Skeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α.

AIM/HYPOTHESIS: The peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) plays a critical role in the maintenance of glucose, lipid and energy homeostasis by orchestrating metabolic programs in multiple tissues in response to environmental cues. In skeletal muscles, PGC-1α dysregulation has been associated with insulin resistance and type 2 diabetes but the underlying mechanisms have remained elusive. This research aims to understand the role of TET3, a member of the ten-eleven translocation (TET) family dioxygenases, in PGC-1α dysregulation in skeletal muscles in obesity and diabetes. METHODS: TET expression levels in skeletal muscles were analysed in humans with or without type 2 diabetes, as well as in mouse models of high-fat diet (HFD)-induced or genetically induced (ob/ob) obesity/diabetes. Muscle-specific Tet3 knockout (mKD) mice were generated to study TET3's role in muscle insulin sensitivity. Genome-wide expression profiling (RNA-seq) of muscle tissues from wild-type (WT) and mKD mice was performed to mine deeper insights into TET3-mediated regulation of muscle insulin sensitivity. The correlation between PGC-1α and TET3 expression levels was investigated using muscle tissues and in vitro-derived myotubes. PGC-1α phosphorylation and degradation were analysed using in vitro assays. RESULTS: TET3 expression was elevated in skeletal muscles of humans with type 2 diabetes and in HFD-fed and ob/ob mice compared with healthy controls. mKD mice exhibited enhanced glucose tolerance, insulin sensitivity and resilience to HFD-induced insulin resistance. Pathway analysis of RNA-seq identified 'Mitochondrial Function' and 'PPARα Pathway' to be among the top biological processes regulated by TET3. We observed higher PGC-1α levels (~25%) in muscles of mKD mice vs WT mice, and lower PGC-1α protein levels (~25-60%) in HFD-fed or ob/ob mice compared with their control counterparts. In human and murine myotubes, increased PGC-1α levels following TET3 knockdown contributed to improved mitochondrial respiration and insulin sensitivity. TET3 formed a complex with PGC-1α and interfered with its phosphorylation, leading to its destabilisation. CONCLUSIONS/INTERPRETATION: Our results demonstrate an essential role for TET3 in the regulation of skeletal muscle insulin sensitivity and suggest that TET3 may be used as a potential therapeutic target for the metabolic syndrome. DATA AVAILABILITY: Sequences are available from the Gene Expression Omnibus ( https://www.ncbi.nlm.nih.gov/geo/ ) with accession number of GSE224042.

Development and validation of a machine learning model to predict prognosis in HIV-negative cryptococcal meningitis patients: a multicenter study.

PURPOSE: To predict prognosis in HIV-negative cryptococcal meningitis (CM) patients by developing and validating a machine learning (ML) model. METHODS: This study involved 523 HIV-negative CM patients diagnosed between January 1, 1998, and August 31, 2022, by neurologists from 3 tertiary Chinese centers. Prognosis was evaluated at 10 weeks after the initiation of antifungal therapy. RESULTS: The final prediction model for HIV-negative CM patients comprised 8 variables: Cerebrospinal fluid (CSF) cryptococcal count, CSF white blood cell (WBC), altered mental status, hearing impairment, CSF chloride levels, CSF opening pressure (OP), aspartate aminotransferase levels at admission, and decreased rate of CSF cryptococcal count within 2 weeks after admission. The areas under the curve (AUCs) in the internal, temporal, and external validation sets were 0.87 (95% CI 0.794-0.944), 0.92 (95% CI 0.795-1.000), and 0.86 (95% CI 0.744-0.975), respectively. An artificial intelligence (AI) model was trained to detect and count cryptococci, and the mean average precision (mAP) was 0.993. CONCLUSION: A ML model for predicting prognosis in HIV-negative CM patients was built and validated, and the model might provide a reference for personalized treatment of HIV-negative CM patients. The change in the CSF cryptococcal count in the early phase of HIV-negative CM treatment can reflect the prognosis of the disease. In addition, utilizing AI to detect and count CSF cryptococci in HIV-negative CM patients can eliminate the interference of human factors in detecting cryptococci in CSF samples and reduce the workload of the examiner.

Effect of Task-Oriented Biomechanical Perception-Balance Training on Motor Gait in Stroke Patients With Hemiplegia.

Objective: To investigate the effects of task-oriented biomechanical sensors-balance training on lower limb motor function and gait balance function in stroke patients with hemiplegia. Methods: Researchers divided 106 stroke patients with hemiplegia into observation and control groups. All received essential rehabilitation training treatment. The observation group's rehabilitation consisted of task-oriented biomechanical sensors-balance training. The modified Ashworth Scale score, FuGL-Meyer Motor Function Scale score, and other indicators measured the results of the two groups. Results: The Berg balance scale score and FuGL-Meyer Motor Function Scale score in the observation group were higher than in the control group (P < .05). The modified Ashworth Scale score of the triceps calf muscle in the observation group was significantly lower than that in the control group (P < .05). The observation group's step length, step frequency, maximum angle of hip extension, and knee flexion exceeded those of the control group. In contrast, the maximum angle of knee extension was smaller than those in the control group (P < .05). Conclusion: Basic rehabilitation training combined with task-oriented biomechanical perception-balance training can improve the lower limb motor function of stroke patients with hemiplegia.

A Fast Approach to Removing Muscle Artifacts for EEG with Signal Serialization Based Ensemble Empirical Mode Decomposition.

An electroencephalogram (EEG) is an electrophysiological signal reflecting the functional state of the brain. As the control signal of the brain-computer interface (BCI), EEG may build a bridge between humans and computers to improve the life quality for patients with movement disorders. The collected EEG signals are extremely susceptible to the contamination of electromyography (EMG) artifacts, affecting their original characteristics. Therefore, EEG denoising is an essential preprocessing step in any BCI system. Previous studies have confirmed that the combination of ensemble empirical mode decomposition (EEMD) and canonical correlation analysis (CCA) can effectively suppress EMG artifacts. However, the time-consuming iterative process of EEMD may limit the application of the EEMD-CCA method in real-time monitoring of BCI. Compared with the existing EEMD, the recently proposed signal serialization based EEMD (sEEMD) is a good choice to provide effective signal analysis and fast mode decomposition. In this study, an EMG denoising method based on sEEMD and CCA is discussed. All of the analyses are carried out on semi-simulated data. The results show that, in terms of frequency and amplitude, the intrinsic mode functions (IMFs) decomposed by sEEMD are consistent with the IMFs obtained by EEMD. There is no significant difference in the ability to separate EMG artifacts from EEG signals between the sEEMD-CCA method and the EEMD-CCA method (p > 0.05). Even in the case of heavy contamination (signal-to-noise ratio is less than 2 dB), the relative root mean squared error is about 0.3, and the average correlation coefficient remains above 0.9. The running speed of the sEEMD-CCA method to remove EMG artifacts is significantly improved in comparison with that of EEMD-CCA method (p < 0.05). The running time of the sEEMD-CCA method for three lengths of semi-simulated data is shortened by more than 50%. This indicates that sEEMD-CCA is a promising tool for EMG artifact removal in real-time BCI systems.

A Vital Sign-Based Model to Predict Clinical Deterioration in Hospitalized Children.

OBJECTIVES: Clinical deterioration in hospitalized children is associated with increased risk of mortality and morbidity. A prediction model capable of accurate and early identification of pediatric patients at risk of deterioration can facilitate timely assessment and intervention, potentially improving survival and long-term outcomes. The objective of this study was to develop a model utilizing vital signs from electronic health record data for predicting clinical deterioration in pediatric ward patients. DESIGN: Observational cohort study. SETTING: An urban, tertiary-care medical center. PATIENTS: Patients less than 18 years admitted to the general ward during years 2009-2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome of clinical deterioration was defined as a direct ward-to-ICU transfer. A discrete-time logistic regression model utilizing six vital signs along with patient characteristics was developed to predict ICU transfers several hours in advance. Among 31,899 pediatric admissions, 1,375 (3.7%) experienced the outcome. Data were split into independent derivation (yr 2009-2014) and prospective validation (yr 2015-2018) cohorts. In the prospective validation cohort, the vital sign model significantly outperformed a modified version of the Bedside Pediatric Early Warning System score in predicting ICU transfers 12 hours prior to the event (C-statistic 0.78 vs 0.72; p < 0.01). CONCLUSIONS: We developed a model utilizing six commonly used vital signs to predict risk of deterioration in hospitalized children. Our model demonstrated greater accuracy in predicting ICU transfers than the modified Bedside Pediatric Early Warning System. Our model may promote opportunities for timelier intervention and risk mitigation, thereby decreasing preventable death and improving long-term health.

Cerebral cortex functional networks of magnetic stimulation at acupoints along the pericardium meridian.

The coordinated regulating mechanism of magnetic stimulation at acupoints along the pericardium meridian was studied by cerebral cortical functional networks. Electroencephalogram signals of 14 subjects (eight males and six females) were recorded in resting state and following magnetic stimulation at Neiguan and Daling acupoints along the pericardium meridian. The corresponding cortical functional networks were constructed and analyzed by group independent component analysis, standard low-resolution brain electromagnetic tomography, short-time Fourier transform, and complex network theory. Results showed that during magnetic stimulation at Daling and Neiguan acupoints, the functional connections of the nodes in the brain areas associated with movement respectively decreased by 7.3% and 19.9%, and the functional connections of the nodes in brain areas associated with advanced cognitive functions such as emotion, memory and language respectively increased by 24.9% and 18.8%. Changes of topological structure were similarly related to the efficacy of acupoints along the pericardium meridian. Magnetic stimulation also caused different topological changes consistent with the therapeutic function of specific acupoint. This study provided new evidence revealing mechanisms of brain functional integration and network synergy in the acupoint stimulation pathway.

Challenges and recent advances in MOF-based gas separation membranes.

Membrane-based gas separation, characterized by a small footprint, low energy consumption and no pollution, has gained widespread attention as an environmentally friendly alternative to traditional gas separation. Metal-organic-frameworks (MOFs) are considered to be one of the most promising membrane-based gas separation materials because of their large specific surface area and high porosity. One of the hottest studies at the moment is how to utilize the characteristics of MOFs to prepare higher performance gas separation membranes. This paper provides a review of gas separation membranes used in recent years. Firstly, the synthesis methods of MOFs and MOF membranes are briefly introduced. Then, methods to improve the membrane properties of MOFs are described in detail, and include applications of lamellar MOFs, ionic liquid (IL) spin coating, functionalization of MOFs, defect engineering and mixed fillers. In addition, the challenges of MOF-based gas separation membranes are presented, including pore size, environmental disturbances, plasticization, interfacial compatibility, and so on. Finally, based on the current development status of the MOF membranes, the development prospects of MOF gas separation membranes are discussed. It is hoped to provide reliable and complete ideas for researchers to prepare high-performance gas separation membranes in the future.

Minimally invasive delivery of human umbilical cord-derived mesenchymal stem cells by an injectable hydrogel via Diels-Alder click reaction for the treatment of intrauterine adhesions.

Intrauterine adhesions (IUA) are the most common cause of uterine infertility, and conventional treatments have not consistently achieved satisfactory pregnancy rates. Stem cell therapy shows promising potential for the clinical treatment of IUA. Although various advanced biomaterials have been designed for delivering stem cells to the uterine cavity, there remain significant challenges, particularly in devising therapeutic strategies for clinical application that minimize surgical incisions and conform to the intricate structure of uterine cavity. Herein, an injectable hydrogel loaded with human umbilical cord-derived mesenchymal stem cells (UCMSCs) was synthesized via the Diels-Alder click reaction for endometrial regeneration and fertility restoration, exhibiting suitable mechanical properties, good biocompatibility, and desirable degradation properties. Notably, this hydrogel permitted minimally invasive administration and integrated seamlessly with surrounding tissue. Our study revealed that the UCMSCs-laden injectable hydrogel enhanced cell proliferation, migration, angiogenesis, and exhibited anti-fibrotic effects in vitro. The implantation of this hydrogel significantly facilitated endometrium regeneration and restored fertility in a rat endometrial damage model. Mechanistically, in vivo results indicated that the UCMSCs-laden injectable hydrogel effectively promoted macrophage recruitment and facilitated M2 phenotype polarization. Collectively, this hydrogel demonstrated efficacy in regenerating damaged endometrium, leading to the restoration of fertility. Consequently, it holds promise as a potential therapeutic strategy for endometrial damage and fertility decline arising from intrauterine adhesions. STATEMENT OF SIGNIFICANCE: Severe endometrial traumas frequently lead to intrauterine adhesions and subsequent infertility. Stem cell therapy shows promising potential for the clinical treatment of IUA; however, challenges remain, including low delivery efficiency and compromised stem cell activity during the delivery process. In this study, we fabricated an injectable hydrogel loaded with UCMSCs via the Diels-Alder click reaction, which exhibited unique bioorthogonality. The in situ-gelling hydrogels could be introduced through a minimally invasive procedure and adapt to the intricate anatomy of the uterus. The UCMSCs-laden injectable hydrogel promoted endometrial regeneration and fertility restoration in a rat endometrial damage model, efficaciously augmenting macrophage recruitment and promoting their polarization to the M2 phenotype. The administration of UCMSCs-laden injectable hydrogel presents a promising therapeutic strategy for patients with severe intrauterine adhesion.

Single-dose Administration of Recombinant Human Thrombopoietin Enhances Survival and Hematopoietic Reconstruction in Canines Irradiated with 3 Gy Gamma Radiation.

We conducted this study to investigate the radioprotective effects of recombinant human thrombopoietin (rhTPO) on beagle dogs irradiated with 3.0 Gy 60Co gamma rays. Fifteen healthy adult beagles were randomly assigned to a control group with alleviating care, and 5 and 10 µg/kg rhTPO treatment group. All animals received total-body irradiation using 60Co γ-ray source at a dose of 3.0 Gy (dose rate was 69.1 cGy/min). The treatment group received intramuscular injection of rhTPO 5 and 10 µg/kg at 2 h postirradiation, and the control group was administrated the same volume of normal saline. The survival rate, clinical signs, peripheral hemogram, serum biochemistry, and histopathological examination of animals in each group were assessed. Single administration of 10 µg/kg rhTPO at 2 h postirradiation promoted the recovery of multilineage hematopoiesis and improved the survival rate of beagles irradiated with 3 Gy 60Co γ rays. The administration of 10 µg/kg rhTPO alleviated fever and bleeding, reduced the requirement for supportive care, and may have mitigated multiple organ damage.

Two-dimensional nanomaterial MXenes for efficient gas separation: a review.

Transition metal carbides/nitrides (MXenes) are emerging two-dimensional (2D) materials that have been widely investigated in recent years. In general, these materials can be obtained from MAX phase ceramics after intercalation, etching, and exfoliation to obtain multilayer MXene nanosheet structures; moreover, they have abundant end-group functional groups on their surface. In recent years, the excellent high permeability, fine sieving ability and diverse processability of MXene series materials make the membranes prepared using them particularly suitable for membrane-based separation processes in the field of gas separation. 2D membranes enhance the diversity of the pristine membrane transport channels by regulating the gas transport channels through in-plane pores (intrinsic defects), in-plane slit-like pores, and planar to planar interlayer channels, endowing the membrane with the ability to effectively sieve gas energy efficiently. Herein, we review MXenes, a class of 2D nanomaterials, in terms of their unique structure, synthesis method, functionalization method, and the structure-property relationship of MXene-based gas separation membranes and list examples of MXene-based membranes used in the field of gas separation. By summarizing and analyzing the basic properties of MXenes and demonstrating their unique advantages compared to other 2D nanomaterials, we lay a foundation for the discussion of MXene-based membranes with outstanding carbon dioxide (CO2) capture performance and outline and exemplify the excellent separation performances of MXene-based gas separation membranes. Finally, the challenges associated with MXenes are briefly discussed and an outlook on the promising future of MXene-based membranes is presented. It is expected that this review will provide new insights and important guidance for future research on MXene materials in the field of gas separation.

Synthesis and up-to-date applications of 2D microporous g-C3N4 nanomaterials for sustainable development.

In recent years, with the development of industrial technology and the increase of people's environmental awareness, the research on sustainable materials and their applications has become a hot topic. Among two-dimensional (2D) materials that have been selected for sustainable research, graphitic phase carbon nitride (g-C3N4) has become a hot research topic because of its many outstanding advantages such as simple preparation, good electrochemical properties, excellent photochemical properties, and better thermal stability. Nevertheless, the inherent limitations of g-C3N4 due to its relatively poor specific surface area, rapid charge recombination, limited light absorption range, and inferior dispersion in aqueous and organic media have limited its practical application. In the review, we summarize and analyze the unique structure of the 2D microporous nanomaterial g-C3N4, its synthesis method, chemical modification method, and the latest application examples in various fields in recent years, highlighting its advantages and shortcomings, with a view to providing ideas for overcoming the difficulties in its application. Furthermore, the pressing challenges faced by g-C3N4 are briefly discussed, as well as an outlook on the application prospects of g-C3N4 materials. It is expected that the review in this paper will provide more theoretical strategies for the future practical application of g-C3N4-based materials, as well as contributing to nanomaterials in sustainable applications.

Altered brain functional connectivity in vegetative state and minimally conscious state.

Objectives: The pathological mechanism for a disorder of consciousness (DoC) is still not fully understood. Based on traditional behavioral scales, there is a high rate of misdiagnosis for subtypes of DoC. We aimed to explore whether topological characterization may explain the pathological mechanisms of DoC and be effective in diagnosing the subtypes of DoC. Methods: Using resting-state functional magnetic resonance imaging data, the weighted brain functional networks for normal control subjects and patients with vegetative state (VS) and minimally conscious state (MCS) were constructed. Global and local network characteristics of each group were analyzed. A support vector machine was employed to identify MCS and VS patients. Results: The average connection strength was reduced in DoC patients and roughly equivalent in MCS and VS groups. Global efficiency, local efficiency, and clustering coefficients were reduced, and characteristic path length was increased in DoC patients (p < 0.05). For patients of both groups, global network measures were not significantly different (p > 0.05). Nodal efficiency, nodal local efficiency, and nodal clustering coefficient were reduced in frontoparietal brain areas, limbic structures, and occipital and temporal brain areas (p < 0.05). The comparison of nodal centrality suggested that DoC causes reorganization of the network structure on a large scale, especially the thalamus. Lobal network measures emphasized that the differences between the two groups of patients mainly involved frontoparietal brain areas. The accuracy, sensitivity, and specificity of the classifier for identifying MCS and VS patients were 89.83, 78.95, and 95%, respectively. Conclusion: There is an association between altered network structures and clinical symptoms of DoC. With the help of network metrics, it is feasible to differentiate MCS and VS patients.

A conductive multifunctional hydrogel dressing with the synergistic effect of ROS-scavenging and electroactivity for the treatment and sensing of chronic diabetic wounds.

Chronic diabetic wound with persistent inflammatory responses is still a serious threat to human health and life. Ideal wound dressings can be applied not only for covering the injury area, but also for regulating the inflammation to accelerate the wound healing and long-term monitoring of wound condition. However, there remains a challenge to design a multifunctional wound dressing for simultaneous treatment and monitoring of wound. Herein, an ionic conductive hydrogel with intrinsic reactive oxygen species (ROS)-scavenging properties and good electroactivity was developed for achieving the synergetic treatment and monitoring of diabetic wounds. In this study, we modified dextran methacrylate with phenylboronic acid (PBA) to prepare a ROS-scavenging material (DMP). Then the hydrogel was constructed by phenylboronic ester bonds induced dynamic crosslinking network, photo-crosslinked DMP and choline-based ionic liquid as the second network, and the crystallized polyvinyl alcohol as the third network, realizing good ROS-scavenging performance, high electroactivity, durable mechanical properties, and favorable biocompatibility. In vivo results showed that the hydrogel combined with electrical stimulation (ES) demonstrated good performance in promoting re-epithelization, angiogenesis and collagen deposition in chronic diabetic wound treatment by alleviating inflammation. Notably, with desirable mechanical properties and conductivity, the hydrogel could also precisely monitor movements of human body and possible tensile and compressive stresses of the wound site, providing timely alerts of excessive mechanical stress applied to the wound tissue. Thus, this "all-in-one" hydrogel exhibits great potential in constructing the next generation flexible bioelectronics for wound treatment and monitoring. STATEMENT OF SIGNIFICANCE: Chronic diabetic wounds characterized by overexpressed reactive oxygen species (ROS) are still a serious threat to human health and life. However, there remains a challenge to design a multifunctional wound dressing for simultaneous wound treatment and monitoring. Herein, a flexible conductive hydrogel dressing with intrinsic ROS-scavenging properties and electroactivity was developed for the combined treatment and monitoring of the wound. The antioxidant hydrogel combined with electrical stimulation synergistically accelerated chronic diabetic wound healing by regulating oxidative stress, alleviating inflammation, promoting re-epithelization, angiogenesis and collagen deposition. Notably, with desirable mechanical properties and conductivity, the hydrogel also presented great potential in monitoring possible stresses of the wound site. The "all-in-one" bioelectronics integrating the treatment and monitoring functions present great application potential for accelerating chronic wound healing.

Magnetic resonance imaging assessment of the lateral geniculate nucleus volume and height in patients with glaucoma: a Meta-analysis.

AIM: To evaluate the lateral geniculate nucleus (LGN) volume and height using magnetic resonance imaging (MRI) in glaucoma patients. METHODS: Literatures retrieval was carried out through PubMed, Web of Science, Embase, and Cochrane Library. Studies that compared the volume and height of LGN in glaucoma patients with that in control subjects were included. The volume and height of LGN were extracted from the included studies. The Review Manager 5.4.1 software was used for the Meta-analysis. RESULTS: This Meta-analysis included 10 cross-sectional studies, including the eyes of 223 glaucoma patients and 185 healthy controls. Compared with the control subjects, the volume and height of LGN in glaucoma patients measured by MRI were significantly reduced {-29.13 mm3, 95% [confidence interval (CI): -44.82 to -13.43, P=0.0003; -0.61 mm, 95%CI: -0.78 to -0.44, P<0.00001, respectively]}. Subgroup analysis demonstrated that the differences of LGN volume and height between glaucoma patients and control subjects in the older group were smaller than that in the younger group, and LGN volume decreased with the increase of glaucoma severity. CONCLUSION: The results demonstrate that the volume and height of LGN are decreased in glaucoma patients, and LGN volume can be considered a parameter of glaucoma severity.

ADSC-derived exosomes-coupled decellularized matrix for endometrial regeneration and fertility restoration.

Endometrium is suspectable to severe injury due to recurrent abortion, curettage or intrauterine infection which could lead to pathological conditions and sabotage women's fertility. Promoting endometrium regeneration is the core of the treatments to uterine related infertility. Patients who received traditional treatments can only expect limited effects, thereby novel therapies are badly in need to promote endometrium regeneration. Here we generated a decellularized extracellular matrix (ECM) from porcine dermis, and composited adipose stem cell derived exosomes (ADSC-exos) on it (ECM@ADSC-exos). In vitro experiments proved that ECM@ADSC-exos exhibited good cytocompatibility and could improve cell proliferation, migration and angiogenesis. We also observed that, when implanted in the uterine cavity of a rat model of endometrium injury, ECM@ADSC-exos improved endometrium regeneration, enhanced local angiogenesis, promoted myometrium repair and finally preserved fertility. Our results proved that ECM@ADSC-exos could be a novel option for endometrium regeneration.

A construct of adipose-derived mesenchymal stem cells-laden collagen scaffold for fertility restoration by inhibiting fibrosis in a rat model of endometrial injury.

Severe endometrium damage causes pathological conditions such as thin endometrium and intrauterine adhesion, resulting in uterine factor infertility. Mesenchymal stem cell (MSC) therapy is a promising strategy in endometrial repair; yet, exogenous MSCs still raise concerns for safety and ethical issues. Human adipose-derived mesenchymal stem cells (ADMSCs) residing in adipose tissue have high translational potentials due to their autologous origin. To harness the high translation potentials of ADMSC in clinical endometrium regeneration, here we constructed an ADMSCs composited porous scaffold (CS/ADMSC) and evaluated its effectiveness on endometrial regeneration in a rat endometrium-injury model. We found that CS/ADMSC intrauterine implantation (i) promoted endometrial thickness and gland number, (ii) enhanced tissue angiogenesis, (iii) reduced fibrosis and (iv) restored fertility. We ascertained the pro-proliferation, pro-angiogenesis, immunomodulating and anti-fibrotic effects of CS/ADMSC in vitro and revealed that the CS/ADMSC influenced extracellular matrix composition and organization by a transcriptomic analysis. Our results demonstrated the effectiveness of CS/ADMSC for endometrial regeneration and provided solid proof for our future clinical study.

A prediction model for bacteremia and transfer to intensive care in pediatric and adolescent cancer patients with febrile neutropenia.

Febrile neutropenia (FN) is a common condition in children receiving chemotherapy. Our goal in this study was to develop a model for predicting blood stream infection (BSI) and transfer to intensive care (TIC) at time of presentation in pediatric cancer patients with FN. We conducted an observational cohort analysis of pediatric and adolescent cancer patients younger than 24 years admitted for fever and chemotherapy-induced neutropenia over a 7-year period. We excluded stem cell transplant recipients who developed FN after transplant and febrile non-neutropenic episodes. The primary outcome was onset of BSI, as determined by positive blood culture within 7 days of onset of FN. The secondary outcome was transfer to intensive care (TIC) within 14 days of FN onset. Predictor variables include demographics, clinical, and laboratory measures on initial presentation for FN. Data were divided into independent derivation (2009-2014) and prospective validation (2015-2016) cohorts. Prediction models were built for both outcomes using logistic regression and random forest and compared with Hakim model. Performance was assessed using area under the receiver operating characteristic curve (AUC) metrics. A total of 505 FN episodes (FNEs) were identified in 230 patients. BSI was diagnosed in 106 (21%) and TIC occurred in 56 (10.6%) episodes. The most common oncologic diagnosis with FN was acute lymphoblastic leukemia (ALL), and the highest rate of BSI was in patients with AML. Patients who had BSI had higher maximum temperature, higher rates of prior BSI and higher incidence of hypotension at time of presentation compared with patients who did not have BSI. FN patients who were transferred to the intensive care (TIC) had higher temperature and higher incidence of hypotension at presentation compared to FN patients who didn't have TIC. We compared 3 models: (1) random forest (2) logistic regression and (3) Hakim model. The areas under the curve for BSI prediction were (0.79, 0.65, and 0.64, P < 0.05) for models 1, 2, and 3, respectively. And for TIC prediction were (0.88, 0.76, and 0.65, P < 0.05) respectively. The random forest model demonstrated higher accuracy in predicting BSI and TIC and showed a negative predictive value (NPV) of 0.91 and 0.97 for BSI and TIC respectively at the best cutoff point as determined by Youden's Index. Likelihood ratios (LRs) (post-test probability) for RF model have potential utility of identifying low risk for BSI and TIC (0.24 and 0.12) and high-risk patients (3.5 and 6.8) respectively. Our prediction model has a very good diagnostic performance in clinical practices for both BSI and TIC in FN patients at the time of presentation. The model can be used to identify a group of individuals at low risk for BSI who may benefit from early discharge and reduced length of stay, also it can identify FN patients at high risk of complications who might benefit from more intensive therapies at presentation.

Atg9A-mediated mitophagy is required for decidual differentiation of endometrial stromal cells.

Endometrial decidualization is the foundation of a healthy pregnancy. Mitochondrial dysfunction is an independent cause of disease for energy-intensive organs. Mitochondrial homeostasis plays a key role in the differentiation processes of many cell types. We showed increased activation of mitophagy (mitochondrial autophagy) in the decidua compared with proliferative or secretory endometrium. To better comprehend the mechanisms underlying healthy conception, understanding the mechanism of endometrial stromal cell decidualization is of great importance. Here, we artificially induced decidualization of a human endometrial stromal cell line (T HESCs) and characterized subsequent activation of mitophagy using immunofluorescence assay, electron microscopy and Western blot assay. Knockdown of autophagy-related 9A (ATG9A) led to an obvious reduction of mitophagy and deficiencies in decidualization. Our findings demonstrate a key role for proper mitochondrial dynamics in decidual differentiation and identify ATG9A-mediated mitophagy as a novel therapeutic target for repeated implantation failure or recurrent abortion.

In situ delivery of apoptotic bodies derived from mesenchymal stem cells via a hyaluronic acid hydrogel: A therapy for intrauterine adhesions.

Stem cell-based and stem cell-derived exosome-based therapies have shown promising potential for endometrial regeneration and the clinical treatment of intrauterine adhesions (IUAs). Evidence shows that apoptosis occurs in a majority of grafted stem cells, and apoptotic bodies (ABs) play a critical role in compensatory tissue regeneration. However, the therapeutic potential of AB-based therapy and its mechanism have not been explored in detail. Here, a cell-free therapeutic strategy was developed by incorporating mesenchymal stem cell-derived ABs into a hyaluronic acid (HA) hydrogel to achieve endometrial regeneration and fertility restoration. Specifically, we found that the ABs could induce macrophage immunomodulation, cell proliferation, and angiogenesis in vitro. The HA hydrogel promoted the retention of ABs and facilitated their continuous release. In a murine model of acute endometrial damage and a rat model of IUAs, in situ injection of the AB-laden HA hydrogel could efficiently reduce fibrosis and promote endometrial regeneration, resulting in the fertility restoration. Consequently, ABs show good potential as therapeutic vesicles, and the AB-laden HA hydrogel appears to be a clinically feasible and cell-free alternative for endometrial regeneration and IUA treatment.

[Therapeutic Effect of Single Intramuscular Administration of Recombinant Human Thrombopoietin on Rhesus Monkeys with Acute radiation Sickness].

OBJECTIVE: To confirm the therapeutic effect of recombinant human thrombopoietin (rhTPO) on rhesus monkeys irradiated with 5.0 Gy 60Co γ-ray, and provide experimental basis for clinical treatment of similar patients. METHODS: Fourteen adult rhesus monkeys were irradiated with 60Co γ-ray on both sides at the dose of 5.0 Gy (dose rate 69.2 cGy/min) to establish the acute radiation sickness model. The monkeys were divided into irradiation group (n=5), rhTPO 5 µg/kg group (n=4) and rhTPO 10 µg/kg group (n=5). Two hours after irradiation, the three groups of monkeys were injected with saline 0.1 ml/kg, rhTPO 5 µg/kg（0.1 ml/kg） and rhTPO 10 µg/kg(0.2 ml/kg), respectively. The general signs, survival, peripheral hemogram and serum biochemistry of rhesus monkeys were observed before and after irradiation, and the differences between rhTPO group and irradiation control group were compared. RESULTS: After total body irradiation with 5.0 Gy60Co γ-ray, rhesus monkeys successively showed fever, hemorrhage, sharp decrease of whole blood cell counts in peripheral blood and disorder of serum biochemical indexes. Compared with the irradiated control group, a single intramuscular injection of rhTPO 5 µg/kg or 10 µg/kg 2 hours after irradiation could improve the symptoms of fever and bleeding, increase the nadir of peripheral red blood cells and platelets counts, shorten the duration of hemocytopenia, and advance the time for blood cells to return to the pre-irradiation level. The serum biochemical results showed that rhTPO could improve the abnormality of serum biochemical indexes in rhesus monkeys induced by 5.0 Gy total body irradiation to some extent. Compared with the two administration groups, the therapeutic effect of rhTPO 10 µg/ kg was better. CONCLUSION: A single injection of rhTPO 5 µg/ kg or 10 µg/ kg 2 hours after irradiation can alleviate the injury of multilineage hematopoiesis and promote the recovery in monkeys irradiated by 5.0 Gy γ-ray. It also improves animal signs and has obvious therapeutic effect on acute radiation sickness.