BACKGROUND AIMSMesenchymal stromal cells (MSCs) are recognized as a potential cell-based therapy for regenerative medicine. Short-term inflammatory cytokine pre-stimulation (cytokine priming) is a ...promising approach to enhance regenerative efficacy of MSCs. However, it is unclear whether their intrinsic heterogenic nature causes an unequal response to cytokine priming, which might blunt the accessibility of clinical applications.METHODSIn this study, by analyzing the single-cell transcriptomic landscape of human bone marrow MSCs from a naïve to cytokine-primed state, we elucidated the potential mechanism of superior therapeutic potential in cytokine-primed MSCs.RESULTSWe found that cytokine-primed MSCs had a distinct transcriptome landscape. Although substantial heterogeneity was identified within the population in both naïve and primed states, cytokine priming enhanced the several characteristics of MSCs associated with therapeutic efficacy irrespective of heterogeneity. After cytokine-priming, all sub-clusters of MSCs possessed high levels of immunoregulatory molecules, trophic factors, stemness-related genes, anti-apoptosis markers and low levels of multi-lineage and senescence signatures, which are critical for their therapeutic potency.CONCLUSIONSIn conclusion, our results provide new insights into MSC heterogeneity under cytokine stimulation and suggest that cytokine priming reprogrammed MSCs independent of heterogeneity.
Atrial fibrillation (AF) is the most common arrhythmia and its incidence increases with sepsis. However, data on new-onset AF during sepsis hospitalization remain limited in China. We aimed to ...evaluate the incidence, risk factors, and associated mortality of new-onset AF in sepsis patients in China. We conducted a retrospective study using the National Data Center for Medical Service system, from 1923 tertiary and 2363 secondary hospitals from 31 provinces in China from 2017 to 2019.In total we included 1,425,055 sepsis patients ≥ 18 years without prior AF. The incidence of new-onset AF was 1.49%. Older age, male sex, hypertension, heart failure, coronary disease, valvular disease, and mechanical ventilation were independent risk factor. New-onset AF was associated with a slight increased risk of mortality (adjusted RR 1.03, 95% CI 1.01-1.06). Population attributable fraction suggested AF accounted for 0.2% of sepsis deaths. In this large nationwide cohort, new-onset AF occurred in 1.49% of sepsis admissions and was associated with a small mortality increase. Further research should examine whether optimized AF management can improve sepsis outcomes in China.
The triglyceride-glucose index (TyG) is a reliable indicator for predicting the prognosis of patients with coronary heart disease (CAD) after percutaneous coronary intervention (PCI). However, its ...influence on patients with in-stent restenosis (ISR) is unclear. This study was designed to evaluate the association between the TyG index and the occurrence of major adverse cardiovascular events (MACEs) after PCI in patients with ISR.BackgroundThe triglyceride-glucose index (TyG) is a reliable indicator for predicting the prognosis of patients with coronary heart disease (CAD) after percutaneous coronary intervention (PCI). However, its influence on patients with in-stent restenosis (ISR) is unclear. This study was designed to evaluate the association between the TyG index and the occurrence of major adverse cardiovascular events (MACEs) after PCI in patients with ISR.This retrospective study included 1654 patients who underwent PCI between 2016 and 2022 at Nanjing First Hospital. Patients were stratified into three groups based on the quantile level of the TyG index. The TyG index was determined as Ln (triglycerides mg/dL × fasting plasma glucose mg/dL/2).MethodsThis retrospective study included 1654 patients who underwent PCI between 2016 and 2022 at Nanjing First Hospital. Patients were stratified into three groups based on the quantile level of the TyG index. The TyG index was determined as Ln (triglycerides mg/dL × fasting plasma glucose mg/dL/2).Individuals with the highest TyG index showed an increased risk of MACEs compared to those with the lowest level of the TyG index (HR 1.60; 95% CI 1.11-2.30; P = 0.01). When analyzing the TyG index as a continuous variable, each standard deviation increase was associated with an HR of 1.51 (95% CI: 1.11-2.05; P = 0.01). For the male subgroup and the diabetes subgroup, this trend was even more pronounced (HR 1.269; 95% CI 1.055-1.527; P = 0.011; HR 1.385; 95% CI 1.125-1.706; P = 0.002). Additionally, the landmark analysis showed that patients with the highest level of TyG had an increased risk of MACEs 6 months after the PCI (P = 0.019).ResultsIndividuals with the highest TyG index showed an increased risk of MACEs compared to those with the lowest level of the TyG index (HR 1.60; 95% CI 1.11-2.30; P = 0.01). When analyzing the TyG index as a continuous variable, each standard deviation increase was associated with an HR of 1.51 (95% CI: 1.11-2.05; P = 0.01). For the male subgroup and the diabetes subgroup, this trend was even more pronounced (HR 1.269; 95% CI 1.055-1.527; P = 0.011; HR 1.385; 95% CI 1.125-1.706; P = 0.002). Additionally, the landmark analysis showed that patients with the highest level of TyG had an increased risk of MACEs 6 months after the PCI (P = 0.019).Elevated TyG index is associated with increased risk of adverse cardiovascular events in patients with ISR, and the extent of increase in the risk is more significant in male patients with diabetes.ConclusionElevated TyG index is associated with increased risk of adverse cardiovascular events in patients with ISR, and the extent of increase in the risk is more significant in male patients with diabetes.
Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise ...due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate odds ratio (OR) = 2.78 is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.
The organ damage incurred during the cold storage (CS) of intestinal grafts has short and long‐term consequences. Animal studies suggest that additional luminal preservation (LP) with polyethylene ...glycol (PEG) may alleviate this damage. This study aims to validate these findings using human intestines. Ileal segments, perfused intravascularly with IGL‐1 solution, were procured from 32 multiorgan donors and divided into two parts: one containing a PEG 3350‐based solution introduced luminally (LP group) and another one without luminal treatment (control). Sampling was performed after 4 h, 8 h, 14 h, and 24 h of CS. Histology was assessed using the Chiu/Park score. Tight junctions (TJ), several inflammatory markers, and transcription factors were examined by immunofluorescence, ddPCR, and western blot. Tissue water content (edema) was also measured. Apoptotic activity was assessed with caspase ‐2, ‐3, and ‐9 assays. LP significantly lowered mucosal injury at all time points. Redistribution of TJ proteins occurred earlier and more severely in the control group. After 24 h of CS, LP intestines showed an emerging unfolding protein response. Increased caspase‐3 and −9 activity was found in the control group. The current results indicate that luminal PEG is safe and effective in reducing damage to the intestinal epithelium during CS.
A simple, widely available polyethylene glycol solution introduced into the small intestine during organ procurement significantly improves mucosal histology and alleviates the preservation injury after transplantation.
Radiotherapy is an effective tool in the treatment of malignant brain tumors, but irradiation-induced late-onset toxicity remains a major problem. The purpose of this study was to investigate if ...genetic inhibition of autophagy has an impact on subcortical white matter development in the juvenile mouse brain after irradiation. Ten-day-old selective neural
Atg7
knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6-Gy dose of whole-brain irradiation and evaluated at 5 days after irradiation. Neural
Atg7
deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell loss in the subcortical white matter, and
Atg7
deficiency partly prevented this. There was no significant change between the KO and WT mice in the number of microglia and astrocytes in the subcortical white matter after irradiation. Transcriptome analysis showed that the GO mitochondrial gene expression pathway was significantly enriched in the differentially expressed genes between the KO and WT group after irradiation. Compared with WT mice, expression of the mitochondrial fusion protein OPA1 and phosphorylation of the mitochondrial fission protein DRP1 (P-DRP1) were dramatically decreased in KO mice under physiological conditions. The protein levels of OPA1and P-DRP1 showed no differences in WT mice between the non-irradiated group and the irradiated group but had remarkably increased levels in the KO mice after irradiation. These results indicate that inhibition of autophagy reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission.
Transplanting human gut microbiotas into germ-free (GF) mice is a popular approach to disentangle cause-and-effect relationships between enteric microbes and disease. Algorithm development has ...enabled sequence variant (SV) identification from 16S rRNA gene sequence data. SV analyses can identify which donor taxa colonize recipient GF mice, and how SV abundance in humans is replicated in these mice. Fecal microbiotas from 8 human subjects were used to generate 77 slurries, which were transplanted into 153 GF mice. Strong correlations between fecal and slurry microbial communities were observed; however, only 42.15 ± 9.95% of SVs successfully transferred from the donor to the corresponding recipient mouse. Firmicutes had a particularly low transfer rate and SV abundance was poorly correlated between donor and recipient pairs. Our study confirms human fecal microbiotas colonize formerly GF mice, but the engrafted community only partially resembles the input human communities. Our findings emphasize the importance of reporting a standardized transfer rate and merit the exploration of other animal models or in silico tools to understand the relationships between human gut microbiotas and disease.
Background
Lifestyle risk factors have been associated with increased all-cause and cause-specific mortality, but the influence of reverse causation has been underappreciated as a limitation in ...epidemiological studies.
Methods
Prospective cohort study including 457,021 US adults from the National Health Interview Survey 1997–2013 linked to the National Death Index records through December 31, 2015. Multivariable Cox models were performed to examine the association of lifestyle risk factors with all-cause and cause-specific mortality. Participants with prevalent diseases and the first 2, 5, 10, and 15 years of follow-up were excluded to account for reverse causation.
Results
During 4,441,609 person-years, we identified 60,323 total deaths. Heavy alcohol drinking (HR 1.12; 95% CI 1.08 to 1.16), smoking (HR 1.78; 95% CI 1.74 to 1.83) and lack of physical activity (HR 1.51; 95% CI 1.47 to 1.54) were associated with increased all-cause mortality. Overweight was associated with lower all-cause mortality (HR 0.88; 95% CI 0.86 to 0.90). After exclusion of participants with diseases and first 10 years of follow-up, associations changed to: heavy alcohol drinking (HR 1.31; 95% CI 1.20 to 1.43), smoking (HR 1.99; 95% CI 1.87 to 2.11), lack of physical activity (HR 1.21; 95% CI 1.15 to 1.27), and overweight (HR 1.05; 95% CI 1.00 to 1.10).
Conclusions
Methods to account for reverse causation suggest different effects of reverse causation on the associations between lifestyle risk factors and mortality. Exclusion of participants with diseases at baseline, and exclusion of 5–10 years of follow-up may be necessary to mitigate reverse causation.
Insulin-sensitizing drugs of the thiazolidinedione class and metformin are commonly prescribed to treat diabetes in patients with heart failure despite strong warnings from the Food and Drug ...Administration against this practice. Whether this results in adverse outcomes is unknown.
We conducted a retrospective cohort study of 16,417 Medicare beneficiaries with diabetes discharged after hospitalization with the principal discharge diagnosis of heart failure. The association between antidiabetic drug prescriptions and outcomes was assessed in multivariable hierarchical Cox proportional hazards models, with adjustment for patient, physician, and hospital variables and accounting for the clustering of patients within hospitals. The primary outcome of the study was time to death due to all causes. Secondary outcomes included time to readmission for all causes or for heart failure. Crude 1-year mortality rates were lower among the 2226 patients treated with a thiazolidinedione (30.1%) or the 1861 treated with metformin (24.7%) compared with that among the 12,069 treated with neither insulin-sensitizing drug (36.0%, P= or <0.0001 for both comparisons). In multivariable models, treatment with the thiazolidinediones (hazard ratio HR 0.87, 95% CI 0.80 to 0.94) or metformin (HR=0.87, 95% CI 0.78 to 0.97) was associated with significantly lower risks of death. There was no association with treatment with sulfonylureas (HR=0.99, 95% CI 0.91 to 1.08) or insulin (HR=0.96, 95% CI 0.88 to 1.05) and mortality. Admissions for all causes did not differ with either insulin sensitizer. There was a higher risk of readmission for heart failure with thiazolidinedione treatment (HR 1.06, 95% CI 1.00 to 1.09) and a lower risk with metformin treatment (HR 0.92, 95% CI 0.92 to 0.99).
This observational study suggests that thiazolidinediones and metformin are not associated with increased mortality and may improve outcomes in older patients with diabetes and heart failure. Randomized trials are warranted to corroborate these findings.
An array of ZnO/Fe2O3 core-shell nanowires (NW) for the highly efficient absorption of light and carrier collection is developed for use in photoelectrochemical (PEC) water-splitting. The oriented NW ...architecture favors physical matching, providing a direct electron conduction pathway and reducing the diffusion length of photogenerated holes. This work involves a combination of spectral imaging, spectromicroscopy and in situ x-ray absorption spectroscopy; spectra are obtained under operando conditions. Direct investigation of oriented nanowires using polarization-dependent x-ray spectromicroscopy enables the determination of the relationship between anisotropic electronic orbitals and charge carrier water-splitting efficiency. The results of O K-edge STXM demonstrated that the ZnO/Fe2O3 core-shell NW exhibits strong anisotropy and thus provides higher electron-hole transport efficiency than bare ZnO. In situ XAS revealed that interfacial charge transfer between Fe 3d and Zn 4p states enhances the photoelectrochemical reaction in the ZnO/Fe2O3 core-shell NW. The photogenerated electrons of Fe2O3 are transferred from Fe 3d states to the Zn 4p state under photoelectrochemical conditions.
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