduct compounds [(TCHPNCN)Ca(THF)3] and [(TCHPNCN)Sr(THF)4], the differing number of THF ligands in which is a result of the different sizes of the metals involved. The described complexes hold potential as precursors to kinetically protected, low oxidation state group 2 metal species.
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Acute hepatitis can result from a wide variety of noninfectious causes that include, but are not limited to, drugs (drug-induced hepatitis), alcohol (alcoholic hepatitis), immunologic (autoimmune hepatitis, primary biliary cholangitis), or as a result of indirect insult secondary to biliary tract dysfunction (cholestatic hepatitis), pregnancy-related liver dysfunction, shock, or metastatic disease. In clinical settings, these causes are not uncommon to overlap with each other or are masked by obviously visible causes in medical history. We reported our scenario of a patient who has a heavy history of alcohol use and presented with alcohol withdrawal symptoms and a marked elevation of liver enzymes. Interestingly, further investigations suggested Wilson's disease could be an underlying culprit of acute hepatitis in this patient. This case again emphasized that Wilson's disease can be masked under multiple causes and various scenarios, which alerts clinicians that a broad approach should be made for every case of acute hepatitis.
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This first study investigated the presence of dioxins and furans in river sediments around a craft village in Vietnam, focusing on Secondary Steel Recycling. Sediment samples were collected from various locations along the riverbed near the Da Hoi Secondary Steel Recycling village in Bac Ninh province. The analysis was conducted using a HRGC/HRMS-DFS device, detecting a total of 17 dioxin/furan isomers in all samples, with an average total concentration of 288.86 ng/kg d.w. The concentrations of dioxin/furan congeners showed minimal variation among sediment samples, ranging from 253.9 to 344.2 ng/kg d.w. The predominant compounds in the dioxin group were OCDD, while in the furan group, they were 1,2,3,4,6,7,8-HpCDF and OCDF. The chlorine content in the molecule appeared to be closely related to the concentration of dioxins and their percentage distribution. However, the levels of furan isomers did not vary significantly. The distribution of these compounds was not dependent on the flow direction, as they were mainly found in solid waste and are not water-soluble. Although the hepta and octa congeners had high concentrations, when converted to TEQ values, the tetra and penta groups (for dioxins) and the penta and hexa groups (for furans) contributed more to toxicity. Furthermore, the source of dioxins in sediments at Da Hoi does not only originate from steel recycling production activities but also from other combustion sites. The average total toxicity was 10.92 ng TEQ/kg d.w, ranging from 4.99 to 17.88 ng TEQ/kg d.w, which did not exceed the threshold specified in QCVN 43:2017/BTNMT, the National Technical Regulation on Sediment Quality. Nonetheless, these levels are still concerning. The presence of these toxic substances not only impacts aquatic organisms in the sampled water environment but also poses potential health risks to residents living nearby.
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Dioxinas , Monitoramento Ambiental , Furanos , Sedimentos Geológicos , Rios , Aço , Poluentes Químicos da Água , Rios/química , Vietnã , Sedimentos Geológicos/química , Sedimentos Geológicos/análise , Dioxinas/análise , Aço/química , Poluentes Químicos da Água/análise , Furanos/análise , Furanos/química , Monitoramento Ambiental/métodos , ReciclagemRESUMO
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1-4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass6-8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.
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Proteína Forkhead Box O1 , Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Células-Tronco , Linfócitos T , Humanos , Camundongos , Linhagem Celular Tumoral , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Mitocôndrias/metabolismo , Fenótipo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/citologia , Microambiente Tumoral/imunologia , Células-Tronco/citologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapiaRESUMO
Endolysins are bacteriophage-encoded hydrolases that show high antibacterial activity and a narrow substrate spectrum. We hypothesize that an mRNA-based approach to endolysin therapy can overcome some challenges of conventional endolysin therapy, namely organ targeting and bioavailability. We show that synthetic mRNA applied to three human cell lines (HEK293T, A549, HepG2 cells) leads to expression and cytosolic accumulation of the Cpl-1 endolysin with activity against Streptococcus pneumoniae. Addition of a human lysozyme signal peptide sequence translocates the Cpl-1 to the endoplasmic reticulum leading to secretion (hlySP-sCpl-1). The pneumococcal killing effect of hlySP-sCpl-1 was enhanced by introduction of a point mutation to avoid N-linked-glycosylation. hlySP-sCpl-1N215D, collected from the culture supernatant of A549 cells 6 h post-transfection showed a significant killing effect and was active against nine pneumococcal strains. mRNA-based cytosolic Cpl-1 and secretory hlySP-sCpl-1N215D show potential for innovative treatment strategies against pneumococcal disease and, to our best knowledge, represent the first approach to mRNA-based endolysin therapy. We assume that many other bacterial pathogens could be targeted with this novel approach.
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An extremely bulky p-terphenyl bis(aniline), p-C6H4{C6H4[N(H)TCHP]-2}2 (TCHP = 2,4,6-tricyclohexylphenyl) TCHPTerphH2, has been developed. Deprotonation of a less bulky analogue, DipTerphH2 (Dip = 2,6-diisopropylphenyl), with BePh2 affords the bimetallic system, [(BePh)2(µ-DipTerph)] 1. Treating either TCHPTerphH2 or DipTerphH2 with Mg{CH2(SiMe3)}2 gives the monomeric bis(anilide) complexes [Mg(ArTerph)] (Ar = Dip 2, TCHP 3) which display rare examples of η6-arene coordination to the metal center. Treating 2 with THF leads to partial dissociation of the Mg···arene interaction and formation of [Mg(DipTerph)(THF)] 4. Reactions of the bis(aniline)s with the group 2 metal amides [M{N(SiMe3)2}2] afford dimeric, structurally analogous compounds [{M(ArTerph)}2] (Ar = Dip, M = Ca 5, Sr 6, Ba 7; Ar = TCHP, M = Ca 8, Sr 9, Ba 10) which display intermolecular M···arene interactions in the solid state. Computational studies have shown that the intramolecular M···Î·6-arene interactions in models of the ether-free metal bis(anilide) compounds are largely electrostatic in nature. Reductions of these compounds with alkali metals led to mixtures of unidentified products.
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Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, leads to durable weight loss and improves obesity-related comorbidities. However, it induces abnormalities in bone metabolism. One unexplored potential contributor is the gut microbiome, which influences bone metabolism and is altered after surgery. We characterized the relationship between the gut microbiome and skeletal health in severe obesity and after LSG. In a prospective cohort study, 23 adults with severe obesity underwent skeletal health assessment and stool collection preoperatively and 6 mo after LSG. Gut microbial diversity and composition were characterized using 16S rRNA gene sequencing, and fecal concentrations of short-chain fatty acids (SCFA) were measured with LC-MS/MS. Spearman's correlations and PERMANOVA analyses were applied to assess relationships between the gut microbiome and bone health measures including serum bone turnover markers (C-terminal telopeptide of type 1 collagen [CTx] and procollagen type 1 N-terminal propeptide [P1NP]), areal BMD, intestinal calcium absorption, and calciotropic hormones. Six months after LSG, CTx and P1NP increased (by median 188% and 61%, P < .01) and femoral neck BMD decreased (mean -3.3%, P < .01). Concurrently, there was a decrease in relative abundance of the phylum Firmicutes. Although there were no change in overall microbial diversity or fecal SCFA concentrations after LSG, those with greater within-subject change in gut community microbial composition (ß-diversity) postoperatively had greater increases in P1NP level (ρ = 0.48, P = .02) and greater bone loss at the femoral neck (ρ = -0.43, P = .04). In addition, within-participant shifts in microbial richness/evenness (α-diversity) were associated with changes in IGF-1 levels (ρ = 0.56, P < .01). The lower the postoperative fecal butyrate concentration, the lower the IGF-1 level (ρ = 0.43, P = .04). Meanwhile, the larger the decrease in butyrate concentration, the higher the postoperative CTx (ρ = -0.43, P = .04). These findings suggest that LSG-induced gut microbiome alteration may influence skeletal outcomes postoperatively, and microbial influences on butyrate formation and IGF-1 are possible mechanisms.
Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, is a highly effective treatment for obesity because it produces dramatic weight loss and improves obesity-related medical conditions. However, it also results in abnormalities in bone metabolism. It is important to understand how LSG affects the skeleton, so that bone loss after surgery might be prevented. We studied adult men and women before and 6 mo after LSG, and we explored the relationship between the altered gut bacteria and bone metabolism changes. We found that: Those with greater shifts in their gut bacterial composition had more bone loss.Butyrate, a metabolite produced by gut bacteria from fermentation of dietary fiber, was associated with less bone breakdown and higher IGF-1 level (a bone-building hormone). We conclude that changes in the gut bacteria may contribute to the negative skeletal impact of LSG and reduced butyrate production by the gut bacteria leading to lower IGF-1 levels is a possible mechanism.
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Osso e Ossos , Gastrectomia , Microbioma Gastrointestinal , Laparoscopia , Humanos , Feminino , Masculino , Adulto , Osso e Ossos/metabolismo , Pessoa de Meia-Idade , Fezes/microbiologia , Biomarcadores/metabolismoRESUMO
Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1-KO cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global KO of Spns1 caused embryonic lethality between E12.5 and E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC), and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1-KO mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1-KO mice affected liver functions and altered the PI3K/AKT signaling pathway. Furthermore, we identified 3 human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.
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Modelos Animais de Doenças , Doenças por Armazenamento dos Lisossomos , Lisossomos , Camundongos Knockout , Animais , Feminino , Humanos , Masculino , Camundongos , Fígado/metabolismo , Lisofosfolipídeos/metabolismo , Doenças por Armazenamento dos Lisossomos/metabolismo , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/patologia , Lisossomos/metabolismo , Esfingolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismoRESUMO
FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis.
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Mutations in the orphan transporter MFSD7c (also known as Flvcr2), are linked to Fowler syndrome. Here, we used Mfsd7c knockout (Mfsd7c-/-) mice and cell-based assays to reveal that MFSD7c is a choline transporter at the blood-brain barrier (BBB). We performed comprehensive metabolomics analysis and detected differential changes of metabolites in the brains and livers of Mfsd7c-/-embryos. Particularly, we found that choline-related metabolites were altered in the brains but not in the livers of Mfsd7c-/- embryos. Thus, we hypothesized that MFSD7c regulates the level of choline in the brain. Indeed, expression of human MFSD7c in cells significantly increased choline uptake. Interestingly, we showed that choline uptake by MFSD7c is greatly increased by choline-metabolizing enzymes, leading us to demonstrate that MFSD7c is a facilitative transporter of choline. Furthermore, single-cell patch clamp analysis showed that the import of choline by MFSD7c is electrogenic. Choline transport function of MFSD7c was shown to be conserved in vertebrates, but not in yeasts. We demonstrated that human MFSD7c is a functional ortholog of HNM1, the yeast choline importer. We also showed that several missense mutations identified in patients exhibiting Fowler syndrome had abolished or reduced choline transport activity. Mice lacking Mfsd7c in endothelial cells of the central nervous system suppressed the import of exogenous choline from blood but unexpectedly had increased choline levels in the brain. Stable-isotope tracing study revealed that MFSD7c was required for exporting choline derived from lysophosphatidylcholine in the brain. Collectively, our work identifies MFSD7c as a choline exporter at the BBB and provides a foundation for future work to reveal the disease mechanisms of Fowler syndrome.
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Barreira Hematoencefálica , Células Endoteliais , Síndrome do Ovário Policístico , Transtornos Urinários , Animais , Humanos , Camundongos , Transporte Biológico , Encéfalo , ColinaRESUMO
In this paper, we provide an in-depth assessment on the Bjøntegaard Delta. We construct a large data set of video compression performance comparisons using a diverse set of metrics including PSNR, VMAF, bitrate, and processing energies. These metrics are evaluated for visual data types such as classic perspective video, 360° video, point clouds, and screen content. As compression technology, we consider multiple hybrid video codecs as well as state-of-the-art neural network based compression methods. Using additional supporting points in-between standard points defined by parameters such as the quantization parameter, we assess the interpolation error of the Bjøntegaard-Delta (BD) calculus and its impact on the final BD value. From the analysis, we find that the BD calculus is most accurate in the standard application of rate-distortion comparisons with mean errors below 0.5 percentage points. For other applications and special cases, e.g., VMAF quality, energy considerations, or inter-codec comparisons, the errors are higher (up to 5 percentage points), but can be halved by using a higher number of supporting points. We finally come up with recommendations on how to use the BD calculus such that the validity of the resulting BD-values is maximized. Main recommendations are as follows: First, relative curve differences should be plotted and analyzed. Second, the logarithmic domain should be used for saturating metrics such as SSIM and VMAF. Third, BD values below a certain threshold indicated by the subset error should not be used to draw recommendations. Fourth, using two supporting points is sufficient to obtain rough performance estimates.
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Ambient sensors can continuously and unobtrusively monitor a person's health and well-being in everyday settings. Among various sensing modalities, wireless radio-frequency sensors offer exceptional sensitivity, immunity to lighting conditions, and privacy advantages. However, existing wireless sensors are susceptible to environmental interference and unable to capture detailed information from multiple body sites. Here, we present a technique to transform passive surfaces in the environment into highly sensitive and localized health sensors using metamaterials. Leveraging textiles' ubiquity, we engineer metamaterial textiles that mediate near-field interactions between wireless signals and the body for contactless and interference-free sensing. We demonstrate that passive surfaces functionalized by these metamaterials can provide hours-long cardiopulmonary monitoring with accuracy comparable to gold standards. We also show the potential of distributed sensors and machine learning for continuous blood pressure monitoring. Our approach enables passive environmental surfaces to be harnessed for ambient sensing and digital health applications.
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Saúde Digital , Engenharia , Humanos , Iluminação , Aprendizado de Máquina , PrivacidadeRESUMO
Reduction of the magnesium(II) diamide [Mg(TripNON)] (TripNON = 4,5-bis(2,4,6-triisopropylanilido)-2,7-diethyl-9,9-dimethyl-xanthene) with 5% w/w K/KI leads to a good yield of a dianionic dimagnesium(I) species, as its potassium salt, [{K(TripNON)Mg}2]. An X-ray crystallographic analysis shows the molecule to contain a very long Mg-Mg bond (3.137(2) Å). The formation of [{K(TripNON)Mg}2] contrasts with a previously reported reduction of a magnesium(II) complex incorporating a bulkier diamide ligand, which instead afforded a magnesium-dinitrogen complex. In the current study, [{K(TripNON)Mg}2] has been shown to be a viable reagent for the reductive activation of CO, H2 and N2O.
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OBJECTIVES: Profound dengue shock syndrome (DSS) complicated by severe respiratory failure necessitating mechanical ventilation (MV) accounts for high case fatality rates among PICU-admitted patients. A major challenge to management is the assessment of intravascular volume, which can be hampered by severe plasma leakage and the use of MV. DESIGN: Retrospective cohort, from 2013 to 2021. PATIENTS: Sixty-seven children with profound DSS supported by MV, some of whom underwent bedside point-of-care ultrasound (POCUS) for assessment and monitoring of hemodynamics and fluid administration. SETTING: PICU of the tertiary Children's Hospital No. 2 in Vietnam. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data clinical and laboratory data during PICU stay. In particular, during use of MV (i.e., at times 0-, 6-, and 24-hr after commencement) and fluid resuscitation. The primary study outcome was 28-day in-hospital mortality, and the secondary outcomes were associations with changes in hemodynamics, blood lactate, and vasoactive-inotrope score (VIS). Patients had a median age of 7 years (interquartile range, 4-9). Use of POCUS during fluid management (39/67), as opposed to not using (28/67), was associated with lower mortality (6/39 [15%] vs. 18/28 [64%]; difference 49 % [95% CI, 28-70%], p < 0.001). Use of POCUS was associated with lower odds of death (adjusted odds ratio 0.17 [95% CI, 0.04-0.76], p = 0.02). The utilization of POCUS, versus not, was associated with greater use of resuscitation fluid, and reductions in VIS and pediatric logistic organ dysfunction (PELOD-2) score at 24 hours after MV and PICU discharge. CONCLUSIONS: In our experience of pediatric patients with profound DSS and undergoing MV (2013-2021), POCUS use was associated with lower odds of death, a higher volume of resuscitation fluid, and improvements in the blood lactate levels, VIS, and PELOD-2 score.
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Respiração Artificial , Dengue Grave , Criança , Humanos , Lactente , Estudos Retrospectivos , Sistemas Automatizados de Assistência Junto ao Leito , Lactatos , Unidades de Terapia Intensiva PediátricaRESUMO
Background: Vaccination plays a central role in protecting children against severe diseases and preventing child mortality. Objectives: This study aimed to determine the rate and factors associated with complete and timely vaccination in 2-year-old children, as well as maternal knowledge on expanded vaccination in Go Cong Tay district, Tien Giang province, Vietnam. Methods: A cross-sectional descriptive study was conducted on 558 2-year-old children and their mothers residing in Go Cong Tay district, Tien Giang province, Vietnam. The study employed a systematic random sampling method from June to September 2021. Results: The rate of complete vaccination in children was 74.7%. Factors associated with the rate of complete vaccination were occupation (OR=0.3; 95%CI: 0.1-0.7; p=0.006), economic status (OR=3.8; 95%CI: 1.7-8.6; p=0.001), and maternal general knowledge on expanded vaccination (OR=1.7; 95%CI: 1.1-2.6; p=0.01). The rate of timely vaccination was 47.8%. Factors associated with the rate of timely vaccination were maternal age group (OR=3.1; 95%CI: 1.6-6.0; p=0.001; OR=3.0; 95%CI: 1.3-6.6; p=0.006) and economic status (OR=0.4; 95%CI: 0.2-0.9; p=0.04). The rate of both complete and timely vaccination was 22.6%. Factors associated with the rate of complete and timely vaccination were maternal age group (OR=3.1; 95%CI: 1.3-7.2; p=0.009; OR=3.3; 95%CI: 1.2-9.1; p=0.02) and maternal general knowledge on expanded vaccination (OR=1.5; 95%CI: 1.0-2.4; p=0.03). The rate of maternal general knowledge on expanded vaccination was 57.5%. Conclusion: The rates of complete and timely vaccination are still low, and various factors influence expanded vaccination. The-refore, it is crucial to continue health education campaigns to improve knowledge on expanded vaccination, remind mothers of vaccination schedules, strengthen confidence in vaccination programs and vaccine safety, attract customers to vaccination services, provide adequate healthcare for children, and ensure vaccination activities during disease outbreaks.
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Early life gut microbiome composition has been correlated with childhood obesity, though microbial functional contributions to disease origins remain unclear. Here, using an infant birth cohort (n = 349) we identify a distinct fecal microbiota composition in 1-month-old infants with the lowest rate of exclusive breastfeeding, that relates with higher relative risk for obesity and overweight phenotypes at two years. Higher-risk infant fecal microbiomes exhibited accelerated taxonomic and functional maturation and broad-ranging metabolic reprogramming, including reduced concentrations of neuro-endocrine signals. In vitro, exposure of enterocytes to fecal extracts from higher-risk infants led to upregulation of genes associated with obesity and with expansion of nutrient sensing enteroendocrine progenitor cells. Fecal extracts from higher-risk infants also promoted enterocyte barrier dysfunction. These data implicate dysregulation of infant microbiome functional development, and more specifically promotion of enteroendocrine signaling and epithelial barrier impairment in the early-life developmental origins of childhood obesity.