Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: results from the 36-month TOPAZ study.

Background and purpose: At 12 months in the phase 2 TOPAZ study, treatment with apitegromab was associated with both an improved motor function in patients with Type 2 or 3 spinal muscular atrophy (SMA) and with a favorable safety profile. This manuscript reports the extended efficacy and safety in the nonambulatory group of the TOPAZ study at 36 months. Methods: Patients who completed the primary study (NCT03921528) could enroll in an open-label extension, during which patients received apitegromab 20 mg/kg by intravenous infusion every 4 weeks. Patients were assessed periodically via the Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), World Health Organization (WHO) motor development milestones, Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Daily Activities and Mobility domains, and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Results: Of the 58 patients enrolled in TOPAZ, 35 were nonambulatory (mean age 7.3 years). The mean change at 36 months in HFMSE score from baseline was +4.0 (standard deviation [SD]: 7.54), and + 2.4 (3.24) for RULM score (excluding n = 7 after scoliosis surgery). Caregiver-reported outcomes (PEDI-CAT and PROMIS Fatigue) showed improvements from baseline over 36 months. In addition, most patients (28/32) improved or maintained WHO motor milestones achieved at baseline. The most frequently reported treatment-emergent adverse events were pyrexia (48.6%), nasopharyngitis (45.7%), COVID-19 infection (40.0%), vomiting (40.0%), and upper respiratory tract infection (31.4%). Conclusion: The benefit of apitegromab treatment observed at 12 months was sustained at 36 months with no new safety findings.

Spore Oil enhances the effect of cyclophosphamide inhibiting programmed death-1 and prolongs the survival of H22 tumor-bearing mice.

OBJECTIVE: To investigate the effect of Ganoderma Lucidum Spore Oil (GLSO) on the tumor growth and survival of H22 tumor-bearing mice treated with cyclophosphamide (CTX), and explore the underlying mechanism. METHODS: Allograft H22 hepatocellular carcinoma mouse model was applied to investigate the effect of GLSO on the tumor growth and survival of animals, and Kaplan-Meier survival analysis was used to analyze the life span. Plasma biochemical examination was used to determine the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea (UREA) and creatinine (CRE). Western blot analysis was performed to detect Programmed Death-1 (PD-1), Programmed Death Ligand 1 (PD-L1), Janus Kinase 2 (JAK2), phosphorylated Signal Transducer and Activator of Transcription 3 (p-STAT3), and Signal Transducer and Activator of Transcription 3 (STAT3) expression. RESULTS: GLSO increased the anti-tumor effect of CTX and prolonged the survival of H22 tumor-bearing mice treated with CTX. Meanwhile, GLSO increased the thymus index and showed no obvious toxicity to liver functions of animals. GLSO also decreased the level of UREA in H22 tumor-bearing mice treated with CTX. Furthermore, GLSO could inhibit the expression of PD-1 in spleen, which was independent of JAK2 expression and STAT3 phosphorylation. However, GLSO did not affect the expression of PD-L1, JAK2, and p-STAT3 in tumor tissue. CONCLUSION: GLSO could strengthen the anti-tumor effect of CTX and prolong the life span of H22 tumor-bearing mice, while the underlying mechanism might be relevant to the amelioration effect of thymus function and inhibition of PD-1 expression in spleen. Furthermore, these findings implied the promising role of GLSO in combination with CTX to extend the survival of patients in clinical chemotherapy of hepatocellular carcinoma.

[Association between diabetes prevalence and mortality risk in the elderly aged 60 years and above in Liaoning Province, 2017-2019].

Objective: To investigate the prevalence of diabetes in the elderly aged ≥60 years in Liaoning Province from 2017 to 2019 and analyze the impact of blood glucose control on all-cause mortality and cardiovascular disease (CVD) mortality. Methods: A survey was conducted in the elderly aged ≥60 years in Liaoning from 2017 to 2019 to collect the information about the prevalence of diabetes and other chronic diseases in the diabetes patients. The mortality of the enrolled subjects was investigated in September 2023. Cox proportional hazards regression models were used to estimate the association between blood glucose control in the elderly with diabetes and the risks of all-cause mortality and CVD mortality. Results: The crude prevalence of diabetes in the elderly aged ≥60 years was 20.2% (2 014/9 958) in Liaoning from 2017 to 2019, and the standardized prevalence rate was 19.9%. The prevalence rates of hypertension, dyslipidemia, and overweight/obesity in the diabetes patients were 77.0%, 51.7%, and 67.5% respectively. The median follow-up time was 5.5 years, and the all-cause mortality and CVD mortality rates in the diabetes patients were 244.3/10 000 person-years and 142.9/10 000 person-years, respectively. The results of the Cox proportional hazards regression model analysis showed that compared with non-diabetic individuals, diabetes patients had an increased risk of all-cause mortality by 1.68 times [hazard ratio (HR)=1.68, 95%CI: 1.44-1.94] and an increased risk of CVD mortality by 1.56 times (HR=1.56, 95%CI: 1.29-1.89). The differences in risks of all-cause mortality and CVD mortality between the diabetes patients with normal fasting blood glucose and glycated hemoglobin levels and people without diabetes were not significant (all P>0.05). The failure to meet either the FPG or HbA1c target increased the risk of all-cause mortality (all P<0.05). For individuals who failed to meet the HbA1c target, there was an increased risk of CVD mortality (all P<0.05). Conclusions: The comorbidity rate of chronic diseases was higher in the elderly with diabetes than in the elderly without diabetes in Liaoning. Elderly diabetes patients can benefit from good blood glucose control.

Antibody-Suppressor CXCR5+CD8+ T Cells Are More Potent Regulators of Humoral Alloimmunity after Kidney Transplant in Mice Compared to CD4+ Regulatory T Cells.

Adoptive cell therapy (ACT), especially with CD4+ regulatory T cells (CD4+ Tregs), is an emerging therapeutic strategy to minimize immunosuppression and promote long-term allograft acceptance, although much research remains to realize its potential. In this study, we investigated the potency of novel Ab-suppressor CXCR5+CD8+ T cells (CD8+ TAb-supp) in comparison with conventional CD25highFoxp3+CD4+ Tregs for suppression of humoral alloimmunity in a murine kidney transplant (KTx) model of Ab-mediated rejection (AMR). We examined quantity of peripheral blood, splenic and graft-infiltrating CD8+ TAb-supp, and CD4+ Tregs in KTx recipients and found that high alloantibody-producing CCR5 knockout KTx recipients have significantly fewer post-transplant peripheral blood and splenic CD8+ TAb-supp, as well as fewer splenic and graft-infiltrating CD4+ Tregs compared with wild-type KTx recipients. ACT with alloprimed CXCR5+CD8+ T cells reduced alloantibody titer, splenic alloprimed germinal center (GC) B cell quantity, and improved AMR histology in CCR5 knockout KTx recipients. ACT with alloprimed CD4+ Treg cells improved AMR histology without significantly inhibiting alloantibody production or the quantity of splenic alloprimed GC B cells. Studies with TCR transgenic mice confirmed Ag specificity of CD8+ TAb-supp-mediated effector function. In wild-type recipients, CD8 depletion significantly increased alloantibody titer, GC B cells, and severity of AMR pathology compared with isotype-treated controls. Anti-CD25 mAb treatment also resulted in increased but less pronounced effect on alloantibody titer, quantity of GC B cells, and AMR pathology than CD8 depletion. To our knowledge, this is the first report that CD8+ TAb-supp cells are more potent regulators of humoral alloimmunity than CD4+ Treg cells.

CXCR5 + CD8 + T Cell-mediated Suppression of Humoral Alloimmunity and AMR in Mice Is Optimized With mTOR and Impaired With Calcineurin Inhibition.

BACKGROUND: Adoptive cellular therapy (ACT) with antibody-suppressor CXCR5 + CD8 + T cells (CD8 + T Ab-supp ) inhibits alloantibody production, antibody-mediated rejection (AMR), and prolongs graft survival in multiple transplant mouse models. However, it is not known how conventional immunosuppressive agents impact the efficacy of CD8 + T Ab-supp ACT. METHODS: We investigated the efficacy of CD8 + T Ab-supp cell ACT when combined with calcineurin inhibitor (CNi) or mammalian target of rapamycin inhibitor (mTORi) in a murine model of kidney transplant. RESULTS: ACT-mediated decrease in germinal center B cells, posttransplant alloantibody titer, and amelioration of AMR in high alloantibody-producing CCR5 knockout kidney transplant recipients were impaired when ACT was combined with CNi and enhanced when combined with mTORi. CNi (but not mTORi) reduced ACT-mediated in vivo cytotoxicity of IgG + B cells and was associated with increased quantity of germinal center B cells. Neither CNi nor mTORi treatment impacted the expression of cytotoxic effector molecules (FasL, Lamp1, perforin, granzyme B) by CD8 + T Ab-supp after ACT. Concurrent treatment with CNi (but not mTORi) reduced in vivo proliferation of CD8 + T Ab-supp after ACT. The increase in quantity of splenic CD44 + CXCR5 + CD8 + T cells that occurs after ACT was reduced by concurrent treatment with CNi but not by concurrent treatment with mTORi (dose-dependent). CONCLUSIONS: Impaired efficacy of ACT by CNi is attributed to reduced persistence and/or expansion of CD8 + T Ab-supp cells after ACT. In contrast, concurrent immunosuppression with mTORi preserves CD8 + T Ab-supp cells quantity, in vivo proliferation, and in vivo cytotoxic effector function after ACT and enhances suppression of humoral alloimmunity and AMR.

Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist.

Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared with ApoE3 or the absence of ApoE. However, the role of ApoE isoforms and lipid metabolism in contributing to tau-mediated degeneration is unknown. We demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation and perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via an LXR agonist or Abca1 overexpression strongly attenuates tau pathology and neurodegeneration in P301S/ApoE4 mice. We also demonstrate reductions in reactive astrocytes and microglia, as well as changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.

[Clinical characteristics of aplastic anemia patients with abnormal autoantibodies and the impact of autoantibodies on immunosuppressive therapy response].

Objective: To investigate the clinical characteristics of patients with acquired aplastic anemia (AA) accompanied by abnormal antinuclear antibody (ANA) and autoantibodies and their effects on the efficacy of immunosuppressive therapy (IST). Method: A retrospective case-control study was conducted, analyzing the clinical data of 291 patients with AA who underwent IST and were screened for autoantibodies at initial diagnosis between January 2018 and December 2019 at Blood Diseases Hospital, Chinese Academy of Medical Sciences. According to the titer of ANA at the initial diagnosis, extracted nuclear antigen antibodies (ENAs) abnormality and the change of ANA titer after treatment, the treatment responses of 3 months and 6 months after IST were compared. The correlation between clinical features and ANA abnormality was analyzed by univariate and multivariate logistic regression analysis. The parameters of univariate analysis P<0.1 were included in multivariate analysis, stepwise regression analysis and subgroup analysis. Results: A total of 291 patients were included in the study, of which 145 (49.83%) were male. Among all patients, 147 (50.52%) tested positive for ANA at initial diagnosis, with titers of 1∶100, 1∶320, and 1∶1 000 observed in 94, 47, and 6 cases, respectively. Female gender, older age, presence of paroxysmal nocturnal hemoglobinuria (PNH) clone, and higher levels of IgG, IgA, and thyroid hormone were significantly associated with ANA positivity at initial diagnosis, while white cell counts, reticulocytes, and free triiodothyronine were significantly lower than that of ANA-negatively patients (all P<0.05). Furthermore, logistic regression analyses revealed that female gender (OR=1.980, 95%CI 1.206-3.277), older age (OR=1.017, 95%CI 1.003-1.032), and presence of PNH clone (OR=1.875, 95%CI 1.049-3.408) were independent risk factors for ANA positivity at initial diagnosis. Subgroup analysis indicated that the risk of ANA positivity at initial diagnosis was even higher in PNH clone-positive patients in the subgroups of females (OR=1.24, 95%CI 1.02-1.51), severe AA (OR=1.26, 95%CI 1.07-1.47), and age≥40 years (OR=1.26, 95%CI 1.05-1.52) (all P<0.05). However, ANA titers at initial diagnosis, presence of other abnormal ENAs, and changes in ANA titers after treatment with IST were not correlated with treatment response (all P>0.05). Conclusions: Approximately 50% of patients with AA had abnormal ANA, and their presence was significantly associated with female gender, older age, and presence of PNH clone at initial diagnosis. However, the presence of abnormal ANA and changes in ANA titers after treatment did not affect the efficacy of IST in patients with AA.

[Structural changes of the frontal cortex in depressed mice are associated with decreased expression of brain-derived neurotrophic factor].

OBJECTIVE: To investigate the changes in gray matter volume in depressive-like mice and explore the possible mechanism. METHODS: Twenty-four 6-week-old C57 mice were randomized equally into control group and model group, and the mice in the model group were subjected to chronic unpredictable mild stimulation (CUMS) for 35 days. Magnetic resonance imaging was performed to examine structural changes of the grey matter volume in depressive-like mice. The expression of brain-derived neurotrophic factor (BDNF) in the grey matter of the mice was detected using Western blotting and immunofluorescence staining. RESULTS: Compared with the control mice, the mice with CUMS showed significantly decreased central walking distance in the open field test (P < 0.05) and increased immobile time in forced swimming test (P < 0.05). Magnetic resonance imaging showed that the volume of the frontal cortex was significantly decreased in CUMS mice (P < 0.001, when the mass level was greater than or equal to 10 756, the FDRc was corrected with P=0.05). Western blotting showed that the expression of mature BDNF in the frontal cortex was significantly decreased in CUMS mice (P < 0.05), and its expression began to decrease after the exposure to CUMS as shown by immunofluorescence staining. The volume of different clusters obtained by voxel-based morphometry (VBM) analysis was correlated with the expression level of mature BDNF detected by Western blotting (P < 0.05). CONCLUSION: The decrease of frontal cortex volume after CUMS is related with the reduction of mature BDNF expression in the frontal cortex.

[The effect of on-demand glucocorticoid strategy on the occurrence and outcome of p-ALG-associated serum sickness in aplastic anemia].

Objective: To investigate the effect of on-demand glucocorticoid strategy on the occurrence and outcome of porcine anti-lymphocyte globulin (p-ALG) -associated serum sickness in aplastic anemia (AA) . Methods: The data of AA patients who received in the Anemia Diagnosis and Treatment Center of Haematology Hospital, CAMS & PUMC from January 2019 to January 2022 were collected. Among them, 35 patients were enrolled in the on-demand group, with the glucocorticoid strategy adjusted based on the occurrence and severity of serum sickness; 105 patients were recruited in the usual group by matching the age and disease diagnosis according to 1∶3 ratio in patients who received a conventional glucocorticoid strategy in the same period. The incidences, clinical manifestations, treatment outcomes of serum sickness, and glucocorticoid dosage between the two groups were analyzed. Results: The incidences of serum sickness in the on-demand group and the usual group were 65.7% and 54.3% (P=0.237) , respectively. The median onset of serum sickness was the same [12 (9, 13) d vs the 12 (10, 13) d, P=0.552], and clinical symptoms and signs, primarily joint, and/or muscle pain, fever, and rash were similar. Severity grades were both dominated by Grades 1-2 (62.8% vs 51.4%) , with only a few Grade 3 (2.9% vs 2.9%) , and no Grades 4-5. No significant difference in the serum sickness distribution (P=0.530) . The median duration of serum sickness was the same [5 (3, 7) d vs 5 (3, 6) d, P=0.529], and all patients were completely cured after glucocorticoid therapy. In patients without serum sickness, the average dosage of prophylactic glucocorticoid per patient in the usual group was (469.48 ±193.57) mg (0 in the on-demand group) . When compared to the usual group, the average therapeutic glucocorticoid dosage per patient in the on-demand group was significantly lower [ (125.91±77.70) mg vs (653.90±285.56) mg, P<0.001]. Conclusions: In comparison to the usual glucocorticoid strategy, the on-demand treatment strategy could significantly reduce glucocorticoid dosage without increasing the incidence of serum sickness; in addition, the duration of serum sickness and the incidence of above Grade 2-serum sickness were similar.

[Metagenomic next-generation sequencing of plasma for the identification of bloodstream infectious pathogens in severe aplastic anemia].

Objective: To analyze the diagnostic value of cell-free plasma metagenomic next-generation sequencing (mNGS) pathogen identification for severe aplastic anemia (SAA) bloodstream infection. Methods: From February 2021 to February 2022, mNGS and conventional detection methods (blood culture, etc.) were used to detect 33 samples from 29 consecutive AA patients admitted to the Anemia Diagnosis and Treatment Center of the Hematology Hospital of the Chinese Academy of Medical Sciences to assess the diagnostic consistency of mNGS and conventional detection, as well as the impact on clinical treatment benefits and clinical accuracy. Results: ①Among the 33 samples evaluated by mNGS and conventional detection methods, 25 cases (75.76%) carried potential pathogenic microorganisms. A total of 72 pathogenic microorganisms were identified from all cases, of which 65 (90.28%) were detected only by mNGS. ②All 33 cases were evaluated for diagnostic consistency, of which 2 cases (6.06%) were Composite, 18 cases (54.55%) were mNGS only, 2 cases (6.06%) were Conventional method only, 1 case (3.03%) was both common compliances (mNGS/Conventional testing) , and 10 cases (30.3%) were completely non-conforming (None) . ③All 33 cases were evaluated for clinical treatment benefit. Among them, 8 cases (24.24%) received Initiation of targeted treatment, 1 case (3.03%) received Treatment de-escalation, 13 cases (39.39%) received Confirmation, and the remaining 11 cases (33.33%) received No clinical benefit. ④ The sensitivity of 80.77%, specificity of 70.00%, positive predictive value of 63.64%, negative predictive value of 84.85%, positive likelihood ratio of 2.692, and negative likelihood ratio of 0.275 distinguished mNGS from conventional detection methods (21/12 vs 5/28, P<0.001) . Conclusion: mNGS can not only contribute to accurately diagnosing bloodstream infection in patients with aplastic anemia, but can also help to guide accurate anti-infection treatment, and the clinical accuracy is high.

[Clinical and gene mutation characteristics of patients with hereditary ellipsocytosis: nine cases report and literature review].

Objective: To report gene mutations in nine patients with hereditary elliptocytosis (HE) and analyze the characteristics of pathogenic gene mutations in HE. Methods: The clinical and gene mutations of nine patients clinically diagnosed with HE at Institute of Hematology & Blood Diseases Hospital from June 2018 to February 2022 were reported and verified by next-generation sequencing to analyze the relationship between gene mutations and clinical phenotypes. Results: Erythrocyte membrane protein gene mutations were detected among nine patients with HE, including six with SPTA1 mutation, one with SPTB mutation, one with EPB41 mutation, and one with chromosome 20 copy deletion. A total of 11 gene mutation sites were involved, including 6 known mutations and 5 novel mutations. The five novel mutations included SPTA1: c.1247A>C (p. K416T) in exon 9, c.1891delG (p. A631fs*17) in exon 15, E6-E12 Del; SPTB: c.154C>T (p. R52W) ; and EPB41: c.1636A>G (p. I546V) . Three of the six patients with the SPTA1 mutation were SPTA1 exon 9 mutation. Conclusion: SPTA1 is the most common mutant gene in patients with HE.

Concomitant Immunosuppressive Therapy and Eculizumab Use in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Analysis.

INTRODUCTION: Complement C5 inhibitor eculizumab is the first approved treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder caused by uncontrolled terminal complement activation. Approximately 50% of patients with aplastic anemia (AA) have PNH cells. Limited data are available for patients with AA-PNH taking concomitant immunosuppressive therapy (IST) and eculizumab. METHODS: Data from the International PNH Registry (NCT01374360) were used to evaluate the safety and effectiveness of eculizumab and IST in patients taking IST followed by concomitant eculizumab (IST + c-Ecu) or eculizumab followed by concomitant IST (Ecu + c-IST). RESULTS: As of January 1, 2018, 181 Registry-enrolled patients were included in the eculizumab effectiveness analyses (n = 138, IST + c-Ecu; n = 43, Ecu + c-IST); 87 additional patients received IST alone. Reductions from baseline with eculizumab were observed in the least squares mean lactate dehydrogenase ratio (IST + c-Ecu, -3.4; Ecu + c-IST, -3.5); thrombotic event incidence rates were similar between groups (IST + c-Ecu, 1.3; Ecu + c-IST, 0.7). Red blood cell transfusion rate ratios decreased from baseline for IST + c-Ecu (0.7) and increased for Ecu + c-IST (1.2); there were none for IST alone. Hematological parameters generally improved for IST + c-Ecu and IST alone, and changed minimally or worsened for Ecu + c-IST. Safety signals were generally consistent with those previously described for the respective therapies. DISCUSSION/CONCLUSION: Although some intergroup differences were seen, concomitant eculizumab and IST were safe and effective regardless of treatment sequence.

Meta-analysis of clinical efficacy of ankle arthrodesis and total ankle arthroplasty in the treatment of end-stage ankle arthritis / 中国骨伤

OBJECTIVE@#To systematically review the clinical efficacy of total ankle arthroplasty (TAA) and ankle arthrodesis (AA) in the treatment of end-stage ankle arthritis.@*METHODS@#The PubMed, EMBASE and Cochrane Library databases were searched for articles published in the treatment of end-stage ankle arthritis with AA or TAA from the establishment of the database to June 2021. Bias risk tool was used to evaluate the quality of the literature. The American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale(AOFAS), visual analog scale (VAS), ankle osteoarthritis scale(AOS), gait analysis (pace, frequency, stride), range of motion (ROM), satisfaction, complications and reoperation rate were analyzed by meta-analysis between AA and TAA groups by RevMan 5.3 software.@*RESULTS@#A total of 12 articles were included, including 1 050 patients in the AA group and 3 760 patients in the TAA group, totaling 4 810 patients. Meta-analysis showed that the total score of AOFAS[MD=-3.12, 95%CI(-9.02, 2.96), P=0.31], pain score [MD=1.60, 95%CI(-1.35, 4.54), P=0.29], alignmentl score[MD=-0.04, 95%CI(-0.52, 0.44), P=0.88], VAS[MD=0.10, 95%CI(-0.49, 0.68), P=0.74], and AOS total score [MD=-4.01, 95%CI(-8.28, 0.25), P=0.06], the difference was not statistically significant (P>0.05). The score of AOFAS functional in TAA group was significantly higher than that in TAA group[MD=44.22, 95%CI(-8.01, -0.43), P=0.03]. There was no significant difference in gait analysis between the two groups (P>0.05). Postoperative ROM [MD=-4.93, 95%CI(-6.35, -3.52), P<0.000 01] and change in ROM from preoperative to follow-up[MD=-5.74, 95%CI(-8.88, -2.61), P=0.0003] between two groups, the difference was statistically significant. There was no significant difference in satisfaction between the two groups [OR=1.011, 95%CI(0.46, 2.23), P=0.98]. Complications [OR=1.61, 95%CI(1.26, 2.06), P=0.0002] and non-revision reoperation [OR=1.61, 95%CI(1.17, 2.21), P=0.003] were significantly lower in the TAA group than in the AA group. There was no significant difference in the rate of revision and reoperation(P>0.05) between the two groups [OR=1.02, 95%CI(0.37, 2.78), P=0.97].@*CONCLUSION@#The clinical efficacy of AA is similar to that of TAA, but the non revision reoperation rate and main surgical complications of TAA are significantly reduced. Therefore, further high-quality methodological research and long-term follow-up are needed to confirm this conclusion.

Potential cerebrovascular protective functions of lycium barbarum polysaccharide in alleviating hyperglycemia-aggravated cerebral ischemia/reperfusion injury in hyperglycemic rats.

OBJECTIVE: Lycium barbarum polysaccharide (LBP) is the efficient primary compound of Lycium barbarum and has been shown to alleviate hyperglycemia-aggravated cerebral ischemia/reperfusion (I/R) injury. However, the cerebrovascular changes related to diabetes mellitus (DM) and the potential cerebrovascular protective effects of LBP are still unknown. This study aimed to explore the cerebrovascular protective functions of LBP on cerebral I/R injury in diabetic rats and its potential mechanisms. MATERIALS AND METHODS: Sprague Dawley (SD) rats were separated into three groups: the normoglycemic (NG), diabetic hyperglycemic (HG), and HG + LBP (50 mg/kg) treatment groups. A 30 min transient middle cerebral artery occlusion (tMCAO) with 24 h reperfusion was established. The neurological deficits, cerebral water content, infarct volume, and cerebrovascular permeability were assessed to evaluate the extent of cerebral injury. Histopathological alterations were assessed by hematoxylin and eosin, Nissl, immunohistochemical, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. A transmission electron microscope was used to detect ultrastructural alterations, and a western blot was used to examine protein expression. RESULTS: The HG rats exhibited a significant increase in neurological deficits, cerebral water content, infarct volume, cerebrovascular permeability, neural cell death, and apoptosis compared with the NG rats, and the LBP treatment alleviated these effects. Cerebrovascular structure analysis showed that the cross-sectional area (CSA) and wall thickness were remarkably altered in the HG rats compared with the NG rats. The LBP treatment protected the cerebrovascular structure and vasoreactivity by decreasing the wall thickness and increasing the CSA, α-smooth muscle actin, and endothelial nitric oxide synthase expression of cerebral vessels. CONCLUSIONS: The intake of LBP benefits the cerebrovascular structure and vasoreactivity in diabetic rats. Our research provides a possible new strategy for treating stroke in patients with DM.

Textbook Outcome as a Quality Metric in Living and Deceased Donor Kidney Transplantation.

BACKGROUND: Quality in kidney transplantation is measured using 1-year patient and graft survival. Because 1-year patient and graft survival exceed 95%, this metric fails to measure a spectrum of quality. Textbook outcomes (TO) are a composite quality metric offering greater depth and resolution. We studied TO after living donor (LD) and deceased donor (DD) kidney transplantation. STUDY DESIGN: United Network for Organ Sharing data for 69,165 transplant recipients between 2013 and 2017 were analyzed. TO was defined as patient and graft survival of 1 year or greater, 1-year glomerular filtration rate of greater than 40 mL/min, absence of delayed graft function, length of stay of 5 days or less, no readmissions during the first 6 months, and no episodes of rejection during the first year after transplantation. Bivariate analysis identified characteristics associated with TO, and covariates were incorporated into multivariable models. Five-year conditional survival was measured, and center TO rates were corrected for case complexity to allow center-level comparisons. RESULTS: The national average TO rates were 54.1% and 31.7% for LD and DD transplant recipients. The hazard ratio for death at 5 years for recipients who did not experience TO was 1.92 (95% CI 1.68 to 2.18, p ≤ 0.0001) for LD transplant recipients and 2.08 (95% CI 1.93 to 2.24, p ≤ 0.0001) for DD transplant recipients. Center-level comparisons identify 18% and 24% of centers under-performing in LD and DD transplantation. High rates of TO do not correlate with transplantation center volume. CONCLUSION: Kidney transplant recipients who experience TO have superior long-term survival. Textbook outcomes add value to the current standards of 1-year patient and graft survival.

[Evaluation of two biomechanical stiffness indexes in the diagnosis of eratoconus and their changes after corneal collagen cross-linking surgery].

Objective: To evaluate the diagnostic efficacy of stress-strain index (SSI) for different stages or degrees of keratoconus and changes of SSI and stiffness parameter A1 (SPA1) after corneal collagen cross-linking (CXL) surgery. Methods: Cross-sectional study and retrospective case series study. Ninety-four patients (113 eyes) diagnosed as clinical keratoconus (CKC) in Qingdao Eye Hospital from July 2019 to August 2021 were enrolled in the CKC group, including 69 males and 25 females, aged (20.82±4.53) years, and further divided into subgroups of mild (35 patients, 36 eyes), moderate (36 patients, 40 eyes) and severe (33 patients, 37 eyes) CKC. Fifty-six unaffected eyes of monocular keratoconus patients were enrolled in the subclinical keratoconus (SKC) group. Ninety-one healthy subjects (91 eyes) were recruited as the control group. All subjects were examined by Pentacam topography and Corvis ST measurements to obtain mean keratometry, maximal keratometry, deformation amplitude (DA) ratio at 2 mm, integrated radius (IR), Ambrósio's relational thickness to the horizontal profile, corneal central thickness, SPA1 and SSI for comparison. Forty-eight CKC patients (65 eyes) underwent CXL surgery, and the above parameters were recorded before and 3, 6 and 12 months after operation. Data were analyzed by the ANOVA test, Kruskal-Wallis H test, paired sample test, receiver operating characteristic curves and Pearson correlation. Results: The value of SPA1 in the SKC group accounted for 85.53% (87.92±12.38 vs. 102.79±11.74; t=-6.614, P<0.001) compared with the control group, but the value of SSI had no difference in the two groups (t=0.105, P=0.916). The value of SPA1 in the CKC group accounted for 52.87% (54.35±14.70 vs. 102.79±11.74; t=25.985, P<0.001) compared with the control group. The value of SSI in the CKC group accounted for 67.96% (0.70±0.14 vs. 1.03±0.14; t=-15.305, P<0.001) compared with the control group. The more severe the disease was, the smaller the SPA1 and SSI values were 64.27±12.12, 55.22±12.23, 43.75±12.33; 0.78±0.14, 0.71±0.11, 0.61±0.09, and there were significant statistical differences among groups (mild vs. moderate, mild vs. severe, moderate vs. severe; SPA1: t=3.257, -7.249, -4.159; all P<0.001. SSI: t=2.383, 5.065, 2.798; P=0.018,<0.001,=0.006). Receiver operating characteristic analysis showed that SPA1 had good diagnostic efficiency for subclinical patients [area under curve (AUC)=0.802], while the SSI had no diagnostic value (P=0.802). SPA1 had better diagnostic efficiency than the SSI for keratoconus in different stages, especially in the mild CKC and SKC groups (AUC: 0.914 vs. 0.847). The SSI had a significant positive correlation with SPA1 and a significant negative correlation with DA ratio and IR in the control, SKC and CKC groups (r=0.278, 0.368, 0.550; r=-0.346, -0.462, -0.547; r=-0.612, -0.591, -0.718; P<0.01). For patients who received CXL, maximal keratometry decreased significantly at 6 and 12 months postoperatively (t=4.029, 3.633; all P<0.001), whereas SPA1 increased significantly (t=-3.960, -4.500; all P<0.001). However, the SSI only increased significantly at 3 months (t=-2.577, P=0.012) and returned to the preoperative level at 6 and 12 months postoperatively, with no statistical difference compared with the preoperative level (t=-0.544, -0.257; P=0.589, 0.798). Conclusions: While there was no significant change in the SSI of SKC, the SSI of CKC decreased, and the more severe the disease was, the smaller the value was. The SSI was significantly and consistently correlated with DA ratio, IR and SPA1. The SSI compared with SPA1 had a lower degree of identification in different stages and degrees of keratoconus. The consistency of SPA1 with clinical effects after CXL surgery was higher than that of the SSI parameter.

[Reassessing the six months prognosis of patients with severe or very severe aplastic anemia without hematological responses at three months after immunosuppressive therapy].

Objective: To reassess the predictors for response at 6 months in patients with severe or very severe aplastic anemia (SAA/VSAA) who failed to respond to immunosuppressive therapy (IST) at 3 months. Methods: We retrospectively analyzed the clinical data of 173 patients with SAA/VSAA from 2017 to 2018 who received IST and were classified as nonresponders at 3 months. Univariate and multivariate logistic regression analysis were used to evaluate factors that could predict the response at 6 months. Results: Univariate analysis showed that the 3-month hemoglobin (HGB) level (P=0.017) , platelet (PLT) level (P=0.005) , absolute reticulocyte count (ARC) (P<0.001) , trough cyclosporine concentration (CsA-C0) (P=0.042) , soluble transferrin receptor (sTfR) level (P=0.003) , improved value of reticulocyte count (ARC(△)) (P<0.001) , and improved value of soluble transferrin receptor (sTfR(△)) level (P<0.001) were related to the 6-month response. The results of the multivariate analysis showed that the PLT level (P=0.020) and ARC(△) (P<0.001) were independent prognostic factors for response at 6 months. If the ARC(△) was less than 6.9×10(9)/L, the 6-month hematological response rate was low, regardless of the patient's PLT count. Survival analysis showed that both the 3-year overall survival (OS) [ (80.1±3.9) % vs (97.6±2.6) %, P=0.002] and 3-year event-free survival (EFS) [ (31.4±4.5) % vs (86.5±5.3) %, P<0.001] of the nonresponders at 6 months were significantly lower than those of the response group. Conclusion: Residual hematopoietic indicators at 3 months after IST are prognostic parameters. The improved value of the reticulocyte count could reflect whether the bone marrow hematopoiesis is recovering and the degree of recovery. A second treatment could be performed sooner for patients with a very low ARC(△).