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Abstract The small Extracellular vesicles (sEV) has been recognized to be significant for intercellular communication due to their ability to transfer important cellular cargoes like miRNAs through circulation. The pituitary gland has not been clearly known about the role of its secreted sEV under normal physiological conditions. And Liver disease is a global public health burden. The present study is the first to investigate the effect of pituitary sEV on the liver. Sequencing and qRT-PCR revealed miR-143-3p is one of the richest in the pituitary sEV. MiR-143 Knockout (KO) mice resulted in a remarkable decrease in insulin-like growth factor 1 (IGF-1) levels and a significant increase in insulin-like growth factor binding protein 5 (IGFBP5) levels along with a reduction in liver primary cell growth. More importantly, compared with miR-143-KO-sEV, WT-sEV possesses a more robust capacity to improve miR-143 KO mice liver repair through the Wnt/β-catenin pathway after an acute injury caused by carbon tetrachloride (CCl4). Our results indicate that pituitary-derived sEV promotes hepatocyte proliferation and liver repair by its cargo miR-143-3p and provides new insight into the regulation mechanism of the pituitary-liver axis, and open a new window for endocrine regulation by using sEV.

Abstract: The prediction skill for precipitation anomalies in late spring and summer months—a significant component of extreme climate events—has remained stubbornly low for years. This paper presents a new idea that utilizes information on boreal spring land surface temperature/subsurface temperature (LST/SUBT) anomalies over the Tibetan Plateau (TP) to improve prediction of subsequent summer droughts/floods over several regions over the world, East Asia and North America in particular. The work was performed in the framework of the GEWEX/LS4P Phase I (LS4P-I) experiment, which focused on whether the TP LST/SUBT provides an additional source for subseasonal-to-seasonal (S2S) predictability. The summer 2003, when there were severe drought/flood over the southern/northern part of the Yangtze River basin, respectively, has been selected as the focus case. With the newly developed LST/SUBT initialization method, the observed surface temperature anomaly over the TP has been partially produced by the LS4P-I model ensemble mean, and 8 hotspot regions in the world were identified where June precipitation is significantly associated with anomalies of May TP land temperature. Consideration of the TP LST/SUBT effect has produced about 25–50% of observed precipitation anomalies in most hotspot regions. The multiple models have shown more consistency in the hotspot regions along the Tibetan Plateau-Rocky Mountain Circumglobal (TRC) wave train. The mechanisms for the LST/SUBT effect on the 2003 drought over the southern part of the Yangtze River Basin are discussed. For comparison, the global SST effect has also been tested and 6 regions with significant SST effects were identified in the 2003 case, explaining about 25–50% of precipitation anomalies over most of these regions. This study suggests that the TP LST/SUBT effect is a first-order source of S2S precipitation predictability, and hence it is comparable to that of the SST effect. With the completion of the LS4P-I, the LS4P-II has been launched and the LS4P-II protocol is briefly presented.

BackgroundSurgical patients often experience intraoperative hypothermia or hyperthermia. However, the relationship of intraoperative hypothermia and hyperthermia with postoperative pulmonary infection (PPI) and surgical site infection (SSI) is unclear. Here, we conducted a retrospective cohort study to address these issues.MethodsAdult patients who underwent major non-cardiac surgery under general anesthesia were eligible for the study and were recruited. Three indices of core body temperature under hypothermia (37.3°C) were calculated as mentioned in the following: absolute value (0C), duration of exposure (min), and area under the curve (AUC,°C× min). The outcomes were in-hospital PPI and SSI. The risk-adjusted association of intraoperative hypothermia and hyperthermia with PPI and SSI was determined.ResultsThe absolute value (the nadir value of hypothermia and the peak value of hyperthermia) was not associated with PPI and SSI. PPI was associated with (1) duration: hypothermia >90 min [adjusted odds ratio (aOR): 1.425, 95% confidence interval (CI): 1.131–1.796] and hyperthermia >75 min (aOR: 1.395, 95%CI: 1.208–1.612) and (2) AUC: hypothermia >3,198 (aOR: 1.390, 95%CI: 1.128–1.731) and hyperthermia >7,945 (aOR: 2.045, 95%CI: 1.138–3.676). SSI was associated with (1) duration: hypothermia > 195 min (aOR: 2.900, 95%CI: 1.703–4.937) and hyperthermia >75 min (aOR: 1.395, 95%CI: 1.208–1.612) and (2) AUC: hypothermia >6,946 (aOR: 2.665, 95%CI: 1.618–4.390), hyperthermia >7,945 (aOR: 2.619, 95%CI: 1.625–4.220). Interactions were not observed between hyperthermia and hypothermia on the outcomes.ConclusionsIt was observed that intraoperative hypothermia and hyperthermia are associated with postoperative pulmonary infection and surgical site infection in major non-cardiac surgery.

Background: Chronic fatigue is a predominant symptom of post COVID-19 condition, or long COVID. We aimed to evaluate the efficacy and safety of Traditional, Complementary and Integrative Medicine (TCIM) for fatigue post COVID-19 infection. Methods: Ten English and Chinese language databases and grey literature were searched up to 12 April 2023 for randomized controlled trials (RCTs). Cochrane “Risk of bias” (RoB) tool was applied. Evidence certainty was assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Effect estimates were presented as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI). Results: Thirteen RCTs with 1632 participants were included. One RCT showed that Bufei Huoxue herbal capsules reduced fatigue (n=129, MD -14.90, 95%CI -24.53 to -5.27), one RCT reported that Ludangshen herbal liquid lowered fatigue (n=184, MD -1.90, 95%CI -2.38 to -1.42), and the other one RCT shown that fatigue disappearance rate was higher with Ludangshen herbal liquid (n=184, RR 4.19, 95%CI 2.06 to 8.53). Compared to traditional Chinese medicine rehabilitation (TCM-rahab) alone, one RCT showed that fatigue symptoms were lower following Qingjin Yiqi granules plus TCM-rehab (n=388, MD -0.48, 95%CI -0.50 to -0.46). Due to concerns with RoB and/or imprecision, the certainty in this evidence was low to very low. No serious adverse events was reported. Conclusions: Limited evidence suggests that various TCIM interventions might reduce post COVID-19 fatigue. Larger, high quality RCTs of longer duration are required to confirm these preliminary findings. Study Registration: The protocol of this review has been registered at PROSPERO: CRD42022384136.

Subseasonal-to-seasonal (S2S) precipitation prediction in boreal spring and summer months, which contains a significant number of high-signal events, is scientifically challenging and prediction skill has remained poor for years. Tibetan Plateau (TP) spring observed surface temperatures show a lag correlation with summer precipitation in several remote regions, but current global land-atmosphere coupled models are unable to represent this behavior due to significant errors in producing observed TP surface temperatures. To address these issues, the Global Energy and Water Exchanges (GEWEX) program launched the "Impact of Initialized Land Temperature and Snowpack on Subseasonal-to-Seasonal Prediction"(LS4P) initiative as a community effort to test the impact of land temperature in high-mountain regions on S2S prediction by climate models: more than 40 institutions worldwide are participating in this project. After using an innovative new land state initialization approach based on observed surface 2-m temperature over the TP in the LS4P experiment, results from a multimodel ensemble provide evidence for a causal relationship in the observed association between the Plateau spring land temperature and summer precipitation over several regions across the world through teleconnections. The influence is underscored by an out-of-phase oscillation between the TP and Rocky Mountain surface temperatures. This study reveals for the first time that high-mountain land temperature could be a substantial source of S2S precipitation predictability, and its effect is probably as large as ocean surface temperature over global "hotspot"regions identified here; the ensemble means in some "hotspots"produce more than 40% of the observed anomalies. This LS4P approach should stimulate more follow-on explorations.

Abstract Background The overall comprehensive consideration of the factors influencing the recommendations in the traditional Chinese medicine (TCM) guidelines remains poorly studied. This study systematically evaluate the factors influencing recommendations formation in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) clinical practice guidelines (CPGs) and TCM CPGs. Methods This was a methodological review in which we searched six databases and multiple related websites. The GRADE CPGs were identified as the guidelines developed by the GRADE Working Group or the two Co-Chairs. For the TCM CPGs, we randomly selected guidelines that were published by the TCM or integrative medicine academic societies from China mainland (published by the TCM or integrative medicine academic societies of China mainland). Two reviewers independently screened and extracted data. We included CPGs published in 2018–2022. We extracted information on the influencing factors of evidence to recommendation and conducted the analyses using descriptive statistics and calculated the proportion of relevant items by IBM SPSS Statistics and Microsoft Excel to compare the differences between the GRADE CPGs and the TCM CPGs. Results Forty-five GRADE CPGs (including 912 recommendations) and 88 TCM CPGs (including 2452 recommendations) were included. TCM recommendations mainly considered the four key determinants of desirable anticipated effects, undesirable anticipated effects, balance between desirable and undesirable effects, certainty of evidence, with less than 20% of other dimensions. And TCM CPGs presented more strong recommendations (for or against) and inappropriate discordant recommendations than GRADE CPGs. GRADE CPGs were more comprehensive considered about the factors affecting the recommendations, and considered more than 70% of all factors in the evidence to recommendation. Conclusions The TCM CPGs lack a comprehensive consideration of multiple influencing determinants from evidence to recommendations. In the future, the correct application of the GRADE approaches should be emphasized.

Due to the low oxidation potential and high electrochemiluminescence (ECL) quantum yield, Luminol has been widely applied in analytical and detection fields, especially in immunoassay, food safety and environmental monitoring. However, there is a lack of sufficient experimental evidence on the ECL mechanism of Luminol, which affects the further improvement of its ECL efficiency. Herein, an electrochemistry-micro tube-mass spectrometry (EC-MT-MS) device was constructed for on-line monitoring of Luminol ECL reaction. In this EC-MT-MS device, a high borosilicate glass tube with a nano tip was used as electrochemical cell and electrospray ionization source, a platinum working electrode and a platinum counter electrode were inserted into the tube and connected to a customized power station, which could simultaneously input a low voltage (volt level) for the ECL reaction and a high voltage (kilovolt level) for the formation of electrospray. Prior to the EC-MT-MS experiment, the composition of the reaction solution was optimized to obtain the highest MS signal response, and Luminol was dissolved in acetonitrile-water (4:1, V/V) solvent with ammonium acetate as the electrolyte. The concentrations of Luminol and ammonium acetate in the prepared solution were both 0.1 mmol/L, and the pH was adjusted to 11 using ammonium aqueous. The oxidation potential of Luminol was subsequently studied using a traditional three-electrode system by cyclic voltammetry in the same solution, and the determined oxidation potential for ECL reaction was 0.87 V. During the EC-MT-MS measurements, (2.5 kV+0.87 V) and 2.5 kV were input to the working and counter through the power station, respectively. A series of short-lived intermediates and products such as L1 (m/z 198) and the luminescent precursor AP- (m/z 180) in the Luminol ECL reaction process were successfully captured and analyzed by MS. The molecular structures of these products were characterized by tandem mass spectrometry (MSn) technique. There are mainly two fragments of m/z 163, 136 present in the MS2 spectrum of luminescent precursor AP-, attributed to the (NH2+H) and COO losses, respectively. In addition, the promotion mechanism of hydrogen peroxide (H2O2) for the ECL performance of Luminol was also investigated. A key reaction intermediate LO2H- was found in the MS spectrum at m/z 208. Meanwhile, the peak intensity of luminescent precursor AP- significantly increased from 1.3% to 15.7%, proving that the presence of H2O2 effectively promoted the generation of key luminescent intermediate. Finally, by adding 1,4-benzoquinone to the Luminol-H2O2 system, the central role of the superoxide anion radical (O2·-) derived from H2O2 in the Luminol ECL process was confirmed. The relevant results provide a direct data reference for the study of the Luminol ECL mechanism.

Rare cases of human herpesvirus 8 (HHV8)-negative effusion-based large B-cell lymphoma (EB-LBCL) occur in body cavities without antecedent or concurrent solid mass formation. In contrast to HHV8 + primary effusion lymphoma (PEL), EB-LBCL has no known association with HIV or HHV8 infection. However, the small sample sizes of case reports and series worldwide, especially from non-Japanese regions, have precluded diagnostic uniformity. Therefore, we conducted a retrospective, multi-institutional study of 55 cases of EB-LBCL and performed a comprehensive review of an additional 147 cases from the literature to identify distinct clinicopathologic characteristics. In our study, EB-LBCL primarily affected elderly (median age 80 years), immunocompetent patients and manifested as lymphomatous effusion without a solid component. The lymphomatous effusions mostly occurred in the pleural cavity (40/55, 73%), followed by the pericardial cavity (17/55, 31%). EB-LBCL expressed CD20 (53/54, 98%) and PAX5 (23/23, 100%). Most cases (30/36, 83%) were of non-germinal center B-cell subtype per the Hans algorithm. HHV8 infection was absent (0/55, 0%), while Epstein-Barr virus was detected in 6% (3/47). Clinically, some patients were managed with drainage alone (15/34, 44%), while others received rituximab alone (4/34, 12%) or chemotherapy (15/34, 44%). Eventually, 56% (22/39) died with a median overall survival (OS) of 14.9 months. Our findings were similar to those from the literature; however, compared to the non-Japanese cases, the Japanese cases had a significantly higher incidence of pericardial involvement, a higher rate of chemotherapy administration, and longer median OS. Particularly, we have found that Japanese residence, presence of pericardial effusion, and absence of MYC rearrangement are all favorable prognostic factors. Our data suggest that EB-LBCL portends a worse prognosis than previously reported, although select patients may be managed conservatively. Overall, EB-LBCL has distinct clinicopathologic characteristics, necessitating the establishment of separate diagnostic criteria and consensus nomenclature.

Snake venoms, comprising a complex array of protein-rich components, an important part of which are snake venom metalloproteinases (SVMPs). These SVMPs, which are predominantly isolated from viperid venoms, are integral to the pathology of snakebites. However, SVMPs derived from elapid venoms have not been extensively explored, and only a handful of SVMPs have been characterized to date. Atrase A, a nonhemorrhagic P-III class metalloproteinase from Naja atra venom, exhibits weak proteolytic activity against fibrinogen in vitro but has pronounced anticoagulant effects in vivo. This contrast spurred investigations into its anticoagulant mechanisms. Research findings indicate that atrase A notably extends the activated partial thromboplastin time, diminishes fibrinogen levels, and impedes platelet aggregation. The anticoagulant action of atrase A primarily involves inhibiting coagulation factor VIII and activating the endogenous fibrinolytic system, which in turn lowers fibrinogen levels. Additionally, its effect on platelet aggregation further contributes to its anticoagulant profile. This study unveils a novel anticoagulant mechanism of atrase A, significantly enriching the understanding of the roles of cobra venom metalloproteinases in snake venom. Furthermore, these findings underscore the potential of atrase A as a novel anticoagulant drug, offering insights into the functional evolutions of cobra venom metalloproteinases.

Introduction Traditional Chinese medicine (TCM) may have special advantages in facilitating smoking cessation, but consensus on effectiveness is lacking. We aim to comprehensively review, update, and refine current evidence on TCM effectiveness and safety. Methods Nine databases were searched from their inception up to 28 February 2023. Systematic reviews (SRs) and meta-analysis of TCM for smoking cessation were identified and retrieved. Additional databases and hand searches of RCTs from included SRs were performed for data pooling. Cochrane ROB tools and AMSTAR-2 were used to evaluate the methodological quality of RCTs and SRs, respectively. RCT data are presented as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CI) using RevMan 5.4. Results Thirteen SRs involving 265 studies with 33081 participants were included. Among these 265 studies, 157 were duplicates (58.36%) and 52 were non-RCTs (19.62%). Combined with the remaining 56 RCTs identified through hand searches, 88 RCTs involving 12434 participants were finally included for data synthesis. All the SRs focused on acupoint stimulation, and the majority were of low or very low quality. The methodological quality of RCTs was either unclear or high risk. For continuous abstinence rate, TCM external interventions were better than placebo in 6 months to 1 year (RR=1.60; 95% CI: 1.14–2.25; I2=27%; n=5533 participants). Compared with placebo, TCM external application was effective in reducing nicotine withdrawal symptoms, and the effect was gradually stable and obvious in the fourth week (MD= -4.46; 95% CI: -5.43 – -3.49; n=165 participants). Twelve RCTs reported adverse events as outcome indicators for safety evaluation, and no serious adverse events occurred. Conclusions Despite the methodological limitations of the original studies, our review suggests that TCM intervention shows potential effectiveness on the continuous abstinence rate. Extending the intervention time can enhance the effect of TCM on nicotine withdrawal symptoms. Referred to adverse events, more data for safety evaluation are required.