Relationship Between Intimal Thickness on Ultrasonography and Long-Term Patency of Arteriovenous Fistula Restenosis After Cutting Balloon Versus High Pressure Balloon Angioplasty.

BACKGROUND: To investigate the relationship between intimal thickness on ultrasonography and long-term patency of arteriovenous fistula restenosis after cutting balloon and high pressure balloon angioplasty. METHODS: We retrospectively compared the outcomes between cutting balloon angioplasty and high pressure balloon angioplasty in 149 patients with hemodialysis access restenosis. The relationship of intimal thickness and primary assisted patency of hemodialysis access on ultrasonography was investigated as the primary outcome, using Kaplan-Meier survival analysis and Cox proportional hazards model. The second outcomes included residual diameter, blood flow, and venous pressure of hemodialysis access before and after angiography and balloon diameter and inflation pressure. RESULTS: Primary assisted patency in cutting balloon angioplasty was 90.6%, which was significantly (P = 0.001) more than that of 37.9% in high pressure balloon angioplasty during the 20-month follow-up period. Cox proportional hazards model screened significant factors including procedure type (high pressure or cutting, P = 0.004), inflation pressure (P = 0.013), preoperative intimal thickness (P = 0.009), and difference of intimal thickness (P = 0.029). Finally, procedure type (P = 0.012) and preoperative intimal thickness (P = 0.033) were identified for predicting primary assisted patency by multivariate Cox proportional hazards model. CONCLUSIONS: Compared to high pressure balloon angioplasty for treating patients with hemodialysis access restenosis, cutting balloon angioplasty had a better primary assisted patency. The increase of intimal thickness on ultrasonography after angiography was inversely correlated with primary assisted patency.

Parathyroidectomy Is Associated With Reversed Nondipping Heart Rate That Impacts Mortality in Chronic Kidney Disease Patients.

OBJECTIVE: Nondipping heart rate (HR), defined as a night/day HR ratio >0.90, has been associated with increased mortality in epidemiologic studies. However, its prognostic value in stage 5 chronic kidney disease (CKD5) patients and the effects of parathyroidectomy (PTX) on nondipping HR remain unknown. METHODS: This case-control study of 162 healthy controls and 502 CKD5 patients was performed between 2011 and 2018, in which CKD5 patients were further divided into non-PTX (n = 186) and severe secondary hyperparathyroidism (SHPT) with PTX (n = 316) subgroups. Each participant underwent 24-hour Holter monitoring for HR ratio. Mortality was followed up in CKD5 patients (median time: 46.0 months). RESULTS: The HR ratio in CKD5 patients was higher than in controls (0.92 ± 0.08 vs 0.81 ± 0.08, P <.001), associated with a 44% increase in mortality risk per 0.1 increment (hazard ratio, 1.44; 95% CI: 1.02-2.03; P =.04), and was positively related to serum intact parathyroid hormone levels (P <.001). PTX reversed nondipping HR in SHPT patients (n = 50, median time: 6.3 months, P <.001). Survival probabilities for PTX (n = 294) were better than non-PTX (n = 47) (hazard ratio, 0.31; 95% CI: 0.14-0.67; P <.01) in SHPT patients (serum intact parathyroid hormone >500.0 pg/mL). CONCLUSION: CKD5 patients displayed a nondipping HR pattern, which is a prognostic marker of all-cause mortality. PTX for SHPT patients was associated with a reversal in nondipping HR ratio, which may mediate a better outcome.

Diagnostic Values of Intraoperative (1-84) Parathyroid Hormone Levels are Superior to Intact Parathyroid Hormone for Successful Parathyroidectomy in Patients With Chronic Kidney Disease.

OBJECTIVE: Persistent secondary hyperparathyroidism (SHPT) may occur because of residual cervicothoracic parathyroids in parathyroidectomy (PTX) patients with chronic kidney disease. We prospectively compared the predictive values of intraoperative plasma (1-84) parathyroid hormone (PTH) and intact PTH (iPTH) levels to improve the safety and efficacy of PTX. METHODS: We included 100 healthy controls, 162 stage 5 chronic kidney disease patients without SHPT, and 214 patients who underwent PTX because of SHPT. Plasma iPTH and (1-84) PTH levels were measured before incision (io-iPTH0 and io-[1-84]PTH0, respectively) and 10 minutes (io-iPTH10 and io-[1-84]PTH10, respectively) and 20 minutes (io-iPTH20 and io-[1-84]PTH20, respectively) after removing all parathyroids. The percentage reduction of iPTH and (1-84) PTH at 10 minutes (io-iPTH10% and io-[1-84]PTH10%, respectively) and 20 minutes (io-iPTH20%, and io-[1-84]PTH20%, respectively) was calculated. iPTH and (1-84) PTH were measured using second- and third-generation PTH assays, respectively. RESULTS: Compared with the controls and non-PTX patients, the PTX group had more obvious mineral metabolism disorders. There were 187 successful PTXs, 19 patients with persistent SHPT, and 8 patients lost to follow-up. The receiver operating characteristic curves revealed that io-(1-84)PTH10% >86.6% and io-(1-84)PTH20% >87.5% suggested successful PTX. The sensitivity of io-iPTH20% and io-(1-84)PTH20% were higher than those at the timepoint of 10 minutes. Moreover, the specificity and sensitivity of the (1-84) PTH reduction percentage were superior to that of iPTH. CONCLUSION: Intraoperative reduction percentages of plasma (1-84) PTH levels are superior to iPTH for accurately predicting successful PTX, especially at 20 minutes after all cervicothoracic parathyroids had been resected.

Effects of parathyroidectomy on plasma PTH fragments and heart rate variability in stage 5 chronic kidney disease patients.

INTRODUCTION: Circulating intact parathyroid hormone (iPTH) levels include full-length (1-84) PTH and long C-PTH fragments, but primarily (7-84) PTH, which have been reported to have antagonistic effects on the bones and kidneys. However, their effects on the cardiovascular system remain unclear. In this study, the relationships between the plasma PTH fragments levels and heart rate variability (HRV) in stage 5 chronic kidney disease (CKD5) patients are explored. Furthermore, the effects of parathyroidectomy (PTX) on the above indices are investigated. METHODS: In this cross-sectional study, 164 healthy controls and 354 CKD5 patients, including 208 secondary hyperparathyroidism (SHPT) subgroup with PTX, were enrolled. Circulating (7-84) PTH levels were calculated by subtracting plasma (1-84) PTH levels from iPTH levels. The HRV parameters were measured using a 24-hour Holter. RESULTS: The baseline levels of plasma iPTH, (1-84) PTH, and (7-84) PTH in the CKD5 patients were 930.40 (160.65, 1792.50) pg/mL, 448.60 (99.62, 850.45) pg/mL, and 468.20 (54.22, 922.55) pg/mL, respectively. In the CKD5 patients, plasma (1-84) PTH levels were independently correlated with the standard deviation of the normal-to-normal R-R intervals (SDNN) and the standard deviation of the five-minute average of the normal R-R intervals (SDANN). With a median follow up time of 6.50 months after PTX in the SHPT patients (n = 30), improved SDNN and SDANN markers were related with decreased (1-84) PTH levels. Furthermore, an improved SDNN was related with decreased (7-84) PTH levels. CONCLUSIONS: The CKD5 patients' baseline (1-84) PTH levels were correlated with the SDNN and SDANN. After PTX, an improved SDNN was related with decreased (1-84) PTH and (7-84) PTH levels, while improved SDANN was related with decreased (1-84) PTH levels. No antagonistic effects of (1-84) PTH and (7-84) PTH on HRV were found in the CKD5 patients.

Dynamic features of placebo effects addressing persistent insomnia disorder: A meta-analysis of placebo-controlled randomized clinical trials.

It has been accepted knowledge that placebo effects have been significant in insomnia clinical trials. However, the dynamic features of placebo effects have not been clarified. Our aim was therefore to conduct a meta-analysis of placebo-controlled randomized clinical trials to characterize the dynamic features of placebo effects addressing persistent insomnia disorder. We performed a comprehensive literature search for randomized, placebo-controlled, double-blind clinical trials evaluating the efficacy of therapeutic regimens addressing persistent insomnia disorder. We pooled separate effect size estimates (Hedge's g) of placebo and regimen conditions across trials for outcome measures, and multilevel mixed-effects models were used to explore potential sources of heterogeneity. The placebo effects were significant and robust to improve the symptoms of insomnia, and subjective measures were significantly smaller than objective measures (p < .001), but placebo response rates were nearly identical between subjective and objective measures. The overall placebo effects were influenced by publication year (p = .015), treatment duration (p = .010), sample size (p < .001) and therapeutic regimen (p < .001). Placebo effects showed a diphasic feature within treatment duration: initially a decrease and subsequently being stable; a sustained decline trend after withdrawals; and a steady-to-upward trend for a mixed therapeutic regimens in a large-scale period over decades. The dynamic features of placebo effects addressing persistent insomnia disorder may lead to the development and validation of dosing strategies that require less medication exposure to maintain clinical effects.

Effect-size seed-based d mapping of resting-state fMRI for persistent insomnia disorder.

BACKGROUND: Recently, several functional neuroimaging studies have been conducted in patients with persistent insomnia disorder, but these studies have yielded diverse findings. We aimed to identify convergence in function across the heterogeneity of patients, modalities, and methods for insomnia disorder by performing a quantitative coordinate-based meta-analysis. MATERIALS AND METHODS: We performed a quantitative, voxel-wise meta-analysis of resting-state fMRI studies using seed-based d mapping to find convergence of functional alterations in persistent insomnia disorder. RESULTS: We included 28 studies comprising 287 peak foci involving 951 patients with insomnia disorder and 884 healthy controls. Patients with persistent insomnia disorder showed that increased activity was more frequently reported in right parahippocampal gyrus (p < 0.001) and left median cingulate/paracingulate gyri (p < 0.001); while decreased activity was more frequently reported in right cerebellum (p < 0.001) and left superior frontal gyrus/medial orbital (p < 0.001). CONCLUSION: The altered functional networks in patients with persistent insomnia disorder converge in median cingulate/paracingulate gyri and right parahippocampal gyrus with increased activity, and cerebellum and superior frontal gyrus/medial orbital with reduced activity. As a potential target in future, the identification of these altered or unbalanced networks is very important because they may be noninvasively rebalanced to sleep homeostasis by noninvasive brain stimulation methods.

Insomnia Disorder Increases the Risk of Mortality: Pooled Analysis of Annual Cumulative Time-to-Event Data.

The association of mortality risk and insomnia disorder with daytime impairments has been plausible. The purpose of this study was to evaluate the strength of evidence for this relationship. We performed a comprehensive literature search for clinical Cohort trials including annual cumulative time-to-event data that evaluated the risk of mortality in insomnia disorder patients with daytime impairments. We used pooled hazard ratio (HR) as the main outcome measure and Kaplan-Meier survive curve to display outcome measures. The weighted cumulative mortality of 4.5% for patients with insomnia disorder was higher than that of 2.6% for those without insomnia (p<0.001). Higher risk of mortality presented in patients with insomnia disorder when compared to those without insomnia (HR = 1.66, 95% CI = 1.25-2.19, p<0.001). Patients with duration of more than 10 years were at a greater risk of annual cumulative mortality (R2 = 0.891, p<0.001). Insomnia disorder with daytime impairments increased the risk of mortality, and patients with duration of more than 10 years were at a greater risk of annual cumulative mortality.

Nomogram Model Based on Clinical Risk Factors and Heart Rate Variability for Predicting All-Cause Mortality in Stage 5 CKD Patients.

Background: Heart rate variability (HRV), reflecting circadian rhythm of heart rate, is reported to be associated with clinical outcomes in stage 5 chronic kidney disease (CKD5) patients. Whether CKD related factors combined with HRV can improve the predictive ability for their death remains uncertain. Here we evaluated the prognosis value of nomogram model based on HRV and clinical risk factors for all-cause mortality in CKD5 patients. Methods: CKD5 patients were enrolled from multicenter between 2011 and 2019 in China. HRV parameters based on 24-h Holter and clinical risk factors associated with all-cause mortality were analyzed by multivariate Cox regression. The relationships between HRV and all-cause mortality were displayed by restricted cubic spline graphs. The predictive ability of nomogram model based on clinical risk factors and HRV were evaluated for survival rate. Results: CKD5 patients included survival subgroup (n = 155) and all-cause mortality subgroup (n = 45), with the median follow-up time of 48 months. Logarithm of standard deviation of all sinus R-R intervals (lnSDNN) (4.40 ± 0.39 vs. 4.32 ± 0.42; p = 0.007) and logarithm of standard deviation of average NN intervals for each 5 min (lnSDANN) (4.27 ± 0.41 vs. 4.17 ± 0.41; p = 0.008) were significantly higher in survival subgroup than all-cause mortality subgroup. On the basis of multivariate Cox regression analysis, the lnSDNN (HR = 0.35, 95%CI: 0.17-0.73, p = 0.01) and lnSDANN (HR = 0.36, 95% CI: 0.17-0.77, p = 0.01) were associated with all-cause mortality, their relationships were negative linear. Spearman's correlation analysis showed that lnSDNN and lnSDANN were highly correlated, so we chose lnSDNN, sex, age, BMI, diabetic mellitus (DM), ß-receptor blocker, blood glucose, phosphorus and ln intact parathyroid hormone (iPTH) levels to build the nomogram model. The area under the curve (AUC) values based on lnSDNN nomogram model for predicting 3-year and 5-year survival rates were 79.44% and 81.27%, respectively. Conclusion: In CKD5 patients decreased SDNN and SDANN measured by HRV were related with their all-cause mortality, meanwhile, SDNN and SDANN were highly correlated. Nomogram model integrated SDNN and clinical risk factors are promising for evaluating their prognosis.

A novel long-term intravenous combined with local treatment with human amnion-derived mesenchymal stem cells for a multidisciplinary rescued uremic calciphylaxis patient and the underlying mechanism.

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Preclinical release inspections of hAMSCs, efficacy, and safety assessment, including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro, were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the preclinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multidifferentiation, re-epithelialization, and restoration of integrity.

Optimal level of 25-(OH)D in children in Nanjing (32°N Lat) during winter.

BACKGROUND: The optimal serum level of 25-hydroxyvitamin D (25-(OH)D) for bone health is still unclear, especially in children. Hypovitaminosis D is also re-emerging in developed and developing countries. The purpose of the present study was therefore to determine optimal serum 25-(OH)D level and preliminarily identify the vitamin D nutritional status in Nanjing children. METHODS: All subjects (76 healthy, 66 suffering from infectious diseases) aged 0-10 years were recruited during the period December 2007-March 2008. Venous blood samples were collected before breakfast and the levels of serum 25-(OH)D, parathyroid hormone (PTH), bone-specific alkaline phosphatase (BAP), calcium (Ca), phosphorus (P) were determined. The optimal level of serum 25-(OH)D was explored using the three response curves of 25-(OH)D versus PTH, 25-(OH)D versus BAP, and 25-(OH)D versus Ca×P product. RESULTS: For 25-(OH)D ≤ 50 nmol/L, PTH and BAP were both inversely correlated with 25-(OH)D (PTH, r=-0.864, P < 0.01; BAP, r=-0.856, P < 0.01). For 25-(OH)D > 50-60 nmol/L, levels of PTH and BAP remained steady. With regard to the Ca×P product, for 25-(OH)D ≤ 50 nmol/L, Ca×P product increased as 25-(OH)D increased (r= 0.037, P > 0.05). For 25-(OH)D > 50-60 nmol/L, Ca×P product remained steady. The mean serum level of 25-(OH)D was 80.5 ± 29.3 nmol/L (mean ± SD) in the healthy children, and 65.7 ± 32.3 nmol/L in the sick children. CONCLUSION: The optimal 25-(OH)D level may be 50-60 nmol/L for bone health in Nanjing children. The vitamin D nutritional status of Nanjing children is relatively good in winter.

Long-term outcomes of microwave ablation for secondary hyperparathyroidism in maintenance hemodialysis patients.

Microwave ablation has been increasingly used to secondary hyperparathyroidism (SHPT) in patients with maintenance hemodialysis. However, the current data are inconclusive. This study was to assess the long-term outcomes of microwave ablation on SHPT. We enrolled 53 SHPT patients who underwent microwave ablation. Primary outcome measures were the rate of achieving recommended goal for iPTH and the events of all-cause death during the follow-up period. Survival analysis was performed to assess the long-term prognosis. During follow-up period of 42.4 ± 15.6 months (range, 12-70 months), there were 12 all-cause deaths, and the cumulative proportion surviving was 0.74. The rates of achieving the recommended goal for iPTH were 62.3% at 1 month, 57.7% at 6 months, 51.0% at 12 months, 62.5% at 24 months, and 68.8% at 36 months, respectively. Microwave ablation produces a lasting resolution of secondary hyperparathyroidism in about 60% of patients with maintenance hemodialysis. The characteristics of patients suitable for microwave ablation should be clarified in the future.

Shed antigen-induced blocking effect on CAR-T cells targeting Glypican-3 in Hepatocellular Carcinoma.

BACKGROUND: Glypican-3 (GPC3), a cell surface glycoprotein that is pathologically highly expressed in hepatocellular carcinoma (HCC), is an attractive target for immunotherapies, including chimeric antigen receptor (CAR) T cells. The serum GPC3 is frequently elevated in HCC patients due to the shedding effect of cell surface GPC3. The shed GPC3 (sGPC3) is reported to block the function of cell-surface GPC3 as a negative regulator. Therefore, it would be worth investigating the potential influence of antigen shedding in anti-GPC3 CAR-T therapy for HCC. METHODS: In this study, we constructed two types of CAR-T cells targeting distinct epitopes of GPC3 to examine how sGPC3 influences the activation and cytotoxicity of CAR-T cells in vitro and in vivo by introducing sGPC3 positive patient serum or recombinant sGPC3 proteins into HCC cells or by using sGPC3-overexpressing HCC cell lines. RESULTS: Both humanized YP7 CAR-T cells and 32A9 CAR-T cells showed GPC3-specific antitumor functions in vitro and in vivo. The existence of sGPC3 significantly inhibited the release of cytokines and the cytotoxicity of anti-GPC3 CAR-T cells in vitro. In animal models, mice carrying Hep3B xenograft tumors expressing sGPC3 exhibited a worse response to the treatment with CAR-T cells under both a low and high tumor burden. sGPC3 bound to CAR-T cells but failed to induce the effective activation of CAR-T cells. Therefore, sGPC3 acted as dominant negative regulators when competed with cell surface GPC3 to bind anti-GPC3 CAR-T cells, leading to an inhibitory effect on CAR-T cells in HCC. CONCLUSIONS: We provide a proof-of-concept study demonstrating that GPC3 shedding might cause worse response to CAR-T cell treatment by competing with cell surface GPC3 for CAR-T cell binding, which revealed a new mechanism of tumor immune escape in HCC, providing a novel biomarker for patient enrolment in future clinical trials and/or treatments with GPC3-targeted CAR-T cells.

Efficacy and Placebo Response of Multimodal Treatments for Primary Insomnia: A Network Meta-Analysis.

BACKGROUND: Pharmacotherapy, psychotherapy, and complementary therapy have been used for primary insomnia. However, the efficacy and placebo response are not exactly clear because of limited clinical data. We therefore conducted a systematic review to examine the efficacy and placebo response of multimodal treatments. METHODS: We performed a comprehensive literature search for randomized placebo-controlled clinical trials evaluating the efficacy of multimodal treatments addressing primary insomnia. To pool effect size estimates (Hedges' g) of active and placebo conditions across studies for outcome measures, a meta-analysis was done according to the Cochrane guideline. RESULTS: The results of network meta-analysis for sleep efficiency showed that orexin receptor antagonists had the maximum effect size of 1.35 (95% confidence interval [CI], 0.88-1.82), followed by γ-aminobutyric acid agonists of 1.28 (95% CI, 0.85-1.71), cognitive behavioral therapy for insomnia of 1.07 (95% CI, 0.10-2.05), acupuncture of 0.64 (95% CI, -0.17 to 2.36), and repetitive transcranial magnetic stimulation of 0.61 (95% CI, -0.52 to 1.75), respectively. However, the placebo response was also significant and robust to improve insomnia symptoms, and 65.9% (95% CI, 49.3%-82.5%) of the effect size of multimodal treatments was actually produced by placebo conditions. CONCLUSIONS: The pharmacotherapy seems the most effective in improving sleep efficiency. However, the optimal therapeutic regimen is still uncertain. In addition, the placebo response is significant and robust in treatments of primary insomnia.

Microwave ablation vs. parathyroidectomy for secondary hyperparathyroidism in maintenance hemodialysis patients.

INTRODUCTION: Secondary hyperparathyroidism (SHPT) is a serious and common problem in patients undergoing maintenance hemodialysis. Minimally invasive microwave ablation (MWA) has been used to treat SHPT and shows some advantages. However, its efficacy is still undefined. The primary purpose of this study was to determine the efficacy and safety of MWA compared to total parathyroidectomy plus forearm autotransplantation. METHODS: The SHPT patients who were undergoing maintenance hemodialysis (follow-up for 6 to 24 months after treatments) were divided into a MWA group (n = 33) and a parathyroidectomy group (n = 48). The efficacy (serum intact parathyroid hormone [iPTH], calcium, and phosphorus levels) and safety (hoarseness, hypocalcaemia, and persistently low iPTH) were compared between the two groups. Additionally, the study explored potential predictors of response to MWA by a logistic regression analysis. FINDINGS: There were no significant differences in baseline characteristics between the two groups. The rates of achieving the recommended goal for iPTH were significantly higher in the MWA group than that in the parathyroidectomy group at all follow-up times: 57.58% vs. 12.50% at one-day (P < 0.001), 45.45% vs. 16.67% at 1-week (P = 0.005), 57.58% vs. 16.67% at 2-week (P < 0.001), 57.58% vs. 22.92% at 1-month (P = 0.002), and 69.70% vs. 35.42% at 3-month (P = 0.002), 76.47% vs. 28.57% at 6-month (P = 0.005), 87.50% vs. 47.37% at 12-month (P = 0.008), and 81.82% vs. 52.63% at 24-month (P = 0.015), respectively. However, there were no significant differences for phosphorus or calcium at any of the follow-up times (P > 0.05). The persistently low iPTH was more in the parathyroidectomy group (64.6%) than that in the MWA group (0%) (P < 0.001), but there was no significant difference in hoarseness or hypocalcaemia (P > 0.05). Baseline levels of iPTH (P = 0.021) and patient age (P = 0.011) were determined as predictors by univariate logistic regression analysis. CONCLUSION: The MWA could be an alternative to parathyroidectomy for SHPT but its eventual superiority has to be demonstrated by a proper study.