Ultrahigh-energy photons up to 1.4 petaelectronvolts from 12 γ-ray Galactic sources.

The extension of the cosmic-ray spectrum beyond 1 petaelectronvolt (PeV; 1015 electronvolts) indicates the existence of the so-called PeVatrons-cosmic-ray factories that accelerate particles to PeV energies. We need to locate and identify such objects to find the origin of Galactic cosmic rays1. The principal signature of both electron and proton PeVatrons is ultrahigh-energy (exceeding 100 TeV) γ radiation. Evidence of the presence of a proton PeVatron has been found in the Galactic Centre, according to the detection of a hard-spectrum radiation extending to 0.04 PeV (ref. 2). Although γ-rays with energies slightly higher than 0.1 PeV have been reported from a few objects in the Galactic plane3-6, unbiased identification and in-depth exploration of PeVatrons requires detection of γ-rays with energies well above 0.1 PeV. Here we report the detection of more than 530 photons at energies above 100 teraelectronvolts and up to 1.4 PeV from 12 ultrahigh-energy γ-ray sources with a statistical significance greater than seven standard deviations. Despite having several potential counterparts in their proximity, including pulsar wind nebulae, supernova remnants and star-forming regions, the PeVatrons responsible for the ultrahigh-energy γ-rays have not yet been firmly localized and identified (except for the Crab Nebula), leaving open the origin of these extreme accelerators.

Comparison of different derivatisation for amino acids determination of foie gras by high performance liquid chromatography (HPLC).

1. In order to compare the difference between different derivatisations for amino acids determination of foie gras via, reversed phase high performance liquid chromatography (HPLC), O-phthalaldehyde and 9-fluorenyl-methyl chloroformate (OPA-FMOC group), phenylisothiocyanate (PITC group) and 6-Aminoquinolyl-N-hydrox-ysuccinimidyl Carbamate (AQC group) were applied to derivatisation reagent in this current experiment. The determination results of automatic amino acid analyser were applied, and 17 amino acids were detected by these three derivatisation methods.2. The running times of OPA-FMOC group, PITC group and AQC group were 18, 45 and 35 min, respectively. There was a large difference between the results of OPA-FMOC group and results from the automatic amino acid analyser, although the difference between the results from PITC and the automatic amino acid analyser was minimal.3. In conclusion, the running time of OPA-FMOC group was shorter than that of PITC group and AQC group; the accuracy of the former was better than the OPA-FMOC group and AQC group for the determination of amino acid of foie gras.

[Effect of peripheral blood inflammatory indicators on the efficacy of immunotherapy in patients with advanced non-small cell lung cancer and chronic obstructive pulmonary disease].

Objective: To investigate the impact of peripheral blood inflammatory indicators on the efficacy of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) complicated with chronic obstructive pulmonary disease (COPD). Methods: A retrospective cohort study was performed to include 178 patients with Ⅲ-Ⅳ NSCLC complicated with COPD who received at least 2 times of immunotherapy in Xinqiao Hospital of the Army Medical University from January 2019 to August 2021. Baseline peripheral blood inflammatory indicators such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α) were collected within 2 weeks before the first treatment, with the last one being on or before February 7, 2022. X-tile software was used to determine the optimal cut-off value of peripheral blood inflammatory indicators. The Cox multivariate regression models were used to analyze the factors affecting progression free survival (PFS) and overall survival (OS). Results: Among the 178 patients, there were 174 males (97.8%) and 4 females (2.2%); the age ranged from 42 to 86 (64.3±8.3) years old.There were 30 cases (16.9%) of immunotherapy monotherapy, 114 cases (64.0%) of immunotherapy combined with chemotherapy, 21 cases (11.8%) of immunotherapy combined with antivascular therapy, and 13 cases (7.3%) of immunotherapy combined with radiotherapy. The median follow-up period was 14.5 months (95%CI: 13.6-15.3 months). The objective response rate (ORR) and disease control rate (DCR) were 44.9% (80/178) and 90.4% (161/178) for the whole group, the median PFS was 14.6 months (95%CI: 11.6-17.6 months), and the median OS was 25.7 months (95%CI: 18.0-33.4 months). The results of Cox multivariate analysis showed that IL-6>9.9 ng/L (HR=5.885, 95%CI: 2.558-13.543, P<0.01), TNF-α>8.8 ng/L (HR=3.213, 95%CI: 1.468-7.032, P=0.003), IL-8>202 ng/L (HR=2.614, 95%CI: 1.054-6.482, P=0.038), systemic immune inflammatory index (SII)>2 003.95 (HR=2.976, 95%CI: 1.647-5.379, P<0.001) were risk factors for PFS, and advanced lung cancer inflammation index (ALI)>171.15 was protective factor for PFS (HR=0.545, 95%CI: 0.344-0.863, P=0.010). IL-6>9.9 ng/L(HR=6.124, 95%CI: 1.950-19.228, P<0.002), lactate dehydrogenase (LDH)>190.7 U/L (HR=2.776, 95%CI: 1.020-7.556, P=0.046), SII>2 003.95 (HR=4.521, 95%CI: 2.241-9.120, P<0.001) were risk factors for OS, and ALI>171.15 was a protective factor for OS (HR=0.434, 95%CI: 0.243-0.778, P=0.005). Conclusion: Baseline high levels of IL-6, TNF-α, IL-8, SII, LDH, and low levels of ALI are risk factors for poor prognosis in patients with advanced NSCLC-COPD receiving immunotherapy.

Establishment of gestational diabetes risk prediction model and clinical verification.

OBJECTIVE: The present study aimed to evaluate the risk factors for gestational diabetes mellitus (GDM) and build and validate an early risk prediction model of GDM by comparing the differences in the indicators of the first trimester of pregnancy between pregnant women with GDM and non-gestational diabetes mellitus (NGDM). Thus, this study provided a theoretical basis for early intervention of GDM. METHODS: A total of 6000 pregnant women who underwent a routine prenatal examination in Qinhuangdao Maternal and Child Health Hospital (Qinhuangdao City, Hebei Province, China) from January 2016-2022 were retrospectively selected and randomly divided into a modeling cohort (4200 cases) and validation cohort (1800 cases) at a ratio of 3:7. According to the results of oral glucose tolerance test (OGTT), they were divided into NGDM and GDM groups. The modeling cohort consisted of 2975 NGDM and 1225 GDM cases, while the validation cohort consisted of 1281 NGDM and 519 GDM cases. The differences in general conditions and laboratory indicators between different groups were compared, and logistic regression analysis was further used to establish a risk prediction model for GDM in the first trimester. The receiver operating characteristic curve (ROC) and Hosmer-Lemeshow (HL) tests were used to evaluate the prediction of the model efficacy. RESULTS: Age, pre-pregnancy body mass index (BMI), glycosylated hemoglobin (HbA1c), blood uric acid (UA), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) in the first trimester were independent risk factors for GDM (P < 0.05). The model equation was Y = 1/{1 + exp[- (- 18.373 + age × 0.065 + BMI × 0.030 + first-trimester HbA1c × 2.519 + UA × 0.014 + TG × 0.224-HDL-C × 0.635)]}. The area under the ROC curve (AUC) of the model cohort was 0.803 (0.788-0.817), the sensitivity was 72.0%, and the specificity was 73.5%. The AUC of the validation cohort was 0.782 (0.759-0.806), the sensitivity was 68.6%, and the specificity was 73.8%. The P values of the HL test in both the training and validation sets were > 0.05, indicating a satisfactory model fit. CONCLUSION: Age, pre-pregnancy BMI, HbA1C in early pregnancy, blood UA, TG, and HDL-C are independent risk factors for GDM. The risk prediction model established by combining age, pre-pregnancy BMI, and laboratory indicators in the first trimester can provide a theoretical basis for early screening, monitoring, and intervention of GDM high-risk pregnant women.

MicroRNA-137 inhibits pituitary prolactinoma proliferation by targeting AKT2.

PURPOSE: Prolactinoma is the most common type of pituitary adenoma. Most prolactinoma need medical treatment, but some of them are aggressive and require surgery. In previous decades, some miRNAs have been manifested as oncogenes or tumor suppressors. Consequently, miRNAs' abnormal expression involves tumorigenesis, invasion, and metastasis of different types of tumors, including pituitary tumors. The current study aim to explore the aggressiveness-associated miRNAs in prolactinoma and underlying molecular mechanisms based on the bioinformatic analysis and fundamental experiment studies. METHODS: GSE46294 miRNA expression profile from the Gene Expression Omnibus (GEO) database was downloaded. Differentially expressed miRNAs (DEMs) were filtered from this data. Subsequently, the target genes of downregulated miRNAs were analyzed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. RT-qPCR, western blot, and CCK-8 assays were used to validate the effect of miR-137 on the proliferation of MMQ cells through AKT2. Finally, the binding site of rat miR-137 to AKT2 were predicted by Targetscan and Bibiserv database, and verified by double luciferase reporter assay. RESULTS: Twenty-four changed DEMs (fourteen upregulated and ten downregulated) were identified. Target genes of downregulated DEMs were classified into three groups by GO terms. KEGG pathway enrichment analysis revealed these target genes enriched in the PI3K-Akt pathway. We also confirmed that miR-137 can target AKT2 and inhibit the proliferation of MMQ cells induced by AKT2. CONCLUSION: MiR-137 suppressed prolactinomas' aggressive behavior by targeting AKT2.

Effect of Intrapartum Azithromycin vs Placebo on Neonatal Sepsis and Death: A Randomized Clinical Trial.

Importance: Neonatal sepsis is a leading cause of neonatal mortality. New interventions are needed to decrease neonatal sepsis and mortality in regions with highest burden. Objective: To evaluate the efficacy of intrapartum azithromycin to reduce neonatal sepsis or mortality, as well as neonatal and maternal infections. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial enrolled and followed up birthing parents and their infants at 10 health facilities in The Gambia and Burkina Faso, West Africa, between October 2017 and May 2021. Interventions: Participants were assigned at random to receive oral azithromycin (2 g) or placebo (ratio 1:1) during labor. Main Outcomes and Measures: The primary outcome was a composite of neonatal sepsis or mortality, with the former defined based on microbiologic or clinical criteria. Secondary outcomes were neonatal infections (skin, umbilical, eye and ear infections), malaria, and fever; postpartum infections (puerperal sepsis, mastitis), fever, and malaria; and use of antibiotics during 4-week follow-up. Results: The trial randomized 11 983 persons in labor (median age, 29.9 years). Overall, 225 newborns (1.9% of 11 783 live births) met the primary end point. The incidence of neonatal mortality or sepsis was similar in the azithromycin and placebo groups (2.0% [115/5889] vs 1.9% [110/5894]; risk difference [RD], 0.09 [95% CI, -0.39 to 0.57]), as was the incidence of neonatal mortality (0.8% vs 0.8%; RD, 0.04 [95% CI, -0.27 to 0.35]) and neonatal sepsis (1.3% vs 1.3%; RD, 0.02 [95% CI, -0.38 to 0.43]). Newborns in the azithromycin group compared with the placebo group had lower incidence of skin infections (0.8% vs 1.7%; RD, -0.90 [95% CI, -1.30 to -0.49]) and need for antibiotics (6.2% vs 7.8%; RD, -1.58 [95% CI, -2.49 to -0.67]). Postpartum parents in the azithromycin group had lower incidence of mastitis (0.3% vs 0.5%; RD, -0.24 [95% CI, -0.47 to -0.01]) and puerperal fever (0.1% vs 0.3%; RD, -0.19 [95% CI, -0.36 to -0.01]). Conclusions and Relevance: Azithromycin administered orally during labor did not reduce neonatal sepsis or mortality. These results do not support routine introduction of oral intrapartum azithromycin for this purpose. Trial Registration: ClinicalTrials.gov Identifier: NCT03199547.

Effects of testis testosterone deficiency on gene expression in the adrenal gland and skeletal muscle of ducks.

1. Testosterone has an anabolic effect on skeletal muscle. The testes produce most of the testosterone in vivo, while the adrenal glands contribute smaller amounts. When testis testosterone is deficient the adrenal gland increases steroid hormone synthesis, which is referred to as compensatory testicular adaptation (CTA).2. To reveal the effects of testis testosterone deficiency on adrenal steroid hormones synthesis and skeletal muscle development, gene expression related to adrenal steroid hormones synthesis and skeletal muscle development were determined by RNA-seq.3. The results showed that castrating male ducks had significant effects on their body weight but no significant impact on cross-sectional area (CSA) or density of pectoral muscle fibres. In skeletal muscle protein metabolism, expression levels of the catabolic gene atrogin1/MAFbx and the anabolic gene eEF2 were significantly higher, with concomitant increases after castration. The adrenal glands' alteration of the steroid hormone 11ß-hydroxylase (CYP11B1) was significantly lower following castration.4. Expression pattern analysis showed that the adrenal glands' glucocorticoid receptor (NR3C1/GR) had a potential regulatory relationship with the skeletal muscle-related genes (Pax7, mTOR, FBXO32, FOXO3, and FOXO4).5. The data showed that castration affected muscle protein metabolism, adrenal steroid and testosterone synthesis. In addition, it was speculated that, after castration, steroid hormones produced by the adrenal gland could have a compensatory effect, which might mediate the changes in skeletal muscle protein metabolism and development.

Genome-wide association analysis of neck ring traits in NongHua ma male ducks.

1. Male NongHua ma ducks have more colourful feathers than females, especially considering that the former have a distinctive neck ring that is different from that of females. This ring development might be influenced by sex selection, the environment, genetics and other elements.2. Genome-wide association analysis (GWAS) was used to locate candidate genes that affect the neck ring formation of male ducks to investigate the genetic basis of this phenomenon.3. In this study, the neck ring area and width of 180 male ducks were assessed at ages 80, 90, 100, 110 and 120 d. GWAS was used to identify associated genes. There were 0, 7, 14, 48 and 21 possible candidate genes annotated around the 0, 12, 25, 76 and 40 SNP loci n corresponding regions. A total of 13 candidate genes were identified around 21 SNP sites at the neck ring width of 120 d.4. These significant genes were annotated and GO and KEGG enrichment analyses were performed. All SNPs that exceeded the significance threshold were annotated and preliminarily screened as candidate genes affecting neck ring formation. From analysis of gene function and enriched KEGG pathways, genes such as THSD1, SLC6A4, DGAT2, PRKDC, B3GAT2, ROR1, GRK7, EXTL3, TXNDC12, COL4A2, PRKG1, ACTR3, were considered important candidate marker sites related to the neck ring. This provided a reference starting point for the genetic mechanism underlying duck feather colour.

[Clinical analysis of sirolimus as an alternative GVHD prophylaxis for patients with kidney injury undergoing allo-HSCT].

Objective: To explore the feasibility of sirolimus as an alternative graft versus host disease (GVHD) prophylaxis in patients with kidney injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Retrospective case series study. Medical records of 11 patients in Peking University People's Hospital from 1 August 2008 to 31 October 2022, who received sirolimus instead of cyclosporine to prevent GVHD, due to renal insufficiency after allo-HSCT, were analyzed retrospectively. Incidence of GVHD, infection, and transplant-associated thrombotic microangiopathy (TA-TMA), as well as renal function, were evaluated. Results: Among the 11 patients who received sirolimus, 6 were treated with haploidentical donor HSCT, and 5 were treated using matched sibling donor HSCT. The median (range) time of sirolimus administration was 30 (7-167) days after allo-HSCT, and the median (range) sirolimus course duration was 52 (9-120) days. During sirolimus treatment, 1 case did not undergo combined treatment with other prophylactic drugs, 3 cases received combined mycophenolate mofetil (MMF), and 1 case underwent combined CD25 monoclonal antibody treatment, while 6 cases had combined therapy with both MMF and CD25 monoclonal antibody. Of the 11 patients, 2 developed Grade Ⅲ acute GVHD, 1 developed severe pneumonia and died, and 1 developed TA-TMA, while nine patients had normal or improved renal function. Median (range) follow-up time was 130 (54-819) days. Non-relapse mortality was observed in 1 patient. Relapse mortality was also observed in 1 patient. Conclusion: Sirolimus-based alternative GVHD prophylaxis is a potentially viable option for patients undergoing allo-HSCT who cannot tolerate cyclosporine, but its efficacy and safety require further optimization and verification in prospective studies.

[Clinical analysis of the usefulness of letermovir for prevention of cytomegalovirus infection after haploidentical hematopoietic stem cell transplantation].

Objective: To analyze the efficacy and safety of letermovir in primary prophylaxis of cytomegalovirus (CMV) reactivation in patients receiving haploidentical hematopoietic stem cell transplantation. Methods: This retrospective, cohort study was conducted using data of patients who underwent haploidentical transplantation at Peking University Institute of Hematology and received letermovir for primary prophylaxis between May 1, 2022 and August 30, 2022. The inclusion criteria of the letermovir group were as follows: letermovir initiation within 30 days after transplantation and continuation for≥90 days after transplantation. Patients who underwent haploidentical transplantation within the same time period but did not receive letermovir prophylaxis were selected in a 1∶4 ratio as controls. The main outcomes were the incidence of CMV infection and CMV disease after transplantation as well as the possible effects of letermovir on acute graft versus host disease (aGVHD), non-relapse mortality (NRM), and bone marrow suppression. Categorical variables were analyzed by chi-square test, and continuous variables were analyzed by Mann-Whitney U test. The Kaplan-Meier method was used for evaluating incidence differences. Results: Seventeen patients were included in the letermovir prophylaxis group. The median patient age in the letermovir group was significantly greater than that in the control group (43 yr vs. 15 yr; Z=-4.28, P<0.001). The two groups showed no significant difference in sex distribution and primary diseases, etc. (all P>0.05). The proportion of CMV-seronegative donors was significantly higher in the letermovir prophylaxis group in comparison with the control group (8/17 vs. 0/68, χ2=35.32, P<0.001). Three out of the 17 patients in the letermovir group experienced CMV reactivation, which was significantly lower than the incidence of CMV reactivation in the control group (3/17 vs. 40/68, χ2=9.23, P=0.002), and no CMV disease development observed in the letermovir group. Letermovir showed no significant effects on platelet engraftment (P=0.105), aGVHD (P=0.348), and 100-day NRM (P=0.474). Conclusions: Preliminary data suggest that letermovir may effectively reduce the incidence of CMV infection after haploidentical transplantation without influencing aGVHD, NRM, and bone marrow suppression. Prospective randomized controlled studies are required to further verify these findings.

[Pelvic coronal inclination change in adolescent flexible flatfoot surgically treated with arthroereisis].

Objective: To evaluate adolescent pelvic coronal inclination angle change after flatfoot treated with arthroereisis. Method: A case-series study. From June 2018 to September 2020, 25 children with flexible flat foot and pelvic obliquity were included in this retrospective study in Peking University Shenzhen Hospital. There were 17 males and 8 females with a mean age of (11.2±2.2) years (9-15 years). There were 5 cases of unilateral flatfoot and 20 cases of bilateral flatfoot. All of the patients were surgically treated with arthroereisis. Regular follow-up was done in 3 months, 1 and 2 years postoperatively. Weightbearing fluoroscopy of entire lower limb and foot were investigated to measure Meary's angle, calcaneal pitch angle, height difference at ankle and pelvic plane, pelvic inclination and sacrum-iliac distance (F value) on coronal plane. Results: The mean Mearys' angle at 3 month postoperatively was improved when compared with that before the operation (3.1°±1.5° vs 25.9°±4.3°, P<0.001), and it remained at the same level 2 years after the operation (compared with that at 1 year after the operation, P=0.748). The calcaneal pitch angle improved significantly at 3-month follow-up when compared with that before the operation (16.6°±2.4° vs 9.9°±1.5°, P<0.001), and there was no significant change between 1 year and 2 years after operation (P=0.542). The height difference at mortise plane were also reduced at the 3-month follow-up(P<0.001), and it remained at the same level at 1 year and 2 years after the operation (P=0.159). Pelvic height difference decreased dramatically from (12.4±1.7) mm (before operation) to (7.1±1.2) mm(3 month after the operation) (P<0.001), it decreased to (3.6±1.8) mm 1 year after the operation (compared with that at 3 months after the operation, P<0.001), and no further reduction was observed 2 years after the surgery (P=0.483). The pelvic inclination angle and sacrum-iliac distance were also improved at 3-month follow-up when compared with those before the operation (both P<0.001), and they declined further 1 year after the operation(both P<0.05), but the decreasing trend disappeared at the 2-year follow-up (both P>0.05). Conclusion: For adolescent flexible flat foot patients with pelvic obliquity, the coronal inclination and pelvic height discrepancy would partially recovered with correction of flatfoot deformity, but it could not be completely corrected in the mean follow-up period of 2 years after the operation.

[Effect of Friday surgery on clinical outcome of elderly patients with hip fracture under multidisciplinary treatment].

Objective: To assess the impact of Friday surgery on clinical outcomes in elderly patients with hip fracture under multidisciplinary treatment. Methods: A retrospective cohort study. The clinical data of 414 geriatric patients with hip fractures admitted to Zhongda Hospital Affiliated with Southeast University from January 2018 to March 2021 were analyzed retrospectively, including 126 males and 288 females with a mean age of (81.3±7.6) years. The patients were divided into two groups based on whether they underwent surgery on Friday or not. The Friday group(n=69) and the non-Friday group(n=345) were compared in terms of general information, American Society of Anesthesiologists(ASA) classification, fracture type, injury to admission time, preoperative waiting time, surgical method, anesthesia type and use of intensive care unit (ICU) fast track. Propensity score matching (PSM) was performed based on age, ASA grade, time from injury to admission, preoperative waiting time, hemoglobin and albumin levels at admission. Clinical outcomes were collected and compared between the two groups, including length of hospital stay, total hospitalization cost and 30-day, 90-day and 1-year mortality rates, and postoperative complications. Multivariate logistic regression analyses were conducted to identify influencing factors for 1-year mortality in geriatric patients with hip fracture. Results: Baseline data showed statistically significant differences in hemoglobin, albumin and preoperative waiting time between the two groups (all P<0.05). After PSM matching, 69 patients were included in each group, and no significant differences were observed in baseline data between the two groups (all P>0.05). There was no significant differences in 30-day mortality rate (4.3% vs 0, P=0.080), 90-day mortality rate (7.2% vs 1.4%, P=0.095), length of hospital stay [(10.85±4.45)d vs (10.92±3.68)d, P=0.919], total hospitalization cost [(60.9±15.4) thousands yuan vs (59.1±15.4) thousands yuan, P=0.489], postoperative complications [pneumonia (11.6% vs 13.0%, P=0.796), cardio-cerebrovascular complications (11.6% vs 8.7%, P=0.573) and delirium (5.7% vs 2.9%, P=0.245)] between the Friday group and the non-Friday group (all P>0.05). However, the 1-year mortality rate was higher in the Friday group than that in the non-Friday group(18.8% vs 4.3%, P=0.008). Multivariate analysis revealed that surgery on Friday (OR=11.222, 95%CI: 2.198-57.291, P=0.004), low hemoglobin levels at admission (OR=0.920, 95%CI: 0.875-0.967, P=0.001), hemiarthroplasty treatment (OR=5.127, 95%CI: 1.308-20.095, P=0.019) and longer surgery duration (OR=0.958, 95%CI: 0.927-0.989, P=0.009) were influencing factors for 1-year mortality in geriatric patients with hip fracture. Conclusions: In the context of multidisciplinary treatment, Friday surgery does not increase short-term mortality, length of hospital stay, total hospitalization cost or incidence of complications in geriatric patients with hip fracture. However, it remains a influencing factor for 1-year mortality in those patients.

[Research progress of non-biological artificial liver support system therapy for paitents with liver failure].

Liver failure progresses quickly with high mortality. Non-biological artificial liver support system therapy is one of the important treatments for patients with liver failure. The basic techniques of non-biological artificial liver support system therapy include plasma exchange, plasma adsorption and continuous renal replacement therapy. In this paper, the effect and choice of these basic techniques, the treatment timing, the possible patients who may benefit, and the existing problems are summarized and discussed. We hope to provide a reference for the rational use of non-biological artificial liver support system therapy in clinical practice.

[Epidemiological characteristics of familiar adult inherited metabolic liver disease].

Inherited metabolic liver diseases can occur in multi-age groups such as children, adolescents, adults, and others. With the improvement of diagnosis and treatment levels, more and more patients with childhood-onset diseases are surviving into adulthood. Some diseases originally faced by pediatric hepatologists also appear in adult hepatology clinics. This raises new challenges for adult hepatologists, requiring them to master more professional knowledge. However, specific data on the incidence rate of most inherited metabolic liver diseases is still lacking in our country. This article reviews the research progress of hereditary metabolic liver diseases and summarizes the epidemiological characteristics of familiar hereditary metabolic liver diseases in China.

OCCURRENCE OF METFORMIN IN ENVIRONMENTAL WATER SAMPLES AND COMPARISON WITH CONSUMPTION DATA FROM A SURROUNDING HOSPITAL OVER 5 YEARS: A RETROSPECTIVE CASE STUDY.

Context: The environmental occurrence of metformin has been frequently world-widely reported. Despite the diabetes susceptibility in the Chinese population, the studies on occurrence of metformin as environment disruptor in China are insufficient. Objective: To determine the occurrence trends and possible environmental pollution sources of metformin as an emerging micropollutant. Methods: High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry system was used to detect the metformin levels in water samples collected from the Xi'an city Moat, China once a year from 2017 to 2021. Correlations among the metformin levels in moat water, in surrounding hospital wastewater, and hospital metformin consumption data were assessed using Pearson, Spearman and Kendall's tau-b correlation coefficients. Results: Occurrence of metformin was found in Xi'an city Moat water with levels in the range of 304-793 ng/L. Significant correlations were found between the metformin levels in city moat water and the total (or outpatient) metformin utilization data of the hospital. Conclusion: Data suggested the potential environmental issues posed by metformin in Xi'an city in China. The metformin consumption volume in the surrounding hospitals, especially at the outpatient services, could be used to predict the metformin concentrations in the moat water.

Exploring Lorentz Invariance Violation from Ultrahigh-Energy γ Rays Observed by LHAASO.

Recently, the LHAASO Collaboration published the detection of 12 ultrahigh-energy γ-ray sources above 100 TeV, with the highest energy photon reaching 1.4 PeV. The first detection of PeV γ rays from astrophysical sources may provide a very sensitive probe of the effect of the Lorentz invariance violation (LIV), which results in decay of high-energy γ rays in the superluminal scenario and hence a sharp cutoff of the energy spectrum. Two highest energy sources are studied in this work. No signature of the existence of the LIV is found in their energy spectra, and the lower limits on the LIV energy scale are derived. Our results show that the first-order LIV energy scale should be higher than about 10^{5} times the Planck scale M_{Pl} and that the second-order LIV scale is >10^{-3}M_{Pl}. Both limits improve by at least one order of magnitude the previous results.

Constraints on Heavy Decaying Dark Matter from 570 Days of LHAASO Observations.

The kilometer square array (KM2A) of the large high altitude air shower observatory (LHAASO) aims at surveying the northern γ-ray sky at energies above 10 TeV with unprecedented sensitivity. γ-ray observations have long been one of the most powerful tools for dark matter searches, as, e.g., high-energy γ rays could be produced by the decays of heavy dark matter particles. In this Letter, we present the first dark matter analysis with LHAASO-KM2A, using the first 340 days of data from 1/2-KM2A and 230 days of data from 3/4-KM2A. Several regions of interest are used to search for a signal and account for the residual cosmic-ray background after γ/hadron separation. We find no excess of dark matter signals, and thus place some of the strongest γ-ray constraints on the lifetime of heavy dark matter particles with mass between 10^{5} and 10^{9} GeV. Our results with LHAASO are robust, and have important implications for dark matter interpretations of the diffuse astrophysical high-energy neutrino emission.

The efficacy and safety of dupilumab in Chinese patients with moderate-to-severe atopic dermatitis: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Dupilumab is an antibody against interleukin-4 receptor α, used in the treatment of atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of dupilumab in adult Chinese patients with moderate-to-severe AD. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group, phase III study, conducted between December 2018 and February 2020, patients with AD received dupilumab (300 mg) or placebo once every 2 weeks for 16 weeks, and were followed up for 12 weeks. The primary efficacy endpoint was the proportion of patients with both an Investigator's Global Assessment score of 0-1 and a reduction from baseline of ≥ 2 points at week 16. RESULTS: Overall, 165 patients (mean age 30·6 years; 71·5% male patients) were randomized; 82 patients were randomized to dupilumab and 83 patients were randomized to placebo. At week 16, 26·8% of patients in the dupilumab group and 4·8% of patients in the placebo group achieved the primary endpoint [difference 22·0%, 95% confidence interval (CI) 11·37-32·65; P < 0·001]. Compared with placebo, higher proportions of patients in the dupilumab group achieved ≥ 75% reduction in the Eczema Area and Severity Index score (57·3% vs. 14·5%; difference 42·9%, 95% CI 29·75-55·97; P < 0·001) and had ≥ 3-point (52·4% vs. 9·6%; difference 42·8%, 95% CI 30·26-55·34; P < 0·001) and ≥ 4-point (39·0% vs. 4·8%; difference 34·2%, 95% CI 22·69-45·72; P < 0·001) reductions in weekly average daily peak daily pruritus numerical rating scale scores. The incidence of treatment-emergent adverse events during the treatment period was similar in the two groups. The incidence of conjunctivitis, allergic conjunctivitis and injection site reaction was higher in the dupilumab group than in the placebo group. CONCLUSIONS: In adult Chinese patients, dupilumab was effective in improving the signs and symptoms of AD and demonstrated a favourable safety profile.

First Report of Alternaria alternata Causing Leaf Spot Disease on Daylily in China.

Daylilies (Hemerocallis spp.; Xanthorrhoeaceae) originated from Eastern Asia and are widely cultivated as perennial ornamentals from the tropics to their native high latitudes. In June 2021, daylily cultivar 'Tao Hua Zhai' with leaf spot symptoms were found at the Shanghai Institute of Technology, Shanghai, China. The disease prevalence was about 14.5 % in a 33,000 m2 planting area indicated by survey statistics. Symptoms of the disease initially appeared as small, circular, brown spots on the leaves. As disease progressed, spots increased gradually until they were distributed uniformly over the lamina, the leaf tip became withered and the rest of the leaf became chlorotic. Symptomatic leaf tissue pieces (5 × 5 mm) from lesion margins were sterilized with 75 % ethanol for 1 min, rinsed three times with sterile distilled water, then incubated on potato dextrose agar (PDA) plates at 28 °C in the dark. A pure culture (ATHF-1) was obtained. Its upper surface on PDA was olive green with loose aerial hyphae, and its lower surface was brown.Conidiophores were brown, single or branched, producing numerous short chains conidia. Conidia were obclavate to obpyriform or ellipsoid, pale brown to dark brown, with a short cylindrical beak at the tip, contained 2-6 transverse septa and 0-4 longitudinal septa. The size of conidia were 15.9-47.3 µm × 7.6-16.6 µm (n=50), and length/width ratios were 1.51 to 4.92. Based on the morphological characteristics, the fungus was identified as Alternaria spp. (Simmons, 2007). For molecular characterization, three genes (the internal transcribed spacers [ITS], plasma membrane ATPase [ATPase] and major allergen Alt a 1) of ATHF-1 were amplified with primer pairs ITS1/ITS4 (White et al. 1990), ATPDF1/ATPDR1 (Lawrence et al. 2013) and Alt-for/Alt-rev (Hong et al. 2005), respectively. The sequences were deposited in GenBank (ITS, MZ983611; ATPase, MZ962978; Alt a 1, OK021654). Blastn searches showed the nucleotide sequences of ATHF-1 were highly similar to the reference sequences of Alternaria tenuissima (ITS, 99 % to KU982591; ATPase, 98 % to MT833928; Alt a 1, 100 % to MT109294). A phylogenetic tree based on the ITS, ATPase and Alt a 1 sequences was constructed by MEGA7.0, which showed that ATHF-1 was closely related to A. tenuissima and A. alternata. But according to Woudenberg et al. (2015), they were synonymized under the species name A. alternata. So, based on morphological and molecular characteristics, the fungus was identified as A. alternata. For pathogenicity tests, ten healthy two-month-old potted seedlings from tissue culture daylilies were sprayed with 20 ml of suspension (approximately 2×105 spores/ml), ten daylilies were used as controls and sprayed with sterile water. After covering with transparent plastic bags for 48 h to maintain humidity, the plants were placed in the greenhouse at 25 ℃ with 12 h photoperiod. The pathogenicity tests were repeated twice. Seven days after inoculation, lesions appeared on the plants inoculated with the pathogen, which were consistent with the symptoms observed in the field, while the controls remained symptomless. The morphological characteristics and gene sequences of the re-isolated strain from the diseased leaves were consistent with those of the inoculated strain. To our knowledge, this is the first report of A. alternata affecting leaf spot disease on daylily in China. Identification of the causal agent of the disease is important for developing effective disease management strategies. References: Hong, S.G., et al. 2005. Fungal Genet Biol. 42(2):119-129. https://doi.org/10.1016/j.fgb.2004.10.009 Lawrence, D.P., et al. 2013. Mycologia. 105(3):530-546. https://doi.org/10.3852/12-249 Simmons, E.G. 2007. Alternaria: An Identification Manual. CBS Fungal Biodiversity Centre, Utrecht, the Netherlands. White, T. J., et al. 1990. Amplification and Direct Sequencing of Fungal Ribosomal RNA Genes for Phylogenetics. PCR protocols: a guide to methods and applications, 18(1), 315-322. Woudenberg J.H.C., et al. 2015. Studies in Mycology. 82(82):1-21. https://doi.org/10.1016/j.simyco.2015.07.001.

Dynamic transcriptome profiling reveals essential roles of the receptor tyrosine kinases (RTK) family in feather development of duck.

1. The following study examined the expression profiles of the receptor tyrosine kinases (RTK) family in the developing feather follicles of Pekin ducks and Nonghua ducks at 6-9 weeks of age. The RTK subfamilies related to feather development were summarised, and other candidate genes related to feather development were enriched.2. To reveal the potential role of all RTK members in feather development, the feather follicles of two duck breeds (Pekin and Nonghua ducks) at 6-9 weeks were isolated and chosen for RNA-Seq determination.3. A total of 53 RTK members were confirmed in the duck genome, and 42 were expressed in duck feather follicles. Among RTK subfamilies, the VEGFR, PDGFR, FGFR, EGFR, and InsR subfamilies, along with and Met and KIT genes, were the main ones regulating feather growth.4. Genes with a similar expression pattern to the RTK were identified, and KEGG and PPI analyses were performed to explore the new potential feather development genes associated with RTK genes. Results showed that BCAR1, PXN, LAMA2, LAMC1 and LAMC3 are essential candidate genes for regulating feather growth.