Objective To understand the changing distribution and antimicrobial resistance profiles of Klebsiella strains in 52 hospitals across China in the CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021.Methods Antimicrobial susceptibility testing was carried out according to the unified CHINET protocol.The susceptibility results were interpreted according to the breakpoints in the Clinical & Laboratory Standards Institute(CLSI)M100 document.Results A total of 241,549 nonduplicate Klebsiella strains were isolated from 2015 to 2021,including Klebsiella pneumoniae(88.0％),Klebsiella aerogenes(5.8％),Klebsiella oxytoca(5.7％),and other Klebsiella species(0.6％).Klebsiella strains were mainly isolated from respiratory tract(48.49±5.32)％.Internal medicine(22.79±3.28)％,surgery(17.98±3.10)％,and ICU(14.03±1.39)％were the top 3 departments where Klebsiella strains were most frequently isolated.K.pneumoniae isolates showed higher resistance rate to most antimicrobial agents compared to other Klebsiella species.Klebsiella isolates maintained low resistance rates to tigecycline and polymyxin B.ESBLs-producing K.pneumoniae and K.oxytoca strains showed higher resistance rates to all the antimicrobial agents tested compared to the corresponding ESBLs-nonproducing strains.The K.pneumoniae and carbapenem-resistant K.pneumoniae(CRKP)strains isolated from ICU patients demonstrated higher resistance rates to majority of the antimicrobial agents tested than the strains isolated from non-ICU patients.The CRKP strains isolated from adult patients had higher resistance rates to most of the antimicrobial agents tested than the corresponding CRKP strains isolated from paediatric patients.Conclusions The prevalence of carbapenem-resistant strains in Klebsiella isolates increased greatly from 2015 to 2021.However,the Klebsiella isolates remained highly susceptible to tigecycline and polymyxin B.Antimicrobial resistance surveillance should still be strengthened for Klebsiella strains.

Objective:To study the early predictors of refractory septic shock (RSS) in neonates.Methods:From July 2020 to December 2021, clinical data of neonates with septic shock admitted to the Neonatal Department of our hospital were retrospectively reviewed. According to the maximum septic shock score (SSS) during clinical course, the neonates were assigned into RSS group and non-RSS group. Perinatal data, laboratory results and hemodynamic parameters at diagnosis were compared between the two groups. Multiple logistic regression analysis was used to identify independent risk factors of RSS and septic shock-related death. Receiver operating characteristic (ROC) curve was constructed to evaluate the early predictors of poor prognosis.Results:A total of 130 neonates were enrolled, including 54 in RSS group and 76 in non-RSS group. Compared with the non-RSS group, the RSS group had significantly lower pH, base excess (BE), stroke volume index (SVI), cardiac output (CO) and cardiac index (CI).Meanwhile, the RSS group had significantly higher mean arterial pressure (MAP) to CI ratio (MAP/CI) and SSS [including bedside SSS (bSSS), computed SSS (cSSS) and modified version of cSSS (mcSSS)] (all P<0.05). Multiple logistic regression analysis showed that increased MAP/CI was an independent predictor of RSS. The cut-off value of MAP/CI was 11.6 [sensitivity 62%, specificity 87%, positive predictive value (PPV) 79% and negative predictive value (NPV) 77%], with an area under the curve (AUC) of 0.734. Increased mcSSS was an independent predictor of septic shock-related death. The cut-off value of mcSSS was 5.8 (sensitivity 83%, specificity 72%, PPV 21% and NPV 97%), with an AUC of 0.845. Conclusions:Increased MAP/CI (≥11.6) and mcSSS (≥5.8) may be early predictors of RSS and septic shock-related death in neonates.

Purpose: This study aims to explore whether neoadjuvant chemotherapy with immunotherapy (NACI) leads to different tumor shrinkage patterns, based on magnetic resonance imaging (MRI), compared to neoadjuvant chemotherapy (NAC) alone in patients with triple-negative breast cancer (TNBC). Additionally, the study investigates the relationship between tumor shrinkage patterns and treatment efficacy was investigated. Methods: This retrospective study included patients with TNBC patients receiving NAC or NACI from January 2019 until July 2021 at our center. Pre- and post-treatment MRI results were obtained for each patient, and tumor shrinkage patterns were classified into three categories as follows: 1) concentric shrinkage (CS); 2) diffuse decrease; and 3) no change.Tumor shrinkage patterns were compared between the NAC and NACI groups, and the relevance of the patterns to treatment efficacy was assessed. Results: Of the 99 patients, 65 received NAC and 34 received NACI. The CS pattern was observed in 53% and 20% of patients in the NAC and NACI groups, respectively. Diffuse decrease pattern was observed in 36% and 68% of patients in the NAC and NACI groups. The association between the treatment regimens (NAC and NACI) and tumor shrinkage patterns was statistically significant (p = 0.004). The postoperative pathological complete response (pCR) rate was 45% and 82% in the NAC and NACI groups (p < 0.001), respectively. In the NACI group, 17% of patients with the CS pattern and 56% of those with the diffuse decrease pattern achieved pCR (p = 0.903). All tumor shrinkage patterns were associated with achieved a high pCR rate in the NACI group. Conclusion Our study demonstrates that the diffuse decrease pattern of tumor shrinkage is more common following NACI than that following NAC. Furthermore, our findings suggest that all tumor shrinkage patterns are associated with a high pCR rate in patients with TNBC treated with NACI.

Objective:To study the predictive value of vasoactive-inotropic score (VIS), fluid overload (FO) and lactate level for the outcome of preterm infants with refractory septic shock.Methods:Preterm infants diagnosed with refractory septic shock and required hydrocortisone treatment in our Department from January 2016 to December 2021 were analyzed retrospectively. Preterm infants were assigned into three gestational age groups (<28 weeks, 28-31 weeks, 32-36 weeks). According to the outcome of the disease, the children were further divided into good prognosis group and poor prognosis group. The relationship between the maximum VIS, FO and the mean lactic acid before hydrocortisone and the outcome of refractory septic shock was analyzed by receiver operating characteristic (ROC) curve, the cut-off point of ROC curve was calculated to obtain the predictive efficacy of the three indicators for the outcome of refractory septic shock in preterm infants.Results:A total of 50 preterm infants with refractory septic shock and received hydrocortisone treatment were enrolled, including 20 in the good prognosis group and 30 in the poor prognosis group. There were no significant differences in the maximum VIS, FO and mean lactic acid before hydrocortisone treatment between the two groups of gestational age of <32 weeks ( P> 0.05). The maximum VIS, FO and mean lactic acid of gestational age of 32-36 weeks in the poor prognosis group were higher than those in the good prognosis group, VIS: 56.1±15.7 vs. 37.1±12.9, FO (%): 108.2 (78.6,137.7) vs. 55.5 (10.3, 100.7), and mean lactic acid (mmol/L): 8.3 (4.6, 12.0) vs. 4.8 (-0.8, 10.5), all P<0.05. The area under the ROC curve of the mean lactic acid was the largest, the cut-off value was 4.1 mmol/L, and the Youden index was 1.732. Conclusions:VIS, FO and lactate level are difficult to be used for determining the outcome of refractory septic shock in preterm infants of <32 weeks. While the mean lactic acid has the best predictive performance in preterm infants of 32-36 weeks.

Delayed wound healing in diabetes is a global challenge, and the development of related drugs is a clinical problem to be solved. In this study, purpurolide C (PC), a small-molecule secondary metabolite of the endophytic fungus Penicillium purpurogenum, was found to promote diabetic wound healing. To investigate the key regulation targets of PC, in vitro RNA-seq, molecular docking calculations, TLR4-MD2 dimerization SDS-PAGE detection, and surface plasmon resonance (SPR) were performed, indicating that PC inhibited inflammatory macrophage activation by inhibiting both TLR4-MD2 dimerization and MYD88 phosphorylation. Tlr4 knockout in vivo attenuated the promotion effect of PC on wound healing. Furthermore, a delivery system consisting of macrophage liposome and GelMA-based microneedle patches combined with PC (PC@MLIP MN) was developed, which overcame the poor water solubility and weak skin permeability of PC, so that successfully punctured the skin and delivered PC to local tissues, and accurately regulated macrophage polarization in diabetic wound management. Overall, PC is an anti-inflammatory small molecule compound with a well-defined structure and dual-target regulation, and the PC@MLIP MN is a promising novel biomaterial for the management of diabetic wound.

Objective:To explore the effect of quality improvement of hemodynamic monitoring on fluid overload (FO) and outcome in newborns with septic shock.Methods:Non-invasive cardiac output monitoring and functional cardiac ultrasound quality improvement program was started during January 2020 in our hospital. Neonates with septic shock admitted before and after the program were retrospectively analyzed. From January 2018 to December 2019 was pre-improvement period when fluid resuscitation was routinely performed and vasoactive drugs was selected empirically. From January 2020 to December 2021 was post-improvement period when fluid resuscitation and/or use and adjustment of vasoactive drugs were guided by hemodynamic parameters. The 24 h, 48 h, 72 h FO, duration of invasive respiratory support, vasoactive-inotropic score, septic shock score, incidences of complications and all-cause mortality were compared between the two groups.Results:A total of 284 eligible cases were enrolled, including 136 cases in pre-improvement group and 148 cases in post-improvement group. Post-improvement group had significantly lower gestational age (GA), birth weight (BW) and body weight at disease onset than pre-improvement group ( P<0.05). Incidences of 48 h and 72 h FO, fluid resuscitation volume within 72 h, pulmonary hemorrhage and periventricular leukomalacia (PVL) were significantly lower in the post-improvement group ( P<0.05). No significant differences existed in 24 h FO, other complications and all-cause mortality between the two groups ( P>0.05). No significant differences existed in GA and BW for neonates with pulmonary hemorrhage and PVL between the two groups ( P>0.05). Conclusions:Quality improvement of hemodynamic monitoring can effectively improve FO and reduce the incidences of pulmonary hemorrhage and PVL.

Objective:To determine lysophosphatidic acid receptor 6 (LPAR6) expression in patients with mycosis fungoides (MF) , a variant of cutaneous T-cell lymphoma (CTCL) , and to investigate its role and mechanism of action in the development and prognosis of CTCL.Methods:A total of 110 patients with confirmed MF were collected from Department of Dermatology, Peking University First Hospital from 2011 to 2020, including 24 with large-cell transformation (LCT) and 25 with non-large cell transformation (NLCT) in the discovery cohort, and 24 with LCT and 37 with NLCT in the validation cohort. RNA sequencing and RT-PCR were conducted to determine the LPAR6 expression in patients in the discovery cohort and validation cohort respectively. LPAR6 expression was compared between patients with LCT and those with NLCT, and its effect on the prognosis of patients was evaluated. Two LPAR6-overexpressing CTCL cell lines MyLa and Sz4 were constructed to evaluate the effect of LPAR6 overexpression on proliferative activity of MyLa and Sz4 cells, with the cells normally expressing LPAR6 as the control group; after the treatment with LPAR6-related ligand lysophosphatidic acid (LPA) , 2S-OMPT, adenosine triphosphate (ATP) or adenosine (ADO) , the effects of LPAR6 activation on the proliferative activity and apoptosis of LPAR6-overexpressing MyLa and Sz4 cells were evaluated by the MTS method and flow cytometry respectively. Log-rank test was used for prognostic analysis, and t test or Mann-Whitney U test was used for comparisons between two groups. Results:As RNA sequencing showed, LPAR6 was one of the significantly underexpressed genes in the LCT group in the discovery cohort; in the validation cohort, LPAR6 expression (median[ Q1, Q3]) was significantly lower in the LCT group (204.90[81.90, 512.70]) than in the NLCT group (809.40[417.50, 1 829.20], U= 242.00, P= 0.002) ; in the two cohorts, the underexpression of LPAR6 was significantly associated with increased risk of poor prognosis (both P < 0.01) . Cell proliferation assay showed no significant difference in the proliferative activity of MyLa or Sz4 cells between the LPAR6 overexpression group and control group at 0, 24, 48 and 72 hours during the experiment (all P > 0.05) ; 48 hours after activation of LPAR6 by LPA, 2S-OMPT, ATP and ADO in MyLa cells, the LPAR6 overexpression group showed significantly decreased cellular proliferative activity (1.38 ± 0.01, 1.04 ± 0.01, 1.09 ± 0.03, 1.23 ± 0.01, respectively) compared the control group (1.73 ± 0.04, 1.23 ± 0.01, 1.24 ± 0.01, 1.42 ± 0.03, t= 30.33, 18.38, 4.78, 5.75, respectively, all P < 0.05) , but significantly increased cell apoptosis rate (17.93% ± 0.88%, 17.75% ± 0.35%, 23.97% ± 0.57%, 31.44% ± 0.34%, respectively) compared the control group (3.98% ± 0.03%, 7.81% ± 0.59%, 11.95% ± 0.85%, 12.02% ± 0.48%, t= 15.93, 14.49, 11.74, 33.01, respectively, all P < 0.05) ; 48 hours after activation of LPAR6 by 2S-OMPT and ADO in Sz4 cells, compared with the control group, the LPAR6 overexpression group also showed significantly decreased cellular proliferative activity (2S-OMPT: 1.29 ± 0.04 vs. 1.48 ± 0.01; ADO: 1.27 ± 0.01 vs. 1.51 ± 0.02; both P < 0.05) , but significantly increased cell apoptosis rate (2S-OMPT: 41.70% ± 0.70% vs. 29.35% ± 0.55%; ADO: 37.05% ± 0.15% vs. 24.60% ± 1.00%; both P < 0.05) . Conclusions:LPAR6 was underexpressed in the patients with LCT, and its underexpression was significantly associated with increased risk of poor prognosis. In vitro activation of LPAR6 could inhibit the proliferation of CTCL cells and promote their apoptosis, suggesting that the decrease of LPAR6 expression may be one of the important mechanisms underlying disease progression in patients with LCT.

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

Heart failure and stroke are the important causes of death worldwide, and both are closely related. This article reviews the prevention and reperfusion therapy of ischemic stroke in patients with heart failure.

Objective:To study the efficacy of norepinephrine in the treatment of neonates with septic shock.Methods:A prospective observation study of neonates with septic shock, who received norepinephrine in the neonatal intensive care unit of Guangdong Women and Children's Hospital from January 2019 to November 2020. All infants had functional echocardiography for hemodynamic monitoring before norepinephrine treatment and 1 hour thereafter blood pressure, heart rate, arterial blood gas analyses were recorded at the same time. The intravenous fluid volume and urine volume from the diagnosis of shock to the commencement of norepinephrine therapy (T0) and 24 hours thereafter (T1) were recorded, and the hemodynamic parameters, vasoactive drugs and clinical outcomes were analyzed.Results:A total of 66 newborns were enrolled, including 27 cases of mild shock, 33 cases of moderate shock and 6 cases of severe shock. 48 were male infants, 38 cases were premature infants. The gestational age was (35.2±4.1) weeks and the birth weight was (2 476±909) g. The median time of shock diagnosis was 2 days after birth, and the median shock score was 4 points. The median time from the diagnosis of shock to the start of norepinephrine treatment was 7.5 hours. Compared with that before norepinephrine treatment, stroke volume, stroke volume index, cardiac output, cardiac index, left ventricular ejection fraction, shortening fraction, systolic blood pressure, diastolic blood pressure, mean arterial pressure, blood pH and BE at 1 hour after treatment were increased, heart rate and blood lactic acid were decreased, the differences were statistically significant ( P<0.05). Urine volume was increased 24 hours after treatment ( P<0.05), and fluid overload decreased ( P<0.05). The maximum dopamine dose, the down-regulation time and duration of vasoactive drugs were positively correlated with the time to start norepinephrine therapy ( r=0.325、 r=0.383、 r=0.319, P<0.05). Among the 66 infants, 58 infants with shock had been corrected and 14 infants died within 28 days. Conclusions:Norepinephrine is effective and feasible in the treatment of neonatal septic shock and can significantly improve hemodynamic parameters.