Consensus for antifungal stewardship in China (2024 edition).

Background: Invasive fungal disease (IFD) has become a serious threat to human health in China and around the world, with high mortality and morbidity. Currently, the misdiagnosis rate of IFD is extremely high, compounded with the low quality of prescription antifungals and the high incidence of adverse events associated with IFD treatment, resulting in lengthy hospitalization, low clinical response, and high disease burden, which have become serious challenges in clinical practice. Antifungal stewardship (AFS) can not only significantly increase the early diagnosis rate of IFD, reduce inappropriate utilization of antifungal drugs, improve patient prognosis, but can also improve therapeutic safety and reduce healthcare expenses. Thus, it is urgent to identify key AFS metrics suitable for China's current situation. Methods: Based on metrics recommended by international AFS consensuses, combined with the current situation of China and the clinical experience of authoritative experts in various fields, several metrics were selected, and experts in the fields of respiratory diseases, hematology, intensive care units (ICUs), dermatology, infectious diseases, microbiology laboratory and pharmacy were invited to assess AFS metrics by the Delphi method. Consensus was considered to be reached with an agreement level of ≥80% for the metric. Results: Consensus was reached for 24 metrics, including right patient metrics (n=4), right time metrics (n=3), and right use metrics (n=17). Right use metrics were further subdivided into drug choice (n=8), drug dosage (n=4), drug de-escalation (n=1), drug duration (n=2), and drug consumption (n=2) metrics. Forty-six authoritative experts assessed and reviewed the above metrics, and a consensus was reached with a final agreement level of ≥80% for 22 metrics. Conclusions: This consensus is the first to propose a set of AFS metrics suitable for China, which helps to establish AFS standards in China and is also the first AFS consensus in Asia, and may improve the standard of clinical diagnosis and treatment of IFD, and guide hospitals to implement AFS, ultimately promoting the rational use of antifungal drugs and improving patient prognosis.

Effect of modified Baduanjin exercise on nutritional status in patients with nasopharyngeal carcinoma: a randomized controlled trial.

BACKGROUND: As a traditional Chinese fitness technique, Baduanjin is a low- to medium-intensity aerobic exercise that has a common regulatory effect on both body and mind and is also an important means of disease prevention and treatment. However, the role of Baduanjin in improving patients' nutritional status and promoting tumor recovery remains to be confirmed. OBJECTIVE: This study aims to investigate the effectiveness of the modified Baduanjin exercise on the nutritional status of patients with nasopharyngeal carcinoma. DESIGN: This is a randomized controlled trial. SETTING(S): The participants were recruited from patients in the Radiotherapy Department of the First Affiliated Hospital of Guangxi Medical University in China. PARTICIPANTS: A total of 121 patients with nasopharyngeal carcinoma were randomly divided into the control group and the Baduanjin group. Finally, 106 patients completed the study (53 cases each in the control group and the Baduanjin group) with the intervention time from the beginning to the end of radiotherapy. METHODS: The control group received conventional care (health education and regular conventional exercise), and the Baduanjin exercise group received health education and regularly improved Baduanjin exercise, with the intervention time from the beginning to the end of the radiotherapy. Patient-generated subjective global assessment (PG-SGA) was evaluated before, during (15 times), and at the end of radiotherapy as the main evaluation index to compare nutritional status between the two groups. RESULTS: From August 2022 to December 2022, 121 patients with nasopharyngeal carcinoma were randomly divided into the control group and the Baduanjin group. During the intervention, 15 patients withdrew from the study, leading to 53 of 59 patients in the control group and 53 of 62 patients in the Baduanjin group. After the intervention, the PG-SGA score, radioactive oral mucositis, and oropharyngeal pain score were lower (P < 0.05), whereas anorexia scores, the levels of hemoglobin, albumin, prealbumin, and total protein were higher than those in the control group (P < 0.05). CONCLUSIONS: Modified Baduanjin exercise can improve the nutritional status of patients with nasopharyngeal carcinoma and deserves further clinical application. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry under the registration number ChiCTR2200064519, registered on August 27, 2022. The public research topic is the construction and intervention research based on Internet + nasopharyngeal carcinoma.

NPh3-Mediated WO3-Photocatalyzed Semiheterogeneous Hydroxylation of Aryl and Alkyl Boronic Acids.

With an inexpensive and commercially available WO3 semiconductor as the heterogeneous photocatalyst, a catalytic amount of NPh3 as the single-electron donor, and ambient air as the single-electron acceptor and oxygen source, the semiheterogeneous photocatalytic hydroxylation of alkyl and aryl boronic acids was developed. A broad range of hydroxylated compounds can be obtained in excellent yields.

Cytology or Multiparameter Flow Cytometry Positivity in the Cerebrospinal Fluid Before Transplantation is Predictive of Poor Outcomes After Allotransplantation in Acute Myeloid Leukemia Patients.

INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.

Risk factors for positive post-transplantation measurable residual disease in patients with acute lymphoblastic leukemia.

BACKGROUND: The level of measurable residual disease (MRD) before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-hematopoietic stem cell transplantation measurable residual disease (pre-HSCT MRD). However, only a few work has been devoted to the risk factors for positive post-HSCT MRD in patients with acute lymphoblastic leukemia (ALL). This study evaluated the risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 1683 ALL patients from Peking University People's Hospital between January 2009 and December 2019 were enrolled to evaluate the cumulative incidence of post-HSCT MRD. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis. RESULTS: Both in total patients and in T-cell ALL or B-cell ALL, pediatric or adult, human leukocyte antigen-matched sibling donor transplantation or haploidentical SCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity (P <0.001 for all). Disease status (complete remission 1 [CR1] vs. ≥CR2) was also a risk factor for post-HSCT MRD positivity in all patients and in the B cell-ALL, pediatric, or haploidentical SCT subgroups (P = 0.027; P = 0.003; P = 0.035; P = 0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively (P <0.001). Multivariate analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as leukemia-free survival and overall survival. CONCLUSION: Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allo-HSCT.

Safety and efficacy of baricitinib in steroid-resistant or relapsed immune thrombocytopenia: An open-label pilot study.

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 109/L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 109/L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.

Rapid and Amplification-free Nucleic Acid Detection with DNA Substrate-Mediated Autocatalysis of CRISPR/Cas12a.

To enable rapid and accurate point-of-care DNA detection, we have developed a single-step, amplification-free nucleic acid detection platform, a DNA substrate-mediated autocatalysis of CRISPR/Cas12a (DSAC). DSAC makes use of the trans-cleavage activity of Cas12a and target template-activated DNA substrate for dual signal amplifications. DSAC employs two distinct DNA substrate types: one that enhances signal amplification and the other that negatively modulates fluorescent signals. The positive inducer utilizes nicked- or loop-based DNA substrates to activate CRISPR/Cas12a, initiating trans-cleavage activity in a positive feedback loop, ultimately amplifying the fluorescent signals. The negative modulator, which involves competitor-based DNA substrates, competes with the probes for trans-cleaving, resulting in a signal decline in the presence of target DNA. These DNA substrate-based DSAC systems were adapted to fluorescence-based and paper-based lateral flow strip detection platforms. Our DSAC system accurately detected African swine fever virus (ASFV) in swine's blood samples at femtomolar sensitivity within 20 min. In contrast to the existing amplification-free CRISPR/Dx platforms, DSAC offers a cost-effective and straightforward detection method, requiring only the addition of a rationally designed DNA oligonucleotide. Notably, a common ASFV sequence-encoded DNA substrate can be directly applied to detect human nucleic acids through a dual crRNA targeting system. Consequently, our single-step DSAC system presents an alternative point-of-care diagnostic tool for the sensitive, accurate, and timely diagnosis of viral infections with potential applicability to human disease detection.

Measurable residual disease testing by next generation sequencing is more accurate compared with multiparameter flow cytometry in adults with B-cell acute lymphoblastic leukemia.

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34-8.5; P = 0.01) and worse survival (HR = 4.87 [1.53-15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTROPC-14005546]).

Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: A real-world multicenter study.

Membranous nephropathy (MN) is a rare complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MN patients may develop nephrotic syndrome or even kidney failure, which greatly affects their quality of life and prognosis. However, current knowledge regarding MN after allo-HSCT is limited. Thus, a multicenter nested case‒control study was conducted. Patients who had been diagnosed with MN after allo-HSCT were retrospectively identified at 8 HSCT centers. A total of 51 patients with MN after allo-HSCT were included. The median age of MN patients after allo-HSCT was 38 years, and the median duration from HSCT to MN was 18 months. The use of HLA-matched donors (P = 0.0102) and peripheral blood as the graft source (P = 0.0060) were identified as independent predisposing risk factors for the onset of MN after allo-HSCT. Compared to those in the control group, the incidence of extensive chronic graft-versus-host disease was greater in the MN patients (P = 0.0002). A total of 31 patients developed nephrotic syndrome. Patients receiving combination treatments of corticosteroids and immunosuppressants appeared to have better outcomes. In conclusion, MN is a rare but occasionally severe complication following HSCT and may require active treatment.

Three-Dimensional Mechanical Microenvironment Rescued the Decline of Osteogenic Differentiation of Old Human Jaw Bone Marrow Mesenchymal Stem Cells.

Resorption and atrophy of the alveolar bone, as two consequences of osteoporosis that remarkably complicate the orthodontic and prosthodontic treatments, contribute to the differentiated biological features and force-induced response of jaw bone marrow-derived mesenchymal stem cells (JBMSCs) in elderly patients. We isolated and cultured JBMSCs from adolescent and adult patients and then simulated the loading of orthodontic tension stress by constructing an in vitro three-dimensional (3D) stress loading model. The decline in osteogenic differentiation of aged JBMSCs was reversed by tensile stress stimulation. It is interesting to note that tension stimulation had a stronger effect on the osteogenic differentiation of elderly JBMSCs compared to the young ones, indicating a possible mechanism of aging rescue. High-throughput sequencing of microRNA (miRNAs) was subsequently performed before and after tension stimulation in all JBMSCs, followed by the comprehensive comparison of mechanically responsive miRNAs in the 3D strain microenvironment. The results suggested a significant reduction in the expression of miR-210-3p and miR-214-3p triggered by the 3D strain microenvironment in old-JBMSCs. Bioinformatic analysis indicated that both miRNAs participate in the regulation of critical pathways of aging and cellular senescence. Taken together, this study demonstrated that the 3D strain microenvironment efficiently rescued the cellular senescence of old-JBMSCs via modulating specific miRNAs, which provides a novel strategy for coordinating periodontal bone loss and regeneration of the elderly.

Risk factors and molecular epidemiology of intestinal colonization by carbapenem-resistant Gram-negative bacteria in patients with hematological diseases: a multicenter case‒control study.

Patients with hematological diseases are considered to be at high risk for intestinal colonization by carbapenem-resistant Gram-negative bacteria (CR-GNB). However, the epidemiological data regarding risk factors and molecular characteristics of intestinal colonized CR-GNB isolates in this population are insufficient in China. A multicenter case‒control study involving 4,641 adult patients with hematological diseases from 92 hospitals across China was conducted. Following culture of collected rectal swabs, mass spectrometry and antimicrobial susceptibility tests were performed to identify GNB species and CR phenotype. Risk factors were assessed through retrospective clinical information. Whole-genome sequencing was used to analyze the molecular characteristics of CR-GNB isolates. This trial is registered with ClinicalTrials.gov as NCT05002582. Our results demonstrated that among 4,641 adult patients, 10.8% had intestinal colonization by CR-GNB. Of these, 8.1% were colonized by carbapenem-resistant Enterobacterales (CRE), 2.6% were colonized by carbapenem-resistant Pseudomonas aeruginosa (CRPA), and 0.3% were colonized by carbapenem-resistant Acinetobacter baumannii (CRAB). The risk factors for CR-GNB colonization include male gender, acute leukemia, hematopoietic stem cell transplantation, ß-lactam antibiotic usage, and the presence of non-perianal infections within 1 week. Compared with CRPA-colonized patients, patients using carbapenems were more likely to be colonized with CRE. NDM was the predominant carbapenemase in colonized CRE. This study revealed a high CR-GNB intestinal colonization rate among adult patients with hematological diseases in China, with CRE being the predominant one. Notably, a significant proportion of CRE exhibited metallo-ß-lactamase production, indicating a concerning trend. These findings emphasize the importance of active screening for CR-GNB colonization in patients with hematological diseases.IMPORTANCECarbapenem-resistant Gram-negative bacteria (CR-GNB) has emerged as a significant threat to public health. Patients with hematological diseases are at high risk of CR-GNB infections due to their immunosuppressed state. CR-GNB colonization is an independent risk factor for subsequent infection. Understanding the risk factors and molecular characteristics of CR-GNB associated with intestinal colonization in patients with hematological diseases is crucial for empirical treatment, particularly in patients with febrile neutropenia. However, the epidemiology data are still insufficient, and our study aims to determine the intestinal colonization rate of CR-GNB, identify colonization risk factors, and analyze the molecular characteristics of colonized CR-GNB isolates.

Basiliximab Treatment for Patients With Steroid-Refractory Acute Graft-Versus-Host Disease Following Matched Sibling Donor Hematopoietic Stem Cell Transplantation.

Basiliximab is an important treatment for steroid-refractory acute graft-versus-host disease (SR-aGVHD). We performed this retrospective study to evaluate the efficacy and safety of basiliximab treatment in SR-aGVHD patients following matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) (n = 63). Overall response rate (ORR) was 63.5% and 54% at any time and at day 28 after basiliximab treatment. Grade III-IV aGVHD before basiliximab treatment predicted a poor ORR after basiliximab treatment. The rates of virus, bacteria, and fungi infections were 54%, 23.8%, and 3.1%, respectively. With a median follow-up of 730 (range, 67-3,042) days, the 1-year probability of overall survival and disease-free survival after basiliximab treatment were 58.6% (95% confidence interval [CI] = 47.6%-72.2%) and 55.4% (95% CI = 44.3%-69.2%), respectively. The 3-year cumulative incidence of relapse and non-relapse mortality after basiliximab treatment were 18.9% (95% CI = 8.3%-29.5%) and 33.8% (95% CI = 21.8%-45.7%), respectively. Comorbidities burden before allo-HSCT, severity of aGVHD and liver aGVHD before basiliximab treatment showed negative influences on survival. Thus, basiliximab was safe and effective treatment for SR-aGVHD following MSD-HSCT.

CD56bright NK cell expansion correlated with EBV reactivation control post allogeneic hematopoietic stem cell transplantation.

Natural killer (NK) cells are equipped with anti-Epstein-Barr virus (EBV) function, however, whether EBV infection will affect NK cells reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. To identify the characteristics of NK cells, we prospectively enrolled 11 patients who occurred EBV reactivation post allo-HSCT and 11 patients without EBV infection as control. We found that that EBV infection induced the expansion of CD56bright and NKG2A+KIR- NK subsets,and decreased the cytotoxicity function of NK cells. The frequency of NKG2A+KIR- NK cells were higher in patients who progressed into post-transplant lymphoproliferative disorder (PTLD) than EBV viremia patients, which also correlated with decreased proliferation and cytotoxic function. By screening the activation receptors of NK cells, we found the DNAM-1+CD56bright NK cells is significantly increased after EBV stimulation, further we demonstrated that DNAM-1 is essential for EBV induced NK cells activation as the cytokine release against EBV-transformed lymphoblastoid cell lines(EBV-LCLs) of CD56bright NK cells were significantly decreased after DNAM-1 blockade. NK cells infusion suppressed the progression of EBV-related tumor mice model. A prospective cohort indicated that old donor age was an independent risk factor for EBV infection. Rapid CD56bri expansion and high expression of DNAM-1 on CD56bri NK cells in response to EBV reactivation correlated with rapid EBV clearance post allo-HSCT in patients with younger donors. In summary, our data showed that high expression of DNAM-1 receptors on NK cell may participate protective CD56bri NK cells response to EBV infection after allo-HSCT.

Insights into dynamic evolution of glucuronofucogalactoglucan from water extract of Agrocybe cylindracea during maturation.

This study explored the physicochemical properties and structural characteristics of Agrocybe cylindracea polysaccharides at four developmental stages, as well as their dynamic evolution during maturation. Results showed that the polysaccharides from A. cylindracea water extract exhibited similar structural characteristics across all four maturity stages, despite a significant reduction in yields. Four water-soluble heteroglycans, including one high molecular weight (ACPM-Et50-I) and three low molecular weight (ACPM-Et50-II, ACPM-Et60, ACPM-Et80), were isolated from A. cylindracea at each maturity stage. ACPM-Et50-I was identified as branched heterogalactans, while ACPM-Et60 and ACPM-Et80 were branched heteroglucans. However, ACPM-Et50-II was characterized as a branched glucuronofucogalactoglucan at the tide-turning stage but a glucuronofucoglucogalactan at the pileus expansion stage due to the increase of its α-(1 â†’ 6)-D-Galp. In general, although the structural skeletons of most A. cylindracea heteroglycans were similar during maturation as shown by their highly consistent glycosyl linkages, there were still differences in the distribution of some heteroglucans. This work has for the first time reported a glucuronofucogalactoglucan in A. cylindracea and its dynamic evolution during maturation, which may facilitate the potential application of A. cylindracea in food and biomedicine industries.

Recent infection with SARS-CoV-2 in donors was associated with a higher incidence of acute graft-versus-host disease in recipients undergoing allogeneic haematopoietic stem cell transplantation.

The global pandemic has resulted in the common occurrence of SARS-CoV-2 infection in the population. In the post-pandemic era, it is imperative to understand the influence of donor SARS-CoV-2 infection on outcomes after allogeneic haematopoietic stem cell transplantation (allo-HSCT). We retrospectively analysed allo-HSCTs from donors with mild SARS-CoV-2 infection or early recovery stage (ERS) (group 1, n = 65) and late recovery stage (group 2, n = 120). Additionally, we included allo-HSCT from donors without prior SARS-CoV-2 infection as group 0 (n = 194). Transplants from donors with different SARS-CoV-2 infection status had comparable primary engraftment and survival rates. However, group 1 had higher incidences of acute graft-versus-host disease (aGvHD), grade II-IV (41.5% vs. 28.1% in group 0 [p = 0.014] and 30.6% in group 2 [p = 0.067]) and grade III-IV (22.2% vs. 9.6% [p = 0.004] in group 0 and 12.2% in group 2 [p = 0.049]). Conversely, the risk of aGvHD in group 2 was similar to that in group 0 (p > 0.5). Multivariable analysis identified group 1 associated with grade II-IV (hazard ratio [HR] 2.307, p = 0.010) and grade III-IV (HR 2.962, p = 0.001) aGvHD, which yielded no significant risk factors for survival. In conclusion, we preliminarily demonstrated donors in the active infection state or ERS of mild SARS-CoV-2 infection were associated with higher incidences of aGvHD in transplants from related donors.

Biochemical risk factors and outcomes of acute promyelocytic leukemia patients with thrombotic events: a matched pair analysis.

Acute promyelocytic leukemia (APL) stands out as a distinctive form of acute leukemia, exhibiting a higher occurrence of thrombotic events when contrasted with other leukemia subtypes. Since thrombosis is a relatively rare but unfavorable condition with poor prognostic implications, it is crucial to determine the risk factors for thrombotic events in APL(thrombosis in large venous or arterial from onset to differentiation therapy in 30d). We performed a retrospective study involving 950 APL patients between January 2000 and October 2022, from which 123 were excluded by younger than 16 years of age, 95 were excluded by incomplete data, and 6 were excluded by thrombosis related to CVC or PICC. A total of 23 APL patients with thrombosis for inclusion in our analysis were performed a 1:5 ratio matching based on sex (perfect match) and age (within 5 years) to patients without thrombosis. These patients were continuously monitored in the outpatient department over a period of 5 years. We meticulously examined clinical and laboratory data to pinpoint the risk factors related to thrombotic events in APL. Our primary clinical endpoints were all-cause mortality and achieving complete remission, while secondary clinical outcomes included APL relapse. Thrombotic events were observed in 2.4% (23/950) of APL patients. Compared to patients without thrombosis, patients with thrombosis had higher lactate dehydrogenase (LDH) [313 (223, 486) vs. 233 (188, 367) U/L, p = 0.020], higher indirect bilirubin [11.2 (7.4, 18.6) vs.8.3 (6.0, 10.7) umol/L, p = 0.004], higher creatinine [72 (62, 85) vs. 63 (54, 74) umol/L, p = 0.026], higher CD2 expression (65.2 vs. 15.2%, p < 0.001), higher CD15 expression (60.9 vs. 24.3%, p = 0.001), and PML/RARαisoforms (p < 0.001). Multivariate-logistic-regression analysis revealed several factors that were markedly related to thrombosis, including LDH (OR≈1.003, CIs≈1.000-1.006, p = 0.021), indirect bilirubin (OR≈1.084, CIs≈1.000-1.188, p = 0.043), CD2 expression positive (OR≈16.629, CIs≈4.001-62.832, p < 0.001), and CD15 expression positive (OR≈7.747, CIs≈2.005-29.941, p = 0.003). The S-type (OR≈0.012, CIs≈0.000-0.310, p = 0.008) and L-type (OR≈0.033, CIs≈0.002-0.609, p = 0.022) PML/RARα isoforms were negatively associated with thrombosis. Kaplan-Meier curves indicated that the survival rates were remarkably varied between APL patients with and without thrombosis (HR:21.34, p < 0.001). LDH and indirect bilirubin are variables significantly associated with thrombosis in APL, S-type and L-type PML/RARαisoforms exhibit a negative association with thrombotic events. The thrombotic events of APL can predict the subsequent survival of thrombosis. The findings of our study have the potential to facilitate early detection of thrombosis and enhance the prognosis for individuals with APL who develop thrombosis. Further validation of our findings will be essential through future prospective or multicenter studies.

Antiviral C-geranylated flavonoids from Artocarpus communis.

Ten C-geranylated flavonoids, along with three known analogues, were isolated from the leaves of Artocarpus communis. The chemical structures of these compounds were unambiguously determined via comprehensive spectroscopic analysis, single-crystal X-ray diffraction experiments, and quantum chemical electronic circular dichroism calculations. Structurally, artocarones A-I (1-9) represent a group of unusual, highly modified C-geranylated flavonoids, in which the geranyl chain is cyclised with the ortho-hydroxy group of flavonoids to form various heterocyclic scaffolds. Notably, artocarones E and G-I (5 and 7-9) feature a 6H-benzo[c]chromene core that is hitherto undescribed in C-geranylated flavonoids. Artocarone J (10) is the first example of C-9-C-16 connected C-geranylated aurone. Meanwhile, the plausible biosynthetic pathways for these rare C-geranylated flavonoids were also proposed. Notably, compounds 1, 2, 4, 8, 11, and 12 exhibited promising in vitro inhibitory activities against respiratory syncytial virus and herpes simplex virus type 1.

COVID-19 was associated with the complications after allogeneic hematopoietic stem cell transplantation.

We aimed to identify the severity and duration of COVID-19 infection on complications after allo-HSCT. Enrolled 179 hospitalized patients with COVID-19 were categorized into long-term infection (> 18 days, n = 90) or short-term infection group (≤ 18 days, n = 89) according to the median duration of COVID-19. The severity of COVID-19 was categorized as asymptomatic infection, mild, moderate, severe, and critical illness according to guidelines of National Institutes of Health. Particularly, severe illness and critical illness were classified as serious infection. Asymptomatic infection, mild illness and moderate illness were classified as non-serious infection. The 150-day probabilities of poor graft function (PGF), cytomegalovirus (CMV) pneumonia and non-relapse mortality (NRM) were significantly higher in long-term infection group. The 150-day probabilities of CMV pneumonia and NRM after COVID-19 were higher in serious infection group. The 150-day probabilities of overall survival (OS) was significantly lower in long-term and serious infection group. In multivariable analysis, the severity of COVID-19 was associated with NRM and OS, and the duration of COVID-19 was associated with PGF. In summary, our data reported that the severity and duration of COVID-19 were associated with several complications and contribute to poor outcomes after allo-HSCT.

Technical efficiency and its convergence among village clinics in rural China: evidence from Shanxi Province.

Introduction: Village clinics (VCs) are the foundation of the three-tiered health service system in China, delivering basic and routine outpatient services to citizens in rural China. VC technical efficiency and its convergence play a critical role in policy decisions regarding the distribution of health service resources in rural China. Methods: This study measured VC technical efficiency (using the slacks-based measure model), its convergence (using the convergence model), and the factors that influence the convergence in Shanxi Province, China. Data were obtained from the Shanxi Rural Health Institute 2014-2018 Health Statistics Report, which involved 3,543 VCs. Results: The results showed that VC technical efficiency was low and differed by region. There was no α convergence in VC technical efficiency, but evidence of ß convergence was found in Shanxi. The main factors that influence convergence were the building area of each VC (BA), proportion of government subsidies (PGS), and ratio of total expenditure to total income of each VC (RTETI). Conclusion: The government should increase investments in VCs and improve VC technical efficiency. Meanwhile, the government should be aware of and take measures to curb the inequity in VC technical efficiency among different regions and take suitable measures to curb this disparity.

Human amniotic epithelial stem cell is a cell therapy candidate for preventing acute graft-versus-host disease.

Graft-versus-host disease (GVHD), an immunological disorder that arises from donor T cell activation through recognition of host alloantigens, is the major limitation in the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Traditional immunosuppressive agents can relieve GVHD, but they induce serious side effects. It is highly required to explore alternative therapeutic strategy. Human amniotic epithelial stem cells (hAESCs) were recently considered as an ideal source for cell therapy with special immune regulatory property. In this study, we evaluated the therapeutic role of hAESCs in the treatment of GVHD, based on our previous developed cGMP-grade hAESCs product. Humanized mouse model of acute GVHD (aGVHD) was established by injection of huPBMCs via the tail vein. For prevention or treatment of aGVHD, hAESCs were injected to the mice on day -1 or on day 7 post-PBMC infusion, respectively. We showed that hAESCs infusion significantly alleviated the disease phenotype, increased the survival rate of aGVHD mice, and ameliorated pathological injuries in aGVHD target organs. We demonstrated that hAESCs directly induced CD4+ T cell polarization, in which Th1 and Th17 subsets were downregulated, and Treg subset was elevated. Correspondingly, the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs. We found that hAESCs regulated CD4+ subset polarization in a paracrine mode, in which TGFß and PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition, respectively. In addition, transplanted hAESCs preserved the graft-versus-leukemia (GVL) effect by inhibiting leukemia cell growth. More intriguingly, hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study. We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect. The clinical trial was registered at www.clinicaltrials.gov as #NCT03764228.