High Vitamin D Level in Female Mice Increases the Number of Live Fetuses.

Little is known about the impact of high-normal range of 25-hydroxyvitamin D [25(OH)D] on reproductive function. The aim of this study was to investigate the effect of different dose vitamin D supplementation in female mice on the pregnancy outcomes. Three groups of female mice were fed with fodder containing different dose of vitamin D at both pre-gestational and gestational stages. Serum 25(OH)D and calcium concentrations were monitored. The expression levels of vitamin D receptor (VDR) mRNA and protein in placenta were determined by real-time RT-PCR and western blot. Pregnancy outcomes were evaluated and compared among the three groups. Compared with the medium and low dose groups, serum 25(OH)D concentration was significantly increased and approximated to high-normal range in the high dose group (pre-gestational: 81.3±5.75 vs 52.8±6.24 and 25.0±3.99 ng/mL; gestational: 86.8±5.99 vs 52.6±9.29 and 27.9±4.96 ng/mL, respectively; all p<0.001). Interestingly, the average number of live fetuses per litter was much larger in the high dose group than in other two groups (19.8±5.31 vs 13.8±1.30 and 12.8±3.55 respectively, both p<0.05). However, no significant differences of the expression levels of VDR mRNA and protein in placenta were identified among the three groups. Supplementation of high dose vitamin D can enhance the female mice reproductive function. Further study is warranted to explore the mechanism by which high level of 25(OH)D in female mice increases the number of fetuses.

m6A demethylase ALKBH5 attenuates doxorubicin-induced cardiotoxicity via posttranscriptional stabilization of Rasal3.

The clinical application of anthracyclines such as doxorubicin (DOX) is limited due to their cardiotoxicity. N6-methyladenosine (m6A) plays an essential role in numerous biological processes. However, the roles of m6A and m6A demethylase ALKBH5 in DOX-induced cardiotoxicity (DIC) remain unclear. In this research, DIC models were constructed using Alkbh5-knockout (KO), Alkbh5-knockin (KI), and Alkbh5-myocardial-specific knockout (ALKBH5flox/flox, αMyHC-Cre) mice. Cardiac function and DOX-mediated signal transduction were investigated. As a result, both Alkbh5 whole-body KO and myocardial-specific KO mice had increased mortality, decreased cardiac function, and aggravated DIC injury with severe myocardial mitochondrial damage. Conversely, ALKBH5 overexpression alleviated DOX-mediated mitochondrial injury, increased survival, and improved myocardial function. Mechanistically, ALKBH5 regulated the expression of Rasal3 in an m6A-dependent manner through posttranscriptional mRNA regulation and reduced Rasal3 mRNA stability, thus activating RAS3, inhibiting apoptosis through the RAS/RAF/ERK signaling pathway, and alleviating DIC injury. These findings indicate the potential therapeutic effect of ALKBH5 on DIC.

Construct Validity of a Novel Assessment System for Laparoscopic Suture Accuracy Based on Stereoscopy.

BACKGROUND: An accurate and objective measuring tool is lacking for laparoscopic suture accuracy assessment in simulation training. We designed and developed the suture accuracy testing system (SATS) and aimed to determine its construct validity in this study. METHODS: Twenty laparoscopic experts and 20 novices were recruited to perform a suturing task in three sessions using traditional laparoscopic instruments (Tra. session), a handheld multi-degree-of-freedom (MDoF) laparoscopic instrument (MDoF session) and a surgical robot (Rob. session), respectively. The needle entry and exit errors were calculated using the SATS and compared between the two groups. RESULTS: No significant difference of the needle entry error was found in all comparisons. As for the needle exit error, the value of the novice group was significantly higher than that of the expert group in Tra. session (3.48 ± 0.61 mm vs. 0.85 ± 0.14 mm; p = 1.451e-11) and MDoF session (2.65 ± 0.41 mm vs. 1.06 ± 0.17 mm; p = 1.451e-11) but not in Rob. session (0.51 ± 0.12 mm vs. 0.45 ± 0.08 mm; p = 0.091). CONCLUSIONS: The SATS demonstrates construct validity. Surgeons' experience in conventional laparoscopic instruments could be transferred to the MDoF instrument. Surgical robot helps to improve suture accuracy and may bridge the experience gap between laparoscopic experts and novices in basic exercises.

Electrospun Core-Sheath Fibers with a Uniformly Aligned Polymer Network Liquid Crystal (PNLC).

Electrospun polymer-liquid crystal (PLC) fibers have potential applications such as wearable sensors and adaptive textiles because of their rapid response and high flexibility. However, existing PLC fibers only have a narrow responsive range and poor resistance to heat and chemicals. Herein, a new type of PLC fiber is prepared by using a coaxial electrospinning process. The core solution is 4'-pentyl-4-biphenylcarbonitrile (5CB), and the sheath solution is a mixture containing 13 wt % PVP and 10 wt % reactive mesogen (RM). After UV exposure of the fibers, 5CB in the core and RM diffusing from the core are cross-linked into an LC polymer. The fibers have a highly uniform morphology with an average diameter of 3.2 ± 0.5 µm, and mesogens inside the fibers align unidirectionally with the long axis of the fibers. The fibers show a broad phase-transition temperature range between 13.5 and 155.5 °C and have a response time of less than 10 s. The temperature range can also be controlled by adjusting components in the electrospun fibers and UV exposure time. The core-sheath fibers prepared in such a manner exhibit excellent heat and chemical resistance with reversible optical responses. Moreover, when the fibers are exposed to volatile organic compounds (VOCs) such as toluene, the fibers show a rapid optical response to toluene vapor within 25 s. This study demonstrates that the fibers are potentially useful for preparing flexible temperature and chemical sensors.

Research Progress on the Osteogenesis-Related Regulatory Mechanisms of Human Umbilical Cord Mesenchymal Stem Cells.

In recent years, research on human umbilical cord mesenchymal stem cells (hUCMSCs) derived from human umbilical cord tissue has accelerated and entered clinical application research. Compared with mesenchymal stem cells (MSCs) from other sources, hUCMSCs can be extracted from different parts of umbilical cord or from the whole umbilical cord. It has the characteristics of less ethical controversy, high differentiation potential, strong proliferation ability, efficient expansion in vitro, avoiding immune rejection and immune privilege, and avoids the limitations of lack of embryonic stem cells, heterogeneity, ethical and moral constraints. hUCMSCs avoid the need for embryonic stem cell sources, heterogeneity, and ethical and moral constraints. Bone defects are very common in clinical practice, but completely effective bone tissue regeneration treatment is challenging. Currently, autologous bone transplantation and allogeneic bone transplantation are main treatment approaches in clinical work, but each has different shortcomings, such as limited sources, invasiveness, immune rejection and insufficient osteogenic ability. Therefore, to solve the bottleneck of bone tissue regeneration and repair, a great amount of research has been carried out to explore the clinical advantages of hUCMSCs as seed cells to promote osteogenesis.However, the regulation of osteogenic differentiation of hUCMSCs is an extremely complex process. Although a large number of studies have demonstrated that the role of hUCMSCs in enhancing local bone regeneration and repair through osteogenic differentiation and transplantation into the body involves multiple signaling pathways, there is no relevant article that summarize the findings. This article discusses the osteogenesis-related regulatory mechanisms of hUCMSCs, summarizes the currently known related mechanisms, and speculates on the possible signals.

Reduction of mRNA m6A associates with glucose metabolism via YTHDC1 in human and mice.

AIMS: N6-methyladenosine (m6A) in mRNA is involved in glucose metabolism. Our goal is to investigate the relationship of glucose metabolism, m6A and YTH domain-containing protein 1 (YTHDC1), a binding protein to m6A, in the development of type 2 diabetes (T2D). METHODS: HPLC-MS/MS and qRT-PCR were used to quantify m6A and YTHDC1 levels in white blood cells from patients with T2D and healthy individuals. MIP-CreERT and tamoxifen treatment were used to create ß-cell Ythdc1 knockout mice (ßKO). m6A sequencing and RNA sequencing were performed in wildtype/ßKO islets and MIN6 cells to identify the differential genes. RESULTS: In T2D patients, both of m6A and YTHDC1 levels were reduced and associated with fasting glucose. Deletion of Ythdc1 resulted in glucose intolerance and diabetes due to decreased insulin secretion, even though ß-cell mass in ßKO mice was comparable to wildtype mice. Moreover, Ythdc1 was shown to bind to SRSF3 (serine/arginine-rich splicing factor 3) and CPSF6 (cleavage and polyadenylation specific factor 6) in ß-cells. CONCLUSIONS: Our data suggested that YTHDC1 may regulate mRNA splicing and export by interacting with SRSF3 and CPSF6 to modulate glucose metabolism via regulating insulin secretion, implying YTHDC1 might be a novel potential target for lowing glucose.

Trends in the Prevalence of Metabolically Healthy Obesity Among US Adults, 1999-2018.

Importance: Improved understanding of trends in the proportion of individuals with metabolically healthy obesity (MHO) may facilitate stratification and management of obesity and inform policy efforts. Objectives: To characterize trends in the prevalence of MHO among US adults with obesity, overall and by sociodemographic subgroups. Design, Setting, and Participants: This survey study included 20 430 adult participants from 10 National Health and Nutrition Examination Survey (NHANES) cycles between 1999-2000 and 2017-2018. The NHANES is a series of cross-sectional and nationally representative surveys of the US population conducted continuously in 2-year cycles. Data were analyzed from November 2021 to August 2022. Exposures: National Health and Nutrition Examination Survey cycles from 1999-2000 to 2017-2018. Main Outcomes and Measures: Metabolically healthy obesity was defined as a body mass index of 30.0 (calculated as weight in kilograms divided by height in meters squared) without any metabolic disorders in blood pressure, fasting plasma glucose (FPG), high-density lipoprotein cholesterol (HDL-C), or triglycerides based on established cutoffs. Trends in the age-standardized prevalence of MHO were estimated using logistic regression analysis. Results: This study included 20 430 participants. Their weighted mean (SE) age was 47.1 (0.2) years; 50.8% were women, and 68.8% self-reported their race and ethnicity as non-Hispanic White. The age-standardized prevalence (95% CI) of MHO increased from 3.2% (2.6%-3.8%) in the 1999-2002 cycles to 6.6% (5.3%-7.9%) in the 2015-2018 cycles (P < .001 for trend). There were 7386 adults with obesity. Their weighted mean (SE) age was 48.0 (0.3) years, and 53.5% were women. The age-standardized proportion (95% CI) of MHO among these 7386 adults increased from 10.6% (8.8%-12.5%) in the 1999-2002 cycles to 15.0% (12.4%-17.6%) in the 2015-2018 cycles (P = .02 for trend). Substantial increases in the proportion of MHO were observed for adults aged 60 years or older, men, non-Hispanic White individuals, and those with higher income, private insurance, or class I obesity. In addition, there were significant decreases in the age-standardized prevalence (95% CI) of elevated triglycerides (from 44.9% [40.9%-48.9%] to 29.0% [25.7%-32.4%]; P < .001 for trend) and reduced HDL-C (from 51.1% [47.6%-54.6%] to 39.6% [36.3%-43.0%]; P = .006 for trend). There was also a significant increase in elevated FPG (from 49.7% [95% CI, 46.3%-53.0%] to 58.0% [54.8%-61.3%]; P < .001 for trend) but no significant change in elevated blood pressure (from 57.3% [53.9%-60.7%] to 54.0% [50.9%-57.1%]; P = .28 for trend). Conclusions and Relevance: The findings of this cross-sectional study suggest that the age-standardized proportion of MHO increased among US adults from 1999 to 2018, but differences in trends existed across sociodemographic subgroups. Effective strategies are needed to improve metabolic health status and prevent obesity-related complications in adults with obesity.

PEDOT:PSS hydrogels with high conductivity and biocompatibility for in situ cell sensing.

Conducting polymer hydrogels, especially poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) hydrogels, show great promise in soft bioelectronics due to their high conductivity and the ability of electrical coupling with tissues for sensing and stimulation. However, it is challenging to solve the problem of poor biocompatibility of PEDOT:PSS hydrogels due to the existing harsh preparation methods with the use of toxic and harmful reagents. Herein, we report the synthesis of PEDOT:PSS hydrogels with positively charged conductive polymers as a cross-linker and the application of PEDOT:PSS hydrogels as in situ electrochemical sensors for living cells. The conductivities of PEDOT:PSS hydrogels prepared using this method without any toxic or harmful reagents can reach up to 3265 S m-1. The facile synthesis approach with a simple mixture of PEDOT:PSS aqueous solution and the monomers of conductive polymers at room temperature also enables the printability of PEDOT:PSS hydrogels to fabricate patterned electrodes. Moreover, all the proposed PEDOT:PSS hydrogels demonstrated good biocompatibility. The in situ electrochemical detection of dopamine secreted from PC12 cells cultured within PEDOT:PSS hydrogels suggests that our PEDOT:PSS hydrogels with high conductivity and biocompatibility offer great potential for the integration of biosensors within 3D cell culture.

Nacre-inspired bacterial cellulose/mica nanopaper with excellent mechanical and electrical insulating properties by biosynthesis.

The exploration of extreme environments has become necessary for understanding and changing nature. However, the development of functional materials suitable for extreme conditions is still insufficient. Herein, we report a kind of nacre-inspired bacterial cellulose (BC)/synthetic mica (S-Mica) nanopaper with excellent mechanical and electrical insulating properties that has excellent tolerance to extreme conditions. Benefited from the nacre-inspired structure and the three-dimensional network of BC, the nanopaper exhibits excellent mechanical properties, including high tensile strength (375 MPa), outstanding foldability, and bending fatigue resistance. In addition, S-Mica arranged in layers endows the nanopaper with remarkable dielectric strength (∼145.7 kV mm-1 ) and ultralong corona resistance life. Moreover, the nanopaper is highly resistant to alternating high and low temperatures, ultraviolet (UV) light, and atomic oxygen (AO), making it an ideal candidate for extreme environment-resistant materials. This article is protected by copyright. All rights reserved.

Recent progress of hydrogel-based local drug delivery systems for postoperative radiotherapy.

Surgical resection and postoperative radiotherapy remained the most common therapeutic modalities for malignant tumors. However, tumor recurrence after receiving such combination is difficult to be avoided because of high invasiveness and radiation resistance of cancer cells during long-term therapy. Hydrogels, as novel local drug delivery systems, presented excellent biocompatibility, high drug loading capacity and sustained drug release property. Compared with conventional drug formulations, hydrogels are able to be administered intraoperatively and directly release the entrapped therapeutic agents to the unresectable tumor sites. Therefore, hydrogel-based local drug delivery systems have their unique advantages especially in sensitizing postoperative radiotherapy. In this context, classification and biological properties of hydrogels were firstly introduced. Then, recent progress and application of hydrogels for postoperative radiotherapy were summarized. Finally, the prospects and challenges of hydrogels in postoperative radiotherapy were discussed.

A global daily soil moisture dataset derived from Chinese FengYun Microwave Radiation Imager (MWRI)(2010-2019).

Surface soil moisture (SSM) is an important variable in drought monitoring, floods predicting, weather forecasting, etc. and plays a critical role in water and heat exchanges between land and atmosphere. SSM products from L-band observations, such as the Soil Moisture Active Passive (SMAP) Mission, have proven to be optimal global estimations. Although X-band has a lower sensitivity to soil moisture than that of L-band, Chinese FengYun-3 series satellites (FY-3A/B/C/D) have provided sustainable and daily multiple SSM products from X-band since 2008. This research developed a new global SSM product (NNsm-FY) from FY-3B MWRI from 2010 to 2019, transferred high accuracy of SMAP L-band to FY-3B X-band. The NNsm-FY shows good agreement with in-situ observations and SMAP product and has a higher accuracy than that of official FY-3B product. With this new dataset, Chinese FY-3 satellites may play a larger role and provide opportunities of sustainable and longer-term soil moisture data record for hydrological study.

Identification and Characterization of the Determinants of Copper Resistance in the Acidophilic Fungus Acidomyces richmondensis MEY-1 Using the CRISPR/Cas9 System.

Copper (Cu) homeostasis has not been well documented in filamentous fungi, especially extremophiles. One of the main obstacles impeding their characterization is the lack of a powerful genome-editing tool. In this study, we applied a CRISPR/Cas9 system for efficient targeted gene disruption in the acidophilic fungus Acidomyces richmondensis MEY-1, formerly known as Bispora sp. strain MEY-1. Using this system, we investigated the basis of Cu tolerance in strain MEY-1. This strain has extremely high Cu tolerance among filamentous fungi, and the transcription factor ArAceA (A. richmondensis AceA) has been shown to be involved in this process. The ArAceA deletion mutant (ΔArAceA) exhibits specific growth defects at Cu concentrations of ≥10 mM and is transcriptionally more sensitive to Cu than the wild-type strain. In addition, the putative metallothionein ArCrdA was involved in Cu tolerance only under high Cu concentrations. MEY-1 has no Aspergillus nidulans CrpA homologs, which are targets of AceA-like transcription factors and play a role in Cu tolerance. Instead, we identified the Cu-transporting P-type ATPase ArYgA, homologous to A. nidulans YgA, which was involved in pigmentation rather than Cu tolerance. When the ΔArYgA mutant was grown on medium supplemented with Cu ions, the black color was completely restored. The lack of CrpA homologs in A. richmondensis MEY-1 and its high tolerance to Cu suggest that a novel Cu detoxification mechanism differing from the AceA-CrpA axis exists. IMPORTANCE Filamentous fungi are widely distributed worldwide and play an important ecological role as decomposers. However, the mechanisms of their adaptability to various environments are not fully understood. Various extremely acidophilic filamentous fungi have been isolated from acidic mine drainage (AMD) with extremely low pH and high heavy metal and sulfate concentrations, including A. richmondensis. The lack of genetic engineering tools, particularly genome-editing tools, hinders the study of these acidophilic and heavy metal-resistant fungi at the molecular level. Here, we first applied a CRISPR/Cas9-mediated gene-editing system to A. richmondensis MEY-1. Using this system, we identified and characterized the determinants of Cu resistance in A. richmondensis MEY-1. The conserved roles of the Cu-binding transcription factor ArAceA in Cu tolerance and the Cu-transporting P-type ATPase ArYgA in the Cu-dependent production of pigment were confirmed. Our findings provide insights into the molecular basis of Cu tolerance in the acidophilic fungus A. richmondensis MEY-1. Furthermore, the CRISPR/Cas9 system used here would be a powerful tool for studies of the mechanisms of adaptability of acidophilic fungi to extreme environments.

Acupuncture ameliorates Mobile Phone Addiction with sleep disorders and restores salivary metabolites rhythm.

Objectives: Mobile Phone Addiction (MPA) is a novel behavioral addiction resulting in circadian rhythm disorders that severely affect mental and physical health. The purpose of this study is to detect rhythmic salivary metabolites in MPA with sleep disorder (MPASD) subjects and investigate the effects of acupuncture. Methods: Six MPASD patients and six healthy controls among the volunteers were enrolled by MPA Tendency Scale (MPATS) and Pittsburgh Sleep Quality Index (PSQI), then the salivary samples of MPASD and healthy controls were collected every 4-h for three consecutive days. Acupuncture was administered for 7 days to MPASD subjects, then saliva samples were collected again. Salivary metabolomes were analyzed with the method of LC-MS. Result: According to our investigation, 70 (57.85%) MPA patients and 56 (46.28%) MPASD patients were identified among 121 volunteers. The symptoms of the 6 MPASD subjects were significantly alleviated after acupuncture intervention. The number of rhythmic saliva metabolites dropped sharply in MPASD subjects and restored after acupuncture. Representative rhythmic saliva metabolites including melatonin, 2'-deoxyuridine, thymidine, thymidine 3',5'-cyclic monophosphate lost rhythm and restored after acupuncture, which may attribute to promising MPASD treatment and diagnosis biomarkers. The rhythmic saliva metabolites of healthy controls were mainly enriched in neuroactive ligand-receptor interaction, whereas polyketide sugar unit biosynthesis was mainly enriched in MPASD patients. Conclusion: This study revealed circadian rhythm characteristics of salivary metabolites in MPASD and that acupuncture could ameliorate MPASD by restoring part of the dysrhythmia salivary metabolites.

Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment.

Ischemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI). The role of N6-methyladenosine (m6A) modification in AKI remains unclear. Here, we characterize the role of AlkB homolog 5 (ALKBH5) and m6A modification in an I/R-induced renal injury model in male mice. Alkbh5-knockout mice exhibit milder pathological damage and better renal function than wild-type mice post-IRI, whereas Alkbh5-knockin mice show contrary results. Also conditional knockout of Alkbh5 in the tubular epithelial cells alleviates I/R-induced AKI and fibrosis. CCL28 is identified as a target of ALKBH5. Furthermore, Ccl28 mRNA stability increases with Alkbh5 deficiency, mediating by the binding of insulin-like growth factor 2 binding protein 2. Treg recruitment is upregulated and inflammatory cells are inhibited by the increased CCL28 level in IRI-Alkbh5fl/flKspCre mice. The ALKBH5 inhibitor IOX1 exhibits protective effects against I/R-induced AKI. In summary, inhibition of ALKBH5 promotes the m6A modifications of Ccl28 mRNA, enhancing its stability, and regulating the Treg/inflammatory cell axis. ALKBH5 and this axis is a potential AKI treatment target.

Minimally Invasive Direct Coronary Artery Bypass Versus Percutaneous Coronary Intervention for Isolated Left Anterior Descending Artery Stenosis: An Updated Meta-Analysis.

BACKGROUND: The optimal revascularization strategy for isolated left anterior descending (LAD) coronary artery lesion between minimally invasive direct coronary artery bypass (MIDCAB) and percutaneous coronary intervention (PCI) remains controversial. This updated meta-analysis aims to compare the long- and short-term outcomes of MIDCAB versus PCI for patients with isolated LAD coronary artery lesions. METHODS: The Pubmed, Web of Science, and Cochrane databases were searched for retrieving potential publications from 2002 to 2022. The primary outcome was long-term survival. Secondary outcomes were long-term target vessel revascularization (TVR), long-term major adverse cardiovascular events (MACEs), and short-term outcomes, including postoperative mortality, myocardial infarction (MI), TVR, and MACEs of any cause in-hospital or 30 days after the revascularization. RESULTS: Six randomized controlled trials (RCTs) and eight observational studies were included in this updated meta-analysis. In total, 1757 patients underwent MIDCAB and 15245 patients underwent PCI. No statistically significant difference was found between the two groups in the rates of long-term survival. MIDCAB had a lower long-term MACE rate compared with PCI. Besides, PCI resulted in an augmented risk of TVR. Postoperative mortality, MI, TVR, and MACEs were similar between the two groups. CONCLUSIONS: The updated meta-analysis presents the evidence that MIDCAB has a reduced risk of long-term TVR and MACEs, with no benefit in terms of long-term mortality and short-term results, in comparison with PCI. Large multicenter RCTs, including patients treated with newer techniques, are warranted in the future.

Effect of STK3 on proliferation and apoptosis of pancreatic cancer cells via PI3K/AKT/mTOR pathway.

Pancreatic cancer, as a malignant tumor with a very poor prognosis, has a high mortality. It is imperative to clarify the mechanism of pancreatic cancer development and find suitable targets for diagnosis and treatment. Serine/threonine kinase 3 (STK3) is one of the core kinases of the Hippo pathway and has the ability to inhibit tumor growth. But the biological function of STK3 in pancreatic cancer remains unknown. Here, we confirmed that STK3 has an impact on the growth, apoptosis, and metastasis of pancreatic cancer cells and investigated the related molecular mechanisms. In our research, we found that STK3 is reduced in pancreatic cancer by RT-qPCR, IHC and IF, its expression level is correlated with the clinicopathological features. CCK-8 assay, colony formation assay and flow cytometry were used to detect the effect of STK3 on the proliferation and apoptosis of pancreatic cancer cells. In addition, the Transwell assay was used to detect the ability of cell migration and invasion. The results showed that STK3 promoted apoptosis and inhibited cell migration, invasion and proliferation in pancreatic cancer. Gene set enrichment analysis (GSEA) and western blotting are used to predict and verify the pathways related to STK3. Subsequently, we found that the effect of STK3 on proliferation and apoptosis is closely related to the PI3K/AKT/mTOR pathway. Moreover, the assistance of RASSF1 plays a significant role in the regulation of PI3K/AKT/mTOR pathway by STK3. The nude mouse xenograft experiment demonstrated the tumor suppressive ability of STK3 in vivo. Collectively, this study found that STK3 regulates pancreatic cancer cell proliferation and apoptosis by suppressing the PI3K/AKT/mTOR pathway with the assistance of RASSF1.

Cost-effectiveness analysis of ceftazidime-avibactam as definitive treatment for treatment of carbapenem-resistant Klebsiella pneumoniae bloodstream infection.

Background: Ceftazidime-avibactam (CAZ-AVI) is a novel antibiotic that has been confirmed in the United States and China for use in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infection (BSI). However, the cost-effectiveness of CAZ-AVI is unknown in China. This study aimed to evaluate the cost-effectiveness of CAZ-AVI compared to polymyxin B (PMB) monotherapy or PMB-based therapy for the treatment of CRKP BSI from the Chinese healthcare perspective. Methods: A hybrid decision tree and Markov model were constructed for a hypothetical cohort of patients with CRKP BSI. The time horizon of the Markov model was 5 years with an annual discount rate of 5% used in both costs and quality-adjusted life-years (QALYs). The model data was derived from published literature and publicly available database. Regimens with an incremental cost-effectiveness ratio (ICER) lower than the willingness-to-pay (WTP) threshold of $ 11,600 per QALY were considered cost-effective. Deterministic and probabilistic sensitivity analyses were performed to examine the robustness of model analysis. Results: In the base-analysis, CAZ-AVI provided an additional 60 QALYs and reduced the cost by $ 2,218,300, yielding an ICER of $ -36,730.9/QALY, well below the WTP threshold of $ 11,600 per QALY when compared with PMB-based therapy. CAZ-AVI provided an additional 350 QALYs and increased the cost of $ 208,400, producing an ICER of $ 591.7/QALY that was below the WTP threshold compared to PMB monotherapy. At a $ 11,600/QALY threshold, results were sensitive to the cost of PMB-based strategy, the cost of CAZ-AVI strategy, the probability of cure with CAZ-AVI, and the probability of cure with PMB or PMB-based therapy. CAZ-AVI was an optimal regimen in 76.9% and 80.8% of 10,000 Monte Carlo simulations at $ 11,600/QALY and $ 34,800/QALY, respectively. Meanwhile, CAZ-AVI was cost-effective at the WTP thresholds of all 31 Chinese provinces in 61.4% (Gansu) to 83.1% (Beijing) of simulations. Conclusions: Ceftazidime-avibactam is expected to be a cost-effective treatment compared with PMB monotherapy or PMB-based therapy for CRKP BSI from the Chinese healthcare perspective.

Diagnostic aid to subepidermal calcified nodule with dermoscopy and reflectance confocal microscopy: a case report.

BACKGROUND: Subepidermal calcified nodule (SCN) is a type of calcinosis cutis that usually occurs in children. The lesions in the SCN resemble those of other skin diseases, such as pilomatrixoma, molluscum contagiosum, and juvenile xanthogranuloma, leading to a high rate of misdiagnoses. Noninvasive in vivo imaging techniques, represented by dermoscopy and reflectance confocal microscopy (RCM), have dramatically accelerated skin cancer research over the past decade, and their applications have greatly expanded into other skin disorders. However, the features of an SCN in dermoscopy and RCM have yet to be reported previously. Combining these novel approaches with conventional histopathological examinations is a promising method for increasing diagnostic accuracy. CASE PRESENTATION: We report on a case of SCN of the eyelid diagnosed with the aid of dermoscopy and RCM. A 14-year-old male patient who presented with a painless yellowish-white papule on his left upper eyelid was previously diagnosed with a common wart. Unfortunately, treatment with recombinant human interferon gel was not effective. To achieve a correct diagnosis, dermoscopy and RCM were performed. The former showed closely grouped multiple yellowish-white clods surrounded by linear vessels, and the latter exhibited hyperrefractile material nests at the dermal-epidermal junction level. The alternative diagnoses were, therefore, excluded because of in vivo characterizations. Subsequent surgical excision, histological examination, and von Kossa staining were performed. Pathology showed hyperkeratosis of the epidermis, a downward-directed basal-layer expansion, and small amorphous basophilic deposits scattered throughout the papillary dermis. The von Kossa staining confirmed calcium deposits in the lesion. An SCN was then diagnosed. During the 6-month follow-up, no relapse was observed. CONCLUSIONS: Patients with SCN could benefit from dermoscopy and RCM, which help achieve an accurate diagnosis. Clinicians should consider the possibility of an SCN for an adolescent patient with painless yellowish-white papules.

Transcranial direct current stimulation combined with bodyweight support-tai chi footwork for motor function of stroke survivors: a study protocol of randomised controlled trial.

INTRODUCTION: Our previous studies have proposed the bodyweight support-t'ai chi (BWS-TC) footwork training for stroke survivors with severe motor dysfunction and fear of falling, and have proven its positive effects for motor function. Transcranial direct current stimulation (tDCS) provides a non-invasive and safe way to modulate neuronal activity and provoke neuroplastic changes and to improve the motor function of stroke survivors. However, it is unclear whether the integration of BWS-TC and tDCS has synergistic effects on improving motor function of the stroke survivors. METHODS AND ANALYSIS: This study will be an assessor-blinded randomised controlled trial involving 12-week intervention and 6-month follow-up. One hundred and thirty-five individuals with stroke will be randomly divided in a ratio of 1:1:1 into three groups. Control group A, control group B and intervention group C will receive tDCS and conventional rehabilitation programmes (CRPs), BWS-TC and CRP, tDCS-BWS-TC and CRP for 12 weeks, respectively. The primary outcome measures will include the efficacy (Fugl-Meyer Assessment), acceptability and safety of these interventions. The secondary outcome measures will include balance ability (ie, limits of stability and modified clinical test of sensory integration), walking function, brain structure and function, risk of falling, Barthel Index and 36-Item Short Form Survey. All outcomes will be assessed at baseline, 6 and 12 weeks during intervention, and 1, 3 and 6 months during the follow-up period. Two-way analysis of variance with repeated measures will be applied to examine the main effects of the group and the time factor and group-time interaction effects for all outcome measures. ETHICS AND DISSEMINATION: Ethics approval was obtained from the ethics committee of the Shanghai Seventh People's Hospital (2021-7th-HIRB-017). The results of the study will be published in a peer-reviewed journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2200059329.

Long non-coding RNA SNHG11 regulates the Wnt/ß-catenin signaling pathway through rho/ROCK in trabecular meshwork cells.

Trabecular meshwork (TM) cell dysfunction is the leading cause of elevated intraocular pressure (IOP) and glaucoma. The long non-coding RNA (lncRNA) small nucleolar RNA host gene 11 (SNHG11) is associated with cell proliferation and apoptosis, but its biological functions and role in glaucoma pathogenesis remain unclear. In the present study, we investigated the role of SNHG11 in TM cells using immortalized human TM and glaucomatous human TM (GTM3 ) cells and an acute ocular hypertension mouse model. SNHG11 expression was depleted using siRNA targeting SNHG11. Transwell assays, quantitative real-time PCR analysis (qRT-PCR), western blotting, and CCK-8 assay were used to evaluate cell migration, apoptosis, autophagy, and proliferation. Wnt/ß-catenin pathway activity was inferred from qRT-PCR, western blotting, immunofluorescence, and luciferase reporter and TOPFlash reporter assays. The expression of Rho kinases (ROCKs) was detected using qRT-PCR and western blotting. SNHG11 was downregulated in GTM3 cells and mice with acute ocular hypertension. In TM cells, SNHG11 knockdown inhibited cell proliferation and migration, activated autophagy, and apoptosis, repressing the Wnt/ß-catenin signaling pathway, and activated Rho/ROCK. Wnt/ß-catenin signaling pathway activity increased in TM cells treated with ROCK inhibitor. SNHG11 regulated Wnt/ß-catenin signaling through Rho/ROCK by increasing GSK-3ß expression and ß-catenin phosphorylation at Ser33/37/Thr41 while decreasing ß-catenin phosphorylation at Ser675. We demonstrate that the lncRNA SNHG11 regulates Wnt/ß-catenin signaling through Rho/ROCK via ß-catenin phosphorylation at Ser675 or GSK-3ß-mediated phosphorylation at Ser33/37/Thr41, affecting cell proliferation, migration, apoptosis, and autophagy. Through its effects on Wnt/ß-catenin signaling, SNHG11 is implicated in glaucoma pathogenesis and is a potential therapeutic target.