Background Parkinson’s disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota. Results The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice. Conclusions Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate.

OBJECTIVES: Light sedation is recommended over deep sedation for invasive mechanical ventilation to improve clinical outcome but may increase the risk of agitation. This study aimed to develop and prospectively validate an ensemble machine learning model for the prediction of agitation on a daily basis. DESIGN: Variables collected in the early morning were used to develop an ensemble model by aggregating four machine learning algorithms including support vector machines, C5.0, adaptive boosting with classification trees, and extreme gradient boosting with classification trees, to predict the occurrence of agitation in the subsequent 24 hours. SETTING: The training dataset was prospectively collected in 95 ICUs from 80 Chinese hospitals on May 11, 2016, and the validation dataset was collected in 20 out of these 95 ICUs on December 16, 2019. PATIENTS: Invasive mechanical ventilation patients who were maintained under light sedation for 24 hours prior to the study day and who were to be maintained at the same sedation level for the next 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 578 invasive mechanical ventilation patients from 95 ICUs in 80 Chinese hospitals, including 459 in the training dataset and 119 in the validation dataset, were enrolled. Agitation was observed in 36% (270/578) of the invasive mechanical ventilation patients. The stepwise regression model showed that higher body temperature (odds ratio for 1°C increase: 5.29; 95% CI, 3.70–7.84; p < 0.001), greater minute ventilation (odds ratio for 1 L/min increase: 1.15; 95% CI, 1.02–1.30; p = 0.019), higher Richmond Agitation-Sedation Scale (odds ratio for 1-point increase: 2.43; 95% CI, 1.92–3.16; p < 0.001), and days on invasive mechanical ventilation (odds ratio for 1-d increase: 0.95; 95% CI, 0.93–0.98; p = 0.001) were independently associated with agitation in the subsequent 24 hours. In the validation dataset, the ensemble model showed good discrimination (area under the receiver operating characteristic curve, 0.918; 95% CI, 0.866–0.969) and calibration (Hosmer-Lemeshow test p = 0.459) in predicting the occurrence of agitation within 24 hours. CONCLUSIONS: This study developed an ensemble model for the prediction of agitation in invasive mechanical ventilation patients under light sedation. The model showed good calibration and discrimination in an independent dataset.

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Abstract:There is a lack of appropriate classification criteria for the determination of atretic follicles in guinea pigs. In the present study, new criteria were established based on the latest morphologic criteria for cell death proposed by the Nomenclature Committee on Cell Death (NCCD) in 2009. Ovaries of guinea pigs were sampled on different stages of estrous cycle, and the morphologic observations of atretic follicles were investigated in serial sections. The results showed that the process of follicular atresia could be classified into four continuous stages: (1) the granulosa layer became loose, and some apoptotic bodies began to appear; (2) the granulosa cells were massively eliminated; (3) the theca interna cells differentiated; and (4) the residual follicular cells degenerated. In addition, the examination revealed that these morphologic criteria were accurate and feasible. In conclusion, this study provides new criteria for the classification of atretic follicles in guinea pigs, and this knowledge can inform future research in the area.

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Background:This meta-analysis was to determine the association of the cumulative dose of 130/0.4 or 0.42 (hydroxyethyl starch [HES] 130/0.4*) or delta daily fluid balance (i.e., daily fluid balance in HES group over or below control group) with the heterogeneity of risk ratio (RR) for mortality in randomized control trials (RCTs).Methods:Three databases (PubMed, EMBASE, Cochrane) were searched to identify prospective RCTs reporting mortality in adult patients with sepsis to compare HES130/0.4* with crystalloids or albumin. Meta-analysis was performed using random effects. Sensitivity and meta-regression analyses were used to examine the heterogeneity sources of RR for mortality.Results:A total number of 4408 patients from 11 RCTs were included. The pooled RR showed no significant difference for overall mortality in patients with administration of HES130/0.4* compared with treatment of control fluids (RR: 1.02, 95% confidence interval: 0.90–1.17; P = 0.73). Heterogeneity was moderate across recruited trials (I2 = 34%, P = 0.13). But, a significant variation was demonstrated in subgroup with crystalloids as control fluids (I2= 42%, P < 0.1). Sensitivity analysis revealed that trials with high risk of bias did not significantly impact the pooled estimates for mortality. Meta-regression analysis also did not determine a dose-effect relationship of HES130/0.4* with mortality (P = 0.298), but suggested daily delta fluid balance being likely associated with mortality in septic patients receiving HES130/130/0.4* (P = 0.079).Conclusions:Inappropriate daily positive fluid balance was likely an important source of heterogeneity in these trials reporting HES130/0.4* associated with excess mortality in septic patients.

Patients with diabetic foot ulcers usually suffer from inefficient epithelisation and angiogenesis accompanied by chronic wound healing. Diabetic foot ulcers remain a major challenge in clinical medicine; however, traditional treatments are incapable of transdermal drug delivery, resulting in a low drug delivery rate. We report the development of Ti2C3 MXenes-integrated poly-γ-glutamic acid (γ-PGA) hydrogel microneedles to release asiaticoside (MN-MXenes-AS). Asiaticoside was loaded into PGA-MXenes hydrogel to facilitate cell proliferation while regulating angiogenesis. The characterisation and mechanical strength of the microneedles were investigated in vitro, and the wound-healing efficacy of the microneedles was confirmed in diabetic mice. MXenes significantly improved the mechanical strength of microneedles, while γ-PGA hydrogels provided a moist microenvironment for wound healing. Mice treated with MN-MXenes-AS demonstrated obvious improvements in wound healing process. We successfully fabricated an MXenes-integrated microneedle that possesses sufficient rigidity to penetrate the cuticle for subcutaneous drug delivery, thereby accelerating diabetic wound healing. We demonstrated that MN-MXenes-AS is effective in promoting growth both in vivo and in vitro. Collectively, our data show that MN-MXenes-AS accelerated the healing of diabetic foot ulcers, supporting the use of these microneedles in the treatment of chronic wounds. Graphical Abstract

The levels of serum endotoxin, TNF-alpha and IL-6 and the expression of iNOS mRNA by Kupffer cells were increased in rats with obstructive jaundice. Internal biliary drainage could entirely reverse the changes, but external drainage only partially did.