Objective:To explore the impact of the two-way referral model on compliance and prognosis in patients with heart failure.Methods:This bidirectional cohort study enrolled chronic heart failure (CHF) patients treated at Qilu Hospital of Shandong University or designated primary hospitals between March 2018 and March 2022. Patients were categorized into two groups based on referral status: two-way referral group (participating in the referral model with≥1 follow-up visit at primary hospitals) and the core hospital group (receiving treatment and follow-up exclusively at Qilu Hospital). Baseline clinical characteristics were collected and compared between groups. Patients underwent followed-up, with primary endpoints including follow-up rate, drug (β-blockers, angiotension converting enzyme inhibitor (ACEI)/angiotensin Ⅱ receptor blockers (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists) utilization rate and target dose achievement rate. Secondary endpoints encompassed changes from baseline in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDd), and N-terminal pro-brain natriuretic peptide (NT-proBNP), plus cardiovascular mortality and heart failure rehospitalization. Generalized linear mixed models analyzed longitudinal trends in LVEF, LVEDd, and NT-proBNP levels. Kaplan-Meier curves and Cox regression evaluated LVEF recovery rates, supplemented by subgroup analyses. Multivariate logistic regression was used to identify factors influencing target dose achievement rate for β-blockers and ACEI/ARB/ARNI therapies in CHF patients.Results:A total of 357 patients were enrolled, aged 53 (41, 63) years, including 256 males (71.7%). 157 patients were in the two-way referral group and 200 patients in the core hospital-treated group. Compared with the core hospital-treated group, the two-way referral group had lower baseline LVEF (28 (22, 34)% vs. 31 (23, 36)%, P=0.021) and systolic blood pressure (116 (104, 125) mmHg vs. 121 (109, 134) mmHg (1 mmHg=0.133 kPa), P=0.010). The 12-month follow-up rate of the two-way referral group was higher than the core hospital-treated group (73.8% vs. 56.0%, P=0.004). No significant between-group differences were observed in drug utilization rate of β-blockers, ACEI/ARB/ARNI, or sodium-glucose cotransporter 2 inhibitors during follow-up (all P>0.05), while mineralocorticoid receptor antagonists use showed a declining trend in both groups. Although the core hospital-treated group had higher target dose achievement rates for β-blockers (65.4% vs. 49.3%, P=0.042) and ACEI/ARB/ARNI (79.8% vs. 65.8%, P=0.046) than the two-way referral group, multivariate logistic regression indicated that the two-way referral model was not a negative predictor for these outcomes (all P>0.05). Both groups showed improved NT-proBNP, LVEDd, and LVEF from baseline (all P<0.001) with no significant difference in trends between groups (all P>0.05). There was no significant difference in the composite incidence (7.6% vs. 6.5%, P=0.674) and cumulative incidence (log-rank P=0.684) of cardiovascular death and heart failure rehospitalization at 12 months between two groups. Conclusion:The two-way referral model demonstrates advantages in improving medication adherence, drug utilization rates, and targetdoseachievement rates among CHF patients. This model not only promotes cardiac functional recovery but also reduces risks of cardiovascular mortality and heart failure rehospitalization, achieving comparable therapeutic and management outcomes to those observed in core hospital-treated patients.

Perimenopause raises the risk and incidence of depression, whereas the underlying molecular mechanism remains unclear. Disturbed glucose regulation has been widely documented in depressive disorders, which renders the brain susceptible to various stresses such as estrogen depletion. However, whether and how glucose dysfunction regulates depression-like behaviors and neuronal damage in perimenopausal transition remains unexplored. Here, a prominent depressive phenotype was found in perimenopausal mice induced by the ovarian toxin 4-vinylcyclohexene diepoxide (VCD). The VCD depression susceptible group (VCD^SS) and the VCD depression resilient group (VCD^RES) were determined using a ROC-based behavioral screening approach. We found that the hippocampus, a crucial region linked to depression, had hyperglycemia and mitochondrial abnormalities. Interestingly, oral administration of the SGLT2 inhibitor empagliflozin (EMPA) and intrahippocampal glucose infusion suggest a close relationship between hyperglycemia in the hippocampus and the susceptibility to depression. We verified that cytochrome c oxidase 7c (COX7C) downregulation is a potential cause of the high glucose-induced neuronal injury using proteomic screening and biochemical validations. High glucose causes COX7C to be ubiquitinated in a S-phase kinase associated protein 1 (SKP1)-dependent manner. According to these results, SKP1/COX7C represents a unique therapeutic target and a novel molecular route for treating perimenopausal depression.

Objective:To explore the clinical characteristics and risk factors for the progression of severe scrub typhus in children.Methods:Clinical data, laboratory and auxiliary examination results, treatment and prognosis data of children with scrub typhus admitted to Xiamen Children's Hospital from July 2014 to March 2024 were collected. The clinical characteristics of scrub typhus in children were analyzed, and the study subjects were divided into severe group and mild group according to their condition. The relevant risk factors for progression to severe cases were analyzed.Results:A total of 42 cases were included, with 34 cases (80.95%) in the mild group and 8 cases (19.05%) in the severe group. All patients(100%) had fever, with the highest incidence of eschar or ulceration (95.24%), followed by lymphadenopathy and splenomegaly. All 42 patients improved or recovered after treatment with azithromycin or doxycycline, with no deaths reported. Compared with the mild group，the severe group had a higher incidence of cough, lymphadenopathy，and hepatomegaly, with statistically significant differences( P<0.05). Compared with the mild group, the severe group showed a decrease in hemoglobin(Hb), platelet, and fibrinogen(Fib) levels, while serum C-reactive protein(CRP), procalcitonin, aspartate aminotransferase, creatine kinase MB, and lactate dehydrogenase (LDH) levels increased, with statistically significant differences( P<0.05). Multivariate Tobit model analysis showed that a decrease in Hb ( OR -0.006，95% CI -0.012-0.000， P<0.05), an increase in CRP ( OR 2.72，95% CI 0.001-0.008， P=0.010), an increase in LDH ( OR 1.76，95% CI 0.000-0.000， P=0.027), and a decrease in Fib ( OR -3.78，95% CI -0.309-0.093， P=0.001) were risk factors for scrub typhus progressing to severe cases. Conclusion:During the epidemic season of scrub typhus, fever accompanied by eschar or ulceration, along with splenomegaly and lymphadenopath aids in the diagnosis of scrub typhus. Decreased Hb and Fib, as well as elevated CRP and LDH, are risk factors for the development of severe scrub typhus in children.

Objective:To investigate the detection and clinical features of human rhinovirus（HRV）infection in children from the Xiamen area.Methods:A retrospective analysis was conducted on children treated at Xiamen Children's Hospital from November 2021 to October 2022.Thirteen types of multiplex respiratory pathogen detection kits were used to screen for 13 common respiratory pathogens. Clinical data of HRV-positive hospitalized children were collected.Results:（1）Among 8 420 children with acute respiratory infections，HRV had the highest detection rate at 20.40%（1 718/8 420），followed by HMPV（10.12%），H3N2（7.46%），HRSV（6.94%），and HPIV（6.59%）.HRV was detected throughout the year，with the highest proportion in May（18.42%）.（2）Out of 1 718 children with HRV infection，863 cases were hospitalized for pneumonia（50.23%，863/1 718）.The median age of hospitalized children was 2.58（1.07，4.20）years old，with 53.77% under 3 years old.（3）The main clinical manifestations of HRV pneumonia were cough（97.68%，843/863），fever（58.05%，501/863），runny nose（57.01%，492/863），nasal congestion（36.96%，319/863），and wheezing（24.33%，210/843）. The HRV pneumonia co-infection group showed statistically significant differences in fever and hospitalization days compared to the single HRV pneumonia infection group（all P<0.05）.（4）Compared to the common pneumonia group，the severe HRV pneumonia group showed statistically significant differences in fever，runny nose，wheezing and hospitalization days the CRP, PCT, LDH levels, and the number of antibiotic applications after hospitalization（all P<0.05）. Conclusion:HRV infection is detected year-round in Xiamen，pneumonia is common，with children under 3 years old being particularly susceptible.It is important to be alert to mixed infections or severe pneumonia.Clinical treatment should avoid unnecessary antibiotic use，actively and provide appropriate treatment.

Objective:To explore the clinical characteristics and risk factors for the progression of severe scrub typhus in children.Methods:Clinical data, laboratory and auxiliary examination results, treatment and prognosis data of children with scrub typhus admitted to Xiamen Children's Hospital from July 2014 to March 2024 were collected. The clinical characteristics of scrub typhus in children were analyzed, and the study subjects were divided into severe group and mild group according to their condition. The relevant risk factors for progression to severe cases were analyzed.Results:A total of 42 cases were included, with 34 cases (80.95%) in the mild group and 8 cases (19.05%) in the severe group. All patients(100%) had fever, with the highest incidence of eschar or ulceration (95.24%), followed by lymphadenopathy and splenomegaly. All 42 patients improved or recovered after treatment with azithromycin or doxycycline, with no deaths reported. Compared with the mild group，the severe group had a higher incidence of cough, lymphadenopathy，and hepatomegaly, with statistically significant differences( P<0.05). Compared with the mild group, the severe group showed a decrease in hemoglobin(Hb), platelet, and fibrinogen(Fib) levels, while serum C-reactive protein(CRP), procalcitonin, aspartate aminotransferase, creatine kinase MB, and lactate dehydrogenase (LDH) levels increased, with statistically significant differences( P<0.05). Multivariate Tobit model analysis showed that a decrease in Hb ( OR -0.006，95% CI -0.012-0.000， P<0.05), an increase in CRP ( OR 2.72，95% CI 0.001-0.008， P=0.010), an increase in LDH ( OR 1.76，95% CI 0.000-0.000， P=0.027), and a decrease in Fib ( OR -3.78，95% CI -0.309-0.093， P=0.001) were risk factors for scrub typhus progressing to severe cases. Conclusion:During the epidemic season of scrub typhus, fever accompanied by eschar or ulceration, along with splenomegaly and lymphadenopath aids in the diagnosis of scrub typhus. Decreased Hb and Fib, as well as elevated CRP and LDH, are risk factors for the development of severe scrub typhus in children.

Objective:To investigate the detection and clinical features of human rhinovirus（HRV）infection in children from the Xiamen area.Methods:A retrospective analysis was conducted on children treated at Xiamen Children's Hospital from November 2021 to October 2022.Thirteen types of multiplex respiratory pathogen detection kits were used to screen for 13 common respiratory pathogens. Clinical data of HRV-positive hospitalized children were collected.Results:（1）Among 8 420 children with acute respiratory infections，HRV had the highest detection rate at 20.40%（1 718/8 420），followed by HMPV（10.12%），H3N2（7.46%），HRSV（6.94%），and HPIV（6.59%）.HRV was detected throughout the year，with the highest proportion in May（18.42%）.（2）Out of 1 718 children with HRV infection，863 cases were hospitalized for pneumonia（50.23%，863/1 718）.The median age of hospitalized children was 2.58（1.07，4.20）years old，with 53.77% under 3 years old.（3）The main clinical manifestations of HRV pneumonia were cough（97.68%，843/863），fever（58.05%，501/863），runny nose（57.01%，492/863），nasal congestion（36.96%，319/863），and wheezing（24.33%，210/843）. The HRV pneumonia co-infection group showed statistically significant differences in fever and hospitalization days compared to the single HRV pneumonia infection group（all P<0.05）.（4）Compared to the common pneumonia group，the severe HRV pneumonia group showed statistically significant differences in fever，runny nose，wheezing and hospitalization days the CRP, PCT, LDH levels, and the number of antibiotic applications after hospitalization（all P<0.05）. Conclusion:HRV infection is detected year-round in Xiamen，pneumonia is common，with children under 3 years old being particularly susceptible.It is important to be alert to mixed infections or severe pneumonia.Clinical treatment should avoid unnecessary antibiotic use，actively and provide appropriate treatment.

Objective:To explore the impact of the two-way referral model on compliance and prognosis in patients with heart failure.Methods:This bidirectional cohort study enrolled chronic heart failure (CHF) patients treated at Qilu Hospital of Shandong University or designated primary hospitals between March 2018 and March 2022. Patients were categorized into two groups based on referral status: two-way referral group (participating in the referral model with≥1 follow-up visit at primary hospitals) and the core hospital group (receiving treatment and follow-up exclusively at Qilu Hospital). Baseline clinical characteristics were collected and compared between groups. Patients underwent followed-up, with primary endpoints including follow-up rate, drug (β-blockers, angiotension converting enzyme inhibitor (ACEI)/angiotensin Ⅱ receptor blockers (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists) utilization rate and target dose achievement rate. Secondary endpoints encompassed changes from baseline in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDd), and N-terminal pro-brain natriuretic peptide (NT-proBNP), plus cardiovascular mortality and heart failure rehospitalization. Generalized linear mixed models analyzed longitudinal trends in LVEF, LVEDd, and NT-proBNP levels. Kaplan-Meier curves and Cox regression evaluated LVEF recovery rates, supplemented by subgroup analyses. Multivariate logistic regression was used to identify factors influencing target dose achievement rate for β-blockers and ACEI/ARB/ARNI therapies in CHF patients.Results:A total of 357 patients were enrolled, aged 53 (41, 63) years, including 256 males (71.7%). 157 patients were in the two-way referral group and 200 patients in the core hospital-treated group. Compared with the core hospital-treated group, the two-way referral group had lower baseline LVEF (28 (22, 34)% vs. 31 (23, 36)%, P=0.021) and systolic blood pressure (116 (104, 125) mmHg vs. 121 (109, 134) mmHg (1 mmHg=0.133 kPa), P=0.010). The 12-month follow-up rate of the two-way referral group was higher than the core hospital-treated group (73.8% vs. 56.0%, P=0.004). No significant between-group differences were observed in drug utilization rate of β-blockers, ACEI/ARB/ARNI, or sodium-glucose cotransporter 2 inhibitors during follow-up (all P>0.05), while mineralocorticoid receptor antagonists use showed a declining trend in both groups. Although the core hospital-treated group had higher target dose achievement rates for β-blockers (65.4% vs. 49.3%, P=0.042) and ACEI/ARB/ARNI (79.8% vs. 65.8%, P=0.046) than the two-way referral group, multivariate logistic regression indicated that the two-way referral model was not a negative predictor for these outcomes (all P>0.05). Both groups showed improved NT-proBNP, LVEDd, and LVEF from baseline (all P<0.001) with no significant difference in trends between groups (all P>0.05). There was no significant difference in the composite incidence (7.6% vs. 6.5%, P=0.674) and cumulative incidence (log-rank P=0.684) of cardiovascular death and heart failure rehospitalization at 12 months between two groups. Conclusion:The two-way referral model demonstrates advantages in improving medication adherence, drug utilization rates, and targetdoseachievement rates among CHF patients. This model not only promotes cardiac functional recovery but also reduces risks of cardiovascular mortality and heart failure rehospitalization, achieving comparable therapeutic and management outcomes to those observed in core hospital-treated patients.

Objective:To ulteriorly explore the differences of psychotic symptoms and neurocognitive between patients with first-episode deficit subtype of schizophrenia (FDS) and patients with first-episode nondeficit subtype of schizophrenia (FNDS).Methods:From January 2021 to September 2021, a total of 88 first-episode treatment-naive schizophrenia were recruited from the Mental Health Center of West China Hospital and divided into FDS group( n=44) and FNDS group( n=44) according to the schedule for the deficit syndrome (SDS), and 44 healthy subjects were included as healthy control group (HC group, n=44). Positive and negative syndrome scale (PANSS) was used to assess psychotic symptoms of patients and Wechsler adult intelligence scale, trail making test and logic memory test were used to evaluate intelligence quotient and neurocognitive function of all subjects.SPSS 22.0 was used for statistical analysis, and independent samples t-test and one-way analysis of variance (ANOVA) were used to compare variables that met normal distribution, while the Mann-Whitney U test and Kruskal-Wallis H test were used to compare variables that did not meet normal distribution. Results:(1) There were significant differences in psychotic symptoms between the FDS group and the FNDS group.Compared with the FNDS group, the FDS group had higher total score of PANSS ((95.95±16.82) vs (88.39±16.29)), negative symptoms ((27.57±7.52) vs (16.57±5.76)) and anergastic reaction ((13.43±3.82) vs (7.00(5.00, 9.00)), and lower positive symptoms scores ((21.95±6.88) vs (25.41±6.07)), activation ((8.00(5.00, 9.00) vs (9.27±3.47)), depression ((5.50(4.00, 9.00) vs (8.00(6.00, 12.00)) and supplementary item ((13.60±4.17) vs (17.30±5.39))(all P<0.05). (2) There were differences in neurocognitive functions between FDS group and FNDS group, and which in FDS and FNDS group were worse than that in HC group.Spatial memory (block design test: (23.70±11.05) vs (31.72±11.49)) and information processing speed (digit symbol test: (38.38±15.85) vs (47.97±14.99)) of FDS group were significantly lower than those of FNDS group(both P<0.05). Intelligence quotient, information processing speed and spatial memory of FDS group and FNDS group were lower than those of HC group(all P<0.05). Conclusion:FDS patients has more severe negative symptoms and anergastic reaction, and exit worse information processing speed and spatial memory dysfunction than FNDS patients.This unique pattern of impairment suggests that information processing speed and spatial memory may be important classification indicators for differentiating the deficit subtype of schizophrenia in the early stage.

New Delhi metallo-β-lactamase-1 (NDM-1) is capable of hydrolyzing nearly all β-lactam antibiotics, posing an emerging threat to public health. There are currently less effective treatment options for treating NDM-1 positive “superbug”, and no promising NDM-1 inhibitors were used in clinical practice. In this study, structure–activity relationship based on thiosemicarbazone derivatives was systematically characterized and their potential activities combined with meropenem (MEM) were evaluated. Compounds 19bg and 19bh exhibited excellent activity against 10 NDM-positive isolate clinical isolates in reversing MEM resistance. Further studies demonstrated compounds 19bg and 19bh were uncompetitive NDM-1 inhibitors with Ki = 0.63 and 0.44 μmol/L, respectively. Molecular docking speculated that compounds 19bg and 19bh were most likely to bind in the allosteric pocket which would affect the catalytic effect of NDM-1 on the substrate meropenem. Toxicity evaluation experiment showed that no hemolysis activities even at concentrations of 1000 mg/mL against red blood cells. In vivo experimental results showed combination of MEM and compound 19bh was markedly effective in treating infections caused by NDM-1 positive strain and prolonging the survival time of sepsis mice. Our finding showed that compound 19bh might be a promising lead in developing new inhibitor to treat NDM-1 producing superbug.

Endophytic fungi are promising producers of bioactive small molecules. Bioinformatic analysis of the genome of an endophytic fungus