BACKGROUND: Chronic kidney disease (CKD)-associated anemia (CKD-anemia) is associated with poor survival, and hemoglobin targets are often not achieved with current therapies. Phase 3 trials have demonstrated the treatment efficacy of roxadustat for CKD-anemia. This phase 4 study aims to evaluate the long-term (52-week) safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China. METHODS: This Phase 4 multicenter, open-label, prospective study, conducted from 24 November 2020 to 11 November 2022, evaluated the long-term safety and effectiveness of roxadustat for CKD-anemia in China. Patients aged ≥18 years with CKD-anemia with or without dialysis were included. The initial oral dose was 70-120 mg (weight-based followed by dose adjustment) over 52 weeks. The primary endpoint was safety based on adverse events (AEs). The secondary endpoints were hemoglobin changes from baseline and the proportion of patients who achieved mean hemoglobin ≥100 g/L. Effectiveness evaluable populations 1 (EE1) and EE2 included roxadustat-naïve and previously roxadustat-treated patients, respectively. The safety analysis set (SAF) included all patients who received ≥1 occasion. RESULTS: The EE1, EE2, and SAF populations included 1804, 193, and 2021 patients, respectively. In the SAF, the mean age was 50 ± 14 years, and 1087 patients (53.8%) were male. Mean baseline hemoglobin was 96.9 ± 14.0 g/L in EE1 and 100.3 ± 12.9 g/L in EE2. In EE1, the mean (95% confidence interval) hemoglobin changes from baseline over weeks 24-36 and 36-52 were 14.2 (13.5-14.9) g/L and 14.3 (13.5-15.0) g/L, respectively. Over weeks 24-36 and 36-52, 83.3% and 86.1% of patients in EE1 and 82.7% and 84.7% in EE2 achieved mean hemoglobin ≥100 g/L, respectively. In the SAF, 1643 (81.3%) patients experienced treatment-emergent AEs (TEAEs). Overall, 219 (10.8%) patients experienced drug-related TEAEs. Thirty-eight (1.9%) patients died of TEAEs (unrelated to the study drug). Vascular access thrombosis was uncommon. CONCLUSIONS: Roxadustat (52 weeks) increased hemoglobin and maintained the treatment target in Chinese patients with CKD-anemia with acceptable safety, supporting its use in real-world settings. REGISTRATION Chinese Clinical Trial Registry ( www.chictr.org.cn ) ChiCTR2100046322; CDE ( www.chinadrugtrials.org.cn ) CTR20201568.
Humans ; Male ; Female ; Anemia/etiology* ; Middle Aged ; Renal Insufficiency, Chronic/complications* ; Glycine/adverse effects* ; Isoquinolines/adverse effects* ; Aged ; Prospective Studies ; Adult ; Hemoglobins/metabolism* ; Treatment Outcome ; China ; Registries ; East Asian People

L-citrulline is a nonprotein amino acid that plays an important role in human health and has great market demand. Although microbial cell factories have been widely used for biosynthesis, there are still challenges such as genetic instability and low efficiency in the biosynthesis of L-citrulline. In this study, an efficient, plasmid-free, non-inducible L-citrulline-producing strain of Escherichia coli BL21(DE3) was engineered by combined strategies. Firstly, a chassis strain capable of synthesizing L-citrulline was constructed by block of L-citrulline degradation and removal of feedback inhibition, with the L-citrulline titer of 0.43 g/L. Secondly, a push-pull-restrain strategy was employed to enhance the L-citrulline biosynthesis, which realized the L-citrulline titer of 6.0 g/L. Thirdly, the NADPH synthesis and L-citrulline transport were strengthened to promote the synthesis efficiency, which achieved the L-citrulline titer of 11.6 g/L. Finally, fed-batch fermentation was performed with the engineered strain in a 3 L fermenter, in which the L-citrulline titer reached 44.9 g/L. This study lays the foundation for the industrial production of L-citrulline and provides insights for the modification of other amino acid metabolic networks.
Citrulline/biosynthesis* ; Escherichia coli/genetics* ; Metabolic Engineering/methods* ; Fermentation ; NADP/biosynthesis*

Background The substantial health damage attributed to heat waves, along with their increasing intensity and frequency in the context of global warming, highlights the importance of exploring the health effects of heat waves. Objective To calculate the excess heat stroke cases during heat waves in the summer of 2013—2023 in Shanghai, analyze the association between heat waves and heat stroke, and to further explore the modifying effects of heat wave characteristics on heat stroke. Methods Using a retrospective ecological study design, data on heat stroke cases were collected from the heat stroke case reporting system of the Chinese Center for Disease Control and Prevention, and concurrent meteorological data from Xujiahui Meteorological Station. A heat wave was defined as at least 3 consecutive days with daily maximum temperature meeting or exceeding 35 ℃ in this study, excess heat stroke cases related to heat waves were assessed as the difference between the numbers of heat stroke cases observed on a given day and the corresponding 31 d (15 d before and after that day) moving average, and statistical analyses using generalized linear model based on time series study were performed to assess the impact of heat waves on heat stroke. Results Overall 25 heat waves during the study period were observed, leading to a total of estimated 792.6 extra heat stroke cases. The risk of heat stroke significantly increased during heat waves (RR=2.60, 95%CI: 2.08, 3.26), but no statistically significant differences in heat wave effects were observed among different genders, ages, or regions. In terms of the timing of heat waves, the risk of heat stroke was highest during the first heat wave (RR=3.58, 95%CI: 2.82, 4.55), which was significantly higher than that during the second heat wave (RR=2.19, 95%CI: 1.66, 2.90), and no significant effect was observed during the third or subsequent heat waves. The impact of heat waves on heat stroke persisted for more than 4 d, with the risk higher on the fourth day and beyond (RR=2.95, 95%CI: 2.28, 3.83), significantly higher than on the first day of heat wave (RR=1.74, 95%CI: 1.18, 2.56). Conclusion Heat waves had a substantial effect on heat stroke in Shanghai from 2013 to 2023, and special attention need to be paid to heat waves with early onset and long duration.

The pathological classification and diagnostic criteria for lung neuroendocrine neoplasms (NENs) in the 2021 World Health Organization (WHO) lung tumor classification are similar to the prior classifications. However, the advances on the molecular studies of lung NENs have shown that both small cell lung carcinoma and large cell neuroendocrine carcinoma are highly heterogeneous tumors with neuroendocrine characteristics and can be subclassified based on the features of genomics or transcriptomics, which are valuable in the diagnosis of lung NENs subtypes and patient treatment. In addition, it is necessary to interpret emerging concepts such as "lung neuroendocrine tumor G3" and "histological transformation" from pathological perspectives, as well as to know the novel neuroendocrine biomarkers such as INSM1 and POU2F3. This article summarized the diagnostic changes and the advances of molecular pathology of lung NENs based on the latest WHO classification and molecular research.

Background:Following the short-term outbreak of coronavirus disease 2019(COVID-19)in December 2022 in China,clinical data on kidney transplant recipients(KTRs)with COVID-19 are lacking.Methods:We conducted a single-center retrospective study to describe the clinical features,complications,and mortality rates of hospitalized KTRs infected with COVID-19 between Dec.16,2022 and Jan.31,2023.The patients were followed up until Mar.31,2023.Results:A total of 324 KTRs with COVID-19 were included.The median age was 49 years.The median time between the onset of symptoms and admission was 13 d.Molnupiravir,azvudine,and nirmatrelvir/ritonavir were administered to 67(20.7%),11(3.4%),and 148(45.7%)patients,respectively.Twenty-nine(9.0%)patients were treated with more than one antiviral agent.Forty-eight(14.8%)patients were treated with tocilizumab and 53(16.4%)patients received baricitinib therapy.The acute kidney injury(AKI)occurred in 81(25.0%)patients and 39(12.0%)patients were admitted to intensive care units.Fungal infections were observed in 55(17.0%)patients.Fifty(15.4%)patients lost their graft.The 28-d mortality rate of patients was 9.0%and 42(13.0%)patients died by the end of follow-up.Multivariate Cox regression analysis identified that cerebrovascular disease,AKI incidence,interleukin(IL)-6 level of>6.8 pg/mL,daily dose of corticosteroids of>50 mg,and fungal infection were all associated with an increased risk of death for hospitalized patients.Conclusions:Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of mortality.The administration of immunomodulators or the late application of antiviral drugs does not improve patient survival,while higher doses of corticosteroids may increase the death risk.

Objective:To evaluate the feasibility and safety of PT Scope (short for intelligent pressure and temperature controlled flexible ureteroscopy)combined with Thulium laser in the intracavitary treatment of upper urinary tract stones.Methods:A retrospective analysis was conducted on the clinical data of 13 patients with upper urinary tract stones who were treated with PT Scope combined with Thulium laser lithotripsy in Sun Yat-Sen Memorial Hospital from February to April 2024. There were 7 males and 6 females. The patients had a mean age of (46±10) years old, with an accumulated stone diameter of (25.8±13.3) mm. There were 7 cases of lower calyx stones (53.8%), and 3 cases of concomitant ureteral stones (23.1%).Four patients (30.8%) had positive preoperative urine cultures, and six patients (46.2%) had leukocyte counts greater than 100 cells/μl in their urine tests. The Thulium laser power was set at 45 W (1.5 J at 30 Hz, 0.3 J at 150 Hz). The renal pelvic pressure threshold was set at 30 mmHg (1 mmHg=0.133 kPa), and the temperature threshold at 43 ℃. Postoperatively, double J stents were placed for 2 to 4 weeks.Results:All 13 patients successfully completed the surgery. The median operative time was 30 (25, 90) minutes. The intraoperative average renal pelvic pressure in these 13 patients ranged from 8 mmHg to 24 mmHg, and the average renal pelvic temperature ranged from 25 ℃ to 34 ℃. Postoperatively, 1 patient experienced a fever (38.0 ℃) and 2 patients required analgesic treatment due to postoperative pain. There were no other intraoperative or postoperative complications. The median postoperative hospital stay was (1.5±0.8) days. The stone-free rate of 1 month was 84.6%(11/13).Conclusions:PT Scope combined with Thulium laser could effectively control renal pelvic pressure and temperature, achieve a high stone-free rate, and have a low complication rate. It is a safe and effective treatment for upper urinary tract stones.

Objective To explore PM_2.5 concentration modeling and prediction based on the monthly average concentrations of PM_2.5 in Shanghai since 2015, and to provide new ideas about PM_2.5 prediction methods. Methods The seasonal factors were introduced into the Grey Model (GM). GM(1,1) model modified with seasonal factors was established and compared with seasonal autoregressive integrated moving average model (ARIMA) model. The data of 2015-2021 was used for modeling and prediction, and the data from January to October in 2022 was used as a validation set to evaluate the prediction effectiveness. The monthly average PM_2.5 concentrations in Shanghai from November to December in 2022 were predicted. Results Seasonal ARIMA model showed RMSE=4.02 and MAPE=15.50% in the validation set, while GM(1,1) model modified with seasonal factors showed RMSE=3.30 and MAPE=11.59%. GM(1,1) model modified with seasonal factors predicted the monthly average PM_2.5 concentrations in Shanghai from November to December in 2022 to be 24.99 and 34.83μg/m3, respectively. Conclusion The prediction effect of GM(1,1) model modified with seasonal factors has better predictive performance than seasonal ARIMA model. The grey prediction model modified with seasonal factors can be considered when predicting seasonal time series such as the concentration of PM_2.5.

Objective:To explore the influencing factors of acute rejection (AR) within one year after pediatric kidney transplantation (KT) and the effect of AR onset time on prognosis.Methods:From January 2011 to October 2021, a total of 112 patients aged under 18 years at the time of transplantation were selected.After excluding 6 of them with early renal non-function caused by non-rejection, 106 cases were examined.There were 63 males and 43 females with the age of 15(12, 16) years.The donors were living related (n=26) and deceased (n=80).According to the presence/absence and onset time of AR, they were assigned into three groups of AR within one year, AR after one year and non-AR.The relevant clinical data of donor/recipient, influencing factors of AR and therapeutic outcomes of AR were retrospectively compared.One-way ANOVA or Kruskal-Wallis test was utilized for comparing 1-year renal function after the occurrence of AR among three groups.With graft-function loss as an end-point event of follow-up, the effects of AR within one year and AR after one year on survival rate and function of graft-kidney were analyzed by Kaplan-Meier survival curve.Results:The median follow-up period of 106 pediatric KT recipients was 35 months.During follow-ups, 19 episodes of AR occurred in 17(16.0%) patients and 89 recipients exhibited no AR episode by the end of follow-up (non-AR group).As for initial AR, 9 episodes of AR occurred within one year (AR within one year group) and 8 episodes of AR after one year (AR after one year group).After anti-rejection treatment, 8 patients (47.1%) achieved full recovery and 6 patients (35.3%) failed to completely normalize and 3 patients (17.6%) developed graft failure.Univariate analysis indicated that, as compared with non-AR group, female recipients, donors aged under 8 years and early postoperative infection with parvovirus B19 were risk factors of AR within one year ( P=0.032, P=0.039, P=0.047).Kaplan-Meier survival analysis revealed that the incidence rates of AR within one year in patients with donors aged under 8 years and early postoperative parvoviral infection were 14.5%(8/55) and 30.0%(3/10) respectively.They were significantly higher than 2.0%(1/51) and 6.3%(6/96) of patients with donors aged above 8 years and those without parvoviral infection ( P=0.012, P=0.004).With graft-function loss as an end-point event of follow-up, Kaplan-Meier survival analysis showed that 10-year kidney graft survival rate in AR within one year and AR after one year groups were 88.9% and 65.6%.Both were significantly lower than that in non-AR group (98.9%).And the inter-group differences were statistically significant ( χ2=4.286, P=0.038; χ2=7.787, P=0.005).However, no significant difference existed in survival rate between AR within one year and AR after one year groups ( P=0.689).One-way ANOVA and Kruskal-Wallis test indicated that estimated glomerular filtration rates at 3/6/12 months after an onset of AR in AR within one year group were (76.8±51.6), (80.6±56.6) and (85.6±40.2) ml·min -1·1.73 m -2.The values of 3/6 months were lower than (125.3±39.2) and (124.7±38.2) ml·min -1·1.73 m -2 in AR after one year group.And the inter-group differences were statistically significant ( P=0.021, P=0.039).The values of 3/6/12 months were lower than (112.2±34.2), (115.3±33.2) and (117.4±30.2) ml·min -1·1.73 m -2 in non-AR group.And the inter-group differences were also statistically significant ( P=0.019, P=0.020, P=0.020). Conclusions:Female recipients, donors aged under 8 years and early postoperative infection with parvovirus B19 may elevate the risks of AR in children within one year of KT.AR within one year affects the survival rate of graft-kidney and renal function.