The MdNAC72-MdABI5 module acts as an interface integrating jasmonic acid and gibberellin signals and undergoes ubiquitination-dependent degradation regulated by MdSINA2 in apple.

Jasmonic acid (JA) and gibberellin (GA) coordinately regulate plant developmental programs and environmental cue responses. However, the fine regulatory network of the cross-interaction between JA and GA remains largely elusive. In this study, we demonstrate that MdNAC72 together with MdABI5 positively regulates anthocyanin biosynthesis through an exquisite MdNAC72-MdABI5-MdbHLH3 transcriptional cascade in apple. MdNAC72 interacts with MdABI5 to promote the transcriptional activation of MdABI5 on its target gene MdbHLH3 and directly activates the transcription of MdABI5. The MdNAC72-MdABI5 module regulates the integration of JA and GA signals in anthocyanin biosynthesis by combining with JA repressor MdJAZ2 and GA repressor MdRGL2a. MdJAZ2 disrupts the MdNAC72-MdABI5 interaction and attenuates the transcriptional activation of MdABI5 by MdNAC72. MdRGL2a sequesters MdJAZ2 from the MdJAZ2-MdNAC72 protein complex, leading to the release of MdNAC72. The E3 ubiquitin ligase MdSINA2 is responsive to JA and GA signals and promotes ubiquitination-dependent degradation of MdNAC72. The MdNAC72-MdABI5 interface fine-regulates the integration of JA and GA signals at the transcriptional and posttranslational levels by combining MdJAZ2, MdRGL2a, and MdSINA2. In summary, our findings elucidate the fine regulatory network connecting JA and GA signals with MdNAC72-MdABI5 as the core in apple.

Apple SINA E3 ligase MdSINA3 negatively mediates JA-triggered leaf senescence by ubiquitinating and degrading the MdBBX37 protein.

Jasmonic acid (JA) induces chlorophyll degradation and leaf senescence. B-box (BBX) proteins play important roles in the modulation of leaf senescence, but the molecular mechanism of BBX protein-mediated leaf senescence remains to be further studied. Here, we identified the BBX protein MdBBX37 as a positive regulator of JA-induced leaf senescence in Malus domestica (apple). Further studies showed that MdBBX37 interacted with the senescence regulatory protein MdbHLH93 to enhance its transcriptional activation on the senescence-associated gene MdSAG18, thereby promoting leaf senescence. Moreover, the JA signaling repressor MdJAZ2 interacted with MdBBX37 and interfered with the interaction between MdBBX37 and MdbHLH93, thereby negatively mediating MdBBX37-promoted leaf senescence. In addition, the E3 ubiquitin ligase MdSINA3 delayed MdBBX37-promoted leaf senescence through targeting MdBBX37 for degradation. The MdJAZ2-MdBBX37-MdbHLH93-MdSAG18 and MdSINA3-MdBBX37 modules realized the precise modulation of JA on leaf senescence. In parallel, our data demonstrate that MdBBX37 was involved in abscisic acid (ABA)- and ethylene-mediated leaf senescence through interacting with the ABA signaling regulatory protein MdABI5 and ethylene signaling regulatory protein MdEIL1, respectively. Taken together, our results not only reveal the role of MdBBX37 as an integration node in JA-, ABA- and ethylene-mediated leaf senescence, but also provide new insights into the post-translational modification of BBX proteins.

The E3 ubiquitin ligases SINA1 and SINA2 integrate with the protein kinase CIPK20 to regulate the stability of RGL2a, a positive regulator of anthocyanin biosynthesis.

Although DELLA protein destabilization mediated by post-translational modifications is essential for gibberellin (GA) signal transduction and GA-regulated anthocyanin biosynthesis, the related mechanisms remain largely unknown. In this study, we report the ubiquitination and phosphorylation of an apple DELLA protein MdRGL2a in response to GA signaling and its regulatory role in anthocyanin biosynthesis. MdRGL2a could interact with MdWRKY75 to enhance the MdWRKY75-activated transcription of anthocyanin activator MdMYB1 and interfere with the interaction between anthocyanin repressor MdMYB308 and MdbHLH3 or MdbHLH33, thereby promoting anthocyanin accumulation. A protein kinase MdCIPK20 was found to phosphorylate and protect MdRGL2a from degradation, and it was essential for MdRGL2a-promoting anthocyanin accumulation. However, MdRGL2a and MdCIPK20 were ubiquitinated and degraded by E3 ubiquitin ligases MdSINA1 and MdSINA2, respectively, both of which were activated in the presence of GA. Our results display the integration of SINA1/2 with CIPK20 to dynamically regulate GA signaling and will be helpful toward understanding the mechanism of GA signal transduction and GA-inhibited anthocyanin biosynthesis. The discovery of extensive interactions between DELLA and SINA and CIPK proteins in apple will provide reference for the study of ubiquitination and phosphorylation of DELLA proteins in other species.

The BTB protein MdBT2 recruits auxin signaling components to regulate adventitious root formation in apple.

Ubiquitination is an important post-translational protein modification. Although BROAD-COMPLEX, TRAMTRACK AND BRIC A BRAC and TRANSCRIPTION ADAPTOR PUTATIVE ZINC FINGER domain protein 2 (BT2) is involved in many biological processes, its role in apple (Malus domestic) root formation remains unclear. Here, we revealed that MdBT2 inhibits adventitious root (AR) formation through interacting with AUXIN RESPONSE FACTOR8 (MdARF8) and INDOLE-3-ACETIC ACID INDUCIBLE3 (MdIAA3). MdBT2 facilitated MdARF8 ubiquitination and degradation through the 26S proteasome pathway and negatively regulated GRETCHEN HAGEN 3.1 (MdGH3.1) and MdGH3.6 expression. MdARF8 regulates AR formation through inducing transcription of MdGH3s (MdGH3.1, MdGH3.2, MdGH3.5, and MdGH3.6). In addition, MdBT2 facilitated MdIAA3 stability and slightly promoted its interaction with MdARF8. MdIAA3 inhibited AR formation by forming heterodimers with MdARF8 as well as other MdARFs (MdARF5, MdARF6, MdARF7, and MdARF19). Our findings reveal that MdBT2 acts as a negative regulator of AR formation in apple.

E3 ubiquitin ligases SINA4 and SINA11 regulate anthocyanin biosynthesis by targeting the IAA29-ARF5-1-ERF3 module in apple.

Auxin/indole-3-acetic acid (AUX/IAA) and auxin response factor (ARF) proteins are important components of the auxin signalling pathway, but their ubiquitination modification and the mechanism of auxin-mediated anthocyanin biosynthesis remain elusive. Here, the ARF MdARF5-1 was identified as a negative regulator of anthocyanin biosynthesis in apple, and it integrates auxin and ethylene signals by inhibiting the expression of the ethylene response factor MdERF3. The auxin repressor MdIAA29 decreased the inhibitory effect of MdARF5-1 on anthocyanin biosynthesis by attenuating the transcriptional inhibition of MdERF3 by MdARF5-1. In addition, the E3 ubiquitin ligases MdSINA4 and MdSINA11 played negative and positive regulatory roles in anthocyanin biosynthesis by targeting MdIAA29 and MdARF5-1 for ubiquitination degradation, respectively. MdSINA4 destabilized MdSINA11 to regulate anthocyanin accumulation in response to auxin signalling. In sum, our data revealed the crosstalk between auxin and ethylene signals mediated by the IAA29-ARF5-1-ERF3 module and provide new insights into the ubiquitination modification of the auxin signalling pathway.

Synchronized and proportional sub-diaphragmatic unloading in an animal model of respiratory distress.

BACKGROUND: A sealed abdominal interface was positioned below the diaphragm (the "NeoVest") to apply synchronized and proportional negative pressure ventilation (NPV) and was compared to positive pressure ventilation (PPV) using neurally adjusted ventilatory assist (NAVA). Both modes were controlled by the diaphragm electrical activity (Edi). METHODS: Eleven rabbits (mean weight 2.9 kg) were instrumented, tracheotomized, and ventilated with either NPV or PPV (sequentially) with different loads (resistive, dead space, acute lung injury). Assist with either PPV or NPV was titrated to reduce Edi by 50%. RESULTS: In order to achieve a 50% reduction in Edi, NPV required slightly more negative pressure (-8 to -12 cm H2O) than observed in PPV (+6 to +10 cm H2O). The efficiency of pressure transmission from the NeoVest into gastric pressure was 69.6% (range 61.3-77.4%). Swings in esophageal pressure were more negative during NPV than PPV, for all conditions, due to transmission of negative pressure. Transpulmonary pressure was lower during NPV. Transdiaphragmatic pressure swings were reduced similarly for PPV and NPV, suggesting equivalent unloading of the diaphragm. NPV did not affect hemodynamics. CONCLUSIONS: It is feasible to apply NPV sub-diaphragmatically in synchrony and in proportion to Edi in an animal model of respiratory distress. IMPACT: Negative pressure ventilation (NPV), for example, the "Iron Lung," may offer advantages over positive pressure ventilation. In the present work, we describe the "NeoVest," a system consisting of a sealed abdominal interface and a ventilator that applies NPV in synchrony and in proportion to the diaphragm electrical activity (Edi).

Functional characterization of MdERF113 in apple.

The AP2/ERF family is an important class of transcription factors involved in plant growth and various biological processes. One of the AP2/ERF transcription factors, RAP2.6L, participates in various stresses responses. However, the function of RAP2.6L is largely unknown in apples (Malus domestica). In this study, an apple gene homologous to Arabidopsis AtRAP2.6L, MdERF113, was analyzed by bioinformatic characterization, gene expression analysis and subcellular localization assessment. MdERF113 was highly expressed in the sarcocarp and was responsive to hormonal signals and abiotic stresses. MdERF113-overexpression apple calli were less sensitive to low temperature, drought, salinity, and abscisic acid than wild-type. Subcellular localization revealed that MdERF113 was a nuclear-localized transcription factor, and yeast experiments confirmed that MdERF113 has no autonomous activation activity. Overall, this study indicated that MdERF113 plays a role in regulating plant growth under abiotic conditions.

Click postsynthesis of microporous organic network@silica composites for reversed-phase/hydrophilic interaction mixed-mode chromatography.

Recently, the good physical and chemical properties, well-defined pore architectures, and designable topologies have made microporous organic networks (MONs) excellent potential candidates in high-performance liquid chromatography (HPLC). However, their superior hydrophobic structures restrict their application in the reversed-phase mode. To solve this obstacle and to expand the application of MONs in HPLC, we realized the thiol-yne "click" postsynthesis of a novel hydrophilic MON-2COOH@SiO2-MER (MER denotes mercaptosuccinic acid) microsphere for reversed-phase/hydrophilic interaction mixed-mode chromatography. SiO2 was initially decorated with MON-2COOH using 2,5-dibromoterephthalic acid and tetrakis(4-ethynylphenyl)methane as monomers, and MER was then grafted via thiol-yne click reaction to yield MON-2COOH@SiO2-MER microspheres (5 µm) with a pore size of ~1.3 nm. The -COOH groups in 2,5-dibromoterephthalic acid and the post-modified MER molecules considerably improved the hydrophilicity of pristine MON and enhanced the hydrophilic interactions between the stationary phase and analytes. The retention mechanisms of the MON-2COOH@SiO2-MER packed column were fully discussed with diverse hydrophobic and hydrophilic probes. Benefiting from the numerous -COOH recognition sites and benzene rings within MON-2COOH@SiO2-MER, the packed column exhibited good resolution for the separation of sulfonamides, deoxynucleosides, alkaloids, and endocrine-disrupting chemicals. A column efficiency of 27,556 plates per meter was obtained for the separation of gastrodin. The separation performance of the MON-2COOH@SiO2-MER packed column was also demonstrated by comparing with those of MON-2COOH@SiO2, commercial C18, ZIC-HILIC, and bare SiO2 columns. This work highlights the good potential of the thiol-yne click postsynthesis strategy to construct MON-based stationary phases for mixed-mode chromatography.

Estimation of transpulmonary driving pressure during synchronized mechanical ventilation using a single lower assist maneuver (LAM) in rabbits: a comparison to measurements made with an esophageal balloon.

BACKGROUND: Mechanical ventilation is applied to unload the respiratory muscles, but knowledge about transpulmonary driving pressure (ΔPL) is important to minimize lung injury. We propose a method to estimate ΔPL during neurally synchronized assisted ventilation, with a simple intervention of lowering the assist for one breath ("lower assist maneuver", LAM). METHODS: In 24 rabbits breathing spontaneously with imposed loads, titrations of increasing assist were performed, with two neurally synchronized modes: neurally adjusted ventilatory assist (NAVA) and neurally triggered pressure support (NPS). Two single LAM breaths (not sequentially, but independently) were performed at each level of assist by acutely setting the assist to zero cm H2O (NPS) or NAVA level 0 cm H2O/uV (NAVA) for one breath. NPS and NAVA titrations were followed by titrations in controlled-modes (volume control, VC and pressure control, PC), under neuro-muscular blockade. Breaths from the NAVA/NPS titrations were matched (for flow and volume) to VC or PC. Throughout all runs, we measured diaphragm electrical activity (Edi) and esophageal pressure (PES). We measured ΔPL during the spontaneous modes (PL_PES) and controlled mechanical ventilation (CMV) modes (PL_CMV) with the esophageal balloon. From the LAMs, we derived an estimation of ΔPL ("PL_LAM") using a correction factor (ratio of volume during the LAM and volume during assist) and compared it to measured ΔPL during passive (VC or PC) and spontaneous breathing (NAVA or NPS). A requirement for the LAM was similar Edi to the assisted breath. RESULTS: All animals successfully underwent titrations and LAMs for NPS/NAVA. One thousand seven-hundred ninety-two (1792) breaths were matched to passive ventilation titrations (matched Vt, r = 0.99). PL_LAM demonstrated strong correlation with PL_CMV (r = 0.83), and PL_PES (r = 0.77). Bland-Altman analysis revealed little difference between the predicted PL_LAM and measured PL_CMV (Bias = 0.49 cm H2O and 1.96SD = 3.09 cm H2O). For PL_PES, the bias was 2.2 cm H2O and 1.96SD was 3.4 cm H2O. Analysis of Edi and PES at peak Edi showed progressively increasing uncoupling with increasing assist. CONCLUSION: During synchronized mechanical ventilation, a LAM breath allows for estimations of transpulmonary driving pressure, without measuring PES, and follows a mathematical transfer function to describe respiratory muscle unloading during synchronized assist.

Virtual screening of novel mTOR inhibitors for the potential treatment of human colorectal cancer.

The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 µM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 µM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 µM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.

BioSeq-BLM: a platform for analyzing DNA, RNA and protein sequences based on biological language models.

In order to uncover the meanings of 'book of life', 155 different biological language models (BLMs) for DNA, RNA and protein sequence analysis are discussed in this study, which are able to extract the linguistic properties of 'book of life'. We also extend the BLMs into a system called BioSeq-BLM for automatically representing and analyzing the sequence data. Experimental results show that the predictors generated by BioSeq-BLM achieve comparable or even obviously better performance than the exiting state-of-the-art predictors published in literatures, indicating that BioSeq-BLM will provide new approaches for biological sequence analysis based on natural language processing technologies, and contribute to the development of this very important field. In order to help the readers to use BioSeq-BLM for their own experiments, the corresponding web server and stand-alone package are established and released, which can be freely accessed at http://bliulab.net/BioSeq-BLM/.

Two new compounds from Verbena bonariensis.

Two new compounds verboncin A (1) and verboncin B (4) and 14 known compounds (2-3 and 5-16) were isolated from Verbena bonariensis, and these 14 compounds were first obtained from this plant. Their chemical structures were established by one and two-dimensional NMR and HRESIMS analysis and the results were compared with literature values. The absolute configuration of 1 was determined by calculating electronic circular dichroism (ECD). The cytotoxicity of some of the compounds against MCF-7, HCT-116, MDA-MB-231, and SW620 human cancer cell lines were evaluated, in which compound 4 showed negligible cytotoxic activity with an IC50 value of 68.08 ± 0.35 µM against the MCF-7 cell line.

The E3 ubiquitin ligase SINA1 and the protein kinase BIN2 cooperatively regulate PHR1 in apple anthocyanin biosynthesis.

PHR1 (PHOSPHATE STARVATION RESPONSE1) plays key roles in the inorganic phosphate (Pi) starvation response and in Pi deficiency-induced anthocyanin biosynthesis in plants. However, the post-translational regulation of PHR1 is unclear, and the molecular basis of PHR1-mediated anthocyanin biosynthesis remains elusive. In this study, we determined that MdPHR1 was essential for Pi deficiency-induced anthocyanin accumulation in apple (Malus × domestica). MdPHR1 interacted with MdWRKY75, a positive regulator of anthocyanin biosynthesis, to enhance the MdWRKY75-activated transcription of MdMYB1, leading to anthocyanin accumulation. In addition, the E3 ubiquitin ligase SEVEN IN ABSENTIA1 (MdSINA1) negatively regulated MdPHR1-promoted anthocyanin biosynthesis via the ubiquitination-mediated degradation of MdPHR1. Moreover, the protein kinase apple BRASSINOSTEROID INSENSITIVE2 (MdBIN2) phosphorylated MdPHR1 and positively regulated MdPHR1-mediated anthocyanin accumulation by attenuating the MdSINA1-mediated ubiquitination degradation of MdPHR1. Taken together, these findings not only demonstrate the regulatory role of MdPHR1 in Pi starvation induced anthocyanin accumulation, but also provide an insight into the post-translational regulation of PHR1.

The combination of arterial lactate level with GCS-pupils score to evaluate short term prognosis in traumatic brain injury: a retrospective study.

BACKGROUND: The aim of the study was to determine whether the combination of Glasgow Coma Scale (GCS) and Pupil responses score (GCSP) with arterial lactate level would be an index to predict the short term prognosis in patients with traumatic brain injury (TBI). METHODS: A retrospective study was performed enrolling all TBI patients admitted to intensive care unit (ICU) from 2019 to 2020. The demographics, clinical characteristics, and arterial lactate concentration were recorded. The GCSP and arterial blood analysis (ABG) with lactate was tested as soon as the patient was admitted to ICU. The Glasgow Outcome Scale (GOS) after discharge was regarded as the clinical outcome. A new index named GCSP-L was the combination of GCSP and lactate concentration. GCSP-L was the GCSP score (range 1-15) plus the lactate score (range 0-2). The lactate score was defined based on different lactate concentrations. If lactate was below 2 mmol/L, lactate score was 0, which above 5 mmol/L was 2 and between 2 and 5 mmol/L, the score was 1. As the range of GCSP was 1-15, the range of the GCSP-L was 1 to 17. The area under receiver operating characteristic curve (AUC) was calculated to evaluate the predictive ability of GCSP, lactate and GCSP-L. Statistical significance was set when p value < 0.05. RESULTS: A total of 192 TBI patients were included in the study. Based on GCSP, mild, moderate, and severe TBI were 13.02, 14.06 and 72.92%, respectively. There were 103 (53.65%) patients with the lactate concentration below 2 mmol/L (1.23 ± 0.37 mmol/l), 63 (32.81%) of the range from 2 to 5 (3.04 ± 2.43 mmol/l) and 26 (13.54%) were above 5 mmol/l (7.70 ± 2.43 mmol/l). The AUC was 0.866 (95% CI 0.827-0.904) for GCSP-L, 0.812 (95% CI 0.765-0.858) for GCSP and 0.629 (95% CI 0.570-0.0.688) for lactate. The AUC of GCSP-L was higher than the other two, GCSP and lactate alone. CONCLUSIONS: The combination of GCSP and lactate concentration can be used to predict the short term prognosis in TBI patients.

Callicarpnoids A-C, structurally intriguing ent-Clerodane diterpenoid dimers with cytotoxicity against MCF-7 and HCT-116 cell lines from Callicarpa arborea Roxb.

Callicarpnoids A-C (1-3), three new ent-clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with IC50 ranging from 5.2 to 7.2 µM, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bcl2 were decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells.

Association Between Lipid Profiles and Left Ventricular Hypertrophy: New Evidence from a Retrospective Study.

Objective To explore the association between lipid profiles and left ventricular hypertrophy in a Chinese general population. Methods We conducted a retrospective observational study to investigate the relationship between lipid markers [including triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL-cholesterol, apolipoprotein A-I, apolipoprotein B, lipoprotein[a], and composite lipid profiles] and left ventricular hypertrophy. A total of 309,400 participants of two populations (one from Beijing and another from nationwide) who underwent physical examinations at different health management centers between 2009 and 2018 in China were included in the cross-sectional study. 7,475 participants who had multiple physical examinations and initially did not have left ventricular hypertrophy constituted a longitudinal cohort to analyze the association between lipid markers and the new-onset of left ventricular hypertrophy. Left ventricular hypertrophy was measured by echocardiography and defined as an end-diastolic thickness of the interventricular septum or left ventricle posterior wall > 11 mm. The Logistic regression model was used in the cross-sectional study. Coxmodel and Coxmodel with restricted cubic splines were used in the longitudinal cohort. Results In the cross-sectional study, for participants in the highest tertile of each lipid marker compared to the respective lowest, triglycerides [odds ratio (OR): 1.250, 95%CI: 1.060 to 1.474], HDL-cholesterol (OR: 0.780, 95%CI: 0.662 to 0.918), and lipoprotein(a) (OR: 1.311, 95%CI: 1.115 to 1.541) had an association with left ventricular hypertrophy. In the longitudinal cohort, for participants in the highest tertile of each lipid marker at the baseline compared to the respective lowest, triglycerides [hazard ratio (HR): 3.277, 95%CI: 1.720 to 6.244], HDL-cholesterol (HR: 0.516, 95%CI: 0.283 to 0.940), non-HDL-cholesterol (HR: 2.309, 95%CI: 1.296 to 4.112), apolipoprotein B (HR: 2.244, 95%CI: 1.251 to 4.032) showed an association with new-onset left ventricular hypertrophy. In the Coxmodel with forward stepwise selection, triglycerides were the only lipid markers entered into the final model. Conclusion Lipids levels, especially triglycerides, are associated with left ventricular hypertrophy. Controlling triglycerides level potentiate to be a strategy in harnessing cardiac remodeling but deserve to be further investigated.

Global and Regional Trends and Projections of Infective Endocarditis-Associated Disease Burden and Attributable Risk Factors from 1990 to 2030.

Objective To forecast the future burden and its attributable risk factors of infective endocarditis (IE). Method We analyzed the disease burden of IE and its risk factors from 1990 to 2019 using the Global Burden of Disease 2019 database and projected the disease burden from 2020 to 2030 using a Bayesian age-period-cohort model. Results By 2030, the incidence of IE will increase uncontrollably on a global scale, with developed countries having the largest number of cases and developing countries experiencing the fastest growth. The affected population will be predominantly males, but the gender gap will narrow. The elderly in high-income countries will bear the greatest burden, with a gradual shift to middle-income countries. The incidence of IE in countries with middle/high-middle social-demographic indicators (SDI) will surpass that of high SDI countries. In China, the incidence rate and the number of IE will reach 18.07 per 100,000 and 451,596 in 2030, respectively. IE-associated deaths and heart failure will continue to impose a significant burden on society, the burden on women will increase and surpass that on men, and the elderly in high-SDI countries will bear the heaviest burden. High systolic blood pressure has become the primary risk factor for IE-related death. Conclusions This study provides comprehensive analyses of the disease burden and risk factors of IE worldwide over the next decade. The IE-associated incidence will increase in the future and the death and heart failure burden will not be appropriately controlled. Gender, age, regional, and country heterogeneity should be taken seriously to facilitate in making effective strategies for lowering the IE disease burden.

Feasibility of low-dose dexmedetomidine for prevention of postoperative delirium after intracranial operations: a pilot randomized controlled trial.

BACKGROUND: Clinical trials have shown that dexmedetomidine might decrease the occurrence of postoperative delirium after major surgery, but neurosurgical patients were excluded from these studies. We aimed to determine the feasibility of conducting a full-scale randomized controlled trial of the effect of prophylactic low-dose dexmedetomidine on postoperative delirium in patients after elective intracranial operation for brain tumors. METHODS: In this single-center, parallel-arm pilot randomized controlled trial, adult patients who underwent an elective intracranial operation for brain tumors were recruited. Dexmedetomidine (0.1 µg/kg/hour) or placebo was continuously infused from intensive care unit (ICU) admission on the day of surgery until 08:00 AM on postoperative day one. Adverse events during the study-drug administration were recorded. The primary feasibility endpoint was the occurrence of study-drug interruption. Delirium was assessed twice daily with the Confusion Assessment Method for the ICU during the first five postoperative days. The assessable rate of delirium evaluation was documented. RESULTS: Sixty participants were randomly assigned to receive either dexmedetomidine (n = 30) or placebo (n = 30). The study-drug was stopped in two patients (6.7%) in the placebo group due to desaturation after new-onset unconsciousness and an unplanned reoperation for hematoma evacuation and in one patient (3.3%) in the dexmedetomidine group due to unplanned discharge from the ICU. The absolute difference (95% confidence interval) of study-drug interruption between the two groups was 3.3% (- 18.6 to 12.0%), with a noninferiority P value of 0.009. During the study-drug infusion, no bradycardia occurred, and hypotension occurred in one patient (3.3%) in the dexmedetomidine group. Dexmedetomidine tended to decrease the incidence of tachycardia (10.0% vs. 23.3%) and hypertension (3.3% vs. 23.3%). Respiratory depression, desaturation, and unconsciousness occurred in the same patient with study-drug interruption in the placebo group (3.3%). Delirium was evaluated 600 times, of which 590 (98.3%) attempts were assessable except in one patient in the placebo group who remained in a coma after an unplanned reoperation. CONCLUSIONS: The low rate of study-drug interruption and high assessable rate of delirium evaluation supported a fully powered trial to determine the effectiveness of low-dose dexmedetomidine on postoperative delirium in patients after intracranial operation for brain tumors. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT04494828) on 31/07/2020.

Prevalence of mental health problems in frontline healthcare workers after the first outbreak of COVID-19 in China: a cross-sectional study.

BACKGROUND: More than 210,000 medical workers have fought against the outbreak of Coronavirus Disease 2019 (COVID-19) in Hubei in China since December 2019. However, the prevalence of mental health problems in frontline medical staff after fighting COVID-19 is still unknown. METHODS: Medical workers in Wuhan and other cities in Hubei Province were invited to participate a cross-sectional and convenience sampling online survey, which assessed the prevalence of anxiety, insomnia, depression, and post-traumatic stress disorder (PTSD). RESULTS: A total of 1,091 responses (33% male and 67% female) were valid for statistical analysis. The prevalence was anxiety 53%, insomnia 79%, depression 56%, and PTSD 11%. Healthcare workers in Wuhan were more likely to face risks of anxiety (56% vs. 52%, P = 0.03) and PTSD (15% vs. 9%, P = 0.03) than those in other cities of Hubei. In terms of educational attainment, those with doctoral and masters' (D/M) degrees may experience more anxiety (median of 7.0, [interquartile range (IQR) 2.0-8.5] vs. median 5.0 [IQR 5.0-8.0], P = 0.02) and PTSD (median 26.0 [IQR 19.5-33.0] vs. median 23.0 [IQR 19.0-31.0], P = 0.04) than those with lower educational degrees. CONCLUSIONS: The mental problems were an important issue for the healthcare workers after COVID-19. Thus, an early intervention on such mental problems is necessary for healthcare workers.

A gap existed between physicians' perceptions and performance of pain, agitation-sedation and delirium assessments in Chinese intensive care units.

BACKGROUND: Pain, agitation-sedation and delirium management are crucial elements in the care of critically ill patients. In the present study, we aimed to present the current practice of pain, agitation-sedation and delirium assessments in Chinese intensive care units (ICUs) and investigate the gap between physicians' perception and actual clinical performance. METHODS: We sent invitations to the 33 members of the Neuro-Critical Care Committee affiliated with the Chinese Association of Critical Care Physicians. Finally, 24 ICUs (14 general-, 5 neuroscience-, 3 surgical-, and 2 emergency-ICUs) from 20 hospitals participated in this one-day point prevalence study combined with an on-site questionnaire survey. We enrolled adult ICU admitted patients with a length of stay ≥24 h, who were divided into the brain-injured group or non-brain-injured group. The hospital records and nursing records during the 24-h period prior to enrollment were reviewed. Actual evaluations of pain, agitation-sedation and delirium were documented. We invited physicians on-duty during the 24 h prior to the patients' enrollment to complete a survey questionnaire, which contained attitude for importance of pain, agitation-sedation and delirium assessments. RESULTS: We enrolled 387 patients including 261 (67.4%) brain-injured and 126 (32.6%) non-brain-injured patients. There were 19.9% (95% confidence interval [CI]: 15.9-23.9%) and 25.6% (95% CI: 21.2-29.9%) patients receiving the pain and agitation-sedation scale assessment, respectively. The rates of these two types of assessments were significantly lower in brain-injured patients than non-brain-injured patients (p = 0.003 and < 0.001). Delirium assessment was only performed in three patients (0.8, 95% CI: 0.1-1.7%). In questionnaires collected from 91 physicians, 70.3% (95% CI: 60.8-79.9%) and 82.4% (95% CI: 74.4-90.4%) reported routine use of pain and agitation-sedation scale assessments, respectively. More than half of the physicians (52.7, 95% CI: 42.3-63.2%) reported daily screening for delirium using an assessment scale. CONCLUSIONS: The actual prevalence of pain, agitation-sedation and delirium assessment, especially delirium screening, was suboptimal in Chinese ICUs. There is a gap between physicians' perceptions and actual clinical practice in pain, agitation-sedation and delirium assessments. Our results will prompt further quality improvement projects to optimize the practice of pain, agitation-sedation and delirium management in China. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03975751 . Retrospectively registered on 2 June 2019.