Rubisco condensate formation by CcmM in ß-carboxysome biogenesis.

Cells use compartmentalization of enzymes as a strategy to regulate metabolic pathways and increase their efficiency1. The α- and ß-carboxysomes of cyanobacteria contain ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco)-a complex of eight large (RbcL) and eight small (RbcS) subunits-and carbonic anhydrase2-4. As HCO3- can diffuse through the proteinaceous carboxysome shell but CO2 cannot5, carbonic anhydrase generates high concentrations of CO2 for carbon fixation by Rubisco6. The shell also prevents access to reducing agents, generating an oxidizing environment7-9. The formation of ß-carboxysomes involves the aggregation of Rubisco by the protein CcmM10, which exists in two forms: full-length CcmM (M58 in Synechococcus elongatus PCC7942), which contains a carbonic anhydrase-like domain8 followed by three Rubisco small subunit-like (SSUL) modules connected by flexible linkers; and M35, which lacks the carbonic anhydrase-like domain11. It has long been speculated that the SSUL modules interact with Rubisco by replacing RbcS2-4. Here we have reconstituted the Rubisco-CcmM complex and solved its structure. Contrary to expectation, the SSUL modules do not replace RbcS, but bind close to the equatorial region of Rubisco between RbcL dimers, linking Rubisco molecules and inducing phase separation into a liquid-like matrix. Disulfide bond formation in SSUL increases the network flexibility and is required for carboxysome function in vivo. Notably, the formation of the liquid-like condensate of Rubisco is mediated by dynamic interactions with the SSUL domains, rather than by low-complexity sequences, which typically mediate liquid-liquid phase separation in eukaryotes12,13. Indeed, within the pyrenoids of eukaryotic algae, the functional homologues of carboxysomes, Rubisco adopts a liquid-like state by interacting with the intrinsically disordered protein EPYC114. Understanding carboxysome biogenesis will be important for efforts to engineer CO2-concentrating mechanisms in plants15-19.

A small proton charge radius from an electron-proton scattering experiment.

Elastic electron-proton scattering (e-p) and the spectroscopy of hydrogen atoms are the two methods traditionally used to determine the proton charge radius, rp. In 2010, a new method using muonic hydrogen atoms1 found a substantial discrepancy compared with previous results2, which became known as the 'proton radius puzzle'. Despite experimental and theoretical efforts, the puzzle remains unresolved. In fact, there is a discrepancy between the two most recent spectroscopic measurements conducted on ordinary hydrogen3,4. Here we report on the proton charge radius experiment at Jefferson Laboratory (PRad), a high-precision e-p experiment that was established after the discrepancy was identified. We used a magnetic-spectrometer-free method along with a windowless hydrogen gas target, which overcame several limitations of previous e-p experiments and enabled measurements at very small forward-scattering angles. Our result, rp = 0.831 ± 0.007stat ± 0.012syst femtometres, is smaller than the most recent high-precision e-p measurement5 and 2.7 standard deviations smaller than the average of all e-p experimental results6. The smaller rp we have now measured supports the value found by two previous muonic hydrogen experiments1,7. In addition, our finding agrees with the revised value (announced in 2019) for the Rydberg constant8-one of the most accurately evaluated fundamental constants in physics.

SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance. PATIENTS AND METHODS: In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1 : 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m2 every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety. RESULTS: A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel [median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144]. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively. CONCLUSIONS: Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports.

Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

Improved Tensor Current Limit from

A precision measurement of the ß^{+} decay of ^{8}B was performed using the Beta-decay Paul Trap to determine the ß-ν angular correlation coefficient a_{ßν}. The experimental results were combined with new ab initio symmetry-adapted no-core shell-model calculations to yield the second-most precise measurement from Gamow-Teller decays, a_{ßν}=-0.3345±0.0019_{stat}±0.0021_{syst}. This value agrees with the standard model value of -1/3 and improves uncertainties in ^{8}B by nearly a factor of 2. By combining results from ^{8}B and ^{8}Li, a tight limit on tensor current coupling to right-handed neutrinos was obtained. A recent global evaluation of all other precision ß decay studies suggested a nonzero value for right-handed neutrino coupling in contradiction with the standard model at just above 3σ. The present results are of comparable sensitivity and do not support this finding.

Causal effects of diabetic retinopathy on depression, anxiety and bipolar disorder in the European population: a Mendelian randomization study.

PURPOSE: To verify the causal effects of diabetic retinopathy (DR) on depression, anxiety and bipolar disorder (BD). METHODS: Mendelian randomization (MR) analysis was performed to identify the causal relationships between DR and depression or anxiety or BD via using DR-related GWAS data (14,584 cases and 176,010 controls), depression-related GWAS data (59,851 cases and 113,154 controls), anxiety-related GWAS data (7016 cases and 14,745 controls) and BD-related GWAS data (41,917 cases and 371,549 controls). The inverse-variance weighted (IVW) model was adopted to estimate the causal relationship. The outcome was expressed as odds ratio (OR) with 95% confidence intervals (CI). RESULTS: The MR analysis results presented that DR was causally associated with a significantly increased risk of BD in the European population (IVW, OR = 1.06, 95%CI [1.03, 1.08], P = 2.44 × 10-6), while DR was unable to causally influence the risk of depression (IVW, OR = 1.01, 95%CI [0.99, 1.04], P = 0.32) and anxiety (IVW, OR = 0.97, 95%CI [0.89, 1.06], P = 0.48) in the European population. Subgroup analysis based on BD identified DR causally increased the risk of bipolar I disorder (BD I) but not bipolar II disorder (BD II). Sensitivity analysis results did not show any pleiotropy and heterogeneity in both groups of analyses, indicating that the results were stable and reliable. CONCLUSIONS: The results of the current MR analysis indicated a causal relationship between DR and BD in the European population, while there was no causal connection between DR and depression or anxiety. However, further research is needed to confirm these conclusions.

Diagnostic value of serum squamous cell carcinoma antigen and cytokeratin fragment antigen 21-1 for sinonasal inverted papilloma: an exploratory study.

BACKGROUND: Serum tumor markers have not yet been developed for the clinical diagnosis and treatment of sinonasal inverted papilloma (SNIP), one of the most significant sinonasal tumors. Therefore, this study aimed to determine the diagnostic value of serum squamous cell carcinoma antigen (SCCA) and cytokeratin fragment antigen 21-1 (CYFRA 21-1) for SNIP. METHODS: Clinical data were obtained from 101, 56, and 116 patients with SNIP, sinonasal squamous cell carcinoma (SNSCC), and unilateral chronic rhinosinusitis (CRS), respectively. Preoperative serum SCCA and CYFRA 21-1 levels were compared, and logistic regression analyses were performed to screen serum tumor markers, which may be used to diagnose SNIP. Diagnostic cut-off values were determined using receiver operating characteristic (ROC) curves, and their diagnostic power was verified. RESULTS: Serum SCCA and CYFRA 21-1 differentiated SNIP from CRS with the cut-off values of 1.97 ng/mL and 2.64 ng/mL and the areas under the ROC curves (AUC) of 0.895 and 0.766, respectively, and the AUC of the combination of the two markers was 0.909. CYFRA 21-1 differentiated SNIP with malignant transformation from that without malignant transformation with a cut-off value of 3.51 ng/mL and an AUC of 0.938. CYFRA 21-1 distinguished SNIP with malignant transformation from SNSCC with a cut-off value of 3.55 ng/mL and an AUC of 0.767. CONCLUSIONS: This study provides novel potential diagnostic tools for SNIP by demonstrating the use of serum SCCA and CYFRA 21-1 in the diagnosis of SNIP.

The differences between sinonasal respiratory epithelial adenomatoid hamartoma and nasal polyps: insights into immunopathology.

BACKGROUND: Respiratory epithelial adenomatoid hamartoma (REAH) is a benign lesion commonly occurring in the nasal cavity and sinuses. It is often accompanied by nasal polyps (NP). While the histological features of these two conditions have been studied, there is limited knowledge about their differences in the underlying immunopathology. METHODS: Nasal tissue specimens were collected from 8 patients with concurrent REAH and NP and 10 controls. The expression levels of inflammatory cytokines, tight junctions (TJ), and epithelial-mesenchymal transition (EMT)-related factors in the tissues were analyzed. The mRNA expression of the aforementioned factors was measured using qRT-PCR, while the expression of TJ and EMT-related proteins was analyzed through Western blotting and immunohistochemistry. RESULTS: Compared to the control group, levels of inflammatory cytokines (IFN-γ, IL-5, IL-17A, IL-31, IL-33, and TNF-α) and EMT-related factors (α-SMA, COL1A1, MMP9, TGF-ß1, and Vimentin) were significantly increased in both REAH and NP tissues. Conversely, E-Cadherin and TJ-related factors (Claudin-4 and Occludin) significantly decreased. When comparing REAH with NP, it was observed that the expression of IL-4, IL-5, and IL-33 was lower in REAH, while TNF-α was higher. Regarding TJ-related factors, the expression of Occludin was lower in REAH. Furthermore, in terms of EMT-related factors, except for E-Cadherin, the expressions of α-SMA, COL1A1, CTGF, MMP9, TGF-ß1, and Vimentin were higher in REAH. CONCLUSION: REAH and NP exhibit different immunopathological mechanisms. NP demonstrates a more severe inflammatory response, whereas REAH is characterized by a more pronounced TJ and EMT breakdown than NP.

[Differentiation of temporal lobe epilepsy and temporal plus epilepsy using radiomics nomogram based on MPRAGE images].

A total of 82 patients with temporal lobe epilepsy (TLE) and temporal plus epilepsy (TPE)admitted in Xuanwu Hospital from January 1, 2019, to January 1, 2021 were restrospectively analyzed, including 41 males and 41 females, aged 2 to 52 (24±10) years. The patients were randomly divided into the training set (58 cases) and test set (24 cases) by Python. FreeSurfer software was used to segment the cortex of the affected hemisphere, defining 33 regions of interest (ROIs), and radiomics features were extracted by Python. After selecting features using the filter-based feature selection method, a radiomics model was constructed with a logistic regression classifier, and radiomics scores were calculated. Combining clinical characteristics with radiomics scores, a nomogram model was constructed using R software, the predictive accuracy of the model was assessed with the concordance index (C-index), and the model's goodness-of-fit was tested with the Hosmer-Lemeshow method. The results showed statistically significant differences between TLE and TPE patients in disease duration, intracranial electrode implantation, and hippocampal sclerosis (both P<0.05). The accuracy of the radiomics model in the training set and the test set was 91.4% and 87.5%, respectively. The nomogram model uses C-index to predict accuracy. Hosmer-Lemeshow method was used to test the goodness of fit, with AUCs of 0.95 (95%CI: 0.853-0.991) in the training set and 0.84 (95%CI: 0.676-0.999) in the test set. The study indicates that the radiomics nomogram model based on MPRAGE sequences can effectively differentiate TLE from TPE, providing reference for the development of personalized treatment plans in clinical practice.

[Serum glycocalyx markers in patients after cardiac arrest: association with outcomes].

Objective: To assess the levels of serum glycocalyx markers in the first 24 hours after cardiac arrest (CA) and investigate their relationship with 30-day outcomes. Methods: A retrospective cohort study was conducted on prospectively collected data from CA patients, who were admitted to the intensive care units of the Affiliated Hospital of Xuzhou Medical University and obtained return of spontaneous circulation for more than 24 hours between September 2021 and October 2022. Serum samples obtained at the 24-hour after CA were utilized to measure the levels of glycocalyx markers, including heparan sulfate (HS), hyaluronic acid (HA), and syndecan-1 (Sdc-1). Patients were allocated into good function (CPC1-2) and poor function (CPC3-5) groups on the basis of cerebral performance category (CPC) at 30 days post-CA. Logistic regression analysis was used to determine the association between serum glycocalyx markers and neurological outcomes. Patients were regrouped in light of 30-d mortality and Cox regression analysis was used to determine the association between serum glycocalyx markers and 30-d mortality. Results: A total of 71 patients were included in the study, including 31 (43.7%) females and 40 (56.3%) males, with an average age of (59.0±17.0) years. The poor function group (n=49) demonstrated significantly elevated levels of HS and HA when compared to the good function group (n=22) [HS: 2 461.0(1 623.0, 5 492.0) µg/L vs 1 492.0 (914.0, 2 550.0) µg/L, P=0.008; HA: 124.0(97.0, 365.0)µg/L vs 337.0(135.0, 1 421.0) µg/L, P=0.033]. Adjusted logistic regression analysis revealed that HS was independently associated with poor neurological outcome [odds ratio (OR)=0.389, 95% confidence interval (CI): 0.182-0.828, P=0.014]. In the 30-day mortality analysis, the death group (n=32) exhibited significantly higher levels of HS and HA when compared to the survival group (n=39) [HS: 1 880.0(1 011.0, 3 554.0) µg/L vs 2 500.0(1 726.0, 6 276.0) µg/L, P=0.027; HA: 162.0(99.0, 537.0) µg/L vs 813.0(148.0, 1 531.0) µg/L, P=0.025]. Adjusted Cox regression analysis indicated that elevated levels of HS and HA were independent risk factors (HS: HR=1.697, 95%CI: 1.126-2.557, P=0.011; HA: HR=1.336, 95%CI: 1.047-1.705, P=0.020) for 30-day mortality. Conclusions: High level of serum HS in 24 hours after CA may serve as a potential predictive marker for both neurological function and 30-day mortality. However, high level of serum HA appears to primarily predict 30-day mortality. Sdc-1 does not seem to contribute to outcome prediction.

[Relationship between serum 1, 5-anhydroglucitol level and insulin resistance, microvascular complications in type 2 diabetes mellitus].

Objective: To explore the relationship between serum 1, 5-dehydratoglucitol (1, 5-AG) level and insulin resistance, microvascular complications in patients with type 2 diabetes mellitus (T2DM). Methods: The clinical data of 836 patients with T2DM admitted to the Changsha Central Hospital Affiliated to University of South China from May to December 2023 were retrospectively and cross-sectionally analyzed. Serum 1, 5-AG levels were detected by pyranose oxidase method. According to the microvascular complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy), the patients were divided into simple group (no microvascular complications, n=490), complication group 1 (1 microvascular complications, n=217), and complication group 2 (2 or more microvascular complications, n=129). The relationship between serum 1, 5-AG level and the related indicators of insulin resistance in T2DM patients were explored by Spearman correlation analysis, and the influencing factors of microvascular complications in T2DM patients were explored by multiple ordered logistic regression analysis. Results: The levels of FBG(fasting blood glucose) [(7.37±0.56) mmol/L], FINS(fasting insulin) [(11.34±1.86) mU/L] and HOMA-IR(homeostatic model assessment of insulin resistance) (0.96±0.31) in simple group were lower than those in complication group 1 [(8.37±1.02) mmol/L, (16.26±2.32) mU/L, (1.32±0.41)], complication group 2 [(10.25±2.13) mmol/L, (18.53±2.67) mU/L, (1.54±0.44)], and FBG, FINS and HOMA-IR in complication group 1 were lower than those in complication group 2, and the differences were statistically significant (F=537.470, 791.690, 136.340, P<0.001). Serum 1, 5-AG level in simple group [77.16 (16.30, 128.07) µg/ml] was higher than that in complication group 1 [51.05 (14.67, 63.18) µg/ml] and complication group 2 [30.42 (12.53, 47.26) µg/ml], and the serum level of 1, 5-AG in complication group 1 was higher than that in complication group 2, and the difference was statistically significant (H=210.020, P<0.001). The results of Spearman correlation analysis showed that serum 1, 5-AG level was negatively correlated with FBG, FINS and HOMA-IR in T2DM patients (r=-0.431, -0.372, -0.546, P<0.001). The results of multiple ordered logistic regression analysis showed that Longer duration of diabetes (OR=2.261, 95%CI: 1.564-3.269), increased HbA1c (OR=2.040, 95%CI: 1.456-2.858), and increased HOMA-IR (OR=2.158, 95%CI: 1.484-3.137) and decreased 1, 5-AG (OR=2.512, 95%CI: 1.691-3.732) were independent risk factors for microvascular complications in T2DM patients (P<0.05). The results of ROC curve analysis showed that the area under the curve of serum 1, 5-AG in the identification of one microvascular complication was 0.763 (95%CI: 0.731-0.795), and the area under the curve of serum 1, 5-AG in the identification of two or more microvascular complications was 0.730 (95%CI: 0.692-0.767). Conclusion: Serum 1, 5-AG level is negatively correlated with insulin resistance in T2DM patients. Low serum 1, 5-AG level may be an independent risk factor for microvascular complications in T2DM patients.

[Clinical analysis of adverse reactions in patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis treated with delamanid-containing regimen].

Objective: To explore the characteristics of adverse drug reactions during the 24-week therapy with delamanid-containing regimen for patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB). Methods: The prospective multicenter study was conducted from June 2020 to June 2023. A total of 608 eligible patients with MDR/RR-PTB were enrolled in 26 tuberculosis medical institutions in China including 364 males and 79 females, aged 39.6(19.0-68.0) years. Patients were treated with chemotherapy regimens containing delamanid. Patients were closely supervised during treatment of medication, and all adverse reactions occurring during treatment were monitored and recorded. The clinical characteristics of adverse reactions were evaluated by descriptive analysis. Chi-square test and multivariate logistic regression were used to analyze the related factors of QTcF interval prolongation (QT corrected with Fridericia's formula). Results: Of the 608 patients enrolled in this study, 325 patients (53.5%) reported 710 adverse events within 24 weeks of treatment. The top 6 most common complications were hematological abnormalities (143 patients, 23.5%), QT prolongation (114 patients, 18.8%), liver toxicity (85 patients, 14.0%), gastrointestinal reaction (41 patients, 6.7%), peripheral neuropathy (25 patients, 4.1%) and mental disorders (21 patients, 3.5%). The prolongation of QT interval mostly occurred in the 12th week after the first dose of medication. Serious adverse reactions occurred in 21 patients (3.5%). There were 7 patients (1.2%) with mental disorders, including 2 patients (0.3%) with severe mental disorders. Conclusions: The safety of dalamanid-based regimen in the staged treatment of MDR/RR-PTB patients was generally good, and the incidence of adverse reactions was similar to that reported in foreign studies. This study found that the incidence of QT interval prolongation in Chinese patients was higher than that reported overseas, suggesting that the monitoring of electrocardiogram should be strengthened when using drugs containing delamanid that may cause QT interval prolongation.

Mass Measurement of Upper fp-Shell N=Z-2 and N=Z-1 Nuclei and the Importance of Three-Nucleon Force along the N=Z Line.

Using a novel method of isochronous mass spectrometry, the masses of ^{62}Ge, ^{64}As, ^{66}Se, and ^{70}Kr are measured for the first time, and the masses of ^{58}Zn, ^{61}Ga, ^{63}Ge, ^{65}As, ^{67}Se, ^{71}Kr, and ^{75}Sr are redetermined with improved accuracy. The new masses allow us to derive residual proton-neutron interactions (δV_{pn}) in the N=Z nuclei, which are found to decrease (increase) with increasing mass A for even-even (odd-odd) nuclei beyond Z=28. This bifurcation of δV_{pn} cannot be reproduced by the available mass models, nor is it consistent with expectations of a pseudo-SU(4) symmetry restoration in the fp shell. We performed ab initio calculations with a chiral three-nucleon force (3NF) included, which indicate the enhancement of the T=1 pn pairing over the T=0 pn pairing in this mass region, leading to the opposite evolving trends of δV_{pn} in even-even and odd-odd nuclei.

Mass spectrometry-based metabolic profiling for identification of biomarkers related to footpad dermatitis in ducks.

1. A new assessment method for duck footpad dermatitis (FPD) evaluation was developed, combining visual and histological characters using the images and sections of 400 ducks' feet at 340 d of age. All ducks were graded as G0 (healthy), G1 (mild), G2 (moderate) and G3 (severe) according to the degree of FPD.2. To reveal the potential biomarkers in serum related to duck FPD, non-targeted metabolomics and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to explore differential metabolites in each group.3. There were 57, 91 and 210 annotated differential metabolites in groups G1, G2 and G3 compared with G0, which meant that the severity of FPD increased in line with the number of metabolites. Four metabolites, L-phenylalanine, L-arginine, L-leucine and L-lysine, were considered potential biomarkers related to FPD.4. KEGG enrichment analysis showed that the FPD was mainly involved in glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway and amino acid metabolism. These are related to production metabolism and can affect the physiological activities of ducks, which might explain the decrease in production performance.

[Safety and efficacy of the early administration of levosimendan in patients with acute non-ST-segment elevation myocardial infarction and elevated NT-proBNP levels: An Early Management Strategy of Acute Heart Failure (EMS-AHF)].

Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.

[Assessment of prevalence of malnutrition among Chinese primary and secondary school students and analysis of policy effect during the period of the Program for the Development of Chinese Children 2011-2020].

OBJECTIVE: To evaluate the change of prevalence of malnutrition among Chinese primary and secondary school students and to analyze the policy effect during the period of the Program for the Development of Chinese Children 2011-2020 (PDCC 2011-2020). METHODS: The data of Chinese students aged 7 to 18 years were extracted from 8 successive cross-sectional surveys of the Chinese National Survey on Students ' Constitution and Health (CNSSCH) from 1985 to 2019. Malnutrition of students was evaluated according to the screening standard for malnutrition of school-age children and adolescents. The changes of prevalence of malnutrition among primary and secondary school students were described by gender, urban and rural areas, age group and province, from 2010 to 2019. The Joinpoint regression model was used to analyze the trajectory of the prevalence of malnutrition among students aged 7 to 18 years from 1985 to 2019, so as to evaluate the policy effect of the PDCC 2011-2020. RESULTS: The prevalence of malnutrition among primary and secondary school students in China decreased from 12.7% in 2010 to 8.5% in 2019. The prevalence of malnutrition among boys and girls, urban and rural students, and students of all age groups showed a continuous downward trend (Ptrend < 0.001) from 2010 to 2019. From 2010 to 2019, 27 of the 31 provinces (autonomous regions and municipalities) saw a significant decrease in the prevalence of malnutrition among primary and secondary school students. Joinpoint regression model showed that the prevalence of malnutrition among Chinese primary and secondary school students continued to decline from 1985 to 2019, but 2010 was the turning point in the downward trend. From 1985 to 2010, the prevalence of malnutrition among primary and secondary school students decreased by an average of 2.4% per year (95%CI: 1.9%-2.8%, P < 0.001), and the downward trend accelerated after 2010, with an average annual decline of 4.3% (95%CI: 2.4%-6.2%, P < 0.001). CONCLUSION: The prevalence of malnutrition among primary and secondary school students in China continued to decline from 2010 to 2019, achieving the goal of controlling the prevalence of malnutrition among primary and secondary school students in the PDCC 2011-2020. The PDCC 2011-2020 may have played an important role in improving the malnutrition among primary and secondary school students. However, the problem of malnutrition among primary and secondary school students still exists, and it is still necessary to adhere to the coverage and financial support of the nutrition improvement plan in areas with high incidence of malnutrition.

[Alterations in erythrocytic oligomeric alpha-synuclein in patients with Parkinson's disease and multiple system atrophy].

Objective: To analyze the content of α-synuclein oligomer(O-α-Syn) in erythrocytes in patients with Parkinson's disease (PD) and multiple system atrophy (MSA) and the correlation with clinical symptoms. Methods: Two hundred and ninety-six PD patients and 85 MSA patients were recruited from the Department of Functional Neurosurgery and Neurology of Xuanwu Hospital, Capital Medical University from July 2020 to October 2021. Four hundred and three healthy controls (HC) were recruited from the Beijing Longitudinal Study of Aging community cohort during the same period. The levels of RBC-O-α-Syn were measured by enzyme-linked immunosorbent assay (ELISA). Univariate linear regression model was used to analyze the correlation between the content of RBD-O-α-Syn and various motor and non-motor functional scores, such as Unified Parkinson Disease Rating Scale (UPDRS) Ⅲ, Unified Multiple System Atrophy Rating Scale (UMSARS) Ⅲ, Mini-Mental State Examination (MMSE), rapid eye movement sleep disorder questionnaire-HongKong(RBDQ-HK) and Montreal Cognitive Assessment (MoCA). Receiver operating characteristic (ROC) curves was used to evaluate the specificity, sensitivity, and the area under the curve (AUC) of RBC-O-α-Syn in distinguishing PD and MSA patients from HC subjects. Results: The average age of HC subjects was (70±8) years old, the average age of PD patients was (64±9) years old, including 115 (38.9%) cases with tremor dominant PD (TD-PD), 132 cases (44.6%) of postural instability disorder predominant PD (PIGD-PD), and 142 cases (48.0%) of patients with H-Y stage 2. UPDRS Ⅲ score was 31.2±17.8. The mean age of MSA patients was (64±9) years, with the mean UMSARS Ⅱ score of 18.9±10.3. The non-motor symptoms of PD and MSA patients were significantly different from those of HC subjects (P<0.001). The levels of RBC-O-α-Syn in PD [(50±17) ng/mg] and MSA [(52±19) ng/mg] were significantly higher than those in HC subjects [(21±10) ng/mg] (P<0.001). The sensitivity and specificity of RBC-O-α-Syn in distinguishing PD patients and HC subjects were 87.16% (95%CI: 82.87%-90.50%) and 86.10% (95%CI: 82.38%-89.14%), with an AUC of 0.933 (95%CI: 0.914-0.951), and the sensitivity and specificity in distinguishing MSA patients and HC subjects were 85.88% (95%CI: 76.93%-91.74%) and 81.39% (95%CI: 77.30%-84.89%), with an AUC of 0.921 (95%CI: 0.884-0.957). The levels of RBC-O-α-Syn in PD patients with rapid eye movement sleep behavior disorder (RBD) were higher than that in PD patients without RBD [(53±16) ng/mg vs (48±17) ng/mg, P=0.029].The content of RBC-O-α-Syn in female PD patients and HC subjects was higher than that in male, but there was no significant difference between subjects of different ages and disease duration (P>0.05). In addition, RBC-O-α-Syn content was positively correlated with UPDRS Ⅲ (r=0.18, P=0.002) and the score of rapid eye movement sleep behavior disorder questionnaire(Hong Kong) (RBDQ-HK)(r=0.19, P<0.001). But there was no correlation with H-Y stage, non-motor symptoms scale (NMSS), MMSE, Moca, Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA) scores (all P>0.05). There was no correlation between RBC-O-α-Syn content and UMSARS Ⅱ, NMSS, MMSE, MoCA, HAMD, HAMA in patients with MSA (all P>0.05). Conclusions: Levels of RBC-O-α-Syn are significantly increased in PD and MSA patients. There are positive correlations between levels of RBC-O-α-Syn and scores of UPDRS Ⅲ and RBDQ-HK.

[Analysis of management efficacy in patients with heavy menstrual bleeding associated with antithrombotic therapy].

Objective: To evaluate different methods' efficacy of controlling acute bleeding and managing long-term menstruation in patients with heavy menstrual bleeding (HMB) associated with antithrombotic therapy. Methods: The clinical data of 22 cases with HMB associated with antithrombotic therapy admitted to Peking University People's Hospital from January 2010 to August 2022 were analyzed, aged 39 years old (26-46 years). Changes in menstrual volume, hemoglobin (Hb), and quality of life were collected after control of acute bleeding and long-term menstrual management. Menstrual volume was assessed by pictorial blood assessment chart (PBAC), and quality of life was assessed by menorrhagia multi-attribute scale (MMAS). Results: (1) Treatment of acute bleeding: of the 22 cases with HMB associated with antithrombotic therapy, 16 cases were treated in our hospital and 6 in other hospital for emergency bleeding; of the 16 cases treated in our hospital, 3 underwent emergency intrauterine Foley catheter balloon compression due to severe bleeding (Hb decreased by 20 to 40 g/L within 12 hours). Of the 22 cases with antithrombotic therapy-related HMB, 15 (including 2 cases with severe bleeding) underwent emergency aspiration or endometrial resection, and intraoperative placement of levonorgestrel-releasing intrauterine system (LNG-IUS) followed by a significant reduction in bleeding volume; 3 cases had controlled acute bleeding after rivaroxaban dose reduction and continued observation; 2 cases were given gonadotropin-releasing hormone agonists to control acute bleeding in other hospital, of which 1 case was temporarily treated with periodic blood transfusion, and the other one patient underwent total hysterectomy; and 2 cases had temporary amenorrhea with oral mifepristone after intrauterine balloon compression or oral norethindrone. (2) Long-term menstrual management: of the 22 cases with antithrombotic therapy-related HMB, 15 had LNG-IUS placement and 12 had LNG-IUS placement for 6 months, and menstrual volume was significantly reduced [PBAC scores were 365.0 (272.5-460.0) vs 25.0 (12.5-37.5), respectively; Z=4.593, P<0.001], Hb was significantly increased [91.5 g/L (71.8-108.2 g/L) vs 128.5 g/L (121.2-142.5 g/L); Z=4.695, P<0.001], and quality of life was significantly improved [MMAS scores were 415.0 (327.5-472.5) vs 580.0 (570.0-580.0), respectively; Z=-3.062, P=0.002] before placement compared with 6 months after placement. Three rivaroxaban dose reduction patients' PBAC scores decreased by 20 to 35 but remained >100, and perceived quality of life did not change significantly. Two cases with temporary amenorrhea treated with oral mifepristone felt significantly improved quality of life, and the MMAS scores increased by 220 and 180, respectively. Conclusion: Intrauterine Foley catheter balloon compression, aspiration or endometrial ablation could be used to control acute bleeding in patients with antithrombotic therapy-related HMB, and LNG-IUS for long-term management could reduce menstrual volume, increase hemoglobin, and improve the quality of life of patients.

[Biomarkers associated with severity classification of asthma identified by comprehensive bioinformatics analysis].

Using an integrated bioinformatics approach to find novel biomarkers that can predict asthma severity. From June 2022 to December 2022, this clinical medical study was conducted and completed in the Department of Allergy, Zhongnan Hospital of Wuhan University. The gene chip dataset GSE43696 was screened and downloaded from the high-throughput Gene Expression Omnibus (GEO) database, and the gene chip data preprocessing was completed using package "affy" in R and "rma" algorithm in turn. Use the the "edgeR" and "limma" packages to screen out the differentially expressed genes (DEGs) between normal controls, mild to moderate asthma patients and severe asthma patients, and then use the "clusterProfiler" package to perform GO enrichment analysis and KEGG pathway enrichment analysis of DEGs, finally use the STRING website to construct a protein-protein interaction (PPI) network of DEGs to further screen key genes. Using the R language "WGCNA" package, the weighted gene co-expression network analysis (WGCNA) was performed on the dataset GSE43696, and the modules significantly related to the severity of asthma were screened out, then the hub genes were obtained by intersecting the WGCNA analysis results with the DEGs screened by PPI. Datasets GSE43696 and GSE63142 were used to verify the expression of hub genes, and the diagnostic value was evaluated according to the ROC curve, then the potential function of hub genes in dataset GSE43696 was further clarified by gene set enrichment analysis (GSEA). The results showed that a total of 251 DEGs were screened, including 39 in the normal group and mild to moderate asthma group, 178 in the normal group and severe asthma group, and 34 in the mild to moderate asthma group and severe asthma group, mainly involved in biological processes such as response to toxic substance, response to oxidative stress, extracellular structure organization, extracellular matrix organization. Two modules significantly correlated with asthma severity were screened out (red module, P=7e-6, r=0.43; pink module, P=5e-8, r=-0.51), and finally six hub genes were obtained, including B3GNT6, CEACAM5, CCK, ERBB2, CSH1 and DPPA5. The comparison of gene expression levels and ROC curve analysis of datasets GSE43696 and GSE63142 further verified the six hub genes, which may associated with o-glycan biosynthesis, alpha linolenic acid metabolism, linoleic acid metabolism, pentose and glucoronate interconversions. In conclusion, through a variety of bioinformatics analysis methods, this study identified six hub genes significantly related to the severity of asthma, which potentially provided a new direction for the prediction and targeted therapy of asthma.

[Clinical characteristics and prognostic factors of patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis associated interstitial lung disease].

Objective: To analyze the clinical characteristics and prognostic factors of patients with anti-melanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis associated interstitial lung disease (DM-ILD). Methods: The patients with MDA5+DM-ILD who were admitted to Department of Respiratory Medicine, Nanjing Drum Tower Hospital from January 2017 to March 2021 were enrolled. The clinical data and survival information were analyzed retrospectively. Patients were divided into survival group or death group, and rapid progressive ILD (RP-ILD) group or non-rapid progressive ILD group, according to their survival status and clinical progression. Results: A total of 105 patients with anti-MDA5+DM-ILD (median age of onset 54 years) were enrolled, 58% being female (61 cases). The main sub-type of dermatomyositis was amyopathic dermatomyositis (n=74, 70%), followed by dermatomyositis (n=31, 30%). The main extrapulmonary manifestations were skin lesions (n=60, 57.1%), muscle manifestations(n=20, 19%) and arthralgia/arthritis (n=20, 19%). 15.4% of the patients had positive ANA (antibody titer≥1∶320), and 61.9% of the patients had anti-RO-52 kDa antibody. A total of 66 patients (62.8%) developed RP-ILD, and 58 patients (56.3%) died. Lower oxygenation index (OR=0.974, 95%CI:0.954-0.994, P=0.012) and no joint pain (OR=0.032, 95%CI: 0.002-0.663 P=0.026) were independent risk factors for RP-ILD. Cox regression analysis showed that RP-ILD (HR=3.194, 95%CI:1.025-9.954, P=0.045), older than 53 years (HR=3.450, 95%CI: 1.388-8.577, P=0.008), ferritin level more than 1 330.5 ng/ml (HR=3.032, 95%CI 1.208-7.610, P=0.018) and C-reactive protein (CRP) above 16.95 mg/L (HR=2.794, 95%CI:1.102-7.084, P=0.030) were independent predictors of mortality. Conclusions: The clinical manifestations of patients with anti-MDA5+DM-ILD presenting to the respiratory department were heterogeneous, with most being amyopathic dermatomyositis, and both the incidence of RP-ILD and the risk of death were high. Even in the absence of associated rash, joint, or muscle manifestations, anti-MDA5 antibody screening should be considered in patients with rapidly progressive ILD who were negative on baseline autoantibody screening but positive for anti-RO52kDa antibody.